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BACKGROUND IL-33, found in high levels in participants with allergic disorders, is thought to mediate allergic reactions. Etokimab, an anti–IL-33 biologic, has previously demonstrated a good safety profile and favorable pharmacodynamic properties in many clinical studies.METHODS In this 6-week placebo-controlled phase 2a study, we evaluated the safety and the ability of a single dose of etokimab to desensitize peanut-allergic adults. Participants received either etokimab (n = 15) or blinded placebo (n = 5). Clinical tests included oral food challenges and skin prick tests at days 15 and 45. Blood samples were collected for IgE levels and measurement of ex vivo peanut-stimulated T cell cytokine production.RESULTS Efficacy measurements for active vs. placebo participants at the day 15 and 45 food challenge (tolerating a cumulative 275 mg of peanut protein, which was the food challenge outcome defined in this paper) demonstrated, respectively, 73% vs. 0% (P = 0.008) to 57% vs. 0% (ns). The etokimab group had fewer adverse events compared with placebo. IL-4, IL-5, IL-9, IL-13, and ST2 levels in CD4+ T cells were reduced in the active vs. placebo arm upon peanut-induced T cell activation (P = 0.036 for IL-13 and IL-9 at day 15), and peanut-specific IgE was reduced in active vs. placebo (P = 0.014 at day 15).CONCLUSION The phase 2a results suggest etokimab is safe and well tolerated and that a single dose of etokimab could have the potential to desensitize peanut-allergic participants and possibly reduce atopy-related adverse events.TRIAL REGISTRATION ClinicalTrials.gov NCT02920021.FUNDING This work was supported by NIH grant R01AI140134, AnaptysBio, the Hartman Vaccine Fund, and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University.
Sharon Chinthrajah, Shu Cao, Cherie Liu, Shu-Chen Lyu, Sayantani B. Sindher, Andrew Long, Vanitha Sampath, Daniel Petroni, Marco Londei, Kari C. Nadeau
Total views: 4056
To develop a systems biology model of fibrosis progression within the human lung we performed RNA sequencing and microRNA analysis on 95 samples obtained from 10 idiopathic pulmonary fibrosis (IPF) and 6 control lungs. Extent of fibrosis in each sample was assessed by microCT-measured alveolar surface density (ASD) and confirmed by histology. Regulatory gene expression networks were identified using linear mixed-effect models and dynamic regulatory events miner (DREM). Differential gene expression analysis identified a core set of genes increased or decreased before fibrosis was histologically evident that continued to change with advanced fibrosis. DREM generated a systems biology model (www.sb.cs.cmu.edu/IPFReg) that identified progressively divergent gene expression tracks with microRNAs and transcription factors that specifically regulate mild or advanced fibrosis. We confirmed model predictions by demonstrating that expression of POU2AF1, previously unassociated with lung fibrosis but proposed by the model as regulator, is increased in B lymphocytes in IPF lungs and that POU2AF1-knockout mice were protected from bleomycin-induced lung fibrosis. Our results reveal distinct regulation of gene expression changes in IPF tissue that remained structurally normal compared with moderate or advanced fibrosis and suggest distinct regulatory mechanisms for each stage.
John E. McDonough, Farida Ahangari, Qin Li, Siddhartha Jain, Stijn E. Verleden, Jose Herazo-Maya, Milica Vukmirovic, Giuseppe DeIuliis, Argyrios Tzouvelekis, Naoya Tanabe, Fanny Chu, Xiting Yan, Johny Verschakelen, Robert J. Homer, Dimitris V. Manatakis, Junke Zhang, Jun Ding, Karen Maes, Laurens De Sadeleer, Robin Vos, Arne Neyrinck, Panayiotis V. Benos, Ziv Bar-Joseph, Dean Tantin, James C. Hogg, Bart M. Vanaudenaerde, Wim A. Wuyts, Naftali Kaminski
Total views: 1962
Aging is a major risk factor for cardiovascular disease. Although the impact of aging has been extensively studied, little is known regarding the aging processes in cells of the heart. Here we analyzed the transcriptomes of hearts of 12-week-old and 18-month-old mice by single-nucleus RNA-sequencing. Among all cell types, aged fibroblasts showed most significant differential gene expression, increased RNA dynamics, and network entropy. Aged fibroblasts exhibited significantly changed expression patterns of inflammatory, extracellular matrix organization angiogenesis, and osteogenic genes. Functional analyses indicated deterioration of paracrine signatures between fibroblasts and endothelial cells in old hearts. Aged heart-derived fibroblasts had impaired endothelial cell angiogenesis and autophagy and augmented proinflammatory response. In particular, expression of Serpine1 and Serpine2 were significantly increased and secreted by old fibroblasts to exert antiangiogenic effects on endothelial cells, an effect that could be significantly prevented by using neutralizing antibodies. Moreover, we found an enlarged subpopulation of aged fibroblasts expressing osteoblast genes in the epicardial layer associated with increased calcification. Taken together this study provides system-wide insights and identifies molecular changes of aging cardiac fibroblasts, which may contribute to declined heart function.
Ramon Vidal, Julian Uwe Gabriel Wagner, Caroline Braeuning, Cornelius Fischer, Ralph Patrick, Lukas Tombor, Marion Muhly-Reinholz, David John, Magdalena Kliem, Thomas Conrad, Nuno Guimarães-Camboa, Richard Harvey, Stefanie Dimmeler, Sascha Sauer
Total views: 1095
BACKGROUND. Weight gain and metabolic changes during treatment with antidepressant drugs have emerged as an important concern, particularly in long-term treatment. It is still a matter of ongoing debate whether weight gain and metabolic perturbations with antidepressant use are the consequence of increased appetite and weight gain, respectively, or represents direct pharmacological effects of the drug on metabolism. METHODS. We therefore conducted a proof-of-concept, open-label clinical trial, hypothesizing that in exceptionally healthy men no change of metabolic parameters would occur under mirtazapine, when environmental factors such as nutrition, sleep, and physical exercise were controlled and kept constant. Over a 3-week preparation phase, 10 healthy, young men were attuned to a standardized diet adjusted to their individual caloric need, to a regular sleep/wake cycle and moderate exercise. Continuing this protocol, we administered 30 mg mirtazapine daily for 7 days. RESULTS. While no significant weight gain or changes in resting energy expenditure were observed under these conditions, hunger and appetite for sweets increased with mirtazapine, accompanied by a shift in energy substrate partitioning towards carbohydrate substrate preference as assessed by indirect calorimetry. Furthermore, with mirtazapine, insulin and C-peptide release increased in response to a standardized meal. CONCLUSION. Our findings provide important insights into weight-independent metabolic changes associated with mirtazapine and allow a better understanding of the long-term metabolic effects observed in patients treated with antidepressant drugs. TRIAL REGISTRATION. ClinicalTrials.gov NCT00878540. FUNDING. Nothing to declare.
Johannes M. Hennings, Sarah Heel, Katharina Lechner, Manfred Uhr, Tatjana Dose, Ludwig Schaaf, Florian Holsboer, Susanne Lucae, Stephany Fulda, Stefan Kloiber
Total views: 1007
The choroid plexus (ChP) is a highly vascularized tissue found in the brain ventricles, with an apical epithelial cell layer surrounding fenestrated capillaries. It is responsible for the production of most of the cerebrospinal fluid (CSF) in the ventricular system, subarachnoid space, and central canal of the spinal cord, while also constituting the blood-CSF barrier (BCSFB). In addition, epithelial cells of the ChP (EChP) synthesize neurotrophic factors and other signaling molecules that are released into the CSF. Here, we show that insulin is produced in EChP of mice and humans, and its expression and release are regulated by serotonin. Insulin mRNA and immune-reactive protein, including C-peptide, are present in EChP, as detected by several experimental approaches, and appear in much higher levels than any other brain region. Moreover, insulin is produced in primary cultured mouse EChP, and its release, albeit Ca2+ sensitive, is not regulated by glucose. Instead, activation of the 5HT2C receptor by serotonin treatment led to activation of IP3-sensitive channels and Ca2+ mobilization from intracellular storage, leading to insulin secretion. In vivo depletion of brain serotonin in the dorsal raphe nucleus negatively affected insulin expression in the ChP, suggesting an endogenous modulation of ChP insulin by serotonin. Here, we show for the first time to our knowledge that insulin is produced by EChP in the brain, and its release is modulated at least by serotonin but not glucose.
Caio Henrique Mazucanti, Qing-Rong Liu, Doyle Lang, Nicholas Huang, Jennifer F. O’Connell, Simonetta Camandola, Josephine M. Egan
Total views: 896
The adult mammalian heart regenerates poorly after injury and, as a result, ischemic heart diseases are among the leading causes of death worldwide. The recovery of the injured heart is dependent on orchestrated repair processes including inflammation, fibrosis, cardiomyocyte survival, proliferation, and contraction properties that could be modulated in patients. In this work we designed an automated high-throughput screening system for small molecules that induce cardiomyocyte proliferation in vitro and identified the small molecule Chicago Sky Blue 6B (CSB). Following induced myocardial infarction, CSB treatment reduced scar size and improved heart function of adult mice. Mechanistically, we show that although initially identified using in vitro screening for cardiomyocyte proliferation, in the adult mouse CSB promotes heart repair through (i) inhibition of CaMKII signaling, which improves cardiomyocyte contractility; and (ii) inhibition of neutrophil and macrophage activation, which attenuates the acute inflammatory response, thereby contributing to reduced scarring. In summary, we identified CSB as a potential therapeutic agent that enhances cardiac repair and function by suppressing postinjury detrimental processes, with no evidence for cardiomyocyte renewal.
Oren Yifa, Karen Weisinger, Elad Bassat, Hanjun Li, David Kain, Haim Barr, Noga Kozer, Alexander Genzelinakh, Dana Rajchman, Tamar Eigler, Kfir Baruch Umansky, Daria Lendengolts, Ori Brener, Nenad Bursac, Eldad Tzahor
Total views: 870
Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first 2 years of life, and 129 healthy matched controls, we found the cytomegalovirus-stimulated (CMV-stimulated) IFN-γ response to be associated with CD8+ T cell activation (Spearman’s rho, P = 6 × 10–8). A CMV-specific IFN-γ response was also associated with increased risk of developing TB disease (conditional logistic regression; P = 0.043; OR, 2.2; 95% CI, 1.02–4.83) and shorter time to TB diagnosis (Log Rank Mantel-Cox, P = 0.037). CMV+ infants who developed TB disease had lower expression of NK cell–associated gene signatures and a lower frequency of CD3–CD4–CD8– lymphocytes. We identified transcriptional signatures predictive of TB disease risk among CMV ELISpot–positive (area under the receiver operating characteristic [AUROC], 0.98, accuracy, 92.57%) and –negative (AUROC, 0.9; accuracy, 79.3%) infants; the CMV– signature was validated in an independent infant study (AUROC, 0.71; accuracy, 63.9%). A 16-gene signature that previously identified adolescents at risk of developing TB disease did not accurately classify case and control infants in this study. Understanding the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.
Julius Müller, Rachel Tanner, Magali Matsumiya, Margaret A. Snowden, Bernard Landry, Iman Satti, Stephanie A. Harris, Matthew K. O’Shea, Lisa Stockdale, Leanne Marsay, Agnieszka Chomka, Rachel Harrington-Kandt, Zita-Rose Manjaly Thomas, Vivek Naranbhai, Elena Stylianou, Stanley Kimbung Mbandi, Mark Hatherill, Gregory Hussey, Hassan Mahomed, Michele Tameris, J. Bruce McClain, Thomas G. Evans, Willem A. Hanekom, Thomas J. Scriba, Helen McShane, Helen A. Fletcher
Total views: 853
Glomerular disease is characterized by proteinuria and glomerulosclerosis, two pathologic features caused by podocyte injury and mesangial cell activation, respectively. However, whether these two events are linked remains elusive. Here, we report that sonic hedgehog (Shh) is the mediator that connects podocyte damage to mesangial activation and glomerulosclerosis. Shh was induced in glomerular podocytes in various models of proteinuric chronic kidney diseases (CKD). However, mesangial cells in the glomeruli, but not podocytes, responded to hedgehog ligand. In vitro, Shh was induced in podocytes after injury and selectively promoted mesangial cell activation and proliferation. In a miniorgan culture of isolated glomeruli, Shh promoted mesangial activation but did not affect the integrity of podocytes. Podocyte-specific ablation of Shh in vivo exhibited no effect on proteinuria after adriamycin injection but hampered mesangial activation and glomerulosclerosis. Consistently, pharmacologic blockade of Shh signaling decoupled proteinuria from glomerulosclerosis. In humans, Shh was upregulated in glomerular podocytes in patients with CKD and its circulating level was associated with glomerulosclerosis but not proteinuria. These studies demonstrate that Shh mechanistically links podocyte injury to mesangial activation in the pathogenesis of glomerular diseases. Our findings also illustrate a crucial role for podocyte-mesangial communication in connecting proteinuria to glomerulosclerosis.
Dong Zhou, Haiyan Fu, Yang Han, Lu Zhang, Shijia Liu, Lin Lin, Donna B. Stolz, Youhua Liu
Total views: 798
BACKGROUND Bilateral loss of vestibular (inner ear inertial) sensation causes chronically blurred vision during head movement, postural instability, and increased fall risk. Individuals who fail to compensate despite rehabilitation therapy have no adequate treatment options. Analogous to hearing restoration via cochlear implants, prosthetic electrical stimulation of vestibular nerve branches to encode head motion has garnered interest as a potential treatment, but prior studies in humans have not included continuous long-term stimulation or 3D binocular vestibulo-ocular reflex (VOR) oculography, without which one cannot determine whether an implant selectively stimulates the implanted ear’s 3 semicircular canals.METHODS We report binocular 3D VOR responses of 4 human subjects with ototoxic bilateral vestibular loss unilaterally implanted with a Labyrinth Devices Multichannel Vestibular Implant System vestibular implant, which provides continuous, long-term, motion-modulated prosthetic stimulation via electrodes in 3 semicircular canals.RESULTS Initiation of prosthetic stimulation evoked nystagmus that decayed within 30 minutes. Stimulation targeting 1 canal produced 3D VOR responses approximately aligned with that canal’s anatomic axis. Targeting multiple canals yielded responses aligned with a vector sum of individual responses. Over 350–812 days of continuous 24 h/d use, modulated electrical stimulation produced stable VOR responses that grew with stimulus intensity and aligned approximately with any specified 3D head rotation axis.CONCLUSION These results demonstrate that a vestibular implant can selectively, continuously, and chronically provide artificial sensory input to all 3 implanted semicircular canals in individuals disabled by bilateral vestibular loss, driving reflexive VOR eye movements that approximately align in 3D with the head motion axis encoded by the implant.TRIAL REGISTRATION ClinicalTrials.gov: NCT02725463.FUNDING NIH/National Institute on Deafness and Other Communication Disorders: R01DC013536 and 2T32DC000023; Labyrinth Devices, LLC; and Med-El GmbH.
Peter J. Boutros, Desi P. Schoo, Mehdi Rahman, Nicolas S. Valentin, Margaret R. Chow, Andrianna I. Ayiotis, Brian J. Morris, Andreas Hofner, Aitor Morillo Rascon, Andreas Marx, Ross Deas, Gene Y. Fridman, Natan S. Davidovics, Bryan K. Ward, Carolina Treviño, Stephen P. Bowditch, Dale C. Roberts, Kelly E. Lane, Yoav Gimmon, Michael C. Schubert, John P. Carey, Andreas Jaeger, Charles C. Della Santina
Total views: 792
BACKGROUND Metabolic syndrome (MetS) is highly correlated with obesity and cardiovascular risk, but the importance of dietary carbohydrate independent of weight loss in MetS treatment remains controversial. Here, we test the theory that dietary carbohydrate intolerance (i.e., the inability to process carbohydrate in a healthy manner) rather than obesity per se is a fundamental feature of MetS.METHODS Individuals who were obese with a diagnosis of MetS were fed three 4-week weight-maintenance diets that were low, moderate, and high in carbohydrate. Protein was constant and fat was exchanged isocalorically for carbohydrate across all diets.RESULTS Despite maintaining body mass, low-carbohydrate (LC) intake enhanced fat oxidation and was more effective in reversing MetS, especially high triglycerides, low HDL-C, and the small LDL subclass phenotype. Carbohydrate restriction also improved abnormal fatty acid composition, an emerging MetS feature. Despite containing 2.5 times more saturated fat than the high-carbohydrate diet, an LC diet decreased plasma total saturated fat and palmitoleate and increased arachidonate.CONCLUSION Consistent with the perspective that MetS is a pathologic state that manifests as dietary carbohydrate intolerance, these results show that compared with eucaloric high-carbohydrate intake, LC/high-fat diets benefit MetS independent of whole-body or fat mass.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02918422.FUNDING Dairy Management Inc. and the Dutch Dairy Association.
Parker N. Hyde, Teryn N. Sapper, Christopher D. Crabtree, Richard A. LaFountain, Madison L. Bowling, Alex Buga, Brandon Fell, Fionn T. McSwiney, Ryan M. Dickerson, Vincent J. Miller, Debbie Scandling, Orlando P. Simonetti, Stephen D. Phinney, William J. Kraemer, Sarah A. King, Ronald M. Krauss, Jeff S. Volek
Total views: 772