tbuckley/cabot-search huggingface dataset:
Overexpression of Mitochondrial Transcription Factor A Ameliorates Mitochondrial Deficiencies and Cardiac Failure After Myocardial Infarction
Authors: MasakiIkeuchi, HidenoriMatsusaka, DongchonKang, ShoujiMatsushima, TomomiIde, ToruKubota, ToshiyukiFujiwara, NaotakaHamasaki, AkiraTakeshita, KenjiSunagawa, HiroyukiTsutsui
Journal: Circulation (2005)

Background— Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state. Methods and Results— We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermate...
Genome-Wide Linkage Scan Identifies a Novel Genetic Locus on Chromosome 5p13 for Neonatal Atrial Fibrillation Associated With Sudden Death and Variable Cardiomyopathy
Authors: CarlosOberti, LejinWang, LinLi, JiameiDong, ShaoqiRao, WeiDu, QingWang
Journal: Circulation (2004)

Background— Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and patients with AF have a significantly increased risk for ischemic stroke. Approximately 15% of all strokes are caused by AF. The molecular basis and underlying mechanisms and pathophysiology of AF remain largely unknown. Methods and Results— We have identified a large AF family with an autosomal recessive inheritance pattern. The AF in the family manifests with early onset at the fetal stage and is associated with neonatal sudden death and, in some cases, ventricular tachyarrhythmias and waxing and waning cardiomyopathy. Genome-wide linkage analysis was performed for 36 family members and generated a 2-point logarithm of the odds (LOD) score of 3.05 for marker D5S455. The maximum multipoint LOD score of 4.10 was obtained for 4 markers: D5S426, D5S493, D5S455, and D5S1998. Heterozygous carriers have significant prolongation of P-wave duration on ECGs compared with noncarriers (107 versus 85 ms on average; P=0.000012),...
Abstract 21286: Outcomes and Trends of Percutaneous Coronary Interventions in Chronic Total Coronary Occlusion
Authors: Sopan Lahewala, Nirali Patel, Prashant Patel, Shilpkumar Arora, Byomesh Tripathi, Varun Kumar, Apurva Badheka
Journal: Circulation (2017)

Background: Percutaneous coronary intervention (PCI) of Chronic Total Coronary Occlusion (CTO) remains challenging, with observed success rates that are significantly lower than those for non-occluded lesions. Methods: HCUP’s Nationwide Inpatient Sample (NIS) database from 2008-2014 was utilized. CTO was identified using the ICD-9-CM diagnostic code 414.2, while PCI was identified using appropriate ICD 9 procedural codes. Complications were identified using previously published ICD9 codes and patient safety indicators tagged by data vendor. Cochran-Armitage test for trend was used to test the statistical significance. Result: 878112 CTO admissions were identified during study period, of which 47.6% went for revascularization with PCI (26.7% female, 69.8% white, 51.1% age ≥ 65). Compared to 2008, there was a relative decline of 5.7%(p &lt; 0.0001) in 2014. Population undergoing PCI showed significant relative increase in comorbidities (p- trend &lt; 0.0001) such as heart failure (+68.6%), renal failure (+ 50.7%), chronic pulmonary disease (+22.2%). In-hospital mortality (+ 101%) and complication rates (+ 29.4%) increased during the study period (p &lt; 0.0001). There was a significant increase in Renal and respiratory complication rates (relative increase 466.7% &amp; 201.7%, p &lt; 0.0001), while cardiac complication did not show any relative change during study period and vascular complications showed decline of 29.6% from 2008 to 2014 (p &lt; 0.0001). Conclusion: PCI in CTO is increasingly being done in sicker patients with higher burden of comorbidities. Improvement in interventional technical expertise has led to decline in vascular complications and steady rate of cardiac complications, though overall mortality and complications has risen mainly driven by non cardiac non vascular complications.
Abstract 167: Mir-195-3p/-5p Decrease Cardiac Fibroblast Proliferation and the Transdifferentiation into Myofibroblasts
Authors: ShutongShen, XiuzhiWang, DongjieXu, LichanTao, XiaotingWu, JunjieXiao, XinliLi
Journal: Circulation Research (2015)

Aims: MicroRNAs (miRNAs, miRs) contribute to many essential physiological and pathological processes including fibrosis. This study aims at investigating the role of miR-195-3p/-5p in cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Methods and results: In isolated primary neonatal cardiac fibrobasts (NRCFs), forced expression of miR-195-3p/-5p with agomiRs could attenuate fibrobast proliferation as determined by EdU and Ki67 staining while inhibition of miR-195-3p/-5p with antagomiRs could increase fibrobast proliferation. By quantitative reverse transcription polymerase chain reactions (RT-PCRs) and western blotting (WB), α-SMA (a marker of myofibroblast transdifferentiation) was found to be suppressed in the miR-195-3p/-5p agomiR-treated NRCFs at both mRNA and protein levels, while was increased in the miR-195-3p/-5p antagomiR-treated NRCFs. Moreover, Chek-1 was identified as a target gene of miR-195-3p/-5p responsible for cardiac fibroblast proliferation and the trans...
Less invasive ventricular reshaping provides sustained reduction of heart failure symptoms
Authors: C. S. Schmitz, P. N. Neuzil, I. S. Skalsky, L. L. Labrousse, H. S. Sievert, C. F. Frerker, T. S. Schmidt, K. K. Kuck, M. B. Biffi, A. C. Calafiore, D. P. Pacini, R. D. B. Dibartolomeo, G. D. Davidavicius, G. Kalinauskas, K. Rucinskas
Journal: European Journal of Heart Failure (2017)
Has Improvement in PTCA Intervention Affected Long-term Prognosis?
Authors: KatherineDetre, WanlinYeh, SherylKelsey, DavidWilliams, PatriceDesvigne-Nickens, DavidHolmes, MartialBourassa, SpencerKing, DavidFaxon, KennethKent
Journal: Circulation (1995)

Background The NHLBI Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry followed 1345 consecutive patients with first PTCA between 1977 and 1981 (registry 1) and 2136 consecutive patients with PTCA between 1985 and 1986 (registry 2). Changes in patient selection and in immediate and 1-year outcome are presented. This report extends to 5 years the comparison of the effects of early and more recent management with PTCA. Methods and Results Sixteen participating centers entered consecutive patients who had angioplasty for the first time between 1977 and 1981 and between 1985 and 1986. Patients with recent myocardial infarction (MI) were excluded. Vessel disease was defined according to the Coronary Artery Surgery Study. Successful dilatation required ≥20% reduction in luminal narrowing and <50% lumen diameter stenosis after intervention. Routine annual follow-up was conducted by telephone interview. The product-limit method was used to estimate freedom from untoward events, Cox regression analysi...
Abstract 2354: Candidate non-coding driver mutations in super-enhancers and long-range chromatin interaction networks across 1,800 whole cancer genomes
Authors: Juri Reimand
Journal: Cancer Research (2018)

Abstract A comprehensive understanding of the mutations that drive tumorigenesis and disease progression is essential to understanding tumor biology and designing precision therapies. The landscape of driver mutations in the protein-coding genome has been well-characterized by large exome-sequencing studies. Surprisingly, many tumors do not have mutations in any known protein-coding driver. Non-coding driver mutations are hypothesized to explain many of these cases, but aside from a few regions, like the TERT promoter, our understanding of drivers in the complex regulatory genome remains limited. To fill this gap, we analyzed 150,000 cis-regulatory modules with clustered transcription factor binding sites in 1,844 whole cancer genomes from the ICGC-TCGA PCAWG project. Using a new statistical method, ActiveDriverWGS, we identified dozens of frequently mutated regulatory elements (FMREs) enriched in non-coding SNVs and indels (FDR&amp;lt;0.05) with many structural rearrangements and focal copy number alterations in additional samples. The FMREs were enriched in super-enhancers, long-range chromatin interactions and H3K27ac marks derived from primary tumors, suggesting a gene regulatory role of these mutations through three-dimensional genome organization. The interaction network of chromatin loops and FMREs revealed putative target genes located dozens to hundreds of kilobases away from the mutated regulatory elements. We found known and putative oncogenes and tumor suppressors whose expression significantly correlated with mutations in FMREs, suggesting novel oncogenic mechanisms. Most of the FMREs were also confirmed by additional driver discovery methods, lending confidence to our statistical approach. We also validated ActiveDriverWGS on protein-coding sequence and accurately recovered known driver genes. The non-coding regulatory genome is characterized by diverse mutational processes, regional hypermutations and technically challenging areas with suboptimal sequencing coverage. Thus our findings, most of which are reported for the first time, should be carefully vetted and experimentally validated in future studies. Our integrative analysis of somatic mutations, cis-regulatory regions and long-range chromatin interaction networks is a novel framework for cancer discovery and reveals the currently largest set of potential non-coding drivers in a pan-cancer cohort. Citation Format: Juri Reimand. Candidate non-coding driver mutations in super-enhancers and long-range chromatin interaction networks across 1,800 whole cancer genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2354.
Intraplatelet Tetrahydrobiopterin Plays an Important Role in Regulating Canine Coronary Arterial Thrombosis by Modulating Intraplatelet Nitric Oxide and Superoxide Generation
Authors: SeijiKanaya, HisaoIkeda, NobuyaHaramaki, ToyoakiMurohara, TsutomuImaizumi
Journal: Circulation (2001)

Background Platelet-derived nitric oxide inhibits platelet aggregation via constitutive NO synthase (NOS). Tetrahydrobiopterin (BH4), a cofactor of NOS, augments NO formation, whereas its deficiency decreases NO bioactivity and increases superoxide generation by NOS. The roles of intraplatelet BH4 in platelet aggregation and thrombus formation, however, are unknown. Accordingly, we investigated whether intraplatelet BH4 is involved in regulating cyclic flow variations (CFVs) and platelet aggregation in a canine model with stenosed and endothelium-injured coronary arteries that mimics acute coronary syndromes in humans. Methods and Results After developing CFVs, dogs received saline or BH4 (10 or 30 mg/kg) intravenously. Intraplatelet BH4 and cGMP levels were decreased and intraplatelet nitrotyrosine production was increased during CFVs. ADP- and U46619-induced ex vivo platelet aggregation and platelet P-selectin expression were augmented during CFVs. BH4 administration restored intraplatelet BH4 and cGMP ...
Inhibition of Sarcolemmal Na+,K+-ATPase Activity Reduces the Infarct Size–Limiting Effect of Preconditioning in Rabbit Hearts
Authors: RyuzoNawada, TomoyukiMurakami, TomoyukiIwase, KunihikoNagai, YasuhiroMorita, IchiroKouchi, MasaharuAkao, ShigetakeSasayama
Journal: Circulation (1997)

Background The inhibition of sarcolemmal Na+,K+-ATPase activity is closely related to ischemic myocardial cell injury. However, the involvement of this enzyme in preconditioning has not been determined. Methods and Results We assessed the effect of ischemia on sarcolemmal Na+,K+-ATPase activity. Control and preconditioned rabbits were subjected to 0, 10, 20, 30, and 60 minutes of coronary occlusion. Ten to 60 minutes of ischemia reduced Na+,K+-ATPase activity, whereas preconditioning preserved the activity of this enzyme only during the first 20 minutes of ischemia. To determine whether the preservation of Na+,K+-ATPase activity in the early phase of ischemia contributed to limiting the infarct size, additional rabbits underwent 30 minutes of occlusion followed by 3 hours of reperfusion with or without pretreatment with digoxin, an inhibitor of Na+,K+-ATPase. Infarct size in animals pretreated with digoxin in the absence of preconditioning did not differ from that in controls. It was markedly reduced by p...
Abstract 1453: SLC25A32 sustains cancer cell proliferation by regulating flavin adenine dinucleotide (FAD) metabolism
Authors: Valeria Santoro, Ilya Kovalenko, Kim Vriens, Stefan Christen, Andreas Bernthaler, Andrea Haegebarth, Sarah-Maria Fendt, Sven Christian
Journal: Cancer Research (2018)

Abstract SLC25A32 is a member of the solute carrier 25 family of mitochondrial transporters. SLC25A32 transports tetrahydrofolate (THF) as well as FAD into mitochondria and regulates mitochondrial one-carbon metabolism and redox balance. While it is known that cancer cells require one-carbon and FAD-dependent mitochondrial metabolism for generation of nucleotides, lipids and for maintenance of redox homeostasis to sustain growth, the role of SLC25A32 in cancer cell survival remains unexplored. Our results indicate that the SLC25A32 gene is highly amplified in different tumors and that its amplification correlates with increased mRNA expression and with reduced patient survival. SiRNA-mediated knock-down and CRISPR-mediated knock-out of SLC25A32 in cancer cells of different origins, resulted in the identification of sensitive and resistant cells to SLC25A32 inhibition. Mechanistically, tracing of deuterated serine upon SLC25A32 knock-down did not affect the mitochondrial/cytosolic folate flux as measured by Liquid Chromatography coupled Mass Spectrometry (LC-MS). Instead, SLC25A32 inhibition resulted in respiratory chain dysfunction at the FAD-dependent complex II enzyme, induction of Reactive Oxygen Species (ROS) and depletion of reduced glutathione (GSH), impairing cancer cell proliferation. Moreover, Buthionine sulfoximine (BSO) treatment further sensitized cells to ROS-mediated inhibition of cell proliferation upon SLC25A32 knock-down. Treatment of cells with the FAD precursor riboflavin and with GSH rescued cancer cell proliferation upon SLC25A32 down-regulation. Our results indicate that inhibition of mitochondrial FAD transport by targeting SLC25A32 has potential clinical applications as a single agent or in combination with approved cancer drugs that lead to increased oxidative stress and reduced tumor growth. Citation Format: Valeria Santoro, Ilya Kovalenko, Kim Vriens, Stefan Christen, Andreas Bernthaler, Andrea Haegebarth, Sarah-Maria Fendt, Sven Christian. SLC25A32 sustains cancer cell proliferation by regulating flavin adenine dinucleotide (FAD) metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1453.
Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease
Authors: ShuichiJono, YujiIkari, AtsushiShioi, KatsuhitoMori, TakamiMiki, KazuhiroHara, YoshikiNishizawa
Journal: Circulation (2002)

Background— Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD). Methods and Results— Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increa...
Abstract 19432: Difference in Outcomes After Repeat Percutaneous Coronary Intervention for Sirolimus-Eluting Stent Restenosis Lesions With or Without Stent Fracture
Authors: YasunariSakamoto, ToshiyaMuramatsu, ReikoTsukahara, YoshiakiIto, HiroshiIshimori, KeisukeHirano, MasatsuguNakano, MasahiroYamawaki, MotoharuAraki
Journal: Circulation (2013)

Background: Presence of stent fracture (SF) after sirolimus-eluting stent (SES) implantation has reported to be associated with an increased risk of in-stent restenosis and target lesion revascularization (TLR). Incidence of SF and the relevance to cardiovascular events are previously reported. But little is known about the outcomes after repeat percutaneous coronary intervention (PCI) for SES restenosis lesion with SF. So this study compared the outcomes after repeat PCI for SES restenosis lesion with or without SF. Method: From April 2007 to September 2011, total 2020 lesions implanted SES during PCI at our hospital. Total 148 lesions, 7.3% had restenosis (defined as % diameter stenosis >50%) in follow up angiogram. Of the restenosis lesion, 107 lesions went to TLR those consisted of 75 lesions with repeat DES implantation and 32 lesions with balloon angioplasty alone. SF was defined as complete or partial separation of the stent as assessed by plain fluoroscopy and detected in 61 lesions of SES resteno...
Real-Time Use of Artificial Intelligence in Identification of Diminutive Polyps During Colonoscopy
Authors: Yuichi Mori, Shin-ei Kudo, Masashi Misawa, Yutaka Saito, Hiroaki Ikematsu, Kinichi Hotta, Kazuo Ohtsuka, Fumihiko Urushibara, Shinichi Kataoka, Yushi Ogawa, Yasuharu Maeda, Kenichi Takeda, Hiroki Nakamura, Katsuro Ichimasa, Toyoki Kudo, Takemasa Hayashi, Kunihiko Wakamura, Fumio Ishida, Haruhiro Inoue, Hayato Itoh, Masahiro Oda, Kensaku Mori
Journal: Annals of Internal Medicine (2018)

Background: Computer-aided diagnosis (CAD) for colonoscopy may help endoscopists distinguish neoplastic polyps (adenomas) requiring resection from nonneoplastic polyps not requiring resection, potentially reducing cost. Objective: To evaluate the performance of real-time CAD with endocytoscopes (×520 ultramagnifying colonoscopes providing microvascular and cellular visualization of colorectal polyps after application of the narrow-band imaging [NBI] and methylene blue staining modes, respectively). Design: Single-group, open-label, prospective study. (UMIN [University hospital Medical Information Network] Clinical Trial Registry: UMIN000027360). Setting: University hospital. Participants: 791 consecutive patients undergoing colonoscopy and 23 endoscopists. Intervention: Real-time use of CAD during colonoscopy. Measurements: CAD-predicted pathology (neoplastic or nonneoplastic) of detected diminutive polyps (≤5 mm) on the basis of real-time outputs compared with pathologic diagnosis of the resected specimen (gold standard). The primary end point was whether CAD with the stained mode produced a negative predictive value (NPV) of 90% or greater for identifying diminutive rectosigmoid adenomas, the threshold required to "diagnose-and-leave" nonneoplastic polyps. Best- and worst-case scenarios assumed that polyps lacking either CAD diagnosis or pathology were true- or false-positive or true- or false-negative, respectively. Results: Overall, 466 diminutive (including 250 rectosigmoid) polyps from 325 patients were assessed by CAD, with a pathologic prediction rate of 98.1% (457 of 466). The NPVs of CAD for diminutive rectosigmoid adenomas were 96.4% (95% CI, 91.8% to 98.8%) (best-case scenario) and 93.7% (CI, 88.3% to 97.1%) (worst-case scenario) with stained mode and 96.5% (CI, 92.1% to 98.9%) (best-case scenario) and 95.2% (CI, 90.3% to 98.0%) (worst-case scenario) with NBI. Limitation: Two thirds of the colonoscopies were conducted by experts who had each experienced more than 200 endocytoscopies; 186 polyps not assessed by CAD were excluded. Conclusion: Real-time CAD can achieve the performance level required for a diagnose-and-leave strategy for diminutive, nonneoplastic rectosigmoid polyps. Primary Funding Source: Japan Society for the Promotion of Science.
Percutaneous Transluminal Mitral Valvuloplasty Normalizes Baroreflex Sensitivity and Sympathetic Activity in Patients With Mitral Stenosis
Authors: KazuhiroAshino, EijiGotoh, Shin-ichiSumita, AkihikoMoriya, MasaoIshii
Journal: Circulation (1997)

Background In patients with mitral stenosis, reduced cardiac output or altered pulmonary hemodynamics may increase sympathetic nerve activity. However, the magnitude of the increase in sympathetic activity in such patients and the effect of valvuloplasty on this activity are unknown. Methods and Results We microneurographically measured muscle sympathetic nerve activity before and after mitral valvuloplasty in 10 patients (mean±SEM age, 48±2 years) with mitral stenosis and in 10 healthy volunteers (47±4 years); hemodynamic variables were also measured. Baroreflex sensitivity was assessed on the basis of the ratio of the change in heart rate or muscle sympathetic activity to the change in mean arterial pressure during intravenous infusion of sodium nitroprusside or phenylephrine. At baseline, muscle sympathetic activity was significantly higher in the patients with mitral stenosis than in the control subjects (42.1±3.2 versus 26.1±3.7 bursts/min, P<.05). However, there was no significant difference between...