tbuckley/cabot-search huggingface dataset:
Abstract 16763: Unchanged Central Aortic Blood Pressure and Increased Myocardial Perfusion in Patients With Stable Coronary Artery Disease Receiving Ivabradine
Authors: Bernard I. Levy, Jean-Guillaume Dillinger, Patrick Henry, Damien Logeart, Stephane Manzo Silberman, Guillaume Allee, Vincent Maher, Cristiana Vitale
Journal: Circulation (2015)

Background: Treatment of hypertensive patients with beta-blockers reduces heart rate (HR) and increases central blood pressure, implying that the decrease in HR could explain reported increases in cardiovascular risk with beta-blocker. This analysis from a randomized, double-blind study explores whether HR reduction with the I f inhibitor ivabradine had an impact on central blood pressure and coronary perfusion. Methods and results: We included 12 normotensive patients with stable CAD, HR ≥70 bpm (sinus rhythm), and stable background beta-blocker therapy. Patients received ivabradine 7.5 mg bid or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting HR after 3 weeks versus no change with placebo (-15.8±7.7 versus +0.3±5.8 bpm, p=0.0010). There was no relevant between-group difference in change in central aortic SBP (-4.0±9.6 versus +2.4±12.0 mm Hg, p=0.13) or augmentation index (-0.8±10.0% versus +0.3±7.6%, p=0.87). Treatment with ivabradine was associated with prolongation of diastolic perfusion time by 41% from baseline to 3 weeks (+215.6±105.3 versus -3.0±55.8 ms with placebo, p=0.0005) (Figure) and with a pronounced increase in an index of myocardial viability (Buckberg index, +39.3±27.6% versus -2.5±13.5% with placebo, p=0.0015). There were no safety issues during the study. Conclusion: Heart rate reduction with ivabradine does not modify central aortic blood pressure and is associated with a marked prolongation of diastolic perfusion time and an improvement in myocardial perfusion.
Atorvastatin Attenuates Remnant Lipoprotein-Induced Monocyte Adhesion to Vascular Endothelium Under Flow Conditions
Authors: AkioKawakami, AkiraTanaka, KatsuyukiNakajima, KentaroShimokado, MasayukiYoshida
Journal: Circulation Research (2002)

Remnant lipoproteins have been reported to play a causative role in atherogenesis. We investigated the effect of remnant-like lipoprotein particles (RLPs) on monocyte-endothelial interaction and their potential regulation by atorvastatin. Monocytic U937 cells were incubated with RLPs isolated from hypertriglyceridemia subjects and their adhesion to human umbilical vein endothelial cells (HUVECs) was examined under flow conditions. Incubation of U937 cells with 15 μg protein/mL RLPs increased their adhesion to HUVECs activated with IL-1β (untreated: 6.8±1.6 cells/HPF versus RLPs: 16.2±3.3 cells/HPF, P<0.05). Flow cytometric analysis revealed that incubation with RLPs increased expression levels of CD11a, CD18, and CD49d in U937 cells. Moreover, RLP-induced RhoA activation as well as FAK activation was seen in U937 cells, and RLP-induced RhoA activation seemed to be involved with PKC-dependent signaling. To explore the effect of atorvastatin on RLP-induced U937 cell adhesion to HUVECs, U937 cells were incub...
Abstract 2029: Notch signaling inhibitor increases E-selectin/ligand interactions and alters cell migration of mesenchymal-like breast cancer cells
Authors: Christian A. Showalter, Monica M. Burdick
Journal: Cancer Research (2018)

Abstract Activation of Notch signaling has been shown to promote cell migration properties and hematogenous metastasis by inducing a dramatic phenotypic change in breast cancer cells via the epithelial-to-mesenchymal transition (EMT). In response to these findings, Notch signaling inhibitors are being explored as therapeutics to prevent EMT in cancers. However, research examining the effects of Notch inhibitors on the activity of sialofucosylated ligands used by circulating tumor cells to adhere to vascular endothelial E-selectin during metastasis is lacking. To advance knowledge in this area, our study investigated the use of an indirect Notch signaling inhibitor (DAPT) on modifying E-selectin ligand activity of breast cancer cell lines by shear flow adhesion assays performed at physiological bone marrow shear stress. DAPT exposure to mesenchymal-like MDA-MB-231 and MDA-MB-468 (induced to the mesenchymal-like state by exogenous epidermal growth factor) breast cancer cells increased E-selectin ligand activity. Furthermore, mesenchymal-like MDA-MB-468 cells after DAPT exposure demonstrated E-selectin ligand activity similar to that of epithelial-like MDA-MB-468 cells. This supports the hypothesis by our group that epithelial-like and mesenchymal-like phenotypes determine activity of functional E-selectin ligands in breast cancer cells, as we have previously shown that epithelial cells display high E-selectin ligand activity while mesenchymal cells display little or no ligand activity. Cell migration ability was assessed using wound closure assays. Mesenchymal-like MDA-MB-468 cells exposed to DAPT exhibited decreased migration compared to mesenchymal-like MDA-MB-468 cells exposed to the DMSO diluent control, whereas mesenchymal-like MDA-MB-231 cells demonstrated no difference in migration compared to DMSO exposed cells. Altogether, our results suggest Notch inhibitors may both increase fluid-shear resistant adhesion and alter migration ability of mesenchymal-like breast cancer cells, and that factors present in the blood might impact the metastatic potential of cancer cells via regulating cellular phenotypes. Citation Format: Christian A. Showalter, Monica M. Burdick. Notch signaling inhibitor increases E-selectin/ligand interactions and alters cell migration of mesenchymal-like breast 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 2029.
Abstract 17519: Virtual Environment for Diabetes Self-Management Education and Support: Preliminary RCT Outcomes
Authors: Allison Vorderstrasse, Gail D Melkus, Mark Feinglos, Wei Pan, Jianhong Chang, Katherine Pereira, Louise Reagan, Kathryn Kreider, Susan Totten, Andrew Burd, Sarah Nowlin, Stacia Birdsall, Constance M Johnson
Journal: Circulation (2017)

Introduction: Internet interventions are vital to reaching the growing population with type 2 diabetes. Methods: Based on our promising pilot study, we are conducting an RCT to test the efficacy of...
Estrogen Increases Bone Marrow–Derived Endothelial Progenitor Cell Production and Diminishes Neointima Formation
Authors: KerstinStrehlow, NikosWerner, JanBerweiler, AndreasLink, UlrichDirnagl, JosefPriller, KerstinLaufs, LeyliGhaeni, MilanMilosevic, MichaelBöhm, GeorgNickenig
Journal: Circulation (2003)

Background— Estrogens improve endothelial function and accelerate reendothelialization after vascular injury via largely unknown mechanisms. Bone marrow–derived endothelial progenitor cells (EPCs) are thought to positively influence endothelialization, vascular repair, and angiogenesis. Methods and Results— In mice subjected to sham operation, ovariectomy, or ovariectomy and estrogen replacement treatment, estrogen deficiency significantly decreased EPCs circulating in the peripheral blood and residing in the bone marrow, as well as EPCs that were in vitro expanded from spleen-derived mononuclear cells. These effects were completely prevented by estrogen replacement. Human women with increased estrogen plasma concentrations also displayed profoundly increased levels of circulating EPCs. Estrogens increase EPC numbers through a decreased apoptosis rate, which is mediated via a caspase-8–dependent pathway. Estrogen deficiency increased neointima formation after carotid artery injury in mice, but this effect...
TRPC1 Associates With BKCa Channel to Form a Signal Complex in Vascular Smooth Muscle Cells
Authors: Hiu-YeeKwan, BingShen, XinMa, Yuk-ChiKwok, YuHuang, Yu-BunMan, ShanYu, XiaoqiangYao
Journal: Circulation Research (2009)

TRPC1 (transient receptor potential canonical 1) is a Ca2+-permeable cation channel involved in diverse physiological function. TRPC1 may associate with other proteins to form a signaling complex, which is crucial for channel function. In the present study, we investigated the interaction between TRPC1 and large conductance Ca2+-sensitive K+ channel (BKCa). With the use of potentiometric fluorescence dye DiBAC4(3), we found that store-operated Ca2+ influx resulted in membrane hyperpolarization of vascular smooth muscle cells (VSMCs). The hyperpolarization was inhibited by an anti-TRPC1 blocking antibody T1E3 and 2 BKCa channel blockers, charybdotoxin and iberiotoxin. These data were confirmed by sharp microelectrode measurement of membrane potential in VSMCs of intact arteries. Furthermore, T1E3 treatment markedly enhanced the membrane depolarization and contraction of VSMCs in response to several contractile agonists including phenylephrine, endothelin-1, and U-46619. In coimmunoprecipitation experiments...
Prediction of Successful Ablation Site of Concealed Posteroseptal Accessory Pathways by a Novel Algorithm Using Baseline Electrophysiological Parameters
Authors: Chern-EnChiang, Shih-AnnChen, Ching-TaiTai, Tsu-JueyWu, Shih-HuangLee, Chen-ChuanCheng, Chuen-WangChiou, Kuo-ChangUeng, Zu-ChiWen, Mau-SongChang
Journal: Circulation (1996)

Background Radiofrequency catheter ablation of concealed posteroseptal accessory pathways (APs) has been a relatively difficult task for electrophysiologists. Without a detailed mapping procedure, the left versus the right posteroseptal AP could not be distinguished. We investigated the electrophysiological characteristics of concealed posteroseptal APs and defined criteria from baseline parameters to predict the successful ablation site. Validity of the criteria was prospectively verified. Methods and Results Eighty-nine consecutive patients with a single concealed posteroseptal AP underwent successful radiofrequency catheter ablation. Of the initial 48 patients (group 1), the right posteroseptal area was first mapped. If no ideal electrogram could be obtained, or after several ineffective radiofrequency pulses, the left posteroseptal area was then mapped. Special attention was paid to the stability of the coronary sinus catheter with the most proximal electrode straddling the ostium, verified by coronar...
Feedback Remodeling of Cardiac Potassium Current Expression
Authors: LingXiao, JieningXiao, XiaobinLuo, HuixianLin, ZhiguoWang, StanleyNattel
Journal: Circulation (2008)

Background— Inhibition of individual K+ currents causes functionally based compensatory increases in other K+ currents that minimize changes in action potential duration, a phenomenon known as repolarization reserve. The possibility that sustained K+ channel inhibition may induce remodeling of ion current expression has not been tested. Accordingly, we assessed the effects of sustained inhibition of one K+ current on various other cardiac ionic currents. Methods and Results— Adult canine left ventricular cardiomyocytes were incubated in primary culture and paced at a physiological rate (1 Hz) for 24 hours in the presence or absence of the highly selective rapid delayed-rectifier K+ current (IKr) blocker dofetilide (5 nmol/L). Sustained dofetilide exposure led to shortened action potential duration and increased repolarization reserve (manifested as a reduced action potential duration–prolonging response to IKr blockade). These repolarization changes were accompanied by increased slow delayed-rectifier (IK...
Vasoactive Potential of the B1 Bradykinin Receptor in Normotension and Hypertension
Authors: IrenaDuka, EkaterinaKintsurashvili, IreneGavras, ConradoJohns, MargaretBresnahan, HaralambosGavras
Journal: Circulation Research (2001)

Abstract—The B1 type receptor of bradykinin (Bk B1R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B1R in blood pressure (BP) regulation, we studied mice with deleted Bk B2R gene with induced experimental hypertension, either salt-dependent (subtotal nephrectomy with 0.5% NaCl as drinking water) or renin/angiotensin-dependent (renovascular 2-kidney–1-clip). Compared with the wild-type controls, the B2R gene knockout mice had a higher baseline BP (109.7±1.1 versus 101.1±1.3 mm Hg, P=0.002), developed salt-induced hypertension faster (in 19.3±2.3 versus 27.7±2.4 days, P=0.024), and had a more severe end point BP (148±3.7 versus 133±3.1 mm Hg, P<0.05). On the contrary, renovascular hypertension developed to the same extent (149.7±4.3 versus 148±3.6 mm Hg) and in the same time frame (14±2.2 versus 14±2.1 days). A bolus infusion of a selective B1R antagonist at baseline produced a significant hypertensi...
Abstract 309: MiR-31a-5p Controls Cardiomyocyte Proliferation in Postnatal Hearts
Authors: Hui Liu, Jing Shi, Hui Wang, Qingkao Xuan, Yihua Bei, Wei Sun, Xinli Li, Junjie Xiao, Xiangqing Kong
Journal: Circulation Research (2015)

Backgroud: MicroRNAs (miRNAs, miRs) are a class of endogenous non-codingRNAs, participating in a variety of essential biological processes including development, differentiation, proliferation and apoptosis. Rodents have the capacity to regenerate their hearts in response to injury while the capacity would be lost 7 day after birth, suggesting that mammals gradually lose their regenerative potential during postnatal development. The roles of miRNAs in regulating cardiomyocyte proliferation in postnatal hearts are largely unclear. Methods and Results: Cardiomyocytes were isolated from rat at day 0 and day 10. Agilent rat miRNA arrays were performed to determine the dysregulated miRNAs in cardiomyocytes between day 0 and day 10. A total of 32 miRNAs were found to be dysregulated between day 0 and day 10 (Fold change over 2 and P values less than 0.05). As determined by quantitative reverse transcription polymerase chain reactions and functional assays using EdU staining and Ki-67 staining, miR-31a-5p was found to be able to promote neonatal cardiomyocyte proliferation. Moreover, the expression of proliferation maker- Proliferating Cell Nuclear Antigen (PCNA) was also increased in cardiomyocytes transfected with miR-31a-5p mimics as determined by PCRs and Western blotting analysis. Tumor suppressor RhoBTB1 was found to be negatively regulated by miR-31a-5p in cardiomyocytes and also was responsible for the pro-proliferation effects of miR-31a-5p in neonatal cardiomyocytes. Conclusions: These studies demonstrate that miR-31a-5p regulates cardiomyocytes proliferation in postnatal hearts by targeting RhoBTB1. miR-31a-5p represents a therapeutic target for cardiac repair and regeneration.
Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser312 and Ser616 in Human Umbilical Vein Endothelial Cells
Authors: FrancescoAndreozzi, EmanuelaLaratta, AngelaSciacqua, FrancescoPerticone, GiorgioSesti
Journal: Circulation Research (2004)

It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr612 and Tyr632, two sites essential for engaging the p85 subunit o...
PDL1 test to assess the dynamic range of mRNA expression from platelet enriched plasma in patients with NSCLC.
Authors: Hestia S. Mellert, Leisa Jackson, Gary Anthony Pestano
Journal: Journal of Clinical Oncology (2017)

e23063 Background: Therapeutic options for patients with non-small cell lung cancer (NSCLC) continue to expand with the advent of immunotherapies. Lack of tissue and drawbacks with IHC have increased the need for blood-based diagnostics that measure continuous variables. Thus these tests are of increasing relevance for clinical testing. Methods: We focused on mechanisms of blood-based testing for the sensitive measurement of circulating RNA using ddPCR. Specifically, we optimized methods for the detection of PD-L1 and cytokeratin 19 (CK19) transcripts recovered from plasma. Specimens included tumor derived cell-lines, activated and resting immune cells, normal donor plasma and NSCLC (stages 1-4) donor plasma. Results: Assessing PD-L1 in circulation is complicated by its expression in both immune and cancer cells. Analytic performance was initially evaluated with cancer cell lines and activated lymphocytes and monocytes expressing variable levels of cytokeratins and PD-L1. A preliminary threshold was defined based on CK19 expression levels in normal donor plasma (n = 35). Of the 79 NSCLC donors tested 49% expressed CK19 above the threshold, indicating they contained sufficient circulating RNA derived from tumor. These donor samples tested either positive for EGFR del19 E746-A750 or L858R (n = 13), negative for EGFR (n = 10) or positive for KRAS G12C/V (n = 16). We found no differentiation in PD-L1 levels on the basis of EGFR sensitizing and EGFR wild-type status. We observed only three donors that expressed PD-L1 at high levels, and this was regardless of EGFR mutation status. In contrast, 30% of KRAS mutation-positive donor samples were above the pre-defined PDL1 threshold (n = 6 of 16 samples tested). These data are consistent with tissue-based studies that report trends of higher PD-L1 expression in KRAS positive NSCLC patients. Conclusions: We have developed sensitive and specific methods to measure the dynamic range of PD-L1 in circulation and have shown utility of these methods by evaluating key immune and cancer-specific RNAs.
Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance
Authors: HirohideMatsuura, ToshihiroIchiki, ErikoInoue, MasatoshiNomura, RyoheiMiyazaki, ToruHashimoto, JiroIkeda, RyoichiTakayanagi, Guo-HuaFong, KenjiSunagawa
Journal: Circulation (2013)

Background—Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of PHD2, the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities. Methods and Results—To delete PHD2 in adipocyte, PHD2-floxed mice were crossed with aP2-Cre transgenic mice (Phd2f/f/aP2-Cre). Phd2f/f/aP2-Cre mice were resistant to high-fat diet–induced obesity (36.7±1.7 versus 44.3±2.0 g in control; P<0.01) and showed better glucose tolerance and homeostasis model assessment–insulin resistance index than control mice (3.6±1.0 versus 11.1±2.1; P<0.01). The weight of white adipose tissue was lighter (epididymal fat, 758±35 versus 1208±507 mg in control; P<0.01) with a reduction in adipocyte size. Macrophage infiltration into whi...
Abstract 3487: Bioenergetic profiling of cancer cell lines: Quantifying the impact of glycolysis on cell proliferation
Authors: Natalia Romero, Pamela M. Swain, Yoonseok Kam, George Rogers, Brian P. Dranka
Journal: Cancer Research (2018)

Abstract Fast proliferating cells require tight regulation to achieve a balance between the use of nutrients for ATP production (through glycolysis and oxidative phosphorylation) and the use of intermediate metabolites to sustain the increased biosynthetic activity. Cancer cells, but also high proliferative non-transformed cells exhibit high glycolytic activity during rapid proliferation even in the presence of normal oxygen concentrations in culture. However, despite the high glycolytic activity, the role of glycolysis is not necessary as a major contributor of ATP but to allow nutrient assimilation into biosynthetic precursors. Using Agilent Seahorse extracellular flux analysis, we have developed a cell-based assay which allows simultaneous measurement of the two-main cellular metabolic pathways to calculate the total rate of cellular ATP production as well as the fractional contribution from each pathway. The assay allows for real time changes in total ATP production rate to be quantified, and also the relative source of that ATP after exposure to drugs or changes in extracellular fuel supply. When we applied this new assay to a panel of 20 cancer and highly proliferative cell lines, we found that even in cell lines considered highly glycolytic, ATP production from glycolysis never represents more than 65% of total energy production and between 30-50% for most of the cell lines analyzed. The correlation between glycolytic ATP contribution to total ATP production and other cell phenotypes such as proliferation rate and motility was also analyzed. The use of this assay will allow for improved characterization of the bioenergetic profile of cancer cell variants, discrimination between normal and cancer cell types, and allow researchers to better understand the role of aerobic glycolysis in cell proliferation. Citation Format: Natalia Romero, Pamela M. Swain, Yoonseok Kam, George Rogers, Brian P. Dranka. Bioenergetic profiling of cancer cell lines: Quantifying the impact of glycolysis on cell proliferation [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 3487.