tbuckley/cabot-search huggingface dataset:
LDL Downregulates CYP51 in Porcine Vascular Endothelial Cells and in the Arterial Wall Through a Sterol Regulatory Element Binding Protein-2–Dependent Mechanism
Authors: CristinaRodríguez, JoséMartínez-González, SoniaSánchez-Gómez, LinaBadimon
Journal: Circulation Research (2001)

Abstract—Hypercholesterolemia is associated with endothelial dysfunction and atherosclerotic lesion formation. By mRNA–differential display analysis, we have identified lanosterol 14α-demethylase (CYP51) as a gene highly regulated by native LDLs (nLDLs) in endothelial cells. CYP51 is a cytochrome P-450 enzyme involved in the postsqualene phases of cholesterol biosynthesis. CYP51 mRNA levels decrease in nLDL-treated cells in a dose- and time-dependent manner (9-fold after 24 hours with 180 mg of LDL cholesterol per deciliter), an effect that is blocked by cycloheximide. In parallel, sterol regulatory element (SRE) binding protein-2 (SREBP-2) expression falls (10-fold), without alteration in SREBP-1 level. N-Acetyl-leucyl-leucyl-norleucinal, which inhibits catabolism of the active form of SREBPs, abolished the effect of high concentrations of nLDL on CYP51 expression. Gel-shift assays performed with the SRE of the cyp51 gene (cyp51-SRE) revealed a diminished SREBP-SRE interaction in LDL-treated cells. Moreo...
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Increase Fibrinolytic Activity in Rat Aortic Endothelial Cells
Authors: MarieEssig, GenevièveNguyen, DominiquePrié, BrigitteEscoubet, Jean-DanielSraer, GérardFriedlander
Journal: Circulation Research (1998)

Abstract—3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HRIs) have been recently shown to prevent atherosclerosis progression. Clinical benefit results from combined actions on various components of the atherosclerotic lesion. This study was designed to identify the effects of HRI on one of these components, the endothelial fibrinolytic system. Aortas isolated from rats treated for 2 days with lovastatin (4 mg/kg body wt per day) showed a 3-fold increase in tissue plasminogen activator (tPA) activity. In a rat aortic endothelial cell line (SVARECs) and in human nontransformed endothelial cells (HUVECs), HRI induced an increase in tPA activity and antigen in a time- and concentration-dependent manner. In SVARECs, the maximal response was observed when cells were incubated for 48 hours with 50 μmol/L HRI. An increase of tPA mRNA was also in evidence. In contrast, HRI inhibited plasminogen activator inhibitor-1 activity and mRNA. The effects of HRI were reversed by mevalonate and geran...
Abstract 20015: Clinical Presentation of Patients Undergoing Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry
Authors: Judit Karacsonyi, Khaldoon Alaswad, Dimitri Karmpaliotis, Farouc A Jaffer, Robert W Yeh, Mitul Patel, John Bahadorani, Anthony Doing, Catalin Toma, James Choi, Barry Uretsky, Aaron Grantham, Jeffrey W Moses, Ajay Kirtane, Manish Parikh, Ziad Ali, William Lombardi, David Kandzari, Nicholas Lembo, Santiago Garcia, Michael R Wyman, Aris Karatasakis, Jose R Martinez Parachini, Aya J Alame, Barbara A Danek, Erica Resendes, Bavana V Rangan, Imre Ungi, Craig A Thompson, Subhash Banerjee, Emmanouil S Brilakis
Journal: Circulation (2016)

Introduction: We examined the clinical presentation of patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in a multicenter registry. Methods: The baseline cl...
Abstract 2508: Effect of ALK-inhibitors in synovial sarcoma (SS) cell line HS-SYII
Authors: Hiroshi Gyotoku
Journal: Cancer Research (2018)

Abstract Synovial sarcoma (SS) accounts for approximately 8% of all soft tissue sarcomas (STS). The prognosis is poor because of a few effective chemotherapy regimens for STS such as Doxorubicin, Eribulin, and Trabectedin. Pazopanib, a multi-targeted tyrosine kinase inhibitor of PDGFR, VEGFR and c-Kit, is the first molecular targeted drug approved by FDA for STS. Recently, a preclinical efficacy of MET-inhibitor and ALK-inhibitor for a synovial sarcoma cell line was reported. We found that the response to ALK-inhibitors (Alectinib, Crizotinib and Lorlatinib) for SS cell line HS-SY-II different from Aska-SS cell line in a previous report. In addition, a combination of ALK-inhibitor and Pazopanib, previously reported that single-agent is effective in HS-SY-II, potentiates a cytotoxic effect by MTT assay than each single agent. Western blotting revealed that both of ALK-inhibitor single agent and the combination of Pazopanib and ALK-inhibitor suppress the phosphorylation of ERK and AKT, downstream of MAPK and PI3K pathway. Our data suggests that the combination therapy Pazopanib and ALK-inhibitor may be effective to SS patients clinically. Citation Format: Hiroshi Gyotoku. Effect of ALK-inhibitors in synovial sarcoma (SS) cell line HS-SYII [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 2508.
Ultrasound Measurement of the Fibrous Cap in Symptomatic and Asymptomatic Atheromatous Carotid Plaques
Authors: GéraldDevuyst, PatrickRuchat, TheodorosKarapanayiotides, LisaJonasson, OlivierCuisinaire, Johannes-AlexanderLobrinus, MarcPusztaszeri, AskenadiosKalangos, Paul-AndréDespland, Jean-PhilippeThiran, JulienBogousslavsky
Journal: Circulation (2005)

Background— Fibrous cap thickness (FCT) is an important determinant of atheroma stability. We evaluated the feasibility and potential clinical implications of measuring the FCT of internal carotid artery plaques with a new ultrasound system based on boundary detection by dynamic programming. Methods and Results— We assessed agreement between ultrasound-obtained FCT values and those measured histologically in 20 patients (symptomatic [S]=9, asymptomatic [AS]=11) who underwent carotid endarterectomy for stenosing (>70%) carotid atheromas. We subsequently measured in vivo the FCT of 58 stenosing internal carotid artery plaques (S=22, AS=36) in 54 patients. The accuracy in discriminating symptomatic from asymptomatic plaques was assessed by receiver operating characteristic curves for the minimal, mean, and maximal FCT. Decision FCT thresholds that provided the best correct classification rates were identified. Agreement between ultrasound and histology was excellent, and interobserver variability was small. ...
Abstract 14062: Cardiac Xenotransplantation-Associated Consumptive Thrombocytopenia is Attenuated With Use of Anti-CD40 Antibody Co-Stimulation Blockade
Authors: Joshua L Chan, Avneesh K Singh, Marvin L Thomas, David L Ayares, Keith A Horvath, Muhammad M Mohiuddin
Journal: Circulation (2016)

Introduction: Advances in the field of cardiac xenotransplantation may be able to address allogenic donor heart pool constraints. Costimulation blockade with anti-CD154 antibody is necessary to prevent xenograft rejection. However, this therapy has been found to be associated with critical consumptive thrombocytopenia, often limiting recipient survival. An alternative approach to costimulation blockade can be achieved with anti-CD40 therapy, without potentially evoking similar platelet consumption. Hypothesis: We assessed the hypothesis that anti-CD40 antibody lessens post-xenotransplant thrombocytopenia and is associated with improved survival. Methods: Baboons received heterotopic cardiac xenografts from genetically engineered swine. Immunosuppression comprised of conventional anti-rejection therapies along with either anti-CD154 or anti-CD40 antibody. Telemetry, video monitoring, and scheduled complete blood count panel were used to monitor recipients. Results: Recipients treated with anti-CD154 (n=16)...
Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression
Authors: KyosukeTakeshita, ToshihikoFujimori, YokoKurotaki, HaruoHonjo, HiroshiTsujikawa, KenjiYasui, Jong-KookLee, KaichiroKamiya, KiyoyukiKitaichi, KojiYamamoto, MasafumiIto, TakahisaKondo, ShigeoIino, YasuyaInden, MakotoHirai, ToyoakiMurohara, ItsuoKodama, Yo-ichiNabeshima
Journal: Circulation (2004)

Background— Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes. Methods and Results— The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380±33 versus 470±44 bpm; n=7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392±37 versus 233±24 ms; n=6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in ...
Single-Beat Estimation of End-Systolic Elastance Using Bilinearly Approximated Time-Varying Elastance Curve
Authors: ToshiakiShishido, KazukoHayashi, KenjiShigemi, TakayukiSato, MasaruSugimachi, KenjiSunagawa
Journal: Circulation (2000)

Background—Although left ventricular end-systolic elastance (Ees) has often been used as an index of contractility, technical difficulties in measuring volume and in changing loading conditions have made its clinical application somewhat limited. By approximating the time-varying elastance curve by 2 linear functions (isovolumic contraction phase and ejection phase) and estimating the slope ratio of these, we developed a method to estimate Ees on a single-beat basis from pressure values, systolic time intervals, and stroke volume. Methods and Results—In 11 anesthetized dogs, we compared single-beat Ees with that obtained with caval occlusion. Although the decrease (but not the increase) in contractility (5.3 to 11.4 mm Hg/mL) and the change in loading conditions (3.7 to 34.0 mm Hg/mL) over wide ranges significantly altered the slope ratio, the estimation of Ees was reasonably accurate (y=0.97x+0.46, r=0.929, SEE=2.1 mm Hg/mL). Conclusions—Ees can be estimated on a single-beat basis from easily obtainable ...
Coronary Heart Disease in Women
Authors: Ristéardmulcahy, Noelhickey, Brianmaurer
Journal: Circulation (1967)

One hundred women with classical coronary heart disease were studied in an attempt to identify etiological factors. Three dominant factors were hypertension, cigarette smoking, and hypercholesterolemia. Cigarette smoking and hypertension were present together or separately in 80 to 90% of the patients. Four patients were diabetics; six had grossly abnormal serum cholesterol levels; and there was one case each of associated myxedema, aortic stenosis, and postoperative hypotension. Comments are made about the role of family history, obesity, hypercholesterolemia, abnormal glucose tolerance, exercise and dietary experience, and the influence of the menopause. It is believed that the proper control of hypertension in the population and the elimination of cigarette smoking would cause an appreciable or even dramatic reduction in the incidence of precocious and middle-aged coronary heart disease in women.
Abstract 15421: Central Hemodynamic Response to Oral Glucose Loading Are Blunted in Patients with Impaired Glucose Tolerance or Diabetes
Authors: TadanaoHigaki, SatoshiKurisu, NoriakiWatanabe, HirokiIkenaga, TakashiShimonaga, TakatoshiIwasaki, KenIshibashi, YukihiroFukuda, YasukiKihara
Journal: Circulation (2014)

Introduction: Impaired glucose tolerance (IGT) as well as diabetes is associated with the development of cardiovascular disease. We tested the hypothesis that central hemodynamic responses to oral glucose loading were different according to the status of glucose tolerance. Methods: This study enrolled 89 patients with known or suspected coronary artery disease who underwent 75g oral glucose tolerance test (OGTT). Augmentation index (AIx) and central systolic blood pressure (cSBP) were measured using radial applanation tonometry (Omron, HEM 9000-AI) at fasting, and 1, 2 hours after oral glucose loading. Results: In overall patients, oral glucose loading increased pulse rate (60.0 ± 10.4 to 64.7 ± 11.9 bpm, p<0.001), and decreased AIx normalized to a heart rate of 75 bpm (AIx@75) (81.6 ± 13.9 to 74.5 ± 14.1 %, p<0.001) and cSBP (114.7 ± 22.2 to 108.6 ± 21.3 mmHg, p<0.001) at 2h. OGTT identified normal glucose tolerance (NGT) in 40 patients, IGT in 36 patients and diabetes in 13 patients. Decrease in AIx@75 ...
Mineralocorticoid Receptor Antagonism in Experimental Atherosclerosis
Authors: SanjayRajagopalan, DamonDuquaine, StevenKing, BertramPitt, PareshPatel
Journal: Circulation (2002)

Background— Aldosterone has been implicated in the effects of angiotensin II in the vasculature. We hypothesized that there is local expression of the mineralocorticoid receptor (MR) in the vasculature and that the use of a selective aldosterone receptor antagonist (SARA) improves endothelial function in early atherosclerosis. Methods and Results— New Zealand rabbits were placed on normal chow or 1% cholesterol diets, randomized to placebo or SARA (eplerenone, 50 mg/kg twice daily), and killed at the end of 6 weeks for various studies. In the hyperlipidemic (HL) chow group, there was a 2.3-fold increase in superoxide (O2·−) generation. SARA normalized O2· − generation in intact aortas and reduced NADH and NADPH oxidase activity to basal levels (0.31±0.04 and 0.27±0.02 in HL versus 0.16±0.05 and 0.07±0.02 in HL-SARA, respectively; P<0.01 by ANOVA). This was associated with improvements in peak relaxations to the endothelial-dependent agonist acetylcholine (82±6% in HL-SARA versus 61±4 in HL; P<0.01 by ANOV...
Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies
Authors: Eleanor L. Watts, Paul N. Appleby, Aurora Perez-Cornago, H. Bas Bueno-de-Mesquita, June M. Chan, Chu Chen, Barbara A. Cohn, Michael B. Cook, Leon Flicker, Neal D. Freedman, Graham G. Giles, Edward Giovannucci, Randi E. Gislefoss, Graeme J. Hankey, Rudolf Kaaks, Paul Knekt, Laurence N. Kolonel, Tatsuhiko Kubo, Loïc Le Marchand, Robert N. Luben, Tapio Luostarinen, Satu Männistö, E. Jeffrey Metter, Kazuya Mikami, Roger L. Milne, Kotaro Ozasa, Elizabeth A. Platz, J. Ramón Quirós, Harri Rissanen, Norie Sawada, Meir Stampfer, Frank Z. Stanczyk, Pär Stattin, Akiko Tamakoshi, Catherine M. Tangen, Ian M. Thompson, Konstantinos K. Tsilidis, Shoichiro Tsugane, Giske Ursin, Lars Vatten, Noel S. Weiss, Bu B. Yeap, Naomi E. Allen, Timothy J. Key, Ruth C. Travis
Journal: European Urology (2018)

Experimental and clinical evidence implicates testosterone in the aetiology of prostate cancer. Variation across the normal range of circulating free testosterone concentrations may not lead to changes in prostate biology, unless circulating concentrations are low. This may also apply to prostate cancer risk, but this has not been investigated in an epidemiological setting. To examine whether men with low concentrations of circulating free testosterone have a reduced risk of prostate cancer. Analysis of individual participant data from 20 prospective studies including 6933 prostate cancer cases, diagnosed on average 6.8 yr after blood collection, and 12 088 controls in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group. Odds ratios (ORs) of incident overall prostate cancer and subtypes by stage and grade, using conditional logistic regression, based on study-specific tenths of calculated free testosterone concentration. Men in the lowest tenth of free testosterone concentration had a lower risk of overall prostate cancer (OR = 0.77, 95% confidence interval [CI] 0.69–0.86; p < 0.001) compared with men with higher concentrations (2nd–10th tenths of the distribution). Heterogeneity was present by tumour grade (phet = 0.01), with a lower risk of low-grade disease (OR = 0.76, 95% CI 0.67–0.88) and a nonsignificantly higher risk of high-grade disease (OR = 1.56, 95% CI 0.95–2.57). There was no evidence of heterogeneity by tumour stage. The observational design is a limitation. Men with low circulating free testosterone may have a lower risk of overall prostate cancer; this may be due to a direct biological effect, or detection bias. Further research is needed to explore the apparent differential association by tumour grade. In this study, we looked at circulating testosterone levels and risk of developing prostate cancer, finding that men with low testosterone had a lower risk of prostate cancer.
Abstract 531: HeterozygousIDH1R132H/WTcreated by “single base editing” inhibits human astroglial cell growth by downregulating YAP
Authors: Shuang Wei, Jie Wang, Olutobi Oyinlade, Ding Ma Ma, Shuyan Wang, Shuli Xia
Journal: Cancer Research (2018)

Abstract Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified in a number of cancer types, including brain cancer. The Cancer Genome Atlas project has revealed that IDH1 mutations occur in 70-80% of grade II and grade III gliomas. Until recently, most of the functional studies of IDH1 mutations in cellular models have been conducted in overexpression systems with the IDH1 wild type background. In this study, we employed a modified CRISPR/Cas9 genome editing technique called “single base editing”, and efficiently introduced heterozygous IDH1 R132H mutation in human astroglial cells (~20%). Compared with astroglial cells with IDH1 wild type, monoallelic IDH1 R132H mutation (IDH1R132H/WT) inhibited cell proliferation and promoted cell migration. Global gene expression analysis identified molecular targets and pathways altered by IDH1R132H/WT, including cell proliferation, extracellular matrix, and cell migration, consistent with our phenotype characterization. Global DNA methylation profiling showed hypermethylation as well as hypomethylation induced by IDH1R132H/WT. Using our mutated IDH1 models generated by genome editing, we identified novel molecular targets of IDH1R132H/WT, namely Yes-associated protein (YAP) and its downstream signaling pathway Notch, to mediate the cell growth-inhibiting effect of IDH1R132H/WT. Our findings are in line with the clinical observations that brain tumor patients with mutated IDH1 have a better prognosis. In summary, the “single base editing” strategy has successfully created heterozygous IDH1 R132H mutation that recapitulate the naturally occurring IDH1 mutant. Our isogenic cellular systems that differ in a single nucleotide in one allele of the IDH1 gene provide a valuable model for novel discoveries of IDH1R132H/WT-driven biological events. Citation Format: Shuang Wei, Jie Wang, Olutobi Oyinlade, Ding Ma Ma, Shuyan Wang, Shuli Xia. Heterozygous IDH1R132H/WT created by “single base editing” inhibits human astroglial cell growth by downregulating YAP [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 531.
Abstract 19137: Twice Daily Dosing Normalyzes the Impaired Antiplatelet Effect of Low-Dose Aspirin Due to Enhanced Platelet Turnover in Patients Undergoing On-Pump Cardiac Surgery
Authors: Carlo Patrono, Viviana Cavalca, Bianca Rocca, Fabrizio Veglia, Raimondo De Cristofaro, Alessandro Parolari, Elena Tremoli
Journal: Circulation (2016)

Previous studies reported reduced platelet cyclooxygenase (COX)-1 inhibition by once-daily (od) low-dose aspirin early after cardiac surgery. We hypothesized that on-pump cardiac surgery enhances platelet turnover, leading to faster platelet COX-1 renewal. We measured: serum thromboxane (TX)B2 (sTXB2) and its urinary metabolite (TXM) to assess aspirin pharmacodynamics; thrombopoietin (TPO), interleukin (IL)-6, glycocalycin, immature platelet fraction (IPF), C-reactive protein to investigate the kinetics of platelet turnover. We also assessed whether a regimen of 100 mg twice-daily (bid) or 200 mg od aspirin could restore sTXB2 inhibition 7 days and 3 months post-surgery, and tested the vascular safety of these regimens, as reflected by prostacyclin (PGI2) metabolite (PGIM) excretion. Thirty-seven patients (aged 67±6 years, 83% M) on aspirin 100 mg od were studied the day before surgery, randomized 24-36 hrs post-surgery to 100 mg od, 100 mg bid or 200 mg od for 3 months, and sampled at 8 am and 8 pm befor...
Abstract 5050: Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia
Authors: Maaike CG Bleeker, Dorian RA Swarts, Quirinus JM Voorham, Saskia M. Wilting, Marc van Beurden, Renske DM Steenbergen
Journal: Cancer Research (2018)

Abstract Vulvar squamous cell carcinoma (VSCC) and precancerous high-grade vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinical and histological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in 24 VSCC and 41 VIN lesions. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during &amp;gt;10 year follow-up (VINnoVSCC). HPV-testing resulted in 41 HPV-positive lesions (16 VINVSCC, 14 VINnoVSCC and 11 VSCC) and 24 HPV-negative lesions (11 VINVSCC and 13 VSCC). HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than VSCC (P = 0.009), mainly 8q gains and 8p losses. In HPV-positive lesions, CNA frequencies were lower in VINnoVSCC than in VINVSCC (P = 0.022) and VSCC. Interestingly, a 1pq gain was detected in 81% of VINVSCC and only 29% of VINnoVSCC. In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Progression risk in VIN is reflected by the extent of CNA, in particularly chromosome 1 gain. Citation Format: Maaike CG Bleeker, Dorian RA Swarts, Quirinus JM Voorham, Saskia M. Wilting, Marc van Beurden, Renske DM Steenbergen. Molecular heterogeneity in HPV-dependent and -independent vulvar carcinogenesis: Chromosome 1 gain reflects the cancer risk in vulvar intraepithelial neoplasia [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 5050.