tbuckley/cabot-search huggingface dataset:
Assessment of Insulin Resistance Among Drug-Naive Patients With First-Episode Schizophrenia in the Context of Hormonal Stress Axis Activation
Authors: Johann Steiner, Maximus Berger, Paul C. Guest, Henrik Dobrowolny, Sabine Westphal, Kolja Schiltz, Zoltán Sarnyai
Journal: JAMA Psychiatry (2017)

Before the introduction of antipsychotics, links between schizophrenia and abnormal glucose metabolism levels were found in the late 1800s as an increased prevalence of diabetes in families with a history of “insanity.”1 Furthermore, it is known that some patients with psychosis require higher dosages than other patients when applying insulin therapy, suggestive of insulin resistance.2 A recent meta-analysis by Pillinger et al1 assessed insulin resistance and found an elevated homeostatic model assessment of insulin resistance (HOMA-IR) among drug-naive patients with first-episode schizophrenia (n = 560) compared with controls (n = 450).1 They highlighted hormonal stress axis activation and lifestyle factors as potential confounders.1 Stress hormones, such as cortisol and catecholamines, are catabolic and functional antagonists of insulin. Antipsychotic-naive individuals with first-episode psychosis exhibit higher baseline cortisol levels and a blunted cortisol awakening response compared with controls.1,3 To test whether insulin resistance in schizophrenia can be discerned from stress-related and medication effects, we assessed HOMA-IR and stress hormone levels among drug-naive patients with first-episode schizophrenia and matched controls.
FSGS as an Adaptive Response to Growth-Induced Podocyte Stress
Authors: Ryuzoh Nishizono, Masao Kikuchi, Su Q. Wang, Mahboob Chowdhury, Viji Nair, John Hartman, Akihiro Fukuda, Larysa Wickman, Jeffrey B. Hodgin, Markus Bitzer, Abhijit Naik, Jocelyn Wiggins, Matthias Kretzler, Roger C. Wiggins
Journal: Journal of the American Society of Nephrology (2017)

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function.
Osimertinib-Induced Interstitial Lung Disease Presenting as Eosinophilic Pneumonia
Authors: Hiroaki Tachi, Toshihiro Shiozawa, Chio Sakai, Mariko Kasuga, Kensuke Nakazawa, Yuko Morishima, Hiroaki Satoh, Nobuyuki Hizawa, Shingo Sakashita, Ikuo Sekine
Journal: Journal of Thoracic Oncology (2017)
Cytogenetics and Somatic Cell Genetics of Malignancy Workshop
Authors: Warren W. Nichols, M.D., Ph.D., Alfred G. Knudson, M.D., Ph.D., Louis Siminovitch, Ph.D.
Journal: JNCI Journal of the National Cancer Institute (1982)

Journal Article Cytogenetics and Somatic Cell Genetics of Malignancy Workshop Get access Warren W. Nichols, M.D., Ph.D., Warren W. Nichols, M.D., Ph.D. Department of Cytogenetics Institute for Medical Research, Camden, New Jersey 08103 Search for other works by this author on: Oxford Academic PubMed Google Scholar Alfred G. Knudson, M.D., Ph.D., Alfred G. Knudson, M.D., Ph.D. The Institute for Cancer Research, Philadelphia, Pennsylvania 19111 Search for other works by this author on: Oxford Academic PubMed Google Scholar Louis Siminovitch, Ph.D. Louis Siminovitch, Ph.D. Department of Medical Genetics University of Toronto, Toronto, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 69, Issue 2, August 1982, Pages 543–544, https://doi.org/10.1093/jnci/69.2.543 Published: 01 August 1982
Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40+ monocyte differentiation
Authors: Jin Dai, Pu Fang, Jason Saredy, Hang Xi, Cueto Ramon, William Yang, Eric T. Choi, Yong Ji, Wei Mao, Xiaofeng Yang, Hong Wang
Journal: Journal of Hematology & Oncology (2017)

Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response. We classify immune checkpoint into two categories: one-way immune checkpoint for forward signaling towards TC only, and two-way immune checkpoint for both forward and reverse signaling towards TC and APC, respectively. Recently, we and others provided evidence suggesting that metabolic risk factors (RF) activate innate and adaptive immunity, involving the induction of immune checkpoint molecules. We summarize these findings and suggest a novel theory, metabolism-associated danger signal (MADS) recognition, by which metabolic RF activate innate and adaptive immunity. We emphasize that MADS activates the reverse immune checkpoint which leads to APC inflammation in innate and adaptive immunity. Our recent evidence is shown that metabolic RF, such as uremic toxin or hyperhomocysteinemia, induced immune checkpoint molecule CD40 expression in monocytes (MC) and elevated serum soluble CD40 ligand (sCD40L) resulting in CD40+ MC differentiation. We propose that CD40+ MC is a novel pro-inflammatory MC subset and a reliable biomarker for chronic kidney disease severity. We summarize that CD40:CD40L immune checkpoint can induce TC and APC activation via forward stimulatory, reverse stimulatory, and TC contact-independent immune checkpoints. Finally, we modeled metabolic RF-induced two-way stimulatory immune checkpoint amplification and discussed potential signaling pathways including AP-1, NF-κB, NFAT, STAT, and DNA methylation and their contribution to systemic and tissue inflammation.
Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis
Authors: Q. Wei, Z. Ye, X. Zhong, L. Li, C. Wang, R.E. Myers, J.P. Palazzo, D. Fortuna, A. Yan, S.A. Waldman, X. Chen, J.A. Posey, A. Basu-Mallick, B.H. Jiang, L. Hou, J. Shu, Y. Sun, J. Xing, B. Li, H. Yang
Journal: Annals of Oncology (2017)
Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a population-based cohort study
Authors: Philipp K A Agyeman, Luregn J Schlapbach, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Matthias Schindler, Insa Korten, Gabriel Konetzny, Anita Niederer-Loher, Christian R Kahlert, Alex Donas, Antonio Leone, Paul Hasters, Christa Relly, Walter Baer, Claudia E Kuehni, Christoph Aebi, Christoph Berger
Journal: The Lancet Child & Adolescent Health (2017)
CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Traditional Chinese Version)
Authors: Chung-wah Cheng, Tai-xiang Wu, Hong-cai Shang, You-ping Li, Douglas G. Altman, David Moher, Zhao-xiang Bian
Journal: Annals of Internal Medicine (2017)

Editors' Note: This article (available in PDF format) is the traditional Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. (Cheng C, Wu T, Shang H, Li, Y, Altman D, Moher D; CONSORT-CHM Formulas 2017 Group. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;167:112-21. [Epub 27 June 2017]. doi:10.7326/M16-2977).
Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer
Authors: Roberto Rangel, Liliana Guzman-Rojas, Takahiro Kodama, Michiko Kodama, Justin Y. Newberg, Neal G. Copeland, Nancy A. Jenkins
Journal: Cancer Research (2017)

Abstract Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step sleeping beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG, whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A, and ZNF326 showed TS activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple epithelial–mesenchymal transition and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new TS genes in TNBC demonstrate the utility of two-step forward genetic screens in mice and offer an invaluable tool to identify novel candidate therapeutic pathways and targets. Cancer Res; 77(15); 4089–101. ©2017 AACR.
Heading for trouble: is dementia a game changer for football?
Authors: A Rutherford, William Stewart, Davide Bruno
Journal: British Journal of Sports Medicine (2017)

After fevered media coverage of a possible link between football (soccer) heading and long-term damage to the brain, 2016 saw the Professional Footballers’ Association call for a review of the game to decide whether to follow the lead of the United States Soccer and ban heading for younger players. Given these concerns, and the fact the relevant Rules of Football were conceived over 100 years ago, is it time for major rule changes? Is there evidence that football increases risk of neurodegenerative disease (eg, dementia) and heading is to blame?

Remarkably, despite phenomenal football participation rates globally and over a century of participation, there is little evidence regarding football’s impact on brain health, and dementia in particular. Football is a contact sport and concussive head injuries do occur, but multiple reviews of the available research literature have drawn the same conclusions: football concussion outcomes are consistent with the general concussion literature, with weak to non-existent evidence for a link between football play and long-term neurological or cognitive deficits.1–3 However, a common feature of most football research …
Multicellular Transcriptional Analysis of Mammalian Heart Regeneration
Authors: Gregory A. Quaife-Ryan, Choon Boon Sim, Mark Ziemann, Antony Kaspi, Haloom Rafehi, Mirana Ramialison, Assam El-Osta, James E. Hudson, Enzo R. Porrello
Journal: Circulation (2017)

The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time.Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56).Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation.This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes.
Distribution, Retention, and Elimination of C&lt;sup&gt;14&lt;/sup&gt;-3,4-Benzpyrene After Administration to Mice and Rats&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Paul Kotin, M.D., Hans L. Falk, Ph.D., Ray Busser
Journal: JNCI Journal of the National Cancer Institute (1959)

The localization and rate of systemic elimination of carbon-labeled (C14) 3,4-benzypyrene (benzo[a]pyrene) after subcutaneous injection and intratracheal instillation are significantly modified by the vehicle chosen for administration. This vehicle effect is less noticeable when benzopyrene is injected intravenously. The primary method of benzopyrene elimination from the host is through the feces, with maximum metabolic alteration occurring in the hepatobiliary system. The excretion of benzopyrene metabolites (radioactivity) in the bile, and subsequently into the feces, increases in proportion to the dose until a maximum is reached, with a resulting plateau that persists despite heroic increases in doses. Approximately 1 percent unchanged benzopyrene is recoverable in the bile and feces, but only within the first 10 to 15 minutes after intravenous injection. In animals with biliary fistulas, urinary excretion of benzopyrene metabolites is reduced by half, which suggests that the enterohepatic system contributes to the urinary concentration of benzopyrene metabolites.
Prognostic Value of Exercise-Stress Echocardiography in Asymptomatic Patients With Aortic Valve Stenosis
Authors: Coppelia Goublaire, Maria Melissopoulou, David Lobo, Naozumi Kubota, Constance Verdonk, Claire Cimadevilla, Isabelle Codogno, Eric Brochet, Alec Vahanian, David Messika-Zeitoun
Journal: JACC. Cardiovascular imaging (2017)
A Chemical APC Mimetic Protects Endothelium from Thromboinflammatory Injury
Authors: Karen E.P. De Ceunynck, Christian G. Peters, Sharjeel A. Chaudhry, Abhishek Jain, Sarah J. Higgins, Omozuanvbo Aisiku, Jennifer Fitch-Tewfik, Christopher Dockendorff, Samir Parikh, Donald E. Ingber, Robert C. Flaumenhaft
Journal: Blood (2016)
PTH-078 Thiopurine maintenance therapy for ibd: which is the best method to measure medication adherence?
Authors: A Ochieng, V George, C Selinger
Journal: Gut (2017)

Introduction  For the majority of patients with IBD long-term therapy is required to maintain remission; yet 30%–45% of patients do not adhere to their IBD medication. Medication adherence can be assessed with prescription refill rates, biological measures (metabolites, trough levels, etc) and patient self-report tools. There is currently no accepted gold standard and the feasibility and utility of different adherence assessment tools in the routine outpatient clinic setting has not been fully examined. The aim of this service improvement project was to test the acceptability of self-report tools assessing thiopurine adherence in the IBD clinic and to correlate the results with thioguanine-nucleotide (TGN) levels.  Method  Consecutive outpatients on thiopurine maintenance therapy for IBD for >3 months were recruited from clinic. Patients self-reported adherence using a visual analogue scale (VAS), the validated Morisky adherence tool (MOR) and the validated Medication Adherence Report Scale (MARS). TGN levels were classed as complete non-adherence ( 235 or MMP high). Correlation analysis was performed using Pearson tests.  Results  Of 100 approached patients none refused participation and TGN levels were available for 69. These included 38 women. Diagnoses were Crohn’s disease in 27, ulcerative colitis in 41 and IBD-U in 1 cases. Concomitant therapy included 5-ASA (25 cases), anti-TNF (13 cases) and Vedolizumab (2 cases). The proportion of adherent patients was according to the relevant report tool 71% (TGN), 87% (VAS), 87% (Morisky) and 77% (MARS). VAS (Pearson 0.315; p=0.005) and Morisky (Pearson −0.363; p=0.001) correlated moderately with TGN, but MARS (Pearson 0.09; p=0.39) did not. The 7 patients, who were non-adherent by TGN were detected by VAS in 3, Morisky in 6 and MARS in 3 cases. However, patients showing non-adherence according to self-report tools had normal TGN levels in 6 of 10 cases for VAS, 10 of 26 for Morisky and 4 of 15 for MARS.  Conclusion  Self-report tools provided a patient friendly and inexpensive way of assessing adherence, but correlation with TGN levels was only moderate. While providing a more objective assessment TGN levels are problematic for routine use in all patients. TGN require a more invasive and expensive approach. Furthermore TGN cannot detect “white coat adherence” (patients take medication only around appointments), which is the most likely explanation for normal TGN levels in patients reporting to be poorly adherent. Neither TGN levels nor self-report tools can be seen as the gold standard at present.  Disclosure of Interest  None Declared
Big data’s big bias: bringing noise and conflicts to US drug regulation
Authors: Jeanne Lenzer
Journal: BMJ (2017)

A little known private foundation to support FDA’s “regulatory science” takes money out of the FDA’s coffers to support analyses using levels of evidence recommended by industry; many of the foundation’s directors have financial links to the drug and device makers that the FDA regulates. <b>Jeanne Lenzer</b> investigates
Adventitial Remodeling Of Experimental Pulmonary Hypertension Induces Myofibroblast-Produced Collagen V In A Th17-Pathways-Related Manner
Authors: A. T. Fabro, J. R. Machado, W. R. Teodoro, A. L. Dos Santos, A. A. Dos Santos, H. R. Crunivel, P. F. Milsoni, S. D. M. Fernezlian, A. B. G. Dos Santos, R. A. Oliveira, M. C. R. Medeiros, C. A. Rainho, V. L. Capelozzi
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Recent developments in immunotherapy of acute myeloid leukemia
Authors: Felix S. Lichtenegger, Christina Krupka, Sascha Haubner, Thomas Köhnke, Marion Subklewe
Journal: Journal of Hematology & Oncology (2017)

The advent of new immunotherapeutic agents in clinical practice has revolutionized cancer treatment in the past decade, both in oncology and hematology. The transfer of the immunotherapeutic concepts to the treatment of acute myeloid leukemia (AML) is hampered by various characteristics of the disease, including non-leukemia-restricted target antigen expression profile, low endogenous immune responses, and intrinsic resistance mechanisms of the leukemic blasts against immune responses. However, considerable progress has been made in this field in the past few years.Within this manuscript, we review the recent developments and the current status of the five currently most prominent immunotherapeutic concepts: (1) antibody-drug conjugates, (2) T cell-recruiting antibody constructs, (3) chimeric antigen receptor (CAR) T cells, (4) checkpoint inhibitors, and (5) dendritic cell vaccination. We focus on the clinical data that has been published so far, both for newly diagnosed and refractory/relapsed AML, but omitting immunotherapeutic concepts in conjunction with hematopoietic stem cell transplantation. Besides, we have included important clinical trials that are currently running or have recently been completed but are still lacking full publication of their results.While each of the concepts has its particular merits and inherent problems, the field of immunotherapy of AML seems to have taken some significant steps forward. Results of currently running trials will reveal the direction of further development including approaches combining two or more of these concepts.