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JCI Insight

Alexander A Merleev, Alina I Marusina, Chelsea Ma, James T Elder, Lam C Tsoi, Siba P Raychauduri, Stephan Weidinger, Elizabeth A Wang, Iannis E Adamopoulos, Guillaume Luxardi, Johann E Gudjonsson, Michiko Shimoda, Emanual Maverakis
Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-γ segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A)...
July 12, 2018: JCI Insight
Jane Rasaiyaah, Christos Georgiadis, Roland Preece, Ulrike Mock, Waseem Qasim
T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3-specific CAR T cells...
July 12, 2018: JCI Insight
Sungsam Gong, Ulla Sovio, Irving Lmh Aye, Francesca Gaccioli, Justyna Dopierala, Michelle D Johnson, Angela M Wood, Emma Cook, Benjamin J Jenkins, Albert Koulman, Robert A Casero, Miguel Constância, D Stephen Charnock-Jones, Gordon Cs Smith
Preeclampsia and fetal growth restriction (FGR) are major causes of the more than 5 million perinatal and infant deaths occurring globally each year, and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males, but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction (POP) study, a prospective cohort study that followed 4,212 women having first pregnancies from their dating ultrasound scan through delivery...
July 12, 2018: JCI Insight
Omar H Maarouf, Mayuko Uehara, Vivek Kasinath, Zhabiz Solhjou, Naima Banouni, Baharak Bahmani, Liwei Jiang, Osman A Yilmam, Indira Guleria, Scott B Lovitch, Jane L Grogan, Paolo Fiorina, Peter T Sage, Jonathan S Bromberg, Martina M McGrath, Reza Abdi
The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significant expansion in the extracellular matrix...
July 12, 2018: JCI Insight
J Brian McAlvin, Ryan G Wylie, Krithika Ramchander, Minh T Nguyen, Charles K Lok, Morgan Moroi, Andre Shomorony, Nikolay V Vasilyev, Patrick Armstrong, Jason Yang, Alexander M Lieber, Obiajulu S Okonkwo, Rohit Karnik, Daniel S Kohane
Cytokines play an important role in dysregulated immune responses to infection, pancreatitis, ischemia/reperfusion injury, burns, hemorrhage, cardiopulmonary bypass, trauma, and many other diseases. Moreover, the imbalance between inflammatory and antiinflammatory cytokines can have deleterious effects. Here, we demonstrated highly selective blood-filtering devices - antibody-modified conduits (AMCs) - that selectively eliminate multiple specific deleterious cytokines in vitro. AMCs functionalized with antibodies against human vascular endothelial growth factor A or tumor necrosis factor α (TNF-α) selectively eliminated the target cytokines from human blood in vitro and maintained them in reduced states even in the face of ongoing infusion at supraphysiologic rates...
July 12, 2018: JCI Insight
Geir Ringstad, Lars M Valnes, Anders M Dale, Are H Pripp, Svein-Are S Vatnehol, Kyrre E Emblem, Kent-Andre Mardal, Per K Eide
To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus)...
July 12, 2018: JCI Insight
Dan B Swartzlander, Nicholas E Propson, Ethan R Roy, Takashi Saito, Takaomi Saido, Baiping Wang, Hui Zheng
Nonneuronal cell types in the CNS are increasingly implicated as critical players in brain health and disease. While gene expression profiling of bulk brain tissue is routinely used to examine alterations in the brain under various conditions, it does not capture changes that occur within single cell types or allow interrogation of crosstalk among cell types. To this end, we have developed a concurrent brain cell type acquisition (CoBrA) methodology, enabling the isolation and profiling of microglia, astrocytes, endothelia, and oligodendrocytes from a single adult mouse forebrain...
July 12, 2018: JCI Insight
Juhyun Lee, Vijay Vedula, Kyung In Baek, Junjie Chen, Jeffrey J Hsu, Yichen Ding, Chih-Chiang Chang, Hanul Kang, Adam Small, Peng Fei, Cheng-Ming Chuong, Rongsong Li, Linda Demer, René R Sevag Packard, Alison L Marsden, Tzung K Hsiai
Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf...
July 12, 2018: JCI Insight
Swati Bhattacharyya, Wenxia Wang, Wenyi Qin, Kui Cheng, Sara Coulup, Sherry Chavez, Shuangshang Jiang, Kirtee Raparia, Lucia Maria V De Almeida, Christian Stehlik, Zenshiro Tamaki, Hang Yin, John Varga
Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies...
July 12, 2018: JCI Insight
Kevin C Ma, Edward J Schenck, Ilias I Siempos, Suzanne M Cloonan, Eli J Finkelzstein, Maria A Pabon, Clara Oromendia, Karla V Ballman, Rebecca M Baron, Laura E Fredenburgh, Angelica Higuera, Jin Young Lee, Chi Ryang Chung, Kyeongman Jeon, Jeong Hoon Yang, Judie A Howrylak, Jin-Won Huh, Gee Young Suh, Augustine Mk Choi
BACKGROUND: Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS: Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea...
July 12, 2018: JCI Insight
Ekaterina Taneva, Shada Sinclair, Pedro Mm Mesquita, Brian Weinrick, Scott A Cameron, Natalia Cheshenko, Kerry Reagle, Bruce Frank, Sujatha Srinivasan, David Fredricks, Marla J Keller, Betsy C Herold
Tenofovir gel and dapivirine ring provided variable HIV protection in clinical trials, reflecting poor adherence and possibly biological factors. We hypothesized that vaginal microbiota modulates pharmacokinetics and tested the effects of pH, individual bacteria, and vaginal swabs from women on pharmacokinetics and antiviral activity. Tenofovir, but not dapivirine, uptake by human cells was reduced as pH increased. Lactobacillus crispatus actively transported tenofovir leading to a loss in drug bioavailability and culture supernatants from Gardnerella vaginalis, but not Atopobium vaginae, blocked tenofovir endocytosis...
July 12, 2018: JCI Insight
Leesun Kim, David Liebowitz, Karen Lin, Kassandra Kasparek, Marcela F Pasetti, Shaily J Garg, Keith Gottlieb, George Trager, Sean N Tucker
BACKGROUND: Noroviruses are the leading cause of epidemic acute gastroenteritis and foodborne diarrheal disease in humans. However, there are no approved vaccines for noroviruses. Potential correlates of protection identified through human challenge studies include mucosal IgA, memory B cells, and serum-blocking antibody titers (BT50). METHODS: We conducted a single-site, randomized, double-blind, placebo-controlled clinical trial of an oral norovirus vaccine to determine safety and immunogenicity...
July 12, 2018: JCI Insight
Ray El Boustany, Irina Tasevska, Esther Meijer, Lyanne M Kieneker, Sofia Enhörning, Guillaume Lefèvre, Kamel Mohammedi, Michel Marre, Frédéric Fumeron, Beverley Balkau, Nadine Bouby, Lise Bankir, Stephan Jl Bakker, Ronan Roussel, Olle Melander, Ron T Gansevoort, Gilberto Velho
BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands)...
July 12, 2018: JCI Insight
Diane Goltz, Heidrun Gevensleben, Timo J Vogt, Joern Dietrich, Carsten Golletz, Friedrich Bootz, Glen Kristiansen, Jennifer Landsberg, Dimo Dietrich
Recent years have witnessed the groundbreaking success of immune checkpoint blockage (ICB) in metastasized malignant melanoma. However, biomarkers predicting the response to ICB are still urgently needed. In the present study, we investigated CTLA4 promoter methylation (mCTLA4) in 470 malignant melanoma patients from The Cancer Genome Atlas (non-ICB cohort) and in 50 individuals with metastasized malignant melanomas under PD-1/CTLA-4-targeted immunotherapy (ICB cohort). mCTLA4 levels were quantified using the Infinium HumanMethylation450 BeadChip (non-ICB cohort) and methylation-specific quantitative real-time PCR in DNA formalin-fixed and paraffin-embedded tissues (ICB cohort)...
July 12, 2018: JCI Insight
Michele Di Mascio, Sharat Srinivasula, Insook Kim, Gorka Duralde, Alexis St Claire, Paula DeGrange, Marisa St Claire, Keith A Reimann, Erin E Gabriel, Jorge Carrasquillo, Richard C Reba, Chang Paik, Henry C Lane
The peripheral blood represents only a small fraction of the total number of lymphocytes in the body. To develop a more thorough understanding of T cell dynamics, including the effects of SIV/SHIV/HIV infection on immune cell depletion and immune reconstitution following combination antiretroviral therapy (cART), one needs to utilize approaches that allow direct visualization of lymphoid tissues. In the present study, noninvasive in vivo imaging of the CD4+ T cell pool has revealed that the timing of the CD4+ T cell pool reconstitution following initiation of ART in SIV-infected nonhuman primates (NHPs) appears seemingly stochastic among clusters of lymph nodes within the same host...
July 12, 2018: JCI Insight
Mary K McCarthy, Bennett J Davenport, Glennys V Reynoso, Erin D Lucas, Nicholas A May, Susan A Elmore, Beth A Tamburini, Heather D Hickman, Thomas E Morrison
Chikungunya virus (CHIKV) causes acute and chronic rheumatologic disease. Pathogenic CHIKV strains persist in joints of immunocompetent mice, while the attenuated CHIKV strain 181/25 is cleared by adaptive immunity. We analyzed the draining lymph node (dLN) to define events in lymphoid tissue that may contribute to CHIKV persistence or clearance. Acute 181/25 infection resulted in dLN enlargement and germinal center (GC) formation, while the dLN of mice infected with pathogenic CHIKV became highly disorganized and depleted of lymphocytes...
July 12, 2018: JCI Insight
Matthieu Sawaf, Jean-Daniel Fauny, Renaud Felten, Flora Sagez, Jacques-Eric Gottenberg, Hélène Dumortier, Fanny Monneaux
Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls...
July 12, 2018: JCI Insight
Tinhinane Fali, Véronique Fabre-Mersseman, Takuya Yamamoto, Charles Bayard, Laura Papagno, Solène Fastenackels, Rima Zoorab, Richard A Koup, Jacques Boddaert, Delphine Sauce, Victor Appay
The maintenance of effective immunity over time is dependent on the capacity of hematopoietic stem cells (HSCs) to sustain the pool of immunocompetent mature cells. Decline of immune competence with old age may stem from HSC defects, including reduced self-renewal potential and impaired lymphopoiesis, as suggested in murine models. To obtain further insights into aging-related alteration of hematopoiesis, we performed a comprehensive study of blood hematopoietic progenitor cells (HPCs) from older humans. In the elderly, HPCs present active oxidative phosphorylation and are pressed to enter cell cycling...
July 12, 2018: JCI Insight
Alexander C Hopkins, Mark Yarchoan, Jennifer N Durham, Erik C Yusko, Julie A Rytlewski, Harlan S Robins, Daniel A Laheru, Dung T Le, Eric R Lutz, Elizabeth M Jaffee
BACKGROUND: Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes. METHODS: We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab...
July 12, 2018: JCI Insight
Geoffrey J Markowitz, Lauren S Havel, Michael Jp Crowley, Yi Ban, Sharrell B Lee, Jennifer S Thalappillil, Navneet Narula, Bhavneet Bhinder, Olivier Elemento, Stephen Tc Wong, Dingcheng Gao, Nasser K Altorki, Vivek Mittal
Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression...
July 12, 2018: JCI Insight
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