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Journal of Clinical Investigation
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A new batch of articles is now available online at
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August 2015 issue published:
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Pharmacological inhibition of PTP1B ameliorates Rett syndrome in mice
Rett syndrome is an X-linked neurodevelopmental disorder predominately caused by mutations of the methyl CpG-binding protein 2 (MECP2). Navasona Krishnan and colleagues demonstrate that PTPN1, which encodes the phosphatase PTP1B, is a direct target of MECP2 and that PTP1B levels were markedly increased in both Mecp2-mutant mice and Rett syndrome patient fibroblasts. Treatment with PTP1B inhibitors increased the lifespan of male Rett mice (Mecp2-/y) and improved the performance of female Rett mice (Mecp2-/+) in behavioral assays. Mechanistically, PTP1B inhibition enhanced phosphorylation of tropomyosin receptor kinase B (TRKB), which mediates brain-derived neurotrophic factor signaling. In the accompanying commentary, Lutz Tautz discusses how these results indicate that PTP1B inhibition is a potential therapeutic strategy for the treatment of Rett syndrome.
Read the article in JCI: http://buff.ly/1JDBisU
Read the accompanying commentary: http://buff.ly/1JDBgBp #ResearchArticle #Neuroscience
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Repairing broken bones
Every year, millions of patients suffer bone fractures and a proportion of these heal improperly, resulting in pain and loss of function. Fibrin matrices form at the fracture site and are thought to support the early stages of bone formation and repair. However, excess fibrin accumulation impairs wound healing and was recently shown to promote inflammatory osteoporosis in mice. Masato Yuasa, Nicholas Mignemi, and colleagues at Vanderbilt University Medical Center determined that fibrin deposition is not required for fracture repair, but clearance of fibrin is critical for the healing process.
Read the Scientific Show Stopper in JCI: http://buff.ly/1emkUUN #ScientificShowStopper #BoneBiology
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Epigenetic marks distinguish liposarcoma subtypes
Liposarcoma (LPS) is a common form of soft tissue sarcoma that can be divided into four subtypes, with well differentiated (WDLPS) and dedifferentiated (DDLPS) being the most common. Emily Keung and colleagues examined the contribution of epigenetic modifications to the development of these two subtypes by profiling nine epigenetic marks in 151 patients. They found that DDLPS tumors exhibited elevated levels of trimethylated lysine-9 on histone 3 (H3K9me3). Integrated chromatin immunoprecipitation-sequencing and gene expression analyses revealed that increased H3K9me3 levels decreased expression of genes involved in cellular migration and differentiation, including Krüppel-like factor 6 (KLF6). Pharmacological inhibition of H3K9 methylation decreased DDLPS proliferation and increased factors that mediate adipogenesis. These effects were partially replicated by overexpression of KLF6 (see the accompanying image). These data indicate that epigenetic changes may underlie the transition between WDLPS and DDLPS.
Read the article in JCI: http://buff.ly/1gFpMGD #ResearchArticle #Oncology
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A cause for genetic instability in uterine leiomyomas
Uterine leiomyomas are benign, monoclonal tumors that are the single largest cause of hysterectomy. Leiomyomas frequently have karyotypic abnormalities. Additionally, whole exome sequencing has identified a number of heterozygous somatic mutations in mediator complex subunit 12 (MED12), which occur in roughly 70% of patients. Priya Mittal, Yong-hyun Shin, and colleagues examined the role of MED12 in the pathogenesis of leiomyoma by generating a mouse model that conditionally expresses a common Med12 missense variant, Med12 c. 131G>A. Expression of this variant caused leiomyomas and hyperplasia on either a WT or Med12 knockout background. Leiomyomas induced by mutant MED12 developed chromosomal rearrangements similar to those seen in human leiomyomas. The accompanying image shows uteri from control mice (left) and mice expressing Med12 c. 131G>A (right).
Read the article in JCI: http://buff.ly/1MfqVkU #BriefReport #Genetics
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Targeting myofibroblast proliferation in kidney fibrosis
Interstitial fibrosis is a key feature of chronic kidney disease (CKD), a process mediated by myofibroblasts, whichsecrete matrix proteins. The hedgehog signaling pathway transcription factors GLI1 and GLI2 are expressed in myofibroblast progenitors, but their role in fibrosis is not well understood. Using murine models of kidney disease, Rafael Kramann and colleagues demonstrate that GLI2, but not GLI1, drives cell cycle proliferation in myofibroblasts. Either selective knockout of Gli2 or suppression of the hedgehog pathway through expression of the transcriptional repressor GLI3 in myofibroblast progenitors induced cell cycle arrest and abrogated fibrosis. Additionally, treatment with darinaparsin, an agent that is currently in clinical trials as an anti-neoplastic agent, reduced GLI2 protein levels to promote cell cycle arrest and reduce fibrosis (see the accompanying image). Kramann and colleagues found that GLI1 and GLI2 are overexpressed in human kidney fibrosis, indicating that GLI2 may be a suitable therapeutic target in CKD.
Read the article in JCI: http://buff.ly/1J5ocIY #ResearchArticle #Nephrology
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Cardiospheres direct myocardial macrophages to a cardioprotective phenotype

Cardiospheres are self-assembling, multicellular clusters that contain primitive, proliferating cells, mesenchymal/stromal cells, and differentiating cells that express cardiomyocyte proteins. Administration of cardiosphere-derived cells (CDCs) reduces infarct size and improves cardiac function after myocardial infarction (MI) in both humans and animal models. Using a rat model of ischemia/reperfusion-induced MI, Geoffrey de Couto and colleagues found that CDCs modify the myocardial leukocyte population, reducing the number of CD68+ macrophages and polarizing macrophages to a specific cardioprotective phenotype; clodronate-mediated depletion of macrophages abolished the protective effects of CDCs. Moreover, adoptive transfer of macrophages exposed to CDC-conditioned media recapitulated the affects of CDC administration (see the accompanying image), indicating that CDCs secrete factors that mediate macrophage polarization. In the accompanying commentary, Nikolaos Frangogiannis discusses how these studies demonstrate a critical role for macrophages in mediating CDC-induced cardioprotection.
Read the article in JCI: http://buff.ly/1JDBFnr
Read the accompanying commentary: http://buff.ly/1JDBFns #ResearchArticle #Cardiology
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GATA2 serves as a lymphatic rheostat
Emberger syndrome is a rare blood disorder that results in a variety of clinical outcomes and is characterized by lymphedema and a predisposition for acute myeloid leukemia. Loss-of-function mutations in transcription factor GATA2 are causative of Emberger syndrome, implicating GATA2 activity in the regulation of lymphatic vasculature development and valve maturation. GATA2 mutations are also associated with several other hematological disorders that do not result in lymphedema, suggesting differential targets and regulation of GATA2-dependent genes in the lymphatic and hematological compartments. Jan Kazenwadel, Kelly Betterman, and colleagues at the University of South Australia demonstrate that Emberger-associated GATA2 mutations result in lymphovenous valve dysfunction. GATA2 directly regulated the transcription factors PROX1 and FOXC2, both of which are required for lymphovenous valve development.
Read the Scientific Show Stopper in JCI: http://buff.ly/1OqV0M8 #ScientificShowStopper #VascularBiology
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Lymphatic valves grow with the flow
The flow of fluids along a boundary, such as occurs at the inner lining of vascular tissue, produces shear stress force. Fluid shear forces influence several developmental and pathological processes, including cardiovascular development and atherosclerosis. The lymphatic vascular system is a low-pressure, low-flow system that carries lymph through an intricate network of vessels to the venous system. As primary lymphatic vessels mature into collecting vessels, they develop valves that prevent lymph backflow. Daniel Sweet and colleagues at the University of Pennsylvania determined that proper flow of lymph is required to initiate the transcriptional program in lymphatic endothelial cells (LECs) that directs lymphatic vessel maturation.
Read the Scientific Show Stopper in JCI: http://buff.ly/1MpM4Ir #ScientificShowStopper #VascularBiology
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Drug provides long-term benefit for patients with type 1 diabetes
Type 1 diabetes (T1D) results from destruction of insulin-producing ß cells of the pancreas Daily insulin injections are required to manage T1D-associated symptoms. However, effective treatments are urgently needed to preserve insulin production during disease progression. A new study in the Journal of Clinical Investigation indicates that the immunosuppressant drug alefacept has the potential to provide long-lasting clinical benefit to patients with T1D. Mark Rigby and colleagues in conjunction with the Immune Tolerance Network (ITN) T1DAL Study Group evaluated long-term clinical responses in T1D patients given alefacept at the onset of disease. Patients treated with alefacept soon after their T1D diagnosis showed clinical benefits, including preserved insulin production and fewer incidents of major hypoglycemia compared to the placebo group. These therapeutic responses were present even 15 months after drug treatment. Treated individuals also had prolonged changes in the immune system, including a lower number of the immune cells thought to be responsible for ß cell production. The results of this study suggest that alefacept should be further explored for treatment of individuals with T1D.
Read the article in JCI: http://buff.ly/1DljNvp #ClinicalMedicine #ClinicalTrials
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62 people
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Anne Wright's profile photo
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Kaitlin Emmons's profile photo
CarDia X's profile photo
Cure Brain Cancer Foundation's profile photo
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Premiere venue for discoveries in basic and clinical biomedical science.
Introduction
The Journal of Clinical Investigation (JCI) is a top-tier venue for discoveries in basic and clinical biomedical research that will advance the practice of medicine. Founded in 1924, the journal is published by the American Society for Clinical Investigation (ASCI) and has a 2013 Impact Factor of 13.765. Since 2012, the JCI has been headed by Dr. Howard A. Rockman, Editor, with an Editorial Board of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. The JCI provides free access to all of its research articles.