tbuckley/cabot-search huggingface dataset:
Abstract A08: A novel system determines the functional significance of ovarian tumor mutations in the homologous recombination gene RAD51C
Authors: Meghan R. Sullivan, Rohit Prakash, Michael J. Mihalevic, Jared M. Baird, Maria Jasin, Kara A. Bernstein
Journal: Clinical Cancer Research (2018)

Abstract Homologous recombination (HR) deficiency is associated with hereditary ovarian carcinomas. HR deficiency can occur through somatic and germline mutations in BRCA1, BRCA2, and other associated genes such as RAD51C. Understanding the impact of HR gene mutations on DNA double-strand break (DSB) repair is critical for developing targeted therapeutic strategies for these patients. Although BRCA1 and BRCA2 deficiency has been well characterized, limited functional analysis has occurred in patients harboring mutations in RAD51C. RAD51C mutations are found in familial breast and ovarian cancers and in Fanconi anemia-like syndrome, FANCO. To determine which RAD51C-tumor associated mutations disrupt HR, we utilized a novel RAD51C conditional knockout breast epithelial cell line (MCF10A) generated by Dr. Maria Jasin. In collaboration with the Jasin laboratory, we complemented these cells with RAD51C and RAD51C cancer-associated mutants. Using yeast-two-hybrid and co-immunoprecipitation strategies, we identified RAD51C mutations that disrupt RAD51C protein-protein interactions. For example, we identified RAD51C mutations that impair RAD51C interaction with either its binding partner RAD51B, RAD51D, or XRCC3. We next measured RAD51C mutant cells for viability and HR proficiency at an I-SceI-induced DSB using a DR-GFP reporter assay. We identified RAD51C mutations that impact HR repair, suggesting that patients harboring these mutations would be good candidates for PARPi. Our goal is to identify specific RAD51C mutations that disrupt HR to predict which RAD51C-deficient tumors will respond to therapy. Citation Format: Meghan R. Sullivan, Rohit Prakash, Michael J. Mihalevic, Jared M. Baird, Maria Jasin, Kara A. Bernstein. A novel system determines the functional significance of ovarian tumor mutations in the homologous recombination gene RAD51C. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A08.
Abstract 2346: ARDE: Detecting selectively expressed cancer driver mutations through integration of exome and transcriptome sequencing data
Authors: Fang Wang, Shaojun Zhang, Yiwen Chen, Traver Hart, Kenna Shaw, Funda Meric-Bernstam, Gordon Mills, Ken Chen
Journal: Cancer Research (2018)

Abstract Integrating multi-omics data from cancer patient samples can potentially advance the discovery of cancer driver mutations (CDM) towards establishing a knowledgebase for cancer precision medicine. However, it remains unclear whether CDMs are selectively expressed at RNA levels unexpected from DNA copy numbers and whether identifying such selectivity will enable more accurate discovery of CDMs. To answer this question, we developed a novel statistical algorithm, ARDE (Allelic RNA DNA expression), which estimates tumor purity, allele-specific copy number and intratumor heterogeneity (ITH) from matched whole-exome and whole-transcriptome sequencing data, deconvolutes tumor allele-specific expression levels (ASEL) and uses a two-component mixture probability model to identify selectively expressed alleles (SEAs) in the tumor compartment of heterogeneous tumor tissues. We applied ARDE to analyze melanoma and breast samples from The Cancer Genome Atlas (TCGA). Tumor purities estimated by ARDE were highly correlated with estimation from pathology review, DNA methylation array, gene expression microarray and SNP array data. ITH scores can significantly stratify breast cancer subtypes and survival time of melanoma patients. The deconvoluted tumor ASEL showed consistently higher correlation with the averaged gene expression levels in tissue-matched single tumor cells than in normal cells. Higher proportions of somatic mutations are selectively expressed than germline. Top SEAs are highly enriched in deleterious and gain-of-function (GOF) mutations. Stratifying melanoma patients by the expression selectivity of BRAF V600E mutation resulted in a 10-fold improvement of significance in survival analysis. These results indicate that ARDE will likely be an effective, widely applicable approach for accurate discovery of CDMs from tumor tissue sequencing data. (See Table 1.) Table 1. Top 10 significant positive-selectively expressed somatic mutations MelanomaBreast cancerGenepSNVFunctionSIFTGenepSNVFunctionSIFTBRAFp. V600EGOFDAKT1p.E17KGOFDNRASp. Q61RGOFDPIK3CAp.H1047RGOFTCDKN2Ap. R114LGOFDERBB2p.L755SGOFDIDH1p. R132CSwitch of functionDTP53p.R273HGOFDEEF1A1p. H349YDGATA3p.M293KDRAC1p. P29SGOFDTP53p.P278TDNRASp. Q61KGOFDFOXA1p.S250FDSF3B1p. R625HGOFDTP53p. R175HGOFDNRASp. Q61LGOFDPIK3CAp.H1047LGOFTMAP2K1p. P124SGOFDERBB2p.V777LGOFT Citation Format: Fang Wang, Shaojun Zhang, Yiwen Chen, Traver Hart, Kenna Shaw, Funda Meric-Bernstam, Gordon Mills, Ken Chen. ARDE: Detecting selectively expressed cancer driver mutations through integration of exome and transcriptome sequencing data [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 2346.
Abstract 4859: JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent <i>in vitro</i> and <i>in vivo</i> activity, demonstrated in several lung cancer models
Authors: Tongfei Wu, Hillary Millar, Dana Gaffney, Lijs Beke, Geert Mannens, Petra Vinken, Ivan Sommers, Jan-Willem Thuring, Weimei Sun, Christopher Moy, Vineet Pande, Junguo Zhou, Nahor Haddish-Berhane, Mark Salvati, Sylvie Laquerre, Matthew V. Lorenzi, Dirk Brehmer
Journal: Cancer Research (2018)

Abstract PRMT5 is a type II methyltransferase that symmetrically di-methylates arginine residues on proteins involved in signal transduction and cellular transcription. For example, PRMT5 acts as the enzymatic machinery of the methylosome complex, crucial for spliceosome assembly and activity. Although not frequently mutated or amplified in tumors, an elevated PRMT5 protein level that leads to higher methylosome activity and promotes epithelial–mesenchymal transition, has recently been correlated with a poor survival of cancer patients. The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency, paired with favorable oral pharmacokinetics and safety properties. JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Chemical proteomics, methylomics and RNA-sequencing analyses of PRMT5 inhibitor treated cell line samples support the current biological understanding of PRMT5 as a regulator of alternative splicing events. JNJ-64619178 showed potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. Ongoing investigations will explore the potential synthetic lethal correlation between PRMT5 inhibition and cancer driver pathways, including those addicted to altered splicing. Oral administration of JNJ-64619178 resulted in efficient inhibition of di-methylation of SMD1/3 proteins, components of the splicing machinery and direct substrates of the methylosome, in several human NSCLC and SCLC cancer mouse xenograft models. JNJ-64619178 demonstrated dose-dependent tumor growth inhibition and regression in several human NSCLC and SCLC cancer mouse xenograft models with sustained blockage of tumor re-growth after dosing cessation. In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in patients with lung cancer and other malignancies. Citation Format: Tongfei Wu, Hillary Millar, Dana Gaffney, Lijs Beke, Geert Mannens, Petra Vinken, Ivan Sommers, Jan-Willem Thuring, Weimei Sun, Christopher Moy, Vineet Pande, Junguo Zhou, Nahor Haddish-Berhane, Mark Salvati, Sylvie Laquerre, Matthew V. Lorenzi, Dirk Brehmer. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models [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 4859.
MiR-378 Controls Cardiac Hypertrophy by Combined Repression of Mitogen-Activated Protein Kinase Pathway Factors
Authors: JayavarshniGanesan, DeepakRamanujam, YassineSassi, AndreaAhles, ClaudiaJentzsch, StanislasWerfel, SimonLeierseder, XavierLoyer, MauroGiacca, LorenaZentilin, ThomasThum, BernhardLaggerbauer, StefanEngelhardt
Journal: Circulation (2013)

Background—Several microRNAs (miRs) have been shown to regulate gene expression in the heart, and dysregulation of their expression has been linked to cardiac disease. miR-378 is strongly expressed in the mammalian heart but so far has been studied predominantly in cancer, in which it regulates cell survival and tumor growth. Methods and Results—Here, we report tight control of cardiomyocyte hypertrophy through miR-378. In isolated primary cardiomyocytes, miR-378 was found to be both necessary and sufficient to repress cardiomyocyte hypertrophy. Bioinformatic prediction suggested that factors of the mitogen-activated protein kinase (MAPK) pathway are enriched among miR-378 targets. Using mRNA and protein expression analysis along with luciferase assays, we validated 4 key components of the MAPK pathway as targets of miR-378: MAPK1 itself, insulin-like growth factor receptor 1, growth factor receptor-bound protein 2, and kinase suppressor of ras 1. RNA interference with these targets prevented the prohyper...
Abstract 9947: Predictors of Left Ventricular Dysfunction After Aortic Valve Replacement in Patients With Mixed Aortic Valve Disease
Authors: AlexanderEgbe, JoesephPoterucha, CaroleWarnes
Journal: Circulation (2015)

Objectives: Predictors of left ventricular dysfunction (LVD) after aortic valve replacement (AVR) in mixed aortic valve disease (MAVD) have not been studied. Objective was to determine prevalence and predictors of early and late LVD at 1 and 5 years post-AVR. Methods: Retrospective review of 247 patients (Age 63±8 years, males 81%) with moderate/severe MAVD who underwent AVR at the Mayo Clinic from 1994-2013. Only patients with follow-up data at 1 year post AVR were included (n=239). Cohort divided into 3 groups based on data collected prior to AVR, 1 and 5 years post AVR. LVD was defined as ejection fraction  70 years (HR: 3.12, CI: 2.33-4.18, p= <0.0001), CABG (HR: 2.17, CI: 2.24-5.93, p= <0.0001), and severe MAVD pre-operatively (HR: 2.87, CI: ...
Arteriogenic Therapy by Intramyocardial Sustained Delivery of a Novel Growth Factor Combination Prevents Chronic Heart Failure
Authors: SébastienBanquet, ElodieGomez, LionelNicol, FlorenceEdwards-Lévy, Jean-PaulHenry, RenhaiCao, DamienSchapman, BrigitteDautreaux, FrancoiseLallemand, FabriceBauer, YihaiCao, ChristianThuillez, PaulMulder, VincentRichard, EbbaBrakenhielm
Journal: Circulation (2011)

Background—Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure. Methods and Results—First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro. Using 2 in vivo angiogenesis assays (n=5 mice per group), we found that the growth factor combination results in a more potent and durable angiogenic response than either growth factor used alone. Furthermore, we determined that the molecular mechanisms involve potentiation of Akt and mitogen-activated protein kinase signal transduction pathways, as well as upr...
PPARα Activators Inhibit Vascular Endothelial Growth Factor Receptor-2 Expression by Repressing Sp1-Dependent DNA Binding and Transactivation
Authors: MarkusMeissner, MonikaStein, CarmenUrbich, KerstinReisinger, GuntramSuske, BartStaels, RolandKaufmann, JensGille
Journal: Circulation Research (2004)

Peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors, originally implicated in the regulation of lipid and glucose homeostasis. In addition, natural and synthetic PPAR activators may control inflammatory processes by inhibition of distinct proinflammatory genes. As signaling via the vascular endothelial growth factor receptor-2 (VEGFR2) pathway is critical for angiogenic responses during chronic inflammation, we explored whether known antiinflammatory effects of PPAR ligands are mediated in part through diminished VEGFR2 expression. In this study, PPARα agonists are found to inhibit endothelial VEGFR2 expression, whereas predominant PPARγ ligands remained without discernible effects. Time- and concentration-dependent inhibition is demonstrated both at the level of protein and mRNA VEGFR2 expression. Inhibitory effects of PPARα agonists on transcriptional activity of the VEGFR2 promoter are conveyed by an element located between base pairs −60 and −37 that contains...
Précis of <i>Regard for Reason in the Moral Mind</i>
Authors: Joshua May
Journal: Behavioral and Brain Sciences (2018)

Abstract Regard for Reason in the Moral Mind argues that a careful examination of the scientific literature reveals a foundational role for reasoning in moral thought and action. Grounding moral psychology in reason then paves the way for a defense of moral knowledge and virtue against a variety of empirical challenges, such as debunking arguments and situationist critiques. The book attempts to provide a corrective to current trends in moral psychology, which celebrate emotion over reason and generate pessimism about the psychological mechanisms underlying commonsense morality. Ultimately, there is rationality in ethics not just despite but in virtue of the neurobiological and evolutionary materials that shape moral cognition and motivation.
Abstract 1700: Metabolic adaptations confer immunotherapy resistance in melanoma
Authors: Ashvin R. Jaiswal, Shivanand Pudakalakatti, Dutta Prasanta, Arthur Liu, Todd Bartkowiak, Casey Ager, Michael A. Davies, Richard E. Davis, Jennifer Wargo, Pratip K. Bhattacharya, David S. Hong, Michael A. Curran
Journal: Cancer Research (2018)

Abstract Background: Despite the success of T-cell checkpoint blockade antibodies in treating an array of cancers, the majority of patients still fail to respond to these therapies, or respond transiently and then relapse. The molecular mechanisms that drive lack of response to checkpoint blockade, whether pre-existing or evolved on therapy, remain unclear. Materials and Methods: To address this critical gap in clinical knowledge, we established a mouse model of melanoma designed to elucidate the molecular mechanisms underlying immunotherapy resistance. Through multiple in vivo passages, we selected a B16 melanoma tumor line that evolved complete resistance to combination blockade of CTLA-4, PD-1, and PD-L1, which cures ~75% of mice of the parental tumor. Using gene expression analysis, proteomics, and immunogenomics, we determined the adaptations engaged by this melanoma to become completely immunotherapy resistant. NMR spectroscopy, Seahorse XF Analysis, flow cytometry, confocal microscopy and Western blot analysis provided further insight into the mechanisms driving checkpoint blockade resistance. Results: Acquisition of immunotherapy resistance by these melanomas was driven by acquisition of a hypermetabolic state through coordinate upregulation of both glycolysis and oxidative phosphorylation (OxPhos). Depletion of essential nutrients from the tumor microenvironment by these resistant tumors functionally compromises infiltrating T cells to an extent that cannot be rescued by even triple checkpoint blockade. The glycolysis and OxPhos-associated genes most highly induced by these resistant melanomas were capable of conferring enhanced resistance to checkpoint blockade when reintroduced monogenically into the parental tumor. We have validated upregulation of these pathways in a unique cohort of melanoma patients who failed dual checkpoint blockade. Additionally, we employed a novel MRI imaging technique to visualize metabolic changes acquired by resistant tumors in live mice. Clinical application of this technique could provide a much-needed noninvasive tool to predict immunotherapeutic sensitivity of patient cancers. Conclusion: Acquisition of a hypermetabolic state by melanoma tumor cells cripples T cells in the microenvironment and confers complete resistance to checkpoint blockade. Citation Format: Ashvin R. Jaiswal, Shivanand Pudakalakatti, Dutta Prasanta, Arthur Liu, Todd Bartkowiak, Casey Ager, Michael A. Davies, Richard E. Davis, Jennifer Wargo, Pratip K. Bhattacharya, David S. Hong, Michael A. Curran. Metabolic adaptations confer immunotherapy resistance in melanoma [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 1700.
Bmx Tyrosine Kinase Is Specifically Expressed in the Endocardium and the Endothelium of Large Arteries
Authors: NiklasEkman, AthinaLymboussaki, ImreVästrik, KristaSarvas, ArjaKaipainen, KariAlitalo
Journal: Circulation (1997)

Background The growth and differentiation of endothelial cells are regulated by signal transduction through tyrosine protein kinases. Recently, a novel cytoplasmic tyrosine kinase gene, Bmx (Bone Marrow tyrosine kinase gene in chromosome X), was identified in human bone marrow RNA and found to be expressed predominantly in myeloid hematopoietic cell lineages. Our preliminary analyses indicated that the Bmx gene was also highly expressed in human heart. Methods and Results Mouse Bmx cDNA was isolated, sequenced, and found to encode a polypeptide ≈91% identical to the human Bmx tyrosine kinase. Northern blotting and in situ hybridization of tissue sections indicated that Bmx mRNA is specifically expressed in the endocardium of the developing heart as well as in the endocardium of the left ventricle and in the endothelium of large arteries in adult mice. A weak signal was seen also in coronary arterial endothelium. Conclusions Bmx shows a unique specificity of expression among tyrosine kinase genes and may b...
Abstract 16091: Racial and Socioeconomic Predictors of Out of Hospital Cardiac Arrest Mortality
Authors: Brian S Moyers, Thomas A Dewland, Gregory M Marcus, Zian H Tseng
Journal: Circulation (2013)

Background: Prior studies have demonstrated that African-Americans (AA) have higher rates of out of hospital cardiac arrest (OHCA) and worse survival than Caucasians (W). The short-term survival of other racial groups relative to W, and the effects of income and insurance have not been examined. Methods: Using Healthcare Cost and Utilization Project data, which captures >95% of adult California hospitalizations, we identified patients receiving emergency department (ED) or inpatient care between 1/1/2005 and 12/31/2009. OHCA was defined by victims transported to the ED for VF (ICD-9 427.4) or cardiac arrest (427.5); inpatient arrests and cases of primary trauma and sepsis were excluded. Survival rates to hospital discharge were evaluated. Multivariate regression models were used to evaluate the effects of race, income, and insurance on survival adjusting for age, gender, comorbidities, median income, hospital location, and length of stay. Results: Of 118,281 OHCA admissions, 30,128 (25%) survived to hospi...
Increased QT Dispersion in Patients With Vasospastic Angina
Authors: MakotoSuzuki, MitsuhiroNishizaki, MasatakaArita, TakashiAshikaga, NoriyoshiYamawake, TsunekazuKakuta, FujioNumano, MasayasuHiraoka
Journal: Circulation (1998)

Background—The risk factors for ventricular arrhythmias in patients with coronary vasospasm have not been identified. We evaluated QT dispersion in patients with vasospastic angina and its relation to susceptibility to ventricular arrhythmias during myocardial ischemia and reperfusion. Methods and Results—We assessed the corrected QT (QTc) dispersion before induction of coronary artery spasm by intracoronary injection of acetylcholine (baseline) and 30 minutes after administration of isosorbide dinitrate in 50 patients with vasospastic angina and 50 patients with atypical chest pain. The baseline QTc dispersion was significantly greater in patients with vasospastic angina than in patients with atypical chest pain (mean±SD: 69±24 versus 44±19 ms, 95% confidence interval of mean difference [CI]: 16 to 33 ms; P<0.001). QTc dispersion decreased significantly, to 48±15 ms (CI: 15 to 26 ms; P<0.001 versus baseline), after administration of isosorbide dinitrate in patients with vasospastic angina but did not cha...
Abstract 1409: p53 negatively regulates keratin 17 expression in oral squamous cell carcinoma
Authors: Mayu Enaka, Masako Nakanishi, Yasuteru Muragaki
Journal: Cancer Research (2018)

Abstract Background: Cytokeratin 17 (K17) has been shown to promote tumorigenesis and aggressiveness in oral squamous cell carcinomas (OSCCs) and other various carcinomas. Although p53 reportedly induces K17 transcription by irradiation, the correlation between p53 and K17 in OSCCs remains unknown. Methods: Human OSCC cell lines SAS and Ca9-22 were examined by Western blot, immunohistochemistry, ChIP assays, and overexpression of wild-type p53. Biopsy specimens from patients with OSCC were used for immunohistochemistry.Results: Western blot and immunohistochemistry showed that K17 expression negatively correlated with p53 expression. In biopsy specimens, positive staining for K17 was observed in OSCC cells that were negative for p53 in a mutually exclusive manner. SAS cells, which have higher K17 expression and almost negative p53 expression, showed more aggressive characteristics than Ca9-22 cells. A mutation to cause a premature stop codon was identified in the TP53 gene in SAS cells by DNA sequencing, whereas no mutation in the TP53 gene was identified in Ca9-22 cells. In addition, ChIP analysis showed that p53 bound specifically to the promoter region of the K17 gene. Furthermore, overexpression of wild-type p53 suppressed K17 expression in SAS cells. Conclusion: p53 acts as a direct transcriptional repressor of K17 in OSCCs. The interaction between p53 and K17 may regulate aggressiveness of the carcinoma cells. Citation Format: Mayu Enaka, Masako Nakanishi, Yasuteru Muragaki. p53 negatively regulates keratin 17 expression in oral 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 1409.