tbuckley/cabot-search huggingface dataset:
New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome
Authors: Leah J. Wilson, Adam Linley, Dean E. Hammond, Fiona E. Hood, Judy M. Coulson, David J. MacEwan, Sarah J. Ross, Joseph R. Slupsky, Paul D. Smith, Patrick A. Eyers, Ian A. Prior
Journal: Cancer Research (2017)

Abstract The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. Cancer Res; 78(1); 15–29. ©2017 AACR.
Abstract 20572: Is Active Participation in Cardiac Rehabilitation Associated With Better Long-Term Prognosis in Patients After Acute Myocardial Infarction Even in the Primary PCI Era?
Authors: Yoichi Goto, Michio Nakanishi, Tetsuo Arakawa, Leon Kumasaka, Kazuhiro Nakao, Masashi Fujino, Kensaku Nishihira, Yu Kataoka, Shigefumi Fukui, Masanobu Yanase, Teruo Noguchi, Satoshi Yasuda, Hisao Ogawa
Journal: Circulation (2016)

Introduction: Although the short-term prognosis of patients with acute myocardial infarction (AMI) has been improved in the era of primary coronary intervention (PCI), the determinants of long-term...
Differences in carbon source usage by dental plaque in children with and without early childhood caries
Authors: Yan Zhao, Wen-Jie Zhong, Zhe Xun, Qian Zhang, Ye-Qing Song, Yun-Song Liu, Feng Chen
Journal: International Journal of Oral Science (2017)

Early childhood caries (ECC) is a considerable pediatric and public health problem worldwide. Preceding studies have focused primarily on bacterial diversity at the taxonomic level. Although these studies have provided significant information regarding the connection between dental caries and oral microbiomes, further comprehension of this microbial community's ecological relevance is limited. This study identified the carbon source metabolic differences in dental plaque between children with and without ECC. We compared the microbial community functional diversity in 18 caries-free subjects with 18 severe ECC patients based on sole carbon source usage using a Biolog assay. The anaerobic microbial community in the ECC patients displayed greater metabolic activity than that of the control group. Specific carbon source metabolism differed significantly between the two groups. Subjects from the two groups were well distinguished by cluster and principal component analyses based on discriminative carbon sources. Our results implied that the microbial functional diversity between the ECC patients and healthy subjects differed significantly. In addition, the Biolog assay furthered our understanding of oral microbiomes as a composite of functional abilities, thus enabling us to identify the ecologically relevant functional differences among oral microbial communities. Bacteria in dental plaque from children with early childhood caries metabolize carbon from different sources than bacteria from healthy individuals. Early childhood caries (ECC) is the most common chronic disease in children. Scientists from the Peking University School and Hospital of Stomatology led by Feng Chen and Yunsong Liu, compared the oral microbe populations of 18 ECC patients and 18 caries-free children. The team found that bacteria in plaque from ECC patients preferred certain sugars and carbohydrates as carbon sources, whereas bacteria from healthy subjects preferred certain amino acids and short protein chains. Analysis showed that anaerobic bacteria in ECC patients exhibited greater metabolic activity than those from the caries-free group. This study indicates that metabolic profiles could act as 'signatures' of disease states, and that further studies might suggest carbohydrates for ECC-susceptible children to avoid.
Abstract 19962: Total Arterial Revascularization is Safe and Efficacious in Patients With Isolated Left Main Coronary Artery Disease
Authors: Piroze Davierwala, Alexander Verevkin, Sergey Leontyev, Farhad Bakhtiary, Martin Misfeld, Friedrich W Mohr
Journal: Circulation (2016)

Objective:  Current guidelines recommend total arterial revascularization (TAR) in patients with reasonable life expectancy. However, controversies still exist on the use of TAR in patients with isolated left main disease (LMD) due to a high degree of competitive flow. Our study aimed to compare the early and late clinical outcomes of TAR in patients with isolated LMD to those with LMD and additional single or multivessel disease.   Methods:  A total of 1142 patients with LMD underwent TAR between September 2001 and October 2015 in our institution. Of these, 151 patients had isolated LMD (Group 1) and 991 patients had additional single or multivessel disease (Group 2). Group 2 patients were older (p=0.004) with a higher prevalence of comorbidities such as peripheral vascular disease (p=0.04), prior cerebrovascular accident (p=0.02) and myocardial infarction (p=0.05) than Group 1 patients. To mitigate bias arising from differences in these covariates, we performed a propensity score matched analysis. The matched cohort consisted of 302 patients; 151 patients in each group.   Results:  In-hospital mortality for Groups 1 and 2 was 1.3% and 1.8% (p=1.0) before and 1.3% and 0.7%, (p=1.0) after matching, respectively. The corresponding 6-year survival was 94.7±2% vs. 84.5±2% (log-rank p=0.004) before and 94.7±2% vs. 92.7±2% (log-rank p=0.53) after matching. Preoperative critical state (odds ratio [OR]:3.6; p=0.03), left ventricular ejection fraction (LVEF) (OR:1.2; p=0.01) and age (OR:1.2; p=0.03) were independent predictors of in-hospital mortality in the unmatched cohort. Long-term mortality for the unmatched cohort was predicted by prior cerebrovascular accident (hazard ratio [HR]:3.0;p   Conclusions:  Our study revealed that TAR in patients with LMD is associated with excellent early and long-term survival. We found no difference in outcomes between patients undergoing TAR for isolated LMD and those undergoing TAR for LM plus single/multivessel disease. Thus, TAR appears to be a safe and efficacious for patients with isolated LMD.
“Drunk tanks” are studied over festive period to see if they ease pressure on emergency departments
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

NHS England is to study how hospitals and ambulance services cope over Christmas and New Year in cities that have “drunk tanks”—where revellers who have overindulged can be treated away from emergency departments—to decide if the schemes should be rolled out nationally.

A 2016 study in the Emergency Medicine Journal found that up to 15% …
Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and frequency of clinically relevant genomic alterations.
Authors: Jeffrey S. Ross, Kai Wang, Milind M. Javle, Daniel Virgil Thomas Catenacci, Rachna T. Shroff, Siraj Mahamed Ali, Julia Andrea Elvin, Juliann Chmielecki, Roman Yelensky, Doron Lipson, Vincent A. Miller, Philip J. Stephens, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2015)

4009 Background: Intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA) typically present at an advanced stage and chemotherapy provides only modest benefit in most cases. We queried whether comprehensive genomic profiling (GCP) of IHCCA, EHCCA and GBCA would reveal distinctive patterns of genomic alterations (GA) and identify clinically relevant GA (CRGA) that could lead to targeted therapies. Methods: DNA was extracted from 412 IHCCA, 57 EHCCA and 85 GBCA. CGP was performed on hybridization-captured libraries to a mean coverage depth of > 600X for 236 cancer-related genes. The CGP assay included base substitutions, INDELs, copy number alterations and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Patient characteristics were similar for all three tumor types. IHCCA and GBCa were more common in females and EHCCA were more common males. Findings in the table below. Multiple antitumor responses to targeted therapies in each of the 3 tumor types will be presented. Conclusions: IHCCA, EHCCA and GBCA share frequent GA in cell cycle regulation (CDKN2B) and chromatin remodeling (ARID1A). IHCCA is further characterized by FGFR fusions, IDH1/2 substitutions, BRAF substitutions and MET amplification with a low KRAS mutation frequency. EHCCA and GBCA have frequent ERBB2 amplifications (GBCA > EHCCA) and PIK3CA/MTOR pathway alterations. KRAS mutation frequency is high in EHCCA and low in GBCA. The diverse landscape of CRGA in biliary tract cancers can serve as targets for therapies, either approved or in clinical trials for the majority of patients with CCA, BDCA and GBCA and have the potential to improve outcomes for patients with these aggressive forms of malignancy. CGP Findings IHCCA EHCCA GBCA Total GA/patient 3.6 4.4 4.0 CRGA/patient 2.0 2.1 2.0 ERBB2 Amplification 4% 11% 16% BRAF Substitutions 5% 3% 1% KRAS Substitutions 22% 42% 11% PI3KCASubstitution 5% 7% 14% FGFR1-3 Fusions and Amplifications 11% 0 3% CDKN2A/B Loss 27% 17% 19% IDH1/2 Substitutions 20% 0 0 ARID1A Alterations 18% 12% 13% MET amplification 2% 0 1%
Standard dose of Ustekinumab for childhood-onset deficiency of interleukin–36 receptor antagonist
Authors: Bilade Cherqaoui, Linda Rossi-Semerano, Maryam Piram, Isabelle Koné-Paut
Journal: Annals of the Rheumatic Diseases (2017)

picture after 12-month treatment with Ustekinumab (October 2017).Figure 2 Our deficiency of interleukin-36 receptor antagonist patient weight and height curves under three types of biological treatments.
Annals Story Slam - Unlisted
Authors: Steven McKee
Journal: Annals of Internal Medicine (2017)

Web Exclusives19 December 2017Annals Story Slam - UnlistedFREESteven McKee, MDSteven McKee, MDUniversity of Pennsylvania, Philadelphia, Pennsylvania (S.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0071 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Unlisted "Unlisted," by Dr. Steven McKee (Duration 5:11)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of Pennsylvania, Philadelphia, Pennsylvania (S.M.)Current Author Address: Steven McKee, MD; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 December 2017Volume 167, Issue 12Page: SS1 ePublished: 19 December 2017 Issue Published: 19 December 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Identifying Important Attributes for Early Detection of Chronic Kidney Disease
Authors: Anandanadarajah Nishanth, Tharmarajah Thiruvaran
Journal: IEEE Reviews in Biomedical Engineering (2017)

Individuals with chronic kidney disease (CKD) are often not aware that the medical tests they take for other purposes may contain useful information about CKD, and that this information is sometimes not used effectively to tackle the identification of the disease. Therefore, attributes of different medical tests are investigated to identify which attributes may contain useful information about CKD. A database with several attributes of healthy subjects and subjects with CKD are analyzed using different techniques. Common spatial pattern (CSP) filter and linear discriminant analysis are first used to identify the dominant attributes that could contribute in detecting CKD. Here, the CSP filter is applied to optimize a separation between CKD and nonCKD subjects. Then, classification methods are also used to identify the dominant attributes. These analyses suggest that hemoglobin, albumin, specific gravity, hypertension, and diabetes mellitus, together with serum creatinine, are the most important attributes in the early detection of CKD. Further, it suggests that in the absence of information on hypertension and diabetes mellitus, random blood glucose and blood pressure attributes may be used.
Eating Disorders
Authors: Anne E. Becker, Steven K. Grinspoon, Anne Klibanski, David B. Herzog
Journal: New England Journal of Medicine (1999)

Eating disorders affect an estimated 5 million Americans every year. These illnesses — anorexia nervosa, bulimia nervosa, binge-eating disorder, and their variants — are characterized by a serious disturbance in eating, such as restriction of intake or bingeing, as well as distress or excessive concern about body shape or body weight. In addition to their effects on psychological well-being, they have a potentially devastating effect on health through the physiologic sequelae of altered nutritional status or purging. The mortality rate associated with anorexia nervosa alone, at 0.56 percent per year, is more than 12 times as high as the mortality . . .
Reconstructing an African haploid genome from the 18th century
Authors: Anuradha Jagadeesan, Ellen D. Gunnarsdóttir, S. Sunna Ebenesersdóttir, Valdis B. Guðmundsdóttir, Elisabet Linda Thordardottir, Margrét S. Einarsdóttir, Hákon Jónsson, Jean-Michel Dugoujon, Cesar Fortes-Lima, Florence Migot-Nabias, Achille Massougbodji, Gil Bellis, Luisa Pereira, Gísli Másson, Augustine Kong, Kári Stefánsson, Agnar Helgason
Journal: Nature Genetics (2018)
Heparinization of Beta Tricalcium Phosphate: Osteo‐immunomodulatory Effects
Authors: Anna Diez‐Escudero, Montserrat Espanol, Mar Bonany, Xi Lu, Cecilia Persson, Maria‐Pau Ginebra
Journal: Advanced Healthcare Materials (2017)

Abstract Immune cells play a vital role in regulating bone dynamics. This has boosted the interest in developing biomaterials that can modulate both the immune and skeletal systems. In this study, calcium phosphates discs (i.e., beta‐tricalcium phosphate, β‐TCP) are functionalized with heparin to investigate the effects on immune and stem cell responses. The results show that the functionalized surfaces downregulate the release of hydrogen peroxide and proinflammatory cytokines (tumor necrosis factor alpha and interleukin 1 beta) from human monocytes and neutrophils, compared to nonfunctionalized discs. The macrophages show both elongated and round shapes on the two ceramic substrates, but the morphology of cells on heparinized β‐TCP tends toward a higher elongation after 72 h. The heparinized substrates support rat mesenchymal stem cell (MSC) adhesion and proliferation, and anticipate the differentiation toward the osteoblastic lineage as compared to β‐TCP and control. The coupling between the inflammatory response and osteogenesis is assessed by culturing MSCs with the macrophage supernatants. The downregulation of inflammation in contact with the heparinized substrates induces higher expression of bone‐related markers by MSCs.
Abstract 16159: Targeted Delivery of a Dual Cathepsin G and Chymase Inhibitor by Immunoliposomes Augments Cardioprotection in Mice
Authors: Bahman Hooshdaran, Mikhail Kolpakov, Xinji Guo, Yulia Bashkirova, Tao Wang, William Schappel, Yuan Tang, Mohammad F Kiani, Abdelkarim Sabri
Journal: Circulation (2016)

Introduction: Neutrophil- and mast-cell-mediated inflammation accounts for a substantial fraction of the myocardial injury occurring after ischemia reperfusion (IR). However, no standard anti-infla...
CDC Grand Rounds: National Amyotrophic Lateral Sclerosis (ALS) Registry Impact, Challenges, and Future Directions
Authors: Paul Mehta, D. Kevin Horton, Edward J. Kasarskis, Ed Tessaro, M. Shira Eisenberg, Susan Laird, John Iskander
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a rapidly progressive fatal neurologic disease. Currently, there is no cure for ALS and the available treatments only extend life by an average of a few months. The majority of ALS patients die within 2-5 years of diagnosis, though survival time varies depending on disease progression (1,2). For approximately 10% of patients, ALS is familial, meaning it and has a genetic component; the remaining 90% have sporadic ALS, where etiology is unknown, but might be linked to environmental factors such as chemical exposures (e.g., heavy metals, pesticides) and occupational history (3).
Abstract 11828: Follow-up of Genetically Confirmed Adult Long QT Syndrome Type 1 and 2 Patients: Clinical Course and Tools for Mutation-specific Risk Stratification
Authors: Mikael Koponen, Annukka Marjamaa, Matti Viitasalo, Lauri Toivonen, Heikki Swan
Journal: Circulation (2016)

Introduction: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). Research has been scarce on its clinical course in genetically confirmed patients not receiving β-blocker therapy. Also, applicability of specific mutations as a part of risk stratification calls for further investigation. Methods: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry comprising 4000 molecularly tested subjects. The inclusion criteria were 1) genetically confirmed KCNQ1 or KCNH2 mutation, or non-carrier status of the family-specific LQTS mutation, and 2) the age of 18-40 years during the follow-up. A questionnaire was sent to the study subjects. Data of all deaths were obtained from Statistics Finland, and data of ICD and pacemaker implantations were acquired from Hospital discharge register (HDR). Results: A total of 2723 subjects fulfilled the inclusion criteria. Of them 14 died during the follow-up, 1495 (55%) responded to the inquiry, and additional 12 subjects with device therapy were drawn from the HDR. The final study population (n=1521) consisted of 867 LQTS mutation carriers (617 with KCNQ1 , 242 with KCNH2 , and seven with ≥1 mutation), and 654 non-carrier relatives. The total follow-up time including retrospectively collected data was 18.3±6.3 years. In mutation carriers, risk factors for cardiac events before initiation of β-blocker included LQT2 genotype (hazard ratio [HR]=2.1, p=0.002), female gender (HR=3.2, p&lt;0.001), a cardiac event before the age of 18 years (HR=5.9, p&lt;0.001), and QTc ≥500 ms (vs &lt;470 ms, HR=2.7, p=0.01). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR=3.0-3.9, p&lt;0.001-0.03) compared to G589D, c.1129-2A&gt;G and other KCNQ1 mutation carriers after adjusting for gender and QTc duration. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR=0.12-0.24, p&lt;0.001) than other KCNH2 mutations. Of the seven SCDs four, and of the 14 aborted cardiac arrests three involved QT-prolonging drug. Conclusions: Specific mutations modulate the risk independently of gender and QTc duration. The avoidance of QT-prolonging drugs is fundamental in the prevention of potentially life-threatening cardiac events.
Abstract 20782: Arrhythmic Risk Evaluation of Native and Combusted Tobacco Flavor Additives in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Matthew A Nystoriak, Peter J Kilfoil, Pawel K Lorkiewicz, Daniel J Conklin, Aruni Bhatnagar
Journal: Circulation (2017)

Introduction: Tobacco and e-cigarette products are flavored to enhance appeal and increase consumption. While many flavor chemicals are conventional food additives and generally regarded as safe, l...
Abstract 19831: Pre-clinical in vivo Evaluation of Cormatrix as Right-sided Valved Conduit
Authors: Hanna Talacua, Khadija Mulder, Geert v Hout, Bart Sanders, Paul Grundeman, Aryan Vink, Carlijn Bouten, Jolanda Kluin
Journal: Circulation (2015)

Introduction: Although not FDA approved for heart valve repair, decellularized porcine small intestinal submucosa (Cormatrix) is currently used in quite a lot of institutes to reconstruct heart valves in patients. Recently, surgeons experienced clinical failures using Cormatrix as a patch in heart valve repair and words of caution were raised. The aim of this study was to pre-clinically evaluate CorMatrix as right-sided heart valved conduit in a xenogeneic animal model. Methods: CorMatrix was used as valved conduit in the right ventricular outflow tract in sheep (n=10) and lambs (n=10). Valved conduits were home-made and explanted after 1 month, 3 months or 6 months. Valve function was assessed by echocardiography directly after implantation and prior to termination. Explants were analyzed using histology, scanning electron microscopy, mechanical testing, biochemical analysis and immunohistochemistry. Results: All valved conduits were successfully implanted. 5 sheep and 2 lambs did not survive until planned follow-up. Diseased animals died due to valve failure after 1 or 2 months. Valve leaflets where thickened with signs of a massive inflammatory response. 5 sheep (1 month n=3, 3 months n=1 and 6 months n=1) and 8 lambs (1 month n=3, 3 months n=3, 6 months n=2) survived until planned follow up. In these animals, on echocardiography a well functioning valve with no signs of stenosis or insufficiency was seen. However all explants showed only limited signs of cellular infiltration or neotissue formation. Conclusions: In the chronic sheep and lamb model, 13 out of 20 CorMatrix pulmonary valved conduits were intact and showed good functionality, although only limited signs of tissue remodeling. However, 7 out of 20 valves failed owing to a massive inflammatory response. Further analysis is needed to understand the disturbing dichotomous outcome before clinical application can be advised