tbuckley/cabot-search huggingface dataset:
Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver
Authors: Siyuan Wang, Zhen‐Zhen Yan, Xia Yang, Shimin An, Kuo Zhang, Yu Qi, Jilin Zheng, Yan‐Xiao Ji, Pi‐Xiao Wang, Chun Fang, Xue‐Yong Zhu, Li‐Jun Shen, Feng‐Juan Yan, Rong Bao, Song Tian, Zhi‐Gang She, Yi‐Da Tang
Journal: Hepatology (2017)

Nonalcoholic fatty liver disease (NAFLD) is a prevalent and complex disease that confers a high risk of severe liver disorders. Despite such public and clinical health importance, very few effective therapies are currently available for NAFLD. We report a protective function and the underlying mechanism of dual-specificity phosphatase 14 (DUSP14) in NAFLD and related metabolic disorders. Insulin resistance, hepatic lipid accumulation, and concomitant inflammatory responses, key pathological processes involved in NAFLD development, were significantly ameliorated by hepatocyte-specific DUSP14 overexpression (DUSP14-HTG) in high-fat diet (HFD)-induced or genetically obese mouse models. By contrast, specific DUSP14 deficiency in hepatocytes (DUSP14-HKO) aggravated these pathological alterations. We provided mechanistic evidence that DUSP14 directly binds to and dephosphorylates transforming growth factor β-activated kinase 1 (TAK1), resulting in the reduced activation of TAK1 and its downstream signaling molecules c-Jun N-terminal kinase 1 (JNK), p38, and nuclear factor kappa B NF-κB. This effect was further evidenced by the finding that inhibiting TAK1 activity effectively attenuated the deterioration of glucolipid metabolic phenotype in DUSP14-HKO mice challenged by HFD administration. Furthermore, we identified that both the binding domain and the phosphatase activity of DUSP14 are required for its protective role against hepatic steatosis, because interruption of the DUSP14-TAK1 interaction abolished the mitigative effects of DUSP14.Hepatocyte DUSP14 is required for maintaining hepatic metabolic homeostasis and for suppressing inflammation, a novel function that relies on constraining TAK1 hyperactivation. (Hepatology 2018;67:1320-1338).
Abstract 12196: ST2 Elevation in Myocardial Infarction - Associations With Cardiac Structure and Function
Authors: William S Jenkins, Veronique L Roger, Allan S Jaffe, Maurice Enriquez-Sarano
Journal: Circulation (2016)

Introduction: Soluble ST2 (sST2) is a serum marker of cardiomyocyte stress associated with a large risk of death and heart failure after myocardial infarction (MI). The relationship between sST2 and cardiac structure and function after MI however remains incompletely defined, and greater characterization is required prior to clinical application. Methods: Olmsted County, Minnesota residents who experienced their first MI between 2007 and 2012 were prospectively recruited. MIs were validated using standardized criteria and patients underwent simultaneous comprehensive Doppler echocardiography and sST2 measurement. The association between cardiac morphology and hemodynamics and sST2 were examined. Published normal values were used as referent ranges for sST2 levels. Results: Among 316 patients (mean age 65 [SD 14] years, 67% men, 32% ST-elevation MI), sST2 was measured 2.5 [SD 1.6] days after MI and within 0.7 [SD 2.3] days of echocardiography. Soluble ST2 was elevated in 33% of patients and univariately associated with decreased LV ejection fraction (LVEF), increased LV mass, impaired LV diastolic function and increased pulmonary artery pressure (ePAP) (Table). After adjustment for age, sex, LVEF and key measures of LV filling pressures, elevated sST2 was independently associated with reduced LVEF (p=0.01) mitral valve deceleration time (p=0.03), greater left atrial volume (p=0.03) and mitral regurgitation (≥mild; p=0.09). LVEF and ePAP exhibited the strongest associations with elevated sST2 (both p&lt;0.001). Conclusions: Soluble ST2 is frequently elevated following MI and is strongly associated with the morphologic and hemodynamic determinants of adverse LV remodeling that infer poor long-term outcome after MI.
Efficacy and Safety of the Use of Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Concomitant Aspirin Therapy
Authors: Naoual Bennaghmouch, Anne J.W.M. de Veer, Kerstin Bode, Bakhtawar K. Mahmoodi, Willem J.M. Dewilde, Gregory Y.H. Lip, Martina Brueckmann, Eva Kleine, Jurriën M. ten Berg
Journal: Circulation (2017)

Current guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) as the first-choice therapy in patients with nonvalvular atrial fibrillation because these drugs have several benefits over the vitamin K antagonists (VKAs). It is unknown whether these benefits remain when NOACs have to be combined with aspirin therapy. To assess the efficacy and safety of NOACs compared with VKAs in patients with atrial fibrillation and concomitant aspirin therapy, we conducted a systematic review and study-based meta-analysis of published randomized controlled trials.A systematic electronic literature search was done in MEDLINE, EMBASE, and Cochrane CENTRAL Register of Controlled Trials for studies including published data of patients ≥18 years of age with nonvalvular atrial fibrillation, randomized to either VKAs or NOACs, or receiving aspirin therapy at any time during the study that report all-cause stroke or systemic embolism, vascular death, myocardial infarction, major bleeding, or intracranial hemorrhage as an outcome. Hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome were extracted from the individual studies and pooled with random-effects meta-analysis.This study-based meta-analysis was restricted to the subgroups of patients on aspirin therapy (n=21 722) from 4 randomized controlled trials comparing VKAs and NOACs (n=71 681) in nonvalvular atrial fibrillation. In this meta-analysis including patients on mainly low-dose aspirin, NOACs were found to be more effective (outcome of stroke or systemic embolism: HR, 0.78; 95% CI, 0.67-0.91; vascular death: HR, 0.85; 95% CI, 0.76-0.93) and as safe as VKAs with respect to major bleeding (HR, 0.83; 95% CI, 0.69-1.01). NOACs were safer with respect to the reduction of intracranial hemorrhage (HR, 0.38; 95% CI, 0.26-0.56).This study-based meta-analysis shows that it may be both safer and more effective to use NOACs compared with VKAs to treat patients with nonvalvular atrial fibrillation and concomitant aspirin therapy.
Comparing the Air Medical Prehospital Triage Score With Current Practice for Triage of Injured Patients to Helicopter Emergency Medical Services
Authors: Joshua B. Brown, Kenneth J. Smith, Mark L. Gestring, Matthew R. Rosengart, Timothy R. Billiar, Andrew B. Peitzman, Jason L. Sperry, Joel S. Weissman
Journal: JAMA Surgery (2017)

<h3>Importance</h3> Little evidence exists to guide helicopter emergency medical services (HEMS) triage, and current practice is inefficient. The Air Medical Prehospital Triage (AMPT) score was developed to identify patients most likely to benefit from HEMS compared with ground EMS. To our knowledge, no studies have evaluated the potential effect on costs and outcomes of a more targeted HEMS triage strategy, such as the AMPT score. <h3>Objective</h3> To evaluate the cost-effectiveness of current practice compared with the AMPT score for HEMS scene triage of trauma patients. <h3>Design, Setting, and Participants</h3> A cost-effectiveness Markov model was developed for the US health care system to compare current practice with the AMPT score as HEMS scene triage strategies from the health care system perspective over a patient lifetime horizon. A base case was estimated using national data of patient characteristics from the National Trauma Databank from 2007 to 2012. Model inputs, including demographic information, health care costs, survival, and utility estimates, were derived from literature and national registries. Triage strategies were modeled as probability of HEMS transport. Multilevel logistic regression was used to evaluate survival probability between HEMS and ground EMS under the triage strategies. Costs considered included transport reimbursements, hospitalization, cost of health care in the first year postinjury, and annual cost of health care after the first year postinjury. Several sensitivity analyses were performed to evaluate robustness of model assumptions. <h3>Main Outcomes and Measures</h3> Incremental cost-effectiveness ratio, with a threshold of $100 000 or less per quality-adjusted life-year defining cost-effectiveness. <h3>Results</h3> The base case had an incremental cost-effectiveness ratio of $255 333 per quality-adjusted life-year for current practice compared with the AMPT score. Assuming 20% of patients have severe injuries and assuming HEMS only benefits these patients, current practice had an incremental cost-effectiveness ratio of $176 686 per quality-adjusted life-year. Probabilistic sensitivity analysis demonstrated that current practice is inferior in 85% of iterations, only becoming favored when the cost-effectiveness threshold is greater than $310 000 per quality-adjusted life-year. <h3>Conclusions and Relevance</h3> Current practice is not cost-effective compared with the AMPT score for HEMS scene triage. The AMPT score was the preferred strategy across a range of model input values in sensitivity analyses. The AMPT score identifies patients most likely to benefit from HEMS while potentially reducing costs to the health care system and should be considered in air medical transport protocols for trauma patients.
Linkage of A-to-I RNA Editing in Metazoans and the Impact on Genome Evolution
Authors: Yuange Duan, Shengqian Dou, Hong Zhang, Changcheng Wu, Mingming Wu, Jian Lu
Journal: Molecular Biology and Evolution (2017)

The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution. Nevertheless, in worms and humans, we only detected modest proportions of linked editing events, the majority of which were not conserved. Furthermore, the linkage of editing in coding regions of worms and humans might be overall deleterious, which drives the evolution of DNA sites to escape promiscuous editing. Altogether, our results suggest that the linkage landscape of A-to-I editing has evolved during metazoan evolution. This present study also suggests that linkage of editing should be considered in elucidating the functional consequences of RNA editing.
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers
Authors: Collin M Blakely, Thomas B K Watkins, Wei Wu, Beatrice Gini, Jacob J Chabon, Caroline E McCoach, Nicholas McGranahan, Gareth A Wilson, Nicolai J Birkbak, Victor R Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A Gubens, Kimberly C Banks, Richard B Lanman, Aleah F Caulin, John St John, Anibal R Cordero, Petros Giannikopoulos, Andrew D Simmons, Philip C Mack, David R Gandara, Hatim Husain, Robert C Doebele, Jonathan W Riess, Maximilian Diehn, Charles Swanton, Trever G Bivona
Journal: Nature Genetics (2017)
TCT-817 Prognostic significance of mean platelet volume in diabetic patients with stable coronary artery disease
Authors: Ping Jiang, Jinqing Yuan, Ying Song, Huan-Huan Wang, Lin Jiang, Jing-jing Xu, Bo Xu, Yuejin Yang, Runlin Gao, Yi Yao
Journal: Journal of the American College of Cardiology (2017)
Decreased c-Myc expression and activity by a growth inhibitory vitamin K analog.
Authors: Lisheng Ge, Ziqiu Wang, Brian I. Carr
Journal: Cancer Research (2004)

3831   We previously showed that a synthetic K vitamin analog, Cpd 5, which is a potent growth inhibitor, inhibited c-myc expression and induced c-Myc phosphorylation (Proc. AACR 2003, 44: 617). To further explore Cpd 5 inhibitory mechanism(s), we examined Cpd 5 effects on c-Myc at the post-translational level. Cpd 5 induced c-Myc phosphorylation through prolonged ERK phosphorylation since it was antagonized by MEK inhibitor, U0126. c-Myc is known to be phosphorylated by GSK-3, which promotes c-Myc degradation. Western blot showed that Cpd 5 increased both GSK-3α and GSK-3β expression in Cpd 5 treated Hep 3B human hepatoma cells. Using GSK-3 inhibitor, SB26153, we found that phosphorylation of c-Myc was dramatically decreased due to inhibition of GSK-3 activity. Further, c-Myc protein levels reduced in Cpd 5 treated cells were restored by SB26153 action. The results show that Cpd 5 can increase GSK-3 activity to phosphorylate c-Myc, resulting in reduction of c-Myc protein levels, probably due to enhanced degradation. To investigate the consequences of reduced c-Myc levels, we measured expression of two c-Myc target genes, ornithine decarboxylase (ODC) and growth arrest gene Gadd45. Cpd 5 inhibited ODC expression in a time-dependent fashion, paralleling the Cpd 5 inhibition of c-Myc levels. Cpd 5 was also found to inhibit c-Myc DNA binding activity by 30–40%. c-Myc is known to repress Gadd45. Contrary to Cpd 5 inhibition of ODC, Cpd 5 strongly induced Gadd45 expression but had no effect on Gadd45 in c-myc null rat fibroblast cells, indicating Cpd 5 de-repressed the Gadd45 gene expression by inhibiting c-myc. These data show that Cpd 5 inhibited c-Myc levels and altered expression of its target genes, ODC and Gadd 45. Both of these may contribute to Cpd 5 mediated growth inhibition.
Postzygotic mosaicism and incontinentia pigmenti in male patients: molecular diagnosis yield
Authors: Z. Alabdullatif, J. Coulombe, J. Steffann, C. Bodemer, S. Hadj-Rabia
Journal: British Journal of Dermatology (2017)

Incontinentia pigmenti (IP, MIM 308300) is an X-linked dominant genodermatosis caused by the more frequently occurring (80% of cases) deletion mutation Δ 4-10 on IKBKG gene, located on chromosome Xq28. Incontinentia Pigmenti is generally lethal in male fetuses, while heterozygous females survive owing to functional mosaicism.1 Two potential mechanisms have been proposed to explain the survival of male patients with IP carrying IKBKG mutation: (1) abnormal karyotype, i.e. 47, XXY Klinefelter syndrome; (2) more frequently postzygotic mosaicism for IKBKG mutation.2 Detection of postzygotic mosaicism is dependant of tissue sampling localization and percentage of mutated cells in the sample.

This article is protected by copyright. All rights reserved.
Angiopoietin-1 is required for Schlemm’s canal development in mice and humans
Authors: Benjamin R. Thomson, Tomokazu Souma, Stuart W. Tompson, Tuncer Onay, Krishnakumar Kizhatil, Owen M. Siggs, Liang Feng, Kristina N. Whisenhunt, Tammy L. Yanovitch, Luba Kalaydjieva, Dimitar N. Azmanov, Simone Finzi, Christine E. Tanna, Alex W. Hewitt, David A. Mackey, Yasmin S. Bradfield, Emmanuelle Souzeau, Shari Javadiyan, Janey L. Wiggs, Francesca Pasutto, Xiaorong Liu, Simon W.M. John, Jamie E. Craig, Jing Jin, Terri L. Young, Susan E. Quaggin
Journal: Journal of Clinical Investigation (2017)

Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
Biological safety and tissue distribution of (16-mercaptohexadecyl)trimethylammonium bromide-modified cationic gold nanorods
Authors: Monika Zarska, Michal Sramek, Filip Novotny, Filip Havel, Andrea Babelova, Blanka Mrazkova, Oldrich Benada, Milan Reinis, Ivan Stepanek, Kamil Musilek, Jiri Bartek, Monika Ursinyova, Ondrej Novak, Rastislav Dzijak, Kamil Kuca, Jan Proska, Zdenek Hodny
Journal: Biomaterials (2017)
Abstract 13431: Safety And Efficacy of Angioseal Deployment in Patients With Common Femoral Artery Access During Electrophysiological Procedures Performed With Uninterrupted Oral Anticoagulation
Authors: Carola Gianni, Jason T Engel, Brent M Powers, Sanghamitra Mohanty, Chintan Trivedi, Rong Bai, Amin Al-Ahmad, J D Burkhardt, G J Gallinghouse, Patrick M Hranitzky, Rodney P Horton, Javier E Sanchez, Salwa Beheiry, Luigi Di Biase, Andrea Natale
Journal: Circulation (2016)

Introduction: Retrograde access is commonly used during EP procedures to access the aortic root as well as the LV. Many patients who undergo these procedures are under uninterrupted oral anticoagulation (OAC), therefore it is important to find a way to minimize arterial access-site complications. Hypothesis: Femoral arterial access closure devices can be safely used to achieve hemostasis after common femoral artery access in EP procedures performed with uninterrupted OAC. Methods: Consecutive patients who underwent femoral arterial access closure with the AngioSeal device in two centers were included in this retrospective analysis. All patients were systemically heparinized with ACT between 300 and 500 s. Success was defined as hemostasis achieved in &lt; 5 minutes. Results: Over a 2-year period, 62 patients underwent femoral arterial access closure. 52% were PVC/VT ablations, 40% AF (NCC), and 8% SVT (NCC/WPW). 53% of the patients were female, with a mean age of 59 ± 13 years and BMI 30.0 ± 5.2; sheath size was 8F for all. 40% on uninterrupted OAC (24% factor Xa inhibitors, 16% warfarin), whereas 23% were on ASA, 5% on dual antiplatelet therapy, and 32% were not receiving any antithrombotic therapy at the time of the procedure. In all patients with uninterrupted OAC, femoral arterial access was ultrasound-guided to ensure that the arteriotomy was located above the bifurcation but below the external iliac artery. Femoral arterial closure was successful in all, without any device-related complication. There were 2 (3%) access-related complications requiring prolonged hospitalization, both related to the additional venous access, as determined by ultrasound: 1 superficial bleeding in a patient with NCC tachycardia during AF ablation who was on uninterrupted rivaroxaban and 1 large hematoma in a patient who underwent VT ablation and was on ASA. The incidence of complications was not significantly different between patients with uninterrupted OAC compared to those with uninterrupted antiplatelet thereapy or no antithrombotic therapy (Fischer’s exact test P = NS). Conclusions: Common femoral artery access closure with the AngioSeal device is safe and effective in achieving hemostasis in patients undergoing EP procedures performed with uninterrupted OAC.
TCT-740 3-year Clinical Outcomes of Durable-Polymer Zotarolimus-Eluting and Biodegradable-Polymer Biolimus-Eluting Coronary Stents in Patients with Acute Coronary Syndroms (a SORT OUT VI Substudy)
Authors: Bent Raungaard, Lisette Okkels Jensen, Svend Eggert Jensen, Henrik Hansen, Leif Thuesen, Jens Aaroe, Anton Villadsen, Karsten Veien, Anders Junker, Morten Madsen, Michael Maeng, Steen Dalby Kristensen, Evald Christiansen
Journal: Journal of the American College of Cardiology (2017)
Epidermal Growth Factor Receptor Expression Licenses Type-2 Helper T Cells to Function in a T Cell Receptor-Independent Fashion
Authors: Carlos M. Minutti, Sebastian Drube, Natalie Blair, Christian Schwartz, Jame C. McCrae, Andrew N. McKenzie, Thomas Kamradt, Michal Mokry, Paul J. Coffer, Maria Sibilia, Alice J. Sijts, Padraic G. Fallon, Rick M. Maizels, Dietmar M. Zaiss
Journal: Immunity (2017)

Gastro-intestinal helminth infections trigger the release of interleukin-33 (IL-33), which induces type-2 helper T cells (Th2 cells) at the site of infection to produce IL-13, thereby contributing to host resistance in a T cell receptor (TCR)-independent manner. Here, we show that, as a prerequisite for IL-33-induced IL-13 secretion, Th2 cells required the expression of the epidermal growth factor receptor (EGFR) and of its ligand, amphiregulin, for the formation of a signaling complex between T1/ST2 (the IL-33R) and EGFR. This shared signaling complex allowed IL-33 to induce the EGFR-mediated activation of the MAP-kinase signaling pathway and consequently the expression of IL-13. Lack of EGFR expression on T cells abrogated IL-13 expression in infected tissues and impaired host resistance. EGFR expression on Th2 cells was TCR-signaling dependent, and therefore, our data reveal a mechanism by which antigen presentation controls the innate effector function of Th2 cells at the site of inflammation.
Macrogenomic engineering via modulation of the scaling of chromatin packing density
Authors: Luay M. Almassalha, Greta M. Bauer, Wenli Wu, Lusik Cherkezyan, Di Zhang, Alexis Kendra, Scott Gladstein, John E. Chandler, David VanDerway, Brandon-Luke L. Seagle, Andrey Ugolkov, Daniel D. Billadeau, Thomas V. O’Halloran, Andrew P. Mazar, Hemant K. Roy, Igal Szleifer, Shohreh Shahabi, Vadim Backman
Journal: Nature Biomedical Engineering (2017)
TCT-836 Comparative Efficacy and Safety of Different Types of Drug-Eluting Stents for Unprotected Left Main Coronary Artery Disease: Insights from Stent-Specific, Multi-Center Prospective Registries
Authors: Osung Kwon, Pil Hyung Lee, Jung-Min Ahn, Cheol Hyun Lee, Do-yoon Kang, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Duk-Woo Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2017)
Management of immune-related adverse events (irAEs) in clinical practice, support team of Chiba University Hospital
Authors: Shunichiro Iwasawa, Takahiro Ebata, Tsukasa Ishiwata, Jun Ikari, Emiko Sakaida, Mari Iwasawa, Makoto Arai, Tatsuro Kanda, Sonoko Misawa, Yuichi Takiguchi
Journal: Annals of Oncology (2017)