tbuckley/cabot-search huggingface dataset:
Prevalence and incidence of hepatitis C virus infection in men who have sex with men: a systematic review and meta-analysis
Authors: Fengyi Jin, Gregory J Dore, Gail Matthews, Niklas Luhmann, Virginia Macdonald, Sahar Bajis, Rachel Baggaley, Bradley Mathers, Annette Verster, Andrew E Grulich
Journal: The Lancet. Gastroenterology & hepatology (2020)
Abstract 14425: Coronary Microvascular Disease in Type 2 Diabetes is Linked to the Upregulation of P53
Authors: Jody Tori O Cabrera, Rui Si, Atsumi Tsuji Hosokawa, Ayako Makino
Journal: Circulation (2020)

Diabetes mellitus is a prominent risk factor of coronary microvascular disease (CMD) and the comorbidity of CMD in diabetic patients leads to an increasing occurrence of cardiac mortality. Increased protein O -linked β-N-acetylglucosaminylation ( O -GlcNAcylation), a post-translational modification of proteins, is implicated in the development of vascular complications in diabetes. Therefore, we investigated the molecular mechanisms in which excess protein O -GlcNAcylation advances the progression of CMD in diabetes through coronary endothelial cell dysfunction. We hypothesize that excess protein O -GlcNAcylation will up-regulate p53 which will induce the development of CMD. We had conducted in vivo and in vitro experiments in control mice, TALLYHO/Jng (TH) mice, a polygenic type 2 diabetic mouse model, and endothelial cell-specific O -GlcNAcase (OGA, a regulatory enzyme that catalyzes the removal of O- GlcNAc from proteins)-overexpressing TH mice. We found that compared to control mice, TH mice exhibited a decrease in coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function), reduced capillary density, and increased endothelial cell apoptosis in the left ventricle. In addition, TH mice showed a significant increase of p53 protein expression in mouse coronary endothelial cells (MCECs) compared to control mice. Moreover, overexpression of OGA lowered protein O -GlcNAcylation and decreased p53 levels in MCECs. p53 inhibition with pifithrin-α restoratively increased CFVR and cardiac contractility in TH mice. From this data, we conclude OGA overexpression lowers p53 expression levels and thus attenuates endothelial cell apoptosis and restores CFVR and cardiac function in diabetes. The downregulation of p53 through OGA overexpression could be a potential therapeutic target for CMD in diabetic patients.
The role of Nrf2 in neural stem/progenitors cells: From maintaining stemness and self-renewal to promoting differentiation capability and facilitating therapeutic application in neurodegenerative disease
Authors: Houman Kahroba, Bahman Ramezani, Hamid Maadi, Mohammad Reza Sadeghi, Hajar Jaberie, Fatemeh Ramezani
Journal: Ageing Research Reviews (2020)
Abstract 15061: Essential Hypertension is Linked to Acetylation of Mitochondrial Superoxide Dismutase and Deacetylation Mimetic Mutation of Lysine 68 to Arginine Protects From Oxidative Stress and Hypertension
Authors: Anna Dikalova, Liliya Tkachuk, Marcos G Lopez, Frederic T Billings, Sergey Dikalov
Journal: Circulation (2020)

Almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. We found that hypertension is associated with inactivation of key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to acetylation of lysine residues at the catalytic center. The role of specific SOD2 lysine residues in hypertension, however, has not been defined. Hypothesis: We proposed that inactivation of key intrinsic antioxidant, SOD2, in hypertension is linked to acetylation of Lysine 68, and mutation of K68 to Arginine mimics SOD2 deacetylation, inhibits vascular oxidative stress and attenuates angiotensin II-induced hypertension. To test this hypothesis, we have investigated SOD2 acetylation in arterioles from patients with essential hypertension and developed a new deacetylation mimic SOD2 mutant K68R mice (SOD2-K68R). Western blot of arterioles isolated from human mediastinal fat showed 3-fold increase in SOD2 acetylation in hypertensive patients compared with normotensive subjects while SOD2 levels were not affected. To define the functional significance of K68 acetylation we performed studies in vivo in SOD2-K68R mice using angiotensin II model of vascular dysfunction and hypertension. Angiotensin II infusion in wild-type C57Bl/6J mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. Mutation of Lysine 68 to Arginine in SOD2-K68R mice completely prevented the increase in mitochondrial superoxide and significantly attenuated the angiotensin II induced hypertension (135 mm Hg). Angiotensin II and TNFα co-operatively induce SOD2 acetylation and hypertension. Treatment of wild-type aortas with angiotensin II and TNFα in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. Conclusions: These data support an important role of SOD2-K68 acetylation in hypertension and targeting Sirt3-mediated deacetylation of SOD2 may have therapeutic potential.
Quantitative Features From CHO PET Distinguish the WHO Grades of Primary Diffuse Glioma
Authors: Ziren Kong, Chendan Jiang, Delin Liu, Wenlin Chen, Wenbin Ma, Xin Cheng, Yu Wang
Journal: Clinical Nuclear Medicine (2020)

The aim of this study was to investigate the quantitative 18F-fluoroethylcholine (CHO) PET characteristics for differentiating lower-grade glioma (LGG) from glioblastoma (GBM).Thirty-nine patients who underwent CHO PET with histopathologically confirmed primary diffuse glioma were prospectively enrolled. The 3-dimensional region of interest was semiautomatically defined based on the SUV threshold, and a total of 74 quantitative features, including 13 shape features, 31 SUV-based features, and 30 normalized SUV-based features, were calculated. Wilcoxon rank sum test, receiver operating characteristic curve, and correlation coefficient analyses were applied to select independent representative features, and patient prognosis was stratified by the World Health Organization (WHO) grade and CHO features.A total of 89.2% of the quantitative features were significantly different between LGG and GBM, and the SUV-based features displayed higher area under the receiver operating characteristic curve (AUC) values than the other feature groups. Among the 5 traditional features, the SUVmax and the total lesion CHO uptake were the most distinguishing, with AUCs of 0.880 and 0.860 (0.938 and 0.927 after reclassification of 2 outliers), respectively, both of which could also stratify patient prognosis better than WHO grade. Five alternative features, including 2 shape features and 3 SUV-based features, were considered representative, with AUCs ranging from 0.754 to 0.854.Quantitative features from CHO PET are reliable in determining the WHO grade of primary diffuse gliomas. Our findings suggest that GBM has a larger volume, a more spherical shape, higher choline activity in most interval segments, and a more symmetrical distribution than LGG.
Abstract 14427: Differences in Molecular Phenotype in Mouse and Human Hypertrophic Cardiomyopathy Suggest Need for Precision Medicine Approach to Treatment Based on Human Studies
Authors: Styliani Vakrou, Yamin Liu, Li Zhu, Yufan Guan, Ryuya Fukunaga, M Roselle Abraham
Journal: Circulation (2020)

Background: Mouse studies at early stage of hypertrophic cardiomyopathy (HCM) indicate allele-specific differences in cardiac gene expression and mitochondrial function. But data at established disease stage in mouse and human HCM are lacking. We hypothesized that 1) allele-specific differences persist at established stage, and 2) mouse and human HCM have distinct molecular biosignatures. Methods: We analyzed the transcriptome (mRNA, miRNA) in 2 HCM mouse models (R92W-TnT, R403Q-MyHC)/littermate controls at 24weeks of age and in human myectomy samples/healthy-control hearts ( GSE36961, GSE36946 ). We examined myocyte redox, mitochondrial DNA copy number (mtDNA-CN), respiration, ROSgeneration/scavenging and Ca 2+ handling in mutant/littermate-control mice . Results: Analysis of mRNA/miRNA expression and Ingenuity Pathway Analysis (IPA) revealed distinct allele-specific gene expression in mouse HCM and marked differences from human HCM. Only CASQ1 and GPT1 were similarly regulated in both mouse HCM/human HCM. KEGG analysis revealed enrichment of several metabolic pathways, but only pyruvate metabolism was enriched in both mouse HCM/human HCM. IPA predicted upregulation of 2 pathways (inflammasome, type 2 diabetes signaling) in MyHC mutants, and upregulation of 18 pathways (including STAT3, ILK, Ca 2+ signaling) in TnT mutants; the anti-hypertrophic/anti-fibrotic LXR/RXR pathway was the most upregulated in human HCM. Losartan was a predicted therapy only in TnT mutants. Myocytes of both mutant mice exhibited an oxidized redox environment. Mitochondrial complex I respiration was lower in both mutants compared to controls. MyHC mutants had similar mtDNA-CN and mitochondrial Ca 2+ handling, but TnT mutants demonstrated lower mtDNA-CN and impaired mitochondrial Ca 2+ handling, compared to respective controls. Conclusions: Molecular profiling reveals allele-specific differences in mRNA/miRNA expression, intracellular signaling and mt-function/number in mouse HCM at established disease stage. Transcriptional differences between mouse and human HCM highlight the need for precision medicine approaches based on human studies.
Genomic Analysis Enlightens Agaricales Lifestyle Evolution and Increasing Peroxidase Diversity
Authors: Francisco J Ruiz-Dueñas, José M Barrasa, Marisol Sánchez-García, Susana Camarero, Shingo Miyauchi, Ana Serrano, Dolores Linde, Rashid Babiker, Elodie Drula, Iván Ayuso-Fernández, Remedios Pacheco, Guillermo Padilla, Patricia Ferreira, Jorge Barriuso, Harald Kellner, Raúl Castanera, Manuel Alfaro, Lucía Ramírez, Antonio G Pisabarro, Robert Riley, Alan Kuo, William Andreopoulos, Kurt LaButti, Jasmyn Pangilinan, Andrew Tritt, Anna Lipzen, Guifen He, Mi Yan, Vivian Ng, Igor V Grigoriev, Daniel Cullen, Francis Martin, Marie-Noëlle Rosso, Bernard Henrissat, David Hibbett, Angel T Martínez
Journal: Molecular Biology and Evolution (2020)

Abstract As actors of global carbon cycle, Agaricomycetes (Basidiomycota) have developed complex enzymatic machineries that allow them to decompose all plant polymers, including lignin. Among them, saprotrophic Agaricales are characterized by an unparalleled diversity of habitats and lifestyles. Comparative analysis of 52 Agaricomycetes genomes (14 of them sequenced de novo) reveals that Agaricales possess a large diversity of hydrolytic and oxidative enzymes for lignocellulose decay. Based on the gene families with the predicted highest evolutionary rates—namely cellulose-binding CBM1, glycoside hydrolase GH43, lytic polysaccharide monooxygenase AA9, class-II peroxidases, glucose–methanol–choline oxidase/dehydrogenases, laccases, and unspecific peroxygenases—we reconstructed the lifestyles of the ancestors that led to the extant lignocellulose-decomposing Agaricomycetes. The changes in the enzymatic toolkit of ancestral Agaricales are correlated with the evolution of their ability to grow not only on wood but also on leaf litter and decayed wood, with grass-litter decomposers as the most recent eco-physiological group. In this context, the above families were analyzed in detail in connection with lifestyle diversity. Peroxidases appear as a central component of the enzymatic toolkit of saprotrophic Agaricomycetes, consistent with their essential role in lignin degradation and high evolutionary rates. This includes not only expansions/losses in peroxidase genes common to other basidiomycetes but also the widespread presence in Agaricales (and Russulales) of new peroxidases types not found in wood-rotting Polyporales, and other Agaricomycetes orders. Therefore, we analyzed the peroxidase evolution in Agaricomycetes by ancestral-sequence reconstruction revealing several major evolutionary pathways and mapped the appearance of the different enzyme types in a time-calibrated species tree.
Abstract 14386: The 2020 ESC-ACVC Quality Indicators for the Management of Acute Myocardial Infarction Applied to the FAST-MI Registries: Validity Criteria Compared to the 2017 Definitions
Authors: Francois Schiele, Hector Bueno, Xavier Rossello, Sergio Leonardi, Frederick Masoudi, Marco Tubaro, Chris P Gale, Etienne Puymirat, Jean Ferrieres, Fiona Ecarnot, Nicolas DANCHIN, tabassome Simon, Nicolas Meneveau
Journal: Circulation (2020)

Introduction: In 2020, the European Society of Cardiology-Acute Cardio Vascular Care (ESC-ACVC) updated the 2017 Quality Indicators (QI) for the management of acute myocardial infarction (AMI). We compared 2017 vs 2020 indicators in terms of feasibility, potential for improvement, association with outcomes, and suitability for center benchmarking. Methods: Data were extracted from three French nationwide cohorts (FAST-MI 2005, 2010 and 2015), using data from AMI survivors at discharge. Applicability and potential for improvement were estimated for each QI by the denominator and numerator. The association between the composite QIs and 1 year mortality were assessed using multivariate logistic regressions. Center benchmarking was based on the mean of the opportunity-based composite QIs (CQI) and the All or None Composite QI. Results: The 2017 and 2020 QIs were measured in 12,660 /13,130 patients discharged alive, respectively. The rates of attainment ranged from 15% to 96% (Figure, left). The mean value of the Composite QI was 0.71 in 2017 versus 0.64 in 2020 (p&lt;0.01). Quartiles of CQI were significantly associated with risk-adjusted 1 year mortality for 2017 and 2020 CQI (Figure, right). Addition of the quartiles of the 2020 CQI improved the discrimination indices. Attainment of the 2020 All-or-None Composite QI was observed in 12% of cases, and was associated with a 63% lower odds of death. The opportunity-based Composite QI and the All-or-None QI were suitable for center benchmarking. Conclusion: Compared to the 2017 QIs, the 2020 updated QIs for AMI can be measured in existing registries, and show greater potential for improvement, a comparable association with mortality and similar suitability for center benchmarking.
Abstract 14908: Anatomic Validation of Induced Pluripotent Stem Cell-derived Aortic Smooth Muscle Cell Model of Loeys Dietz Syndrome
Authors: Albert J Pedroza, Samantha Churovich, Nobu Yokoyama, Ken Nakamura, Cristiana Iosef Husted, Michael P Fischbein
Journal: Circulation (2020)

Introduction: Mutations in TGF-beta (TGF-ß) signaling genes lead to aortic root aneurysm in Loeys Dietz syndrome (LDS). Smooth muscle cells (SMCs) in the proximal aorta develop from two embryologic origins: second heart field (SHF) and neural crest (NC). Induced pluripotent stem cell (iPSC) models simulate these lineages, but direct correlation to clinical disease is lacking. Hypothesis: iPSC-derived SMCs accurately model lineage-specific aortopathy in LDS. Methods: We generated SMC lines from root and ascending aortic surgical tissue and iPSC-derived SMCs through SHF and NC-specific pathways from an LDS patient ( TGFBR1 mutation). Lineage-specific TGF-ß responses were determined by western blot/ELISA. RNA sequencing and RT-PCR identified SMC transcriptomes. Results: Aortic root SMCs showed greater canonical TGF-ß activation (p-SMAD2/3) versus ascending at baseline and with TGF-ß stimulation ( Figure ). Synonymous results were seen in SHF versus NC SMCs from the iPSC pathway. RNAseq identified 1,600 differentially expressed genes between iPSC lineages, including altered TGF-ß receptor and ligand expression profiles. Primary aortic lines validated iPSC data: root SMCs showed enriched TGF-ß receptor 1/2/3 expression (1.7-, 3.9- and 5.9-fold) while ascending SMCs overexpressed TGFB1 and TGFB2 ligands (1.8- and 3.5-fold). Despite discordant TGF-ß activation, SMC contractile gene expression was similar between lineages in aortic and iPSC-SMCs, suggesting alternative downstream effects in LDS aneurysm. Conclusion: iPSC-derived SMCs effectively model lineage-specific aortic root aneurysm pathology, validating this model as a tool for mechanistic testing and therapy discovery.
Colonic Visualization of 99mTc-DMSA Due to Enterovesical Fistula
Authors: Tuğçe Telli, Gürsan Kaya, Zeynep Işik, Murat Tuncel
Journal: Clinical Nuclear Medicine (2020)

A 60-year-old woman with recurrent urinary tract infection who had several operations for colorectal carcinoma underwent Tc-DMSA renal scintigraphy which showed an unexpected accumulation of radiotracer in the colon. When symptoms were reviewed, we noticed that she was suffering from pneumaturia and fecaluria which raised the suspicion of enterovesical fistula. Rectal contrast-enhanced computer tomography of pelvis demonstrated enterovesical and enterovaginal fistulas. Colonic radioactivity was considered to be related to retrograde peristalsis of Tc-DMSA from bladder activity via enterovesical fistula. In patients with pelvic surgeries and radiotherapy, radioactivity in the colon should raise the suspicion of enterovesical fistula.
Abstract 16361: Effects of Low-dose Triple Combination Therapy on Time at Target Blood Pressure - Results From the TRIUMPH Randomized Controlled Trial
Authors: Sonali R Gnanenthiran, Nelson Wang, Abdul Salam, Ruth Webster, Asita de Silva, Anushka Patel, Anthony Rodgers
Journal: Circulation (2020)

Introduction: Cumulative exposure to hypertension is an adverse prognostic marker. However longitudinal assessments of blood pressure (BP), i.e. TIme at TaRgEt (TITRE), are not routinely assessed in practice. Specifically, the effect of low-dose combination anti-hypertensive therapy on TITRE has not been studied. Hypothesis: Low-dose triple combination antihypertensive medication achieves greater TITRE compared to usual care. Methods: TRIUMPH (TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension) was a randomized controlled open-label trial of patients requiring initiation or escalation of antihypertensive therapy. Patients from urban hospital clinics in Sri Lanka were randomised to either once-daily low-dose triple combination polypill (20mg of telmisartan, 2.5mg of amlodipine, and 12.5mg of chlorthalidone) or standard care. This analysis compared TITRE in the intervention and usual care groups over 6 months follow-up, with TITRE defined as percentage of time at target BP. Target BP was defined as &lt;140/90mmHg or &lt;130/80mmHg in patients with diabetes or chronic kidney disease. Results: The trial comprised 700 patients (mean [±SD] age: 56±11 years, 58% women). Patients in the triple pill group (n=349) achieved a higher TITRE compared to those in the standard care group (n=351) at 6 months (64±32% vs 43±34%, risk difference -21%, 95%CI -26% to -6%, p&lt;0.001). Almost twice as many patients in the triple pill group spent the majority of follow-up time at target (TITRE &gt;50%: 64% vs 37%, p&lt;0.001). The effect of the triple pill was seen early, with the majority achieving TITRE &gt;50% by 12 weeks. Those on the triple pill achieved a consistently higher TITRE at all follow-up periods compared to usual care (0-6 weeks: 36±31% vs 21±28%; 6-12 weeks: 74±39% vs 46±43%; 12-24 weeks: 77±37% vs 53±44%, all p&lt;0.001). When predictors of TITRE were examined, only triple pill therapy was predictive of TITRE &gt;75% (odds ratio [OR] 3.41, 95%CI 2.30-5.04, p&lt;0.001). Conclusion: Among patients with mild-moderate hypertension, treatment with a low-dose triple combination pill significantly increased time at target compared to usual care. This study also introduces TITRE as a novel outcome assessing longitudinal BP control in trials.
Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study
Authors: Anna Duckworth, Michael A Gibbons, Richard J Allen, Howard Almond, Robin N Beaumont, Andrew R Wood, Katie Lunnon, Mark A Lindsay, Louise V Wain, Jess Tyrrell, Chris J Scotton
Journal: The Lancet Respiratory Medicine (2020)
Abstract 16091: Cardiac Mechanical Determinants of Exercise Function in Differing Fontan Heart Failure Phenotypes
Authors: Shahryar M Chowdhury, carolyn taylor, Andrew M ATZ
Journal: Circulation (2020)

Introduction: The objective of this study was to investigate the association of contractility, afterload, and diastolic dysfunction to exercise function between patients with heart failure and preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Hypothesis: Cardiac mechanical determinants of exercise would be different in HFrEF versus HFpEF Methods: Core-lab echocardiograms were obtained from the publically-available Pediatric Heart Network Fontan Cross-sectional Study database. Ejection fraction was considered abnormal if &lt; 50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e’/end-diastolic volume) was &gt; 10 th percentile. Patients were divided into three groups: 1 = normal EF and normal diastolic function, 2 = decreased EF with normal diastolic function (HFrEF), 3 = normal EF with abnormal diastolic function (HFpEF). End-systolic elastance (Ees), a measure of contractility, and arterial elastance (Ea), a measure of afterload, were calculated. Results: 238 patients were included. Differences between groups are reported in the Table. In group 1, there were no significant correlations between exercise and echocardiographic measures. In patients with HFrEF, Ea was correlated with percent predicted max O 2 pulse (ppO 2 P-max) (r = -0.40, p = 0.03). In patients with HFpEF, lateral E:e’/EDV was correlated with ppO 2 P-max (r = -0.57, p = 0.02). No measures correlated with percent predicted peak VO 2 in either group. Conclusions: As Fontan patients progress to heart failure, stroke volume during exercise is limited by afterload in patients with HFrEF. Alternatively, stroke volume is limited by diastolic dysfunction in HFpEF patients. These measures of cardiac mechanics may be useful in identifying the mechanisms that drive exercise dysfunction in Fontan patients of varying heart failure phenotypes.