tbuckley/cabot-search huggingface dataset:
TRUSS Exacerbates NAFLD Development by Promoting IκBα Degradation in Mice
Authors: Chang‐Jiang Yu, Qiu‐Shi Wang, Ming‐Ming Wu, Bin‐Lin Song, Chen Liang, Jie Lou, Liang‐Liang Tang, Xiao‐Di Yu, Na Niu, Xu Yang, Bao‐Long Zhang, Yao Qu, Yang Liu, Zhi‐Chao Dong, Zhi‐Ren Zhang
Journal: Hepatology (2018)

There is no effective treatment method for nonalcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor–associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was increased in the human liver specimens with NAFLD or nonalcoholic steatohepatitis, and in the livers of high‐fat diet (HFD)‐induced and genetically obese mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow feeding. All of these HFD‐induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with the inhibitor of nuclear factor κB α (IκB α ) and promotes the ubiquitination and degradation of IκB α , which leads to aberrant activation of nuclear factor κB (NF‐κB). Overexpressing IκB α S32A/S36A , a phosphorylation‐resistant mutant of IκB α , in the hepatocyte‐specific TRUSS overexpressing mice almost abolished HFD‐induced NAFLD and metabolic disorders. Conclusion : Hepatocyte TRUSS promotes pathological stimuli‐induced NAFLD and metabolic disorders, through activation of NF‐κB by promoting ubiquitination and degradation of IκB α . Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS.
RESULTS AFTER FIVE YEARS OF POEM AT KLINIKUM AUGSBURG, GERMANY
Authors: J Rüden, S Gölder
Journal: Endoscopy (2018)

Achalasia refers to the lack of smooth muscle relaxation of the lower esophageal sphincter. Classic endoscopic therapy such as pneumatic dilatation and injection of botulinum toxin are often associated with a poor relief of symptoms as well as a high recurrence rate. Peroral endoscopic Myotomy (POEM) is a new endoscopic treatment for achalasia.
Reductions in dead space ventilation with nasal high flow depend on physiological dead space volume: metabolic hood measurements during sleep in patients with COPD and controls
Authors: Paolo Biselli, Kathrin Fricke, Ludger Grote, Andrew T. Braun, Jason Kirkness, Philip Smith, Alan Schwartz, Hartmut Schneider
Journal: European Respiratory Journal (2018)

Nasal high flow (NHF) reduces minute ventilation and ventilatory loads during sleep but the mechanisms are not clear. We hypothesised NHF reduces ventilation in proportion to physiological but not anatomical dead space. 11 subjects (five controls and six chronic obstructive pulmonary disease (COPD) patients) underwent polysomnography with transcutaneous carbon dioxide (CO 2 ) monitoring under a metabolic hood. During stable non-rapid eye movement stage 2 sleep, subjects received NHF (20 L·min −1 ) intermittently for periods of 5–10 min. We measured CO 2 production and calculated dead space ventilation. Controls and COPD patients responded similarly to NHF. NHF reduced minute ventilation (from 5.6±0.4 to 4.8±0.4 L·min −1 ; p&lt;0.05) and tidal volume (from 0.34±0.03 to 0.3±0.03 L; p&lt;0.05) without a change in energy expenditure, transcutaneous CO 2 or alveolar ventilation. There was a significant decrease in dead space ventilation (from 2.5±0.4 to 1.6±0.4 L·min −1 ; p&lt;0.05), but not in respiratory rate. The reduction in dead space ventilation correlated with baseline physiological dead space fraction (r 2 =0.36; p&lt;0.05), but not with respiratory rate or anatomical dead space volume. During sleep, NHF decreases minute ventilation due to an overall reduction in dead space ventilation in proportion to the extent of baseline physiological dead space fraction.
Combined BRAF and HSP90 Inhibition in Patients with Unresectable <i>BRAF</i>V600E-Mutant Melanoma
Authors: Zeynep Eroglu, Y. Ann Chen, Geoffrey T. Gibney, Jeffrey S. Weber, Ragini R. Kudchadkar, Nikhil I. Khushalani, Joseph Markowitz, Andrew S. Brohl, Leticia F. Tetteh, Howida Ramadan, Gina Arnone, Jiannong Li, Xiuhua Zhao, Ritin Sharma, Lancia N.F. Darville, Bin Fang, Inna Smalley, Jane L. Messina, John M. Koomen, Vernon K. Sondak, Keiran S.M. Smalley
Journal: Clinical Cancer Research (2018)

Purpose: BRAF inhibitors are clinically active in patients with advanced BRAFV600-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888.Patients and Methods: Vemurafenib (960 mg p.o. b.i.d.) combined with escalating doses of XL888 (30, 45, 90, or 135 mg p.o. twice weekly) was investigated in 21 patients with advanced BRAFV600-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.Results: Objective responses were observed in 15 of 20 evaluable patients [75%; 95% confidence interval (CI), 51%-91%], with 3 complete and 12 partial responses. Median progression-free survival and overall survival were 9.2 months (95% CI, 3.8-not reached) and 34.6 months (6.2-not reached), respectively. The most common grade 3/4 toxicities were skin toxicities, such as rash (n = 4, 19%) and cutaneous squamous cell carcinomas (n = 3, 14%), along with diarrhea (n = 3, 14%). Pharmacodynamic analysis of patients' peripheral blood mononuclear cells (PBMC) showed increased day 8 HSP70 expression compared with baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy.Conclusions: XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAFV600-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAFV600-mutant melanoma. Clin Cancer Res; 24(22); 5516-24. ©2018 AACRSee related commentary by Sullivan, p. 5496.
Projecting Age-Stratified Risk of Exposure to Inland Flooding and Wildfire Smoke in the United States under Two Climate Scenarios
Authors: David Mills, Russell Jones, Cameron Wobus, Julia Ekstrom, Lesley Jantarasami, Alexis St. Juliana, Allison Crimmins
Journal: Environmental Health Perspectives (2018)

The public health community readily recognizes flooding and wildfires as climate-related health hazards, but few studies quantify changes in risk of exposure, particularly for vulnerable children and older adults.This study quantifies future populations potentially exposed to inland flooding and wildfire smoke under two climate scenarios, highlighting the populations in particularly vulnerable age groups (≤4 y old and ≥65 y old).Spatially explicit projections of inland flooding and wildfire under two representative concentration pathways (RCP8.5 and RCP4.5) are integrated with static (2010) and dynamic (2050 and 2090) age-stratified projections of future contiguous U.S. populations at the county level.In both 2050 and 2090, an additional one-third of the population will live in areas affected by larger and more frequent inland flooding under RCP8.5 than under RCP4.5. Approximately 15 million children and 25 million older adults could avoid this increased risk of flood exposure each year by 2090 under a moderate mitigation scenario (RCP4.5 compared with RCP8.5). We also find reduced exposure to wildfire smoke under the moderate mitigation scenario. Nearly 1 million young children and 1.7 million older adults would avoid exposure to wildfire smoke each year under RCP4.5 than under RCP8.5 by the end of the century.By integrating climate-driven hazard and population projections, newly created county-level exposure maps identify locations of potential significant future public health risk. These potential exposure results can help inform actions to prevent and prepare for associated future adverse health outcomes, particularly for vulnerable children and older adults. https://doi.org/10.1289/EHP2594.
Differential utilization of preventive care among colon cancer survivors compared to non-cancer patients.
Authors: Sally C Lau, Richard M. Lee-Ying, Davis Sam, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

577 Background: With advances in diagnosis and treatment, many cancer patients survive more than 5 years. The care of these cancer survivors (CS) represent an area of unmet need. We aim to characterize the patterns of preventive care in colon CS compared to non-cancer controls (NCC) and identify areas of deficiencies within the context of a universal health care system. Methods: Adult patients with non-metastatic colon cancer treated at the BC Cancer Agency between 2000-2012 were included. An age and gender matched cohort constructed from the provincial database served as NCC. Areas of preventive care examined include vaccinations, cancer, osteoporosis and cardiovascular diseases (CVD) screening. Multivariate regressions were done to test for associations between CS and preventive care. Results: In total, 9381 colon CS and 47187 NCC, matched at a ratio of 1:5, were analyzed. Among CS, median age of diagnosis was 68, 58% were male and 47% had stage 3 disease. The median overall survivals were 12/10/8 years for stages 1/2/3 disease respectively. 61% of these survivors died from colon cancer, 12% from other cancers and 25% from non-cancer causes. Deaths from colon cancer are more common within 5 years of diagnosis, particularly stage 3 disease. CS were more likely to receive any preventive care. In CS compared to NCC, 90% vs 85%, 47% vs 39% and 53% vs 46% of eligible patients had CVD screening, cancer screening and other preventive care respectively. This remained significant in multivariate analyses (Table). Patients who were female, had higher income and resided in urban areas were more likely to receive screening. Among CS, patients &gt; 65 years (OR1.2, p = 0.04 95%CI 1.0-1.4), females (OR 1.5, p &lt; 0.01 95%CI 1.3-1.8) and stages 1 or 2 disease (OR 1.3, p &lt; 0.01 95%CI 1.1-1.5) had higher uptake of screening. Conclusions: Many colon cancer patients are long term survivors. CS are more likely to receive screening than NCC but uptake is suboptimal in certain areas. Targeted education towards certain sub-groups such as males, ≤65 years, low income and rural area patients may improve long term health outcomes. [Table: see text]
Autologous cell/gene therapy approach of hemophilia B using patient specific induced Pluripotent Stem Cells
Authors: E. Luce, C. Steichen, M. Antonietta, S. Goulinet, T. Lambert, A. Weber, T.H. Nguyen, O. Christophe, A. Dubart-Kupperschmitt
Journal: Journal of Hepatology (2018)
The enzymatic biosynthesis of acylated steroidal glycosides and their cytotoxic activity
Authors: Ming Liu, Jian-Qiang Kong
Journal: Acta Pharmaceutica Sinica B (2018)

Herein we describe the discovery and functional characterization of a steroidal glycosyltransferase (SGT) from Ornithogalum saundersiae and a steroidal glycoside acyltransferase (SGA) from Escherichia coli and their application in the biosynthesis of acylated steroidal glycosides (ASGs). Initially, an SGT gene, designated as OsSGT1, was isolated from O. saundersiae. OsSGT1-containing cell free extract was then used as the biocatalyst to react with 49 structurally diverse drug-like compounds. The recombinant OsSGT1 was shown to be active against both 3β- and 17β-hydroxyl steroids. Unexpectedly, in an effort to identify OsSGT1, we found the bacteria lacA gene in lac operon actually encoded an SGA, specifically catalyzing the acetylations of sugar moieties of steroid 17β-glucosides. Finally, a novel enzymatic two-step synthesis of two ASGs, acetylated testosterone-17-O-β-glucosides (AT-17β-Gs) and acetylated estradiol-17-O-β-glucosides (AE-17β-Gs), from the abundantly available free steroids using OsSGT1 and EcSGA1 as the biocatalysts was developed. The two-step process is characterized by EcSGA1-catalyzed regioselective acylations of all hydroxyl groups on the sugar unit of unprotected steroidal glycosides (SGs) in the late stage, thereby significantly streamlining the synthetic route towards ASGs and thus forming four monoacylates. The improved cytotoxic activities of 3'-acetylated testosterone17-O-β-glucoside towards seven human tumor cell lines were thus observable.
Abstract 17587: Implications of Angina Pectoris on Quality of Life, Functional Capacity and Clinical Outcomes in Chronic Heart Failure Patients: Insights From HF-ACTION
Authors: Robert J Mentz, Kishan Parikh, Adrian Coles, Phillip J Schulte, William E Kraus, Jerome L Fleg, Steven J Keteyian, Ileana L Piña, Mona Fiuzat, David J Whellan, Christopher M O’Connor
Journal: Circulation (2015)

Background: Angina pectoris (AP) is associated with worse outcomes in heart failure (HF) patients, but less is known about implications on health related quality of life (HRQoL) and functional capacity. Methods: We assessed HRQoL, functional capacity and outcomes in chronic HF patients with reduced EF in the HF-ACTION trial of usual care +/- exercise training based on whether patients had AP. AP was patient-reported based on recent symptoms or development during exercise testing. We assessed all-cause mortality/hospitalization in patients with AP vs. no AP using multivariable Cox proportional hazards regression. We assessed for an interaction between AP status and exercise training with respect to outcomes and the change in quality of life and functional capacity from baseline to 3 months. Results: In HF-ACTION, 406 (17%) patients had AP at baseline with 44% of these reporting ≥ class II symptoms. Patients with AP more often had ischemic etiology, but had similar EF, NT-proBNP and beta-blocker use. Baseline 6-minute walk distance and peak VO 2 were similar in both groups, but patients with AP had worse depressive symptoms and HRQoL. After risk adjustment, AP was associated with a 22% greater risk of all-cause mortality/hospitalization (Figure). There was evidence of an interaction between baseline AP and exercise training on change in peak VO 2 (P=0.019), but not for HRQoL or clinical outcomes. The median change in peak VO 2 with exercise training was 0.8 mL/kg/min with AP vs. 0.6 mL/kg/min without AP. Conclusion: AP was associated with worse HRQoL and more depressive symptoms. Despite a greater improvement in peak VO 2 with exercise training, patients with AP experienced more adverse events. Clinicians should consider routine assessment and management of AP in HF patients as well as the associated symptoms related to depression and implications on quality of life.
The kynurenine pathway in cirrhosis. Relationship with the development of acute decompensation and acute-on-chronic liver failure, clinical course and mortality
Authors: J. Clària, R. Moreau, F. Fenaille, A. Amoros, C. Junot, H. Gronbaek, M. Coenraad, K. Oettl, P. Caraceni, C. Alessandria, J. Trebicka, M. Pavesi, C.D. Gomez, A. Albillos, T. Gustot, T. Welzel, J. Fernandez, R.E. Stauber, F. Saliba, N. Butin, B. Colsch, C. Moreno, F. Durand, F. Nevens, R. Bañares, D. Benten, P. Ginès, A. Gerbes, R. Jalan, P. Angeli, M. Bernardi, V. Arroyo
Journal: Journal of Hepatology (2018)
Dietetic Factors in Liver Disease: Part II
Authors: L. J. Witts
Journal: BMJ (1947)

Acute Necrosis of the LiverAcute necrosis of the liver is an anatomical diagnosis which cannot be made with certainty without biopsy or necropsy.Usually, however, we must rely on the indirect evidence of acute hepatic insufficiency.Jaundice is intense and the serum bilirubin rises to 20 mg. per 100 ml. or higher.The patient is critically ill with delirium, stupor, coma, and up- going toes.There are ascites, oedema, purpura, and occult blood in the stools.If we confine the terms " acute necrosis " and " acute hepatic insufficiency " to such cases --and I believe we shall make no therapeutic advance until we establish rigid criteria-we shall find ourselves dealing with a hepatic disorder which is uncommon and which has a mortality of 50 to 100%.From a sample analysis of death certificates carried out for the Jaundice Committee of the Medical Research Council by Dr. W. H. Bradley and Dr. Percy Stocks in 1944 (unpublished report), it appeared that there were approximately 400 deaths a year fromn acute hepatic insufficiency, of which only about 8 % were toxic jaundice, whereas the greater part were probably due to the viruses of infective hepatitis, homologous serum jaundice, and post-arsphenamine jaundice.The average number of deaths from notifiable toxic jaundice during the years 1940-4 was fewer than six a year.I stress the rarity of fatal toxic jaundice in man in view of the fact that so much of our present information has been derived from toxic jaun- dice in animals.The difficulties of carrying out therapeutic trials on a disease which is uncommon and hard to diagnose are great.Much of the literature on the subject is worthless, recording isolated successes, changes of fashion, and the surprising capacity of the organism, even in sickness, to withstand onslaughts on its integrity.This state of things should improve as a result of the careful collection and study of morbidity and mortality statistics which is occurring in several parts of this country.More is to be hoped from animal experiments, which are still curiously incomplete in the matter of treatment.The drawbacks to animal experi- ment are the dissimilarity of animals and man, and the failure to transmit infective hepatitis to animals.Another possibility, which it is to be hoped we shall be spared, is the occurrence of epidemics of infective hepatitis with a mortality of the order of 15%, such as have lately appeared in Denmark and Switzerland.
Abstract 19607: Mechano-Chronotropic Unloading in the Acute Phase of Myocardial Infarction Strikingly Reduces Infarct Size and Prevents Heart Failure in the Long-Term
Authors: Genya Sunagawa, Keita Saku, Takahiro Arimura, Takuya Akashi, Takuya Kishi, Hiroyuki Tsutsui, Kenji Sunagawa
Journal: Circulation (2017)

Introduction: Myocardial infarction (MI) remains a leading cause of chronic heart failure (CHF). Presence of unsalvaged myocardium leads to cardiac remodeling and CHF. Reducing myocardial oxygen co...
Effect of the Duodenal-Jejunal Bypass Liner on Glycemic Control in Patients With Type 2 Diabetes With Obesity: A Meta-analysis With Secondary Analysis on Weight Loss and Hormonal Changes
Authors: Pichamol Jirapinyo, Andrea V. Haas, Christopher C. Thompson
Journal: Diabetes Care (2018)

OBJECTIVE Duodenal-jejunal bypass liner (DJBL) is an endoscopic device that may mimic small bowel mechanisms of Roux-en-Y gastric bypass (RYGB). Previous studies have demonstrated the efficacy of DJBL at inducing weight loss. We assessed the effect of DJBL on glycemic control in patients with type 2 diabetes (T2D) with obesity. RESEARCH DESIGN AND METHODS Data sources included MEDLINE, EMBASE, and Web of Science through 1 July 2017. Included were published studies that assessed DJBL outcomes in obese T2D patients. RESULTS Primary outcomes were change in HbA1c and HOMA of insulin resistance (HOMA-IR). Secondary outcomes were change in weight and gut hormones glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin. Seventeen studies were included. At explant, HbA1c decreased by 1.3% [95% CI 1.0, 1.6] and HOMA-IR decreased by 4.6 [2.9, 6.3]. Compared with control subjects, DJBL subjects had greater HbA1c reduction by 0.9% [0.5, 1.3]. Six months after explant, HbA1c remained lower than baseline by 0.9% [0.6, 1.2]. At explant, patients lost 11.3 kg [10.3, 12.2], corresponding to a BMI reduction of 4.1 kg/m2 [3.4, 4.9], total weight loss of 18.9% [7.2, 30.6], and excess weight loss of 36.9% [29.2, 44.6]. The amount of weight loss remained significant at 1 year postexplantation. After DJBL, GIP decreased, whereas GLP-1, PYY, and ghrelin increased. CONCLUSIONS DJBL improves glycemic control and insulin resistance in T2D patients with obesity. DJBL also appears to induce significant weight loss in this population. Additionally, changes in gut hormones suggest mechanisms similar to RYGB. Study limitations included heterogeneity among studies.
Bacterial Autophagy: How to Take a Complement
Authors: Vanessa Sancho-Shimizu, Serge Mostowy
Journal: Cell Host & Microbe (2018)

Complement, a complex system of serum proteins, contributes to host defense through multiple mechanisms. In this issue of Cell Host & Microbe, Sorbara et al. (2018) discovered that cytosolic pathogens opsonized by complement are restricted by autophagy. This unexpected role for complement is important for cell-autonomous immunity in the intestinal mucosa.
Use of gasotransmitters for the controlled release of polymer-based nitric oxide carriers in medical applications
Authors: Chungmo Yang, Soohyun Jeong, Seul Ku, Kangwon Lee, Min Hee Park
Journal: Journal of Controlled Release (2018)

Nitric Oxide (NO) is a small molecule gasotransmitter synthesized by nitric oxide synthase in almost all types of mammalian cells. NO is synthesized by NO synthase by conversion of l-arginine to l-citrulline in the human body. NO then stimulates soluble guanylate cyclase, from which various physiological functions are mediated in a concentration-dependent manner. High concentrations of NO induce apoptosis or antibacterial responses whereas low NO circulation leads to angiogenesis. The bidirectional effect of NO has attracted considerable attention, and efforts to deliver NO in a controlled manner, especially through polymeric carriers, has been the topic of much research. This naturally produced signaling molecule has stood out as a potentially more potent therapeutic agent compared to exogenously synthesized drugs. In this review, we will focus on past efforts of using the controlled release of NO via polymer-based materials to derive specific therapeutic results. We have also added studies and our future suggestions on co-delivery methods with other gasotransmitters as a step towards developing multifunctional carriers.
TCTAP A-093 Effects of Statin Intensity on Clinical Outcomes in Acute Myocardial Infarction Patients
Authors: Doyeon Hwang, Hyun Kuk Kim, Joo Myung Lee, Ki Hong Choi, Jihoon Kim, Tae-Min Rhee, Jonghanne Park, Taek Kyu Park, Jeong Hoon Yang, Young Bin Song, Jin Ho Choi, Joo-Yong Hahn, Seung-Hyuck Choi, Bon-Kwon Koo, Young Jo Kim, Shung Chull Chae, Myeong-Chan Cho, Chong Jin Choi, Hyeon-Cheol Gwon, Myung-Ho Jeong, Hyo-Soo Kim
Journal: Journal of the American College of Cardiology (2018)
Role of 99mTc-Macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response of patients with locally advanced and inoperable hepatocellular carcinoma (HCC) treated by selective intra-arterial radiation therapy (SIRT) with yttrium-90 resin microspheres, a cohort from SARAH study
Authors: A.-L. Hermann, A. Dieudonné, R. Maxime, S. Manuel, P. Helena, C. Gilles, C. Laurent, L. Rachida, V. Vilgrain, S.T. Group
Journal: Journal of Hepatology (2018)