tbuckley/cabot-search huggingface dataset:
Abstract 4897: An acquired vulnerability of drug resistant melanoma with therapeutic potential
Authors: Rodrigo Leite de Oliveira
Journal: Cancer Research (2018)

Abstract BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here. Citation Format: Rodrigo Leite de Oliveira. An acquired vulnerability of drug resistant melanoma with therapeutic potential [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 4897.
Benefit of Bilateral Over Single Internal Mammary Artery Grafts for Multiple Coronary Artery Bypass Grafting
Authors: MasahiroEndo, HiroshiNishida, YasukoTomizawa, HiroshiKasanuki
Journal: Circulation (2001)

Background The aim of this study was to evaluate the performance of bilateral internal mammary artery (BIMA) grafts in isolated CABG. Methods and Results Beginning in April 1985, elective primary multiple CABG for multivessel disease was performed in 1131 patients. The early and late results of 688 patients who received single internal mammary artery (SIMA) grafts and 443 patients who received BIMA grafts were compared (median follow-up, 6.15 years). Hospital mortality was not significantly different in the SIMA (0.9%) and BIMA (0.9%) groups. Graft patency was 97.3% in the BIMA group and 94.3% in the SIMA group (P 0.4 and age <71 years was lower in the BIMA group (P=0.0499). Conclusions Our data suggest that the use ...
Abstract 4799: Nef-M1 peptide inhibits CXCR4 driven Wnt/β-catenin signaling in breast cancer
Authors: Venkat R. Katkoori, Upender Manne, Harvey L. Bumpers
Journal: Cancer Research (2018)

Abstract Introduction: The Nef-M1 peptide (Nef-M1) competes effectively with the natural ligand of CXCR4, SDF-1α, and exhibits anti-tumorigenic activity in breast cancer (BC). However, the molecular mechanisms of action of Nef-M1 on BC remain unclear. In this study, we evaluated the Nef-M1 inhibition of CXCR4 driven Wnt/β-catenin pathway in BC. Experimental Design: Cell line derived xenografts (CDX), patient derived explant (PDE) and in vitro cell based models were used to examine the mechanisms of action of Nef-M1. The severe combined immunodeficient mice with tumor were treated intraperitoneally either with Nef-M1 or sNef-M1 (control). Preparation of BC tissue, explant complete media, and cultures and treatment for 48 hours was performed for the PDE study. Sections from tumors were evaluated by immunostaining (IHC) for signaling proteins implicating BC progression. Western blot (WB) analyses were also performed on lysates of both cell lines and tumors to assess the effect of Nef-M1 on the Wnt/β-catenin, stem cell or mitogen-activated protein kinase (MAPK) pathways. Results: The present study revealed that PDE recapitulate multiple biological features of the disease and these were found to be very similar to the corresponding original tumors. IHC analysis for Ub-H2B, a stem cell signaling protein that correlates with advanced disease and metastasis indicated that Nef-M1 treated CDX or PDE tumors had low expression of Ub-H2B. However, sNef-M1 treated tumors had high expression of Ub-H2B. WB analyses indicated that Nef-M1 not only suppressed the expression of Ub-H2B, but also significantly suppressed the activation of MAPK (e.g. p38, ERK) and Akt proteins in BC. Nef-M1 treated BC displayed inhibition of Wnt/β-catenin signaling as demonstrated by an increased expression of p21 and decreased expression of beta-catenin, cyclin D1, Axin 2 and survivin. Cells expressing CXCR4 became susceptible to Nef-M1-induced inhibition of MAPK, Akt, Wnt/beta-catenin and stem cell signaling pathways. Conclusions: These results indicate that Nef-M1 suppresses CXCR4 mediated activation of Wnt/β-catenin and MAPK pathways. Therefore, Nef-M1 inhibition of these signaling pathways may be a promising therapeutic strategy for BC. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251. Citation Format: Venkat R. Katkoori, Upender Manne, Harvey L. Bumpers. Nef-M1 peptide inhibits CXCR4 driven Wnt/β-catenin signaling in breast 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 4799.
Influence of Balloon Pressure During Stent Placement in Native Coronary Arteries on Early and Late Angiographic and Clinical Outcome
Authors: JosefDirschinger, AdnanKastrati, Franz-JosefNeumann, PeterBoekstegers, ShpendElezi, JulindaMehilli, HelmutSchühlen, JürgenPache, EckhardAlt, RudolfBlasini, GerhardSteinbeck, AlbertSchömig
Journal: Circulation (1999)

Background—High-pressure dilatation is considered a better stent placement strategy, but this has not yet been proved by appropriately designed studies. The objective of this randomized trial was to assess the role of high-pressure dilatation in the early and late outcome of patients undergoing coronary stent placement. Methods and Results—Consecutive patients with coronary stent placement were randomly assigned to high- (15 to 20 atm, 468 patients) or low- (8 to 13 atm, 466 patients) balloon-pressure dilatation. The primary end point of the study was the event-free survival at 1 year. Secondary end points were the incidence of stent thrombosis at 30 days and angiographic restenosis (≥50% diameter stenosis) at 6 months. The incidence of stent thrombosis was 1.7% in the high-pressure and 1.9% in the low-pressure group (relative risk 0.89; 95% CI 0.30 to 2.56). During the first 30 days, although there was no significant difference in the incidence of Q-wave myocardial infarction, the incidence of non–Q-wave...
Coronary Artery Stenosis After Radiofrequency Catheter Ablation of Accessory Atrioventricular Pathways in Children With Ebstein’s Malformation
Authors: HaraldBertram, ReginaBökenkamp, MatthiasPeuster, GerdHausdorf, ThomasPaul
Journal: Circulation (2001)

Background—Complications concerning the coronary arteries that are directly related to radiofrequency catheter ablation procedures have not been reported in children. Coronary artery lesions, however, have been demonstrated after the endocardial application of radiofrequency current in young animals. Methods and Results—Two boys with Ebstein’s anomaly of the tricuspid valve developed clinically asymptomatic coronary artery stenosis after radiofrequency catheter ablation of right-sided accessory atrioventricular pathways with standard catheter technology. Conclusions—The complication of coronary artery stenosis demonstrates a substantial risk after right atrial free wall radiofrequency current application in children. The risk of late coronary alterations should be considered when the use of catheter ablation procedures to young patients is proposed.
Inhibition of Transforming Growth Factor-β Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice
Authors: ZiadMallat, AndreaGojova, CarmenMarchiol-Fournigault, BrunoEsposito, CarolineKamaté, RégineMerval, DidierFradelizi, AlainTedgui
Journal: Circulation Research (2001)

Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-β1, -β2, and -β3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-β in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-β signaling using a neutralizing anti–TGF-β1, -β2, and -β3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-β signaling favors the development of lesions with increased inflammatory component and decreased collagen cont...
Serum Cholesterol Distribution and Coronary Heart Disease Risk
Authors: PekkaJousilahti, ErkkiVartiainen, JuhaPekkanen, JaakkoTuomilehto, JoukoSundvall, PekkaPuska
Journal: Circulation (1998)

Background—The purpose of the present study was to assess the implications of cholesterol distribution and its change on coronary heart disease (CHD) mortality and disease prevention at a population level. Methods and Results—In five independent risk factor surveys (1972, 1977, 1982, 1987, and 1992) in eastern Finland, serum cholesterol was measured in 27 721 randomly selected men and women aged 30 to 59 years. The association between cholesterol level and CHD risk and the prediction of the effect of different prevention strategies was estimated by use of logistic regression models. The entire cholesterol distribution of the population shifted markedly toward lower levels between 1972 and 1992. The proportion of subjects with a very high cholesterol level (≥8.0 mmol/L), also decreased markedly, from 16% to 3%. The risk of CHD death among subjects with cholesterol ≥8.0 mmol/L was ≈5-fold that of those individuals having cholesterol <5.0 mmol/L. Nevertheless, because CHD risk increases continuously as serum...
Abstract 1446: Glycogen accumulation in aggressive breast cancers under hypoxia
Authors: Megan Ann Altemus, Joel A. Yates, ZhiFen Wu, LiWei Bao, Sofia D. Merajver
Journal: Cancer Research (2018)

Abstract Cancers utilize diverse metabolic pathways to increase survival and proliferation; therefore, the identification of specific metabolic alterations in aggressive triple-negative and inflammatory breast cancers is a compelling avenue for the development of new treatments. The ability to survive and grow in hypoxia is necessary for breast cancer cells in the center of the tumor mass or in the lymphatic system and other organ environments. Glucose reserves are typically stored in liver and muscle cells as the polysaccharide glycogen. Elevated levels of glycogen have been observed in various cancers, and recent studies have suggested that glycogen metabolism is important for promoting cancer cell survival. We hypothesize that aggressive breast cancers modulate glycogen metabolism to provide nutritional flexibility for proliferation and invasion during cancer progression. To test our hypothesis, we investigated the regulation of glycogen levels in breast cancer and normal-like cells in atmospheric and 1% oxygen. The glycogen content of six breast cancer and one normal-like cell line was measured under normoxic and hypoxic conditions. All cell lines had increased glycogen accumulation under hypoxia, but to varying degrees that did not correlate with receptor status. Expression levels of various genes involved in glycogen synthesis and degradation were determined by qRT-PCR, with no consensus expression pattern between all cell lines. Several key alterations were noted in synthesis and degradation enzymes. We will present an integrative picture of glycogen synthesis and degradation in breast cancer cells. Studies are ongoing to determine the mechanisms through which these changes occur and whether the accumulation of glycogen confers an advantage for continued survival and growth of cancer. Citation Format: Megan Ann Altemus, Joel A. Yates, ZhiFen Wu, LiWei Bao, Sofia D. Merajver. Glycogen accumulation in aggressive breast cancers under hypoxia [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 1446.
Research Uncovers How Commensal Bacteria Contribute to Multiple Sclerosis
Authors: Tracy Hampton
Journal: JAMA (2018)

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Abstract 14020: Practice Trends in the Care of Infants With Hypoplastic Left Heart Syndrome: A Report From the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC)
Authors: Waldemar F Carlo, James F Cnota, Jeffrey B Anderson
Journal: Circulation (2015)

Introduction: The NPC-QIC was established in 2008 to improve outcomes of hypoplastic left heart syndrome (HLHS) patients during the interstage period using quality improvement to reduce unnecessary practice variation. Our objective was to evaluate early and recent interstage practice variation within the collaborative. Methods: Data from the first 100 patients (6/2008 - 1/2010) representing 18 centers were compared with the most recent 100 patients (1/2014 - 11/2014) from these same centers. Results: Prenatal diagnosis increased from 72% to 82% (p = 0.09). There were no differences in gestational age or weight at Norwood. A composite of any preoperative risk factor (mechanical ventilation, acidosis, renal insufficiency, arrhythmia, NEC, sepsis) occurred more frequently in the early era (58% vs 34%, p &lt;0.01). While mean age at Norwood was similar (8.3 vs 6.6 days, p = 0.2), the standard deviation for this variable was significantly lower in the recent era (10.5 to 6.4 days, p = 0.03). Use of RV-PA conduit increased (69% to 84%, p = 0.02). Rates of complete discharge communication with both the primary care physician (31 to 97%, p &lt; 0.01) and primary cardiologist (44 to 97%, p &lt; 0.01) increased substantially. There was no change in interstage feeding strategies between eras. Use of interstage outpatient surveillance program increased (76% to 99%, p &lt; 0.01) with all participants in the late era monitoring both oxygen saturation and weight. Conclusions: Among NPC-QIC centers contributing patients to both early and recent cohorts, there were significant changes in preoperative risk factors, Norwood surgical strategy, discharge communication, and interstage surveillance. Practice variation in timing of Norwood has been reduced. Further study is required to determine an association between these practice trends and decreased mortality.
Translocation of Connexin 43 to the Inner Mitochondrial Membrane of Cardiomyocytes Through the Heat Shock Protein 90–Dependent TOM Pathway and Its Importance for Cardioprotection
Authors: AntonioRodriguez-Sinovas, KerstinBoengler, AlbertoCabestrero, PetraGres, MiriamMorente, MarisolRuiz-Meana, InaKonietzka, ElisabetMiró, AndreasTotzeck, GerdHeusch, RainerSchulz, DavidGarcia-Dorado
Journal: Circulation Research (2006)

We have previously shown that connexin 43 (Cx43) is present in mitochondria, that its genetic depletion abolishes the protection of ischemia- and diazoxide-induced preconditioning, and that it is involved in reactive oxygen species (ROS) formation in response to diazoxide. Here we investigated the intramitochondrial localization of Cx43, the mechanism of Cx43 translocation to mitochondria and the effect of inhibiting translocation on the protection of preconditioning. Confocal microscopy of mitochondria devoid of the outer membrane and Western blotting on fractionated mitochondria showed that Cx43 is located at the inner mitochondrial membrane, and coimmunoprecipitation of Cx43 with Tom20 (Translocase of the outer membrane 20) and with heat shock protein 90 (Hsp90) indicated that it interacts with the regular mitochondrial protein import machinery. In isolated rat hearts, geldanamycin, a blocker of Hsp90-dependent translocation of proteins to the inner mitochondrial membrane through the TOM pathway, rapid...
Abstract 19671: Contemporary Patterns of Utilization and Safety Outcomes of Catheter Ablation of Atrial Flutter in the United States
Authors: Dhaval Pau, Nileshkumar J Patel, Apurva O Badheka, Abhishek Deshmukh, Juan Viles-Gonzalez
Journal: Circulation (2015)

Introduction: Atrial flutter ablation has been increasingly offered as first line therapy and has been safely performed over the past few decades. However, limited data exists regarding current utilization and trends in adverse outcomes arising from this procedure. The aim of our study was to examine the frequency of adverse events attributable to atrial flutter (AFL) ablation and the influence of hospital volume on safety outcomes. Hypothesis: We hypothesize an association between hospital volume and adverse outcomes. Methods: With the use of the Nationwide Inpatient Sample, we identified 89,638 AFL patients treated with catheter ablation from 2000-2011. We investigated common complications including cardiac perforation and tamponade, pneumothorax, stroke, transient ischemic attack, vascular access complications, and in-hospital death. We defined these complications by using validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Results: The overall frequency of complications was 3.17%, with combined cardiac complications (1.44%) being the most frequent. Cardiac complications were followed by vascular complications (0.78%), respiratory complications (0.88%), and neurological complications (0.05%). The in-hospital mortality was 0.17%. Low hospital volume (&lt;50 procedures) was significantly associated with increased adverse outcomes. In addition, there was a small, insignificant rise in overall complication rates over time. Conclusions: The overall complication rate was 3.17% in patients undergoing AFL ablation. There was a significant association between low hospital volume and increased adverse outcomes. This suggests a need for future research into identifying the safety measures in AFL ablations and instituting appropriate interventions to improve overall AFL ablation outcomes.
Platelet Activation With Unfractionated Heparin at Therapeutic Concentrations and Comparisons With a Low-Molecular-Weight Heparin and With a Direct Thrombin Inhibitor
Authors: ZihuiXiao, PierreThéroux
Journal: Circulation (1998)

Background—The growing use of heparin in acute thrombotic disorders, coupled with the availability of many new antithrombotic agents, emphasizes the need for adequate characterization of the platelet effects of the various anticoagulants. Controversial platelet effects have been reported with heparin (eg, enhanced platelet activation in vitro with high doses and no such effect in vivo at therapeutic doses). This study examined platelet receptor activation and platelet aggregation at therapeutic concentrations of unfractionated heparin (UFH), of enoxaparin, a low-molecular-weight heparin, and of argatroban, a direct thrombin inhibitor. Methods and Results—Platelet P-selectin (CD62) and activated GP IIb/IIIa (PAC-1) expression on platelet membrane was quantified in whole blood as well as platelet aggregation in platelet-rich plasma in 43 patients with unstable angina before and during treatment with UFH or enoxaparin. Studies were also carried out in blood of seven normal volunteers after addition ex vivo o...
Molecular Mechanisms of Cardiovascular Toxicity of Targeted Cancer Therapeutics
Authors: HuiCheng, ThomasForce
Journal: Circulation Research (2010)

Abstract: In 2002, Hoshijima and Chien drew largely theoretical parallels between the dysregulation of the signaling pathways driving cancer and those driving cardiac hypertrophy (Hoshijima M, Chien KR. J Clin Invest. 2002;109:849–855). On the surface, this statement appeared to stretch the limits of reason, given the fact that cancer cells are known for their proliferative capacity, and adult cardiomyocytes are, except under unusual circumstances, terminally differentiated and incapable of re-entering the cell cycle. However, on closer examination, there are numerous parallels between signaling pathways that drive tumorigenesis and signaling pathways that regulate hypertrophic responses and survival in cardiomyocytes. Indeed, this issue appears to be at the core of the cardiotoxicity (often manifest as a dilated cardiomyopathy) that can result from treatment with agents typically referred to as “targeted therapeutics,” which target specific protein kinases that are dysregulated in cancer. Herein, we exam...