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https://www.readbyqxmd.com/read/28931765/a-type-of-human-skin-dendritic-cell-marked-by-cd5-is-associated-with-the-development-of-inflammatory-skin-disease
#1
Daniel Korenfeld, Laurent Gorvel, Adiel Munk, Joshua Man, Andras Schaffer, Thomas Tung, Caroline Mann, Eynav Klechevsky
Dendritic cells (DCs) are important in regulating immunity and tolerance and consist of functionally distinct subsets that differentially regulate T lymphocyte function. The underlying basis for this subset specificity is lacking, particularly in humans, where the classification of tissue DCs is currently incomplete. Examination of healthy human epidermal Langerhans cells and dermal skin cells revealed a tissue CD5-expressing DC subtype. The CD5+ DCs were potent inducers of cytotoxic T cells and Th22 cells...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931764/functional-correction-of-dystrophin-actin-binding-domain-mutations-by-genome-editing
#2
Viktoriia Kyrychenko, Sergii Kyrychenko, Malte Tiburcy, John M Shelton, Chengzu Long, Jay W Schneider, Wolfram-Hubertus Zimmermann, Rhonda Bassel-Duby, Eric N Olson
Dystrophin maintains the integrity of striated muscles by linking the actin cytoskeleton with the cell membrane. Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD) that result in progressive, debilitating muscle weakness, cardiomyopathy, and a shortened lifespan. Mutations of dystrophin that disrupt the amino-terminal actin-binding domain 1 (ABD-1), encoded by exons 2-8, represent the second-most common cause of DMD. In the present study, we compared three different strategies for CRISPR/Cas9 genome editing to correct mutations in the ABD-1 region of the DMD gene by deleting exons 3-9, 6-9, or 7-11 in human induced pluripotent stem cells (iPSCs) and by assessing the function of iPSC-derived cardiomyocytes...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931763/reversible-retinal-vessel-closure-from-vegf-induced-leukocyte-plugging
#3
Yuanyuan Liu, Jikui Shen, Seth D Fortmann, Jiangxia Wang, Dietmar Vestweber, Peter A Campochiaro
Clinical trials in patients with macular edema due to diabetic retinopathy or retinal vein occlusion (RVO) have shown that suppression of VEGF not only improves macular edema, but also reopens closed retinal vessels, prevents progression of vessel closure, and improves retinopathy. In this study, we show the molecular basis for those clinical observations. Increased retinal levels of VEGF in mice cause plugging of retinal vessels with leukocytes, vessel closure, and hypoxia. Suppression of VEGF reduces leukocyte plugging, causing reperfusion of closed vessels...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931762/emerging-therapies-for-acute-myeloid-leukemia-translating-biology-into-the-clinic
#4
REVIEW
Simon Kavanagh, Tracy Murphy, Arjun Law, Dana Yehudai, Jenny M Ho, Steve Chan, Aaron D Schimmer
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor outcome; overall survival is approximately 35% at two years and some subgroups have a less than 5% two-year survival. Recently, significant improvements have been made in our understanding of AML biology and genetics. These fundamental discoveries are now being translated into new therapies for this disease. This review will discuss recent advances in AML biology and the emerging treatments that are arising from biological studies...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931761/periodontal-induced-chronic-inflammation-triggers-macrophage-secretion-of-ccl12-to-inhibit-fibroblast-mediated-cardiac-wound-healing
#5
Kristine Y DeLeon-Pennell, Rugmani Padmanabhan Iyer, Osasere K Ero, Courtney A Cates, Elizabeth R Flynn, Presley L Cannon, Mira Jung, De'Aries Shannon, Michael R Garrett, William Buchanan, Michael E Hall, Yonggang Ma, Merry L Lindsey
Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931760/inflammation-oxidative-stress-and-glial-cell-activation-characterize-stellate-ganglia-from-humans-with-electrical-storm
#6
Olujimi A Ajijola, Donald B Hoover, Thomas M Simerly, T Christopher Brown, Jane Yanagawa, Reshma M Biniwale, Jay M Lee, Ali Sadeghi, Negar Khanlou, Jeffrey L Ardell, Kalyanam Shivkumar
BACKGROUND: Neuronal remodeling in human heart disease is not well understood. METHODS: Stellate ganglia from patients with cardiomyopathy (CMY) and refractory ventricular arrhythmias undergoing cardiac sympathetic denervation (n = 8), and from organ donors with normal hearts (n = 8) collected at the time of organ procurement were compared. Clinical data on all subjects were reviewed. Electron microscopy (EM), histologic, and immunohistochemical assessments of neurotransmitter profiles, glial activation and distribution, and lipofuscin deposition, a marker of oxidative stress, were quantified...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931759/combination-immunotherapy-with-tlr-agonists-and-checkpoint-inhibitors-suppresses-head-and-neck-cancer
#7
Fumi Sato-Kaneko, Shiyin Yao, Alast Ahmadi, Shannon S Zhang, Tadashi Hosoya, Megan M Kaneda, Judith A Varner, Minya Pu, Karen S Messer, Cristiana Guiducci, Robert L Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Dennis A Carson, Tomoko Hayashi, Ezra Ew Cohen
Checkpoint inhibitors have demonstrated efficacy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, the majority of patients do not benefit from these agents. To improve the efficacy of checkpoint inhibitors, intratumoral (i.t.) injection with innate immune activators, TLR7 and TLR9 agonists, were tested along with programmed death-1 receptor (PD-1) blockade. The combination therapy suppressed tumor growth at the primary injected and distant sites in human papillomavirus-negative (HPV-negative) SCC7 and MOC1, and HPV-positive MEER syngeneic mouse models...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931758/molecular-characterization-of-the-transition-from-acute-to-chronic-kidney-injury-following-ischemia-reperfusion
#8
Jing Liu, Sanjeev Kumar, Egor Dolzhenko, Gregory F Alvarado, Jinjin Guo, Can Lu, Yibu Chen, Meng Li, Mark C Dessing, Riana K Parvez, Pietro E Cippà, A Michaela Krautzberger, Gohar Saribekyan, Andrew D Smith, Andrew P McMahon
Though an acute kidney injury (AKI) episode is associated with an increased risk of chronic kidney disease (CKD), the mechanisms determining the transition from acute to irreversible chronic injury are not well understood. To extend our understanding of renal repair, and its limits, we performed a detailed molecular characterization of a murine ischemia/reperfusion injury (IRI) model for 12 months after injury. Together, the data comprising RNA-sequencing (RNA-seq) analysis at multiple time points, histological studies, and molecular and cellular characterization of targeted gene activity provide a comprehensive profile of injury, repair, and long-term maladaptive responses following IRI...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931757/vista-comp-an-engineered-checkpoint-receptor-agonist-that-potently-suppresses-t-cell-mediated-immune-responses
#9
Aaron Prodeus, Aws Abdul-Wahid, Amanda Sparkes, Nicholas W Fischer, Marzena Cydzik, Nicholas Chiang, Mays Alwash, Alessandra Ferzoco, Nathalie Vacaresse, Michael Julius, Reginald M Gorczysnki, Jean Gariépy
V-domain immunoglobulin suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint ligand that functions to suppress T cell activity. The therapeutic potential of activating this immune checkpoint pathway to reduce inflammatory responses remains untapped, largely due to the inability to derive agonists targeting its unknown receptor. A dimeric construct of the IgV domain of VISTA (VISTA-Fc) was shown to suppress the activation of T cells in vitro. However, this effect required its immobilization on a solid surface, suggesting that VISTA-Fc may display limited efficacy as a VISTA-receptor agonist in vivo...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931756/monocyte-dysregulation-and-systemic-inflammation-during-pediatric-falciparum-malaria
#10
Katherine R Dobbs, Paula Embury, John Vulule, Peter S Odada, Bruce A Rosa, Makedonka Mitreva, James W Kazura, Arlene E Dent
BACKGROUND: Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood. METHODS: We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931755/combination-central-tolerance-and-peripheral-checkpoint-blockade-unleashes-antimelanoma-immunity
#11
Pearl Bakhru, Meng-Lei Zhu, Hsing-Hui Wang, Lee K Hong, Imran Khan, Maria Mouchess, Ajay S Gulati, Joshua Starmer, Yafei Hou, David Sailer, Sandra Lee, Fengmin Zhao, John M Kirkwood, Stergios Moschos, Lawrence Fong, Mark S Anderson, Maureen A Su
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931754/activated-signature-of-antiphospholipid-syndrome-neutrophils-reveals-potential-therapeutic-target
#12
Jason S Knight, He Meng, Patrick Coit, Srilakshmi Yalavarthi, Gautam Sule, Alex A Gandhi, Robert C Grenn, Levi F Mazza, Ramadan A Ali, Paul Renauer, Jonathan D Wren, Paula L Bockenstedt, Hui Wang, Daniel T Eitzman, Amr H Sawalha
Antiphospholipid antibodies, present in one-third of lupus patients, increase the risk of thrombosis. We recently reported a key role for neutrophils - neutrophil extracellular traps (NETs), in particular - in the thrombotic events that define antiphospholipid syndrome (APS). To further elucidate the role of neutrophils in APS, we performed a comprehensive transcriptome analysis of neutrophils isolated from patients with primary APS. Moreover, APS-associated venous thrombosis was modeled by treating mice with IgG prepared from APS patients, followed by partial restriction of blood flow through the inferior vena cava...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931753/ask1-dependent-endothelial-cell-activation-is-critical-in-ovarian-cancer-growth-and-metastasis
#13
Mingzhu Yin, Huanjiao Jenny Zhou, Jiqin Zhang, Caixia Lin, Hongmei Li, Xia Li, Yonghao Li, Haifeng Zhang, David G Breckenridge, Weidong Ji, Wang Min
We have recently reported that tumor-associated macrophages (TAMs) promote early transcoelomic metastasis of ovarian cancer by facilitating TAM-ovarian cancer cell spheroid formation. ASK1 is known to be important for macrophage activation and inflammation-mediated tumorigenesis. In the present study, we show that ASK1 deficiency attenuates TAM-spheroid formation and ovarian cancer progression in an orthotopic ovarian cancer model. Interestingly, ASK1 in stroma, but not in TAMs, is critical for peritoneal tumor growth of ovarian cancer...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931752/l-dopa-sensitizes-vasomotor-tone-by-modulating-the-vascular-alpha1-adrenergic-receptor
#14
Daiki Masukawa, Motokazu Koga, Anna Sezaki, Yuka Nakao, Yuji Kamikubo, Tatsuo Hashimoto, Yuki Okuyama-Oki, Aderemi Caleb Aladeokin, Fumio Nakamura, Utako Yokoyama, Hiromichi Wakui, Hiroshi Ichinose, Takashi Sakurai, Satoshi Umemura, Koichi Tamura, Yoshihiro Ishikawa, Yoshio Goshima
Blood pressure is regulated by extrinsic factors including noradrenaline, the sympathetic neurotransmitter that controls cardiovascular functions through adrenergic receptors. However, the fine-tuning system of noradrenaline signaling is relatively unknown. We here show that l-3,4-dihydroxyphenylalanine (L-DOPA), a precursor of catecholamines, sensitizes the vascular adrenergic receptor alpha1 (ADRA1) through activation of L-DOPA receptor GPR143. In WT mice, intravenous infusion of the ADRA1 agonist phenylephrine induced a transient elevation of blood pressure...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931751/essential-role-of-kir5-1-channels-in-renal-salt-handling-and-blood-pressure-control
#15
Oleg Palygin, Vladislav Levchenko, Daria V Ilatovskaya, Tengis S Pavlov, Oleh M Pochynyuk, Howard J Jacob, Aron M Geurts, Matthew R Hodges, Alexander Staruschenko
Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels Kir4.1 (Kcnj10) and Kir5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of Kir5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16-/-). SSKcnj16-/- rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28931750/adrenal-gipr-expression-and-chromosome-19q13-microduplications-in-gip-dependent-cushing-s-syndrome
#16
Anne-Lise Lecoq, Constantine A Stratakis, Say Viengchareun, Ronan Chaligné, Lucie Tosca, Vianney Deméocq, Mirella Hage, Annabel Berthon, Fabio R Faucz, Patrick Hanna, Hadrien-Gaël Boyer, Nicolas Servant, Sylvie Salenave, Gérard Tachdjian, Clovis Adam, Vanessa Benhamo, Eric Clauser, Anne Guiochon-Mantel, Jacques Young, Marc Lombès, Isabelle Bourdeau, Dominique Maiter, Antoine Tabarin, Jérôme Bertherat, Hervé Lefebvre, Wouter de Herder, Estelle Louiset, André Lacroix, Philippe Chanson, Jérôme Bouligand, Peter Kamenický
GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28878138/stereotyped-antibody-responses-target-posttranslationally-modified-gluten-in-celiac-disease
#17
Omri Snir, Xi Chen, Moriah Gidoni, M Fleur du Pré, Yuguang Zhao, Øyvind Steinsbø, Knut Ea Lundin, Gur Yaari, Ludvig M Sollid
The role of B cells and posttranslational modifications in pathogenesis of organ-specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2-modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28878137/cf-airway-smooth-muscle-transcriptome-reveals-a-role-for-pyk2
#18
Daniel P Cook, Ryan J Adam, Keyan Zarei, Benjamin Deonovic, Mallory R Stroik, Nicholas D Gansemer, David K Meyerholz, Kin Fai Au, David A Stoltz
Abnormal airway smooth muscle function can contribute to cystic fibrosis (CF) airway disease. We previously found that airway smooth muscle from newborn CF pigs had increased basal tone, an increased bronchodilator response, and abnormal calcium handling. Since CF pigs lack airway infection and inflammation at birth, these findings suggest intrinsic airway smooth muscle dysfunction in CF. In this study, we tested the hypothesis that CFTR loss in airway smooth muscle would produce a distinct set of changes in the airway smooth muscle transcriptome that we could use to develop novel therapeutic targets...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28878136/old-age-causes-de-novo-intracortical-bone-remodeling-and-porosity-in-mice
#19
Marilina Piemontese, Maria Almeida, Alexander G Robling, Ha-Neui Kim, Jinhu Xiong, Jeff D Thostenson, Robert S Weinstein, Stavros C Manolagas, Charles A O'Brien, Robert L Jilka
Decreased cortical thickness and increased cortical porosity are the key anatomic changes responsible for osteoporotic fractures in elderly women and men. The cellular basis of these changes is unbalanced endosteal and intracortical osteonal remodeling by the osteoclasts and osteoblasts that comprise the basic multicellular units (BMUs). Like humans, mice lose cortical bone with age, but unlike humans, this loss occurs in the face of sex steroid sufficiency. Mice are therefore an ideal model to dissect age-specific osteoporotic mechanisms...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28878135/rev-erb%C3%AE-ameliorates-heart-failure-through-transcription-repression
#20
Lilei Zhang, Rongli Zhang, Chih-Liang Tien, Ricky E Chan, Keiki Sugi, Chen Fu, Austin C Griffin, Yuyan Shen, Thomas P Burris, Xudong Liao, Mukesh K Jain
A cure for heart failure remains a major unmet clinical need, and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. The pathological remodeling of the myocardium has been associated with a stereotypical gene expression program, which had long been viewed as the consequence and not the driver of the disease until very recently. Despite the advance, there is no therapy available to reverse the already committed gene program. Here, we demonstrate that transcriptional repressor REV-ERB binds near driver transcription factors across the genome...
September 7, 2017: JCI Insight
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