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JCI Insight

Isabel Huang-Doran, Patsy Tomlinson, Felicity Payne, Alexandra Gast, Alison Sleigh, William Bottomley, Julie Harris, Allan Daly, Nuno Rocha, Simon Rudge, Jonathan Clark, Albert Kwok, Stefano Romeo, Emma McCann, Barbara Müksch, Mehul Dattani, Stefano Zucchini, Michael Wakelam, Lazaros C Foukas, David B Savage, Rinki Murphy, Stephen O'Rahilly, Inês Barroso, Robert K Semple
Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis...
October 20, 2016: JCI Insight
Xi Fang, Matthew J Stroud, Kunfu Ouyang, Li Fang, Jianlin Zhang, Nancy D Dalton, Yusu Gu, Tongbin Wu, Kirk L Peterson, Hsien-Da Huang, Ju Chen, Nanping Wang
Adipose tissue is a key endocrine organ that governs systemic homeostasis. PPARγ is a master regulator of adipose tissue signaling that plays an essential role in insulin sensitivity, making it an important therapeutic target. The selective PPARγ agonist rosiglitazone (RSG) has been used to treat diabetes. However, adverse cardiovascular effects have seriously hindered its clinical application. Experimental models have revealed that PPARγ activation increases cardiac hypertrophy. RSG stimulates cardiac hypertrophy and oxidative stress in cardiomyocyte-specific PPARγ knockout mice, implying that RSG might stimulate cardiac hypertrophy independently of cardiomyocyte PPARγ...
October 6, 2016: JCI Insight
Joshua I Siner, Benjamin J Samelson-Jones, Julie M Crudele, Robert A French, Benjamin J Lee, Shanzhen Zhou, Elizabeth Merricks, Robin Raymer, Timothy C Nichols, Rodney M Camire, Valder R Arruda
Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645-1648) in the design of B-domain-deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity...
October 6, 2016: JCI Insight
Ehsan Azimi, Vemuri B Reddy, Kai-Ting C Shade, Robert M Anthony, Sebastien Talbot, Paula Juliana Seadi Pereira, Ethan A Lerner
The challenge of translating findings from animal models to the clinic is well known. An example of this challenge is the striking effectiveness of neurokinin-1 receptor (NK-1R) antagonists in mouse models of inflammation coupled with their equally striking failure in clinical investigations in humans. Here, we provide an explanation for this dichotomy: Mas-related GPCRs (Mrgprs) mediate some aspects of inflammation that had been considered mediated by NK-1R. In support of this explanation, we show that conventional NK-1R antagonists have off-target activity on the mouse receptor MrgprB2 but not on the homologous human receptor MRGPRX2...
October 6, 2016: JCI Insight
Epameinondas Gousopoulos, Steven T Proulx, Samia B Bachmann, Jeannette Scholl, Dimitris Dionyssiou, Efterpi Demiri, Cornelia Halin, Lothar C Dieterich, Michael Detmar
Secondary lymphedema is a common postcancer treatment complication, but the underlying pathological processes are poorly understood and no curative treatment exists. To investigate lymphedema pathomechanisms, a top-down approach was applied, using genomic data and validating the role of a single target. RNA sequencing of lymphedematous mouse skin indicated upregulation of many T cell-related networks, and indeed depletion of CD4(+) cells attenuated lymphedema. The significant upregulation of Foxp3, a transcription factor specifically expressed by regulatory T cells (Tregs), along with other Treg-related genes, implied a potential role of Tregs in lymphedema...
October 6, 2016: JCI Insight
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
Esophageal squamous cell carcinoma (ESCC) is endemic in regions of sub-Saharan Africa (SSA), where it is the third most common cancer. Here, we describe whole-exome tumor/normal sequencing and RNA transcriptomic analysis of 59 patients with ESCC in Malawi. We observed similar genetic aberrations as reported in Asian and North American cohorts, including mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1, and FBXW7. Analyses for nonhuman sequences did not reveal evidence for infection with HPV or other occult pathogens...
October 6, 2016: JCI Insight
Alexandre Kauskot, Sonia Poirault-Chassac, Frédéric Adam, Vincent Muczynski, Gabriel Aymé, Caterina Casari, Jean-Claude Bordet, Christelle Soukaseum, Chantal Rothschild, Valérie Proulle, Audrey Pietrzyk-Nivau, Eliane Berrou, Olivier D Christophe, Jean-Philippe Rosa, Peter J Lenting, Marijke Bryckaert, Cécile V Denis, Dominique Baruch
von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ibα and alter the protein's multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p...
October 6, 2016: JCI Insight
Sarah A Comerford, Elizabeth A Hinnant, Yidong Chen, Hima Bansal, Shawn Klapproth, Dinesh Rakheja, Milton J Finegold, Dolores Lopez-Terrada, Kathryn A O'Donnell, Gail E Tomlinson, Robert E Hammer
Aberrant wnt/β-catenin signaling and amplification/overexpression of Myc are associated with hepatoblastoma (HB), the most prevalent type of childhood liver cancer. To address their roles in the pathogenesis of HB, we generated mice in which Myc and mutant β-catenin were targeted to immature cells of the developing mouse liver. Perinatal coexpression of both genes promoted the preferential development of HBs over other tumor types in neonatal mice, all of which bore striking resemblance to their human counterparts...
October 6, 2016: JCI Insight
Andrew R Osterburg, Rebecca L Nelson, Benyamin Z Yaniv, Rachel Foot, Walter R F Donica, Madison A Nashu, Huan Liu, Kathryn A Wikenheiser-Brokamp, Joel Moss, Nishant Gupta, Francis X McCormack, Michael T Borchers
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules...
October 6, 2016: JCI Insight
Jennifer K Roe, Niclas Thomas, Eliza Gil, Katharine Best, Evdokia Tsaliki, Stephen Morris-Jones, Sian Stafford, Nandi Simpson, Karolina D Witt, Benjamin Chain, Robert F Miller, Adrian Martineau, Mahdad Noursadeghi
BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB...
October 6, 2016: JCI Insight
Kerstin Renner, Sonja Hellerbrand, Fabian Hermann, Christine Riedhammer, Yvonne Talke, Gabriela Schiechl, Manuel Rodriguez Gomez, Simone Kutzi, Dagmar Halbritter, Nicole Goebel, Hilke Brühl, Robert Weissert, Matthias Mack
Little is known about the role of IL-3 in multiple sclerosis (MS) in humans and in experimental autoimmune encephalomyelitis (EAE). Using myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE, we show that CD4(+) T cells are the main source of IL-3 and that cerebral IL-3 expression correlates with the influx of T cells into the brain. Blockade of IL-3 with monoclonal antibodies, analysis of IL-3 deficient mice, and adoptive transfer of leukocytes demonstrate that IL-3 plays an important role for development of clinical symptoms of EAE, for migration of leukocytes into the brain, and for cerebral expression of adhesion molecules and chemokines...
October 6, 2016: JCI Insight
Carrie E McCurdy, Simon Schenk, Byron Hetrick, Julie Houck, Brian G Drew, Spencer Kaye, Melanie Lashbrook, Bryan C Bergman, Diana L Takahashi, Tyler A Dean, Travis Nemkov, Ilya Gertsman, Kirk C Hansen, Andrew Philp, Andrea L Hevener, Adam J Chicco, Kjersti M Aagaard, Kevin L Grove, Jacob E Friedman
Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation...
October 6, 2016: JCI Insight
Julian Mackay-Wiggan, Ali Jabbari, Nhan Nguyen, Jane E Cerise, Charlotte Clark, Grace Ulerio, Megan Furniss, Roger Vaughan, Angela M Christiano, Raphael Clynes
BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA. METHODS...
September 22, 2016: JCI Insight
Milène Kennedy Crispin, Justin M Ko, Brittany G Craiglow, Shufeng Li, Gautam Shankar, Jennifer R Urban, James C Chen, Jane E Cerise, Ali Jabbari, Mårten C G Winge, M Peter Marinkovich, Angela M Christiano, Anthony E Oro, Brett A King
BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8(+) T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined. METHODS: This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU)...
September 22, 2016: JCI Insight
Megan S Inkeles, Rosane M B Teles, Delila Pouldar, Priscila R Andrade, Cressida A Madigan, David Lopez, Mike Ambrose, Mahdad Noursadeghi, Euzenir N Sarno, Thomas H Rea, Maria T Ochoa, M Luisa Iruela-Arispe, William R Swindell, Tom H M Ottenhoff, Annemieke Geluk, Barry R Bloom, Matteo Pellegrini, Robert L Modlin
Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution...
September 22, 2016: JCI Insight
Mei Hua Gao, Dimosthenis Giamouridis, N Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, H Kirk Hammond
Using mice rendered insulin resistant with high fat diets (HFD), we examined blood glucose levels and insulin resistance after i.v. delivery of an adeno-associated virus type 8 encoding murine urocortin 2 (AAV8.UCn2). A single i.v. injection of AAV8.UCn2-normalized blood glucose and glucose disposal within weeks, an effect that lasted for months. Hyperinsulinemic-euglycemic clamps showed reduced plasma insulin, increased glucose disposal rates, and increased insulin sensitivity following UCn2 gene transfer...
September 22, 2016: JCI Insight
Mark Wunderlich, Courtney Stockman, Mahima Devarajan, Navin Ravishankar, Christina Sexton, Ashish R Kumar, Benjamin Mizukawa, James C Mulloy
Transgenic expression of key myelosupportive human cytokines in immune-deficient mice corrects for the lack of cross-species activities of stem cell factor (SCF), IL-3, and GM-CSF. When engrafted with human umbilical cord blood (UCB), these triple-transgenic mice produce BM and spleen grafts with much higher myeloid composition, relative to nontransgenic controls. Shortly after engraftment with UCB, these mice develop a severe, fatal macrophage activation syndrome (MAS) characterized by a progressive drop in rbc numbers, increased reticulocyte counts, decreased rbc half-life, progressive cytopenias, and evidence of chronic inflammation, including elevated human IL-6...
September 22, 2016: JCI Insight
Matthieu Rousseau, H M Sharon Goh, Sarah Holec, Matthew L Albert, Rohan B H Williams, Molly A Ingersoll, Kimberly A Kline
Catheter-associated urinary tract infections (CAUTI) are the most common hospital-associated infections. Here, we report that bladder catheterization initiated a persistent sterile inflammatory reaction within minutes of catheter implantation. Catheterization resulted in increased expression of genes associated with defense responses and cellular migration, with ensuing rapid and sustained innate immune cell infiltration into the bladder. Catheterization also resulted in hypersensitivity to Enterococcus faecalis and uropathogenic Escherichia coli (UPEC) infection, in which colonization was achieved using an inoculum 100-fold lower than the ID90 for infection of an undamaged urothelium with the same uropathogens...
September 22, 2016: JCI Insight
Zakariae Bram, Estelle Louiset, Bruno Ragazzon, Sylvie Renouf, Julien Wils, Céline Duparc, Isabelle Boutelet, Marthe Rizk-Rabin, Rossella Libé, Jacques Young, Dennis Carson, Marie-Christine Vantyghem, Eva Szarek, Antoine Martinez, Constantine A Stratakis, Jérôme Bertherat, Hervé Lefebvre
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters...
September 22, 2016: JCI Insight
Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh-Hei Sonoda
Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog-mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation...
September 22, 2016: JCI Insight
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