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Journal of Clinical Investigation

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https://www.readbyqxmd.com/read/29447131/dna-repair-deficiency-sensitizes-lung-cancer-cells-to-nad-biosynthesis-blockade
#1
Mehdi Touat, Tony Sourisseau, Nicolas Dorvault, Roman M Chabanon, Marlène Garrido, Daphné Morel, Dragomir B Krastev, Ludovic Bigot, Julien Adam, Jessica Frankum, Sylvère Durand, Clement Pontoizeau, Sylvie Souquère, Mei-Shiue Kuo, Sylvie Sauvaigo, Faraz Mardakheh, Alain Sarasin, Ken A Olaussen, Luc Friboulet, Frédéric Bouillaud, Gérard Pierron, Alan Ashworth, Anne Lombès, Christopher J Lord, Jean-Charles Soria, Sophie Postel-Vinay
Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. ERCC1 deficiency is frequently found in non-small cell lung cancers, making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in this disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT)...
February 15, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29438108/stat3-enhancing-germline-mutations-contribute-to-tumor-extrinsic-immune-evasion
#2
Daniel Kogan, Alexander Grabner, Christopher Yanucil, Christian Faul, Vijay Kumar Ulaganathan
Immune evasion and the suppression of anti-tumor responses during cancer progression are considered hallmarks of cancer and are typically attributed to tumor-derived factors. Although the molecular basis for the crosstalk between tumor and immune cells is an area of active investigation, whether host-specific germline variants can dictate immunosuppressive mechanisms has remained a challenge to address. A commonly occurring germline mutation (c.1162G>A/rs351855 G/A) in the FGFR4 (CD334) gene enhances STAT3 signaling and is associated with poor prognosis and accelerated progression of multiple cancer types...
February 13, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29438107/methyldopa-blocks-mhc-class-ii-binding-to-disease-specific-antigens-in-autoimmune-diabetes
#3
David A Ostrov, Aimon Alkanani, Kristen A McDaniel, Stephanie Case, Erin E Baschal, Laura Pyle, Samuel Ellis, Bernadette Pöllinger, Katherine J Seidl, Viral N Shah, Satish K Garg, Mark A Atkinson, Peter A Gottlieb, Aaron W Michels
Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes, the DQ8 molecule is common, confers significant disease risk and is involved in disease pathogenesis. We hypothesized blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft...
February 13, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29431735/vhl-deletion-in-osteoblasts-boosts-cellular-glycolysis-and-improves-global-glucose-metabolism
#4
Naomi Dirckx, Robert J Tower, Evi M Mercken, Roman Vangoitsenhoven, Caroline Moreau-Triby, Tom Breugelmans, Elena Nefyodova, Ruben Cardoen, Chantal Mathieu, Bart Van der Schueren, Cyrille B Confavreux, Thomas L Clemens, Christa Maes
The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin...
February 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29431734/disruption-of-staphylococcal-aggregation-protects-against-lethal-lung-injury
#5
Jaime L Hook, Mohammad N Islam, Dane Parker, Alice S Prince, Sunita Bhattacharya, Jahar Bhattacharya
Infection by Staphylococcus aureus strain USA300 causes tissue injury, multiorgan failure, and high mortality. However, the mechanisms by which the bacteria adhere to, then stabilize on, mucosal surfaces before causing injury remain unclear. We addressed these issues through the first real-time determinations of USA300-alveolar interactions in live lungs. We found that within minutes, inhaled USA300 established stable, self-associated microaggregates in niches at curved, but not at flat, regions of the alveolar wall...
February 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29431733/cardiovascular-outcome-trials-of-diabetes-drugs-lessons-learned
#6
Simeon I Taylor, Bruce R Leslie
No abstract text is available yet for this article.
February 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29431732/stat3-p53-pathway-activation-disrupts-ifn-%C3%AE-induced-dormancy-in-tumor-repopulating-cells
#7
Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F Xiao-Feng Qin, Bo Huang
Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models...
February 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29431731/physiological-genomics-identifies-genetic-modifiers-of-long-qt-syndrome-type-2-severity
#8
Sam Chai, Xiaoping Wan, Angelina Ramirez-Navarro, Paul J Tesar, Elizabeth S Kaufman, Eckhard Ficker, Alfred L George, Isabelle Deschênes
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner...
February 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29408809/foxo-transcription-factors-are-required-for-hepatic-hdl-cholesterol-clearance
#9
Samuel X Lee, Markus Heine, Christian Schlein, Rajasekhar Ramakrishnan, Jing Liu, Gabriella Belnavis, Ido Haimi, Alexander W Fischer, Henry Ginsberg, Joerg Heeren, Franz Rinninger, Rebecca A Haeusler
Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein-cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of insulin's effect on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C...
February 6, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29408808/pain-control-through-selective-chemo-axotomy-of-centrally-projecting-trpv1-sensory-neurons
#10
Matthew R Sapio, John K Neubert, Danielle M LaPaglia, Dragan Maric, Jason M Keller, Stephen J Raithel, Eric L Rohrs, Ethan M Anderson, John A Butman, Robert M Caudle, Dorothy C Brown, John D Heiss, Andrew J Mannes, Michael J Iadarola
Transient vanilloid potential 1 (TRPV1) agonists are emerging as highly efficacious non-opioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma...
February 6, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29408807/modifier-variant-of-mettl13-suppresses-human-gab1-associated-profound-deafness
#11
Rizwan Yousaf, Zubair M Ahmed, Arnaud Pj Giese, Robert J Morell, Ayala Lagziel, Alain Dabdoub, Edward R Wilcox, Sheikh Riazuddin, Thomas B Friedman, Saima Riazuddin
A modifier variant can abrogate risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin-homology-domain of GAB1, an essential scaffold in the MET/HGF pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescues the GAB1 associated morphant phenotype...
February 6, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29408806/loss-of-function-card8-mutation-causes-nlrp3-inflammasome-activation-and-crohn-s-disease
#12
Liming Mao, Atsushi Kitani, Morgan Similuk, Andrew J Oler, Lindsey Albenberg, Judith Kelsen, Atiye Aktay, Martha Quezado, Michael Yao, Kim Montgomery-Recht, Ivan J Fuss, Warren Strober
In these studies we evaluated the contribution of the NLRP3 inflammasome to Crohn's disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified that the affected individuals had a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL-1β in the affected individuals were increased compared with that in healthy controls and their peripheral monocytes produced increased amounts of IL-1β when stimulated by NLRP3 activators...
February 6, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29408805/ribonuclease-inhibitor-1-regulates-erythropoiesis-by-controlling-gata1-mrna-translation
#13
Vijaykumar Chennupati, Diogo Ft Veiga, Kendle M Maslowski, Nicola Andina, Aubry Tardivel, Eric Chi-Wang Yu, Martina Stilinovic, Cedric Simillion, Michel A Duchosal, Manfredo Quadroni, Irene Roberts, Vijay G Sankaran, H Robson MacDonald, Nicolas Fasel, Anne Angelillo-Scherrer, Pascal Schneider, Trang Hoang, Ramanjaneyulu Allam
Ribosomal proteins (RP) regulate specific gene expression by selectively translating subsets of mRNAs. Indeed, in Diamond-Blackfan anaemia and 5q- syndrome, mutations in RP genes lead to a specific defect in erythroid gene translation and cause anaemia. Little is known about the molecular mechanisms of selective mRNA translation and involvement of ribosomal-associated factors in this process. Ribonuclease inhibitor (RNH1) is an ubiquitously expressed protein that binds to and inhibits pancreatic-type ribonucleases...
February 6, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400698/clonally-expanded-%C3%AE-%C3%AE-t-cells-protect-against-staphylococcus-aureus-skin-reinfection
#14
Carly A Dillen, Bret L Pinsker, Alina I Marusina, Alexander A Merleev, Orly N Farber, Haiyun Liu, Nathan K Archer, Da B Lee, Yu Wang, Roger V Ortines, Steven K Lee, Mark C Marchitto, Shuting S Cai, Alyssa G Ashbaugh, Larissa S May, Steven M Holland, Alexandra F Freeman, Loren G Miller, Michael R Yeaman, Scott I Simon, Joshua D Milner, Emanual Maverakis, Lloyd S Miller
The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1β-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400697/randomized-controlled-trial-of-tnf-%C3%AE-antagonist-in-ctl-mediated-severe-cutaneous-adverse-reactions
#15
Chuang-Wei Wang, Lan-Yan Yang, Chun-Bing Chen, Hsin-Chun Ho, Shuen-Iu Hung, Chih-Hsun Yang, Chee-Jen Chang, Shih-Chi Su, Rosaline Chung-Yee Hui, See-Wen Chin, Li-Fang Huang, Yang Yu-Wei Lin, Wei-Yang Chang, Wen-Lang Fan, Chin-Yi Yang, Ji-Chen Ho, Ya-Ching Chang, Chun-Wei Lu, Wen-Hung Chung
BACKGROUND: Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400696/a-tribute-to-terry-strom
#16
Laurence A Turka, Manikka Suthanthiran
No abstract text is available yet for this article.
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400695/claudin-18-mediated-yap-activity-regulates-lung-stem-and-progenitor-cell-homeostasis-and-tumorigenesis
#17
Beiyun Zhou, Per Flodby, Jiao Luo, Dan R Castillo, Yixin Liu, Fa-Xing Yu, Alicia McConnell, Bino Varghese, Guanglei Li, Nyam-Osor Chimge, Mitsuhiro Sunohara, Michael N Koss, Wafaa Elatre, Peter Conti, Janice M Liebler, Chenchen Yang, Crystal N Marconett, Ite A Laird-Offringa, Parviz Minoo, Kunliang Guan, Barry R Stripp, Edward D Crandall, Zea Borok
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400694/all-plugged-up-noninvasive-mucus-score-to-assess-airway-dysfunction-in-asthma
#18
Steve N Georas
Asthma is remarkably heterogeneous, and there are multiple underlying inflammatory pathways and structural airway abnormalities that lead to symptomatic disease. Consequently, a current challenge in the field is to precisely characterize different types of asthma, with the goal of developing personalized approaches to therapy. In the current issue of the JCI, Dunican et al. developed a noninvasive way to assess airway dysfunction in asthma by measuring mucus accumulation using multidetector computed tomography (MDCT) and found that mucus plugging of small airways was remarkably common in subjects with severe asthma...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400693/mucus-plugs-in-patients-with-asthma-linked-to-eosinophilia-and-airflow-obstruction
#19
Eleanor M Dunican, Brett M Elicker, David S Gierada, Scott K Nagle, Mark L Schiebler, John D Newell, Wilfred W Raymond, Marrah E Lachowicz-Scroggins, Selena Di Maio, Eric A Hoffman, Mario Castro, Sean B Fain, Nizar N Jarjour, Elliot Israel, Bruce D Levy, Serpil C Erzurum, Sally E Wenzel, Deborah A Meyers, Eugene R Bleecker, Brenda R Phillips, David T Mauger, Erin D Gordon, Prescott G Woodruff, Michael C Peters, John V Fahy
BACKGROUND: The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS: In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils...
February 5, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29400692/hippo-mediated-suppression-of-irs2-akt-signaling-prevents-hepatic-steatosis-and-liver-cancer
#20
Sun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-Min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, Dae-Sik Lim
Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice...
February 5, 2018: Journal of Clinical Investigation
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