tbuckley/cabot-search huggingface dataset:
Inferring Long-Term Effective Population Size with Mutation–Selection Models
Authors: Thibault Latrille, Vincent Lanore, Nicolas Lartillot
Journal: Molecular Biology and Evolution (2021)

Mutation–selection phylogenetic codon models are grounded on population genetics first principles and represent a principled approach for investigating the intricate interplay between mutation, selection, and drift. In their current form, mutation–selection codon models are entirely characterized by the collection of site-specific amino-acid fitness profiles. However, thus far, they have relied on the assumption of a constant genetic drift, translating into a unique effective population size (Ne) across the phylogeny, clearly an unrealistic assumption. This assumption can be alleviated by introducing variation in Ne between lineages. In addition to Ne, the mutation rate (μ) is susceptible to vary between lineages, and both should covary with life-history traits (LHTs). This suggests that the model should more globally account for the joint evolutionary process followed by all of these lineage-specific variables (Ne, μ, and LHTs). In this direction, we introduce an extended mutation–selection model jointly reconstructing in a Bayesian Monte Carlo framework the fitness landscape across sites and long-term trends in Ne, μ, and LHTs along the phylogeny, from an alignment of DNA coding sequences and a matrix of observed LHTs in extant species. The model was tested against simulated data and applied to empirical data in mammals, isopods, and primates. The reconstructed history of Ne in these groups appears to correlate with LHTs or ecological variables in a way that suggests that the reconstruction is reasonable, at least in its global trends. On the other hand, the range of variation in Ne inferred across species is surprisingly narrow. This last point suggests that some of the assumptions of the model, in particular concerning the assumed absence of epistatic interactions between sites, are potentially problematic.
Predicting genotoxicity of viral vectors for stem cell gene therapy using gene expression-based machine learning
Authors: Adrian Schwarzer, Steven R. Talbot, Anton Selich, Michael Morgan, Juliane W. Schott, Oliver Dittrich-Breiholz, Antonella L. Bastone, Bettina Weigel, Teng Cheong Ha, Violetta Dziadek, Rik Gijsbers, Adrian J. Thrasher, Frank J.T. Staal, Hubert B. Gaspar, Ute Modlich, Axel Schambach, Michael Rothe
Journal: Molecular Therapy (2021)

Hematopoietic stem cell gene therapy is emerging as a promising therapeutic strategy for many diseases of the blood and immune system. However, several individuals who underwent gene therapy in different trials developed hematological malignancies caused by insertional mutagenesis. Preclinical assessment of vector safety remains challenging because there are few reliable assays to screen for potential insertional mutagenesis effects in vitro. Here we demonstrate that genotoxic vectors induce a unique gene expression signature linked to stemness and oncogenesis in transduced murine hematopoietic stem and progenitor cells. Based on this finding, we developed the surrogate assay for genotoxicity assessment (SAGA). SAGA classifies integrating retroviral vectors using machine learning to detect this gene expression signature during the course of in vitro immortalization. On a set of benchmark vectors with known genotoxic potential, SAGA achieved an accuracy of 90.9%. SAGA is more robust and sensitive and faster than previous assays and reliably predicts a mutagenic risk for vectors that led to leukemic severe adverse events in clinical trials. Our work provides a fast and robust tool for preclinical risk assessment of gene therapy vectors, potentially paving the way for safer gene therapy trials.
Two-years experience with intravascular pacemaker lead removal using electrosurgical dissection system (EDS)
Authors: Goya Masahiko, Shimoike Eimei, Ando Kenji, Hiroshima Kenichi, Yasumoto Hitoshi, Nosaka Hideyuki, Nobuyoshi Masakiyo, Yamada Takashi
Journal: Circulation (2008)
Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation
Authors: Shaneice Mitchell, Pu Zhang, Matthew Cannon, Larry Beaver, Amy Lehman, Bonnie Harrington, Deepa Sampath, John C. Byrd, Rosa Lapalombella
Journal: Journal of Hematology & Oncology (2021)

Abstract KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD + production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD + generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.
Characterizing the Clinical Implications of Histologic Regression in Melanoma Requires Clear Diagnostic Criteria That Are Consistently Applied—Reply
Authors: Richard A. Scolyer, Mary-Ann El Sharouni, John F. Thompson
Journal: JAMA Dermatology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
肥大型心筋症患者における非侵襲性イメージングモダリティ(心臓MRIと心筋SPECT)の予後的有用性
Authors: Tohyama Kazuto, Iguti Nobuo, Seki Atushi, Inoue Kanki, Takamisawa Itaru, Aikawa Masaru, Tanizaki Kohei, Watanabe Hiroyuki, Tohbaru Tetsuya, Asano Ryuta, Takayama Morimasa, Nagayama Masatoshi, Umemura Jun, Sumiyoshi Tetsuya
Journal: Circulation (2010)
Association of Serum 25-Hydroxyvitamin D Concentrations With All-Cause and Cause-Specific Mortality Among Individuals With Diabetes
Authors: Zhenzhen Wan, Jingyu Guo, An Pan, Chen Chen, Liegang Liu, Gang Liu
Journal: Diabetes Care (2020)

OBJECTIVE The evidence regarding vitamin D status and mortality among people with diabetes is scarce. This study aimed to examine the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among adults with diabetes. RESEARCH DESIGN AND METHODS This study included 6,329 adults with diabetes from the Third National Health and Nutrition Examination Survey (NHANES III) and NHANES 2001–2014. Death outcomes were ascertained by linkage to National Death Index records through 31 December 2015. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CIs for mortality from all causes, cardiovascular disease (CVD), and cancer. RESULTS The weighted mean (95% CI) level of serum 25(OH)D was 57.7 (56.6, 58.8) nmol/L, and 46.6% had deficient vitamin D (&amp;lt;50 nmol/L [20 ng/mL]). Higher serum 25(OH)D levels were significantly associated with lower levels of glucose, insulin, HOMA of insulin resistance, HbA1c, blood lipids, and C-reactive protein at baseline (all Ptrend &amp;lt; 0.05). During 55,126 person-years of follow-up, 2,056 deaths were documented, including 605 CVD deaths and 309 cancer deaths. After multivariate adjustment, higher serum 25(OH)D levels were significantly and linearly associated with lower all-cause and CVD mortality: there was a 31% reduced risk of all-cause mortality and a 38% reduced risk of CVD mortality per one-unit increment in natural log-transformed 25(OH)D (both P &amp;lt; 0.001). Compared with participants with 25(OH)D &amp;lt;25 nmol/L, the multivariate-adjusted HRs and 95% CI for participants with 25(OH)D &amp;gt;75 nmol/L were 0.59 (0.43, 0.83) for all-cause mortality (Ptrend = 0.003), 0.50 (0.29, 0.86) for CVD mortality (Ptrend = 0.02), and 0.49 (0.23, 1.04) for cancer mortality (Ptrend = 0.12). CONCLUSIONS Higher serum 25(OH)D levels were significantly associated with lower all-cause and CVD mortality. These findings suggest that maintaining adequate vitamin D status may lower mortality risk in individuals with diabetes.
Abstract 74: Cardioprotective Effect of Growth Hormone Releasing Hormone in Mouse Model of Heart Failure with Preserved Ejection Fraction
Authors: Rosemeire M Kanashiro-Takeuchi, Lauro M Takeuchi, Raul A Dulce, Darrell Hardin, Marilia Zuttion, Wayne Balkan, Ren Z Cai, Andrew V Schally, Joshua M Hare
Journal: Circulation Research (2016)

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. We previously showed that activation of GHRH receptor markedly reduces fibrosis in rat and swine models of ischemic myocardial injury. Therefore, we hypothesized that activation of GHRH receptor signaling can improve diastolic dysfunction in a mouse model of HFpEF. C57BL6N mice (n=4-5) were implanted with a mini-osmotic pump to deliver angiotensin-II (Ang-II: 0.8 mg/kg/day) for 4 weeks and randomly assigned to receive daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiac performance was assessed by serial echocardiography and hemodynamic analysis. Chronic administration of Ang-II resulted in increased end-diastolic pressure (EDP, p=0.0186) with no changes in EF (p=ns) or end-systolic pressure (ESP, p=ns) in comparison to control mice. Isovolumetric relaxation time (IVRT, p&lt;0.05) and end-diastolic pressure-volume relationship (EDPVR, p=0.0229) were markedly increased in the Ang-II group consistent with increased ventricular stiffness and poor myocardial relaxation. MR-409 treatment reset these parameters to normal levels (table 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes that mimic HFpEF. Importantly, MR-409 treatment reduces Ang-II-induced elevation of EDP, EDPVR and IVRT; thus preventing HFpEF–like effects, suggesting that activation of the GHRH receptor signaling pathways represents a potential new therapeutic approach for HFpEF.
Recent advances in developing small-molecule inhibitors against SARS-CoV-2
Authors: Rong Xiang, Zhengsen Yu, Yang Wang, Lili Wang, Shanshan Huo, Yanbai Li, Ruiying Liang, Qinghong Hao, Tianlei Ying, Yaning Gao, Fei Yu, Shibo Jiang
Journal: Acta Pharmaceutica Sinica B (2021)

The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.
Acute Leukemias in West Central Mexico: Interinstitutional Experience
Authors: Virgina Campos-Cabrera, Jose-Luis Campos-Villagomez, Salvador Campos-Cabrera, Alicia Rivera-Trujillo, Sonia Hernandez-Rodriguez, Miguel-Angel Gomez-Guijosa, Maria Mora-Torres, Sergio Cuin-Macedo, Maria-Luisa Pedraza-Colin, Sandra-Guadalupe Pulido-Sanchez, Luis Pita-Ramirez, Noe-Benjamin Vega-Tapia, Gregorio Campos-Cabrera
Journal: Blood (2017)
Endoscopic ultrasound-guided ductal access and drainage – thus far and much further
Authors: Kondal R. Kyanam Kabir Baig
Journal: Endoscopy (2021)

Obstructive pancreaticobiliary diseases are morbid conditions associated with significant disease burden. Historically surgical drainage, percutaneous transhepatic biliary drainage (PTBD), and endoscopic retrograde cholangiopancreatography (ERCP) have been the procedures of choice for ductal drainage and access. Recently, endoscopic ultrasound-guided ductal access and drainage (EUS-DAD) has revolutionized pancreaticobiliary therapy. Successful biliary drainage of malignant biliary obstruction has now become the standard of care because neoadjuvant therapy for pancreaticobiliary malignancies prior to surgery has shown improved survival compared with primary surgical resection.
Comparable Outcome of CD3+-/CD19+ Depleted Haploidentical with Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Advanced Stage Sickle Cell Disease: Result of a Pilot Study
Authors: Selim Corbacioglu, Juergen Foell, Daniel Wolff, Ernst Holler, Beatrix Pfirstinger, Klaus Thorsten Rehe, Petra Hoffmann, Matthias Edinger, Anja Troeger, Svatava Srutkova
Journal: Blood (2017)
An integrated magneto-electrochemical device for the rapid profiling of tumour extracellular vesicles from blood plasma
Authors: Jongmin Park, Jun Seok Park, Chen-Han Huang, Ala Jo, Kaitlyn Cook, Rui Wang, Hsing-Ying Lin, Jan Van Deun, Huiyan Li, Jouha Min, Lan Wang, Ghilsuk Yoon, Bob S. Carter, Leonora Balaj, Gyu-Seog Choi, Cesar M. Castro, Ralph Weissleder, Hakho Lee
Journal: Nature Biomedical Engineering (2021)
Cardiac and Noncardiac Determinants of Exercise Capacity in CKD
Authors: Shanmugakumar Chinnappa, Nigel Lewis, Omer Baldo, Ming-Chieh Shih, Yu-Kang Tu, Andrew Mooney
Journal: Journal of the American Society of Nephrology (2021)

Impaired exercise capacity is a significant symptom of CKD and is associated with poor survival. Furthermore, there is a growing interest in applying exercise as a diagnostic tool or as therapy in CKD. However, an in-depth understanding of exercise physiology in CKD is still lacking.To evaluate the role of cardiac (central) and noncardiac (peripheral) determinants of exercise capacity in CKD, we conducted a cross-sectional study of 70 male patients with CKD (stages 2-5) without diabetes or cardiac disease, 35 healthy controls, and 25 patients with heart failure. An integrated cardiopulmonary exercise test using a CO2 rebreathing technique was used to measure peak O2 consumption (VO2peak) and peak cardiac output simultaneously, and to calculate peak peripheral O2 extraction (C[a-v]O2), the peripheral determinant (the ability of exercising skeletal muscles to extract oxygen). We performed multiple regression analysis and used Bayesian information criteria (BIC) changes to quantitatively assess the individual contribution of central and peripheral factors.Compared with healthy controls, in patients with CKD, the VO2peak was impaired proportionate to its severity. Peak cardiac output was the predominant determinant of VO2peak in healthy controls and patients with heart failure, whereas C(a-v)O2 played a more significant role in determining VO2peak in CKD (β=0.68, P<0.001) compared with cardiac output (β=0.63, P<0.001). In addition, the magnitude of BIC reduction was greater for C(a-v)O2 compared with cardiac output (BIC, 298.72 versus 287.68) in CKD.In CKD, both peak cardiac output and peak C(a-v)O2 are independent predictors of VO2peak, and the more significant roleplayed by peak C(a-v)O2 highlights the importance of noncardiac factors in determining exercise capacity in CKD.
Similar Event-Free Survival but Higher Incidence of Mixed T Cell Chimerism after Hematopoietic Cell Transplantation for Sickle Cell Disease Using Rabbit Versus Horse ATG: a Study from the Sickle Transplant Alliance for Research (STAR)
Authors: Allistair Abraham, Elizabeth Stenger, Curtis D Travers, Robert Nickel, Hemalatha G. Rangarajan, Jennifer Krajewski, Sonali Chaudhury, Kimberly A. Kasow, Troy C. Quigg, Alexander I. Ngwube, Jennifer Jaroscak, Gregory M Guilcher, Shalini Shenoy, John T Horan
Journal: Blood (2017)
Primary Myelofibrosis in Younger Patients: A Retrospective Analysis of the Gruppo Laziale MPN Ph-Negative
Authors: Massimo Breccia, Ambra Di Veroli, Marianna De Muro, Malgorzata Monika Trawinska, Sabrina Crescenzi Leonetti, Michele Cedrone, Luca Petriccione, Atelda Romano, Ada D'Addosio, Matteo Molica, Antonia Centra, Raffaele Porrini, Stefano Felici, Luca Maurillo, Marco Montanaro, Alessandro Andriani, Pasquale Niscola, Robin Foa, Roberto Latagliata
Journal: Blood (2017)
Artificial Intelligence in Surveillance of Barrett's Esophagus
Authors: Anant Madabhushi, Paula Toro, Joseph E. Willis
Journal: Cancer Research (2021)

Abstract A study by Waterhouse and colleagues in a previous issue of Cancer Research describes the development and prospective validation of an artificial intelligence approach in conjunction with spectral imaging to enhance endoscopic detection of Barrett's esophagus-related neoplasia. The authors developed a novel spectral endoscope with external optics suitable for routine Barrett's esophagus surveillance with diffuse tissue reflectance to define multispectral data correlated with histopathology. A convolutional neural network was trained on the absis of the spectral signatures acquired as part of a small, prospective clinical trial to distinguish Barrett's esophagus from Barrett's esophagus neoplasia. The results from the study suggest the utility of artificial intelligence for diagnosis of Barrett's esophagus. See related article by Waterhouse et al., Cancer Res 2021;81:3415–25
When and how to evaluate for <i>immediate type</i> food allergy in children with atopic dermatitis
Authors: Charlotte G. Mortz, George du Toit, Kirsten Beyer, Carsten Bindslev‐Jensen, Knut Brockow, Helen Annaruth Brough, Pasquale Comberiati, Thomas Eiwegger, Alexandra Santos, Margitta Worm, Barbara K. Ballmer‐Weber
Journal: Allergy (2021)

Atopic dermatitis (AD) typically develops in infancy and affects up to 20% of children in high-income countries (1).Immediate (IgE-mediated) food allergy (FA) affects around 3% of children (2).Children with AD are at higher risk of immediate-type FA (3, 4).Up to a third of children with moderate to severe AD have FA (3).A Danish population-based study, evaluating children from birth to 6 years, showed that 15% of all
Epigenetic Regulation of Cancer Immune Cells
Authors: Diego M. Avella Patino, Vijay Radhakrishnan, Kanve N. Suvilesh, Yariswamy Manjunath, Guangfu Li, Eric T. Kimchi, Kevin F. Staveley-O’Carroll, Wesley C. Warren, Jussuf T. Kaifi, Jonathan B. Mitchem
Journal: Seminars in Cancer Biology (2021)
Lockdown in Nepal further strains supply of lifesaving maternal health drug
Authors: Marty Logan
Journal: BMJ (2021)

Nepal entered a four month nationwide lockdown in March 2020, during which the number of women accessing maternal and sexual and reproductive health services saw a worrying drop.Births in hospital dropped by more than half, 1 and stillbirths and neonatal mortality in hospital rose.At the start of the lockdown, 72% of health facilities countrywide were providing safe abortion services, but that number fell to 61% in July, according to a survey by the UN Population Fund (UNFPA) and the Nepalese government.Initially, some health facilities closed completely, or women assumed that they weren't operating.Lacking protective equipment, staff at some centres did not report for work, and many women were scared to visit health facilities in case they caught covid-19.Transportation was often unavailable, and drugs and other commodities were in short supply.
Abstract 14627: Methadone-Induced QT Interval Prolongation in Patients Undergoing Maintenance Therapy in a Narcotic Treatment Center: Incidence, Risk Factors, and Association With Stereospecific Serum Methadone and Metabolite Concentrations
Authors: Erika Titus-Lay, Heather A Jaynes, Elena Tomaselli-Muensterman, Todd Walroth, Carol Ott, Gabriela Williams, Paul Moe, James E Tisdale
Journal: Circulation (2019)

Introduction: Methadone can cause QT interval prolongation and torsades de pointes. Objectives: To investigate:1) The incidence of methadone-induced QT prolongation in patients receiving care in a ...