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https://www.readbyqxmd.com/read/28289723/setting-the-target-for-pemphigus-vulgaris-therapy
#1
REVIEW
Christoph T Ellebrecht, Aimee S Payne
Despite the rising incidence of autoimmunity, therapeutic options for patients with autoimmune disease still rely on decades-old immunosuppressive strategies that risk severe and potentially fatal complications. Thus, novel therapeutic approaches for autoimmune diseases are greatly needed in order to minimize treatment-related toxicity. Such strategies would ideally target only the autoreactive immune components to preserve beneficial immunity. Here, we review how several decades of basic, translational, and clinical research on the immunology of pemphigus vulgaris (PV), an autoantibody-mediated skin disease, have enabled the development of targeted immunotherapeutic strategies...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289722/assessment-of-ciliary-phenotype-in-primary-ciliary-dyskinesia-by-micro-optical-coherence-tomography
#2
George M Solomon, Richard Francis, Kengyeh K Chu, Susan E Birket, George Gabriel, John E Trombley, Kristi L Lemke, Nikolai Klena, Brett Turner, Guillermo J Tearney, Cecilia W Lo, Steven M Rowe
Ciliary motion defects cause defective mucociliary transport (MCT) in primary ciliary dyskinesia (PCD). Current diagnostic tests do not assess how MCT is affected by perturbation of ciliary motion. In this study, we sought to use micro-optical coherence tomography (μOCT) to delineate the mechanistic basis of cilia motion defects of PCD genes by functional categorization of cilia motion. Tracheae from three PCD mouse models were analyzed using μOCT to characterize ciliary motion and measure MCT. We developed multiple measures of ciliary activity, integrated these measures, and quantified dyskinesia by the angular range of the cilia effective stroke (ARC)...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289721/platelets-from-pulmonary-hypertension-patients-show-increased-mitochondrial-reserve-capacity
#3
Quyen L Nguyen, Catherine Corey, Pamela White, Annie Watson, Mark T Gladwin, Marc A Simon, Sruti Shiva
Accumulating evidence suggests that altered cellular metabolism is systemic in pulmonary hypertension (PH) and central to disease pathogenesis. However, bioenergetic changes in PH patients and their association with disease severity remain unclear. Here, we hypothesize that alteration in bioenergetic function is present in platelets from PH patients and correlates with clinical parameters of PH. Platelets isolated from controls and PH patients (n = 28) were subjected to extracellular flux analysis to determine oxygen consumption and glycolytic rates...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289720/discerning-functional-hierarchies-of-micrornas-in-pulmonary-hypertension
#4
REVIEW
Vinny Negi, Stephen Y Chan
Pulmonary hypertension (PH) is a multifaceted vascular disease where development and severity are determined by both genetic and environmental factors. Over the past decade, there has been an acceleration of the discovery of molecular effectors that mediate PH pathogenesis, including large numbers of microRNA molecules that are expressed in pulmonary vascular cell types and exert system-wide regulatory functions in all aspects of vascular health and disease. Due to the inherent pleiotropy, overlap, and redundancy of these molecules, it has been challenging to define their integrated effects on overall disease manifestation...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289719/type-i-interferons-regulate-susceptibility-to-inflammation-induced-preterm-birth
#5
Monica Cappelletti, Pietro Presicce, Matthew J Lawson, Vandana Chaturvedi, Traci E Stankiewicz, Simone Vanoni, Isaac T W Harley, Jaclyn W McAlees, Daniel A Giles, Maria E Moreno-Fernandez, Cesar M Rueda, Paranth Senthamaraikannan, Xiaofei Sun, Rebekah Karns, Kasper Hoebe, Edith M Janssen, Christopher L Karp, David A Hildeman, Simon P Hogan, Suhas G Kallapur, Claire A Chougnet, Sing Sing Way, Senad Divanovic
Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection-driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern-driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289718/elucidation-of-mras-mediated-noonan-syndrome-with-cardiac-hypertrophy
#6
Erin M Higgins, J Martijn Bos, Heather Mason-Suares, David J Tester, Jaeger P Ackerman, Calum A MacRae, Katia Sol-Church, Karen W Gripp, Raul Urrutia, Michael J Ackerman
Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289717/retinoic-acid-orphan-receptor-c-inhibition-suppresses-th17-cells-and-induces-thymic-aberrations
#7
Christine Guntermann, Alessandro Piaia, Marie-Laure Hamel, Diethilde Theil, Tina Rubic-Schneider, Alberto Del Rio-Espinola, Linda Dong, Andreas Billich, Klemens Kaupmann, Janet Dawson, Klemens Hoegenauer, David Orain, Samuel Hintermann, Rowan Stringer, Dhavalkumar D Patel, Arno Doelemeyer, Mark Deurinck, Jens Schümann
Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289716/muscular-dystrophy-in-ptfr-cavin-1-null-mice
#8
Shi-Ying Ding, Libin Liu, Paul F Pilch
ice and humans lacking the caveolae component polymerase I transcription release factor (PTRF, also known as cavin-1) exhibit lipo- and muscular dystrophy. Here we describe the molecular features underlying the muscle phenotype for PTRF/cavin-1 null mice. These animals had a decreased ability to exercise, and exhibited muscle hypertrophy with increased muscle fiber size and muscle mass due, in part, to constitutive activation of the Akt pathway. Their muscles were fibrotic and exhibited impaired membrane integrity accompanied by an apparent compensatory activation of the dystrophin-glycoprotein complex along with elevated expression of proteins involved in muscle repair function...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289715/cerebrovascular-adaptations-to-cocaine-induced-transient-ischemic-attacks-in-the-rodent-brain
#9
Jiang You, Nora D Volkow, Kicheon Park, Qiujia Zhang, Kevin Clare, Congwu Du, Yingtian Pan
Occurrence of transient ischemic attacks (TIA) and cerebral strokes is a recognized risk associated with cocaine abuse. Here, we use a rodent model along with optical imaging to study cocaine-induced TIA and the associated dynamic changes in cerebral blood flow velocity (CBFv) and cerebrovasculature. We show that chronic cocaine exposure in mice resulted in marked cortical hypoperfusion, in significant arterial and venous vasoconstriction, and in a sensitized vascular response to an acute cocaine injection...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289714/bile-acids-initiate-cholestatic-liver-injury-by-triggering-a-hepatocyte-specific-inflammatory-response
#10
Shi-Ying Cai, Xinshou Ouyang, Yonglin Chen, Carol J Soroka, Juxian Wang, Albert Mennone, Yucheng Wang, Wajahat Z Mehal, Dhanpat Jain, James L Boyer
Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in Ccl2(-/-) mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289713/th17-cells-are-refractory-to-senescence-and-retain-robust-antitumor-activity-after-long-term-ex-vivo-expansion
#11
Jacob S Bowers, Michelle H Nelson, Kinga Majchrzak, Stefanie R Bailey, Baerbel Rohrer, Andrew D M Kaiser, Carl Atkinson, Luca Gattinoni, Chrystal M Paulos
Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8(+) T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4(+) T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289712/rcan1-4-is-a-thyroid-cancer-growth-and-metastasis-suppressor
#12
Chaojie Wang, Motoyasu Saji, Steven E Justiniano, Adlina Mohd Yusof, Xiaoli Zhang, Lianbo Yu, Soledad Fernández, Paul Wakely, Krista La Perle, Hiroshi Nakanishi, Neal Pohlman, Matthew D Ringel
Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289711/the-volume-regulated-anion-channel-lrrc8-in-nodose-neurons-is-sensitive-to-acidic-ph
#13
Runping Wang, Yongjun Lu, Susheel Gunasekar, Yanhui Zhang, Christopher J Benson, Mark W Chapleau, Rajan Sah, François M Abboud
The leucine rich repeat containing protein 8A (LRRC8A), or SWELL1, is an essential component of the volume-regulated anion channel (VRAC) that is activated by cell swelling and ionic strength. We report here for the first time to our knowledge its expression in a primary cell culture of nodose ganglia neurons and its localization in the soma, neurites, and neuronal membrane. We show that this neuronal VRAC/SWELL1 senses low external pH (pHo) in addition to hypoosmolarity. A robust sustained chloride current is seen in 77% of isolated nodose neurons following brief exposures to extracellular acid pH...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289710/targeting-adhesion-signaling-in-kras-lkb1-mutant-lung-adenocarcinoma
#14
Melissa Gilbert-Ross, Jessica Konen, Junghui Koo, John Shupe, Brian S Robinson, Walter Guy Wiles, Chunzi Huang, W David Martin, Madhusmita Behera, Geoffrey H Smith, Charles E Hill, Michael R Rossi, Gabriel L Sica, Manali Rupji, Zhengjia Chen, Jeanne Kowalski, Andrea L Kasinski, Suresh S Ramalingam, Haian Fu, Fadlo R Khuri, Wei Zhou, Adam I Marcus
Loss of LKB1 activity is prevalent in KRAS mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in LKB1 mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype. We established a lenti-Cre-induced Kras and Lkb1 mutant genetically engineered mouse model (KLLenti) that develops 100% lung adenocarcinoma and showed that high spatiotemporal FAK activation occurs in collective invasive cells that are surrounded by high levels of collagen...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289709/imaging-mass-spectrometry-demonstrates-age-related-decline-in-human-adipose-plasticity
#15
Christelle Guillermier, Pouneh K Fazeli, Soomin Kim, Mingyue Lun, Jonah P Zuflacht, Jessica Milian, Hang Lee, Hugues Francois-Saint-Cyr, Francois Horreard, David Larson, Evan D Rosen, Richard T Lee, Claude P Lechene, Matthew L Steinhauser
Quantification of stable isotope tracers has revealed the dynamic state of living tissues. A new form of imaging mass spectrometry quantifies isotope ratios in domains much smaller than a cubic micron, enabling measurement of cell turnover and metabolism with stable isotope tracers at the single-cell level with a methodology we refer to as multi-isotope imaging mass spectrometry. In a first-in-human study, we utilize stable isotope tracers of DNA synthesis and de novo lipogenesis to prospectively measure cell birth and adipocyte lipid turnover...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289708/interruption-of-ox40l-signaling-prevents-costimulation-blockade-resistant-allograft-rejection
#16
William H Kitchens, Ying Dong, David V Mathews, Cynthia P Breeden, Elizabeth Strobert, Maria E Fuentes, Christian P Larsen, Mandy L Ford, Andrew B Adams
The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289707/eomesodermin-and-t-bet-mark-developmentally-distinct-human-natural-killer-cells
#17
Amélie Collins, Nyanza Rothman, Kang Liu, Steven L Reiner
Immaturity of the immune system of human fetuses and neonates is often invoked to explain their increased susceptibility to infection; however, the development of the fetal innate immune system in early life remains incompletely explored. We now show that the most mature NK cells found in adult (or postnatal) human circulation (CD94(-)CD16(+)) are absent during ontogeny. Human fetal NK cells were found to express the 2 signature T-box transcription factors essential for the development of all murine NK and NK-like cells, eomesodermin (Eomes) and T-bet...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289706/plastin-3-extends-survival-and-reduces-severity-in-mouse-models-of-spinal-muscular-atrophy
#18
Kevin A Kaifer, Eric Villalón, Erkan Y Osman, Jacqueline J Glascock, Laura L Arnold, D D W Cornelison, Christian L Lorson
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289705/als-patients-regulatory-t-lymphocytes-are-dysfunctional-and-correlate-with-disease-progression-rate-and-severity
#19
David R Beers, Weihua Zhao, Jinghong Wang, Xiujun Zhang, Shixiang Wen, Dan Neal, Jason R Thonhoff, Abdullah S Alsuliman, Elizabeth J Shpall, Katy Rezvani, Stanley H Appel
Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28289704/preferential-tnf%C3%AE-signaling-via-tnfr2-regulates-epithelial-injury-and-duct-obstruction-in-experimental-biliary-atresia
#20
Pranavkumar Shivakumar, Tatsuki Mizuochi, Reena Mourya, Sridevi Gutta, Li Yang, Zhenhua Luo, Jorge A Bezerra
Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNFα to apoptosis of the bile duct epithelium in the presence of IFNγ. Here, we investigate if TNFα signaling regulates pathogenic mechanisms of biliary atresia. First, we quantified the expression of TNFA and its receptors TNFR1 and TNFR2 in human livers and found an increased expression of the receptors at the time of diagnosis...
March 9, 2017: JCI Insight
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