tbuckley/cabot-search huggingface dataset:
Genetics of Coronary Artery Disease
Authors: RobertRoberts
Journal: Circulation Research (2014)

There is almost no data on the genetics of acute coronary syndromes, so this review discusses primarily the 50 genetic risk variants associated with coronary artery disease that are of genome-wide significance in the discovery population and replicated in an independent population. All of these risk variants are extremely common with more than half occurring in >50% of the general population. They increased only minimally the relative risk for coronary artery disease. The most striking finding is that 35 of the 50 risk variants act independently of known risk factors, indicating there are several pathways yet to be appreciated, contributing to the pathogenesis of coronary atherosclerosis and myocardial infarction. All of the genetic variants seem to act through atherosclerosis, except for the ABO blood groups, which show that A and B are associated with increased risk for myocardial infarction, mediated by a prolonged von Willebrand plasma half life leading to thrombosis. The potential molecular mechanism...
Association of Definitive Pelvic Radiation Therapy With Survival Among Patients With Newly Diagnosed Metastatic Cervical Cancer
Authors: Yuefeng Wang, Michael Farmer, Enrique W. Izaguirre, David L. Schwartz, Bradley Somer, Todd Tillmanns, Matthew T. Ballo
Journal: JAMA Oncology (2018)

This cohort study investigates overall survival among patients with newly diagnosed metastatic cervical cancer who received chemotherapy alone compared with those who received chemotherapy and pelvic radiation therapy.
Abstract 12481: Myocardial Scar Tissue in Patients with Coronary Artery Disease and Preserved Left Ventricular Function - Lessons Learned from Delayed Enhancement-MRI
Authors: Christian Mahnkopf, Marcel Mitlacher, Stefan Holzmann, Manfred Dúcker, Philip Halbfass, Steffen Schnupp, Konstantin Zintl, Anil M Sinha, Johannes Brachmann
Journal: Circulation (2012)

Background:  In patients with coronary artery disease (CAD), the restricted blood supply to the myocardium can lead into myocardial injury. Delayed enhancement MRI (DE-MRI) allows the accurate detection and visualization of myocardial scar tissue.   Objective:  The aim of this study was the determination of myocardial scar tissue in patients with CAD with preserved left ventricular (LV) function without regional wall motion abnormalities (RWMA) in transthoracic echocardiography (TTE) using DE-MRI.   Methods and Results:  582 patients (458 males, Age: 65.2±12.0 years) were examined for viability determination using DE-MRI. All patients had a history of CAD. 83 of these patients (14,3%; 61 male; Age: 66.3±12.4 years) were found with normal LV function without RWMA in TTE. Out of these eighty-three patients 45 patients (54.2%) suffered from an acute coronary syndrome (elevated Troponin, NSTEMI, STEMI) shortly before the MRI examination while 8 patients were found with a history of ACS further in the past. Myocardial scar tissue was found in 57 patients (68.7%), whereas 26 patients (31.3%, Figure 1) showed no myocardial enhancement using DE-MRI. The number of patients with transmural scar was significantly higher than patients with subendcardial scar (36 (63.2%) vs. 21 (36.8%); p=0.005; Figure 2). Incidence of myocardial scar tissue was independent of the number of diseased coronary vessels (Figure 3).   Conclusion:  From our preliminary results, a significant numbers of patients with CAD, preserved LV function and without regional wall motion abnormalities can suffer from myocardial scar tissue. Transthoracic echocardiography may underestimate myocardial injury in these patients. Thus, MRI examinations of the heart for determination of myocardial viability should be considered in these patients to assess the extent of myocardial injury.
Mechanotransduction by PCDH15 Relies on a Novel cis-Dimeric Architecture
Authors: Gilman Dionne, Xufeng Qiu, Micah Rapp, Xiaoping Liang, Bo Zhao, Guihong Peng, Phinikoula S. Katsamba, Goran Ahlsen, Rotem Rubinstein, Clinton S. Potter, Bridget Carragher, Barry Honig, Ulrich Müller, Lawrence Shapiro
Journal: Neuron (2018)
Unhealthy Effects of Atmospheric Temperature and Pressure on the Occurrence of Myocardial Infarction and Coronary Deaths
Authors: SandrineDanet, FlorenceRichard, MichèleMontaye, StephanetteBeauchant, BrigitteLemaire, CatherineGraux, DominiqueCottel, NadineMarécaux, PhilippeAmouyel
Journal: Circulation (1999)

Background—Associations between an increase in coronary heart disease occurrence and low atmospheric temperatures have been reported from mortality data and hospital admission registries. However, concomitant increases in noncardiovascular case fatality rates and selection bias of hospital cases may weaken this observation. In this study, we addressed the question of the relationships between fatal and nonfatal coronary diseases and meteorological variables in 10-year data (1985 to 1994) collected in a morbidity registry (Lille-WHO MONICA Project) monitoring 257 000 men from 25 to 64 years of age. Methods and Results—The impacts of atmospheric temperature (in Celsius) and pressure (in millibars) on daily rates of myocardial infarction (MI) and coronary deaths were studied. Percentages of variation of event rates according to meteorological variations were derived from the relative risks estimated with a Poisson regression model. During the 10-year longitudinal survey, 3616 events occurred. Rates of events...
Prevalence of rotavirus and rapid changes in circulating rotavirus strains among children with acute diarrhea in China, 2009–2015
Authors: Jianxing Yu, Shengjie Lai, Qibin Geng, Chuchu Ye, Zike Zhang, Yaming Zheng, Liping Wang, Zhaojun Duan, Jing Zhang, Shuyu Wu, Umesh Parashar, Weizhong Yang, Qiaohong Liao, Zhongjie Li
Journal: Journal of Infection (2018)
Relations between epidermal barrier dysregulation and Staphylococcus species–dominated microbiome dysbiosis in patients with atopic dermatitis
Authors: Can Altunbulakli, Matthias Reiger, Avidan U. Neumann, Natalie Garzorz-Stark, Megan Fleming, Claudia Huelpuesch, Francesc Castro-Giner, Kilian Eyerich, Cezmi A. Akdis, Claudia Traidl-Hoffmann
Journal: Journal of Allergy and Clinical Immunology (2018)
Why Cochrane should prioritise sharing data
Authors: Farhad Shokraneh, Clive E Adams, Mike Clarke, Laura Amato, Hilda Bastian, Elaine Beller, Jon Brassey, Rachelle Buchbinder, Marina Davoli, Chris Del Mar, Paul Glasziou, Christian Gluud, Carl Heneghan, Tammy Hoffmann, John PA Ioannidis, Mahesh Jayaram, Joey Kwong, David Moher, Erika Ota, Rebecca Syed Sheriff, Luke Vale, Ben Goldacre
Journal: BMJ (2018)

Packer1 says that the one who submits a research for public good should be ready to receive a request for data sharing for examination and re-analysis and that tax payers assume that a national agency is checking such data and analysis. Here we discuss Cochrane’s practice on data sharing.

Open science, as endorsed by the G7,2 includes sharing data, computer code, and materials. It is essential for reproducibility, collaboration, and innovation. We support the work of Cochrane, but are concerned that Cochrane is not sharing all its reviews’ data. These data should be fully accessible for reuse by third parties.

Cochrane, a non-profit private company3 and registered charity, produces and maintains systematic reviews in health and social care. Its work is undertaken by a global network of thousands of people,4 and its support largely comes from public funding.5 Most people producing Cochrane reviews are volunteers not specifically funded for this work,67 and Cochrane encourages “crowdsourcing” of work.8910

Cochrane editorial bases help volunteers obtain study reports and manually extract the wealth of data needed to generate systematic reviews.111213 Cochrane teams use RevMan software14 to produce files in standard format (XML), storing information on the studies, their methods, and results for publication in the Cochrane Library.

Benefits of sharing extracted data from trials and systematic reviews are well known, as are the costs of not sharing.13151617 Sharing maximises transparency, reliability of data extraction, and syntheses. It improves access to data—saving time and money—and opens new avenues of inquiry.18 Sharing is associated with increased citations,19 more publications,20 and reuse for new purposes.16

Structured data from Cochrane should be fully accessible for download, reuse, and review (box 1). Currently, they are not. …
Making replication prestigious
Authors: Krzysztof J. Gorgolewski, Thomas Nichols, David N. Kennedy, Jean-Baptiste Poline, Russell A. Poldrack
Journal: Behavioral and Brain Sciences (2018)

Abstract Making replication studies widely conducted and published requires new incentives. Academic awards can provide such incentives by highlighting the best and most important replications. The Organization for Human Brain Mapping (OHBM) has led such efforts by recently introducing the OHBM Replication Award. Other communities can adopt this approach to promote replications and reduce career cost for researchers performing them.
Reply to John T. Leppert and James D. Brooks’ Letter to the Editor re: Brandon A. Mahal, David D. Yang, Natalie Q. Wang, et al. Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High-grade Prostate Cancer. Eur Urol 2018;74:146–54
Authors: Brandon A. Mahal, David D. Yang, Paul L. Nguyen
Journal: European Urology (2018)
To make innovations such as replication mainstream, publish them in mainstream journals
Authors: Boris Egloff
Journal: Behavioral and Brain Sciences (2018)

Abstract It was a pleasure to read Zwaan et al.'s wise and balanced target article. Here, I use it as a shining example for bolstering the argument that to make innovations such as replication mainstream, it seems advisable to move the debates from social media to respected “mainstream” psychology journals. Only then will mainstream psychologists be reached and, we hope, convinced.
Osteopontin Transgenic Mice Fed a High-Cholesterol Diet Develop Early Fatty-Streak Lesions
Authors: KikuoIsoda, YashuhiroKamezawa, MakotoAyaori, MasatoshiKusuhara, NorihiroTada, FumitakaOhsuzu
Journal: Circulation (2003)

Background— Osteopontin (OPN) is a noncollagenous adhesion protein found at the site of atherosclerotic lesions. However, it has not yet been clarified whether or not OPN can promote atherosclerotic lesions. Methods and Results— We investigated the contribution of OPN to atherosclerosis by evaluating aortic sinus lesions of both OPN transgenic (Tg) and non-Tg mice fed an atherogenic diet (1.25% cholesterol) for 16 weeks. The atherosclerotic lesions were found to be significantly larger in OPN-Tg compared with those in non-Tg (17 859±2010 versus 6469±485 μm2, P<0.01). The lesions in both mice were fatty-streak lesions with an accumulation of mononuclear cells and lipids. We next investigated the production of interleukin (IL)-10 by macrophages from both mice. Compared with the non-Tg mice, a 42% (P<0.01) and 73% (P<0.001) decrease in the IL-10 production was identified in the OPN-Tg mice either without or with lipopolysaccharide. Conclusions— The expression of OPN induces fatty-streak lesion formation in m...
Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer
Authors: Vinay K. Kartha, Khalid A. Alamoud, Khikmet Sadykov, Bach-Cuc Nguyen, Fabrice Laroche, Hui Feng, Jina Lee, Sara I. Pai, Xaralabos Varelas, Ann Marie Egloff, Jennifer E. Snyder-Cappione, Anna C. Belkina, Manish V. Bais, Stefano Monti, Maria A. Kukuruzinska
Journal: Genome Medicine (2018)

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments. A frequent feature of HNSCC is the inappropriate activation of β-catenin that has been implicated in cell survival and in the maintenance and expansion of stem cell-like populations, thought to be the underlying cause of tumor recurrence and resistance to treatment. However, the therapeutic value of targeting β-catenin activity in HNSCC has not been explored. We utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between β-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays. We validated the anti-tumorigenic activity of ICG-001 in vivo using SCC-derived tumor xenografts in murine models, as well as embryonic zebrafish-based screens of sorted stem cell-like subpopulations. Additionally, ICG-001-inhibition signatures were overlaid with RNA-sequencing data from The Cancer Genome Atlas (TCGA) for human OSCCs to evaluate its association with tumor progression and prognosis. ICG-001 inhibited HNSCC cell proliferation and tumor growth in cellular and murine models, respectively, while promoting intercellular adhesion and loss of invasive phenotypes. Furthermore, ICG-001 preferentially targeted the ability of subpopulations of stem-like cells to establish metastatic tumors in zebrafish. Significantly, interrogation of the ICG-001 inhibition-associated gene expression signature in the TCGA OSCC human cohort indicated that the targeted β-catenin/CBP transcriptional activity tracked with tumor status, advanced tumor grade, and poor overall patient survival. Collectively, our results identify β-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.
Abstract 19140: Targeted Disruption of Endothelial Specific Molecule (ESM)-1 Results in Atrioventricular Valve Malformations Leading to Cardiac Dysfunction
Authors: Prashanthi Menon, Katherine Spokes, David Beeler, Lauren Janes, William Aird
Journal: Circulation (2012)

Background: Endothelial cell specific molecule-1 (ESM-1) or Endocan is a circulating dermatan sulphate proteoglycan secreted primarily by the vascular endothelium. Elevated levels of ESM-1 are observed in the plasma of patients during tumor progression and in inflammatory disorders like sepsis suggesting that it could be potential biomarker for endothelial activation or dysfunction. To date there have been no in vivo studies of ESM-1. In this study we investigated the in vivo functional role of ESM-1 by the targeted deletion of the gene in mice. Methods and Results: To determine the critical functions of ESM-1 in vivo, we generated a global ESM-1 knockout mouse by deletion of exon1 of the ESM-1 mouse gene. ESM-1 knockout mice were born at the normal Mendelian ratio but showed 50% perinatal mortality by postnatal day 3 (P3). Pathological analysis of mice that died at P2 revealed dilated atria engorged with blood and thrombi indicative of possible defect in cardiac contractility. Pulmonary and liver congestion were also observed in ESM-1 knockout mice. Furthermore, histopathological studies revealed structural abnormalities in atrioventricular valves (AV) with an ebstenoid tricuspid malformation and parachute mitral valve abnormality suggesting AV valve regurgitation in ESM-1 knockout mice. In contrast, the semilunar valves appeared normal. Fetal genes associated with cardiac stress response including atrial natriuretic peptide (Nppa), brain natriuretic pepetide (Nppb) and beta-myosin heavy chain (Myh7) were significantly up regulated in ESM1 knockout P2 hearts compared to controls. Conclusion: In conclusion, our findings demonstrate for the first time that targeted disruption of ESM-1 results in atrioventricular valve anomalies leading to cardiac dysfuction. Understanding the mechanisms and signaling networks through which ESM-1 regulates valve formation has implications in the field of congenital heart disease research
Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility
Authors: Joshua Mayourian, Delaine K. Ceholski, Przemek A. Gorski, Prabhu Mathiyalagan, Jack F. Murphy, Sophia I. Salazar, Francesca Stillitano, Joshua M. Hare, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa
Journal: Circulation Research (2018)

The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved.This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies.Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo-mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes.miR-21-5p plays a key role in hMSC-exo-mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.
Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia
Authors: Robert J. Kreitman, Claire Dearden, Pier Luigi Zinzani, Julio Delgado, Lionel Karlin, Tadeusz Robak, Douglas E. Gladstone, Philipp le Coutre, Sascha Dietrich, Mirjana Gotic, Loree Larratt, Fritz Offner, Gary Schiller, Ronan Swords, Larry Bacon, Monica Bocchia, Krimo Bouabdallah, Dimitri A. Breems, Agostino Cortelezzi, Shira Dinner, Michael Doubek, Bjorn Tore Gjertsen, Marco Gobbi, Andrzej Hellmann, Stephane Lepretre, Frederic Maloisel, Farhad Ravandi, Philippe Rousselot, Mathias Rummel, Tanya Siddiqi, Tamar Tadmor, Xavier Troussard, Cecilia Arana Yi, Giuseppe Saglio, Gail J. Roboz, Kemal Balic, Nathan Standifer, Peng He, Shannon Marshall, Wyndham Wilson, Ira Pastan, Nai-Shun Yao, Francis Giles
Journal: Leukemia (2018)

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.
RCGP to stop investing in fossil fuel companies
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

The Royal College of General Practitioners has decided to cease any investment in fossil fuels, a key contributor to climate change.

The RCGP is the UK’s largest medical royal college, with more than 52 000 members. It is also a leading member of the UK Health Alliance on Climate Change and has long recognised the effects that climate change can have on the environment—and its adverse effects on patients’ health.

A spokesperson said that the college invested 4% of its £10.7m (€12m; $14.1) portfolio last year in fossil fuels.

The college’s chair, Helen Stokes-Lampard, said, “Climate change is a clear risk to the health and wellbeing of our patients, with recent research estimating 50 million predicted years of life lost across Great Britain …
Replication is already mainstream: Lessons from small-<i>N</i> designs
Authors: Daniel R. Little, Philip L. Smith
Journal: Behavioral and Brain Sciences (2018)

Abstract Replication is already mainstream in areas of psychology that use small- N designs. Replication failures often result from weak theory, weak measurement, and weak control over error variance. These are hallmarks of phenomenon-based research with sparse data. Small- N designs, which focus on understanding processes, treat the individual rather than the experiment as the unit of replication and largely circumvent these problems.
Therapeutic Approaches to the Treatment of Tinnitus
Authors: Berthold Langguth, Ana Belen Elgoyhen, Christopher R. Cederroth
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Tinnitus is a highly prevalent condition that is associated with hearing loss in most cases. In the absence of external stimuli, phantom perceptions of sounds emerge from alterations in neuronal activity within central auditory and nonauditory structures. Pioneering studies using lidocaine revealed that tinnitus is susceptible to pharmacological interventions. However, lidocaine is not effective in all patients, and no other drug has been identified with clear efficacy for the long-term treatment of tinnitus. In this review, we present recent advances in tinnitus research, including more detailed knowledge of its pathophysiology and involved neurotransmitter systems. Moreover, we summarize results from animal and clinical treatment studies as well as from studies that identified tinnitus as a side effect of pharmacological treatments. Finally, we focus on challenges in the development of pharmacological compounds for the treatment of tinnitus, namely the limitations of available animal models and of standardized clinical research methodologies.