tbuckley/cabot-search huggingface dataset:
Abstract 3896: A big data approach to predicting context specific synergistic drug combinations
Authors: Coryandar M. Gilvary, Neel Madhukar, Olivier Elemento
Journal: Cancer Research (2018)

Abstract Combination therapies for various cancers have been shown to increase efficacy, lower toxicity and escape resistance. However, systematically interrogating all possible synergistic therapies is experimentally unfeasible due to the sheer volume of possible combinations. Computational approaches have proven to be an invaluable tool within pharmacogenomics and have helped with prioritizing the development of perspective therapeutics as well as matching the right drugs with the right patients. Here we apply a novel big data approach in the evaluation and ultimately the prediction of drug synergy by using the recently released NCI-ALMANAC, the largest publically available synergistic drug efficacy dataset to date. First, to better understand drug combinations, we distinguished between those that were synergistic and adverse and evaluated various drug similarity metrics for all pairs. We found that certain features showed significant differences between adverse and synergistic drug combinations, such as post-treatment transcriptional effects similarity (D = 0.17, p &amp;lt; 0.001) and chemical structure similarity (D = 0.25, p &amp;lt; 0.001). By exploiting these significant similarities and dissimilarities and incorporating cell line specific data we developed a machine learning model to predict context specific drug synergy and achieved significant predictive performance (AUC = 0.823). We find that our model can be used to both identify novel synergistic drug pairs, as well as find novel indications for known drug combinations by identifying new sensitive cell lines. Moreover, the interpretability of our model allows for the interrogation of features for a deeper understanding of why certain combinations are predicted synergistic. In addition to identifying the cancer types and subtypes a combination therapy would be most synergistic within, we set out to identify the molecular indication for highly synergistic pairs. Specifically, we systematically identified candidate predictive biomarkers which could be used to stratify patient cohorts. Overall, our model and methodology can expedite the development and expansion of combination therapeutics, which can help battle acquired resistance and increase therapeutic efficacy. The thorough understanding of specific combination efficacy dependencies allows for a true precision medicine application of these therapeutics. Citation Format: Coryandar M. Gilvary, Neel Madhukar, Olivier Elemento. A big data approach to predicting context specific synergistic drug combinations [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 3896.
Endogenous Estrogens Influence Endothelial Function in Young Men
Authors: RobertLew, PaulKomesaroff, MaroWilliams, TyeDawood, KrishnankuttySudhir
Journal: Circulation Research (2003)

Males produce endogenous estrogen from testosterone via the enzyme aromatase. Previous studies have suggested a role for endogenous estrogens in cardiovascular function in men. We examined the effects of endogenous estrogen suppression via aromatase inhibition on endothelial function, systemic arterial compliance, and lipoprotein levels in healthy young men. Using a placebo-controlled double-blind randomized design, 20 healthy men, aged 18 to 32 years, were randomized to receive either the aromatase inhibitor anastrozole (1 mg) or matching placebo. Hormone, lipid levels, C-reactive protein (CRP), and homocysteine were measured. Endothelial function, determined by flow-mediated dilation of the brachial artery, and systemic arterial compliance were assessed at baseline and after 6 weeks of treatment. There was a significant decrease in 17β-estradiol concentrations with aromatase inhibition, from 85.4±4.2 to 64.3±8.1 pmol/L (mean±SD, P=0.042). Compared with baseline, a significant decrease in flow-mediated d...
Supplement of Nitric Oxide Attenuates Neutrophil-Mediated Reperfusion Injury
Authors: HirotsuguFukuda, YoshikiSawa, KeishiKadoba, KazuhiroTaniguchi, YasuhisaShimazaki, HikaruMatsuda
Journal: Circulation (1995)

Background Nitric oxide (NO) derived from the endothelial cell has been identified as a constitutive chemical mediator that regulates the function of the endothelial cell in association with neutrophil (PMN) adhesion and activation. However, its role in the pathogenesis of myocardial reperfusion injury is not clear. Methods and Results Fifteen isolated rat hearts were perfused with modified Krebs-Henseleit solution and subjected to 20 minutes of global and normothermic ischemia. Then the hearts were reperfused for 45 minutes with different protocols: the control (C) group was reperfused without PMNs, the P group was reperfused with PMNs, and the N group was reperfused with PMNs and nitroprusside (10−5 mol/L). The ozone chemiluminescence method was used for direct measurement of NO in the coronary effluent during reperfusion. NO in the coronary effluent in the C group decreased at reperfusion after normoxic perfusion, and this decrease in NO continued for the first 15 minutes of reperfusion. Percentage rec...
Abstract 17545: CD4+CD28null Cells Are an Independent Predictor of Mortality in Patients With Heart Failure
Authors: Lorenz Koller, Georg Goliasch, Bernhard Richter, Steffen Blum, Magdalena Korpak, Alexander Hermann, Gerlinde Zorn, Mira Brekalo, Gerald Maurer, Johann Wojta, Richard Pacher, Martin Hülsmann, Alexander Niessner
Journal: Circulation (2013)

Purpose: Immune activation and subsequent release of proinflammatory cytokines plays a central role in the pathophysiology of chronic heart failure (CHF). Cytotoxic CD4+CD28null cells are rarely found in healthy persons but expand dramatically under inflammatory conditions and therefore are implicated in a variety of pathological processes like atherosclerosis and autoimmune diseases. The study aim was to assess the impact of CD4+CD28null cells on survival in CHF patients. Methods: Circulating lymphocytes from 107 CHF patients were analyzed for the distribution of CD4 subsets by flow cytometry. The presence of CHF was defined by NYHA functional class ≥ II and either left ventricular ejection fraction (LVEF) or pro-BNP >500 pg/ml. Cox regression models were used to assess the influence of CD4+CD28null T cells on survival. The multivariable model was adjusted for age, gender, CHF etiology, NYHA functional class, diabetes, NT-proBNP and estimated glomerular filtration rate (eGFR). Results: During a median fo...
Abstract 1234: Somatic mutations of FAT1 in oral cancer are associated with tumor progression and survival
Authors: Chung Ji Liu, Shu-Chun Lin, Li-Han Lin
Journal: Cancer Research (2018)

Abstract In recent years, the incidence and mortality rates of oral squamous cell carcinoma (OSCC) have increased worldwide. Therefore, understanding genomic alterations in OSCC carcinogenesis is crucial for appropriate diagnosis and therapy. Procadherin FAT1, which encodes 4588 amino acid residues, regulates complex mechanisms to promote oncogenesis or suppression of malignancies. Multiplex polymerase chain reaction (PCR)-based next-generation sequencing (NGS) revealed FAT1 somatic mutations. The clinicopathologic implications of FAT1 in OSCC were investigated using expression assays, and the functional role of FAT1 in HNSCC pathogenesis was determined using ectopic expression and knockdown experiments. Approximately 29% of patients with OSCC harbored damaging FAT1 mutations. Each type of mutation (missense, nonsense, and frameshift mutations) accounted for nearly one-third of deleterious mutations. FAT1 mutations correlated with lower FAT1 expression in tumors. The knockdown of the endogenous expression of FAT1 and exogenous expression of crucial FAT1 domains unequivocally indicated that FAT1 suppressed the migration and invasion capability of OSCC cells. Functional analysis suggested that nonsense mutations in FAT1 result in the loss of the suppression of tumor progression. FAT1 mutations and downregulation defined nodal involvement, lymphovascular permeation, and tumor recurrence. In addition, FAT1 mutations and downregulation are independent predictors of poor disease-free survival in patients with HNSCC. This study is the first to perform multiplex PCR-based NGS to indicate marked nonsynonymous FAT1 mutations in OSCC, which are prognostic indicators. The gene analysis strategy proposed for detecting FAT1 mutations may be a valid method for mutation screening. Citation Format: Chung Ji Liu, Shu-Chun Lin, Li-Han Lin. Somatic mutations of FAT1 in oral cancer are associated with tumor progression and survival [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 1234.
Inhibition of Neointima Hyperplasia of Mouse Vein Grafts by Locally Applied Suramin
Authors: YanhuaHu, YipingZou, HermannDietrich, GeorgWick, QingboXu
Journal: Circulation (1999)

Background—Saphenous vein grafts are widely used for aortocoronary bypass surgery as treatment for severe atherosclerosis and often are complicated by subsequent occlusion of the graft vessel. Methods and Results—We described a mouse model of venous bypass graft arteriosclerosis that can be effectively retarded by locally applied suramin, a growth factor receptor antagonist. Mouse isogeneic vessels of the vena cava veins pretreated with suramin were grafted end to end into the carotid arteries and enveloped with a mixture of suramin (1 mmol/L) and pluronic-127 gel. In the untreated group, vessel wall thickening was observed as early as 1 week after surgery and progressed to 4-fold and 10-fold the original thickness in grafted veins at 4 and 8 weeks, respectively. Pluronic-127 gel alone did not influence neointima formation. Suramin treatment reduced the neointima hyperplasia 50% to 70% compared with untreated controls. Immunohistochemical studies demonstrated that a significant proliferation of vascular s...
Abstract LB-302: Oncolytic poliovirus-mediated inflammation and immunity in breast cancer
Authors: Karenia Landa, Eda Holl, Michael Brown, James Herndon, Lars Grimm, Jeremy Force, Darell Bigner, Shelley Hwang, Matthias Gromeier, Smita Nair
Journal: Cancer Research (2018)

Abstract Breast cancer is the most common malignancy among women in the United States and the second leading cause of cancer deaths in women. Disease prognosis, local recurrence rates and response to therapy are all related to receptor status of the individual cancer. Triple negative breast cancer (TNBC; ER-, PR-, and HER2-negative) is a subset of breast cancer with poor prognosis and high rate of local recurrence and metastasis with limited therapeutic options. The oncolytic poliovirus, PVSRIPO, is a recombinant polio:rhinovirus chimera that has been engineered to eliminate neuropathogenicity and has demonstrated promising responses in patients with recurrent glioblastoma. PVSRIPO is oncolytic in tumor cells and enters cells via its receptor CD155, which is overexpressed in solid malignancies, including TNBC. Treatment of primary TNBC tissue with PVSRIPO induces IFN-I and pro-inflammatory cytokines. In a murine immunotherapy model, intratumoral injection of PVSRIPO induces IFN-I, IL12 and IFN-γ and rapid recruitment of neutrophils into the tumor followed by infiltration of DCs, T cells and B cells. Treatment of orthotopic breast tumors with PVSRIPO results in delayed tumor growth and increased survival in an immunocompetent murine immunotherapy model. We have designed a pilot study to examine the effects of intratumoral injection of PVSRIPO into six women with TNBC with at least 1 cm of residual tumor after chemotherapy. The primary exploratory objective is to describe the changes in the amount of tumor infiltrating immune cells in tumor tissue pre- and post-injection of PVSRIPO. We will also collect blood at different time points during PVSRIPO treatment to evaluate inflammatory and immune signatures. We hypothesize that intratumoral administration of PVSRIPO will cause inflammation thus stimulating innate and adaptive immune activation. This study is funded by the Department of Defense Breast Cancer Research Program award W81XWH-16-1-0354 (PI, Smita Nair). Citation Format: Karenia Landa, Eda Holl, Michael Brown, James Herndon, Lars Grimm, Jeremy Force, Darell Bigner, Shelley Hwang, Matthias Gromeier, Smita Nair. Oncolytic poliovirus-mediated inflammation and immunity 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 LB-302.
Abstract 14859: RyR Phosphorylation by Oxidized CaMKII Contributes to the Cardiotoxic Effects of Cardiac Glycosides
Authors: Hsiang-Ting Ho, Bin Liu, Jedidiah Snyder, Chandan Sen, Xander Wehrens, Thomas Hund, Sandor Gyorke
Journal: Circulation (2012)

Cardiac glycosides (CGs), important agents in the treatment of heart failure, are characterized by proarrhythmic side effects commonly attributed to ionic imbalances due to inhibition of Na+/K+- AT...
Accuracy Of A Clinical Diagnosis Of Idiopathic Pulmonary Fibrosis: A Study Of 275 Pulmonologists From 54 Countries
Authors: S. L. F. Walsh, D. Hansell, K. R. Flaherty, M. Wilsher, R. Nusser, V. Poletti, F. J. Martinez, E. Bendstrup, K. K. Brown, H. Taniguchi, B. Crestani, C. Vancheri, V. Cottin, L. Richeldi, T. M. Maher, D. Valeyre, H. Nunes, M. Kokosi, G. Margaritopoulos, E. P. Judge, M. Wijsenbeek, J. C. Grutters, B. J. Ley, M. Selman, A. Morais, W. A. Wuyts, P. Spagnolo, I. Glaspole, T. J. Corte, S. Tomassetti, Y. Kondoh, M. Kreuter, J. Behr, V. Kouranos, M. Molina-Molina, K. A. Johannson, C. J. Ryerson, M. Jones, A. U. Wells
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Abstract 16461: Genetic Basis of Severe Pulmonary Arterial Hypertension in a Colony of SU5416 “Hyper-responsive” Sprague-dawley Rats
Authors: Ketul R Chaudhary, Yupu Deng, Anli Yang, Edwin Cuppen, Duncan J Stewart
Journal: Circulation (2015)

Introduction: Our lab has identified a unique sub-strain of Sprague Dawley (SD) rats obtained from a colony of Charles River labs (Montreal, Canada) exhibiting hyper-responsiveness (HR) to the VEGFR2 antagonist, SU5416 (SU). These rats developed severe progressive PAH in response to single injection of SU in absence of CH. In the present study, we investigated genetic basis of hyper-responsive (HR) phenotype in the sub-strain of SD rats. Hypothesis: We hypothesized that hyper-responsiveness to SU was conferred by as yet unknown genetic modifiers that modulate the response to VEFR2 blockade. Methods and Results: Male and female rats were injected with SU (20mg/kg, sc) or vehicle (control). Right ventricular systolic pressure (RVSP) was measured at 7 weeks after SU injection. In absence of CH, 72% (13 of 18) male SD rats demonstrated HR-phenotype and developed severe PAH in response to SU with mean RVSP of 97±18 mmHg; whereas only 27% (7 of 26) of the female rats showed HR-phenotype. Furthermore, crossing non-responsive male and female animals markedly decreased the proportion of HR animals in the F1-generation (HR 15% and 0%. male vs. female, respectively), supporting a possible genetic basis for the HR phenotype. Therefore, we undertook whole genome-wide exome sequencing to identify mutations related to the HR phenotype. This resulted in the identification of a number of mutations unique to the HR SD colony (not found in 40 other background strains) and predicted to have a “high effect” on gene function. Preliminary analysis has identified several candidate genes exhibiting mutations tightly associated with the HR phenotype, including the protein C receptor, hypoxia inducible factor 1α and SP110. These and other potential modifier genes identified by a bioinformatics analysis are currently being validated in a larger population of rats from this SD colony, with and without the HR phenotype. Conclusion: For the first time, we have identified modifier genes that play a critical role in determining susceptibility to development of severe PAH in response to SU alone. These data may provide insight into the nature of potential genetic determinants that may influence the penetrance of the PAH phenotype in humans harboring mutations BMPR2 or in other PAH causing genes.
Abstract 453: The role of centrosome amplification in HCC
Authors: Sai Fung Yeung, Yick Pang Ching
Journal: Cancer Research (2018)

Abstract Centrosome is the major microtubule organizing center (MTOC) in mammalian cells which maintain cell polarity, organization of microtubules and regulate cell cycle progression. In normal cells, centrosome duplication cycle is tightly coupled with cell cycle, DNA synthesis, mitosis as these event were controlled by parallel pathways. Centrosomal defect is reported in numerous type of solid and hematologic malignancy, both structurally (enlarged PCM, string-like etc) and numerically (&amp;lt;2 or &amp;gt;=3). Centrosome amplification (CA, n&amp;gt;=3) is the most commonly reported. CA is casually linked to chromosomal instability (CIN), tumor-initiation, advanced tumor stage and chemo-resistance. CA arises through multiple distinct but non-redundant mechanisms in tumor, for example, aberrant cell cycle, hypoxia, and chemotherapy. Recently studies suggest CA might not be responsible for HCC initiation. Yet, around 90% of HCC cells carry certain degree of CA. It is associated with p53 mutation and tumor-aneuploidy but no other clinicopathological features. The role of CA in HCC progression deserve a more comprehensive study. To investigate the role of CA in HCC, first, we use CA20, an expression signature-score includes centrosomal structural genes and genes results in CA when dyregulated. We use CA20 as surrogate marker to evaluate the clinical outcome of CA in HCC from GEO datasets. CA carrying HCC was found to have poor overall survival and larger tumor size. Next, we developed several inducible PLK4 overexpressing HCC cell line. Preliminary data shown that PLK4 overexpression concomitantly leaded to centrosome over-duplication in HCC cell lines. Functionally, PLK4 overexpression resulted in increased cell migration, but retarded growth rate in p53+/+ HCC cells. Furthermore, we identified another cell cycle-related kinase - Aurora A, as a novel interacting partner of PLK4 suggest that these kinases work together to promote malignant transformation. Citation Format: Sai Fung Yeung, Yick Pang Ching. The role of centrosome amplification in HCC [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 453.
Acute Myocardial Infarction Detected in the 12-Lead ECG by Artificial Neural Networks
Authors: BoHedén, HansÖhlin, RalfRittner, LarsEdenbrandt
Journal: Circulation (1997)

Background The 12-lead ECG, together with patient history and clinical findings, remains the most important method for early diagnosis of acute myocardial infarction. Automated interpretation of ECG is widely used as decision support for less experienced physicians. Recent reports have demonstrated that artificial neural networks can be used to improve selected aspects of conventional rule-based interpretation programs. The purpose of this study was to detect acute myocardial infarction in the 12-lead ECG with artificial neural networks. Methods and Results A total of 1120 ECGs from patients with acute myocardial infarction and 10 452 control ECGs, recorded at an emergency department with computerized ECGs, were studied. Artificial neural networks were trained to detect acute myocardial infarction by use of measurements from the 12 ST-T segments of each ECG, together with the correct diagnosis. After this training process, the performance of the neural networks was compared with that of a widely used ECG ...
Glucose Uptake in the Chronically Dysfunctional but Viable Myocardium
Authors: MaijaMäki, MattiLuotolahti, PirjoNuutila, HidehiroIida, Liisa-MariaVoipio-Pulkki, UllaRuotsalainen, MerjaHaaparanta, OlofSolin, JaakkoHartiala, RistoHärkönen, JuhaniKnuuti
Journal: Circulation (1996)

Background The regulation of glucose uptake in the dysfunctional but viable myocardium has not been studied previously in humans. Methods and Results Seven patients with an occluded major coronary artery but no previous infarction were studied twice with 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography, once in the fasting state and once during hyperinsulinemic euglycemic clamping. Myocardial blood flow was measured with [15O]H2O. The myocardial region beyond an occluded artery that showed stable wall-motion abnormality represented chronically dysfunctional but viable tissue. Six of the patients were later revascularized, and wall-motion recovery was detected in the corresponding regions, which confirmed viability. A slightly reduced myocardial blood flow was detected in the dysfunctional than in the remote myocardial regions (0.81±0.27 versus 1.02±0.23 mL·g−1·min−1, P=.036). In the fasting state, glucose uptake was slightly increased in the dysfunctional regions compared with normal myocardiu...
Abstract 2008: Stem cell-associated proteins P63 and Bmi-1 may cooperate in maintaining cancer-initiating cell populations in squamous cell carcinomas
Authors: Linan Ha, Devin Reilly, Roshini Ponnamperuma, Andrea George, Wendy C. Weinberg
Journal: Cancer Research (2018)

Abstract Overexpression of p53-related protein p63, particularly ΔNp63α, is seen in squamous cell carcinomas of the head and neck, lung, cervix and skin. We use primary murine epidermal keratinocytes as a model of human squamous epithelial cells and mimic these elevated levels using adeno- and lentiviral vectors. In previous studies, we established that ΔNp63α inhibits induction of p16ink4a and p19arf, blocks oncogene-induced senescence, and cooperates with activated v-rasHa to enhance conversion of papilloma to carcinoma in a nude mouse grafting model. We evaluated the relationship between ΔNp63α and Bmi-1, a member of the polycomb complex known to repress the INK4a/ARF gene locus, and modulated Bmi-1 expression in the presence or absence of elevated ΔNp63α to assess its impact on p16ink4a and p19arf expression. Bmi-1 protein levels correlate with those of ΔNp63α; however, higher levels of Bmi-1 block p16ink4a but not p19arf. Consistent with this, Bmi-1 is required for the binding of ΔNp63α to the p16ink4a but not the p19arf promoter. These findings may have further important implications in HNSCC as other previously published models have demonstrated that Bmi-1 is important for prevention of senescence in stem cells. Using FACS analysis and cell sorting, we are defining cell populations of keratinocytes with respect to the expression of ΔNp63α, Bmi-1, and other markers of stem cells and senescence and extending these approaches from murine to human HNSCC models with the aim of correlating these distinct patterns with cancer-initiating potential and tumor phenotype. Citation Format: Linan Ha, Devin Reilly, Roshini Ponnamperuma, Andrea George, Wendy C. Weinberg. Stem cell-associated proteins P63 and Bmi-1 may cooperate in maintaining cancer-initiating cell populations in squamous cell carcinomas [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 2008.