tbuckley/cabot-search huggingface dataset:
Abstract P279: Major Dietary Risk Factors for Cardiometabolic Disease: Current Evidence for Causal Effects and Effect Sizes From the Global Burden of Diseases (GBD) 2015 Study
Authors: Masha L Shulkin, Renata Micha, Mayuree Rao, Gitanjali M Singh, Dariush Mozaffarian
Journal: Circulation (2016)

Background: Dietary habits are major contributors to cardiometabolic diseases. Estimating the impact of diet on these conditions requires identification and quantification of evidence for causal effects. Objectives: To comprehensively evaluate the current evidence and quantify the effects of major dietary factors on CHD, stroke, and diabetes as part of the Global Burden of Diseases (GBD) 2015 study. Methods: We assessed probable or convincing evidence for causal effects based on Bradford-Hill, World Health Organization, and WCRF/AICR criteria. We searched PubMed through April 2015 to identify systematic reviews and meta-analyses of well-designed observational studies and clinical trials. Meta-analyses were evaluated and selected based on design, number of studies and events, definition of dietary exposure and disease outcomes, length of follow-up, statistical methods, evidence of bias, and control for confounders. Effect sizes and uncertainty were quantified per standardized units. We focused on dose-response meta-analyses. When necessary, original data were extracted from individual studies within each meta-analysis to perform de novo dose-response meta-analyses using generalized least squares for trend estimation. Results: We identified 11 dietary factors with probable or convincing evidence for causal effects on CHD, 4 on stroke, and 7 on diabetes. ( Table ). Examples of other factors not yet meeting probable or convincing evidence for causal effects included coffee and tea (consistent dose-response, yet plausible biology not well-established), eggs, and dietary cholesterol. Conclusion: This evaluation provides the best current evidence-based quantitative estimates of effects of major dietary factors on CHD, stroke, and diabetes. These findings enable quantitative estimation of disease burdens of suboptimal diet in the US and globally, and also inform policy planning and priorities.
Abstract 4854: Targeting ribonucleotide reductase M2 using didox causes inhibition of estrogen receptor-negative, inflammatory breast cancer cell proliferation and tumor emboli formation in culture
Authors: Pranalee Patel, Ben Mirman, Renzhi Zhan, Gayathri R. Devi
Journal: Cancer Research (2018)

Abstract Ribonucleotide reductase (RR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides during the rate-limiting step of DNA synthesis. Given its significant role in cell cycle regulation, RR and its catalytic subunits are significant molecular targets for inhibiting tumor cell growth and proliferation. Didox (3,4-dihydroxybenzohydroxamic acid) is a known inhibitor of the catalytic RR subunit of RRM2 and overall DNA synthesis. Previous meta-analyses have revealed that RRM2 is highly expressed in estrogen receptor-negative (ER-) breast cancer tumors. As ER negativity is frequent in inflammatory breast cancer (IBC), a distinct and the most aggressive breast cancer subtype, we proposed to evaluate efficacy of didox in IBC cell models. ER- inflammatory breast cancer (IBC) cell lines SUM149 (ER-, PR-, EGFR-activated), lapatinib-resistant SUM149 (rSUM149), and non-IBC BT474M1 metastatic subline of BT474 (ER+, PR+, HER2+) were compared for the cytotoxic and cytostatic effects of didox using cell viability (trypan blue exclusion) and proliferation (MTT) assays. Protein profiling was performed to evaluate changes in molecular expression of key proteins involved in cellular signaling pathways for apoptosis and proliferation. Only ER- cell lines exhibited decreased dose-dependent decrease in viability following didox treatment. In addition, didox inhibited tumor emboli formation in a novel ex vivo tumor emboli in culture assay that mimics the clinicopathologic hallmark of IBC disease in patients. Moreover, didox decreased proliferation in lapatinib-resistant rSUM149, suggesting that the drug may help circumvent lapatinib resistance. Studies are ongoing to evaluate the mechanism of didox in overcoming lapatinib resistance and evaluation in an in vivo IBC invasion model. IBC is rare but accounts for 10% of breast cancer deaths, and despite multimodal therapy the 5-yr survival is only 25-55%. Further, there is a need to identify new therapies that can inhibit IBC tumor emboli formation and migration. Didox has demonstrated minimal toxicity in human phase I/II cancer clinical trials and therefore is an attractive strategy for inflammatory breast cancer therapy. Support in part from the Development funds (GRD) of the Duke Cancer Institute as part of the P30 Cancer Center Support Grant NIH CA014236 and Department of Defense Breakthrough Level 2 W81XWH-17-1-0297 (GRD). Citation Format: Pranalee Patel, Ben Mirman, Renzhi Zhan, Gayathri R. Devi. Targeting ribonucleotide reductase M2 using didox causes inhibition of estrogen receptor-negative, inflammatory breast cancer cell proliferation and tumor emboli formation in culture [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 4854.
Abstract 3750: Xenoestrogens cause estrogen receptor-dependent R-loop formation and DNA damage
Authors: Karen A. Dunphy, Prabin Dhangada Majhi, Aman Sharma, Amy L. Roberts, Elizabeth A. Daniele, Sallie S. Schneider, D Joseph Jerry
Journal: Cancer Research (2018)

Abstract Background: The hormone 17β-estradiol (E2) plays an important role in breast cell proliferation and development but prolonged exposures and higher levels of E2 have been linked to genomic instability and breast cancer. Recent studies show E2 induced transactivations lead to DNA damage. A variety of environmental chemicals mimic the activities of estrogen, referred to as xenoestrogens. Thus, our hypothesis is to determine whether xenoestrogens stimulate transcriptional response and induce DNA damage similarly like E2. Methods: The T-47D breast cancer cell line is used as a model because it expresses both estrogen receptors (ERα &amp; ERβ) as found in normal breast tissue. Cells were exposed a physiologic range of E2 (17β-estradiol) [0.5-100nM] and the xenoestrogens, e.g., benzophenone-3 (BP-3) [0.5-50µM] and propyl paraben (PP) [0.5-10µM] with or without ER-antagonist ICI (1µM) for 24 hours. Transcriptional responses were quantified using an integrated ERE-luciferase reporter and qPCR for endogenous genes. Proliferation was monitored using the Alamar Blue assay. DNA damage was determined using γ-H2AX. R-loops were detected using the S9.6 antibody against DNA-RNA hybrids in the genome. Results: Exposure of T-47D cells to physiologic levels of E2, PP and BP3 causes significant increase in DNA double-strand breaks (DSBs) as determined by γ-H2AX staining. We demonstrate a concomitant increase in R-loop formation with increase in γH2AX intensity. Treatment with RNaseH depletes R-loop intensity, corroborating the result. E2 and PP induce transactivation as determined by Luciferase reporter assay as well as expression of ER-response genes (PGR and AREG), whereas BP3 has modest effect on transactivation of PGR. ER transactivation as well as R-loop formation by E2, PP and BP3 were abrogated with ICI, demonstrating ER-dependency of R-loop formation. Consistent with the transcriptional response, proliferation studies determined that E2 showed highest proliferation followed by PP. However, BP3 showed no increase in proliferation. Conclusions: Our results show that xenoestrogens have strikingly different activities in transactivation and proliferation. However, both xenoestrogens appear to stimulate R-loop accumulation that leads to DSB in an ER-dependent manner. Citation Format: Karen A. Dunphy, Prabin Dhangada Majhi, Aman Sharma, Amy L. Roberts, Elizabeth A. Daniele, Sallie S. Schneider, D Joseph Jerry. Xenoestrogens cause estrogen receptor-dependent R-loop formation and DNA damage [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 3750.
Abstract 4838: R loop-driven genome instability by G-quadruplex binders in BRCA2-silenced human cancer cells
Authors: Alessio De Magis, Stefano Giustino Manzo, Marco Russo, Olivier Sordet, Rita Morigi, Giovanni Capranico
Journal: Cancer Research (2018)

Abstract G-quadruplexes (G4s) and R-loops are non-B DNA structures that can regulate basic processes such as transcription and replication. Unscheduled formation of R-loops is regarded as highly deleterious to cells, as R loops can induce replicative stress and DNA damage leading to genome instability. G4s are formed by four guanine residues held together by Hoogsteen hydrogen bonds and stabilized by monovalent cations. R loops are triple-stranded structures that contain an RNA-DNA hybrid duplex and a displaced single-stranded DNA. We have recently shown that Topoisomerase I (Top1) can affect genome-wide levels of R loops in human cancer cells consistently with the knowledge that DNA superhelical tension is a main driving force allowing non-B DNA structure formation. As G4 ligands were suggested to synergize with Top1 inhibitors, we asked the question of whether G4 ligands can affect R loops. We have thus investigated by immunofluorescence microscopy the effects of two different G4 binders, Pyridostatin (PDS) and FG (compound 1 in Amato et al J Med Chem 2016), on R-loops in human cancer cells. These G4 binders can increase both G4s and R loops while an inactive derivative of FG cannot induce them. Interestingly, the induction of G4s and R loops well correlate to each other in time and intensity with PDS being more effective than FG. After 24 hours, G4 binders induce a cell cycle arrest at the G2/M phase associated to double-stranded DNA cleavage as detected by γH2AX and 53BP1 foci formation and to activation of checkpoint response as shown by ATM phosphorylation. Interestingly, overexpression of RNaseH1 reduces both R loops and γH2AX foci induced by G4 binders showing that the ligands induce DNA cleavage via an R loop-mediated mechanism. Then, we silenced the BRCA2 gene by RNAi in U2OS cells and the results show that BRCA2 depletion increased γH2AX foci induced by PDS while overexpression of RNaseH1 rescue DNA cleavage induction. We also determined genomic R loop maps by DRIP-seq, and bioinformatic analyses of the specific location of G4-stabilized R loops provided information consistent with a model in which a G4 opposite to a DNA:RNA hybrid can stabilize R loops. Our study establishes for the first time that G4 binders stabilize either G4s and R loops in human cancer cells, and that they induce genome instability with a mechanism dependent on R loop formation. Partially supported by AIRC, Milan. Citation Format: Alessio De Magis, Stefano Giustino Manzo, Marco Russo, Olivier Sordet, Rita Morigi, Giovanni Capranico. R loop-driven genome instability by G-quadruplex binders in BRCA2-silenced human 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 4838.
Etomoxir Improves Left Ventricular Performance of Pressure-Overloaded Rat Heart
Authors: MarianTurcani, HeinzRupp
Journal: Circulation (1997)

Background Numerous studies have demonstrated diverse abnormalities in subcellular structures of pressure-overloaded hypertrophied and failing heart. Long-term administration of etomoxir, a carnitine palmitoyltransferase-1 inhibitor, partially normalized the proportion of myosin isozyme V1 and number of active Ca2+ pumps in hypertrophied rat myocardium. Methods and Results To test the hypothesis that long-term etomoxir treatment improves the performance of hypertrophied ventricle, sham-operated rats and rats with ascending aorta constriction were treated with racemic etomoxir (15 mg/kg per day) for 12 weeks. Left ventricular geometry, dynamics of isovolumic contractions, as well as myosin isozymes as marker of etomoxir-induced phenotype changes were assessed. Etomoxir stimulated (P<.05) slight hypertrophic growth in right and left ventricles of sham-operated rats as well as in right ventricles but not in overloaded left ventricles of rats with aortic constriction. In all treated rats, etomoxir increased (...
The Electrical Potential Difference Across the Cell Membrane of Heart Muscle
Authors: Ernestpage
Journal: Circulation (1962)

The electrical potential difference across the cell membrane of heart muscle cells is a diffusion potential arising from the interaction of fixed charges within the membrane pores with NaCl and KCl diffusing into and out of the cell. The magnitude and sign of this potential difference depend on the relative permeabilities, of the membrane to K, Na, and Cl. The resting membrane is predominantly permeable to K, while the action potential is characterized by a transient increase in Na permeability. An intracellular solution of high K concentration and low Na concentration is separated by the cell membrane from an extracellular solution having a low K concentration and a high Na concentration. These concentration differences are maintained by active transport processes that utilize the energy derived from cellular metabolic reactions to transport Na and K uphill against electrical and concentration gradients.
Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis
Authors: Nathalie Ganne-Carrié, Cendrine Chaffaut, Valérie Bourcier, Isabelle Archambeaud, Jean-Marc Perarnau, Frédéric Oberti, Dominique Roulot, Christophe Moreno, Alexandre Louvet, Thông Dao, Romain Moirand, Odile Goria, Eric Nguyen-Khac, Nicolas Carbonell, Térésa Antonini, Stanislas Pol, Victor de Ledinghen, Violaine Ozenne, Jean Henrion, Jean-Marie Péron, Albert Tran, Gabriel Perlemuter, Xavier Amiot, Jean-Pierre Zarski, Michel Beaugrand, Sylvie Chevret
Journal: Journal of Hepatology (2018)
Modulation of Endothelium-Dependent Flow-Mediated Dilatation of the Brachial Artery by Sex and Menstrual Cycle
Authors: MasayoshiHashimoto, MasahiroAkishita, MasatoEto, MichiroIshikawa, KoichiKozaki, KenjiToba, YokoSagara, YujiTaketani, HajimeOrimo, YasuyoshiOuchi
Journal: Circulation (1995)

Background Estrogen has been reported to augment endothelium-dependent vasodilatation. The role of endogenous ovarian hormones in modulating endothelium-dependent vasodilatation, however, remains to be determined. The purpose of the present study was to investigate the effects of sex and menstrual cycle on endothelium-dependent flow-mediated vasodilatation. Methods and Results Seventeen female volunteers 25.1±0.8 years old and 17 age-matched male volunteers were examined. We measured brachial artery diameters noninvasively using a 7.5-MHz ultrasound machine at rest, during reactive hyperemia, and after sublingual nitroglycerin administration. All female subjects were studied three times each, in three different phases of one menstrual cycle (M, menstrual phase; F, follicular phase; and L, luteal phase). Flow-mediated diameter (D) increase (%FMD; ΔD/D×100) in M, when serum estradiol level was low (121.9±12.5 pmol/L), was 11.22±0.58%, and the value was comparable to that in male subjects (10.60±0.75%). %FMD...
Elevated Basic Fibroblast Growth Factor in Pericardial Fluid of Patients With Unstable Angina
Authors: MasatoshiFujita, MasakiIkemoto, MasamichiKishishita, HideoOtani, RyujiNohara, TerumitsuTanaka, Shun-ichiTamaki, ArioYamazato, ShigetakeSasayama
Journal: Circulation (1996)

Background Collateral growth is induced by chemical signals from the ischemic myocardium. We hypothesized that angiogenic growth factors are produced by cardiac tissue; they are diffusible, more concentrated in pericardial fluids, and are increased by myocardial ischemia. Methods and Results With the use of an enzyme-linked immunosorbent assay, we measured the concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in pericardial fluids of 12 patients with unstable angina (group 1) and of 8 patients with nonischemic heart diseases (group 2). The levels of protein in pericardial fluids were quite comparable between the two groups (34±2 versus 32±4 mg/mL). The concentration of bFGF in pericardial fluids in group 1 was 2036±357 pg/mL, significantly (P<.001) higher than the 289±72 pg/mL in group 2. The amount of bFGF per milligram of protein was also significantly (P<.05) higher in group 1 than in group 2 (67±15 versus 12±4 pg/mg). The concentration of VEGF in per...
RETRACTED: Exosome-Derived miR-130a Activates Angiogenesis in Gastric Cancer by Targeting C-MYB in Vascular Endothelial Cells
Authors: Haiou Yang, Haiyang Zhang, Shaohua Ge, Tao Ning, Ming Bai, Jialu Li, Shuang Li, Wu Sun, Ting Deng, Le Zhang, Guoguang Ying, Yi Ba
Journal: Molecular Therapy (2018)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the editors. Molecular Therapy is retracting this article. After investigating concerns of image duplication raised by a reader, evidence for image duplication in identical or altered fashion in Figures 4A, 4G, and S1C was identified. This reuse (and in part, misrepresentation) of data without appropriate attribution represents a severe abuse of the scientific publishing system. The authors do not agree to the retraction. Retraction Notice to: Exosome-Derived miR-130a Activates Angiogenesis in Gastric Cancer by Targeting C-MYB in Vascular Endothelial CellsYang et al.Molecular TherapyMay 23, 2022In Brief(Molecular Therapy 26, 2466–2475, October 2018) Full-Text PDF
Abstract 896: Adjutant therapeutic strategy for sorafenib-resistant hepatocellular carcinoma
Authors: Syue-Wei Peng, Yi-Heng Lin, Ming-Hao Teng, Hung-Cheng Lai, Te-Sheng Chang, Yen-Hua Huang
Journal: Cancer Research (2018)

Abstract Purpose: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the leading cause of cancer mortality worldwide. To date, Sorafenib remains the standard of care for advanced HCCs not amenable to curative therapies such as surgery or local ablation. Unfortunately, clinical efficacy of Sorafenib remains marginal as most HCC patients receiving Sorafenib treatment develop Sorafenib resistance. The recently approved regorafenib is the only rescue therapy for patients who fail Sorafenib treatment. However, the effect of regorafenib is also far from satisfactory. Therefore, new strategies to overcome sorefenib resistance are critically warranted. Recently, one FDA-approved drug, here we tentatively named as “FA”, was shown to suppress different cancer malignancy by various mechanisms including inhibiting the development of drug resistance in cancer. These findings provide a rationale for combination treatment of this FA drug with Sorafenib in Sorafenib-resistant HCC. Results: Two Sorafenib-resistant HCC cell lines of Hep3B and HepG2215 were established. The Sorafenib resistance characteristics of the HCC cells were further verified by western blotting assay detecting protein tyrosine phosphorylation. We also demonstarted the resistant HCC cells expressed stemness-related genes and showed high ability of cell migration and metastasis. Combination use of FA drug and Sorafenib significantly suppressed the cell viability as well as the stemness-related properties of Sorafenib-resistant HCC cells, including stemness-related gene/protein expression, secondary sphere formation, and the cell migration. Conclusion: Combination use of FA drug and Sorafenib would be a potential therapeutic strategy for Sorafenib-resistant HCC treatment. Citation Format: Syue-Wei Peng, Yi-Heng Lin, Ming-Hao Teng, Hung-Cheng Lai, Te-Sheng Chang, Yen-Hua Huang. Adjutant therapeutic strategy for sorafenib-resistant hepatocellular 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 896.
Residual 201Tl Activity in Irreversible Defects as a Marker of Myocardial Viability
Authors: RainerZimmermann, GerhardMall, BernhardRauch, GiselaZimmer, MichaelGabel, JörgZehelein, BerndBubeck, HaraldTillmanns, SiegfriedHagl, WolfgangKübler
Journal: Circulation (1995)

Background The objective of the present study was to characterize the relation between the residual 201Tl activity in irreversible perfusion defects and the extent of irreversible myocardial damage indicated by the volume fraction of myocardial interstitial fibrosis in patients with chronic coronary artery disease. Methods and Results Stress planar 201Tl scintigraphy with tracer reinjection at rest was performed in 37 patients with ≥75% stenosis of the left anterior descending coronary artery, and anteroseptal 201TI activity was quantified by computer-assisted placement of regions of interest from the serial myocardial images. During coronary artery bypass grafting (performed within 6±3 weeks after scintigraphy), two transmural biopsy specimens were taken from the anterior wall of the left ventricle and the amount of interstitial fibrosis was assessed by use of light microscopic morphometry. A wide spectrum of interstitial fibrosis was obtained, ranging from 15 vol% to 60 vol%. Interstitial fibrosis was s...
Abstract 5192: Detection of disseminated prostate cancer cells in bone marrow using tyramide signal amplification
Authors: Sounak Roy, Kenneth C. Valkenburg, Kenneth J. Pienta
Journal: Cancer Research (2018)

Abstract Approximately 28,000 men die of prostate cancer (PCa) each year in the US, and 90-100% of them are due to bone metastasis. It has been demonstrated that PCa cells detach from the primary tumor, “home” to bone, and develop into these incurable metastases. Existing methods of detecting cells early that can lead to bone metastasis have limited sensitivity and current efforts involve liquid biopsy assays to capture and detect disseminated and circulating tumor cells (DTCs and CTCs respectively). A significant challenge during this detection lies in the optimization of the signal-to-noise ratio during immunofluorescent staining. Noise during immunostaining can originate from endogenous immune cells and other bone marrow matrix components and lead to false staining which reduces sensitivity. We have developed an optimized protocol to reduce background noise from these factors while also enhancing signal using tyramide signal amplification (TSA). Following immuno-staining with PCa cell-specific markers, TSA amplifies beyond primary and secondary antibody binding using horseradish peroxidase (HRP) and fluorophore binding. To further apply this novel signal amplification protocol to the visualization of disseminated tumor cells in bone marrow, we will detect, quantify, and image parental and modified PCa cells injected into murine blood. We have previously shown that C-X-C chemokine receptor 4 causes PCa cells to home to bone. We have stably overexpressed CXCR4 in several PCa cell lines and will be able to determine the role of CXCR4 expression on the development of bone metastases. This robust protocol will be quickly modifiable for automated staining to yield higher throughput analysis. Citation Format: Sounak Roy, Kenneth C. Valkenburg, Kenneth J. Pienta. Detection of disseminated prostate cancer cells in bone marrow using tyramide signal amplification [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 5192.