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Journal of Clinical Investigation

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https://www.readbyqxmd.com/read/28805663/yap-taz-regulates-sprouting-angiogenesis-and-vascular-barrier-maturation
#1
Jongshin Kim, Yoo Hyung Kim, Jaeryung Kim, Do Young Park, Hosung Bae, Da-Hye Lee, Kyun Hoo Kim, Seon Pyo Hong, Seung Pil Jang, Yoshiaki Kubota, Young-Guen Kwon, Dae-Sik Lim, Gou Young Koh
Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28805662/clinical-and-immunological-responses-after-cd30-specific-chimeric-antigen-receptor-redirected-lymphocytes
#2
Carlos A Ramos, Brandon Ballard, Huimin Zhang, Olga Dakhova, Adrian P Gee, Zhuyong Mei, Mrinalini Bilgi, Meng-Fen Wu, Hao Liu, Bambi Grilley, Catherine M Bollard, Bill H Chang, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop, Gianpietro Dotti, Barbara Savoldo
BACKGROUND: Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS: We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28805661/the-foxn3-neat1-sin3a-repressor-complex-promotes-progression-of-hormonally-responsive-breast-cancer
#3
Wanjin Li, Zihan Zhang, Xinhua Liu, Xiao Cheng, Yi Zhang, Xiao Han, Yu Zhang, Shumeng Liu, Jianguo Yang, Bosen Xu, Lin He, Luyang Sun, Jing Liang, Yongfeng Shang
The pathophysiological function of the forkhead transcription factor FOXN3 remains to be explored. Here we report that FOXN3 is a transcriptional repressor that is physically associated with the SIN3A repressor complex in estrogen receptor-positive (ER+) cells. RNA immunoprecipitation-coupled high-throughput sequencing identified that NEAT1, an estrogen-inducible long noncoding RNA, is required for FOXN3 interactions with the SIN3A complex. ChIP-Seq and deep sequencing of RNA genomic targets revealed that the FOXN3-NEAT1-SIN3A complex represses genes including GATA3 that are critically involved in epithelial-to-mesenchymal transition (EMT)...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28805660/prolyl-hydroxylase-2-inactivation-enhances-glycogen-storage-and-promotes-excessive-neutrophilic-responses
#4
Pranvera Sadiku, Joseph A Willson, Rebecca S Dickinson, Fiona Murphy, Alison J Harris, Amy Lewis, David Sammut, Ananda S Mirchandani, Eilise Ryan, Emily R Watts, A A Roger Thompson, Helen M Marriott, David H Dockrell, Cormac T Taylor, Martin Schneider, Patrick H Maxwell, Edwin R Chilvers, Massimilliano Mazzone, Veronica Moral, Chris W Pugh, Peter J Ratcliffe, Christopher J Schofield, Bart Ghesquiere, Peter Carmeliet, Moira Kb Whyte, Sarah R Walmsley
Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28805659/the-atypical-antipsychotic-olanzapine-causes-weight-gain-by-targeting-serotonin-receptor-2c
#5
Caleb C Lord, Steven C Wyler, Rong Wan, Carlos M Castorena, Newaz Ahmed, Dias Mathew, Syann Lee, Chen Liu, Joel K Elmquist
Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C)...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783046/epiregulin-and-egfr-interactions-are-involved-in-pain-processing
#6
Loren J Martin, Shad B Smith, Arkady Khoutorsky, Claire A Magnussen, Alexander Samoshkin, Robert E Sorge, Chulmin Cho, Noosha Yosefpour, Sivaani Sivaselvachandran, Sarasa Tohyama, Tiffany Cole, Thang M Khuong, Ellen Mir, Dustin G Gibson, Jeffrey S Wieskopf, Susana G Sotocinal, Jean Sebastien Austin, Carolina B Meloto, Joseph H Gitt, Christos Gkogkas, Nahum Sonenberg, Joel D Greenspan, Roger B Fillingim, Richard Ohrbach, Gary D Slade, Charles Knott, Ronald Dubner, Andrea G Nackley, Alfredo Ribeiro-da-Silva, G Gregory Neely, William Maixner, Dmitri V Zaykin, Jeffrey S Mogil, Luda Diatchenko
The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9...
August 7, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783045/macrophage-derived-il-10-mediates-mucosal-repair-by-epithelial-wisp-1-signaling
#7
Miguel Quiros, Hikaru Nishio, Philipp A Neumann, Dorothee Siuda, Jennifer C Brazil, Veronica Azcutia, Roland Hilgarth, Monique N O'Leary, Vicky Garcia-Hernandez, Giovanna Leoni, Mingli Feng, Gabriela Bernal, Holly Williams, Priya H Dedhia, Christian Gerner-Smidt, Jason Spence, Charles A Parkos, Timothy L Denning, Asma Nusrat
In response to injury, epithelial cells migrate and proliferate to cover denuded mucosal surfaces and repair the barrier defect. This process is orchestrated by dynamic crosstalk between immune cells and the epithelium; however, the mechanisms involved remain incompletely understood. Here, we report that IL-10 was rapidly induced following intestinal mucosal injury and was required for optimal intestinal mucosal wound closure. Conditional deletion of IL-10 specifically in CD11c-expressing cells in vivo implicated macrophages as a critical innate immune contributor to IL-10-induced wound closure...
August 7, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783044/phenotypic-and-pharmacogenetic-evaluation-of-patients-with-thiazide-induced-hyponatremia
#8
James S Ware, Louise V Wain, Sarath K Channavajjhala, Victoria E Jackson, Elizabeth Edwards, Run Lu, Keith Siew, Wenjing Jia, Nick Shrine, Sue Kinnear, Mahli Jalland, Amanda P Henry, Jenny Clayton, Kevin M O'Shaughnessy, Martin D Tobin, Victor Schuster, Stuart Cook, Ian P Hall, Mark Glover
Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone...
August 7, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783043/nbeal2-is-required-for-neutrophil-and-nk-cell-function-and-pathogen-defense
#9
John M Sowerby, David C Thomas, Simon Clare, Marion Espéli, Jose A Guerrero, Kim Hoenderdos, Katherine Harcourt, Morgan Marsden, Juneid Abdul-Karim, Mathew Clement, Robin Antrobus, Yagnesh Umrania, Philippa R Barton, Shaun M Flint, Jatinder K Juss, Alison M Condliffe, Paul A Lyons, Ian R Humphreys, Edwin R Chilvers, Willem H Ouwehand, Gordon Dougan, Kenneth Gc Smith
Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells...
August 7, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783042/inborn-errors-in-rna-polymerase-iii-underlie-severe-varicella-zoster-virus-infections
#10
Benson Ogunjimi, Shen-Ying Zhang, Katrine B Sørensen, Kristian A Skipper, Madalina Carter-Timofte, Gaspard Kerner, Stefanie Luecke, Thaneas Prabakaran, Yujia Cai, Josephina Meester, Esther Bartholomeus, Nikhita Ajit Bolar, Geert Vandeweyer, Charlotte Claes, Yasmine Sillis, Lazaro Lorenzo, Raffaele A Fiorenza, Soraya Boucherit, Charlotte Dielman, Steven Heynderickx, George Elias, Andrea Kurotova, Ann Vander Auwera, Lieve Verstraete, Lieven Lagae, Helene Verhelst, Anna Jansen, Jose Ramet, Arvid Suls, Evelien Smits, Berten Ceulemans, Lut Van Laer, Genevieve Plat Wilson, Jonas Kreth, Capucine Picard, Horst Von Bernuth, Joël Fluss, Stephane Chabrier, Laurent Abel, Geert Mortier, Sebastien Fribourg, Jacob Giehm Mikkelsen, Jean-Laurent Casanova, Søren R Paludan, Trine H Mogensen
Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III...
August 7, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783041/27-hydroxycholesterol-induces-hematopoietic-stem-cell-mobilization-and-extramedullary-hematopoiesis-during-pregnancy
#11
Hideyuki Oguro, Jeffrey G McDonald, Zhiyu Zhao, Michihisa Umetani, Philip W Shaul, Sean J Morrison
Extramedullary hematopoiesis (EMH) is induced during pregnancy to support rapid expansion of maternal blood volume. EMH activation requires hematopoietic stem cell (HSC) proliferation and mobilization, processes that depend upon estrogen receptor α (ERα) in HSCs. Here we show that treating mice with estradiol to model estradiol increases during pregnancy induced HSC proliferation in the bone marrow but not HSC mobilization. Treatment with the alternative ERα ligand 27-hydroxycholesterol (27HC) induced ERα-dependent HSC mobilization and EMH but not HSC division in the bone marrow...
August 7, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758906/activin-a-enhances-mtor-signaling-to-promote-aberrant-chondrogenesis-in-fibrodysplasia-ossificans-progressiva
#12
Kyosuke Hino, Kazuhiko Horigome, Megumi Nishio, Shingo Komura, Sanae Nagata, Chengzhu Zhao, Yonghui Jin, Koichi Kawakami, Yasuhiro Yamada, Akira Ohta, Junya Toguchida, Makoto Ikeya
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758905/neuropeptide-ff-increases-m2-activation-and-self-renewal-of-adipose-tissue-macrophages
#13
Syed F Hassnain Waqas, Anh Cuong Hoang, Ya-Tin Lin, Grace Ampem, Hind Azegrouz, Lajos Balogh, Julianna Thuróczy, Jin-Chung Chen, Ivan C Gerling, Sorim Nam, Jong-Seok Lim, Juncal Martinez-Ibañez, José T Real, Stephan Paschke, Raphaëlle Quillet, Safia Ayachi, Frédéric Simonin, E Marion Schneider, Jacqueline A Brinkman, Dudley W Lamming, Christine M Seroogy, Tamás Röszer
No abstract text is available yet for this article.
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758904/parathyroid-hormone-regulates-fates-of-murine-osteoblast-precursors-in-vivo
#14
Deepak H Balani, Noriaki Ono, Henry M Kronenberg
Teriparatide, a recombinant form of parathyroid hormone (PTH), is the only approved treatment for osteoporosis that increases the rate of bone formation. Teriparatide increases osteoblast numbers by suppressing osteoblast apoptosis and activating bone-lining cells. No direct evidence for teriparatide's actions on early cells of the osteoblast lineage has been demonstrated. Here, we have employed a lineage-tracing strategy that uses a tamoxifen-dependent, promoter-driven cre to mark early cells of the osteoblast lineage in adult mice...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758903/transcriptional-control-of-microglia-phenotypes-in-health-and-disease
#15
Inge R Holtman, Dylan Skola, Christopher K Glass
Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758902/gata4-loss-of-function-in-liver-cancer-impedes-precursor-to-hepatocyte-transition
#16
Francis O Enane, Wai Ho Shuen, Xiaorong Gu, Ebrahem Quteba, Bartlomiej Przychodzen, Hideki Makishima, Juraj Bodo, Joanna Ng, Chit Lai Chee, Rebecca Ba, Lip Seng Koh, Janice Lim, Rachael Cheong, Marissa Teo, Zhenbo Hu, Kwok Peng Ng, Jaroslaw Maciejewski, Tomas Radivoyevitch, Alexander Chung, London Lucien Ooi, Yu Meng Tan, Peng Chung Cheow, Pierce Chow, Chung Yip Chan, Kiat Hon Lim, Lisa Yerian, Eric Hsi, Han Chong Toh, Yogen Saunthararajah
The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758901/stromal-cell-cadherin-11-regulates-adipose-tissue-inflammation-and-diabetes
#17
Sook Kyung Chang, Ayano C Kohlgruber, Fumitaka Mizoguchi, Xavier Michelet, Benjamin J Wolf, Kevin Wei, Pui Y Lee, Lydia Lynch, Danielle Duquette, Victòria Ceperuelo-Mallafré, Alexander S Banks, Michael B Brenner
M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28758900/tnf-is-required-for-tlr-ligand-mediated-but-not-protease-mediated-allergic-airway-inflammation
#18
Gregory S Whitehead, Seddon Y Thomas, Karim H Shalaby, Keiko Nakano, Timothy P Moran, James M Ward, Gordon P Flake, Hideki Nakano, Donald N Cook
Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28737515/cell-biology-of-spinal-cord-injury-and-repair
#19
Timothy M O'Shea, Joshua E Burda, Michael V Sofroniew
Spinal cord injury (SCI) lesions present diverse challenges for repair strategies. Anatomically complete injuries require restoration of neural connectivity across lesions. Anatomically incomplete injuries may benefit from augmentation of spontaneous circuit reorganization. Here, we review SCI cell biology, which varies considerably across three different lesion-related tissue compartments: (a) non-neural lesion core, (b) astrocyte scar border, and (c) surrounding spared but reactive neural tissue. After SCI, axon growth and circuit reorganization are determined by neuron-cell-autonomous mechanisms and by interactions among neurons, glia, and immune and other cells...
July 24, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28737506/microglia-and-c9orf72-in-neuroinflammation-and-als-and-frontotemporal-dementia
#20
Deepti Lall, Robert H Baloh
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease...
July 24, 2017: Journal of Clinical Investigation
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