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Journal of Clinical Investigation

Myron J Levin, Miranda E Kroehl, Michael J Johnson, Andrew Hammes, Dominik Reinhold, Nancy Lang, Adriana Weinberg
The adjuvanted varicella-zoster virus glycoprotein E (VZV gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50- to 85-year-old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su) gE-specific CD4+ and CD8+ T-cell responses were ≥ 10-fold higher in HZ/su compared with ZV recipients...
July 19, 2018: Journal of Clinical Investigation
Lorena Fontán, Qi Qiao, John M Hatcher, Gabriella Casalena, Ilkay Us, Matt Teater, Matthew Durant, Guangyan Du, Min Xia, Natalia Bilchuk, Spandan Chennamadhavuni, Giuseppe Palladino, Giorgio Inghirami, Ulrike Philippar, Hao Wu, David A Scott, Nathanael S Gray, Ari Melnick
The MALT1 paracaspase plays an essential role in Activated B-cell like Diffuse Large B cell Lymphoma (ABC DLBCL) downstream of B cell and Toll-like receptor pathway genes mutated in these tumors. Although MALT1 is considered to be a compelling therapeutic target, development of tractable and specific MALT1 protease inhibitors has thus far been elusive. Herein, we developed a target engagement assay that provides a quantitative readout for specific MALT1 inhibitory effects in living cells. This enabled a structure-guided medicinal chemistry effort culminating in the discovery of pharmacologically tractable irreversible substrate-mimetic compounds that bind the MALT1 active site...
July 19, 2018: Journal of Clinical Investigation
Radwa Sharaf, Guinevere Q Lee, Xiaoming Sun, Behzad Etemad, Layla M Aboukhater, Zixin Hu, Zabrina L Brumme, Evgenia Aga, Ronald J Bosch, Ying Wen, Golnaz Namazi, Ce Gao, Edward P Acosta, Rajesh T Gandhi, Jeffrey M Jacobson, Daniel Skiest, David M Margolis, Ronald Mitsuyasu, Paul Volberding, Elizabeth Connick, Daniel R Kuritzkes, Michael M Lederman, Xu G Yu, Mathias Lichterfeld, Jonathan Z Li
HIV post-treatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1450 proviral sequences after near-full-length amplification for 10 PTCs and 16 post-treatment non-controllers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective and total clonally-expanded viral genomes was not significantly different between the two groups...
July 19, 2018: Journal of Clinical Investigation
John T Liles, Britton K Corkey, Gregory T Notte, Grant Budas, Eric B Lansdon, Ford Hinojosa-Kirschenbaum, Shawn S Badal, Michael Lee, Brian E Schultz, Sarah Wise, Swetha Pendem, Michael Graupe, Laurie Castonguay, Keith A Koch, Melanie H Wong, Giuseppe A Papalia, Dorothy M French, Theodore Sullivan, Erik G Huntzicker, Frank Y Ma, David J Nikolic-Paterson, Tareq Altuhaifi, Haichun Yang, Agnes B Fogo, David G Breckenridge
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. Herein, we describe the discovery and characterization of a potent and selective small molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis...
July 19, 2018: Journal of Clinical Investigation
Bärbel Edelmann, Nibedita Gupta, Tina M Schnöder, Anja M Oelschlegel, Khurrum Shahzad, Jürgen Goldschmidt, Lars Philipsen, Sönke Weinert, Aniket Ghosh, Felix C Saalfeld, Subbaiah Chary Nimmagadda, Peter Müller, Rüdiger C Braun-Dullaeus, Juliane Mohr, Denise Wolleschak, Stefanie Kliche, Holger Amthauer, Florian H Heidel, Burkhart Schraven, Berend Isermann, Andreas Müller, Thomas Fischer
JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) is marked by dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes and leukocytes. However, the mechanism by which the two major leukocyte integrin chains, β1 and β2, mediate CMN pathophysiology remained unclear. β1 (α4β1; VLA-4) and β2 (αLβ2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here show enhanced adhesion of granulocytes from JAK2+/VF knock-in mice to vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) coated surfaces...
July 19, 2018: Journal of Clinical Investigation
Xiaorong Gu, Quteba Ebrahem, Reda Z Mahfouz, Metis Hasipek, Francis Enane, Tomas Radivoyevitch, Nicolas Rapin, Bartlomiej Przychodzen, Zhenbo Hu, Ramesh Balusu, Claudiu V Cotta, David Wald, Christian Argueta, Yosef Landesman, Maria Paola Martelli, Brunangelo Falini, Hetty Carraway, Bo T Porse, Jaroslaw P Maciejewski, Babal K Jha, Yogen Saunthararajah
Nucleophosmin (NPM1) is amongst the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant-NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein-interactome by mass-spectrometry, and discovered abundant amounts of the master transcription factor driver of monocyte lineage-differentiation PU.1 (SPI1). Mutant-NPM1, which aberrantly accumulates in cytoplasm, dislocated PU...
July 17, 2018: Journal of Clinical Investigation
Lintao Qu, Michael J Caterina
Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein-coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain.
July 16, 2018: Journal of Clinical Investigation
Donna M Martin, W Kimryn Rathmell, Sohail F Tavazoie
No abstract text is available yet for this article.
July 16, 2018: Journal of Clinical Investigation
Corine Martineau, Roy Pascal Naja, Abdallah Husseini, Bachar Hamade, Martin Kaufmann, Omar Akhouayri, Alice Arabian, Glenville Jones, René St-Arnaud
The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect...
July 16, 2018: Journal of Clinical Investigation
Motoyuki Tsuda, Akihisa Fukuda, Nilotpal Roy, Yukiko Hiramatsu, Laura Leonhardt, Nobuyuki Kakiuchi, Kaja Hoyer, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Yuichi Yamaga, Grace E Kim, Haruhiko Akiyama, Seishi Ogawa, Christopher V Wright, Dieter Saur, Kyoichi Takaori, Shinji Uemoto, Matthias Hebrok, Tsutomu Chiba, Hiroshi Seno
Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation...
July 16, 2018: Journal of Clinical Investigation
Eugene Braunwald
No abstract text is available yet for this article.
July 16, 2018: Journal of Clinical Investigation
Francesca D'Addio, Andrea Vergani, Luciano Potena, Anna Maestroni, Vera Usuelli, Moufida Ben Nasr, Roberto Bassi, Sara Tezza, Sergio Dellepiane, Basset El Essawy, Maria Iascone, Attilio Iacovoni, Laura Borgese, Kaifeng Liu, Gary Visner, Sirano Dhe-Paganon, Domenico Corradi, Reza Abdi, Randall C Starling, Franco Folli, Gian Vincenzo Zuccotti, Mohamed H Sayegh, Peter S Heeger, Anil Chandraker, Francesco Grigioni, Paolo Fiorina
Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation...
July 16, 2018: Journal of Clinical Investigation
Brandon M Fox, Alexander J Adami, Travis D Hull
No abstract text is available yet for this article.
July 16, 2018: Journal of Clinical Investigation
Michael Rosenbaum, Rudolph L Leibel
Brown et al. report that two weeks of exogenous leptin administration to leptin-naive individuals with lipodystrophy resulted in increased energy expenditure and lipolysis, decreased ectopic liver fat, improved hepatic and peripheral insulin sensitivity, and attenuated dyslipidemia. Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity. This asymmetry in responses to leptin initiation and cessation is consistent with the other aspects of leptin biology that are dependent on the metabolic context in which this adipocyte-derived hormone functions...
July 16, 2018: Journal of Clinical Investigation
Alex McCampbell, Tracy Cole, Amy J Wegener, Giulio S Tomassy, Amy Setnicka, Brandon J Farley, Kathleen M Schoch, Mariah L Hoye, Mark Shabsovich, Linhong Sun, Yi Luo, Mingdi Zhang, Sai Thankamony, David W Salzman, Merit Cudkowicz, Danielle L Graham, C Frank Bennett, Holly B Kordasiewicz, Eric E Swayze, Timothy M Miller
Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application...
July 16, 2018: Journal of Clinical Investigation
Sangsu Bang, Ya-Kai Xie, Zhi-Jun Zhang, Zilong Wang, Zhen-Zhong Xu, Ru-Rong Ji
The mechanisms of pain induction by inflammation have been extensively studied. However, the mechanisms of pain resolution are not fully understood. Here, we report that GPR37, expressed by macrophages (MΦs) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa2+) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa2+ increases in peritoneal MΦs. Activation of GPR37 by NPD1 and TX14 triggers MΦ phagocytosis of zymosan particles via calcium signaling...
July 16, 2018: Journal of Clinical Investigation
Juergen Lohmeyer, Rory E Morty, Susanne Herold
The use of broad-spectrum antibiotics in empirical antimicrobial therapy is a lifesaving strategy for patients in intensive care. At the same time, antibiotics dramatically increase the risk for nosocomial infections, such as hospital‑acquired pneumonia caused by Pseudomonas aeruginosa, and other antibiotic-resistant bacteria. In this issue of the JCI, Robak and colleagues identified a mechanism by which depletion of resident gut and lung microbiota by antibiotic treatment results in secondary IgA deficiency and impaired anti-P...
July 16, 2018: Journal of Clinical Investigation
Fiona Raso, Sara Sagadiev, Samuel Du, Emily Gage, Tanvi Arkatkar, Genita Metzler, Lynda M Stuart, Mark T Orr, David Rawlings, Shaun Jackson, Adam Lacy-Hulbert, Mridu Acharya
Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through toll-like receptors(TLRs) on B cells promotes many aspects of GC B cell responses, including affinity-maturation, class-switching and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αv integrins and non-canonical autophagy...
July 12, 2018: Journal of Clinical Investigation
Chaoqun Wang, Nabora S Reyes de Mochel, Stephanie A Christenson, Monica Cassandras, Rebecca Moon, Alexis N Brumwell, Lauren E Byrnes, Alfred Li, Yasuyuki Yokosaki, Peiying Shan, Julie B Sneddon, David Jablons, Patty J Lee, Michael A Matthay, Harold A Chapman, Tien Peng
Genome-wide association studies have repeatedly mapped susceptibility loci for emphysema to genes that modify hedgehog signaling, but the functional relevance of hedgehog signaling to this morbid disease remains unclear. In the current study, we identified a broad population of mesenchymal cells in the adult murine lung receptive to hedgehog signaling, characterized by higher activation of hedgehog surrounding the proximal airway relative to the distal alveoli. Single cell RNA-sequencing showed that the hedgehog-receptive mesenchyme is composed of mostly fibroblasts with distinct proximal and distal subsets with discrete identities...
July 12, 2018: Journal of Clinical Investigation
Robert Albero, Anna Enjuanes, Santiago Demajo, Giancarlo Castellano, Magda Pinyol, Noelia García, Cristina Capdevila, Guillem Clot, Helena Suárez-Cisneros, Mariko Shimada, Kennosuke Karube, Mónica López-Guerra, Dolors Colomer, Sílvia Beà, José Ignacio Martin-Subero, Elías Campo, Pedro Jares
Cyclin D1 is an oncogene frequently overexpressed in human cancers that plays a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels...
July 10, 2018: Journal of Clinical Investigation
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