tbuckley/cabot-search huggingface dataset:
Abstract A29: The NF1 and NF2 pharmacome project, a course in high-throughput screening to identify targets and profile the sensitivity of MPNST cells to candidate drugs
Authors: Jianman Guo, Michael Grovola, Grace Coggins, Patrick Duggan, Jiale Huang, Claire Song, Gabriela Witek, Danny Lin, Hong Xie, David Schultz, Simon Berritt, Jeffrey Field
Journal: Clinical Cancer Research (2018)

Abstract There are several large-scale efforts to compare the sensitivities of tumor cells to chemotherapeutic drugs and small-molecule pathway probes. However, to date, none of these profiling efforts systematically probed malignant peripheral nerve sheet tumors (MPNST). We initiated a database of drug sensitivities of MPNST as part of a course in high-throughput screening. We first developed a panel of 130 drugs highly relevant to neurofibromatosis (NF1 and NF2) that included a comprehensive set of MEK, RAF, RAS, FTI, PAK, ERK inhibitors, a representative set of drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents such as doxorubicin and taxol. Many of the drugs in our panel are in clinical trials themselves, or closely related to drugs in trials for NF1. The drugs were tested against cells in 384-well plates at eight concentrations ranging from .004 μM to 10 μM. Cells were allowed to attach overnight, incubated for 72 hours with drugs, and then analyzed for ATP content using ATPlite. To date, we have profiled nine MPNST cell lines (ST88-14, ST88-3, 90-8, SNF02.2, STS26, T265, S462TY, SNF96.2, SNF94.3) and one NF2 Schwannoma cell line (HEI193). We also tested several cell lines that were tested in other screens so that we can compare our results to the other databases. The IC50 was calculated as a common measure of how effective each drug is using GraphPad Prism software. NF1 cells were distinguished from NF2 cells and STS26 cells (a spontaneous MPNST cell line derived from a patient who did not have NF1) by their strong sensitivity to MEK and Bromodomain inhibitors. Some drugs, including cytotoxic agents, Pak inhibitors, and HDAC inhibitors, were broadly toxic, inhibiting growth regardless of NF1 and NF2 status. None of the drugs in our panel exclusively inhibited HEI193 cells. With this study we initiated a database to archive the drug sensitivities of NF1 and NF2 cells that will be expanded in future versions of our course. Sponsored by Children's Tumor Foundation. Citation Format: Jianman Guo, Michael Grovola, Grace Coggins, Patrick Duggan, Jiale Huang, Claire Song, Gabriela Witek, Danny Lin, Hong Xie, David Schultz, Simon Berritt, Jeffrey Field. The NF1 and NF2 pharmacome project, a course in high-throughput screening to identify targets and profile the sensitivity of MPNST cells to candidate drugs [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A29.
Action of Driving Stimuli from Intrinsic and Extrinsic Sources on in Situ Cardiac Pacemaker Tissues
Authors: Gertrudelange
Journal: Circulation Research (1965)

The interactions between pacemakers, and the effects on pacemakers, of terminating imposed driving were studied in the in situ heart of anesthetized dogs. Following atrial fibrillation or termination of a fast drive imposed through an artificial pacemaker, pacemaker action in intrinsic pacemakers is suppressed. Pacemakers tend to accelerate and compete with imposed drives which exceed control rates by only a small percentage (10 to 15%). Arrhythmias may result if imposed drive is slower than or identical with intrinsic pacemaker rate. Post-drive depression of pacemakers and the resulting deceleration of the heart is followed normally by an overshoot or supranormal acceleration. The magnitudes and durations of depression and late acceleration are proportional, within limits, to the rate and duration of drive. Atrioventricular and ectopic atrial pacemakers are much more readily depressed than is the sinoatrial pacemaker. Furthermore, beats of ectopic origin are much more likely to occur while subsidiary pac...
Improvement of Endothelial Function by Systemic Transfusion of Vascular Progenitor Cells
Authors: SvenWassmann, NikosWerner, ThomasCzech, GeorgNickenig
Journal: Circulation Research (2006)

Endothelial dysfunction is characterized by abnormalities in vasoreactivity and is a marker of the extent of atherosclerosis. Cellular repair by circulating progenitor cells of ongoing vascular injury may be essential for vascular integrity and function and may limit abnormalities in vasoreactivity. Apolipoprotein E–deficient (apoE−/−) mice were splenectomized and treated with high-cholesterol diet for 5 weeks, resulting in marked impairment of endothelium-dependent vasodilation of aortic segments as compared with wild-type mice. Intravenous transfusion of 2×107 spleen-derived mononuclear cells (MNCs) isolated from wild-type mice on 3 consecutive days restored endothelium-dependent vasodilation in the apoE−/− mice, as measured 7, 14, and 45 days after transfusion. Histological analyses of aortic tissue identified fluorescent-labeled, exogenously applied progenitor cells that expressed the endothelial cell marker CD31 in the endothelial cell layer of atherosclerotic lesions. Progenitor cell treatment led t...
Body-Surface Distribution of Changes in Activation-Recovery Intervals Before and After Catheter Ablation in Patients With Wolff-Parkinson-White Syndrome
Authors: MakotoAkahoshi, MakotoHirai, YasuyaInden, HiroakiSano, AtsuyaShimizu, TakahisaKondo, MitsutakaMakino, MitsuruHoriba, YukihikoYoshida, NaoyaTsuboi, HaruoHirayama, TeruoIto, HiroshiHayashi, HidehikoSaito
Journal: Circulation (1997)

Background T-wave abnormalities after catheter ablation in patients with manifest Wolff-Parkinson-White (WPW) syndrome have been attributed to a continuation of repolarization abnormalities induced by preexcitation (cardiac memory). Methods and Results To clarify changes in repolarization properties, we analyzed the activation-recovery interval (ARI) obtained from body-surface maps and the relationship between the activation time (AT) and ARI in 30 patients with WPW syndrome (group A, 18 patients with manifest left-sided accessory pathway; group B, 7 patients with manifest right-sided accessory pathway; and group C, 5 patients with concealed left-sided accessory pathway) before, 1 day after, and 1 week after ablation. The ARI significantly decreased 1 week after ablation compared with before and 1 day after ablation over the preexcited area in groups A and B. Correlation coefficients between the AT and ARI showed a significantly (P<.01) stronger inverse relationship before (r=−.58) and 1 week after (r=−.6...
John Michael Holden
Authors: Geoff Ridgway
Journal: BMJ (2018)

John Michael Holden’s ambition as a schoolboy was to join the Royal Air Force aircrew. Born in Nigeria, where his father was chief justice, he was educated at a variety of schools in the UK. Problems with eyesight scuppered his RAF intentions, leading to a last minute switch of career to study medicine. As a student he met and married …
Unfavorable Effect of Smoking on the Elastic Properties of the Human Aorta
Authors: ChristodoulosStefanadis, EleftheriosTsiamis, CharalambosVlachopoulos, CostasStratos, KonstantinosToutouzas, ChristosPitsavos, SteliosMarakas, HarisiosBoudoulas, PavlosToutouzas
Journal: Circulation (1997)

Background Smoking is a major risk factor for cardiovascular morbidity and mortality. Because previous studies have shown that smoking affects vasomotor response, we hypothesized that smoking may also acutely alter aortic elastic properties. Methods and Results We studied 40 male current and long-term smokers who underwent diagnostic cardiac catheterization for chest-pain evaluation. Twenty subjects (age, 48±2 years, mean±SEM) were randomly assigned to smoking and 20 (age, 47±2 years) to sham smoking studies. Aortic elastic properties were studied with the determination of the aortic pressure-diameter relation before smoking, every minute for the first 5 minutes after the initiation of smoking or sham smoking, and every 5 minutes for the following 15 minutes. Instantaneous diameter of the thoracic aorta was measured with a special ultrasonic dimension catheter developed in our laboratory and previously validated. Instantaneous aortic pressure was measured at the same site as was diameter with a Millar mic...
Abstract LB-385: <i>miR-3140</i> suppresses tumor cell growth by targeting <i>BRD4</i> via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein
Authors: Tomoki Muramatsu, Erina Tonouchi, Yasuyuki Gen, Hidekazu Hiramoto, Kousuke Tanimoto, Jun Inoue, Johji Inazawa
Journal: Cancer Research (2018)

Abstract Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS). miR-3140 concurrently downregulated BRD3 by bind to its CDS as well as CDK2 and EGFR by binding to their 3' untranslated regions. miR-3140 inhibited tumor cell growth in vitro in various cancer cell lines, including EGFR tyrosine kinase inhibitor-resistant cells. Interestingly, we found that miR-3140 downregulated the BRD4-NUT fusion protein and suppressed in vitro tumor cell growth in a NMC cell line, Ty-82 cells. Furthermore, administration of miR-3140 suppressed in vivo tumor growth in a xenograft mouse model. Our results suggest that miR-3140 is a candidate for the development of miRNA-based cancer therapeutics. Citation Format: Tomoki Muramatsu, Erina Tonouchi, Yasuyuki Gen, Hidekazu Hiramoto, Kousuke Tanimoto, Jun Inoue, Johji Inazawa. miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein [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 LB-385.
Abstract 4309: SPCIP2 enhances breast cancer cell proliferation, cell cycle and tumor formation by expression and interaction with Y1
Authors: Hyunjung Byun, Changhoon Lee
Journal: Cancer Research (2018)

Abstract SPCIP2 is a member of the serine/threonine protein kinase family. However, the working mechanism of SPCIP2 in cellular functions has not yet been properly understood. In this study, we found that SPCIP2 directly interacts with Y1, a multifunctional protein that can act as a regulator of transcription and translation. Furthermore, we determined the binding domains required for the interaction between SPCIP2 and Y1. The ectopic expression of SPCIP2 activates cell growth by inducing Y1. Binding activates is confirmed by SPCIP2-dependent increase of Y1 expression, as well as by the induced cell proliferation and tumor formation. Also, expression of siSPCIP2 and siY1 is found to induce cell cycle arrest and apoptotic activity in breast cancer cells. These insights provide evidence that SPCIP2 induces cell proliferation and tumor formation via expression and interaction with Y1. Citation Format: Hyunjung Byun, Changhoon Lee. SPCIP2 enhances breast cancer cell proliferation, cell cycle and tumor formation by expression and interaction with Y1 [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 4309.
Abstract 19858: Higher Prevalence of Insulin Resistance among Asian Americans despite Lower Body Mass Index
Authors: JiaPu, RobertRomanelli, BeinanZhao, SukyungChung, VaniNimbal, LathaPalaniappan
Journal: Circulation (2014)

Background: This study aims to identify racial/ethnic differences in the relationship between BMI and insulin resistance across Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese), Mexicans, non-Hispanic blacks (NHBs), and non-Hispanic whites (NHWs) in a large, mixed payer ambulatory care setting in northern California. Study Design: This cross-sectional study examined electronic health records of patients aged 18 years or older from 2000-2012. Insulin resistance was indicated by TG/HDL ratio>3. Overweight or obesity was defined as BMI≥25. Results: Although Asian Americans had the lowest rate of overweight and obesity, they had the highest prevalence of insulin resistance in both normal weight (19%, 9,262 of 49,981) and overweight/obese groups (43%, 15,742 of 36,496), followed by Mexicans (normal: 12%, 197 of 1,590; overweight: 39%, 2,106 of 5,377), NHWs (normal: 9%, 6,271 of 65,921; overweight: 32%, 33,475 of 103,695) and NHBs (normal: 6%, 46 of 716; overweight: 16%, ...
Plasma Renin Activity in Patients with Coarctation of the Aorta
Authors: Clauswerning, Manfredschönbeck, Peterweidmann, Klausbaumann, Etzelgysling, Pierrewirz, Waltersiegenthaler
Journal: Circulation (1969)

In 10 patients with coarctation of the aorta, plasma renin activity was measured after recumbency and orthostatism in peripheral venous blood and, in some cases, in renal venous blood also. In nine of these patients, basic plasma renin values and those obtained under stimulatory conditions lay within normal range, and only in one patient were the values elevated. However, since this patient displayed the lowest gradient of mean arterial blood pressure proximal and distal to the stenosis, it can be regarded as improbable that the elevation in plasma renin activity was caused by the coarctation. Plasma renin activity in the renal venous blood of both kidneys, which was measured in three patients, showed no elevation. On the basis of observations of other authors and of our own studies it can be concluded that the kidneys can contribute to the development of prestenotic hypertension in acute constriction of the aorta in experiments with animals, but in chronic coarctation in animals or in man the humoral or ...
In Vivo Formation of 8-Iso-Prostaglandin F2α and Platelet Activation in Diabetes Mellitus
Authors: GiovanniDavı̀, GiovanniCiabattoni, AgostinoConsoli, AndreaMezzetti, AntonioFalco, StellaSantarone, ElsaPennese, EsterVitacolonna, ToninoBucciarelli, FabrizioCostantini, FabioCapani, CarloPatrono
Journal: Circulation (1999)

Background—Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F2-isoprostane 8-iso-prostaglandin (PG)F2α, a bioactive product of arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation. Methods and Results—Urine samples were obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects for measurement of immunoreactive 8-iso-PGF2α and 11-dehydro-thromboxane B2 (TXM), an in vivo index of platelet activation. Sixty-two had non–insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E supplementation, metabolic control, and cyclooxygenase inhibitors were used to investigate the mechanisms of formation of 8-iso-PGF2α in this setting. Urinary 8-iso-PGF2α excretion was significantly higher (P=0.0001) in NIDDM patients (419±208 pg/mg creatinine; range 160 to 1014) than in age-matched control subjects (208±92; 41 to 433). Urinary 8-iso...
A national measles outbreak in Ireland linked to a single imported case, April to September, 2016
Authors: Peter Barrett, Suzanne Cotter, Fiona Ryan, Jeff Connell, Anthony Cronin, Mary Ward, Rose Fitzgerald, Catherine Lynch, Tony Margiotta
Journal: Eurosurveillance (2018)

Endemic measles transmission was interrupted for the first time in Ireland in 2015. In May 2016, a case of measles was confirmed in an adult who had travelled from Hungary to Ireland (index case). Cases subsequently arose in five of the eight public health regions around the country. There were 40 confirmed cases in Ireland between April and September 2016. All sequenced cases were genotype B3. Vaccination status was known for 34 cases, of whom 31 were unvaccinated. Median age was 8 years (range: 3 months to 40 years). Ten cases were nosocomial, and three cases were infected on separate international flights. One linked case occurred in a resident of Slovenia. Nineteen cases were hospitalised; median duration of hospitalisation was 5 days (range: 2-8 days). The primary case was a child who travelled from Romania to Ireland via Budapest, and infected the index adult case on the same flight. This was the first reported outbreak of measles genotype B3 in Ireland. This outbreak demonstrated that Ireland remains at risk of measles outbreaks due to persistent suboptimal vaccination rates.
Abstract 18632: Variation in Patient Profiles and Outcomes in US and non-US Subgroups of the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX Trial
Authors: Muthiah Vaduganathan, Robert A Harrington, Gregg W Stone, Ph. Gabriel Steg, C. Michael Gibson, Christian W Hamm, Matthew J Price, Jayne Prats, Efthymios N Deliargyris, Kenneth W Mahaffey, Harvey D White, Deepak L Bhatt
Journal: Circulation (2015)

Objectives: To describe the clinical profiles, safety and efficacy endpoints, and response to cangrelor in US and non-US subgroups. Background: CHAMPION PHOENIX demonstrated superiority of cangrelor in reducing ischemic events at 48 hours in patients undergoing percutaneous coronary intervention (PCI) compared with clopidogrel. Methods: We analyzed all patients included in the modified intention-to-treat analysis in US (n=4,097; 37.4%) and non-US subgroups (n=6,845; 62.6%). Results: The US cohort was older and had higher rates of cardiovascular risk factors and prior cardiovascular procedures. US patients more frequently underwent PCI for stable angina (72.4% vs. 46.4%). Utilization of clopidogrel loading doses of 600mg and bivalirudin was also higher in US vs. non-US participants. At 48 hours, rates of the primary composite endpoint were lower in the cangrelor arm compared with the clopidogrel arm in US (4.5% vs. 6.4%; OR 0.71 [0.54-0.92]) and in non-US patients (4.8% vs. 5.6%; OR 0.85 [0.69-1.05]); interaction P=0.26 ( Table ). Similarly, rates of the key secondary endpoint, stent thrombosis, were reduced by cangrelor in both regions. Rates of GUSTO (Global Use of Strategies to Open Occluded Arteries)-defined severe bleeding were low and not significantly increased by cangrelor in either region. Conclusions: Despite broad differences in clinical profiles and indications for PCI by region in a large global cardiovascular clinical trial, cangrelor consistently reduced rates of ischemic endpoints compared with clopidogrel without an excess in severe bleeding in both US and non-US subgroups.
Abstract IA15: Genetic predisposition to hematopoietic malignancies
Authors: Lucy A. Godley
Journal: Clinical Cancer Research (2017)

Abstract There is a growing appreciation for the impact of baseline genetic variants in the development of hematopoietic malignancies, and the germline risk factors that make an individual more susceptible to developing bone marrow-derived cancers are being defined through highly informative families and next-generation sequencing with increasing frequency. At the University of Chicago, we use a rigorous pipeline for clinical testing of individuals comprising next-generation sequencing-based molecular testing to detect point mutations as well as microarrays to detect chromosomal rearrangements. Overall, we are now able to identify the causative germline mutation in about 20% of cases, a level commensurate with other cancer risk clinics, but hinting that additional predisposition alleles remain to be discovered. Many of our patients/families also contribute to research by banking samples for future studies designed to identify new predisposition syndromes. This presentation will include a discussion of the new insights into hematopoietic biology that can be appreciated by studying these emerging predisposition syndromes. Citation Format: Lucy A. Godley. Genetic predisposition to hematopoietic malignancies [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA15.
High-Sensitivity Cardiac Troponin in the Distinction of Acute Myocardial Infarction From Acute Cardiac Noncoronary Artery Disease
Authors: PhilipHaaf, BeatriceDrexler, TobiasReichlin, RaphaelTwerenbold, MiriamReiter, JuliaMeissner, NoraSchaub, ClaudiaStelzig, MichaelFreese, AmelyHeinzelmann, ChristopheMeune, CathrinBalmelli, HeikeFreidank, KatrinWinkler, KrisDenhaerynck, WillibaldHochholzer, StefanOsswald, ChristianMueller
Journal: Circulation (2012)

Background—We hypothesized that high-sensitivity cardiac troponin (hs-cTn) and its early change are useful in distinguishing acute myocardial infarction (AMI) from acute cardiac noncoronary artery disease. Methods and Results—In a prospective, international multicenter study, hs-cTn was measured with 3 assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI Siemens) in a blinded fashion at presentation and serially thereafter in 887 unselected patients with acute chest pain. Accuracy of the combination of presentation values with serial changes was compared against a final diagnosis adjudicated by 2 independent cardiologists. AMI was the adjudicated final diagnosis in 127 patients (15%); cardiac noncoronary artery disease, in 124 (14%). Patients with AMI had higher median presentation values of hs-cTnT (0.113 μg/L [interquartile range, 0.049–0.246 μg/L] versus 0.012 μg/L [interquartile range, 0.006–0.034 μg/L]; P<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 μg/L [in...
Adenosine A1 Stimulation Activates δ-Protein Kinase C in Rat Ventricular Myocytes
Authors: PatrickHenry, SophieDemolombe, MichelPucéat, DenisEscande
Journal: Circulation Research (1996)

Abstract By making use of immunoblotting and immunocytochemical analysis, we explored whether stimulation of adenosine A1 receptors would promote the activation of δ-protein kinase C (δ-PKC) immunolabeled with a polyclonal antibody. Immunoblot analysis of Triton X-100–soluble cell membrane and cytosolic fractions revealed the presence of a specific 75-kD band reactive to the δ-PKC polyclonal antibody. In freshly isolated rat cardiac myocytes, 28% of the total immunoreactive δ-PKC was associated with the membrane fraction, whereas 72% was associated with the soluble fraction. Under stimulation with the tumor-promoting phorbol 12-myristate 13-acetate (PMA, 500 nmol/L) used as a positive control, δ-PKC translocated to the cell membrane, with the membrane fraction representing 88% and the cytosolic fraction representing 12% of the total immunoreactive δ-PKC. Transverse optical sections performed with confocal laser microscopy showed that immunostaining with anti–δ-PKC antibody was distributed in the cytosol o...