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https://www.readbyqxmd.com/read/28614805/assessing-rejection-related-disease-in-kidney-transplant-biopsies-based-on-archetypal-analysis-of-molecular-phenotypes
#1
Jeff Reeve, Georg A Böhmig, Farsad Eskandary, Gunilla Einecke, Carmen Lefaucheur, Alexandre Loupy, Philip F Halloran
Conventional histologic diagnosis of rejection in kidney transplants has limited repeatability due to its inherent requirement for subjective assessment of lesions, in a rule-based system that does not acknowledge diagnostic uncertainty. Molecular phenotyping affords opportunities for increased precision and improved disease classification to address the limitations of conventional histologic diagnostic systems and quantify levels of uncertainty. Microarray data from 1,208 kidney transplant biopsies were collected prospectively from 13 centers...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614804/in-vivo-kinetics-and-nonradioactive-imaging-of-rapidly-proliferating-cells-in-graft-versus-host-disease
#2
Nataliya P Buxbaum, Donald E Farthing, Natella Maglakelidze, Martin Lizak, Hellmut Merkle, Andrea C Carpenter, Brittany U Oliver, Veena Kapoor, Ehydel Castro, Gregory A Swan, Liliane M Dos Santos, Nicolas J Bouladoux, Catherine V Bare, Francis A Flomerfelt, Michael A Eckhaus, William G Telford, Yasmine Belkaid, Remy J Bosselut, Ronald E Gress
Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to chemotherapy and radiation. Most HSCT recipients develop chronic graft-versus-host disease (cGVHD), a systemic alloimmune attack on host organs. Diagnosis is based on clinical signs and symptoms, as biopsies are risky. T cells are central to the biology of cGVHD. We found that a low Treg/CD4+ T effector memory (Tem) ratio in circulation, lymphoid, and target organs identified early and established mouse cGVHD. Using deuterated water labeling to measure multicompartment in vivo kinetics of these subsets, we show robust Tem and Treg proliferation in lymphoid and target organs, while Tregs undergo apoptosis in target organs...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614803/delineating-antibody-recognition-against-zika-virus-during-natural-infection
#3
Lei Yu, Ruoke Wang, Fei Gao, Min Li, Jianying Liu, Jian Wang, Wenxin Hong, Lingzhai Zhao, Yingfen Wen, Chibiao Yin, Hua Wang, Qi Zhang, Yangyang Li, Panpan Zhou, Rudian Zhang, Yang Liu, Xiaoping Tang, Yongjun Guan, Cheng-Feng Qin, Ling Chen, Xuanling Shi, Xia Jin, Gong Cheng, Fuchun Zhang, Linqi Zhang
Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that shares a considerable degree of homology with dengue virus (DENV). Here, we examined longitudinal antibody response against ZIKV during natural infection in 2 convalescent individuals. By decomposing the antibody recognition into DI/DII and DIII of the E glycoprotein, we showed their development in humans followed a spatiotemporal hierarchy. Plasma binding to DI/DII appeared to peak and wane during early infection with extensive cross-reactivity with DI/DII of DENV...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614802/mitochondrial-dysregulation-and-glycolytic-insufficiency-functionally-impair-cd8-t-cells-infiltrating-human-renal-cell-carcinoma
#4
Peter J Siska, Kathryn E Beckermann, Frank M Mason, Gabriela Andrejeva, Allison R Greenplate, Adam B Sendor, Yun-Chen J Chiang, Armando L Corona, Lelisa F Gemta, Benjamin G Vincent, Richard C Wang, Bumki Kim, Jiyong Hong, Chiu-Lan Chen, Timothy N Bullock, Jonathan M Irish, W Kimryn Rathmell, Jeffrey C Rathmell
Cancer cells can inhibit effector T cells (Teff) through both immunomodulatory receptors and the impact of cancer metabolism on the tumor microenvironment. Indeed, Teff require high rates of glucose metabolism, and consumption of essential nutrients or generation of waste products by tumor cells may impede essential T cell metabolic pathways. Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the tumor suppressor von Hippel-Lindau (VHL) and altered cancer cell metabolism. Here, we assessed how ccRCC influences the metabolism and activation of primary patient ccRCC tumor infiltrating lymphocytes (TIL)...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614801/dna-methyltransferase-3b-regulates-articular-cartilage-homeostasis-by-altering-metabolism
#5
Jie Shen, Cuicui Wang, Daofeng Li, Taotao Xu, Jason Myers, John M Ashton, Ting Wang, Michael J Zuscik, Audrey McAlinden, Regis J O'Keefe
Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614800/robust-memory-responses-against-influenza-vaccination-in-pemphigus-patients-previously-treated-with-rituximab
#6
Alice Cho, Bridget Bradley, Robert Kauffman, Lalita Priyamvada, Yevgeniy Kovalenkov, Ron Feldman, Jens Wrammert
Rituximab is a therapeutic anti-CD20 monoclonal antibody widely used to treat B cell lymphoma and autoimmune diseases, such as rheumatic arthritis, systemic lupus erythematosus, and autoimmune blistering skin diseases (AIBD). While rituximab fully depletes peripheral blood B cells, it remains unclear whether some preexisting B cell memory to pathogens or vaccines may survive depletion, especially in lymphoid tissues, and if these memory B cells can undergo homeostatic expansion during recovery from depletion...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614799/globalization-and-changing-trends-of-biomedical-research-output
#7
Marisa L Conte, Jing Liu, Santiago Schnell, M Bishr Omary
The US continues to lead the world in research and development (R&D) expenditures, but there is concern that stagnation in federal support for biomedical research in the US could undermine the leading role the US has played in biomedical and clinical research discoveries. As a readout of research output in the US compared with other countries, assessment of original research articles published by US-based authors in ten clinical and basic science journals during 2000 to 2015 showed a steady decline of articles in high-ranking journals or no significant change in mid-ranking journals...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614798/dnmt3a-mediated-inhibition-of-wnt-in-cardiac-progenitor-cells-improves-differentiation-and-remote-remodeling-after-infarction
#8
Aurelia De Pauw, Emilie Andre, Belaid Sekkali, Caroline Bouzin, Hrag Esfahani, Nicolas Barbier, Axelle Loriot, Charles De Smet, Laetitia Vanhoutte, Stéphane Moniotte, Bernhard Gerber, Vittoria di Mauro, Daniele Catalucci, Olivier Feron, Denise Hilfiker-Kleiner, Jean-Luc Balligand
Adult cardiac progenitor cells (CPCs) display a low capacity to differentiate into cardiomyocytes in injured hearts, strongly limiting the regenerative capacity of the mammalian myocardium. To identify new mechanisms regulating CPC differentiation, we used primary and clonally expanded Sca-1+ CPCs from murine adult hearts in homotypic culture or coculture with cardiomyocytes. Expression kinetics analysis during homotypic culture differentiation showed downregulation of Wnt target genes concomitant with increased expression of the Wnt antagonist, Wnt inhibitory factor 1 (Wif1), which is necessary to stimulate CPC differentiation...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614797/neuropeptide-y-expression-marks-partially-differentiated-%C3%AE-cells-in-mice-and-humans
#9
Pope Rodnoi, Mohan Rajkumar, Abu Saleh Md Moin, Senta K Georgia, Alexandra E Butler, Sangeeta Dhawan
β Cells are formed in embryonic life by differentiation of endocrine progenitors and expand by replication during neonatal life, followed by transition into functional maturity. In this study, we addressed the potential contribution of neuropeptide Y (NPY) in pancreatic β cell development and maturation. We show that NPY expression is restricted from the progenitor populations during pancreatic development and marks functionally immature β cells in fetal and neonatal mice and humans. NPY expression is epigenetically downregulated in β cells upon maturation...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614796/%C3%AE-synuclein-in-gut-endocrine-cells-and-its-implications-for-parkinson-s-disease
#10
Rashmi Chandra, Annie Hiniker, Yien-Ming Kuo, Robert L Nussbaum, Rodger A Liddle
Parkinson's disease (PD) is a progressive neurodegenerative disease with devastating clinical manifestations. In PD, neuronal death is associated with intracellular aggregates of the neuronal protein α-synuclein known as Lewy bodies. Although the cause of sporadic PD is not well understood, abundant clinical and pathological evidence show that misfolded α-synuclein is found in enteric nerves before it appears in the brain. This suggests a model in which PD pathology originates in the gut and spreads to the central nervous system via cell-to-cell prion-like propagation, such that transfer of misfolded α-synuclein initiates misfolding of native α-synuclein in recipient cells...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614795/a-3d-microfluidic-model-for-preclinical-evaluation-of-tcr-engineered-t-cells-against-solid-tumors
#11
Andrea Pavesi, Anthony T Tan, Sarene Koh, Adeline Chia, Marta Colombo, Emanuele Antonecchia, Carlo Miccolis, Erica Ceccarello, Giulia Adriani, Manuela T Raimondi, Roger D Kamm, Antonio Bertoletti
The tumor microenvironment imposes physical and functional constraints on the antitumor efficacy of adoptive T cell immunotherapy. Preclinical testing of different T cell preparations can help in the selection of efficient immune therapies, but in vivo models are expensive and cumbersome to develop, while classical in vitro 2D models cannot recapitulate the spatiotemporal dynamics experienced by T cells targeting cancer. Here, we describe an easily customizable 3D model, in which the tumor microenvironment conditions are modulated and the functionality of different T cell preparations is tested...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614794/an-activated-th17-prone-t-cell-subset-involved-in-chronic-graft-versus-host-disease-sensitive-to-pharmacological-inhibition
#12
Edouard Forcade, Katelyn Paz, Ryan Flynn, Brad Griesenauer, Tohti Amet, Wei Li, Liangyi Liu, Giorgos Bakoyannis, Di Jiang, Hong Wei Chu, Mercedes Lobera, Jianfei Yang, David S Wilkes, Jing Du, Kate Gartlan, Geoffrey R Hill, Kelli Pa MacDonald, Eduardo L Espada, Patrick Blanco, Jonathan S Serody, John Koreth, Corey S Cutler, Joseph H Antin, Robert J Soiffer, Jerome Ritz, Sophie Paczesny, Bruce R Blazar
Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146+ CD4 T cells in the 20 patients with active cGvHD with enhanced RORγt expression...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614793/a-single-dose-of-cannabidiol-reduces-blood-pressure-in-healthy-volunteers-in-a-randomized-crossover-study
#13
Khalid A Jadoon, Garry D Tan, Saoirse E O'Sullivan
BACKGROUND: Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans. METHODS: Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614792/cd4-t-lymphocytes-produce-adiponectin-in-response-to-transplants
#14
Sreedevi Danturti, Karen S Keslar, Leah R Steinhoff, Ran Fan, Nina Dvorina, Anna Valujskikh, Robert L Fairchild, William M Baldwin
Adiponectin is a pleiotropic cytokine with diverse immunomodulatory effects on macrophages and lymphocytes. In the current paradigm, lymphocytes and macrophages respond to adiponectin that is produced by adipocytes and other parenchymal cells. Using a model of chronic arterial inflammation in cardiac transplants, we found that T cells derived from the recipient migrate to the heart and produce adiponectin locally. The evidence that T cells produce significant amounts of adiponectin is based on 3 experimental approaches...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614791/human-vaccination-against-plasmodium-vivax-duffy-binding-protein-induces-strain-transcending-antibodies
#15
Ruth O Payne, Sarah E Silk, Sean C Elias, Kathryn H Milne, Thomas A Rawlinson, David Llewellyn, A Rushdi Shakri, Jing Jin, Geneviève M Labbé, Nick J Edwards, Ian D Poulton, Rachel Roberts, Ryan Farid, Thomas Jørgensen, Daniel Gw Alanine, Simone C de Cassan, Matthew K Higgins, Thomas D Otto, James S McCarthy, Willem A de Jongh, Alfredo Nicosia, Sarah Moyle, Adrian Vs Hill, Eleanor Berrie, Chetan E Chitnis, Alison M Lawrie, Simon J Draper
BACKGROUND: Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite's Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614790/genomic-landscape-and-evolution-of-metastatic-chromophobe-renal-cell-carcinoma
#16
Jozefina Casuscelli, Nils Weinhold, Gunes Gundem, Lu Wang, Emily C Zabor, Esther Drill, Patricia I Wang, Gouri J Nanjangud, Almedina Redzematovic, Amrita M Nargund, Brandon J Manley, Maria E Arcila, Nicholas M Donin, John C Cheville, R Houston Thompson, Allan J Pantuck, Paul Russo, Emily H Cheng, William Lee, Satish K Tickoo, Irina Ostrovnaya, Chad J Creighton, Elli Papaemmanuil, Venkatraman E Seshan, A Ari Hakimi, James J Hsieh
Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614789/type-i-interferons-suppress-viral-replication-but-contribute-to-t-cell-depletion-and-dysfunction-during-chronic-hiv-1-infection
#17
Liang Cheng, Haisheng Yu, Guangming Li, Feng Li, Jianping Ma, Jingyun Li, Liqun Chi, Liguo Zhang, Lishan Su
The direct link between sustained type I interferon (IFN-I) signaling and HIV-1-induced immunopathogenesis during chronic infection remains unclear. Here we report studies using a monoclonal antibody to block IFN-α/β receptor 1 (IFNAR1) signaling during persistent HIV-1 infection in humanized mice (hu-mice). We discovered that, during chronic HIV-1 infection, IFNAR blockade increased viral replication, which was correlated with elevated T cell activation. Thus, IFN-Is suppress HIV-1 replication during the chronic phase but are not essential for HIV-1-induced aberrant immune activation...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614788/apelin-modulates-pathological-remodeling-of-lymphatic-endothelium-after-myocardial-infarction
#18
Florence Tatin, Edith Renaud-Gabardos, Anne-Claire Godet, Fransky Hantelys, Francoise Pujol, Florent Morfoisse, Denis Calise, Fanny Viars, Philippe Valet, Bernard Masri, Anne-Catherine Prats, Barbara Garmy-Susini
Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28614787/nell-1-induces-sca-1-mesenchymal-progenitor-cell-expansion-in-models-of-bone-maintenance-and-repair
#19
Aaron W James, Jia Shen, Rebecca Tsuei, Alan Nguyen, Kevork Khadarian, Carolyn A Meyers, Hsin Chuan Pan, Weiming Li, Jin H Kwak, Greg Asatrian, Cymbeline T Culiat, Min Lee, Kang Ting, Xinli Zhang, Chia Soo
NELL-1 is a secreted, osteogenic protein first discovered to control ossification of the cranial skeleton. Recently, NELL-1 has been implicated in bone maintenance. However, the cellular determinants of NELL-1's bone-forming effects are still unknown. Here, recombinant human NELL-1 (rhNELL-1) implantation was examined in a clinically relevant nonhuman primate lumbar spinal fusion model. Prolonged rhNELL-1 protein release was achieved using an apatite-coated β-tricalcium phosphate carrier, resulting in a local influx of stem cell antigen-1-positive (Sca-1+) mesenchymal progenitor cells (MPCs), and complete osseous fusion across all samples (100% spinal fusion rate)...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28570279/optimized-multiplex-immunofluorescence-single-cell-analysis-reveals-tuft-cell-heterogeneity
#20
Eliot T McKinley, Yunxia Sui, Yousef Al-Kofahi, Bryan A Millis, Matthew J Tyska, Joseph T Roland, Alberto Santamaria-Pang, Christina L Ohland, Christian Jobin, Jeffrey L Franklin, Ken S Lau, Michael J Gerdes, Robert J Coffey
Intestinal tuft cells are a rare, poorly understood cell type recently shown to be a critical mediator of type 2 immune response to helminth infection. Here, we present advances in segmentation algorithms and analytical tools for multiplex immunofluorescence (MxIF), a platform that enables iterative staining of over 60 antibodies on a single tissue section. These refinements have enabled a comprehensive analysis of tuft cell number, distribution, and protein expression profiles as a function of anatomical location and physiological perturbations...
June 2, 2017: JCI Insight
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