tbuckley/cabot-search huggingface dataset:
One in 12 deaths could be prevented with 30 minutes of exercise five days a week, finds study
Authors: Susan Mayor
Journal: BMJ (2017)

Being physically active for 150 minutes a week could prevent one in 12 deaths globally and one in 20 cases of cardiovascular disease (CVD), a large study has found.1 Being even more active was associated with additional benefits.

Previous research in high income countries has shown that low levels of physical activity are associated with increased mortality and morbidity from CVD but there has been limited data from low and middle income countries.

Researchers prospectively studied 130 843 healthy volunteers aged 30 to 70 years. They measured their physical activity using the …
α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B
Authors: Diana G Ferreira, Mariana Temido-Ferreira, Hugo Vicente Miranda, Vânia L Batalha, Joana E Coelho, Éva M Szegö, Inês Marques-Morgado, Sandra H Vaz, Jeong Seop Rhee, Matthias Schmitz, Inga Zerr, Luísa V Lopes, Tiago F Outeiro
Journal: Nature Neuroscience (2017)
Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evaluation of filovirus entry inhibitors
Authors: Qing Chen, Ke Tang, Xiaoyu Zhang, Panpan Chen, Ying Guo
Journal: Acta Pharmaceutica Sinica B (2017)

Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4 (BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and drugs. An HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here, we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day 4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious in vitro. The pseudo-filovirus-infection mouse models can be used for in vivo activity evaluation of anti-filovirus drugs. This sequential in vitro and in vivo evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities.
Risk of second thyroid cancer (STC) among survivors of childhood cancer.
Authors: Rafaela Naves, Renata Parada Amorim, A. Lindsay Frazier, Karina Braga Ribeiro, Carlos Rodriguez-Galindo
Journal: Journal of Clinical Oncology (2014)

10084 Background: Thyroid carcinomas account for almost 10% of all second malignant neoplasms. The aim of our study was to assess the risk factors for second thyroid cancer (STC) among childhood cancer survivors (CCS), using population-based data. Methods: Using SEER-9 we identified 40,876 individuals with ages 0-19 diagnosed with any malignancy in the period 1973-2010. Standardized incidence ratios (SIR) and corresponding 95% confidence intervals (95% CI) for STC were calculated using SEERStat 8.1.2. Results: 131 STC were observed (SIR=5.10, 95% CI 4.26-6.05). The risk of STC was higher for males than females (SIR=8.93, 95% CI, 6.38-12.15, vs. SIR=4.29, 95% CI 3.45-5.27, respectively) and for blacks compared to whites (SIR= 10.96, 95% CI 5.26-20.15 vs. SIR=4.86, 95% CI 4.01-5.85). Patients < 10 years at diagnosis had a higher risk than patients diagnosed at an older age. (< 10 yrs SIR=8.73, 95% CI 6.50-11.48 vs.> 10 yrs SIR=4.03, 95% CI 3.20-5.02, respectively). Radiation therapy (RT) was associated with a higher risk of STC; risk associated with RT varied by race (blacks: SIR=15.85, 95% CI 5.15-37.00 vs. whites: SIR=7.21, 95% CI 5.54-9.22) and gender (males: SIR=15.23, 95% CI 9.95-22.31 vs. females: SIR=5.76, 95% CI 4.20-7.71). Black children <10 yrs who received RT had the highest risk of STC (SIR=42.67, 95% CI 11.63-109.24). However, an elevated risk was seen for STC even among children who did not receive RT [leukemia (No RT: SIR=6.57, 95% CI 3.59-11.03; RT: SIR=9.30, 95% CI 4.80-16.24) lymphoma (No RT: SIR=7.99, 95% CI 4.65-12.79; RT: SIR=9.71, 95% CI 6.68-13.64)]. The increased risk for CNS (SIR: 8.43; 95%CI, 4.66 – 14.31) and renal tumors (SIR: 8.54; 95% CI, 1.03 – 30.84) and for neuroblastoma (SIR: 21.83; 95%CI, 5.95 – 55.90) was only observed for individuals who had received RT. The increased risk of STC for bone tumors was not associated with RT (SIR=5.02, 95% CI 1.63-11.71). Conclusions: Risk for STC is higher for males and blacks, as compared to primary thyroid cancers that occur more commonly in whites and females. The risk of STC is elevated among those who received RT, but even CCS who did not receive RT are at risk. Surveillance of all CCS is recommended, particularly those treated at a younger age, and more exploration of non-RT risk factors is warranted.
Induction of Epidermoid Carcinoma in Lungs of Rats: A “New” Method Based Upon Deposition of Methylcholanthrene in Areas of Pulmonary Infarction
Authors: Mearl F. Stanton, Robert Blackwell
Journal: JNCI Journal of the National Cancer Institute (1961)

Multiple pulmonary infarcts were induced in rats by intravenous injection of the halogenated hydrocarbon, hexachlorotetrafluorobutane. When 3-methylcholanthrene (MCA) was mixed with this infarct-inducing vehicle and injected, the resultant infarcts were the sites of invasive epidermoid carcinomas. Transitional lesions in the infarcts indicated that the carcinomas were derived from regenerating epithelium frequently converted to keratinized squamous epithelium by the carcinogen. The tumors are comparable in their morphology and behavior to the bronchogenic carcinoma of man and may serve as a prototype for the study of this disease. In control experiments we used emboli of MCA mixed with tricaprylin. This mixture did not infarct the lung but resulted in the development of massive keratinized cysts that did not become invasive carcinomas. However, when rats were treated similarly with emboli of MCA and the lungs were later infarcted with the fluorocarbon alone, the cysts developed, squamous metaplasia was present in some healed infarcts, and two carcinomas were found. The carcinomas seemed to originate at sites of infarction. These observations suggest that the process of infarction and repair may determine the malignant behavior of the tumors. It seems reasonable that physiological changes at the site of infarction, such as ischemia and regeneration, play a major role in this process. The procedure offers a simple and efficient means of introducing and testing other potential carcinogens in the lung, since it is evident that carcinomas of the lung can be readily induced by a pulmonary carcinogen, if the carcinogen is deposited in lung tissue that is damaged or destined to become damaged through infarction.
Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2
Authors: Paola Caruso, Benjamin J. Dunmore, Kenny Schlosser, Sandra Schoors, Claudia Dos Santos, Carol Perez-Iratxeta, Jessie R. Lavoie, Hui Zhang, Lu Long, Amanda R. Flockton, Maria G. Frid, Paul D. Upton, Angelo D’Alessandro, Charaka Hadinnapola, Fedir N. Kiskin, Mohamad Taha, Liam A. Hurst, Mark L. Ormiston, Akiko Hata, Kurt R. Stenmark, Peter Carmeliet, Duncan J. Stewart, Nicholas W. Morrell
Journal: Circulation (2017)

Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells. However, the mechanisms underlying alterations in energy production have not been identified.Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and patients with idiopathic PAH to determine mechanisms underlying abnormal endothelial glycolysis. We hypothesized that in BOECs from patients with PAH, the downregulation of microRNA-124 (miR-124), determined with a tiered systems biology approach, is responsible for increased expression of the splicing factor PTBP1 (polypyrimidine tract binding protein), resulting in alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and 2) and consequently increased PKM2 expression. We questioned whether this alternative regulation plays a critical role in the hyperglycolytic phenotype of PAH endothelial cells.Heritable PAH and idiopathic PAH BOECs recapitulated the metabolic abnormalities observed in pulmonary artery endothelial cells from patients with idiopathic PAH, confirming a switch from oxidative phosphorylation to aerobic glycolysis. Overexpression of miR-124 or siRNA silencing of PTPB1 restored normal proliferation and glycolysis in heritable PAH BOECs, corrected the dysregulation of glycolytic genes and lactate production, and partially restored mitochondrial respiration. BMPR2 knockdown in control BOECs reduced the expression of miR-124, increased PTPB1, and enhanced glycolysis. Moreover, we observed reduced miR-124, increased PTPB1 and PKM2 expression, and significant dysregulation of glycolytic genes in the rat SUGEN-hypoxia model of severe PAH, characterized by reduced BMPR2 expression and endothelial hyperproliferation, supporting the relevance of this mechanism in vivo.Pulmonary vascular and circulating progenitor endothelial cells isolated from patients with PAH demonstrate downregulation of miR-124, leading to the metabolic and proliferative abnormalities in PAH ECs via PTPB1 and PKM1/PKM2. Therefore, the manipulation of this miRNA or its targets could represent a novel therapeutic approach for the treatment of PAH.
Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure
Authors: Jorge Bartolucci, Fernando J. Verdugo, Paz L. González, Ricardo E. Larrea, Ema Abarzua, Carlos Goset, Pamela Rojo, Ivan Palma, Ruben Lamich, Pablo A. Pedreros, Gloria Valdivia, Valentina M. Lopez, Carolina Nazzal, Francisca Alcayaga-Miranda, Jimena Cuenca, Matthew J. Brobeck, Amit N. Patel, Fernando E. Figueroa, Maroun Khoury
Journal: Circulation Research (2017)

Umbilical cord-derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. Although bone marrow-derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients.Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction.Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×106 cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow-derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, known to be involved in myogenesis, cell migration, and immunoregulation. UC-MSC-treated patients presented no adverse events related to the cell infusion, and none of the patients tested at 0, 15, and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC-treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6, and 12 months of follow-up assessed both through transthoracic echocardiography (P=0.0167 versus baseline) and cardiac MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC-treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy.Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs.URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777.
Plasma biomarkers to diagnose alcoholic hepatitis: Are we there yet?
Authors: Cyriac Abby Philips, Philip Augustine
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. We read with interest the study by Bissonnette et al.1 that was published recently in Hepatology. The authors attempted to fill the gap in noninvasive diagnosis of alcoholic hepatitis in a prospective study. They demonstrate that circulating fragments of cytokeratin‐18 (CK‐18), especially the M65 component, had good diagnostic performance for estimating the presence of alcoholic hepatitis (AH) among patients with clinical suspicion in a test and validation cohort. This was particularly true in patients without recent bacterial infection. They also concluded that analyzing CK‐18 fragment levels could help avoid transjugular liver biopsy (TJLB) in two thirds of AH patients. CK‐18 is not an exclusively validated biomarker for AH but is a direct marker of hepatocyte apoptosis and, as such, probably should not be considered a diagnostic tool.2 High levels of CK‐18 has been most validated in patients with nonalcoholic steatohepatitis (versus simple steatosis)3 and toxin‐associated steatohepatitis.4 Obese alcoholics with AH could have components of nonalcoholic steatohepatitis and AH working in tandem. The current study does not shed light on this matter, hence the proposal of CK‐18 fragments in noninvasive diagnosis of AH should remain a research tool. With an overall incidence of infections approaching approximately 50% in AH, the noninvasive utility of CK‐18 becomes superficial. Discriminating primary liver insults (e.g., drug‐induced liver injury) among heavy drinkers versus AH still requires a liver biopsy for clarity. In the current study, the authors state that the proposed upper limit cutoffs for CK‐18 M65 fragments had a low negative predictive value and that the diagnostic performance was much lower in the validation cohort in which the results were not reproducible using the proposed algorithm, and most patients underwent TJLB. Currently, TJLB is no longer a "cry for the moon," and most liver units have the expertise to implement it. On the contrary, performing advanced laboratory testing for CK‐18 fragments requires more prowess with regard to research personnel, equipment, and costs and is less available at many centers. Diagnosing AH relies on astute history taking—including attention to drug history, careful biochemical interpretation, and histopathology—to be certain in cases where multiple insults or a mimic of AH is expected.
Nicotinamide Phosphoribosyltransferase (NAMPT) as a Therapeutic Target in BRAF-Mutated Metastatic Melanoma
Authors: Valentina Audrito, Antonella Managò, Sofia La Vecchia, Federica Zamporlini, Nicoletta Vitale, Gianna Baroni, Simona Cignetto, Sara Serra, Cinzia Bologna, Aureliano Stingi, Francesca Arruga, Tiziana Vaisitti, Daniela Massi, Mario Mandalà, Nadia Raffaelli, Silvia Deaglio
Journal: JNCI Journal of the National Cancer Institute (2017)

One of the effects of oncogenic signaling is metabolic reprogramming of tumor cells to support anabolic growth, opening the way to therapeutic targeting of metabolic pathways.We studied NAD biosynthesis in BRAF inhibitor (BRAFi)-resistant (BiR) melanoma cell lines. Data in cell lines were confirmed by immunohistochemistry in biopsies from 17 patients with metastatic melanoma (MM) before and after the acquisition of resistance to BRAFi. Therapeutic potential of NAD biosynthesis inhibitors was determined by invitro monitoring cell growth and death and in mouse xenograft models. Mice (n = 6-10 mice/group) were treated with nicotinamide phosphoribosyltranferase inhibitor (NAMPTi), BRAFi, or their combination, and tumor growth and survival were analyzed. All statistical tests were two-sided.BiR cells had higher NAD levels compared with their BRAFi-sensitive counterparts (P < .001 and P = .001 for M14 and A375, respectively) and with normal melanocytes (P < .001), achieved through transcriptional upregulation of the enzyme NAMPT, which became the master regulator of NAD synthesis. Conversely, treatment with BRAFi or MEK inhibitors decreased NAMPT expression and cellular NAD levels. Robust NAMPT upregulation was documented in tissue biopsies from MM patients after development of resistance to BRAFi (P < .001). Treatment of melanoma cells with NAMPTi depleted NAD and ATP, depolarized mitochondrial membrane, and led to reactive oxygen species production, blocking cells in the G2/M phase and inducing apoptosis. Treatment of BiR xenografts with NAMPTi improved mouse survival (median survival of vehicle-treated mice was 52 days vs 100 days for NAMPTi-treated ones in M14/BiR, while in A375/BiR median survival of vehicle-treated mice was 23.5 days vs 43 days for NAMPTi-treated ones, P < .001).BiR melanoma cells overexpress NAMPT, which acts as a connecting element between BRAF oncogenic signaling and metabolism, becoming an actionable target for this subset of MM patients.
Re-challenge with BRAF-directed treatment: A multi-institutional retrospective study.
Authors: Sara Valpione, Matteo S. Carlino, Joanna Mangana, Meghan Mooradian, Grant A. McArthur, Dirk Schadendorf, Axel Hauschild, Georgina V. Long, Ana M. Arance, Paolo Antonio Ascierto, Michele Maio, Francesco De Rosa, James M. G. Larkin, John J. Park, Simone M. Goldinger, Keith Flaherty, Wen Xu, Elisabeth Livingstone, Michael Weichenthal, Paul Lorigan
Journal: Journal of Clinical Oncology (2017)

9512 Background: Most patients treated with BRAF inhibitors (BRAFi) +/- MEK inhibitors (MEKi) eventually progress on treatment. Along with genetic acquired resistance, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse outcomes for patients (pts) retreated with BRAF-directed therapy. Methods: 116 pts who received BRAFi based therapy and, after a break, were re-challenged with BRAFi +/- MEKi treated at 14 centres in Europe, US, and Australia were analysed for progression free survival (PFS) and response rate (RR), as well as factors predicting overall survival (OS) (demographics, disease stage, treatment, LDH level, duration of first BRAFi treatment, reason for first BRAFi discontinuation and interval between BRAFi stop and re-challenge). Multivariate Cox regression, regression trees and Kaplan Meier method were used. Results: Median duration of 1 st BRAFi +/- MEKi treatment was 9.4 months (mts) and 7.7 mts for the subsequent treatment after discontinuation (immunotherapy 72%, other 17 %, drug holiday 11%). Brain metastases were present in 51 pts (44%). RR to re-challenge with BRAFi +/- MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease 24% and progressive disease (PD) 30%, 4% missing. Of 80 pts who previously discontinued BRAFi for PD, 31 (39%) responded (30 PR and 1 CR). Median OS from retreatment was 9.8 mts. Independent prognostic factors for survival at re-challenge included number of metastatic sites (HR = 1.32 for each additional organ with metastases, p &lt; .001), LDH (HR = 1.37 for each multiple of the upper normal limit, p &lt; .001), while combination of BRAFi+MEKi conferred a better prognosis vs BRAFi alone (HR = 0.5, p = .006). Pts with &lt; 3 metastatic sites treated with BRAFi and MEKi had a better survival (median OS not reached) and pts with ≥ 3 metastatic sites and raised LDH treated with BRAFi alone had the worse outcome (median OS 4 mts). Number of metastatic sites (HR = 1.44, p &lt; .001) and combination of BRAFi and MEKi (HR = 0.45, p &lt; .001) were independent prognostic factors for PFS (median 5.0 mts). Conclusions: Re-challenge with BRAFi +/- MEKi induces a clinically significant response and should be considered for selected cases.
Using Big Data to Reveal Chronic Respiratory Disease Mortality Patterns and Identify Potential Public Health Interventions
Authors: David M. Mannino, Wayne T. Sanderson
Journal: JAMA (2017)

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STING-associated vasculopathy develops independently of IRF3 in mice
Authors: James D. Warner, Ricardo A. Irizarry-Caro, Brock G. Bennion, Teresa L. Ai, Amber M. Smith, Cathrine A. Miner, Tomomi Sakai, Vijay K. Gonugunta, Jianjun Wu, Derek J. Platt, Nan Yan, Jonathan J. Miner
Journal: The Journal of Experimental Medicine (2017)

Patients with stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) develop systemic inflammation characterized by vasculopathy, interstitial lung disease, ulcerative skin lesions, and premature death. Autosomal dominant mutations in STING are thought to trigger activation of IRF3 and subsequent up-regulation of interferon (IFN)-stimulated genes (ISGs) in patients with SAVI. We generated heterozygous STING N153S knock-in mice as a model of SAVI. These mice spontaneously developed inflammation within the lung, hypercytokinemia, T cell cytopenia, skin ulcerations, and premature death. Cytometry by time-of-flight (CyTOF) analysis revealed that the STING N153S mutation caused myeloid cell expansion, T cell cytopenia, and dysregulation of immune cell signaling. Unexpectedly, we observed only mild up-regulation of ISGs in STING N153S fibroblasts and splenocytes and STING N154S SAVI patient fibroblasts. STING N153S mice lacking IRF3 also developed lung disease, myeloid cell expansion, and T cell cytopenia. Thus, the SAVI-associated STING N153S mutation triggers IRF3-independent immune cell dysregulation and lung disease in mice.