tbuckley/cabot-search huggingface dataset:
The Clinical Profile and Pathophysiology of Atrial Fibrillation
Authors: JasonAndrade, PaulKhairy, DobromirDobrev, StanleyNattel
Journal: Circulation Research (2014)

Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%–26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant me...
Abstract 1034: Genotyping of patient-derived xenograft tumors using short tandem repeats: Challenges and observations in ensuring concordance across passages for effective preclinical studies
Authors: Bridgette Sisson, Andrew Hesse, Melissa Soucy, Daniel Bergeron, Shelbi Burns, Kevin Kelly, Emily Jocoy, Margaret Bundy, Honey V. Reddi
Journal: Cancer Research (2018)

Abstract Patient derived xenograft (PDX) tumor models represent the closest step to in-human trials for cancer drug research and are therefore an invaluable resource. Implantation of a cancerous tissue from a patient's primary tumor directly into an immune-deficient mouse, generating a xenograft tumor potentially mimics the tumor microenvironment in the patient and allows for the evaluation of therapies specific to a particular tumor. One of the significant challenges associated with PDX tumors is the potential loss of the human component or the take-over by mouse tissue with every passage into a new mouse model. Short tandem repeats (STRs) are short intronic sequences of DNA that are highly polymorphic and contain a pattern of nucleotides repeated in tandem. STRs can be found in distinct regions of both prokaryotes and eukaryotes organisms, with each organism containing a unique combination of the STR allelic frequencies that allow for individuals to be unambiguously identified. STR analysis is routinely used to genotype PDX tumors comparative to the original resected human cancerous tissue, ensuring concordance with original tissue and to identify mouse tissue contamination with progressive passages. The Jackson Laboratory for Genomic Medicine's CLIA laboratory has evaluated over 170 PDX tumor samples from multiple mouse model passages across 105 diverse PDX mouse models. Of those samples analyzed, genomic DNA for 33 had been extracted from fresh frozen tissue and for 143 extracted from Formalin Fixed Paraffin embedded tissue (FFPE). The current study presents the challenges and discrepancies observed in our evaluation relative to number of passages for each tumor, sample type (FFPE vs fresh frozen) - reflective of tumor heterogeneity and also potential encroachment by mouse tissue. We also present results of a cross institutional comparative STR analysis study in 123 samples wherein discordance observed in certain cases were a result of differing sample types, suggestive that tumor heterogeneity can affect the STR results and could be a leading cause for cross institutional discordant genotyping results. Citation Format: Bridgette Sisson, Andrew Hesse, Melissa Soucy, Daniel Bergeron, Shelbi Burns, Kevin Kelly, Emily Jocoy, Margaret Bundy, Honey V. Reddi. Genotyping of patient-derived xenograft tumors using short tandem repeats: Challenges and observations in ensuring concordance across passages for effective preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1034.
Molecular and Structural Biomarkers of Inflammation at Two Years After Acute Anterior Cruciate Ligament Injury Do Not Predict Structural Knee Osteoarthritis at Five Years
Authors: Frank W. Roemer, Martin Englund, Aleksandra Turkiewicz, André Struglics, Ali Guermazi, L. Stefan Lohmander, Staffan Larsson, Richard Frobell
Journal: Arthritis & Rheumatology (2018)

Objective To determine the role of inflammatory biomarkers at 2 years post–anterior cruciate ligament ( ACL ) injury to predict radiographic knee osteoarthritis ( OA ) and magnetic resonance imaging ( MRI )–defined knee OA at 5 years postinjury, with a secondary aim of estimating the concordance of inflammatory biomarkers assessed by MRI and synovial fluid ( SF ) analysis. Methods We studied 113 patients with acute ACL injury. Knee scans using 1.5T MRI s were read for Hoffa‐ and effusion‐synovitis. Biomarkers of inflammation that we assessed included interleukin‐6 ( IL ‐6), IL ‐8, IL ‐10, tumor necrosis factor, and interferon‐ɣ in serum and SF , and IL ‐12p70 in serum. We defined the outcome as radiographic knee OA ( ROA ) or MRI ‐defined OA ( MROA ) at 5 years. The area under the receiver operating characteristic curve ( AUC ), sensitivity, and specificity were evaluated in models that included MRI features only (model 1), inflammation biomarkers only (serum [model 2a] or SF [model 2b]), both MRI features and serum biomarkers (model 3a), or both MRI features and SF (model 3b) biomarkers. Linear regression analysis was used to evaluate the association between MRI features and SF biomarkers. Results At 5 years postinjury, ROA was present in 26% of the injured knees, and MROA was present in 32%. The AUC s for ROA in each model were 0.44 (95% confidence interval [95% CI ] 0.42, 0.47) for model 1, 0.62 (95% CI 0.59, 0.65) for model 2a, 0.53 (95% CI 0.50, 0.56) for model 2b, 0.58 (95% CI 0.55, 0.61) for model 3a, and 0.50 (95% CI 0.46, 0.53) for model 3b. The AUC s for MROA in each model were 0.67 (95% CI 0.64, 0.70) for model 1, 0.49 (95% CI 0.47, 0.52) for model 2a, 0.56 (95% CI 0.52, 0.59) for model 2b, 0.65 (95% CI 0.61, 0.68) for model 3a, and 0.69 (95% CI 0.66, 0.72) for model 3b. The concordance between MRI and SF biomarkers was statistically significant only for effusion‐synovitis and IL ‐8. Conclusion Neither MRI ‐detected inflammation nor selected SF /serum inflammation biomarkers at 2 years postinjury predicted ROA or MROA at 5 years postinjury. Concordance between MRI and SF inflammatory biomarkers was weak.
Abstract 4448: Mutations in the center MATH domain of Speckle Type BTB/POZ Protein lead to enhanced proteinstability in prostate cancer
Authors: Joshua Fried, Vinayak Khattar, Jinlu Ma, Qinghua Zeng, Wei Zhang, Bo Xu
Journal: Cancer Research (2018)

Abstract The Speckle type Poz Protein (SPOP) is a tumor suppressor that is often mutated in prostate cancer. Mutation of SPOP is linked to genomic instability and it plays a critical role in prostate cancer initiation. SPOP mutations are found to be in the heterozygous state in patients. The relevance of these mutations on its protein expression has not been systematically investigated. Here we report that mutations in the center MATH domain of SPOP lead to enhanced protein stability in prostate cancer. Among the mutations, F102C, S119N, F125V and WI31G showed increased protein stability. Further we show that these mutations in the MATH domain increase half-life of SPOP protein. Interestingly, the mutant SPOPs enhanced the endogenous wild-type SPOP level. We further explored the structural insights of these SPOP mutants. We present a computational model to predict how SPOP mutations potentially lead to conformational changes within the protein, promoting its stability. Finally, immunohistochemistry in clinical samples of prostate cancer augment our findings. Together, we highlight a subset of clinically relevant SPOP mutations that have impact on endogenous SPOP protein stability, allowing to further understand its role in prostate cancer initiation and evaluating of potentially altered therapeutic response in patients harboring these mutations. Citation Format: Joshua Fried, Vinayak Khattar, Jinlu Ma, Qinghua Zeng, Wei Zhang, Bo Xu. Mutations in the center MATH domain of Speckle Type BTB/POZ Protein lead to enhanced proteinstability in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4448.
MACROD2, an Original Cause of CIN?
Authors: Ning Jin, Mark E. Burkard
Journal: Cancer Discovery (2018)

Abstract Summary: The fundamental cause of chromosomal instability in colorectal cancer remains elusive. Genetic deletions of the MACROD2 tumor suppressor could play a major role. Cancer Discov; 8(8); 921–3. ©2018 AACR. See related article by Sakthianandeswaren et al., p. 988.
Abstract 20652: Lifespan Predictors of Cardiovascular Morbidity in Individuals Reaching Middle Age: The Bogalusa Heart Study
Authors: Camilo Fernández Alonso, Shengxu Li, Roberto Blandon, Wei Chen, Sathanur R Srinivasan, Gerald S Berenson
Journal: Circulation (2014)

Introduction: Considerable information is available on the clustering of cardiovascular (CV) risk factors across the lifespan and their impact on cardiovascular disease (CVD) morbidity and mortalit...
Abstract 16016: Cardiac Etiologies Underlying Sudden Death in the Community
Authors: Victor Waldmann, Wulfran Bougouin, Marie-Cécile Bories, Kumar Narayanan, Daniel Jost, Bertrand Ludes, Vincent Algalarrondo, Estelle Gandjbakhch, Fabrice Extramiana, Nicolas Lellouche, Frankie Beganton, Lionel Lamhaut, Thomas Lavergne, Xavier Jouven, Eloi Marijon
Journal: Circulation (2016)

Introduction: A comprehensive assessment of cardiac etiologies underlying sudden cardiac death (SCD) in the general population has not been addressed on a large scale so far. Hypothesis: We aimed to evaluate the pattern and distribution of cardiovascular diseases associated with SCD among patients discharged alive from intensive care units. Methods: All cases of sudden cardiac arrest (SCA) in Paris and suburbs (6.6 million inhabitants) were prospectively included in the Paris-SDEC registry, in close collaboration with Emergency Medical Services, Medical examiners, and hospitals. Results: Over a 4-year period, 14,822 out-of-hospital SCA occurred; 785 patients were alive at Intensive Care Unit discharge, of which 556 (3.8%) satisfied the definition for SCD (mean age 56.3 ±15.3 years, 82% male). Among SCD associated with coronary artery disease, the vast majority was related to acute coronary syndrome (295, 79%), whereas the rest had chronic ischemic heart disease (21%). No structural heart disease was ident...
Abstract 4156: Inhibition of NF-kB improves sensitivity to radiation and EGFR inhibitor and decreases radiation-induced lung toxicity in lung cancer
Authors: Wei Wang, Rong Wang, Shunli Peng, Qi Li, Xiaojuan Zhang, Yueyun Ma
Journal: Cancer Research (2018)

Abstract Combination with EGFR-TKIs and radiation seems to be a good strategy against lung cancer, since radiation could enhance EGFR expression. However, the results of clinical trials were controversial. MET activation was involved in resistance to both radiation and EGFR inhibitor, while NF-kB was reported to closely relate to HGF/MET signaling axis. Furthermore, NF-κB has been proved to play a role in bleomycin-induced pulmonary fibrosis, which could be ameliorated by IKKB inhibitor (IMD-0354). Therefore, we evaluated the influence of NF-kB/MET inhibition to the sensitivity of radiation and EGFR-TKIs in lung cancer cells in vitro and in vivo. we also examined the role of NF-κB in radiation-induced lung toxicity. Our data showed that radiation enhanced activation and expression of MET and EGFR, whereas only activation of MET could be reversed by IMD-0354 and p65 depletion, suggesting that radiation-induced MET activation was mediated by NF-kB signaling. Furthermore, NF-kB inhibition increased radiation-induced DNA damage and apoptosis in lung cancer cells. On the other hand, radiation decreased sensitivity to EGFR inhibitor in EGFR mutant lung cancer cells, while inhibition of NF-kB or MET overcame the resistance. Importantly, IMD-0354 increased sensitivity to radiation, EGFR-TKIs, or their combination in mouse xenograft tumors by arresting cell proliferation and inducing cell apoptosis. Interestingly, IMD-0354 significantly reduced the lung toxicity in a mouse model of radiation-induced pneumonia and lung fibrosis. Our preclinical findings indicated that inhibition of NF-kB/MET could improve sensitivity to radiation and EGFR inhibitor and decrease radiation-induced lung toxicity in lung cancer. Citation Format: Wei Wang, Rong Wang, Shunli Peng, Qi Li, Xiaojuan Zhang, Yueyun Ma. Inhibition of NF-kB improves sensitivity to radiation and EGFR inhibitor and decreases radiation-induced lung toxicity in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4156.
Abstract 4555: Potent Conditionally Active Biologic (CAB) PD-1 antibodies to reduce systemic toxicities associated with single agent and combination therapies
Authors: Cathy Chang, Gerhard Frey, Leslie L. Sharp, Haizhen Liu, Jing Wang, Charles Xing, Safak Yalcin, Yong Ben, William J. Boyle, Jay M. Short
Journal: Cancer Research (2018)

Abstract PD-1 is an immune checkpoint inhibitor that limits T cell activity. The use of anti-PD-1 antagonist antibodies has demonstrated anti-tumor efficacy in mouse models and in a subset of human patients. However, blockade of PD-1 as a single agent and in combination with chemotherapy, targeted, and other immunomodulatory therapies has been limited clinically in part due to toxicities related to systemic immune-response related adverse events. In addition, there is increasing concern that systemic immune activation may lead to autoimmune-related adverse events in survivors. The Conditionally Active Biologics (CAB) technology is a patented, proprietary platform that selects antibodies that reversibly bind to target antigen in the context of diseased tissues, but not normal tissues, by taking advantage of the unique cancer microenvironment that is produced largely as a result of glycolytic tumor metabolism including the Warburg effect. Using our CAB technology, we have identified anti-PD-1 Abs that reversibly bind human PD-1, and enhance T cell response to bacterial super-antigen under in vitro conditions that are present in the tumor microenvironment but not in normal tissues. CAB-PD-1 Abs demonstrated anti-tumor efficacy, including tumor regression, against MC38 colorectal tumor in human PD-1 knock-in mouse model in which the mouse PD-1 gene has been replaced with human PD-1. The anti-tumor activity of CAB-PD-1 Abs was similar to a reference PD-1 Ab. In conclusion, our data is consistent with our work on CAB-EGFR-ADC, CAB-AXL and CAB-ROR2-ADC antibodies, and suggests that anti-PD-1 Abs generated using the CAB technology provide potent, effective biologics with potential for increased therapeutic index. Specifically, the CAB-PD-1 is an excellent candidate for evaluation as a treatment for human cancers as a single agent or in combination with other anti-cancer therapies including immuno-oncology agents. Citation Format: Cathy Chang, Gerhard Frey, Leslie L. Sharp, Haizhen Liu, Jing Wang, Charles Xing, Safak Yalcin, Yong Ben, William J. Boyle, Jay M. Short. Potent Conditionally Active Biologic (CAB) PD-1 antibodies to reduce systemic toxicities associated with single agent and combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4555.
Abstract 1319: Edge-based integration of multi-omics data gives more accurate prognostic prediction in pancreatic cancer
Authors: Yidi Sun, Chen Li, Rong Zeng
Journal: Cancer Research (2018)

Abstract Pancreatic cancer (PC) is the fourth leading cause of cancer death worldwide, and predicted to be the second within a decade. Five-year survival of PC is less than 5% with a median survival just a couple of months. Therefore, a better understanding of the molecular pathology of PC is an urgent need to achieve advances in clinical treatment for patients. Genomic analyses previously have revealed heterogeneous landscapes of mutation, copy number variation, structural variation and gene expression in pancreatic cancer. While clinical evidence for this proposition is limited and the signaling and biological effects of genomic variations are not routinely determined in human tumors even though they are rationally considered to be drug targets. Luckily, with recent advances in mass spectrometry (MS), comprehensive proteomic and lipidomics analyses provide a potentially valuable approach to validate genomic findings and discover targeted treatments for pancreatic cancer patients. We generated high-throughput proteomic and lipidomic data for pancreatic cancer patients aged from 40 to 80 years old with matched normal samples using TMT-labeling quantitative proteomic method and target lipidomic method. We found promising protein and lipid biomarkers closely related with the clinical outcome of pancreatic cancer patients. Taking signaling and biologically pathways into consideration, we used an edge-based method to distinguish prognostics, where edge features were constructed based on the correlation between each pair of molecules. We then performed feature selection and prognostic classification for both the original expression dataset and the transformed edge dataset and found the edge-based features can give a more accuracy for prognostic prediction, suggesting the promising role of protein and lipid edge biomarkers for clinical utility in pancreatic cancer. Our preliminary results highlight the usefulness of edge-based integration of proteomics and lipidomics data. To explain the mechanisms in the development of pancreatic cancer, we are going to integrate genomic variations from whole genome sequencing (WGS) into our current progress for further analysis. In conclusion, this initial work demonstrated a strategy that may enable more accurate prediction of the survival of pancreatic cancer by integrating multi-omics data from genomics, proteomics and lipidomics. In principle, we anticipate the declaration of possible mechanisms enabling the treatment of pancreatic cancer patients in the near future. Citation Format: Yidi Sun, Chen Li, Rong Zeng. Edge-based integration of multi-omics data gives more accurate prognostic prediction in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1319.
Abstract 4858: Efficacy of the protein arginine methyltransferase PRMT5 inhibitor GSK591 in glioma stem-like cells
Authors: Vikram Shaw, Yuji Piao, Soon Young Park, Jianwen Dong, Emmanuel Martinez-Ledesma, Caroline Carrillo, Verlene Henry, Ravesanker Ezhilarasan, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot
Journal: Cancer Research (2018)

Abstract Protein arginine methyltransferase (PRMTs) function as epigenetic regulators of transcription and play a major role in gene regulation. PRMTs are upregulated in gastric, colorectal and lung cancer, and lymphoma and leukemia. PRMT5 is capable of forming symmetric dimethylarginine (SDMA) residues, and has been reported as a therapeutic target in glioblastoma, as its expression has been correlated with tumor grade and progression. In this study, the in vitro therapeutic efficacy of PRMT5 inhibitor GSK591 was investigated in a panel of gliomas stem-like cell (GSC) lines with specific molecular subtypes. Genomic, proteiomic (reverse protein lysate array, RPPA), methylation status and GSC subtype were correlated with drug IC50 to find predictors of drug sensitivity. The efficacy of inhibiting PRMT5 activity was retained at low dose of GSK591 in a small number of GSCs. Western blotting data showed high expression of PRMT5 and multiple bands of SDMAs in most GSCs tested (n=31), indicating PRMT5 enzymatic activity in GSC cell lines. Evidence of PRMT5 inhibition was demonstrated at low doses (&amp;lt; 1.5 uM) in 4 GSC lines (13%) as shown by the total inhibition of SDMA expression in a dose- and time-dependent fashion after GSK591 treatment. The sensitivity of GSK591 correlated with low methylation of multiple genes pretreatment, including MAGI2, EGR2, and DUSP16. In addition, upregulated genes in sensitive GSCs correlated with proliferation signatures using gene set enrichment analyses (GSEA). Together, our study demonstrated that inhibition of PRMT5 activity and its substrate product SDMA correlated with inhibition of tumor growth. These promising in vitro results have led to ongoing experiments to evaluate the efficacy of GSK591 in intracranial xenograft models and the underlying mechanism of sensitivity and resistance to PRMT5 inhibition. Citation Format: Vikram Shaw, Yuji Piao, Soon Young Park, Jianwen Dong, Emmanuel Martinez-Ledesma, Caroline Carrillo, Verlene Henry, Ravesanker Ezhilarasan, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Efficacy of the protein arginine methyltransferase PRMT5 inhibitor GSK591 in glioma stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4858.
The Mechanically Active Domain of Titin in Cardiac Muscle
Authors: KárolyTrombitás, Jian-PingJin, HenkGranzier
Journal: Circulation Research (1995)

Abstract One of the main contributors to passive tension of the myocardium is titin. However, it is not exactly known what portions of this ≈1 μm-long molecule are anchored in the sarcomere (hence, are rendered inelastic) and what portions are elastic (hence, are mechanically active in developing passive tension). We assessed the length of the elastic domain of cardiac titin by ultrastructural and mechanical methods. Single cardiac myocytes were stretched by various amounts, and while in the stretched state, they were processed for immunoelectron microscopy. Several monoclonal anti-titin antibodies were used, and the locations of the titin epitopes in the sarcomere were studied as a function of sarcomere length. Only a small fraction (5% to 10%) of the ≈1000-nm-long molecule behaved elastically under physiological conditions. This mechanically active domain is located close to the A/I junction, and its contour length when unstretched is estimated at ≈50 to 100 nm. In sarcomeres that are slack (length ≈1.8...
Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease
Authors: MarcelloTonelli, FrankSacks, MarcPfeffer, ZhiweiGao, GaryCurhan
Journal: Circulation (2005)

Background— Higher levels of serum phosphate are associated with adverse cardiovascular outcomes, especially in the setting of overt hyperphosphatemia. Given the biological importance of phosphorus, it is plausible that higher levels of serum phosphate within the normal range may also be associated with adverse outcomes. Methods and Results— We performed a post hoc analysis of data from the Cholesterol And Recurrent Events (CARE) study. Baseline serum phosphate levels were measured in 4127 fasting participants who were randomized to receive pravastatin 40 mg daily or placebo and followed up for a median of 59.7 months. We used Cox proportional-hazards models to examine the association between serum phosphate and adverse clinical outcomes after adjustment for potential confounders. During nearly 60 months of follow-up, 375 participants died. A significant association was noted between baseline serum phosphate level and the age-, race-, and sex-adjusted risk of all-cause death (hazard ratio per 1 mg/dL, 1.2...