tbuckley/cabot-search huggingface dataset:
Negative Chronotropic Effect of Endothelin 1 Mediated Through ETA Receptors in Guinea Pig Atria
Authors: KageyoshiOno, KojiEto, AijiSakamoto, TomohMasaki, KatsushiShibata, ToshioSada, KeitaroHashimoto, GozohTsujimoto
Journal: Circulation Research (1995)

Abstract Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [125I]endothelin 1 ([125I]ET-1) using the recently developed ETA receptor–selective antagonist BQ123 showed the presence of almost equal populations of ETA (44%) and ETB (56%) receptors in the guinea pig right atria. In a concentration-response study, endothelin 3 (ET-3), an agonist with higher affinity to ETB receptors than to ETA receptors, and sarafotoxin S6c (STXS6c), an ETB receptor–selective agonist, increased the rate of spontaneous beating at all concentrations tested (10 pmol/L to 100 nmol/L). In contrast, ET-1, a nonselective agonist, increased the heart rate at lower concentrations (10 pmol/L to 10 nmol/L) but decreased it at higher concentrations (30 to 100 nmol/L). When ET-1 (100 nmol/L) was applied in a single amount, heart rate was st...
Erythroferrone inhibits the induction of hepcidin by BMP6
Authors: João Arezes, Niall Foy, Kirsty McHugh, Anagha Sawant, Doris Quinkert, Virginie Terraube, Alette Brinth, May Tam, Edward R. LaVallie, Stephen Taylor, Andrew E. Armitage, Sant-Rayn Pasricha, Orla Cunningham, Matthew Lambert, Simon J. Draper, Reema Jasuja, Hal Drakesmith
Journal: Blood (2018)
Abstract 1844: Centriole amplification sensitizes cells to paclitaxel
Authors: Amber L. Lasek, Eric M. Britigan, Beth A. Weaver
Journal: Cancer Research (2018)

Abstract Paclitaxel (Taxol) is a widely utilized treatment for primary and metastatic breast cancer. However, only about 50% of patients respond and no predictive biomarker for paclitaxel efficacy is currently available. Identification of a clinically validated predictive biomarker would substantially improve patient outcomes. Aneuploidy, an aberrant chromosome number, was recognized in the late 1800s as a hallmark of tumor cells. This led to the hypothesis that aneuploidy drives tumorigenesis. However, experiments in animal models have shown that the effect of aneuploidy on tumors depends on the rate of ongoing chromosome missegregation, also known as chromosomal instability (CIN). Low rates of CIN are weakly tumor promoting, while high rates of CIN lead to cell death and tumor suppression due to loss of one or more essential chromosomes. Combining two independent insults that each cause low CIN results in high CIN, cell death, and tumor suppression. We have recently shown that, in primary breast cancer patients, paclitaxel does not reach sufficiently high concentrations to cause mitotic arrest, as it does at typically used concentrations in cell culture. Instead, low clinically relevant doses of paclitaxel cause CIN due to multipolar spindles. We hypothesize that a preexisting low rate of chromosomal instability (CIN), which occurs in about 50% of breast tumors, sensitizes cells to paclitaxel treatment, since paclitaxel increases their rate of CIN over a maximally tolerated threshold. Centrosome amplification is common in breast cancer and can cause CIN through induction of multipolar spindles. To test whether CIN induced by centrosome amplification sensitizes cells to low, clinically relevant doses of paclitaxel, we inducibly overexpressed Polo-like kinase 4 (Plk4), the master regulator of centriole duplication, to generate supernumerary centrioles. Plk4 overexpression induced centriole amplification and increased the incidence of multipolar divisions, even in subclinical levels of paclitaxel. Consistent with our hypothesis, CIN induced by supernumerary centrosomes potentiates the decrease in cell viability caused by paclitaxel treatment. Decreased cell viability is accompanied by an increase in mitotic errors, CIN, and cell death and a reduction in the percentage of cycling cells. This data suggests that the subset of patients whose tumors exhibit centrosome amplification prior to treatment may be more likely to benefit from paclitaxel therapy. Citation Format: Amber L. Lasek, Eric M. Britigan, Beth A. Weaver. Centriole amplification sensitizes cells to paclitaxel [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 1844.
Effects of Lowering Average or Below-Average Cholesterol Levels on the Progression of Carotid Atherosclerosis
Authors: StephenMacMahon, NormanSharpe, GregGamble, HamishHart, JohnScott, JohnSimes, HarveyWhite
Journal: Circulation (1998)

Background—Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels. Methods and Results—In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all 2P<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both 2P<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery...
Abstract 2918: Decursin from <i>Angelica gigas</i> Nakai regulates CXCR7 expression and its downstream signaling in gastric cancer cells
Authors: Solbi Kim, Nayoung Kim, Hyewon Ryu, Gyu-Yong Song, Hyo Jin Lee
Journal: Cancer Research (2018)

Abstract Background: C-X-C motif chemokine receptor 7 (CXCR7) is a member of the G protein-coupled receptor family and is reported to be involved in the invasion, migration and tumor progression of various cancers. However, few compounds regulate CXCR7 expression. Therefore, compounds that negatively regulate CXCR7 may inhibit tumor progression and thus serve as candidates for effective anti-cancer drugs. In this study, we investigated the regulation of CXCR7 by decursin derived from Angelica gigas and its downstream signaling. Methods: A CXCR7-overexpressing stable cell line was established in gastric cancer cells, and the expression of membrane CXCR7 was confirmed by flow cytometry and immunocytochemistry. Cell viability was examined using the CCK-8 assay. We investigated the potential of decursin to inhibit cell migration and invasion using a Transwell system. We also examined the mechanism of CXCR7 regulation by decursin by performing Western blot analysis of downstream proteins using phospho-specific antibodies. Results: CXCR7 overexpression significantly increased the proliferation, invasion and migration of gastric cancer cells. In addition, spheres were well formed under anchorage-independent conditions in CXCR7-expressing gastric cancer cells. Levels of phospho-Stat3 and -Akt, positive regulators of cancer progression, were significantly increased. Decursin treatment reduced CXCR7 expression at the cellular membrane, and significantly decreased cancer cell invasion and migration. When treated with decursin, the sphere formation capacity decreased in a dose-dependent manner. In addition, decursin decreased the phosphorylation of Stat3 and its downstream target, c-Myc; however, it had no effect on Akt phosphorylation. Conclusion: Decursin reduces the invasion, migration and tumor progression of cancer cells by inhibiting CXCR7. Decursin could be proposed as a new anti-cancer drug by decreasing the expression of CXCR7, which is believed to be a therapeutic target in gastric cancer. Citation Format: Solbi Kim, Nayoung Kim, Hyewon Ryu, Gyu-Yong Song, Hyo Jin Lee. Decursin from Angelica gigas Nakai regulates CXCR7 expression and its downstream signaling in gastric cancer cells [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 2918.
Potent Inhibitory Effect of Sirolimus on Circulating Vascular Progenitor Cells
Authors: DaijuFukuda, MasatakaSata, KimieTanaka, RyozoNagai
Journal: Circulation (2005)

Background— Neointimal hyperplasia is the major cause of in-stent restenosis (ISR). The sirolimus-eluting stent (SES) has emerged as a promising therapy to prevent ISR; however, the exact mechanism by which locally delivered sirolimus, an immunosuppressive agent, prevents ISR remains unknown. Recent evidence suggests that circulating progenitor cells may contribute to neointimal formation. Methods and Results— Mononuclear cells (MNCs) were isolated from peripheral blood of healthy human volunteers. Smooth muscle (SM)–like cells outgrew from the culture of MNCs (1×106) in the presence of platelet-derived growth factor-BB and basic fibroblast growth factor, whereas endothelial cell–like cells were obtained in the presence of vascular endothelial growth factor. Sirolimus potently inhibited SM-like cell outgrowth. The number of SM-like cells was significantly reduced at a concentration as low as 0.1 ng/mL (15.9±5.8% of control, P<0.001). Sirolimus also exerted an inhibitory effect on endothelial cell–like cel...
Abstract 16817: Whole Blood Levels of Microrna-34a-5p Predict Survival and Regulate Genes Associated With Pulmonary Arterial Hypertension
Authors: Jianhui Lin, James Iremonger, Josephine A Pickworth, Alexander M Rothman, Helen L Casbolt, Nadine D Arnold, David G Kiely, Allan Lawrie
Journal: Circulation (2016)

Rationale: Despite advanced therapies for pulmonary arterial hypertension (PAH) the progressive hyperproliferative pulmonary vasculopathy persists, and there remains no pharmacological cure for PAH. Circulatory microRNAs (miRs) offer considerable promise as both a prognostic biomarker, and to identify molecular mechanisms in patients with PAH. Previous miRNA microarray studies from our lab on whole blood from patients with PAH identified miR-34a as down-regulated in disease. Objectives: To validate changes in circulating miR-34a in whole blood from patients with PAH and relate them to disease severity and survival, and determine the phenotypic effect on human pulmonary artery smooth muscle cells (PASMC). Methods and Results: RNA was isolated from 27 treatment-naive patients with PAH, and 12 age-matched healthy volunteers (HV). Circulating miR-34a-5p was measured by TaqMan PCR and found to be significantly down-regulated in PAH compared to HV (1.7-fold, p=0.0001). Receiver operating characteristic (ROC) id...
Abstract 19150: Real Time Mitochondrial Monitoring Using Surface Raman Resonance Spectroscopy Detects Impending Cardiac Arrest
Authors: Dorothy A Perry, Joshua Salvin, Brian Polizzotti, Lindsay Thomson, Francis X McGowan, Padraic Romfh, Daryoosh Vakhshoori, John N Kheir
Journal: Circulation (2016)

Aims: Global markers of perfusion (e.g. serum lactic acid) are unable to detect critical defects in myocardial (or other local) tissue oxygen delivery. As oxygen becomes limiting, electrons accumulate and proteins in the mitochondrial electron transport system become more reduced. We sought to continuously monitor mitochondrial redox status in order to rapidly detect impending organ dysfunction. Methods and Results: We developed a Raman resonance spectroscopy system (RRS, A) to quantify the ratio of reduced versus oxidized mitochondrial proteins (reduced mitochondrial fraction, RMF). We first generated oxidized (100% O2) and reduced (100% N2 and sodium dithionate) RRS spectra in isolated rat cardiac mitochondria; the RRS spectra of oxy- and deoxy- hemoglobin and myoglobin spectra were similarly defined (B). Using these spectra, we quantified RMF in an isolated Langendorff rat heart model (C, n=8) where coronary flow rate was decreased in graded fashion from 100% (baseline) to 0% (10 minutes at each flow r...
Abstract 17161: Reduced Ventilatory Function and Gas Exchange are Associated With Cardiac Remodeling and Changes in Systolic and Diastolic Function in the Community
Authors: Matthew Nayor, Meredith D Stevenson, Vanessa Xanthakis, Connie W Tsao, Gary F Mitchell, Ramachandran S Vasan, Susan Cheng, George T O'Connor
Journal: Circulation (2015)

Introduction: Chronic lung disease and heart failure have been reported to be associated, but the pathophysiologic relations between cardiac and pulmonary structure and function in the community are not well understood. We evaluated cross-sectional associations between measures of pulmonary function and echocardiographic traits related to cardiac remodeling and systolic and diastolic function in a large, community-based sample. Hypothesis: We hypothesized that lower ventilatory function and diffusion capacity would be associated with adverse cardiac remodeling and reduced left ventricular (LV) systolic and diastolic function. Methods: Forced expiratory volume in 1 second (FEV1), single-breath carbon monoxide diffusion capacity (DLCO), and comprehensive echocardiographic measures were obtained in approximately 2500 participants (mean age 67±9 years; 55% women) attending the 8 th Framingham Offspring examination cycle. Results: Using multivariable-adjusted linear regression models, we observed lower DLCO to be associated with lower fractional shortening, relatively higher early LV filling (E/A ratio), greater LV filling pressures (E/e’ ratio), and smaller right ventricular (RV) size ( Table) . Similarly, lower FEV1 was associated with smaller left atrial size, relatively higher early LV filling (E/A ratio), smaller RV size, and smaller right atrial area ( Table ). Conclusions: Lower ventilatory function and diffusion capacity are associated with smaller cardiac chamber dimensions, worse LV systolic function, and changes in measures of LV diastolic filling. The mechanisms responsible for these relations require further investigation, but these associations provide evidence for a pathophysiologic association between chronic lung disease and abnormalities in cardiac structure and function in the community.
Effects of Anterior Communicating Artery Diameter on Cerebral Hemodynamics in Internal Carotid Artery Disease
Authors: FrancisCassot, ValérieVergeur, PhilippeBossuet, BerendHillen, MokhtarZagzoule, Jean-PierreMarc-Vergnes
Journal: Circulation (1995)

Background Collateral circulatory pathways are considered the primary determinant of cerebral hemodynamics in patients with obstructive lesions of the internal carotid arteries (ICaAs). However, the hemodynamic effects of the diameter of the anterior communicating artery (ACoA) have never been assessed quantitatively in humans. Methods and Results Two different mathematical models were used to simulate changes affecting blood pressures and flows in cerebral arteries as a function of ACoA diameter and ICaA stenoses or occlusions. Small changes in ACoA diameter were found to have marked hemodynamic effects when they occurred within the range of 0.4 to 1.6 mm, a situation observed in 80% of the cases. Outside this range, changes in ACoA diameter had no effect. Simulated pressure drops through a stenotic ICaA were consistent with those observed. They were found to depend on the degrees of the stenoses in both ICaAs and on ACoA diameter according to a simple equation. Pressure reserve in the middle and anterio...
Treatment with camu camu (<i>Myrciaria dubia</i>) prevents obesity by altering the gut microbiota and increasing energy expenditure in diet-induced obese mice
Authors: Fernando F Anhê, Renato T Nachbar, Thibault V Varin, Jocelyn Trottier, Stéphanie Dudonné, Mélanie Le Barz, Perrine Feutry, Geneviève Pilon, Olivier Barbier, Yves Desjardins, Denis Roy, André Marette
Journal: Gut (2018)

Objective The consumption of fruits is strongly associated with better health and higher bacterial diversity in the gut microbiota (GM). Camu camu ( Myrciaria dubia ) is an Amazonian fruit with a unique phytochemical profile, strong antioxidant potential and purported anti-inflammatory potential. Design By using metabolic tests coupled with 16S rRNA gene-based taxonomic profiling and faecal microbial transplantation (FMT), we have assessed the effect of a crude extract of camu camu (CC) on obesity and associated immunometabolic disorders in high fat/high sucrose (HFHS)-fed mice. Results Treatment of HFHS-fed mice with CC prevented weight gain, lowered fat accumulation and blunted metabolic inflammation and endotoxaemia. CC-treated mice displayed improved glucose tolerance and insulin sensitivity and were also fully protected against hepatic steatosis. These effects were linked to increased energy expenditure and upregulation of uncoupling protein 1 mRNA expression in the brown adipose tissue (BAT) of CC-treated mice, which strongly correlated with the mRNA expression of the membrane bile acid (BA) receptor TGR5. Moreover, CC-treated mice showed altered plasma BA pool size and composition and drastic changes in the GM (eg, bloom of Akkermansia muciniphila and a strong reduction of Lactobacillus ). Germ-free (GF) mice reconstituted with the GM of CC-treated mice gained less weight and displayed higher energy expenditure than GF-mice colonised with the FM of HFHS controls. Conclusion Our results show that CC prevents visceral and liver fat deposition through BAT activation and increased energy expenditure, a mechanism that is dependent on the GM and linked to major changes in the BA pool size and composition.
Letter by Barrios et al Regarding Article, “Impact of Proteinuria and Glomerular Filtration Rate on Risk of Thromboembolism in Atrial Fibrillation: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study”
Authors: VivencioBarrios, CarlosEscobar, RocioEcharri
Journal: Circulation (2009)
Abstract 517: LncRNA expression at the different site of high-grades serous carcinoma
Authors: Natalie Filippov-Levy, Yoav Smith, Claes Gøran Trope, Ben Davidson, Reuven Reich
Journal: Cancer Research (2018)

Abstract Background: High-grades serous carcinoma (HGSC) is the most aggressive subtype of ovary cancer. The disease appears at three anatomic sites: ovary tumor, solid metastasis and effusions. Not much is known about the regulatory pathways involved in cancer progression. Long non coding RNA (lncRNA) is non protein coding RNA with size &amp;gt;200bp. Exosomes are 30-100nm endosomal-derived vesicles containing mRNA, miRNA, lncRNA, transcription factors, proteins and lipids. They are secreted from various cells and their substance and amount alter between healthy and diseases state. Objective: Identification of lncRNA effecting cancer progression and patient survival. Methods: Custom made lncRNA microarray (composed off˜17,000 lncRNAs and˜22,000 mRNAs) followed by validation series of 180 specimens from three anatomic sites, including 77 effusions, 40 ovarian HGSC specimens, 21 solid metastases and exosomes from 42 effusion supernatants. 10 selected lncRNA were subjected to clinicopathologic parameters and survival association analysis. Results: out of 10 lncRNA chosen for validation, 5 lncRNA- ESRG, Link-A, MEG3, GATS and PVT1 - were differently expressed between the anatomic sites and exosomes (all p&amp;lt;0.001). In univariate survival analysis, higher ESRG levels were significantly related to longer overall survival (OS) in the entire cohort (p=0.023), Higher Link-A levels in post-chemotherapy specimens was significantly associated with longer OS (p=0.015). MEG3 levels were significantly higher in pre-chemotherapy effusions tapped at diagnosis (n=40) compared to post-chemotherapy specimens (p=37; p=0.017). Higher GATS expression was seen in specimens from patients who were sub-optimally debulked (p=0.046). Moreover, H19 which did not change significantly between the anatomic sites, was higher in effusions from patients whose tumors showed primary resistance to chemotherapy (PFS≤6 months). Conclusion: lncRNAs are differently express at different anatomic site and exosomes in HGSC and can provide new therapeutic targets. Furthermore, their level in effusion fluids can serve as a prognostic marker. Citation Format: Natalie Filippov-Levy, Yoav Smith, Claes Gøran Trope, Ben Davidson, Reuven Reich. LncRNA expression at the different site of high-grades serous carcinoma [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 517.
Pioglitazone-Induced Reductions in Atherosclerosis Occur via Smooth Muscle Cell–Specific Interaction With PPARγ
Authors: VenkateswaranSubramanian, JonathanGolledge, TalhaIjaz, DennisBruemmer, AlanDaugherty
Journal: Circulation Research (2010)

Rationale:Peroxisome proliferator-activated receptor (PPAR)γ agonists attenuate atherosclerosis and abdominal aortic aneurysms (AAAs). PPARγ, a nuclear receptor, is expressed on many cell types including smooth muscle cells (SMCs). Objective:To determine whether a PPARγ agonist reduces angiotensin II (Ang II)–induced atherosclerosis and AAAs via interaction with SMC-specific PPARγ. Methods and Results:Low-density lipoprotein receptor (LDLR)−/− mice with SMC-specific PPARγ deficiency were developed using PPARγ floxed (PPARγf/f) and SM22 Cre+ mice. PPARγf/f littermates were generated that did not express Cre (Cre0/0) or were hemizygous for Cre (Cre+/0). To assess the contribution of SMC-specific PPARγ in ligand-mediated attenuation of Ang II–induced atherosclerosis and AAAs, both male and female Cre0/0 and Cre+/0 mice were fed a fat-enriched diet with or without the PPARγ agonist pioglitazone (Pio) (20 mg/kg per day) for 5 weeks. After 1 week of feeding modified diets, mice were infused with Ang II (1000 ng...
Novel Molecular Mechanism of Increased Myocardial Endothelin-1 Expression in the Failing Heart Involving the Transcriptional Factor Hypoxia-Inducible Factor-1α Induced for Impaired Myocardial Energy Metabolism
Authors: YoshihikoKakinuma, TakashiMiyauchi, KoichiYuki, NobuyukiMurakoshi, KatsutoshiGoto, IwaoYamaguchi
Journal: Circulation (2001)

Background—Hypoxia-inducible factor (HIF)-1α is an important transcriptional factor that activates the gene expression of glycolytic enzymes, which are activated as compensation for impaired β-oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expression is markedly increased in heart failure. The mechanism, however, is unknown. Because we found an HIF-1α binding site in the 5′-promoter region of the ET-1 gene, we hypothesized that HIF-1α is involved in this mechanism. Methods and Results—In rat cardiomyocytes, luciferase assay and electrophoretic mobility shift assay showed that HIF-1α transcriptionally activates ET-1 gene expression by direct interaction with the predicted DNA binding site in the 5′-promoter region. HIF-1α mRNA and ET-1 mRNA in the failing heart increased during the aggravation of heart failure in vivo in animal models, ie, rats with myocardial infarction and hamsters with cardiomyopathy. In cultured cardiomyocytes treated with a mitochondrial inhib...
Introducing a replication-first rule for Ph.D. projects
Authors: Arnold R. Kochari, Markus Ostarek
Journal: Behavioral and Brain Sciences (2018)

Abstract Zwaan et al. mention that young researchers should conduct replications as a small part of their portfolio. We extend this proposal and suggest that conducting and reporting replications should become an integral part of Ph.D. projects and be taken into account in their assessment. We discuss how this would help not only scientific advancement, but also Ph.D. candidates' careers.