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Journal of Clinical Investigation

Eóin N McNamee
A predominant feature of intestinal inflammation is the accumulation of neutrophils, which dictates a fine balance between epithelial repair or progression to chronic inflammation. While the processes of mucosal healing are well studied, how neutrophils advance an inflammatory insult towards epithelial neoplasia is less understood. In this issue of the JCI, Butin-Israeli et al. outline a mechanism whereby neutrophils control epithelial fitness and genomic instability via delivery of miR-23a-and miR-155-containing microparticles...
January 14, 2019: Journal of Clinical Investigation
Veronika Butin-Israeli, Triet M Bui, Hannah L Wiesolek, Lorraine Mascarenhas, Joseph J Lee, Lindsey C Mehl, Kaitlyn R Knutson, Stephen A Adam, Robert D Goldman, Arthur Beyder, Lisa Wiesmuller, Stephen B Hanauer, Ronen Sumagin
Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBDs). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified what we believe is a new, ROS-independent mechanism whereby activated tissue-infiltrating PMNs release microparticles armed with proinflammatory microRNAs (miR-23a and miR-155). Using IBD clinical samples, and in vitro and in vivo injury models, we show that PMN-derived miR-23a and miR-155 promote accumulation of double-strand breaks (DSBs) by inducing lamin B1-dependent replication fork collapse and inhibition of homologous recombination (HR) by targeting HR-regulator RAD51...
January 14, 2019: Journal of Clinical Investigation
Paul M Armistead
Neoantigen-targeted therapies have typically been based upon personalized neoantigen-specific vaccines; however, in this issue of JCI, van der Lee et al. describe the development of a potential cellular immunotherapy targeting a "public" neoantigen derived from nucleophosmin 1 (NPM1), which is mutated in approximately 30% of acute myeloid leukemias (AMLs). The authors use reverse immunology to predict, and biochemically confirm, NPM1-derived neoepitopes (ΔNPM1) and then generate high-avidity T cell clones and retrovirally transduced T cell populations that kill NPM1-mutated AML...
January 14, 2019: Journal of Clinical Investigation
Dyantha I van der Lee, Rogier M Reijmers, Maria W Honders, Renate S Hagedoorn, Rob Cm de Jong, Michel Gd Kester, Dirk M van der Steen, Arnoud H de Ru, Christiaan Kweekel, Helena M Bijen, Inge Jedema, Hendrik Veelken, Peter A van Veelen, Mirjam Hm Heemskerk, J H Frederik Falkenburg, Marieke Griffioen
The most frequent subtype of acute myeloid leukemia (AML) is defined by mutations in the nucleophosmin 1 (NPM1) gene. Mutated NPM1 (ΔNPM1) is an attractive target for immunotherapy, since it is an essential driver gene and 4 bp frameshift insertions occur in the same hotspot in 30%-35% of AMLs, resulting in a C-terminal alternative reading frame of 11 aa. By searching the HLA class I ligandome of primary AMLs, we identified multiple ΔNPM1-derived peptides. For one of these peptides, HLA-A*02:01-binding CLAVEEVSL, we searched for specific T cells in healthy individuals using peptide-HLA tetramers...
January 14, 2019: Journal of Clinical Investigation
Pat J Morin
The adenomatous polyposis coli (APC) gene plays, among other things, a crucial role in the regulation of cell proliferation and survival through its ability to regulate canonical Wnt signaling. In this issue of the JCI, Wang et al. provide an intriguing new mechanism for APC function involving the regulation of a novel long noncoding RNA (lncRNA), leading to changes in exosome production. APC signaling via this novel pathway can regulate cell proliferation and invasion as well as angiogenesis. In addition to enhancing our understanding of APC function, this new mechanism is of particular clinical significance, as it may provide additional targets for the treatment of APC-mutated cancers...
January 14, 2019: Journal of Clinical Investigation
Alejandro A Pezzulo, Rosarie A Tudas, Carley G Stewart, Luis G Vargas Buonfiglio, Brian D Lindsay, Peter J Taft, Nicholas D Gansemer, Joseph Zabner
Goblet cell metaplasia, a disabling hallmark of chronic lung disease, lacks curative treatments at present. To identify novel therapeutic targets for goblet cell metaplasia, we studied the transcriptional response profile of IL-13-exposed primary human airway epithelia in vitro and asthmatic airway epithelia in vivo. A perturbation-response profile connectivity approach identified geldanamycin, an inhibitor of heat shock protein 90 (HSP90) as a candidate therapeutic target. Our experiments confirmed that geldanamycin and other HSP90 inhibitors prevented IL-13-induced goblet cell metaplasia in vitro and in vivo...
January 14, 2019: Journal of Clinical Investigation
Bochuan Li, Jinlong He, Huizhen Lv, Yajin Liu, Xue Lv, Chenghu Zhang, Yi Zhu, Ding Ai
Local flow patterns determine the uneven distribution of atherosclerotic lesions. This research aims to elucidate the mechanism of regulation of nuclear translocation of Yes-associated protein (YAP) under oscillatory shear stress (OSS) in the atheroprone phenotype of endothelial cells (ECs). We report here that OSS led to tyrosine phosphorylation and strong, continuous nuclear translocation of YAP in ECs that is dependent on integrin α5β1 activation. YAP overexpression in ECs blunted the anti-atheroprone effect of an integrin-α5β1 blocking peptide (ATN161) in Apoe-/- mice...
January 10, 2019: Journal of Clinical Investigation
Daisuke Muraoka, Naohiro Seo, Tae Hayashi, Yoshiro Tahara, Keisuke Fujii, Isao Tawara, Yoshihiro Miyahara, Kana Okamori, Hideo Yagita, Seiya Imoto, Rui Yamaguchi, Mitsuhiro Komura, Satoru Miyano, Masahiro Goto, Shin-Ichi Sawada, Akira Asai, Hiroaki Ikeda, Kazunari Akiyoshi, Naozumi Harada, Hiroshi Shiku
Immune checkpoint inhibitors and adoptive transfer of gene-engineered T cells have emerged as novel therapeutic modalities for hard-to-treat solid tumors; however, many patients are refractory to these immunotherapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. By comparing the tumor microenvironment of checkpoint inhibition-sensitive and -resistant murine solid tumors, we observed that the resistant tumors had low immunogenicity and lacked infiltration of CD8+ T cells at the tumor site...
January 10, 2019: Journal of Clinical Investigation
Alexandra A Soukup, Ye Zheng, Charu Mehta, Jun Wu, Peng Liu, Miao Cao, Inga Hofmann, Yun Zhou, Jing Zhang, Kirby D Johnson, Kyunghee Choi, Sunduz Keles, Emery H Bresnick
The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA2 mutations cause GATA-2-deficiency syndrome involving immunodeficiency, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). GATA-2 physiological activities necessitate that it be strictly regulated, and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans...
January 8, 2019: Journal of Clinical Investigation
Mattias Nd Svensson, Karen M Doody, Benjamin J Schmiedel, Sourya Bhattacharyya, Bharat Panwar, Florian Wiede, Shen Yang, Eugenio Santelli, Dennis J Wu, Cristiano Sacchetti, Ravindra Gujar, Grégory Seumois, William B Kiosses, Isabelle Aubry, Gisen Kim, Piotr Mydel, Shimon Sakaguchi, Mitchell Kronenberg, Tony Tiganis, Michel L Tremblay, Ferhat Ay, Pandurangan Vijayanand, Nunzio Bottini
Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors and loss of PTPN2 promotes T cell expansion and CD4 and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Treg) plays a role in autoimmunity. Here we aimed to model human autoimmune-predisposing PTPN2 variants, which results in a partial loss of PTPN2 expression, in mouse models of RA...
January 8, 2019: Journal of Clinical Investigation
Gergely Karsai, Florian Kraft, Natja Haag, G Christoph Korenke, Benjamin Hänisch, Alaa Othman, Saranya Suriyanarayanan, Regula Steiner, Cordula Knopp, Michael Mull, Markus Bergmann, J Michael Schröder, Joachim Weis, Miriam Elbracht, Matthias Begemann, Thorsten Hornemann, Ingo Kurth
BACKGROUND: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies, however, the entire spectrum of sphingolipid metabolism disorders remained elusive. METHODS: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder...
January 8, 2019: Journal of Clinical Investigation
Devesh C Pant, Imen Dorboz, Agatha Schlüter, Stéphane Fourcade, Nathalie Launay, Javier Joya, Sergio Aguilera-Albesa, Maria Eugenia Yoldi, Carlos Casasnovas, Mary J Willis, Montserrat Ruiz, Dorothée Ville, Gaetan Lesca, Karine Siquier-Pernet, Isabelle Desguerre, Huifang Yan, Jinming Wang, Margit Burmeister, Lauren Brady, Mark Tarnopolsky, Carles Cornet, Davide Rubbini, Javier Terriente, Kiely N James, Damir Musaev, Maha S Zaki, Marc C Patterson, Brendan C Lanpher, Eric W Klee, Filippo Pinto E Vairo, Elizabeth Wohler, Nara Lygia de M Sobreira, Julie S Cohen, Reza Maroofian, Hamid Galehdari, Neda Mazaheri, Gholamreza Shariati, Laurence Colleaux, Diana Rodriguez, Joseph G Gleeson, Cristina Pujades, Ali Fatemi, Odile Boespflug-Tanguy, Aurora Pujol
Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in nineteen patients from thirteen unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity and profound failure to thrive. MRI showed hypomyelination, thinning of corpus callosum and progressive thalami and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance...
January 8, 2019: Journal of Clinical Investigation
Sarah Jackson
The JCI has made all of its research freely available to readers since 1996. As open access mandates from funders, such as Plan S, gain momentum, it's worth revisiting how the JCI has created a durable publication model for free access to research and the benefits that society journals provide to the research community.
January 7, 2019: Journal of Clinical Investigation
Brooke M Ahern, Jonathan Satin
Stressful situations provoke the fight-or-flight response, incurring rapid elevation of cardiac output via activation of protein kinase A (PKA). In this issue of the JCI, Yang et al. focus on the L-type calcium channel complex (LTCC), and their findings require reexamination of dogmatic principles. LTCC phosphorylation sites identified and studied to date are dispensable for PKA modulation of LTCC; however, a CaVβ2-CaV1.2 calcium channel interaction is now shown to be required. Yang et al. suggest a new hypothesis that LTCC modulation involves rearrangement of auxiliary proteins within the LTCC...
January 7, 2019: Journal of Clinical Investigation
Mark W Dewhirst, Yvonne M Mowery, James B Mitchell, Murali K Cherukuri, Timothy W Secomb
No abstract text is available yet for this article.
January 7, 2019: Journal of Clinical Investigation
Elena Gallo MacFarlane, Sarah J Parker, Joseph Y Shin, Shira G Ziegler, Tyler J Creamer, Rustam Bagirzadeh, Djahida Bedja, Yichun Chen, Juan F Calderon, Katherine Weissler, Pamela A Frischmeyer-Guerrerio, Mark E Lindsay, Jennifer P Habashi, Harry C Dietz
The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field-derived (SHF-derived), but not neighboring cardiac neural crest-derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands...
January 7, 2019: Journal of Clinical Investigation
John C Chappell, Laura Beth Payne, W Kimryn Rathmell
The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma...
January 7, 2019: Journal of Clinical Investigation
Lamis Yehia, Joanne Ngeow, Charis Eng
The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies...
January 7, 2019: Journal of Clinical Investigation
Sarah Jackson
The JCI and JCI Insight announce the Reviewer Rewards program to recognize the outstanding contribution of peer reviewers to our evaluation process. As a token of our appreciation, eligible reviewers who have completed 3 or more reviews may designate one of their own research manuscripts for guaranteed external review when they submit to the corresponding journal.
January 2, 2019: Journal of Clinical Investigation
Roman M Chabanon, Gareth Muirhead, Dragomir B Krastev, Julien Adam, Daphné Morel, Marlène Garrido, Andrew Lamb, Clémence Hénon, Nicolas Dorvault, Mathieu Rouanne, Rebecca Marlow, Ilirjana Bajrami, Marta Llorca Cardeñosa, Asha Konde, Benjamin Besse, Alan Ashworth, Stephen J Pettitt, Syed Haider, Aurélien Marabelle, Andrew Nj Tutt, Jean-Charles Soria, Christopher J Lord, Sophie Postel-Vinay
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I interferon transcriptomic signature, and that low ERCC1 expression correlates with increased lymphocytic infiltration...
December 27, 2018: Journal of Clinical Investigation
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