ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
Vacuolar H+-ATPase–dependent (V-ATPase–dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell–derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be re...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Takuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Féraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Jeanne d’Arc Al Bacha, Hiroshi Yamada, Marcel A. Lauterbach, Marc Guillon, Source Type: research

Setting traps for NKG2A gives NK cell immunotherapy a fighting chance
This study provides proof of concept for a new immunotherapeutic approach using NKG2Anull NK cells. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Frank Cichocki, Jeffrey S. Miller Source Type: research

Are we there yet? The never-ending quest for an Epstein-Barr virus vaccine
The Epstein-Barr virus (EBV) is estimated to infect a large part of the population and is associated with a variety of human tumors; therefore, EBV is an important target for vaccine development. In this issue of the JCI, Rühl et al. developed a promising heterologous prime-boost vaccination strategy for EBV-associated malignancies and symptomatic primary infection. The authors show that two prime-boost regimens, using either dendritic cells or an adenovirus approach targeting nuclear antigen EBNA1 followed by a modified vaccinia virus Ankara (MVA) booster, induced significant T cell–mediated, EBV-specific immun...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Sandhya Sharma, Rayne H. Rouce Source Type: research

Yap/Taz regulate alveolar regeneration and resolution of lung inflammation
Alveolar epithelium plays a pivotal role in protecting the lungs from inhaled infectious agents. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery from these insults in order to rebuild the epithelial barrier and restore pulmonary functions. Here, we show that sublethal infection of mice with Streptococcus pneumoniae, the most common pathogen of community-acquired pneumonia, led to exclusive damage in lung alveoli, followed by alveolar epithelial regeneration and resolution of lung inflammation. We show that surfactant protein C–expressing (SPC-expressing) alveolar epithelial ty...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Ryan LaCanna, Daniela Liccardo, Peggy Zhang, Lauren Tragesser, Yan Wang, Tongtong Cao, Harold A. Chapman, Edward E. Morrisey, Hao Shen, Walter J. Koch, Beata Kosmider, Marla R. Wolfson, Ying Tian Source Type: research

Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas
The Epstein-Barr virus (EBV) is one of the predominant tumor viruses in humans, but so far no therapeutic or prophylactic vaccination against this transforming pathogen is available. We demonstrated that heterologous prime-boost vaccination with the nuclear antigen 1 of EBV (EBNA1), either targeted to the DEC205 receptor on DCs or expressed from a recombinant modified vaccinia virus Ankara (MVA) vector, improved priming of antigen-specific CD4+ T cell help. This help supported the expansion and maintenance of EBNA1-specific CD8+ T cells that are most efficiently primed by recombinant adenoviruses that encode EBNA1. These c...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Julia Rühl, Carmen Citterio, Christine Engelmann, Tracey Haigh, Andrzej Dzionek, Johannes Dreyer, Rajiv Khanna, Graham S. Taylor, Joanna B. Wilson, Carol S. Leung, Christian Münz Source Type: research

Improving CAR T cell immunotherapy–mediated remissions for pediatric leukemia
Chimeric antigen receptor (CAR) T cells are an effective therapy for relapsed or refractory pediatric B cell leukemia. Analysis of the starting material, the T cells collected from the patient prior to CAR manufacture, reveals possible biomarkers of cells destined to perform poorly in patients. Long-term follow-up shows that long periods of B cell aplasia, a marker of in vivo CAR activity, are associated with longer remission but also a higher chance of antigen-negative relapse. The role of transplantation as consolidative therapy is unclear in this nonrandomized data, but clearly warrants further study. (Source: Journal o...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: David M. Barrett Source Type: research

CD19 CAR T cell product and disease attributes predict leukemia remission durability
CONCLUSION. These parameters have the potential to prospectively identify patients at risk for therapeutic failure and support the development of approaches to boost CAR T cell activation and proliferation in patients with low levels of CD19 antigen. TRIAL REGISTRATION. ClinicalTrials.gov, NCT02028455. FUNDING. Partial funding for this study was provided by a Stand Up to Cancer and St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113), R01 CA136551-05, an Alex Lemonade Stand Phase I/II Infrastructure Grant, a Conquer Cancer Foundation Career Development Award, the Washington State Life S...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Olivia C. Finney, Hannah Brakke, Stephanie Rawlings-Rhea, Roxana Hicks, Danielle Doolittle, Marisa Lopez, Ben Futrell, Rimas J. Orentas, Daniel Li, Rebecca Gardner, Michael C. Jensen Source Type: research

Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells
A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA class I molecule (HLA-E) in tumor cells, which suppresses NK cell activity via ligation of the NK inhibitory receptor CD94/NK group 2 member A (NKG2A). Gene expression data from approximately 10,000 tumor samples showed widespread HLAE expression, with levels correlating with those of KLRC1 (NKG2A) and KLRD1 (CD94). To bypass HLA-E inhibition, we developed a way to generate highly functional NK cells lacking NKG2A. Constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody were linked to endop...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Takahiro Kamiya, See Voon Seow, Desmond Wong, Murray Robinson, Dario Campana Source Type: research

Nontranslational function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regeneration
Aside from its catalytic function in protein synthesis, leucyl-tRNA synthetase (LRS) has a nontranslational function in regulating cell growth via the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway by sensing amino acid availability. mTOR also regulates skeletal myogenesis, but the signaling mechanism is distinct from that in cell growth regulation. A role of LRS in myogenesis has not been reported. Here we report that LRS negatively regulated myoblast differentiation in vitro. This function of LRS was independent of its regulation of protein synthesis, and it required leucine-binding but not tRNA charging...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Kook Son, Jae-Sung You, Mee-Sup Yoon, Chong Dai, Jong Hyun Kim, Nidhi Khanna, Aditi Banerjee, Susan A. Martinis, Gyoonhee Han, Jung Min Han, Sunghoon Kim, Jie Chen Source Type: research

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice
Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the...
Source: Journal of Clinical Investigation - April 16, 2019 Category: Biomedical Science Authors: Taylor S. Cohen, Virginia Takahashi, Jessica Bonnell, Andrey Tovchigrechko, Raghothama Chaerkady, Wen Yu, Omari Jones-Nelson, Young Lee, Rajiv Raja, Sonja Hess, C. Kendall Stover, John J. Worthington, Mark A. Travis, Bret R. Sellman Source Type: research

Singling out Th2 cells in eosinophilic esophagitis
This study provides an early example of scRNA-seq for identifying relevant cell populations and mechanisms underlying allergic diseases. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Walter L. Eckalbar, David J. Erle Source Type: research

Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis
T cell heterogeneity is highly relevant to allergic disorders. We resolved the heterogeneity of human tissue CD3+ T cells during allergic inflammation, focusing on a tissue-specific allergic disease, eosinophilic esophagitis (EoE). We investigated 1088 single T cells derived from patients with a spectrum of disease activity. Eight disparate tissue T cell subtypes (designated T1–T8) were identified, with T7 and T8 enriched in the diseased tissue. The phenotypes of T7 and T8 resemble putative Treg (FOXP3+) and effector Th2-like (GATA3+) cells, respectively. Prodigious levels of IL-5 and IL-13 were confined to HPGDS+ CR...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Ting Wen, Bruce J. Aronow, Yrina Rochman, Mark Rochman, Kiran KC, Phil J. Dexheimer, Philip Putnam, Vincent Mukkada, Heather Foote, Kira Rehn, Sam Darko, Daniel Douek, Marc E. Rothenberg Source Type: research

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Lauren Elizabeth Walker, Federica Frigerio, Teresa Ravizza, Emanuele Ricci, Karen Tse, Rosalind E. Jenkins, Graeme John Sills, Andrea Jorgensen, Luca Porcu, Thimmasettappa Thippeswamy, Tiina Alapirtti, Jukka Peltola, Martin J. Brodie, Brian Kevin Park, An Source Type: research

Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation
Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a poor prognosis and few treatment options. Pathological remodeling of the extracellular matrix (ECM) is a key factor that drives the disease pathogenesis, although the underlying mechanisms remain unknown. Alternative polyadenylation (APA) has recently been shown to play a major role in cellular responses to stress by driving the expression of fibrotic factors through the alteration of miRNA sensitivity, but a connection to IPF has not been established. Here, we demonstrated that CFIm25, a global regulator of APA, was downregulated in the lungs of patients with ...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Tingting Weng, Junsuk Ko, Chioniso P. Masamha, Zheng Xia, Yu Xiang, Ning-yuan Chen, Jose G. Molina, Scott Collum, Tinne C. Mertens, Fayong Luo, Kemly Philip, Jonathan Davies, Jingjing Huang, Cory Wilson, Rajarajan A. Thandavarayan, Brian A. Bruckner, Soma Source Type: research

miR-142 controls metabolic reprogramming that regulates dendritic cell activation
DCs undergo metabolic reprogramming from a predominantly oxidative phosphorylation (OXPHOS) to glycolysis to mount an immunogenic response. The mechanism underpinning the metabolic reprogramming remains elusive. We demonstrate that miRNA-142 (miR-142) is pivotal for this shift in metabolism, which regulates the tolerogenic and immunogenic responses of DCs. In the absence of miR-142, DCs fail to switch from OXPHOS and show reduced production of proinflammatory cytokines and the ability to activate T cells in vitro and in in vivo models of sepsis and alloimmunity. Mechanistic studies demonstrate that miR-142 regulates fatty ...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Yaping Sun, Katherine Oravecz-Wilson, Sydney Bridges, Richard McEachin, Julia Wu, Stephanie H. Kim, Austin Taylor, Cynthia Zajac, Hideaki Fujiwara, Daniel Christopher Peltier, Thomas Saunders, Pavan Reddy Source Type: research

Deubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancer
Cancer stem cells sustain propagation of the deadly primary brain cancer glioblastoma. Glioblastoma stem cells (GSCs) characterized by a mesenchymal phenotype are aggressive and resistant to therapies and represent a crucial therapeutic target. In this issue of the JCI, Chen et al. show that the intracellular levels of aldehyde dehydrogenase 1A3 (ALDH1A3), known as a functional marker of mesenchymal GSCs, are regulated posttranslationally by ubiquitin-specific protease 9X–mediated (USP9X-mediated) deubiquitination. Increased expression of USP9X stabilizes ALDH1A3, enabling GSCs to exhibit mesenchymal traits and the m...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Hiroaki Wakimoto Source Type: research

Membrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis optica
Neuromyelitis optica (NMO) is an autoimmune CNS disorder mediated by pathogenic aquaporin-4 (AQP4) water channel autoantibodies (AQP4-IgG). Although AQP4-IgG–driven complement-dependent cytotoxicity (CDC) is critical for the formation of NMO lesions, the molecular mechanisms governing optimal classical pathway activation are unknown. We investigated the molecular determinants driving CDC in NMO using recombinant AQP4–specific autoantibodies (AQP4 rAbs) derived from affected patients. We identified a group of AQP4 rAbs targeting a distinct extracellular loop C epitope that demonstrated enhanced CDC on target cel...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: John Soltys, Yiting Liu, Alanna Ritchie, Scott Wemlinger, Kristin Schaller, Hannah Schumann, Gregory P. Owens, Jeffrey L. Bennett Source Type: research

Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors
CONCLUSION. The current study provides feasible pipelines for neoantigen identification. Implementing these strategies to individually tailor neoantigens could facilitate neoantigen-based translational immunotherapy research. TRIAL REGISTRATION. ChiCTR.org ChiCTR-OIC-16010092, ChiCTR-OIC-17011275, ChiCTR-OIC-17011913; ClinicalTrials.gov NCT03171220. FUNDING. This work was funded by grants from the National Key Research and Development Program of China (2017YFC1308900), the National Major Projects for “Major New Drugs Innovation and Development” (2018ZX09301048-003), the National Natural Science Foundation of Ch...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Fangjun Chen, Zhengyun Zou, Juan Du, Shu Su, Jie Shao, Fanyan Meng, Ju Yang, Qiuping Xu, Naiqing Ding, Yang Yang, Qin Liu, Qin Wang, Zhichen Sun, Shujuan Zhou, Shiyao Du, Jia Wei, Baorui Liu Source Type: research

USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells
The mesenchymal (MES) subtype of glioblastoma (GBM) stem cells (GSCs) represents a subpopulation of cancer cells that are notorious for their highly aggressive nature and resistance to conventional therapy. Aldehyde dehydrogenase 1A3 (ALDH1A3) has been recently suggested as a key determinant for the maintenance of MES features of GSCs. However, the mechanisms underpinning aberrant ALDH1A3 expression remain elusive. Here, we identified ubiquitin-specific protease 9X (USP9X) as a bona fide deubiquitinase of ALDH1A3 in MES GSCs. USP9X interacted with, depolyubiquitylated, and stabilized ALDH1A3. Moreover, we showed that FACS-...
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Zhengxin Chen, Hong-Wei Wang, Shuai Wang, Ligang Fan, Shuang Feng, Xiaomin Cai, Chenghao Peng, Xiaoting Wu, Jiacheng Lu, Dan Chen, Yuanyuan Chen, Wenting Wu, Daru Lu, Ning Liu, Yongping You, Huibo Wang Source Type: research

Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination
CONCLUSION. This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses. TRIAL REGISTRATION. This study has been registered at ClinicalTrials.gov (NCT01707602). FUNDING. This work was supported by grants from the French Ministry of Health PHRCN 2012 – RCT 12061, INSERM-DGOS, the Fondation pour la Recherche Médicale, and the Société Française de Dermatologie (to AS). These funding sources had no direct role in any aspect of the research or article. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 9, 2019 Category: Biomedical Science Authors: Eléna Gonçalves, Olivia Bonduelle, Angèle Soria, Pierre Loulergue, Alexandra Rousseau, Marine Cachanado, Henri Bonnabau, Rodolphe Thiebaut, Nicolas Tchitchek, Sylvie Behillil, Sylvie van der Werf, Annika Vogt, Tabassome Simon, Odile Launay, Behazine Co Source Type: research

BETP degradation simultaneously targets acute myelogenous leukemic stem cells and the microenvironment
The antileukemic effect of inhibiting bromodomain and extra-terminal domain-containing (BET-containing) proteins (BETPs) such as BRD4 has largely been largely attributed to transcriptional downregulation of cellular anabolic and antiapoptotic processes, but its effect on the bone marrow microenvironment, a sanctuary favoring the persistence of leukemic stem/progenitor cells, is unexplored. Sustained degradation of BETP with the small-molecule BET proteolysis-targeting chimera (PROTAC) ARV-825 resulted in a marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interactions, in acute myel...
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Sujan Piya, Hong Mu, Seemana Bhattacharya, Philip L. Lorenzi, R. Eric Davis, Teresa McQueen, Vivian Ruvolo, Natalia Baran, Zhiqiang Wang, Yimin Qian, Craig M. Crews, Marina Konopleva, Jo Ishizawa, M. James You, Hagop Kantarjian, Michael Andreeff, Gautam B Source Type: research

Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells
The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44+Helios+CD4+ T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activa...
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Alexander Visekruna, Sabrina Hartmann, Yasmina Rodriguez Sillke, Rainer Glauben, Florence Fischer, Hartmann Raifer, Hans Mollenkopf, Wilhelm Bertrams, Bernd Schmeck, Matthias Klein, Axel Pagenstecher, Michael Lohoff, Ralf Jacob, Oliver Pabst, Paul William Source Type: research

uPAR isoform 2 forms a dimer and induces severe kidney disease in mice
In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Changli Wei, Jing Li, Brian D. Adair, Ke Zhu, Jian Cai, Michael Merchant, Beata Samelko, Zhongji Liao, Kwi Hye Koh, Nicholas J. Tardi, Ranadheer R. Dande, Shuangxin Liu, Jianchao Ma, Salvatore Dibartolo, Stefan Hägele, Vasil Peev, Salim S. Hayek, David J Source Type: research

IL-26 contributes to host defense against intracellular bacteria
IL-26 is an antimicrobial protein secreted by Th17 cells that has the ability to directly kill extracellular bacteria. To ascertain whether IL-26 contributes to host defense against intracellular bacteria, we studied leprosy, caused by the obligate intracellular pathogen Mycobacterium leprae, as a model. Analysis of leprosy skin lesions by gene expression profiling and immunohistology revealed that IL-26 was more strongly expressed in lesions from the self-limited tuberculoid compared with expression in progressive lepromatous patients. IL-26 directly bound to M. leprae in axenic culture and reduced bacteria viability. Fur...
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Angeline Tilly Dang, Rosane M.B. Teles, David I. Weiss, Kislay Parvatiyar, Euzenir N. Sarno, Maria T. Ochoa, Genhong Cheng, Michel Gilliet, Barry R. Bloom, Robert L. Modlin Source Type: research

c-Src is in the effector pathway linking uPAR and podocyte injury
The role of urokinase-type plasminogen activator receptor (uPAR) in kidney physiology and pathology has attracted considerable attention. The protein uPAR has dual functions: as a key regulator of plasmin generation and a component of the innate immune system. In the current issue, Wei and colleagues describe a transgenic mouse expressing Plaur RNA in glomerular podocytes. The mice manifested podocyte injury, including c-Src phosphorylation, proteinuria, and focal segmental glomerulosclerosis (FSGS). Plaur-transgenic mice on a β3 integrin–deficient background were protected from podocyte injury. Renal biopsies f...
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Jeffrey B. Kopp, Jurgen Heymann Source Type: research

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease
It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-α4β7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strong...
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Lyssia Belarif, Richard Danger, Laetitia Kermarrec, Véronique Nerrière-Daguin, Sabrina Pengam, Tony Durand, Caroline Mary, Elise Kerdreux, Vanessa Gauttier, Aneta Kucik, Virginie Thepenier, Jerome C. Martin, Christie Chang, Adeeb Rahman, Nina Salabert-L Source Type: research

Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion
This study shows that molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize therapy management, leading to improved patient outcomes. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 3, 2019 Category: Biomedical Science Authors: Christopher R. McEvoy, Huiling Xu, Kortnye Smith, Dariush Etemadmoghadam, Huei San Leong, David Y. Choong, David J. Byrne, Amir Iravani, Sophie Beck, Linda Mileshkin, Richard W. Tothill, David D. Bowtell, Bindi M. Bates, Violeta Nastevski, Judy Browning, Source Type: research

Empowering ASCI’s support of physician-scientists through stronger institutional connections
The American Society for Clinical Investigation (ASCI), a nonprofit honorary society, was established to support physician-scientists by serving as a benchmark of excellence in medical research, a forum to celebrate advances in medicine, and a vehicle to communicate advances that bridge basic and translational research and their implementation across the growing myriad of medical specialties. A core intention of the Society is to engage the medical research community broadly through transparent communications of our activities and initiatives with the institutions that comprise the base for our membership. Recognizing the ...
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Kieren A. Marr, W. Kimryn Rathmell, John B. Hawley, Karen D. Guth Source Type: research

A conversation with George Church
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Ushma S. Neill Source Type: research

HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Celine Hernandez, Peter Huebener, Jean-Philippe Pradere, Daniel J. Antoine, Richard A. Friedman, Robert F. Schwabe Source Type: research

DNA hypermethylation within TERT promoter upregulates TERT expression in cancer
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Donghyun D. Lee, Ricardo Leão, Martin Komosa, Marco Gallo, Cindy H. Zhang, Tatiana Lipman, Marc Remke, Abolfazl Heidari, Nuno Miguel Nunes, Joana D. Apolónio, Aryeh J. Price, Ramon Andrade De Mello, João S. Dias, David Huntsman, Thomas Hermanns, Peter Source Type: research

HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Celine Hernandez, Peter Huebener, Jean-Philippe Pradere, Daniel J. Antoine, Richard A. Friedman, Robert F. Schwabe Source Type: research

Epithelial cell–derived cytokines: more than just signaling the alarm
The epithelial cell–derived cytokines thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 are central regulators of type 2 immunity, which drives a broad array of allergic responses. Often characterized as “alarmins” that are released by the barrier epithelium in response to external insults, these epithelial cell–derived cytokines were initially thought to act only early in allergic inflammation. Indeed, TSLP can condition dendritic cells to initiate type 2 responses, and IL-33 may influence susceptibility to asthma through its role in establishing the immune environment in the perinatal lungs. H...
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Florence Roan, Kazushige Obata-Ninomiya, Steven F. Ziegler Source Type: research

Newly identified T cell subsets in mechanistic studies of food immunotherapy
Allergen-specific immunotherapy has shown promise for the treatment of food allergy and is currently being evaluated in clinical trials. Although immunotherapy can induce desensitization, the mechanisms underlying this process are not completely understood. Recent advances in high-throughput technologies along with concomitant advances in data analytics have enabled monitoring of cells at the single-cell level and increased the research focus on upstream cellular factors involved in the efficacy of immunotherapy, particularly the role of T cells. As our appreciation of different T cell subsets and their plasticity increase...
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Vanitha Sampath, Kari C. Nadeau Source Type: research

Infectious disease expert Michael S. Diamond wins the 2019 ASCI/Stanley J. Korsmeyer prize
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2019 Category: Biomedical Science Authors: Sarah Jackson Source Type: research

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or PDGFRA gene. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising what we believe to be the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT- and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that in PDGFRA-mutant GISTs, immune cells were more numerous and had higher cytolytic activity than in KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokine...
Source: Journal of Clinical Investigation - March 25, 2019 Category: Biomedical Science Authors: Gerardo A. Vitiello, Timothy G. Bowler, Mengyuan Liu, Benjamin D. Medina, Jennifer Q. Zhang, Nesteene J. Param, Jennifer K. Loo, Rachel L. Goldfeder, Frederic Chibon, Ferdinand Rossi, Shan Zeng, Ronald P. DeMatteo Source Type: research

Lkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activation
Bone osteogenic sarcoma has a poor prognosis, as the exact cell of origin and the signaling pathways underlying tumor formation remain undefined. Here, we report an osteogenic tumor mouse model based on the conditional knockout of liver kinase b1 (Lkb1, also known as Stk11) in Cathepsin K–Cre–expressing (Ctsk-Cre–expressing) cells. Lineage-tracing studies demonstrated that Ctsk-Cre could label a population of periosteal cells. The cells functioned as mesenchymal progenitors with regard to markers and functional properties. LKB1 deficiency increased proliferation and osteoblast differentiation of Ctsk+ per...
Source: Journal of Clinical Investigation - March 25, 2019 Category: Biomedical Science Authors: Yujiao Han, Heng Feng, Jun Sun, Xiaoting Liang, Zhuo Wang, Wenhui Xing, Qinggang Dai, Yang Yang, Anjia Han, Zhanying Wei, Qing Bi, Hongbin Ji, Tiebang Kang, Weiguo Zou Source Type: research

Figure errors, sloppy science, and fraud: keeping eyes on your data
Recent reports suggest that there has been an increase in the number of retractions and corrections of published articles due to post-publication detection of problematic data. Moreover, fraudulent data and sloppy science have long-term effects on the scientific literature and subsequent projects based on false and unreproducible claims. At the JCI, we have introduced several data screening checks for manuscripts prior to acceptance in an attempt to reduce the number of post-publication corrections and retractions, with the ultimate goal of increasing confidence in the papers we publish. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - March 25, 2019 Category: Biomedical Science Authors: Corinne L. Williams, Arturo Casadevall, Sarah Jackson Source Type: research

Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2
Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lun...
Source: Journal of Clinical Investigation - March 25, 2019 Category: Biomedical Science Authors: Serena Lucotti, Camilla Cerutti, Magali Soyer, Ana M. Gil-Bernabé, Ana L. Gomes, Philip D. Allen, Sean Smart, Bostjan Markelc, Karla Watson, Paul C. Armstrong, Jane A. Mitchell, Timothy D. Warner, Anne J. Ridley, Ruth J. Muschel Source Type: research

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model
Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negativ...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Yueqin Zhou, Sharon Carmona, A.K.M.G. Muhammad, Shaughn Bell, Jesse Landeros, Michael Vazquez, Ritchie Ho, Antonietta Franco, Bin Lu, Gerald W. Dorn II, Shaomei Wang, Cathleen M. Lutz, Robert H. Baloh Source Type: research

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Terence K. Lee, Saravana R.K. Murthy, Niamh X. Cawley, Savita Dhanvantari, Stephen M. Hewitt, Hong Lou, Tracy Lau, Stephanie Ma, Thanh Huynh, Robert A. Wesley, Irene O. Ng, Karel Pacak, Ronnie T. Poon, Y. Peng Loh Source Type: research

Finding a new balance to cure Charcot-Marie-Tooth 2A
Motoneurons are particularly sensitive to mutations in mitofusin-2 (MFN2) that cause the neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A). MFN2 is a mitochondrial outer membrane protein that, together with its homologue MFN1, fuses mitochondria in most tissues. In this issue of the JCI, Zhou and colleagues show that increasing MFN1 expression in neurons can curtail neurological defects in a CMT2A mouse model. These results show that the ratio of MFN1 to MFN2 can explain the tissue specificity of CMT2A and indicate that augmentation of MFN1 in the nervous system has potential as a possible therapeutic strat...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Keiko Iwata, Luca Scorrano Source Type: research

The use of biologics for immune modulation in allergic disease
The rising prevalence of allergies represents an increasing socioeconomic burden. A detailed understanding of the immunological mechanisms that underlie the development of allergic disease, as well as the processes that drive immune tolerance to allergens, will be instrumental in designing therapeutic strategies to treat and prevent allergic disease. Improved characterization of individual patients through the use of specific biomarkers and improved definitions of disease endotypes are paving the way for the use of targeted therapeutic approaches for personalized treatment. Allergen-specific immunotherapy and biologic ther...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Willem van de Veen, Mübeccel Akdis Source Type: research

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF–secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory c...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Alex B. Blair, Jennifer Kleponis, Dwayne L. Thomas II, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, Lei Zheng Source Type: research

Nonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonist
Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven’t been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL’s immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation o...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Kwi Hye Koh, Yanxia Cao, Steve Mangos, Nicholas J. Tardi, Ranadheer R. Dande, Ha Won Lee, Beata Samelko, Mehmet M. Altintas, Vincent P. Schmitz, Hyun Lee, Kamalika Mukherjee, Vasil Peev, David J. Cimbaluk, Jochen Reiser, Eunsil Hahm Source Type: research

Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke
Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calcium-activated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, in...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Ana I. Casas, Pamela W.M. Kleikers, Eva Geuss, Friederike Langhauser, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Martin Hrabê de Angelis, Javier Egea, Manuela G. Lopez, Christoph Kleinschnitz, Harald H.H.W. Schmidt Source Type: research

Dengue-specific CD8+ T cell subsets display specialized transcriptomic and TCR profiles
This study provides a transcriptomic definition of DENV-specific activated human CD8+ T cell subsets and defines a benchmark profile that vaccine-specific responses could aim to reproduce. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Yuan Tian, Mariana Babor, Jerome Lane, Grégory Seumois, Shu Liang, N.D. Suraj Goonawardhana, Aruna D. De Silva, Elizabeth J. Phillips, Simon A. Mallal, Ricardo da Silva Antunes, Alba Grifoni, Pandurangan Vijayanand, Daniela Weiskopf, Bjoern Peters, Aless Source Type: research

The vasculature in sepsis: delivering poison or remedy to the brain?
This study highlights an important mechanism by which vascular injury can impair brain function. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Benjamin H. Singer Source Type: research

Circulating heparan sulfate fragments mediate septic cognitive dysfunction
Septic patients frequently develop cognitive impairment that persists beyond hospital discharge. The impact of sepsis on electrophysiological and molecular determinants of learning is underexplored. We observed that mice that survived sepsis or endotoxemia experienced loss of hippocampal long-term potentiation (LTP), a brain-derived neurotrophic factor–mediated (BDNF-mediated) process responsible for spatial memory formation. Memory impairment occurred despite preserved hippocampal BDNF content and could be reversed by stimulation of BDNF signaling, suggesting the presence of a local BDNF inhibitor. Sepsis is associa...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Joseph A. Hippensteel, Brian J. Anderson, James E. Orfila, Sarah A. McMurtry, Robert M. Dietz, Guowei Su, Joshay A. Ford, Kaori Oshima, Yimu Yang, Fuming Zhang, Xiaorui Han, Yanlei Yu, Jian Liu, Robert J. Linhardt, Nuala J. Meyer, Paco S. Herson, Eric P. Source Type: research

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers
Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+CD8+ T cells (GzmB+CD8+ T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-di...
Source: Journal of Clinical Investigation - March 19, 2019 Category: Biomedical Science Authors: Tina Gruosso, Mathieu Gigoux, Venkata Satya Kumar Manem, Nicholas Bertos, Dongmei Zuo, Irina Perlitch, Sadiq Mehdi Ismail Saleh, Hong Zhao, Margarita Souleimanova, Radia Marie Johnson, Anne Monette, Valentina Muñoz Ramos, Michael Trevor Hallett, John Sta Source Type: research