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JCI Insight

Patrizia Mondello, Elliott J Brea, Elisa De Stanchina, Eneda Toska, Aaron Y Chang, Myles Fennell, Venkatraman Seshan, Ralph Garippa, David A Scheinberg, José Baselga, Hans-Guido Wendel, Anas Younes
No abstract text is available yet for this article.
November 15, 2018: JCI Insight
Ning Cheng, Rebekah Watkins-Schulz, Robert D Junkins, Clément N David, Brandon M Johnson, Stephanie A Montgomery, Kevin J Peine, David B Darr, Hong Yuan, Karen P McKinnon, Qi Liu, Lei Miao, Leaf Huang, Eric M Bachelder, Kristy M Ainslie, Jenny P-Y Ting
Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC...
November 15, 2018: JCI Insight
Elodie Pronier, Paolo Cifani, Tiffany R Merlinsky, Katharine Barr Berman, Amritha Varshini Hanasoge Somasundara, Raajit K Rampal, John LaCava, Karen E Wei, Friederike Pastore, Jesper Lv Maag, Jane Park, Richard Koche, Alex Kentsis, Ross L Levine
Mutations in the ER chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins. Mutant CALR caused mislocalization of binding partners and increased recruitment of FLI1, ERP57, and CALR to the MPL promoter to enhance transcription...
November 15, 2018: JCI Insight
Carlee R Giesige, Lindsay M Wallace, Kristin N Heller, Jocelyn O Eidahl, Nizar Y Saad, Allison M Fowler, Nettie K Pyne, Mustafa Al-Kharsan, Afrooz Rashnonejad, Gholamhossein Amini Chermahini, Jacqueline S Domire, Diana Mukweyi, Sara E Garwick-Coppens, Susan M Guckes, K John McLaughlin, Kathrin Meyer, Louise R Rodino-Klapac, Scott Q Harper
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There is currently no pharmacological treatment. The emergence of DUX4 enabled development of cell and animal models that could be used for basic and translational research. Since DUX4 is toxic, animal model development has been challenging, but progress has been made, revealing that tight regulation of DUX4 expression is critical for creating viable animals that develop myopathy...
November 15, 2018: JCI Insight
Allison A Throm, Joshua B Alinger, Jeanette T Pingel, Allyssa L Daugherty, Lauren M Pachman, Anthony R French
Juvenile dermatomyositis (JDM) is a debilitating pediatric autoimmune disease manifesting with characteristic rash and muscle weakness. To delineate signaling abnormalities in JDM, mass cytometry was performed with PBMCs from treatment-naive JDM patients and controls. NK cell percentages were lower while frequencies of naive B cells and naive CD4+ T cells were higher in JDM patients than in controls. These cell frequency differences were attenuated with cessation of active disease. A large number of signaling differences were identified in treatment-naive JDM patients compared with controls...
November 15, 2018: JCI Insight
Fang Zhong, Zhaohong Chen, Liwen Zhang, Yifan Xie, Viji Nair, Wenjun Ju, Matthias Kretzler, Robert G Nelson, Zhengzhe Li, Hongyu Chen, Yongjun Wang, Aihua Zhang, Kyung Lee, Zhihong Liu, John Cijiang He
Our previous work demonstrated a protective role of protein S in early diabetic kidney disease (DKD). Protein S exerts antiinflammatory and antiapoptotic effects through the activation of TYRO3, AXL, and MER (TAM) receptors. Among the 3 TAM receptors, we showed that the biological effects of protein S were mediated largely by TYRO3 in diabetic kidneys. Our data now show that TYRO3 mRNA expression is highly enriched in human glomeruli and that TYRO3 protein is expressed in podocytes. Interestingly, glomerular TYRO3 mRNA expression increased in mild DKD but was suppressed in progressive DKD, as well as in focal segmental glomerulosclerosis (FSGS)...
November 15, 2018: JCI Insight
Damian A Oyong, Enny Kenangalem, Jeanne R Poespoprodjo, James G Beeson, Nicholas M Anstey, Ric N Price, Michelle J Boyle
Anemia is a major complication of malaria, driven largely by loss of uninfected RBCs during infection. RBC clearance through loss of complement regulatory proteins (CRPs) is a significant contributor to anemia in Plasmodium falciparum infection, but its role in Plasmodium vivax infection is unknown. CRP loss increases RBC susceptibility to macrophage clearance, a process that is also regulated by CD47. We compared CRPs and CD47 expression on infected and uninfected RBCs in adult patients with vivax and falciparum malaria and different anemia severities from Papua, Indonesia...
November 15, 2018: JCI Insight
Brahma V Kumar, Radomir Kratchmarov, Michelle Miron, Dustin J Carpenter, Takashi Senda, Harvey Lerner, Amy Friedman, Steven L Reiner, Donna L Farber
Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines...
November 15, 2018: JCI Insight
J Michael Wells, Margaret M Parker, Robert A Oster, Russ P Bowler, Mark T Dransfield, Surya P Bhatt, Michael H Cho, Victor Kim, Jeffrey L Curtis, Fernando J Martinez, Robert Paine, Wanda O'Neal, Wassim W Labaki, Robert J Kaner, Igor Barjaktarevic, MeiLan K Han, Edwin K Silverman, James D Crapo, R Graham Barr, Prescott Woodruff, Peter J Castaldi, Amit Gaggar, The Spiromics And COPDGene Investigators
BACKGROUND: Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD). METHODS: We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available...
November 15, 2018: JCI Insight
Thomas M Savage, Brittany A Shonts, Aleksandar Obradovic, Susan Dewolf, Saiping Lau, Julien Zuber, Michael T Simpson, Erik Berglund, Jianing Fu, Suxiao Yang, Siu-Hong Ho, Qizhi Tang, Laurence A Turka, Yufeng Shen, Megan Sykes
Allograft tolerance, in which a graft is accepted without long-term immunosuppression, could overcome numerous obstacles in transplantation. Human allograft tolerance has been intentionally induced across HLA barriers via combined kidney and bone marrow transplantation (CKBMT) with a regimen that induces only transient chimerism. Tregs are enriched early after CKBMT. While deletional tolerance contributes to long-term tolerance, the role of Tregs remains unclear. We have optimized a method for identifying the donor-specific Treg repertoire and used it to interrogate the fate of donor-specific Tregs after CKBMT...
November 15, 2018: JCI Insight
Michael P Pender, Peter A Csurhes, Corey Smith, Nanette L Douglas, Michelle A Neller, Katherine K Matthews, Leone Beagley, Sweera Rehan, Pauline Crooks, Tracey J Hopkins, Stefan Blum, Kerryn A Green, Zara A Ioannides, Andrew Swayne, Blake T Aftab, Kaye D Hooper, Scott R Burrows, Kate M Thompson, Alan Coulthard, Rajiv Khanna
BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy. METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A...
November 15, 2018: JCI Insight
Jenny Lazarus, Tomasz Maj, J Joshua Smith, Mirna Perusina Lanfranca, Arvind Rao, Michael I D'Angelica, Lawrence Delrosario, Alexander Girgis, Casey Schukow, Jinru Shia, Ilona Kryczek, Jiaqi Shi, Isaac Wasserman, Howard Crawford, Hari Nathan, Marina Pasca Di Magliano, Weiping Zou, Timothy L Frankel
Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival...
November 15, 2018: JCI Insight
Mu Chen, Dong-Zhu Xu, Adonis Z Wu, Shuai Guo, Juyi Wan, Dechun Yin, Shien-Fong Lin, Zhenhui Chen, Michael Rubart-von der Lohe, Thomas H Everett, Zhilin Qu, James N Weiss, Peng-Sheng Chen
The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay...
November 15, 2018: JCI Insight
Jennifer Q Kwong, Jiuzhou Huo, Michael J Bround, Justin G Boyer, Jennifer A Schwanekamp, Nasab Ghazal, Joshua T Maxwell, Young C Jang, Zaza Khuchua, Kevin Shi, Donald M Bers, Jennifer Davis, Jeffery D Molkentin
The mitochondrial Ca2+ uniporter (MCU) complex mediates acute mitochondrial Ca2+ influx. In skeletal muscle, MCU links Ca2+ signaling to energy production by directly enhancing the activity of key metabolic enzymes in the mitochondria. Here, we examined the role of MCU in skeletal muscle development and metabolic function by generating mouse models for the targeted deletion of Mcu in embryonic, postnatal, and adult skeletal muscle. Loss of Mcu did not affect muscle growth and maturation or otherwise cause pathology...
November 15, 2018: JCI Insight
Laura Braud, Maria Pini, Lucie Muchova, Sylvie Manin, Hiroaki Kitagishi, Daigo Sawaki, Gabor Czibik, Julien Ternacle, Geneviève Derumeaux, Roberta Foresti, Roberto Motterlini
Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis...
November 15, 2018: JCI Insight
Amanda Mener, Seema R Patel, Connie M Arthur, Satheesh Chonat, Andreas Wieland, Manjula Santhanakrishnan, Jingchun Liu, Cheryl L Maier, Ryan P Jajosky, Kathryn Girard-Pierce, Ashley Bennett, Patricia E Zerra, Nicole H Smith, Jeanne E Hendrickson, Sean R Stowell
RBC alloimmunization represents a significant immunological challenge for patients requiring lifelong transfusion support. The majority of clinically relevant non-ABO(H) blood group antigens have been thought to drive antibody formation through T cell-dependent immune pathways. Thus, we initially sought to define the role of CD4+ T cells in formation of alloantibodies to KEL, one of the leading causes of hemolytic transfusion reactions. Unexpectedly, our findings demonstrated that KEL RBCs actually possess the ability to induce antibody formation independent of CD4+ T cells or complement component 3 (C3), two common regulators of antibody formation...
November 15, 2018: JCI Insight
Emilie Barruet, Blanca M Morales, Corey J Cain, Amy N Ton, Kelly L Wentworth, Tea V Chan, Tania A Moody, Mariëlle C Haks, Tom Hm Ottenhoff, Judith Hellman, Mary C Nakamura, Edward C Hsiao
BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2)...
November 15, 2018: JCI Insight
Hiroko Ishiwata-Endo, Jiro Kato, Akihiko Tonouchi, Youn Wook Chung, Junhui Sun, Linda A Stevens, Jianfeng Zhu, Angel M Aponte, Danielle A Springer, Hong San, Kazuyo Takeda, Zu-Xi Yu, Victoria Hoffmann, Elizabeth Murphy, Joel Moss
Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP-ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose-arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury...
November 15, 2018: JCI Insight
Pietro E Cippà, Bo Sun, Jing Liu, Liang Chen, Maarten Naesens, Andrew P McMahon
BACKGROUND: The molecular understanding of the progression from acute to chronic organ injury is limited. Ischemia/reperfusion injury (IRI) triggered during kidney transplantation can contribute to progressive allograft dysfunction. METHODS: Protocol biopsies (n = 163) were obtained from 42 kidney allografts at 4 time points after transplantation. RNA sequencing-mediated (RNA-seq-mediated) transcriptional profiling and machine learning computational approaches were employed to analyze the molecular responses to IRI and to identify shared and divergent transcriptional trajectories associated with distinct clinical outcomes...
November 15, 2018: JCI Insight
J Humberto Treviño-Villarreal, Justin S Reynolds, Alexander Bartelt, P Kent Langston, Michael R MacArthur, Alessandro Arduini, Valeria Tosti, Nicola Veronese, Beatrice Bertozzi, Lear E Brace, Pedro Mejia, Kaspar Trocha, Gustavo S Kajitani, Alban Longchamp, Eylul Harputlugil, Rose Gathungu, Susan S Bird, Arnold D Bullock, Robert S Figenshau, Gerald L Andriole, Andrew Thompson, Jöerg Heeren, C Keith Ozaki, Bruce S Kristal, Luigi Fontana, James R Mitchell
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues...
November 2, 2018: JCI Insight
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