tbuckley/cabot-search huggingface dataset:
Abstract 1570: Loss of mismatch repair protein MSH6 sensitizes diffuse-type gastric cancer cells to DNA-PKcs inhibitor KU60648
Authors: Vaidehi Krishnan, Wen Min Lau, Eileen Teng, Jin Wei Tan, Haresh Sankar, Debbie Xiu En Lim, Crystal Kok Yan Pang, Ming Teh, Jimmy Bok Yan So, Patrick Tan, Yoshiaki Ito, Shing Leng Chan
Journal: Cancer Research (2018)

Abstract Diffuse-type gastric cancer (DGC) is a histologic subtype characterized by poor cellular cohesiveness, increased metastasis and poor prognosis. As preclinical models of DGC that reliably predict clinical activity of novel compounds are lacking, we generated patient-derived xenograft (PDX) models using malignant ascites from DGC patients that closely recapitulated the primary cancer. To uncover novel therapeutic targets, we applied the concept of synthetic lethality and asked if DGCs require DNA repair proteins for survival. Major DNA repair kinases ATM, ATR and DNA-PKcs in established DGC cell lines and ex vivo cell lines from PDXs (GAGA3, GAGA6 and GAS24) were inhibited using small-molecule inhibitors KU55933, VE-821 and KU60648, respectively. Interestingly, most diffuse-type gastric cells exhibited elevated lethality when DNA-PKcs, a central kinase that regulates the non-homologous end joining pathway (NHEJ), was inhibited by KU60648 as compared to the nontransformed gastric epithelial line, HFE-145. We confirmed that genetic depletion of DNA-PKcs by siRNA resulted in cell death in two PDX lines GAS24 and GAGA6 cells but not in HFE-145 cells, suggesting the dependence of these cells on DNA-PKcs for survival. Two mechanisms appear to sensitize DGC cells to DNA-PKcs inhibition; firstly, impaired homologous recombination repair in GAS24 and GAGA6 as shown by compromised ability to resolve radiation-induced γH2AX foci, and secondly, transcriptional downregulation of the mismatch repair protein, MSH6, in GAGA3 and GAGA6. Knockdown of MSH6 in GAS24 cells enhanced their sensitivity to KU60648, suggesting a functional link between MSH6 and DNA-PK function. Lastly, to develop MSH6 as a biomarker for predicting DNA-PKcs sensitivity, we analyzed MSH6 levels by immunohistochemical staining in formalin-fixed, paraffin-embedded (FFPE) tissue sample sections derived from PDXs. In these preliminary studies, MSH6 expression was lower with high heterogeneity in GAGA3 and GAGA6 compared to GAS24. In this study, we show for the first time the downregulation of DNA mismatch protein MSH6 in sporadic diffuse gastric cancer, and its potential as a therapeutic predictor for DNA-PKcs inhibition treatment. Citation Format: Vaidehi Krishnan, Wen Min Lau, Eileen Teng, Jin Wei Tan, Haresh Sankar, Debbie Xiu En Lim, Crystal Kok Yan Pang, Ming Teh, Jimmy Bok Yan So, Patrick Tan, Yoshiaki Ito, Shing Leng Chan. Loss of mismatch repair protein MSH6 sensitizes diffuse-type gastric cancer cells to DNA-PKcs inhibitor KU60648 [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 1570.
Novel Technique to Prevent Left Phrenic Nerve Injury During Epicardial Catheter Ablation
Authors: SeiichiroMatsuo, PierreJaïs, SebastienKnecht, Kang-TengLim, MélèzeHocini, NicolasDerval, MatthewWright, FredericSacher, MichelHaïssaguerre
Journal: Circulation (2008)
Abstract 5585: Extracellular vesicle poly(A)+ RNA analysis for cancer biomarker screening
Authors: Taku Murakami, Cindy Yamamoto, Mieko Ogura, Melanie Oakes, Hiroshi Harada
Journal: Cancer Research (2018)

Abstract Extracellular vesicles (EV) are a promising biomarker source and present in several biological fluids such as plasma (8.0 x 1011 particles/mL, 121 ± 2.3 nm in diameter) and urine (1.1 x 1011 particles/mL, 152 ± 11.2 nm in diameter). In order to streamline marker screening and validation in translational studies, we developed and optimized high throughput filter-based EV capture, poly(A)+ RNA isolation and gene expression assay protocols for RT-qPCR and RNA-seq. First, we confirmed that plasma and urinary EV mRNA profiles (12 to 15 genes by RT-qPCR) are stable up to 1 week at 4°C, and up to 5 repeats of freeze-thaw cycles, and urinary EV was stable up to 10 months at -80°C, indicating EV mRNA could be a useful biomarker source. Although EV mRNA is less abundant (550 pg mRNA from 1 mL plasma) compared to tissue mRNA or EV non-coding RNA, the optimized protocol allows quantification of about 9,000 genes in average by RNA-seq from 2 mL frozen plasma (N=3) with high reproducibility among the replicates (Spearman correlation: 0.9086 to 0.9326) and between the commercial EV kits (Spearman correlation: 0.9207 to 0.9683). About 77% of the 1000 most abundant genes in plasma EV are expressed ubiquitously throughout various organs but some are expressed specifically in blood (12%), spleen (4.4%), esophagus mucosa (1.2%), etc. according to the Genotype-Tissue Expression (GTEx) database. In urinary EV, other than ubiquitously expressed genes (88%), the genes specific to liver (1.5%), bladder (1%), brain (1%), etc. are present. These data suggest EV mRNA are released from various organs and circulating in biological fluids. The protocol was further applied to biomarker discovery for bladder cancer, and differential gene expression analysis of EV mRNA was conducted using bladder cancer (N=4), cancer remission (N=2), and healthy/disease control urine samples (N=4). Ingenuity pathway analysis indicated that cancer-related molecular and cellular functions are activated in bladder cancer urinary EV but not in remission, while immune-related functions are activated both in cancer and remission. These data indicate that EV mRNA is a promising biomarker source for cancer biomarker screening, and could be used in translational studies. Citation Format: Taku Murakami, Cindy Yamamoto, Mieko Ogura, Melanie Oakes, Hiroshi Harada. Extracellular vesicle poly(A)+ RNA analysis for cancer biomarker screening [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 5585.
Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity
Authors: Silvia Preite, Jennifer L. Cannons, Andrea J. Radtke, Ivan Vujkovic-Cvijin, Julio Gomez-Rodriguez, Stefano Volpi, Bonnie Huang, Jun Cheng, Nicholas Collins, Julie Reilley, Robin Handon, Kerry Dobbs, Lutfi Huq, Indu Raman, Chengsong Zhu, Quan-Zhen Li, Ming O. Li, Stefania Pittaluga, Gulbu Uzel, Luigi D. Notarangelo, Yasmine Belkaid, Ronald N. Germain, Pamela L. Schwartzberg
Journal: Nature Immunology (2018)
Pathophysiology of Coronary Artery Disease
Authors: PeterLibby, PierreTheroux
Journal: Circulation (2005)

During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well. Aggressive management of modifiable risk factors reduces cardiovascular events and should accompany appropriate revascularization. We now recognize that disruption of plaques that may not produce critical stenoses causes many acute coronary syndromes (ACS). The disrupted plaque represents a “solid-state” stimulus to thrombosis. Alte...
Abstract 11040: Poloxamer 188 Protects Endothelial Cells From Hypoxia/Reoxygenation Injury - Implications for Cardio- and Neuroprotection After Cardiac Arrest
Authors: Michele M Salzman, Aqeela Afzal, Qunli Cheng, Frank S Bates, Matthias L Riess
Journal: Circulation (2015)

Introduction: Cardiac arrest is a leading cause of death. Even with the best CPR, many patients die or suffer severe cardio-cerebral damage. Reintroduction of blood flow at the start of CPR after systemic ischemia may cause additional injury to organs such as the heart and brain beyond that caused by the ischemia itself. Determining the mechanism of action of a compound administered during CPR on the cellular dysfunction caused by ischemia/reperfusion could improve CPR practices in the future. Hypothesis: Poloxamer 188 (P188), with its unique hydro-/lipophilic chemical properties, protects coronary and cerebral endothelial cells against hypoxia/reoxygenation (H/R) injury. Methods: Endothelial cells (human coronary artery [HCAECs] and rat brain [RBECs]) underwent 2 hrs hypoxia (1% O2) then 2 hrs reoxygenation ± P188. Endpoints were markers of cellular injury (lactate dehydrogenase [LDH] release, mitochondrial dehydrogenase activity), proliferation, and nitric oxide (NO) release. Statistics: Student t-test followed by SNK post hoc comparisons, *p&lt;0.05 vs control, † vs normoxia. Results: In HCAECs, H/R caused significant LDH release compared to cells in normoxic conditions (†0.774±0.084 vs 0.562±0.141 abs/mg protein; n=5). P188 significantly decreased LDH release in both hypoxic and normoxic conditions (*0.215±0.024 vs *0.273±0.02). P188 also significantly attenuated decreased mitochondrial dehydrogenase activity caused by H/R (*0.379±0.015 vs 0.468±0.035 abs/mg protein). NO measurement by DAF-2DA fluorescence showed higher levels in cells treated with P188 upon reoxygenation than controls (*164,944±6,716 vs 139,942±2,511 RFUs). In proliferation assays of HCAECs and RBECs, there was significantly lower proliferation following H/R than during normoxia (HCAECs: 16,030±716 vs †7,500±465; RBECs: 13,563±1,251 vs †7,323±297 cells/well). This decrease was dose-dependently attenuated by P188 when compared to control (HCAECs: 1μM, *8,523±495; 1mM, *8,827±375. RBECs: 1μM, *7,782±274; 1mM, *8,930±177). Conclusions: HCAECs and RBECs were protected by P188 against H/R, and P188 also increased NO release in HCAECs. P188 protection of cardiomyocytes and neurons may be mediated by the preservation of NO release from the endothelium.
Abstract 12639: Ventricular Energetics in Fontan Circulation: A Potential Therapeutic Target for Preserving Myocardial Function
Authors: HirofumiSaiki, SeikoKuwata, ClaraKurishima, YoichiIwamoto, HirotakaIshido, SatoshiMasutani, HideakiSenzaki
Journal: Circulation (2014)

Background: Cardiac dysfunction is one of the vital determinants of long-term outcome in patients with Fontan circulation. However, underlying mechanisms for the development of ventricular dysfunction remain unclear. Energy depletion is a key feature of failing ventricles, and heart failure alters ventricular energy consumption for intracellular Ca2+ handling during excitation-contraction (E-C) coupling. We hypothesized that ventricular energetic efficiency for Ca2+ handling as well as for external work production is reduced in Fontan circulation compared with biventricular circulation. Method: A pressure-volume (PV) relationship was constructed during cardiac catheterization in 14 Fontan patients and 29 controls with biventricular heart. Myocardial oxygen consumption (MVO2) was estimated by PV area (PVA), and ventricular mechanical efficiency (Ve) was calculated as the ratio of stroke work (SW) and PVA. The fraction of the total amount of Ca2+ recycled by the sarcoplasmic reticulum during E-C coupling, t...
Abstract 20691: Telehealth Heart Failure Program Associated With Improved Quality of Life
Authors: Mark R Stampehl, Stephen H Jennison, Claire Call, Susan Hickey, Jodi Koehler, Holly S Norman
Journal: Circulation (2017)

Introduction: A telehealth care management program was evaluated for affects on quality of life (QoL) and patient activation in a post-acute heart failure rural population. Hypothesis: A telehealth...
Abstract 1263: TGF-ß inhibition as a novel strategy to prevent breast cancer brain metastases
Authors: Mark V. Pinti
Journal: Cancer Research (2018)

Abstract Background: Incidence of breast cancer brain metastases (BCBM) is on the rise due to improved management of systemic disease and ranges from 15-20% in women with disseminated breast cancer. Common chemotherapeutic strategies have limited efficacy for brain metastases due to the presence of the blood brain barrier (BBB). Prevention of metastasis after diagnosis of primary breast tumors may lead to new treatment strategies. TGF-ß is a biomolecule in the metastatic pathway and inhibition of its expression can be achieved by treatment with the antihypertensive agent Losartan. Herein we hypothesized that treatment with Losartan will decrease metastatic burden and improve survival in a preclinical model BCBM. Methods: Athymic female nude mice were separated into four groups as follows: Vehicle, (saline, 50µL/day), SB431542 (Inhibitor, 5mg/kg/day), Low Dose Losartan (10mg/kg/day) and High Dose Losartan (25mg/kg/day). On day 7 mice were intracardially injected with 175,000 cells of either JIMT-1-Br-LUC-GFP (HER2+) or MDA-MB-231Br-LUC (TNBC) breast cancer cell lines. Tumor burden was monitored once weekly utilizing bioluminescent imaging. Mice were allowed to progress until neurological symptoms arose. Following euthanasia, brains were extracted, sectioned and analyzed to determine number of metastatic lesions and size. Results: With regard to survival, no significance was shown in the JIMT-1 (HER2+) metastatic model. The MDA-MB-231Br (TNBC) model demonstrated an increase in survival in all treatment groups compared to vehicle. End time-point analyses showed no difference in metastases number in either model, however, the low dose treatment group in the MDA-MB-231Br model had a smaller brain burden of metastases than high dose treatment as well as inhibitor treatment. Conclusions: Losartan reduced metastatic seeding in the MDA-MB-231Br (TNBC) brain metastasis model, but had little to no effect in the JIMT-1 (HER2+) model. Citation Format: Mark V. Pinti. TGF-ß inhibition as a novel strategy to prevent breast cancer brain metastases [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 1263.
SCN5A Polymorphism Restores Trafficking of a Brugada Syndrome Mutation on a Separate Gene
Authors: StevenPoelzing, CinziaForleo, MelissaSamodell, LynnDudash, SandroSorrentino, MatteoAnaclerio, RossellaTroccoli, MassimoIacoviello, RobertaRomito, PietroGuida, MohamedChahine, MariavittoriaPitzalis, IsabelleDeschênes
Journal: Circulation (2006)

Background— Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation. Methods and Results— In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy t...
Effects of Long-Term Nitroglycerin Treatment on Endothelial Nitric Oxide Synthase (NOS III) Gene Expression, NOS III–Mediated Superoxide Production, and Vascular NO Bioavailability
Authors: ThomasMünzel, HuigeLi, HankeMollnau, UlrichHink, EdiMatheis, MarkHartmann, MathiasOelze, MikhailSkatchkov, AscanWarnholtz, LindaDuncker, ThomasMeinertz, UlrichFörstermann
Journal: Circulation Research (2000)

Abstract—Long-term nitroglycerin (NTG) treatment has been shown to be associated with cross-tolerance to endothelium-dependent vasodilators. It may involve increased production of reactive oxygen species (such as superoxide, O2·−) that rapidly inactivate the nitric oxide (NO) released from the endothelial cells. It remains to be elucidated, however, whether long-term treatment with NTG alters the activity and expression of the endothelial NO synthase (NOS III) and whether this enzyme can contribute to O2·− formation. We studied the influence of long-term NTG treatment on the expression of NOS III as assessed by RNase protection assay and Western blot. Tolerance was measured ex vivo in organ chamber experiments with rat aortic rings. O2·− and NO formation were quantified using lucigenin- and Cypridina luciferin analog–enhanced chemiluminescence as well as electron spin resonance (ESR) spectroscopy. Treatment of Wistar rats with NTG (Alzet osmotic minipumps, NTG concentration 10 μg · kg−1 · min−1) for 3 day...
Abstract 910: Mechanisms of Ewing sarcoma resistance to LSD1 inhibition
Authors: Kathleen I. Pishas, Sunil Sharma, Stephen L. Lessnick
Journal: Cancer Research (2018)

Abstract Given the modest efficacy of current sarcoma therapeutic modalities, there is a major unmet clinical need for the translation of novel agents to tackle the burden of Ewing sarcoma (pediatric and young adolescent bone cancer). We have recently shown that therapeutic targeting of LSD1, a highly expressed lysine specific demethylase, with the reversible small molecule inhibitor SP-2509, comprehensively disrupts the global transcriptional function of EWS-FLI, and significantly impairs the growth of Ewing sarcoma cell lines both in vitro and in vivo. Prior to clinical trial evaluation, the goal of this study was to elucidate mechanisms of Ewing sarcoma SP-2509 drug resistance. In order to investigate SP-2509 resistance, A673 Ewing sarcoma cells were cultured in escalating concentrations of SP-2509 for 8 months. Cell Titer Glo analysis revealed that these SP-2509 drug resistant (DR) cells were 54.9 fold more resistant to SP-2509 compared to parental A673 cells (72hr IC50 0.138μM versus 7.586μM). SP-2509 DR cells also exhibited a significant decrease in their ability to form anchorage-independent colonies in soft agar. Whole exome (250X coverage) and RNA seq analysis of parental and SP-2509 DR A673 cells revealed 25 drug induced mutations, with 88% of the whole cell population harboring a Glu53* stop-gain mutation in MRPL45 (mitochondrial ribosomal protein L45). In addition, SP-2509 DR cells displayed a distinct transcriptomic profile, with 3250/2376 genes significantly up/down regulated (≥1.5 fold) in SP-2509 DR cells compared to parental controls. KEGG Pathway analysis revealed that the genes were highly enriched for hepatic stellate cell activation/interferon signaling and cholesterol biosynthesis respectively. Lastly, SP-2509 DR cells were shown to be equally sensitive to etoposide, resistant to vincristine/doxorubicin and surprisingly more sensitive to the HDAC inhibitors vorinostat and entinostat compared to parental A673 cells. Together, our preliminary findings provide key insights into the mechanisms of SP-2509 drug resistance, information of which can be used to find combinatorial agents that can potentially be used to circumvent resistant clones to achieve maximal therapeutic effect. Citation Format: Kathleen I. Pishas, Sunil Sharma, Stephen L. Lessnick. Mechanisms of Ewing sarcoma resistance to LSD1 inhibition [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 910.
Endothelial Replacement and Angiogenesis in Arteriosclerotic Lesions of Allografts Are Contributed by Circulating Progenitor Cells
Authors: YanhuaHu, FergusDavison, ZhongyiZhang, QingboXu
Journal: Circulation (2003)

Background— Endothelial regeneration and angiogenesis in the intima of the arterial wall are key events in the pathogenesis of transplantation arteriosclerosis. The traditional hypothesis that damaged endothelial cells are replaced by remaining cells of the donor vessel has been challenged by recent observations, but the cell origins of large arteries and microvessels are still not well established. Methods and Results— Aortic segments were allografted between Balb/c and TIE2-LacZ (C57BL/6) mice expressing β-galactosidase (gal) in endothelial cells. β-gal+ cells in TIE2-LacZ vessels grafted to Balb/c mice completely disappeared, whereas the positive cells found in Balb/c aorta allografted into TIE2-LacZ mice 4 weeks after surgery indicated a host origin. En face analysis of allograft vessels displayed a unique distribution of β-gal+ cells on the surface at 3 days, 1 week, and 4 weeks. Interestingly, 35±19% β-gal+ cells were found in arterial segments allografted into chimeric mice with TIE2-LacZ bone marr...
Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo
Authors: ZhejunCai, YeDing, MiaoZhang, QiulunLu, ShengnanWu, HuaipingZhu, PingSong, Ming-HuiZou
Journal: Circulation Research (2016)

Rationale:Atherosclerotic calcification is highly linked with plaque rapture. How calcification is regulated is poorly characterized. Objective:We sought to determine the contributions of AMP-activated protein kinase (AMPK) in atherosclerotic calcification. Methods and Results:Aortic calcification was evaluated in aortic roots and brachiocephalic arteries of atherosclerotic prone ApoE−/− mice or in mice with dual deficiencies of ApoE and AMPKα isoforms in whole body (ApoE−/−/AMPKα1−/− and ApoE−/−/AMPKα2−/−) or vascular smooth muscle cell (VSMC)–specific or macrophage-specific knockout of AMPKα1 fed with Western diet for 24 weeks. Genetic deficiency of AMPKα1 but not of AMPKα2 promoted atherosclerotic calcification and the expression of Runx2 (Runt-related transcription factor). Conversely, chronic administration of metformin, which activated AMPK, markedly reduced atherosclerotic calcification and Runx2 expression in ApoE−/− mice but had less effects in ApoE−/−/AMPKα1−/− mice. Furthermore, VSMC-specific b...
Abstract 9904: Endothelial Function is Impaired in Subjects With Decreased Frequency of Tooth Brushing
Authors: MasatoKajikawa, YukihitoHigashi, TatsuyaMaruhashi, YumikoIwamoto, AkimichiIwamoto, NozomuOda, TakeshiMatsumoto, TakayukiHidaka, AyumuNakashima, KensukeNoma, AkiraTaguchi, YasukiKihara
Journal: Circulation (2014)

Introduction: Clinical studies have shown a link between oral health, especially periodontitis, and cardiovascular disease. Poor oral health behavior is associated with increasing risk of cardiovascular disease. Several investigators, including us, have shown that periodontitis is associated with endothelial dysfunction and that treatment of periodontitis improves endothelial function in patients with atherosclerosis as well as in healthy subjects. However, there is no information on the association between oral health behavior and endothelial function. The purpose of this study was to determine the relationships between oral health behavior and endothelial function. Methods and Results: We had a questionnaire about oral health behavior, frequency of tooth brushing, and measured vascular function, flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 190 subjects who underwent health examinations (mean age, 57±18 years), including patients with cardiovascular diseases. We divided the...