tbuckley/cabot-search huggingface dataset:
Myocardial Expression of a Dominant-Negative Form of Daxx Decreases Infarct Size and Attenuates Apoptosis in an In Vivo Mouse Model of Ischemia/Reperfusion Injury
Authors: FrançoisRoubille, StéphaneCombes, JuaniLeal-Sanchez, ChristianBarrère, FrédéricCransac, CatherineSportouch-Dukhan, GéraldGahide, IsabelleSerre, ElodieKupfer, SylvainRichard, Anne-OdileHueber, JoëlNargeot, ChristophePiot, StéphanieBarrère-Lemaire
Journal: Circulation (2007)

Background— Apoptosis has been described extensively in acute myocardial infarction and chronic heart failure. Because Daxx (death-associated protein) appears to be essential for stress-induced cell death and acts as an antisurvival molecule, we tested the hypothesis that Daxx is involved in myocardial ischemia/reperfusion–induced cell death in vivo. Methods and Results— Transgenic mice overexpressing a dominant-negative form of Daxx (Daxx-DN) under the control of the β-actin promoter and control wild-type mice underwent an ischemia/reperfusion protocol: 40 minutes of left coronary artery occlusion and 60 minutes of reperfusion. Area at risk and infarct size were measured after dual staining by triphenyltetrazolium chloride and phthalocyanine blue dye. Apoptosis was measured in the ischemic versus the nonischemic part of the left ventricle by terminal deoxynucleotidyl transferase–mediated dUTP biotin nick end labeling staining, enzyme-linked immunosorbent assay, and Western blotting of caspase-3, caspase-...
Abstract 056: The Impact of Periostin as A Regulator of Cardiac Remodeling
Authors: Junya Azuma, Yoshiaki Taniyama, Keita Okayama, Naruto Katsuragi, Iwabayashi Masaki, Rei Otsu, Kazuma Iekushi, Hirohumi Sanada, Hiromi Rakugi, Ryuichi Morishita
Journal: Circulation Research (2013)

Background: Periostin (PN) is a matricellular protein that is induced by mechanostress and regulates organ remodeling. We previously documented that over-expression of full-length periostin (periostin1:Pn1) resulted in ventricular dilation with enhanced interstitial collagen deposition. Controversially, supplement of PN splicing variant lacking exon 17 (periostin2:Pn2) was reported to accelerate cardiac repair with the induction of cardiomyocyte proliferation and angiogenesis. The aim of this study was to investigate the different roles of PN splicing isoforms in cardiac remodeling. Methods: Coronary ligation was employed to induce cardiac remodeling in rat. A neutralizing antibody against exon17 (Pn1Ab) was injected intravenously every 6 days until day 21. Mice were followed ultrasonographically and then euthanized for histological analysis at day 56. In vitro study, the effect of each PN splicing isoform was assessed in rat cardiac fibroblast and HUVEC. Results: Administration of Pn1Ab resulted in 24.1 % decrease in infarct size and 38.2 % decrease in fibrotic area at day 56 post-operation (n=21, P&lt;0.05). Consistently, echocardiography demonstrated 26.3 % better ejection fraction (P&lt;0.05). Inhibition of fibrosis was associated with suppressed fibrosis-related gene expression such as collagen I, collagen III and TGF-beta1. Importantly, the number of myofibroblasts was significantly reduced in the Pn1Ab group, while neither cardiomyocyte proliferation nor angiogenesis was detected. In vitro study, Pn2 administration for HUVEC induced proliferation and tube formation however Pn1 did not. Pn1 administration accelerated maturation of myofibroblast more than Pn2. Conclusions: Pn1Ab preserved cardiac function through anti-fibrotic effect without cardiomyocyte proliferation and angiogenesis. Specific blockade of Pn1 without Pn2 will potentially lead to new therapeutic targets on a molecular basis to limit cardiac remodeling.
Catheter Ablation of Paroxysmal Atrial Fibrillation Initiated by Non–Pulmonary Vein Ectopy
Authors: Wei-ShiangLin, Ching-TaiTai, Ming-HsiungHsieh, Chin-FengTsai, Yung-KuoLin, Hsuan-MingTsao, Jin-LongHuang, Wen-ChungYu, Shih-PingYang, Yu-AnDing, Mau-SongChang, Shih-AnnChen
Journal: Circulation (2003)

Background— Most of the ectopic beats initiating paroxysmal atrial fibrillation (PAF) originate from the pulmonary vein (PV). However, only limited data are available on PAF originating from the non-PV areas. Methods and Results— Two hundred forty patients with a total of 358 ectopic foci initiating PAF were included. Sixty-eight (28%) patients had AF initiated by ectopic beats (73 foci, 20%) from the non-PV areas, including the left atrial posterior free wall (28, 38.3%), superior vena cava (27, 37.0%), crista terminalis (10, 3.7%), ligament of Marshall (6, 8.2%), coronary sinus ostium (1, 1.4%), and interatrial septum (1, 1.4%). Catheter ablation eliminated AF with acute success rates of 63%, 96%, 100%, 50%, 100%, and 0% in left atrial posterior free wall, superior vena cava, crista terminalis, ligament of Marshall, coronary sinus ostium, and interatrial septum, respectively. During a follow-up period of 22±11 months, 43 patients (63.2%) were free of antiarrhythmic drugs without AF recurrence. Conclusio...
Hairy-Related Transcription Factors Inhibit Notch-Induced Smooth Muscle α-Actin Expression by Interfering With Notch Intracellular Domain/CBF-1 Complex Interaction With the CBF-1–Binding Site
Authors: YuefengTang, SumithraUrs, LucyLiaw
Journal: Circulation Research (2008)

Notch signaling regulates smooth muscle cell phenotype and is critical for vascular development. One Notch target is smooth muscle α-actin (SMA), a differentiated smooth muscle cell marker. The Notch intracellular domain (NotchICD) forms a complex with CBF-1 (C-promoter–binding factor-1) and directly induces SMA expression. Using primary human smooth muscle cells, we show that expression of the constitutive active ICD of human Notch1, Notch2, or Notch4 receptors increase SMA levels. NotchICD also induce expression of the transcriptional repressors HRT1 (Hairy-related transcription factor 1) and HRT2, in a CBF-1–dependent manner. However, unlike the activating effects of NotchICD, HRT1 or HRT2 represses basal SMA expression, and both are strong antagonists of NotchICD-induced SMA upregulation. This antagonism does not depend on histone deacetylase activity and occurs at the transcriptional level. Competitive coimmunoprecipitation experiments demonstrate that HRT does not disrupt the association of NotchICD...
Associations Between Lipoprotein(a) Levels and Cardiovascular Outcomes in Black and White Subjects
Authors: Salim S. Virani, Ariel Brautbar, Brian C. Davis, Vijay Nambi, Ron C. Hoogeveen, A. Richey Sharrett, Josef Coresh, Thomas H. Mosley, Joel D. Morrisett, Diane J. Catellier, Aaron R. Folsom, Eric Boerwinkle, Christie M. Ballantyne
Journal: Circulation (2011)

Background— On the basis of studies with limited statistical power, lipoprotein(a) [Lp(a)] is not considered a risk factor for cardiovascular disease (CVD) in blacks. We evaluated associations between Lp(a) and incident CVD events in blacks and whites in the Atherosclerosis Risk in Communities (ARIC) study. Methods and Results— Plasma Lp(a) was measured in blacks (n=3467) and whites (n=9851). Hazards ratios (HRs) for incident CVD events (coronary heart disease and ischemic strokes) were calculated. Lp(a) levels were higher with wider interindividual variation in blacks (median [interquartile range], 12.8 [7.1–21.7] mg/dL) than whites (4.3 [1.7–9.5] mg/dL; P &lt;0.0001). At 20 years of follow-up, 676 CVD events occurred in blacks, and 1821 events occurred in whites. Adjusted HRs (95% confidence interval) per race-specific 1-SD–greater log-transformed Lp(a) were 1.13 (1.04–1.23) for incident CVD, 1.11 (1.00–1.22) for incident coronary heart disease, and 1.21 (1.06–1.39) for ischemic strokes in blacks. For whites, the respective HRs (95% confidence intervals) were 1.09 (1.04–1.15), 1.10 (1.05–1.16), and 1.07 (0.97–1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95% confidence interval], 1.35 [1.06–1.74] for blacks and 1.27 [1.10–1.47] for whites). Similar results were obtained with the use of Lp(a) cutoffs of ≤10 mg/dL, &gt;10 to ≤20 mg/dL, &gt;20 to ≤30 mg/dL, and &gt;30 mg/dL. Conclusions— Lp(a) levels were positively associated with CVD events. Associations were at least as strong, with a larger range of Lp(a) concentrations, in blacks compared with whites.
Abstract A11: Arginine deprivation alters global lipid metabolism in ASS1-deficient sarcomas
Authors: Jeff Kremer, Bethany Prudner, Samuel Chang, Lenny Rogers, Brian Van Tine
Journal: Clinical Cancer Research (2018)

Abstract Objective: Argininosuccinate Synthetase 1 (ASS1) is silenced in ~90% of sarcomas. This deficiency in the urea cycle causes sarcomas to become dependent on extracellular arginine for continued cell growth and survival, a condition named arginine auxotrophy. Arginine starvation induced by pegylated arginine deiminase (ADI-PEG20) induces dramatic alterations in global metabolism as well as an induction of autophagy. We investigated the specific changes in the lipidome of leiomyosarcoma cell lines induced by ADI-PEG20. By examining the alterations in esterified and nonesterified fatty acid metabolism we sought to understand the changes in the lipidome that are capable of being therapeutically exploited. Methods: The cell lines SKLMS1 and SKUT1 were treated with ADI-PEG20. Cell pellets were collected and 33 esterified and nonesterified fatty acids were measured using GC/MS. Pathway analysis was then performed. Cell lines were then treated with a combination of ADI-PEG20 and TOFA (an acetyl CoA carboxylase inhibitor) or etoxomir/perhexiline (beta-oxidation inhibitors) to determine synthetic lethality. Results: There were clear alterations in lipid metabolism induced by arginine deprivation. The fluctuations in lipid metabolism indicated pathways susceptible to inhibition by a variety of small-molecule inhibitors, namely that arginine deprivation sensitizes to inhibition of beta-oxidation. Cell culture experiments with ADI-PEG20 and a number of different small-molecule inhibitors demonstrated synthetic lethality upon cotreatment with ADI-PEG20 and beta-oxidation inhibitors. Conclusion: Arginine deprivation causes global changes in lipid metabolism. The changes in metabolism are capable of being targeted by small-molecule inhibitors with the result being an induction of a synthetic lethality. By understanding the changes in the lipidome induced by arginine deprivation, we are building a multiagent synthetic lethal therapy for sarcoma based on metabolism that avoids chemotherapy. Citation Format: Jeff Kremer, Bethany Prudner, Samuel Chang, Lenny Rogers, Brian Van Tine. Arginine deprivation alters global lipid metabolism in ASS1-deficient sarcomas [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 A11.
Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer
Authors: Tara E. Soumerai, Mark T.A. Donoghue, Chaitanya Bandlamudi, Preethi Srinivasan, Matthew T. Chang, Dmitriy Zamarin, Karen A. Cadoo, Rachel N. Grisham, Roisin E. O'Cearbhaill, William P. Tew, Jason A. Konner, Martee L. Hensley, Vicky Makker, Paul Sabbatini, David R. Spriggs, Tiffany A. Troso-Sandoval, Alexandra Snyder Charen, Claire Friedman, Mila Gorsky, Sarah J. Schweber, Sumit Middha, Rajmohan Murali, Sarah Chiang, Kay J. Park, Robert A. Soslow, Marc Ladanyi, Bob T. Li, Jennifer Mueller, Britta Weigelt, Ahmet Zehir, Michael F. Berger, Nadeem R. Abu-Rustum, Carol Aghajanian, Deborah F. DeLair, David B. Solit, Barry S. Taylor, David M. Hyman
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials. Experimental Design: We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center. Results: Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS1). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit. Conclusions: Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.
Abstract 2997: Epigenomic signatures of acquired platinum resistance in high grade serous ovarian cancer
Authors: Fang Fang, Horacio Cardenas, Guanglong Jiang, Susan M. Perkins, Chi Zhang, Harold Keer, Yunlong Liu, Daniela Matei, Kenneth Nephew
Journal: Cancer Research (2018)

Abstract Epithelial ovarian cancer (OC) is the most lethal gynecologic malignancy. The majority of advanced stage patients develop uniformly fatal resistance to standard platinum-based treatments. Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in OC. The goal of the current study was to identify methylation changes associated with the development of acquired resistance to platinum-based chemotherapy. We hypothesized that OC tumors harboring an aberrant DNA methylome could be reversed by DNMTi and re-sensitized to platinum treatment. To achieve our objective, we generated and compared tumor DNA methylation profiles from patients with recurrent platinum-resistant OC treated on a clinical trial with a DNA methyl transferase inhibitor, guadecitabine, before (n=65) and after (n=19) treatment (NCT01696032), and patients with primary (platinum-naïve) OC (n=20). Human ovarian surface epithelial cells (HOSE) were used as controls (n=5). We examined methylation levels across the genome using the Infinium Human Methylation 450 Bead Chip (Illumina). By comparing the methylome of platinum naive and platinum resistant ovarian tumors, normalized to HOSE, we identified 444 CpG island-containing gene promoters that became hypermethylated in resistant tumors. Of those, 45 gene promoters were hypermethylated at an FDR&amp;lt;0.05 and 19 genes at an FDR&amp;lt;0.05 and Δβ&amp;gt;0.1. Among those significantly hypermethylated genes, acquired promoter CpG island methylation of Ras Association Domain Family 1A (RASSF1A; a tumor suppressor gene in multiple cancer types) was observed. Of the 444 hypermethylated promoters in tumor resistant samples, 93 CpG islands became hypomethylated after guadecitabine treatment, suggesting that these promoters may be associated with reversal of resistance. Of those were the IFNA8 promoter, a gene known to be associated with anti-tumor effects in ovarian and other solid malignancies, and DEFB124, which is involved in the innate immune response. Pathways associated with immune reactivation were highly enriched by guadecitabine treatment, including IL-12 signaling and production of macrophages and MAPK and apoptosis signaling. Together, these results support that aberrant DNA methylation affecting gene networks associate with immune response plays a role in platinum resistant development and could be a therapeutic target. Citation Format: Fang Fang, Horacio Cardenas, Guanglong Jiang, Susan M. Perkins, Chi Zhang, Harold Keer, Yunlong Liu, Daniela Matei, Kenneth Nephew. Epigenomic signatures of acquired platinum resistance in high grade serous ovarian cancer [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 2997.
Electrocardiographic Monitoring for Prevention of Atrial Fibrillation–Associated Cardioembolic Stroke
Authors: Jeffrey J. Goldberger, Raul D. Mitrani
Journal: JAMA (2018)

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Abstract 12599: Visualizing Continuous Nocturnal Cardiac Output by Automatic Analysis of Circulation Time on Polysomnography in Patients With Heart Failure
Authors: KazuyaHosokawa, Shin-ichAndo, TakeshiTohyama, YumiTanaka, HidekiOtsubo, RyoNakamura, ToshiakiKadokami, TakayaFukuyama
Journal: Circulation (2014)

Background: Although several types of non-invasive measurement of cardiac output have been developed, they are not fully satisfactory. Sleep disordered breathing (SDB) is observed in most heart failure (HF) patients. By utilizing oscillation in oxygen saturation accompanied with SDB of HF patients, we can determine lung to finger-tip circulation time (LFCT) by measuring the time delay between respiration and pulse oximetric saturation. By using the fact that LFCT is theoretically correlates to the reciprocal value of cardiac output, we developed an algorithm that automatically and continuously measure LFCT. The aim of this study is to verify whether LFCT determined by this algorithm correlates to actual cardiac output. Method and Result: In 31 patients with HF who were planned to undergo right-sided cardiac catheterization, we performed portable polysomnography. The pulse oximetric saturation monitor was equipped in the left finger-tip. We first developed an algorithm that automatically determines LFCT by...
Abstract 966: Oncogenic signaling pathways differentially regulate clathrin-mediated endocytosis in cancer cells
Authors: Guan-Yu Xiao, Sandra Schmid
Journal: Cancer Research (2018)

Abstract Clathrin-mediated endocytosis (CME), the major endocytic pathway, regulates the rates of internalization of receptors as well as their downstream signaling activities. Recently, our lab has discovered that signaling can reciprocally regulate CME in cancer cells. The crosstalk between signaling and CME contributes to abnormal trafficking of signaling receptors and altered downstream signaling, leading to enhanced cancer metastasis. Accordingly, it is important to understand the nature and extent of interactions between CME and intracellular signaling in cancer cell biology. To address this issue, we targeted a set of prioritized kinases that are often implicated in cancer-relevant signaling pathways using validated pharmacologic inhibitors and compared their effects on CME function using different models for human noncancerous and cancer cells. We found that inhibition of several kinases selectively affected CME function in cancer cells. Notably, ERK inhibition had the most significant and consistent effects on CME activity across different types of cancer cells, while not affecting CME in several noncancerous cell lines tested. We established that a second ERK inhibitor, and importantly inhibition of the essential upstream kinase MEK, had the same cancer cell-specific effects on CME activity. Furthermore, we found that inhibition of ERK dramatically reduced the rate of clathrin-coated pit (CCP) initiation selectively in cancer cells. Characterization of one potential ERK substrate, FCHSD2, showed that knockdown of FCHSD2 had the similar cancer cell-specific effects on CME activity and on CCP initiation rate and that the cells depleted for FCHSD2 were insensitive to ERK inhibition. Surprisingly, the expression level of FCHSD2 is positively correlated with higher cancer patient survival rate, suggesting that FCHSD2 might be a tumor suppressor regulated by ERK. Our study provides new insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells. Citation Format: Guan-Yu Xiao, Sandra Schmid. Oncogenic signaling pathways differentially regulate clathrin-mediated endocytosis in 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 966.
Children’s intensive care units are failing to monitor breathing adequately
Authors: Ingrid Torjesen
Journal: BMJ (2018)

Paediatric and neonatal intensive care units are putting the lives of newborn babies and children at risk by failing to monitor their breathing properly, a survey published in Anaesthesia has found.1

Recommendations made by the landmark 4th National Audit Project in 2011,23 which studied major complications of airway management in adult intensive care units have not been taken up in neonatal and paediatric units, the researchers said.

The audit found that failure to use a …