tbuckley/cabot-search huggingface dataset:
Abstract 3372: Mutations of mismatch repair genes in Her2 overexpressed breast cancer
Authors: Mohammed A. Baghdadi, Turki M. Sobahy, Hosam A. Alardati, Jamal E. Zekri
Journal: Cancer Research (2018)

Abstract The importance of Mismatch Repair (MMR) in therapeutic selection is an area of recent research. Minority of unselected breast tumors exhibit mutations indicative of deficient MMR. Here, we present our preliminary data investigating 7 MMR genes exclusively in Her2-overexpressed (Her2OE) breast cancer (BC). Twenty-five archival formalin-fixed paraffin-embedded samples from 25 Her2OE BC patients underwent targeted next generation sequencing for 7 MMR genes (MLH1, MLH3, MSH2, MSH6, PMS2, POLD1 and EPCAM). The analysis was performed through the Saudi Human Genome Project bioinformatics pipeline. Data filtration was performed to rank genetic variants based on their predicted pathogenicity. Methods of filtration included mutation effect, ClinVar findings, ExAC loss of function index (pLI) and collective proteomics index. Twenty-four out of 25 (96%) tumors contained significant mutations in one or more MMR genes. Three cases (12%) contained mutations in 3-4 MMR genes while 21 (84%) had 1-2 alteration(s) in these gene(s). Only one case showed no significant mutations in any of the studied MMR genes. MLH1, MLH3, MSH2, MSH6, PMS2, POLD1 and EPCAM were mutated in 6(24%), 1(4%), 5(20%), 18(72%), 2(8%), 6(24%) and 3(12%) respectively. In this preliminary report, mutations in MMR genes affect up to 96% of Her2OE BC tumors. Such result may impact on therapeutic choices. This result is to be confirmed in larger cohort. Citation Format: Mohammed A. Baghdadi, Turki M. Sobahy, Hosam A. Alardati, Jamal E. Zekri. Mutations of mismatch repair genes in Her2 overexpressed 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 3372.
Abstract LB-063: Phospholipid drug conjugates show specificity for a broad range of tumor cells and provides a novel approach for targeted or precision therapy
Authors: Jarrod Longcor, Maria Banach, Randall Hoover
Journal: Cancer Research (2018)

Abstract The majority of anticancer drugs in clinical use have their utility limited by their toxicity to all proliferating cells, including normal cells and the inability to exert their effect on all of the tumor cells. Novel cytotoxic agents continue to be developed with unique mechanisms of action meant to provide increased targeting, however, many of these compounds still lack absolute tumor selectivity and continue to be limited in their therapeutic utilization due to off-target effects. Antibody drug conjugates (ADCs) have been design to bind to specific epitopes on the surface of tumor cells and have offered an alternative method to target tumor cells in an effort to reduce associated toxicities. Although highly selective, very few antibody drug conjugates are therapeutically useful since they only achieve modest cellular uptake and limited cell killing activity. Here we describe the development of a novel targeting platform using phospholipid ether (PLE) molecules to provide tumor cell specific targeting. These molecules known as phospholipid drug conjugates (PDCs) show high specificity for tumor cells; 6 to 30-fold increase in targeting tumor cells over normal tissue, result in up to 20% of exposed compound entering in to the tumor cells (as compared to &amp;lt; 1% of an ADC), and show a range of compounds can be conjugated to them. We have tested the uptake of our PDCs across over 80 different tumor cell lines and have shown consistent preferential uptake by tumor cells versus normal cells even when in co-culture. This could result in an improvement of the therapeutic index for many compounds. Citation Format: Jarrod Longcor, Maria Banach, Randall Hoover. Phospholipid drug conjugates show specificity for a broad range of tumor cells and provides a novel approach for targeted or precision therapy [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-063.
Abstract 3320: Discovery and development of DNA methylation biomarkers in human papillomavirus related oropharyngeal squamous cell carcinoma
Authors: Shuling Ren, Daria A. Gaykalova, Theresa W. Guo, Alexander V. Favorov, Elana J. Fertig, Zubair Khan, Peter M. DeJong, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Sunny Haft, Sayed Sadat, J Silvio Gutkind, Wayne M. Koch, Joseph A. Califano
Journal: Cancer Research (2018)

Abstract Purpose: Human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OPSCC) has an improved prognosis compared to cancers associated with tobacco and alcohol exposure, and also exhibits a different composition of epigenetic alterations. In this methylome-wide association study, we identified DNA methylation-based biomarkers with potential utility in screening for HPV positive OPSCC. Experimental Design: In the discovery stage, genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV positive OPSCC tissues and 25 normal tissues. We defined 51 differentially methylated regions (DMRs) with maximal methylation specificity to cancer samples. We used TCGA methylation array data to evaluate the performance of the proposed candidates. Top 20 candidates were validated using quantitative methylation specific PCR (QMSP) in independent 24 HPV related OPSCCs and 22 controls. Results: Supervised hierarchical clustering of 51 DMRs based on TCGA methylation data found that HPV positive OPSCC had significantly higher DNA methylation levels compared to normal samples and head and neck squamous cell carcinoma (HNSCC) without HPV or with different tumor sites. The methylation levels of all top 20 candidates in HPV positive OPSCC were significantly higher than those in normal samples in TCGA data. 16 of these 20 candidates were found by QMSP to have significant higher methylation levels compared with controls. 2 candidates (CCDC181 and OR6S1) had a sensitivity of 100%, while 10 candidates (KCNA3, ITGA4, BEND4, ELMO1, SFMBT2, HOXB4, ZNF439, ZNF93, VSTM2B and ZNF773) had a specificity of 100%. Our 20 candidates were found by the receiver operating characteristic analysis to have a prediction accuracy ranging from 56.3% to 99.8%. Conclusions: This study discovered 20 epigenetic markers for detection of HPV related OPSCC, which can potentially be applied to develop a population based screening test and improve disease management. Citation Format: Shuling Ren, Daria A. Gaykalova, Theresa W. Guo, Alexander V. Favorov, Elana J. Fertig, Zubair Khan, Peter M. DeJong, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Sunny Haft, Sayed Sadat, J Silvio Gutkind, Wayne M. Koch, Joseph A. Califano. Discovery and development of DNA methylation biomarkers in human papillomavirus related oropharyngeal squamous cell 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 3320.
Abstract LB-377: Validation and application of a comprehensive next generation sequencing system for molecular characterization of solid tumor tissues
Authors: Mehdi Dehghani, Lei Li, Reynolds Brobey, Yue Wang, Kevin P. Rosenblatt, Robert J. Amato
Journal: Cancer Research (2018)

Abstract Identification of somatic molecular alterations in solid tumors and metastases can provide critical information regarding tumor biology and tumor heterogeneity. These alterations can also reveal activated pathways in a patient's disease, enabling personalized treatment assignment. However, the optimal methods and panels remain unknown. The present study was conducted to assess the use of the Oncomine Comprehensive Cancer Panel in identifying molecular alterations in fresh and preserved cancer tissues from a solid tumor registry at The University of Texas Health Science Center at Houston. Results were compared with pathologic findings. The assay was found to be highly specific (&amp;gt;99%) and sensitive (&amp;gt;99%), with low false-positive and false-negative rates for single-nucleotide variants, indels, copy number alterations, and gene fusions. This tumor-agnostic molecular assessment assay holds potential as a straightforward and reliable method to determine molecular alterations in solid tumor samples. Overall, 23 (88%) of these 26 patients had at least one loss-of-function or gain-of-function molecular alteration (80/180 total high-priority alterations), of which 68% (66/80) led to selection of targeted therapy. This next-generation sequencing assay not only detected at least one clinically actionable alteration, but also it can be a great translational research tool. For instance, using this panel we detected EGFRvIII in a significant number of renal cell cancer core biopsies (43%). The biological importance of this alteration in renal cancer growth and progression and its clinical importance as a therapeutic or prognostic marker needs to be investigated further. Citation Format: Mehdi Dehghani, Lei Li, Reynolds Brobey, Yue Wang, Kevin P. Rosenblatt, Robert J. Amato. Validation and application of a comprehensive next generation sequencing system for molecular characterization of solid tumor tissues [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-377.
Abstract 11885: Differential Contributions of Abdominal Visceral Fat and Epicardial Fat to Coronary Atherosclerosis in Non-Obese Japanese Patients
Authors: KenHarada, TakashiKataoka, MasahiroTakeshita, KazuhiroHarada, AyakoKunimura, SatoshiOkumura, NorihiroShinoda, BunichiKato, TadayukiUetani, MasatakaKato, NobuyukiMarui, HidekiIshii, TatsuakiMatsubara, TetsuyaAmano, ToyoakiMurohara
Journal: Circulation (2014)

Introduction: Epicardial fat is a source of adipocytokines that have both paracrine and systemic effects and is implicated in coronary atherosclerosis. The relation between epicardial fat volume (EFV) and circulating adipocytokine levels has remained unknown, however. Objectives: We assessed the relation between EFV and both plasma adipocytokine concentrations and coronary atherosclerotic plaque. Methods: Consecutive Japanese patients suspected of having coronary artery disease (n = 216) were examined. Individuals with acute coronary syndrome or with inadequate CT imaging were excluded. A total of 164 patients (65 ± 10 years; 70% men; BMI, 23.8 ± 3.6 kg/m2) was enrolled. Plasma levels of adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and vascular endothelial growth factor (VEGF) were measured. The characteristics of coronary plaque, abdominal visceral fat area, and EFV were determined by 64-slice CT. Results: EFV was greater in subjects with noncalcified plaque than in those...
Abstract 17308: Pharmacological Induction of Beta Common Receptor Amplifies Erythropoietin Attenuation of Spinal Cord Injury
Authors: Katsuhiro Yamanaka, Muhammad Aftab, Marshall T Bell, Lisa S Foley, Joshua Mares, David A Fullerton, Brett T Reece
Journal: Circulation (2016)

Introduction: Paraplegia remains the most feared complication of thoracoabdominal aorticintervention. While erythropoietin (EPO) has demonstrated neuroprotective effects in spinal cord ischemia, EP...
Abstract 1836: Induction of secreted soluble decoy EGFR variants by splicing interference overcomes drug resistance in human non-small cell lung cancer
Authors: Jeong Eun Park, Lee Spraggon, Elisa de Stanchina, Luca Cartegni
Journal: Cancer Research (2018)

Abstract Activation of the epidermal growth factor receptor (EGFR) is involved in the oncogenesis of multiple cancers, particularly lung cancer. Current treatments are limited by the appearance of TKI resistance from secondary somatic mutations in the EGFR gene, such as the T790M mutation (&amp;gt;50% of biopsies) in the EGFR kinase domain following erlotinib or gefitinib treatment. As these tumors are still EGFR-dependent, EGFR remains a prime therapeutic target in NSCLC. We have recently described multiple natural soluble decoy isoforms for multiple RTKs, including EGFR, which depend on the differential inclusion of functional domains by alternative splicing. We employ antisense oligo nucleotide (ASO) to reprogram EGFR pre-mRNA processing in order to increase expression of mRNA variants that encode for dominant-negative, soluble decoys EGFR (sdEGFR), at the expense of the oncogenic full-length EGFR receptor. These alternative splicing isoforms are generated via intronic polyadenylation (IPA) of pre-mRNA in a U1-snRNP (U1)-dependent manner. More specifically, we are able to induce the sdEGFR variants by using specific ASOs, designed to block the upstream U1 binding site and thus activate the appropriate IPA sites. Here, we show that our novel strategy effectively induces the expression of potent natural inhibitors of EGFR signaling in treatment-refractory lung cancer models in vitro and in vivo, leading to suppression of downstream pathways and tumor growth inhibition. The ASO-induced natural sdEGFR compounds function in a dominant-negative manner and induce dramatic cell death in NSCLC cells harboring multiple activating and resistance EGFR mutations, and thus provides a novel alternative strategy for treatment of refractory NSCLC, to overcome resistance mediated by the EGFR secondary mutations (including T790M, C797S and others). Citation Format: Jeong Eun Park, Lee Spraggon, Elisa de Stanchina, Luca Cartegni. Induction of secreted soluble decoy EGFR variants by splicing interference overcomes drug resistance in human non-small cell lung 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 1836.
Effect of Ventricular Septal Defect and Patent Ductus Arteriosus on Left Ventricular Pressure in Complete Transposition of the Great Vessels
Authors: Redashaher, Langfordkidd
Journal: Circulation (1968)

The relationship between the pressures in the left and right ventricles was examined in 80 infants and children who had complete transposition of the great vessels and in whom the presence of a ventricular septal defect or a patent ductus arteriosus was known. All children with obstruction to left ventricular outflow have been excluded. It was found that 92% (34 of 37) of the children with transposition and a ventricular septal defect had left ventricular pressures greater than 70% of the systemic, while 45% (10 of 22) of those with a patent ductus and only 5% (1 of 21) with a closed ventricular septum and no ductus, had pressures in this range. Seventy-six per cent (16 of 21) of the children in this last group had left ventricular pressures less than 50% of the systemic pressure. It is concluded that infants with transposition of the great vessels and a ventricular septal defect stand in high risk of developing obstructive pulmonary vascular disease and therapy should be guided accordingly.
Abstract 18850: A Report on Cardiomyopathy and Arrhythmia Incidence in a Duchenne Muscular Dystrophy Cohort
Authors: Mohammed I Aslam, William R Thompson, Daniel P Judge, Saman Nazarian
Journal: Circulation (2015)

Background: With improved respiratory care and the increasing lifespan of patients with Duchenne Muscular Dystrophy (DMD), morbidity and mortality due to cardiac involvement and sudden cardiac death (SCD) have increased. Nevertheless, data regarding incidence of SCD and the appropriate management of cardiac involvement are sparse; evidence-based guidelines for arrhythmia management in DMD do not exist. We sought to define the characteristics of electrocardiography, cardiac imaging abnormalities, association of therapeutic practices with cardiomyopathy and arrhythmia in a cohort with DMD. Methods and Results: A retrospective review of our current institutional electronic medical records (EMR) identified 125 DMD patients aged 10 or older. Electrocardiography was performed at least every 3 years or as prompted by symptoms. Symptom-prompted and baseline echocardiography, cardiac magnetic resonance (CMR) and Holter monitor data were extracted. Cardiac medical therapy primarily consisted of an angiotensin-converting-enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB; 98.4%) and beta-blockade (44.2%). As of May 2015, 115 of the 125 patients were living as determined by EMR. Left ventricular (LV) dysfunction was present in 52% of patients by age 18.7±5.9 years. Of 16 patients with LV dysfunction that underwent CMR, 13/16 had late gadolinium enhancement (LGE). Importantly, myocardial LGE was noted in 9 of 14 patients with normal LV function. The predominant ECG abnormality was tall R waves in V1, and Q waves in lateral precordial leads. Of 43 patients with Holter monitoring, 5 patients had non-sustained ventricular tachycardia and 5 had supraventricular tachycardia. Of 8 patients with an implantable cardioverter defibrillator (ICD), 1 died due to pulseless electrical activity. ICD placement was pursued in those with NSVT, persistently low EF or FS when patient preference allowed. Conclusions: ACEi or ARB use was universal in our DMD cohort. Evidence of LGE on CMR was noted in DMD patients with and without LV dysfunction. ECG characteristics did not appear to have a clinical impact. Future studies to examine the association of LGE and other clinical variables with SCD are warranted.
8-Oxo-dGTPase, Which Prevents Oxidative Stress-Induced DNA Damage, Increases in the Mitochondria From Failing Hearts
Authors: HiroyukiTsutsui, TomomiIde, TetsuyaShiomi, DongchonKang, ShunjiHayashidani, NobuhiroSuematsu, JingWen, HideoUtsumi, NaotakaHamasaki, AkiraTakeshita
Journal: Circulation (2001)

Background— Reactive oxygen species (ROS) can cause an oxidative modification of nucleotides, such as 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP), which can lead to defects in DNA replication. The misincorporation of 8-oxo-dGTP into DNA is prevented by 8-oxo-dGTPase, which hydrolyzes 8-oxo-dGTP into 8-oxo-dGMP. The changes in this defensive system have not yet been examined in failing hearts, in which the generation of ROS increases. Methods and Results— Myocardial infarction (MI) was created in mice by ligating the left coronary artery. Four weeks later, the left ventricle was dilated and contractility was diminished on echocardiography. The generation of ROS, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, increased in the noninfarcted left ventricle from MI mice. The formation of thiobarbituric acid-reactive substances also increased in the mitochondria from MI mice. 8-Oxo-dGTPase was detected in the mitochondrial fractions isolate...
Abstract 23240: Investigation of Motivational Interviewing and Prevention Consults to Achieve Cardiovascular Targets Trial
Authors: Eugenia Gianos, Antoinette Schoenthaler, Yu Guo, Howard S Weintraub, Arthur Z Schwartzbard, James A Underberg, Jonathan D Newman, Edward A Fisher, Jeffrey S Berger
Journal: Circulation (2016)

Background: Patients undergoing cardiovascular (CV) procedures often have suboptimal risk factor control and would benefit from strategies targeting healthy lifestyle behaviors and education. Imple...
Anti–Monocyte Chemoattractant Protein-1/Monocyte Chemotactic and Activating Factor Antibody Inhibits Neointimal Hyperplasia in Injured Rat Carotid Arteries
Authors: YutakaFurukawa, AkiraMatsumori, NaohiroOhashi, TetsuoShioi, KohOno, AkihisaHarada, KoujiMatsushima, ShigetakeSasayama
Journal: Circulation Research (1999)

Abstract—Monocyte chemoattractant protein-1 (MCP-1)/monocyte chemotactic and activating factor (MCAF) has been suggested to promote atherogenesis. The effects of in vivo neutralization of MCP-1 in a rat model were examined in an effort to clarify the role of MCP-1 in the development of neointimal hyperplasia. Competitive polymerase chain reaction analysis revealed maximum MCP-1 mRNA expression at 4 hours after carotid arterial injury. Increased immunoreactivities of MCP-1 were also detected at 2 and 8 hours after injury. Either anti–MCP-1 antibody or nonimmunized goat IgG (10 mg/kg) was then administered every 12 hours to rats that had undergone carotid arterial injury. Treatment with 3 consecutive doses of anti–MCP-1 antibody within 24 hours (experiment 1) and every 12 hours for 5 days (experiment 2) significantly inhibited neointimal hyperplasia at day 14, resulting in a 27.8% reduction of the mean intima/media ratio (P<0.05) in experiment 1 and a 43.6% reduction (P<0.01) in experiment 2. This effect wa...
Abstract P028: The Prognostic Utility of Vitamin D Across Continents in Patients with Suspected Acute Coronary Syndrome
Authors: Patrycja A Naesgaard, Volker Pönitz, Ricardo Leon de la Fuente, Trygve Brugger-Andersen, Stein Tore Nilsen, Heidi Grundt, Cato Brede, Harry Staines, Dennis W Nilsen
Journal: Circulation (2016)

Background: Several studies have demonstrated a correlation between low vitamin D levels and cardiovascular risk. Vitamin D is a fat soluble vitamin that can either be ingested (mainly from fatty fish), or created in the skin on exposure to sun. Objectives: To assess the collected prognostic utility of vitamin D measured as 25-hydroxyvitamin D [25(OH)D] in 1852 patients hospitalized with chest pain and suspected acute coronary syndrome (ACS) recruited from two continents located at opposite sides of the Equator; coastal-Norway and inland Northern-Argentina, where the vitamin D source is either a combination of diet and sun exposure or mainly sun exposure, respectively. Data from both areas were collected in a similar registry and pooled in the present analysis. Methods: 2-year follow-up data including all-cause mortality, cardiac death and sudden cardiac death (SCD) in the total- as well as in the troponin T (TnT) positive (TnT &gt; 0.01 ng/mL) patient population were analyzed in quartiles of 25(OH)D, applying univariate and multivariable analysis. Variables included in the Cox regression model were country, TnT, hs-CRP, BNP, creatinine, age, gender, BMI, recruitment seasons and 14 other conventional risk factors for coronary heart disease. Results: At follow-up, 292 patients had died. 859 patients were TnT positive and of these 186 died. In multivariable Cox regression models for all-cause mortality, cardiac death and SCD in the total patient population, the adjusted hazard ratios (HR) for 25(OH)D in the highest quartile (Q4) as compared to the lowest quartile (Q1) were 0.52 (95% confidence interval (CI), 0.34-0.80), p=0.003, 0.54 (95% CI, 0.31-0.96), p=0.037 and 0.42 (95% CI, 0.18-0.98), p=0.045, respectively. In the TnT positive patient population the respective HRs were 0.43 (95% CI, 0.26-0.72), p=0.001, 0.47 (95% CI, 0.25-0.90), p=0.023 and 0.32 (95% CI, 0.12-0.87), p=0.025. Conclusion: Vitamin D status may serve as a prognostic indicator in chest pain patients with suspected ACS.