tbuckley/cabot-search huggingface dataset:
Recipient mucosal-associated invariant T cells control GVHD within the colon
Authors: Antiopi Varelias, Mark D. Bunting, Kate L. Ormerod, Motoko Koyama, Stuart D. Olver, Jasmin Straube, Rachel D. Kuns, Renee J. Robb, Andrea S. Henden, Leanne Cooper, Nancy Lachner, Kate H. Gartlan, Olivier Lantz, Lars Kjer-Nielsen, Jeffrey Y.W. Mak, David P. Fairlie, Andrew D. Clouston, James McCluskey, Jamie Rossjohn, Steven W. Lane, Philip Hugenholtz, Geoffrey R. Hill
Journal: Journal of Clinical Investigation (2018)

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I–like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A–/– and MR1–/– mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A–dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.
Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells
Authors: Kristina S. Burrack, Matthew A. Huggins, Emily Taras, Philip Dougherty, Christine M. Henzler, Rendong Yang, Sarah Alter, Emily K. Jeng, Hing C. Wong, Martin Felices, Frank Cichocki, Jeffrey S. Miller, Geoffrey T. Hart, Aaron J. Johnson, Stephen C. Jameson, Sara E. Hamilton
Journal: Immunity (2018)
Abstract 17524: Predictors of Mortality in Patients With Persistent Pulmonary Hypertension Following Transcatheter Aortic Valve Replacement
Authors: Ahmad Masri, Michael S Sharbaugh, Andrew D Althouse, Islam Abdelkarim, Wei Han, William E Katz, Frederick Crock, Mathew Harinstein, Dustin E Kliner, Forozan Navid, Thomas G Gleason, Joon S Lee, John T Schindler, Joao L Cavalcante
Journal: Circulation (2016)

Introduction: Pulmonary hypertension (PH) is highly prevalent in patients with severe aortic stenosis referred for transcatheter aortic valve replacement (TAVR) evaluation. We sought to assess the ...
Abstract 368: Ex vivo Fabrication of Heart Tissue Model With Perfusable Blood Vessels Using Cell Sheet
Authors: Hidekazu Sekine, Tatsuya Shimizu
Journal: Circulation Research (2016)

Introduction: Creation of 3-D tissue model similar to a biological tissue using tissue engineering method are expected as an alternative approach to 2-D culture or animal test in a research for developing a new medicine. We have already developed functional 3-D heart tissue with perfusable blood vessels in vitro using cell sheet based tissue engineering approach. Present study assessed the possibility as 3-D tissue model by performing drug evaluation in the engineered heart tissues. Methods: Firefly luciferase positive cardiac cells co-cultured with endothelial cells were harvested as cell sheets from temperature-responsive culture dishes. Triple-layer cell sheets were overlaid on the vascular bed with an artery and a vein in vitro. Layered cardiac cell sheets were maintained in custom made bioreactor system with perfusion medium. After neovascularization within the first triple-layer tissue, the second triple-layer cardiac cells sheets were overlaid on the first graft after cultivation for 3 days and then the whole construct was further perfused for an additional 3 days. After 6-day perfusion culture, isoproterenol or doxorubicin were administrated to the engineered heart tissues from artery side. The sympathetic and toxic effects were measured by in vitro bioluminescence imaging, electrical potential, and blood pressure. Results: In case of isoproterenol administration, bioluminescence imaging (BLI) demonstrated that adenosine triphosphate (ATP) of the heart tissue improved. In addition, electrograms demonstrated increasing beating rate and amplitude. Moreover, sphygmomanometer showed decreasing arterial pressure. In case of doxorubicin administration, BLI showed that the ATP of the heart tissue worsened after 24 hours. It is now possible to analyze the pharmacological effects such as metabolism and the blood pressure as well as action potential by using our vascularized heart tissue model. Conclusions: We believe that our 3-D heart tissue model offers a new possibilities for evaluation of drug efficacy.
ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism
Authors: Mingyang Liu, Jingxuan Yang, Yuqing Zhang, Zhijun Zhou, Xiaobo Cui, Liyang Zhang, Kar-Ming Fung, Wei Zheng, Felicia D. Allard, Eric U. Yee, Kai Ding, Huanwen Wu, Zhiyong Liang, Lei Zheng, Martin E. Fernandez-Zapico, Yi-Ping Li, Michael S. Bronze, Katherine T. Morris, Russell G. Postier, Courtney W. Houchen, Jing Yang, Min Li
Journal: Clinical Cancer Research (2018)

ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis.
Decreased macrophage inflammatory protein (MIP)-1α and MIP-1β increase the risk of developing nasopharyngeal carcinoma
Authors: Meng‐Jie Yang, Jie Guo, Yan‐Fang Ye, Sui‐Hong Chen, Li‐Xia Peng, Chu‐Yang Lin, Ting Hu, Shang‐Hang Xie, Chuan‐Bo Xie, Qi‐Hong Huang, Yu‐Qiang Lu, Qing Liu, Chao‐Nan Qian, Su‐Mei Cao
Journal: Cancer Communications (2018)

Abstract Background The association of circulating inflammation markers with nasopharyngeal carcinoma (NPC) is still largely unclear. This study aimed to comprehensively explore the relationship between circulating cytokine levels and the subsequent risk of NPC with a two‐stage epidemiologic study in southern China. Methods The serum levels of 33 inflammatory cytokines were first measured in a hospital‐based case–control study (150 NPC patients and 150 controls) using multiplex assay platforms. Marker levels were categorized into two or more groups based on the proportion of sample measurements that was above the lower limit of detection. Odds ratios (ORs) and 95% confidence intervals (CIs) relating the serum marker concentration to the risk of NPC were computed by multivariable logistic regression models. The associations were validated in 60 patients with NPC and 120 controls in a subsequent nested case–control study within a NPC screening trial. Potential interactions between serum cytokines and Epstein–Barr virus (EBV) relating to the risk of NPC were assessed using a likelihood ratio test. Results The levels of serum macrophage inflammatory protein (MIP)‐1α and MIP‐1β in the highest categories were associated with a decreased risk of NPC in both the case–control study (MIP‐1α: OR = 0.49, 95% CI = 0.26–0.95; MIP‐1β: OR = 0.47, 95% CI = 0.22–1.00) and the nested case–control study (MIP‐1α: OR = 0.13, 95% CI = 0.03–0.62; MIP‐1β: OR = 0.20, 95% CI = 0.04–0.94), compared with those in the lowest categories. Furthermore, individuals with lower levels of these two cytokine markers who were EBV seropositive presented with a largely higher risk of NPC compared with patients with higher levels who were EBV seronegative in both the case–control study (MIP‐1α: OR = 16.28, 95% CI = 7.11–37.23; MIP‐1β: OR = 12.86, 95% CI = 5.9–28.05) and the nested case–control study (MIP‐1α: OR = 86.12, 95% CI = 10.58–701.03; MIP‐1β: OR = 115.44, 95% CI = 13.92–957.73). Conclusions Decreased preclinical MIP‐1α and MIP‐1β levels might be associated with a subsequently increased risk of NPC. More mechanistic studies are required to fully understand this finding.
Conflicts Between Regulations and Ethical Principles: Resolving Ambiguity in Favor of the Ethically Preferable Outcome
Authors: Seema K. Shah, Kathryn Porter
Journal: The American Journal of Bioethics (2018)

"Conflicts Between Regulations and Ethical Principles: Resolving Ambiguity in Favor of the Ethically Preferable Outcome." The American Journal of Bioethics, 18(4), pp. 93–94
Change in Topoisomerase 1–Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol
Authors: Hope S. Rugo, Javier Cortes, Ahmad Awada, Joyce O'Shaughnessy, Chris Twelves, Seock-Ah Im, Alison Hannah, Lin Lu, Sherwin Sy, Katie Caygill, Deborah A. Zajchowski, Darren W. Davis, Mary Tagliaferri, Ute Hoch, Edith A. Perez
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan–Meier analyses. Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47–63 CTCs/mL; range, 0–2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348–57. ©2018 AACR.
Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study
Authors: Divya Mohan, Julia R Forman, Matthew Allinder, Carmel M McEniery, Charlotte Emma Bolton, John R Cockcroft, William MacNee, Jonathan Fuld, Mellone Marchong, Nichola Sian Gale, Marie Fisk, Sridevi Nagarajan, Joseph Cheriyan, David A Lomas, Peter M A Calverley, Bruce E Miller, Ruth Tal-Singer, Ian B Wilkinson, Michael I Polkey
Journal: Thorax (2018)

Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator—fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II–IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, χ 2 ). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor.
Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension
Authors: Soni Savai Pullamsetti, Werner Seeger, Rajkumar Savai
Journal: Journal of Clinical Investigation (2018)

Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL-6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH.
Regulation of Vascular Calcification by Growth Hormone–Releasing Hormone and Its Agonists
Authors: Jian Shen, Ning Zhang, Yi-Nuo Lin, PingPing Xiang, Xian-bao Liu, Peng-fei Shan, Xin-yang Hu, Wei Zhu, Yao-liang Tang, Keith A. Webster, Renzhi Cai, Andrew V. Schally, Jian’an Wang, Hong Yu
Journal: Circulation Research (2018)

Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC.The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model.Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409.GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.
What Do We Learn From Disciplined Practice Learning?-Reply
Authors: Donald M. Berwick
Journal: JAMA (1996)

<h3>In Reply.</h3> —I share Dr Haines' concerns about superstitions that can arise from unexamined experience, but there are many useful ways to analyze experience, only one of which is a formal, prospective clinical trial. In fact, one might consider a randomized clinical trial to be a form of "final inspection" of a promising idea that almost always comes from other learning processes. Indeed, most human knowledge comes from sources other than randomized controlled trials. Systematic observation, carefully interpreted, led the Northern New England Cardiovascular Study Group to impressive success and saved lives. By continuing their study and observations together, the surgeons are learning steadily about which specific factors probably contributed to that success and which did not. Perhaps Dr Sheikh is correct that "spontaneous" improvements or "a general trend toward improved outcomes" may explain the gains of the Northern New England group, but I doubt it. First, trended over time, the results
Lack of Association Between Heart Failure and Incident Cancer
Authors: Senthil Selvaraj, Deepak L. Bhatt, Brian Claggett, Luc Djoussé, Sanjiv J. Shah, Jiaying Chen, Tasnim F. Imran, Saadia Qazi, Howard D. Sesso, J. Michael Gaziano, Deborah Schrag
Journal: Journal of the American College of Cardiology (2018)
Cell cycle checkpoint defects in gastrointestinal malignancies.
Authors: Ramya Thota, Mark Andrew Lewis, Lincoln Nadauld, Derrick S. Haslem, Terence Duane Rhodes, Bryce Christensen, Gail Fulde, Tyler Abraham, Robin Romero, Bryce Moulton, Sharanya Raghunath, Tyler Barker
Journal: Journal of Clinical Oncology (2018)

680 Background: Cyclin Dependent Kinases (CDKs) play a significant role in cell cycle regulation. Aberrations involving the cell cycle pathway genes can lead to uncontrolled cell proliferation and genomic instability. These could potentially be targeted with CDK4/6 inhibitors. The frequency and type of these alterations in GI tumors is largely unknown. Methods: We analyzed the frequency of abnormalities in cell cycle genes in patients with diverse GI malignancies (colorectal, liver, pancreas, gastroesophageal, anal, appendix) that underwent next generation sequencing from January 2013 to August 2017. Results: Aberrations in the cell cycle pathway were identified in 33 of 299 (11%) of cancers. The frequency of aberrations was as follows: CDKN2A/B in 10 (30.3%), CCND1 in 7 patients (pts) (21.2%), CCND2 in 2 pts (6%), CEBPA in 2 pts (6%), CDK6 in 2 pts (6%), CDK8 in 2 pts (6%) and CDK2 in 1 (3%). Alteration involving multiple genes of cell cycle noted in 7 patients (21.2%) with combination of CCND1 and CDKN2A being most common combination. The cell cycle checkpoint defects were most frequently seen in 9 pts with colon (27%), 8 pts with hepatobiliary (27%), 8 pts with pancreatic (24%), 7 pts with esophageal (21%), and less commonly in small bowel (6%) and GIST (6%). Conclusions: The alterations in the cell cycle pathway are most common in certain GI tumors mainly colon, pancreatic, hepatobiliary and esophageal tumors. Future clinical trials exploring the potential role of targeted agents such as CDK4/6 inhibitors alone or in combination with other targeted agents such as MEK inhibitors requires further exploration in these tumors.
Long non-coding RNA XLOC_000647 suppresses progression of pancreatic cancer and decreases epithelial-mesenchymal transition-induced cell invasion by down-regulating NLRP3
Authors: Hao Hu, Yandong Wang, Xiangya Ding, Yuan He, Zipeng Lu, Pengfei Wu, Lei Tian, Hao Yuan, Dongfang Liu, Guodong Shi, Tianfang Xia, Jie Yin, Baobao Cai, Yi Miao, Kuirong Jiang
Journal: Molecular Cancer (2018)

Long non-coding RNAs (lncRNAs) play an important role in the development and progression of various tumors, including pancreatic cancer (PC). Recent studies have shown that lncRNAs can 'act in cis' to regulate the expression of its neighboring genes. Previously, we used lncRNAs microarray to identify a novel lncRNA termed XLOC_000647 that was down-regulated in PC tissues. However, the expression and function of XLOC_000647 in PC remain unclear. The expression of XLOC_000647 and NLRP3 in PC specimens and cell lines were detected by quantitative real-time PCR. Transwell assays were used to determine migration and invasion of PC cells. Western blot was carried out for detection of epithelial-mesenchymal transition (EMT) markers in PC cells. The effect of XLOC_000647 on PC cells was assessed in vitro and in vivo. The function of NOD-like receptor family pyrin domain-containing 3 (NLRP3) in PC was investigated in vitro. In addition, the regulation of NLRP3 by XLOC_000647 in PC was examined in vitro. Here, XLOC_000647 expression was down-regulated in PC tissues and cell lines. The expression level of XLOC_000647 was significantly correlated to tumor stage, lymph node metastasis, and overall survival. Overexpression of XLOC_000647 attenuated cell proliferation, invasion, and EMT in vitro and impaired tumor growth in vivo. Further, a significantly negative correlation was observed between XLOC_000647 levels and its genomic nearby gene NLRP3 in vitro and in vivo. Moreover, XLOC_000647 decreased NLRP3 by inhibiting its promoter activity. Knockdown of NLRP3 decreased proliferation of cancer cells, invasion, and EMT in vitro. Importantly, after XLOC_000647 was overexpressed, the corresponding phenotypes of cells invasion and EMT were reversed by overexpression of NLRP3. Together, these results indicate that XLOC_000647 functions as a novel tumor suppressor of lncRNA and acts as an important regulator of NLRP3, inhibiting cell proliferation, invasion, and EMT in PC.
Consanguineous Marriage and the Psychopathology of the Progeny of First-Cousin Couples
Authors: Alison Shaw
Journal: JAMA Psychiatry (2018)

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