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JCI Insight

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https://www.readbyqxmd.com/read/29148985/subtyping-sub-saharan-esophageal-squamous-cell-carcinoma-by-comprehensive-molecular-analysis
#1
Wenjin Liu, Jeff M Snell, William R Jeck, Katherine A Hoadley, Matthew D Wilkerson, Joel S Parker, Nirali Patel, Yohannie B Mlombe, Gift Mulima, N George Liomba, Lindsey L Wolf, Carol G Shores, Satish Gopal, Norman E Sharpless
No abstract text is available yet for this article.
November 16, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093275/neutralization-of-il-8-decreases-tumor-pmn-mdscs-and-reduces-mesenchymalization-of-claudin-low-triple-negative-breast-cancer
#2
Charli Dominguez, Kristen K McCampbell, Justin M David, Claudia Palena
The complex signaling networks of the tumor microenvironment that facilitate tumor growth and progression toward metastatic disease are becoming a focus of potential therapeutic options. The chemokine IL-8 is overexpressed in multiple cancer types, including triple-negative breast cancer (TNBC), where it promotes the acquisition of mesenchymal features, stemness, resistance to therapies, and the recruitment of immune-suppressive cells to the tumor site. The present study explores the utility of a clinical-stage monoclonal antibody that neutralizes IL-8 (HuMax-IL8) as a potential therapeutic option for TNBC...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093274/notch3-regulates-stem-to-mural-cell-differentiation-in-infantile-hemangioma
#3
Andrew K Edwards, Kyle Glithero, Peter Grzesik, Alison A Kitajewski, Naikhoba Co Munabi, Krista Hardy, Qian Kun Tan, Michael Schonning, Thaned Kangsamaksin, Jan K Kitajewski, Carrie J Shawber, June K Wu
Infantile hemangioma (IH) is a vascular tumor that begins with rapid vascular proliferation shortly after birth, followed by vascular involution in early childhood. We have found that NOTCH3, a critical regulator of mural cell differentiation and maturation, is expressed in hemangioma stem cells (HemSCs), suggesting that NOTCH3 may function in HemSC-to-mural cell differentiation and pathological vessel stabilization. Here, we demonstrate that NOTCH3 is expressed in NG2+PDGFRβ+ perivascular HemSCs and CD31+GLUT1+ hemangioma endothelial cells (HemECs) in proliferating IHs and becomes mostly restricted to the αSMA+NG2loPDGFRβlo mural cells in involuting IHs...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093273/genetic-determinants-of-circulating-gip-and-glp-1-concentrations
#4
Peter Almgren, Andreas Lindqvist, Ulrika Krus, Liisa Hakaste, Emilia Ottosson-Laakso, Olof Asplund, Emily Sonestedt, Rashmi B Prasad, Esa Laurila, Marju Orho-Melander, Olle Melander, Tiinamaija Tuomi, Jens Juul Holst, Peter M Nilsson, Nils Wierup, Leif Groop, Emma Ahlqvist
The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093272/t-cells-presenting-viral-antigens-or-autoantigens-induce-cytotoxic-t-cell-anergy
#5
Nathalie E Blachère, Dana E Orange, Emily C Gantman, Bianca D Santomasso, Graeme C Couture, Teresa Ramirez-Montagut, John Fak, Kevin J O'Donovan, Zhong Ru, Salina Parveen, Mayu O Frank, Michael J Moore, Robert B Darnell
In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093271/combined-inhibition-of-atypical-pkc-and-histone-deacetylase-1-is-cooperative-in-basal-cell-carcinoma-treatment
#6
Amar N Mirza, Micah A Fry, Nicole M Urman, Scott X Atwood, Jon Roffey, Gregory R Ott, Bin Chen, Alex Lee, Alexander S Brown, Sumaira Z Aasi, Tyler Hollmig, Mark A Ator, Bruce D Dorsey, Bruce R Ruggeri, Craig A Zificsak, Marina Sirota, Jean Y Tang, Atul Butte, Ervin Epstein, Kavita Y Sarin, Anthony E Oro
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093270/notch1-haploinsufficiency-causes-ascending-aortic-aneurysms-in-mice
#7
Sara N Koenig, Stephanie LaHaye, James D Feller, Patrick Rowland, Kan N Hor, Aaron J Trask, Paul Ml Janssen, Freddy Radtke, Brenda Lilly, Vidu Garg
An ascending aortic aneurysm (AscAA) is a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a potentially novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse model and that heterozygous deletion of Notch1 in the second heart field (SHF) lineage recapitulated this exacerbated phenotype...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093269/b-cell-derived-il-4-acts-on-podocytes-to-induce-proteinuria-and-foot-process-effacement
#8
Alfred Hj Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B Hodgin, Mark J Miller, Thaddeus S Stappenbeck, Jeffrey H Miner, Andrey S Shaw
The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093268/microbiota-control-immune-regulation-in-humanized-mice
#9
Elke Gülden, Nalini K Vudattu, Songyan Deng, Paula Preston-Hurlburt, Mark Mamula, James C Reed, Sindhu Mohandas, Betsy C Herold, Richard Torres, Silvio M Vieira, Bentley Lim, Jose D Herazo-Maya, Martin Kriegel, Andrew L Goodman, Chris Cotsapas, Kevan C Herold
The microbiome affects development and activity of the immune system, and may modulate immune therapies, but there is little direct information about this control in vivo. We studied how the microbiome affects regulation of human immune cells in humanized mice. When humanized mice were treated with a cocktail of 4 antibiotics, there was an increase in the frequency of effector T cells in the gut wall, circulating levels of IFN-γ, and appearance of anti-nuclear antibodies. Teplizumab, a non-FcR-binding anti-CD3ε antibody, no longer delayed xenograft rejection...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093267/loss-of-mir-141-200c-ameliorates-hepatic-steatosis-and-inflammation-by-reprogramming-multiple-signaling-pathways-in-nash
#10
Melanie Tran, Sang-Min Lee, Dong-Ju Shin, Li Wang
Accumulation of lipid droplets and inflammatory cell infiltration is the hallmark of nonalcoholic steatohepatitis (NASH). The roles of noncoding RNAs in NASH are less known. We aim to elucidate the function of miR-141/200c in diet-induced NASH. WT and miR-141/200c-/- mice were fed a methionine and choline deficient (MCD) diet for 2 weeks to assess markers of steatosis, liver injury, and inflammation. Hepatic miR-141 and miR-200c RNA levels were highly induced in human patients with NASH fatty liver and in WT MCD mice...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093266/macrophage-derived-oncostatin-m-contributes-to-human-and-mouse-neurogenic-heterotopic-ossifications
#11
Frédéric Torossian, Bernadette Guerton, Adrienne Anginot, Kylie A Alexander, Christophe Desterke, Sabrina Soave, Hsu-Wen Tseng, Nassim Arouche, Laetitia Boutin, Irina Kulina, Marjorie Salga, Beulah Jose, Allison R Pettit, Denis Clay, Nathalie Rochet, Erica Vlachos, Guillaume Genet, Charlotte Debaud, Philippe Denormandie, François Genet, Natalie A Sims, Sébastien Banzet, Jean-Pierre Levesque, Jean-Jacques Lataillade, Marie-Caroline Le Bousse-Kerdilès
Neurogenic heterotopic ossification (NHO) is the formation of ectopic bone generally in muscles surrounding joints following spinal cord or brain injury. We investigated the mechanisms of NHO formation in 64 patients and a mouse model of spinal cord injury-induced NHO. We show that marrow from human NHOs contains hematopoietic stem cell (HSC) niches, in which mesenchymal stromal cells (MSCs) and endothelial cells provide an environment supporting HSC maintenance, proliferation, and differentiation. The transcriptomic signature of MSCs from NHOs shows a neuronal imprinting associated with a molecular network required for HSC support...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093265/maternal-obesity-and-increased-neonatal-adiposity-correspond-with-altered-infant-mesenchymal-stem-cell-metabolism
#12
Peter R Baker, Zachary Patinkin, Allison Lb Shapiro, Becky A De La Houssaye, Michael Woontner, Kristen E Boyle, Lauren Vanderlinden, Dana Dabelea, Jacob E Friedman
Maternal obesity is a global health problem that increases offspring obesity risk. The metabolic pathways underlying early developmental programming in human infants at risk for obesity remain poorly understood, largely due to barriers in fetal/infant tissue sampling. Utilizing umbilical cord-derived mesenchymal stem cells (uMSC) from offspring of normal weight and obese mothers, we tested whether energy metabolism and gene expression differ in differentiating uMSC myocytes and adipocytes, in relation to maternal obesity exposures and/or neonatal adiposity...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093264/secreted-pla2-group-x-orchestrates-innate-and-adaptive-immune-responses-to-inhaled-allergen
#13
James D Nolin, Ying Lai, Herbert Luke Ogden, Anne M Manicone, Ryan C Murphy, Dowon An, Charles W Frevert, Farideh Ghomashchi, Gajendra S Naika, Michael H Gelb, Gail M Gauvreau, Adrian M Piliponsky, William A Altemeier, Teal S Hallstrand
Phospholipase A2 (PLA2) enzymes regulate the formation of eicosanoids and lysophospholipids that contribute to allergic airway inflammation. Secreted PLA2 group X (sPLA2-X) was recently found to be increased in the airways of asthmatics and is highly expressed in airway epithelial cells and macrophages. In the current study, we show that allergen exposure increases sPLA2-X in humans and in mice, and that global deletion of Pla2g10 results in a marked reduction in airway hyperresponsiveness (AHR), eosinophil and T cell trafficking to the airways, airway occlusion, generation of type-2 cytokines by antigen-stimulated leukocytes, and antigen-specific immunoglobulins...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093263/human-vaccination-against-rh5-induces-neutralizing-antimalarial-antibodies-that-inhibit-rh5-invasion-complex-interactions
#14
Ruth O Payne, Sarah E Silk, Sean C Elias, Kazutoyo Miura, Ababacar Diouf, Francis Galaway, Hans de Graaf, Nathan J Brendish, Ian D Poulton, Oliver J Griffiths, Nick J Edwards, Jing Jin, Geneviève M Labbé, Daniel Gw Alanine, Loredana Siani, Stefania Di Marco, Rachel Roberts, Nicky Green, Eleanor Berrie, Andrew S Ishizuka, Carolyn M Nielsen, Martino Bardelli, Frederica D Partey, Michael F Ofori, Lea Barfod, Juliana Wambua, Linda M Murungi, Faith H Osier, Sumi Biswas, James S McCarthy, Angela M Minassian, Rebecca Ashfield, Nicola K Viebig, Fay L Nugent, Alexander D Douglas, Johan Vekemans, Gavin J Wright, Saul N Faust, Adrian Vs Hill, Carole A Long, Alison M Lawrie, Simon J Draper
The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen - a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29093262/human-regulatory-t-cells-undergo-self-inflicted-damage-via-granzyme-pathways-upon-activation
#15
Esilida Sula Karreci, Siawosh K Eskandari, Farokh Dotiwala, Sujit K Routray, Ahmed T Kurdi, Jean Pierre Assaker, Pavlo Luckyanchykov, Albana B Mihali, Omar Maarouf, Thiago J Borges, Abdullah Alkhudhayri, Kruti R Patel, Amr Radwan, Irene Ghobrial, Martina McGrath, Anil Chandraker, Leonardo V Riella, Wassim Elyaman, Reza Abdi, Judy Lieberman, Jamil Azzi
Tregs hold great promise as a cellular therapy for multiple immunologically mediated diseases, given their ability to control immune responses. The success of such strategies depends on the expansion of healthy, suppressive Tregs ex vivo and in vivo following the transfer. In clinical studies, levels of transferred Tregs decline sharply in the blood within a few days of the transfer. Tregs have a high rate of apoptosis. Here, we describe a new mechanism of Treg self-inflicted damage. We show that granzymes A and -B (GrA and GrB), which are highly upregulated in human Tregs upon stimulation, leak out of cytotoxic granules to induce cleavage of cytoplasmic and nuclear substrates, precipitating apoptosis in target cells...
November 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046486/synaptopodin-is-upregulated-by-il-13-in-eosinophilic-esophagitis-and-regulates-esophageal-epithelial-cell-motility-and-barrier-integrity
#16
Mark Rochman, Jared Travers, J Pablo Abonia, Julie M Caldwell, Marc E Rothenberg
Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus mediated by an IL-13-driven epithelial cell transcriptional program. Herein, we show that the cytoskeletal protein synaptopodin (SYNPO), previously associated with podocytes, is constitutively expressed in esophageal epithelium and induced during allergic inflammation. In addition, we show that the SYNPO gene is transcriptionally and epigenetically regulated by IL-13 in esophageal epithelial cells. SYNPO was expressed in the basal layer of homeostatic esophageal epithelium, colocalized with actin filaments, and expanded into the suprabasal epithelium in EoE patients, where expression was elevated 25-fold compared with control individuals...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046485/dimethyl-fumarate-increases-fetal-hemoglobin-provides-heme-detoxification-and-corrects-anemia-in-sickle-cell-disease
#17
Sriram Krishnamoorthy, Betty Pace, Dipti Gupta, Sarah Sturtevant, Biaoru Li, Levi Makala, Julia Brittain, Nancy Moore, Benjamin F Vieira, Timothy Thullen, Ivan Stone, Huo Li, William E Hobbs, David R Light
Sickle cell disease (SCD) results from a point mutation in the β-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)-like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cell-derived erythroid progenitors...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046484/t-cells-expressing-chimeric-antigen-receptor-promote-immune-tolerance
#18
Antonio Pierini, Bettina P Iliopoulou, Heshan Peiris, Magdiel Pérez-Cruz, Jeanette Baker, Katie Hsu, Xueying Gu, Ping-Ping Zheng, Tom Erkers, Sai-Wen Tang, William Strober, Maite Alvarez, Aaron Ring, Andrea Velardi, Robert S Negrin, Seung K Kim, Everett H Meyer
Cellular therapies based on permanent genetic modification of conventional T cells have emerged as a promising strategy for cancer. However, it remains unknown if modification of T cell subsets, such as Tregs, could be useful in other settings, such as allograft transplantation. Here, we use a modular system based on a chimeric antigen receptor (CAR) that binds covalently modified mAbs to control Treg activation in vivo. Transient expression of this mAb-directed CAR (mAbCAR) in Tregs permitted Treg targeting to specific tissue sites and mitigated allograft responses, such as graft-versus-host disease...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046483/deficiency-of-shank2-causes-mania-like-behavior-that-responds-to-mood-stabilizers
#19
Andrea L Pappas, Alexandra L Bey, Xiaoming Wang, Mark Rossi, Yong Ho Kim, Haidun Yan, Fiona Porkka, Lara J Duffney, Samantha M Phillips, Xinyu Cao, Jin-Dong Ding, Ramona M Rodriguiz, Henry H Yin, Richard J Weinberg, Ru-Rong Ji, William C Wetsel, Yong-Hui Jiang
Genetic defects in the synaptic scaffolding protein gene, SHANK2, are linked to a variety of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and bipolar disorder, but the molecular mechanisms underlying the pleotropic effects of SHANK2 mutations are poorly understood. We generated and characterized a line of Shank2 mutant mice by deleting exon 24 (Δe24). Shank2Δe24-/- mice engage in significantly increased locomotor activity, display abnormal reward-seeking behavior, are anhedonic, have perturbations in circadian rhythms, and show deficits in social and cognitive behaviors...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29046482/blunted-rise-in-brain-glucose-levels-during-hyperglycemia-in-adults-with-obesity-and-t2dm
#20
Janice J Hwang, Lihong Jiang, Muhammad Hamza, Elizabeth Sanchez Rangel, Feng Dai, Renata Belfort-DeAguiar, Lisa Parikh, Brian B Koo, Douglas L Rothman, Graeme Mason, Robert S Sherwin
In rodent models, obesity and hyperglycemia alter cerebral glucose metabolism and glucose transport into the brain, resulting in disordered cerebral function as well as inappropriate responses to homeostatic and hedonic inputs. Whether similar findings are seen in the human brain remains unclear. In this study, 25 participants (9 healthy participants; 10 obese nondiabetic participants; and 6 poorly controlled, insulin- and metformin-treated type 2 diabetes mellitus (T2DM) participants) underwent 1H magnetic resonance spectroscopy scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-hour hyperglycemic clamp (glucose ~220 mg/dl)...
October 19, 2017: JCI Insight
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