tbuckley/cabot-search huggingface dataset:
An Expanding Role for Environmental Microbes in Shaping the Immune Response to Infection with <i>Mycobacterium tuberculosis</i>
Authors: David M. Lewinsohn
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

identify aberrancy of coagulation in patients with bleeding or thrombotic events on ECMO.Northrop and colleagues demonstrated that ECMO patients experienced fewer bleeding events, less exposure to blood products, and increased circuit life after implementation of a comprehensive anticoagulation laboratory protocol that included thromboelastography, stratified in accordance with patient stability and heparin dose (11).This excellent prospective study by Dalton and colleagues adds to our understanding of the frequency and timing of bleeding and thrombotic complications and their associations with clinically important outcomes from ECMO in pediatric patients.With the establishment of a study group, the stage is now set for investigating whether bleeding and thrombotic-associated outcomes are alterable with standardized anticoagulation and patient care practices.Future studies must address the innumerable challenges around coagulation, anticoagulation, and blood-circuit interface in a diverse and increasingly complex population of ECMO patients (12).
Of mice and men, nature and nurture, and a few red herrings
Authors: Marc D Hauser
Journal: Behavioral and Brain Sciences (2017)

Abstract Burkart et al.'s proposal is based on three false premises: (1) theories of the mind are either domain-specific/modular (DSM) or domain-general (DG); (2) DSM systems are considered inflexible, built by nature; and (3) animal minds are deemed as purely DSM. Clearing up these conceptual confusions is a necessary first step in understanding how general intelligence evolved.
GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand
Authors: Linda Yang, Chih-Chuan Chang, Zhe Sun, Dennis Madsen, Haisun Zhu, Søren B Padkjær, Xiaoai Wu, Tao Huang, Karin Hultman, Sarah J Paulsen, Jishu Wang, Anne Bugge, Jane Boesen Frantzen, Per Nørgaard, Jacob Fuglsbjerg Jeppesen, Zhiru Yang, Anna Secher, Haibin Chen, Xun Li, Linu Mary John, Bing Shan, Zhenhua He, Xiang Gao, Jing Su, Kristian T Hansen, Wei Yang, Sebastian Beck Jørgensen
Journal: Nature Medicine (2017)
弁間質細胞張力ホメオスタシスはRhoAシグナル伝達を介して石灰化と細胞外マトリックスのリモデリング過程を指示する【Powered by NICT】
Authors: J Farrar Emily, Pramil Varsha, M Richards Jennifer, Z Mosher Christopher, T Butcher Jonathan
Journal: Biomaterials (2016)
変形性関節症:老化細胞の局所での除去は外傷後変形性関節症の発症を減らし,再生促進環境を作り出す
Authors: Jeon Ok Hee, Kim Chaekyu, Rathod Sona, Chung Jae Wook, Kim Do Hun, Elisseeff Jennifer H, Laberge Remi‐Martin, Demaria Marco, Campisi Judith, Vasserot Alain P, Poon Yan, David Nathaniel, Baker Darren J, Van Deursen Jan M
Journal: Nature Medicine (2017)
A randomized, placebo‐controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis
Authors: Scott L. Friedman, Vlad Ratziu, Stephen A. Harrison, Manal F. Abdelmalek, Guruprasad P. Aithal, Juan Caballeria, Sven Francque, Geoffrey Farrell, Kris V. Kowdley, Antonio Craxi, Krzysztof Simon, Laurent Fischer, Liza Melchor‐Khan, Jeffrey Vest, Brian L. Wiens, Pamela Vig, Star Seyedkazemi, Zachary Goodman, Vincent Wai‐Sun Wong, Rohit Loomba, Frank Tacke, Arun Sanyal, Eric Lefebvre
Journal: Hepatology (2017)

The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double‐blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1‐3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2‐point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent‐to‐treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (H epatology 2018;67:1754‐1767).
The inhibitory effect of PEDF in glioma tumors
Authors: Tao Zhang, Yuan Lu
Journal: Cancer Research (2005)

3017   Malignant gliomas are highly vascularized and invasive neoplasms, which are characterized by a high incidence of recurrence and a poor prognosis. The progressive growth of glioblastoma is thought to be dependent on angiogenesis. Recent studies have shown that pigment epithelium-derived factor (PEDF) can induce differentiation and inhibit angiogenesis of several tumors. In this study, we investigated the effect of PEDF on glioma cell (U87 and A172) growth and angiogenesis by TUNEL and Flow cytometry. Results indicated that the rPEDF-treated cells had a significantly higher percentage of apoptotic cells when compared with the control cells. More analysis of the cell cycle showed that the rPEDF treated cells would arrest in the G(1) phase and block in S phase of the cell cycle. We found that the apoptosis of glioma cells caused by rPEDF is associated with a marked increase of p53 and Bax as well as the down-regulation of Bcl-2. Glioma cells treated with rPEDF exhibited decreased invasiveness. The anti-migratory activity of rPEDF was evident even in the presence of the vascular endothelial growth factor (VEGF), an inducer of glioma indicating that its effect on glioma cells migration was powerful. Real-time PT-PCR and Western-blot were used to evaluate whether rPEDF would affect the production of positive and negative factors of angiogenesis. Glioma cells exhibited a decreased expression of VEGF and an increased expression of TSP-2 (the major negative angiogenic factors in glioma). Both changes were essential and sufficient to shift the angiogenic phenotype of glioma cells to anti-angiogenic. The angiogenic switch seen  in vitro  was maintained  in vivo , where PEDF-expressing cells formed small glioma nodules with reduced vascularization. The rPEDF treatment regimen resulted in significant reduction in the tumor size in 2 weeks compared with the control group after the formation of the glioma tumors. The mechanism underlying the suppressed growth appears to be the anti-angiogenesis function of PEDF. A 55 % decreased MVD in the PEDF-treated glioma closely paralleled the 53 % decreased tumor size inferring a direct relationship between glioma vascularity and growth. Our results demonstrated for the first time that PEDF could significantly reduce the gliomas angiogenesis, proliferation, and migration  in vitro  and  in vivo . Our study presents a novel approach of developing anti-angiogenic therapies to treat gliomas.
Abstract 11793: Early Detection of Chemo-cardiotoxicity Assessed by Layer Specific Strain: Myocardial Layer is Most Vulnerable to Anthracycline Chemotherapy
Authors: Seong-Mi Park, Mi-Na Kim, Kyong-Hwa Park, Wan-Joo Shim
Journal: Circulation (2015)

Background: Anthracycline-based chemotherapy has a progressive dose-dependent toxicity to the myocardium and is related to a poor prognosis. Early detection of subclinical myocardial dysfunction caused by the chemo-cardiotoxicity is thus important for predicting apparent left ventricular (LV) dysfunction and heart failure. Recently, detailed layer-specific analysis of myocardial deformation has been described. This study assessed LV myocardial dysfunction using layer-specific strain in patients who received anthracycline-based chemotherapy. Methods: Consecutive 54 patients (50 ± 14 years old, all women) with preserved LV ejection fraction (≥50%) after receiving anthracycline chemotherapy were included. Two-dimensional speckle tracking was used to assess circumferential strains (CS) from the three acquired parasternal short-axis views at basal, midventricular, and apical level. Peak systolic CS was determined for the total wall thickness (CStotal) and for each of three myocardial layers (CSendo, CSmyo and CSepi for endocardial, mid-myocardial, and epicardial layer, respectively) using EchoPAC PC software. Twenty normal controls were studied for comparisons. Results: CStotal was worse in patients than in controls (-24.5 ± 7.0% vs -22.0 ± 5.8%, P =0.03) even though LV ejection fraction was not different (P = 0.25). Layer-specific strains showed a decreasing gradient from the endocardium to the epicardium both in controls and patients (P &lt;0.001) and it was more apparent from the endocardium to the myocardium in patients than in controls. CS were significantly different between controls and patients in myocardial and epicardial layers (CSmyo, -23.2 ± 8.0% vs -20.8 ± 7.9%, P =0.01; CSepi, -17.8 ± 6.0% vs -16.0 ± 6.8%, P =0.04), but not significant in endocardial layer (CSendo, -29.4 ± 8.4% vs -28.2 ± 9.2%, P =0.09). CStotal was most related to CSmyo (r = 0.943, P &lt;0.001) and CSmyo correlated with the cumulative doxorubicin dose (r = 0.296, P = 0.03). Conclusion: CStotal was reduced and CSmyo was most impaired in patients, which means that myocardial layer is most vulnerable to anthracycline chemotherapy. Layer-specific evaluation of LV may be helpful for early detection of subclinical myocardial dysfunction in these patients.
Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors
Authors: Michael A. Nauck, Juris J. Meier, Matthew A. Cavender, Mirna Abd El Aziz, Daniel J. Drucker
Journal: Circulation (2017)

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], −13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], −24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.
International Olympic Committee consensus statement on pain management in elite athletes
Authors: Brian Hainline, Wayne Derman, Alan Vernec, Richard Budgett, Masataka Deie, Jiří Dvořák, Chris Harle, Stanley A Herring, Mike McNamee, Willem Meeuwisse, G Lorimer Moseley, Bade Omololu, John Orchard, Andrew Pipe, Babette M Pluim, Johan Ræder, Christian Siebert, Mike Stewart, Mark Stuart, Judith A Turner, Mark Ware, David Zideman, Lars Engebretsen
Journal: British Journal of Sports Medicine (2017)

Pain is a common problem among elite athletes and is frequently associated with sport injury. Both pain and injury interfere with the performance of elite athletes. There are currently no evidence-based or consensus-based guidelines for the management of pain in elite athletes. Typically, pain management consists of the provision of analgesics, rest and physical therapy. More appropriately, a treatment strategy should address all contributors to pain including underlying pathophysiology, biomechanical abnormalities and psychosocial issues, and should employ therapies providing optimal benefit and minimal harm. To advance the development of a more standardised, evidence-informed approach to pain management in elite athletes, an IOC Consensus Group critically evaluated the current state of the science and practice of pain management in sport and prepared recommendations for a more unified approach to this important topic.
Early-Onset Sepsis Calculator—Risk of Delaying Treatment—Reply
Authors: Michael W. Kuzniewicz, Gabriel J. Escobar, Karen M. Puopolo
Journal: JAMA Pediatrics (2017)

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Safety and efficacy of MitraClip™ therapy in patients with severely impaired left ventricular ejection fraction: results from the German transcatheter mitral valve interventions (TRAMI) registry
Authors: Nicolas A. Geis, Miriam Puls, Edith Lubos, Christine S. Zuern, Jennifer Franke, Robert Schueler, Ralph S. von Bardeleben, Peter Boekstegers, Taoufik Ouarrak, Ralf Zahn, Hüseyin Ince, Jochen Senges, Hugo A. Katus, Raffi Bekeredjian
Journal: European Journal of Heart Failure (2017)
Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)
Authors: Anja J Will, Giulia Cova, Marco Osterwalder, Wing-Lee Chan, Lars Wittler, Norbert Brieske, Verena Heinrich, Jean-Pierre de Villartay, Martin Vingron, Eva Klopocki, Axel Visel, Darío G Lupiáñez, Stefan Mundlos
Journal: Nature Genetics (2017)
Phase 3 randomized study of cabozantinib (XL184) versus everolimus in subjects with clear cell renal cell carcinoma (METEOR).
Authors: Toni K. Choueiri, Bernard J. Escudier, Thomas Powles, David Cella, Qinhua C. Ru, Christian Scheffold, Robert J. Motzer
Journal: Journal of Clinical Oncology (2014)

TPS4601 Background: Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with potent activity against MET and VEGFR2. Cabozantinib has demonstrated clinical activity in multiple solid tumor types, including heavily pretreated subjects with clear cell renal cell carcinoma (ccRCC) (Choueiri et al.; ASCO 2012, abstract 4504). In ccRCC, VHL tumor suppressor gene dysfunction results in impaired HIF degradation and consequent activation of MET and VEGF pathways. Moreover, MET has been implicated in adaptive resistance to VEGF-pathway targeted agents. Based on the clinical activity seen to date and the scientific rationale, there is strong interest in the evaluation of cabozantinib in ccRCC. Methods: This Phase 3, open-label, multicenter study evaluates the efficacy and safety of cabozantinib compared with everolimus in subjects with ccRCC (NCT01865747).The primary endpoint is progression-free survival (PFS) as evaluated by an independent radiology review committee (IRC). Secondary endpoints are overall survival (OS) and response rate. Exploratory endpoints are safety, tolerability, tumor MET status, circulating tumor cells, serum bone markers and plasma biomarkers, skeletal-related events (SRE), and health-related quality of life (HRQoL). Enrollment started in August 2013. Target recruitment is 650 subjects with ccRCC, which will provide power for both PFS and OS endpoints. Eligible subjects must have progressed after 1 or more prior VEGFR TKI therapy. Subjects are randomized 1:1 to receive either cabozantinib or everolimus. Stratification factors are the number of prior VEGFR TKI therapy and MSKCC prognostic criteria (Motzer et al.; J Clin Oncol 22:454-463, 2004). Radiographic assessments include CT/MRI and bone scintigraphy. PFS and response are determined by IRC using RECIST criteria version 1.1. SREs are defined as radiation therapy to bone, pathological fracture, spinal cord compression, and surgery to bone. The NCCN-Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) questionnaire and the EuroQol Health questionnaire (EQ‐5D-5L) are being used to measure HRQoL. Subjects are being followed for survival. Clinical trial information: NCT01865747.
Treatment of individuals who cannot receive blood products for religious or other reasons
Authors: Carlton D. Scharman, Debora Burger, Joseph J. Shatzel, Edward Kim, Thomas G. DeLoughery
Journal: American Journal of Hematology (2017)

By virtue of their religious principles, Jehovah's Witnesses (JWs) generally object to receiving blood products, raising numerous ethical, legal, and medical challenges for providers who care for these patients, especially in the emergent setting. In this review, we discuss several areas relevant to the care of JWs, including the current literature on "bloodless" medical care in the setting of perioperative and intraoperative management, acute blood loss, trauma, pregnancy, and malignancy. We have found that medical and administrative efforts in the form of bloodless medicine and surgery programs can be instrumental in helping to reduce risks of morbidity and mortality in these patients. Planning prior to an anticipated event associated with blood loss or anemia (such as elective surgery, pregnancy, and chemotherapy) is critical. Specifically, bloodless medicine programs should prioritize vigilant early screening and management of anemias, early establishment of patient wishes regarding transfusion, and the incorporation of those wishes into multidisciplinary medical and surgical care. Although there are now a variety of human-based and nonhuman-based products available as transfusion alternatives, the degree and quality of evidence to support their use varies significantly between products and is also largely dependent on the clinical setting.
Association of Reference Pricing with Drug Selection and Spending
Authors: James C. Robinson, Christopher M. Whaley, Timothy T. Brown
Journal: New England Journal of Medicine (2017)

Background In the United States, prices for therapeutically similar drugs vary widely, which has prompted efforts by public and private insurers to steer patients toward the lower-priced options. Under reference pricing, the insurer or employer establishes a maximum contribution it will make toward the price of a drug or procedure, and the patient pays the remainder. Methods We used difference-in-differences multivariable regression methods to analyze changes in prescriptions and pricing for 1302 drugs in 78 therapeutic classes in the United States, before and after implementation of reference pricing by an alliance of private employers. We assessed trends for the study group relative to those for an employee group that was not subject to reference pricing. The study included 1,122,741 prescriptions that were reimbursed during the period from 2010 through 2014. Results Implementation of reference pricing was associated with a higher percentage of prescriptions that were filled for the lowest-priced reference drug within its therapeutic class (difference in probability, 7.0 percentage points; 95% confidence interval [CI], 4.0 to 9.9), a lower average price paid per prescription (-13.9%; 95% CI, -23.8 to -2.7), and a higher rate of copayment by patients (5.2%; 95% CI, 0.2 to 10.4) than in the comparison group. During the first 18 months after implementation, spending for employers was $1.34 million lower and the amount of copayments for employees was $0.12 million higher than in the comparison group. Conclusions Implementation of reference pricing was associated with significant changes in drug selection and spending for a population of patients covered by employment-based insurance in the United States. (Funded by the Agency for Healthcare Research and Quality and the Genentech Foundation.).