tbuckley/cabot-search huggingface dataset:
Abstract 15289: Stem Cell Therapy in ST-Elevation Myocardial Infarction With Reduced Ejection Fraction: A Multicenter, Randomized, Double-Blind Trial. From MiHeart/AMI Investigators
Authors: Jose C Nicolau, Remo H Furtado, Carlos E Rochitte, Isolmar T Schettert, Hans F Dohmann, Suzana A Silva, Antonio C Carvalho
Journal: Circulation (2016)

Introduction: Left ventricular ejection fraction (LVEF) is a major determinant of long-term prognosis after ST-elevation myocardial infarction (STEMI). STEMI patients with reduced LVEF have poor ou...
Abstract 357: Phosphorylated histone H3 mediates epigenetic regulation of Brf1 and Pol III genes in alcohol-associated breast cancer
Authors: Lei Lu, Zeng Fang, Wen Li, Zhimin He, Shuping Zhong
Journal: Cancer Research (2018)

Abstract Approximately 3.6% human cancers worldwide derive from chronic alcohol drinking, including cancers of breast and multiple other organs. Alcohol intake is consistently associated with an increased risk of BC (breast cancer). Alcohol consumption is more pronounced in ER+ BC cases than in ER- cases. However, the molecular mechanism remains to be determined. RNA polymerase (Pol) III genes, such as 5S rRNA and tRNAs, are elevated in both transformed and tumor cells. Brf1 (TFIIIB-related factor 1), a subunit of TFIIIB complex, specifically regulates Pol III gene transcription. Our studies have demonstrated that Brf1 expression and Pol III gene transcription are increased in alcohol-induced mice liver tumor. Alcohol-induced deregulation of Pol III gene transcription may be fundamental to the development of BC. We have found that alcohol-increased Pol III gene transcription in ER+ BC cells is significantly higher than in ER- normal breast cells and BC cells. The induction is ER dependent. The cellular levels of Brf1 protein and mRNA are increased in ethanol-treated MCF-7 cells. Ethanol markedly stimulates phosphorylation of MSK1 (MSK1ph) and histone H3 (H3ph). Our previous studies demonstrated that MSK1 mediates H3ph. MSK1 mediates ERα expression. Inhibition of MSK1 signal reduces alcohol-induced ERα expression to decrease cellular level of Brf1 and Pol III genes. Repression of Brf1 expression decreases alcohol-induced anchorage-independent cell growth and tumor formation. Furthermore, our analysis indicates that ethanol treatment increases occupancy of ERα to Brf1 promoter. The results by using Co-IP and ChIP assays indicate that MSK1, ERα and Brf1 form a complex to mediate Pol III gene transcription. Studies of human biopsies of BC patients indicate that Brf1 expression is increased in human cases of BC. High expression of Brf1 displays longer overall survival period after Tamoxifen treatment. Co-localization analysis indicate that MSK1ph and H3S10ph localizes in nuclear with Brf1. These results support the idea that alcohol activates MSK1 and induces epigenetic modification of H3ph to enhance ERα and Brf1 expression and Pol III gene transcription, resulting greater phenotypic changes. Together, our studies indicate that ethanol-induced epigenetic modification of H3ph may play a critical role in alcohol-induced cell transformation and alcohol-associated ER+ BC. The project is supported by NIH grants: AA017288, AA021114, AA02324 and AA024169 Citation Format: Lei Lu, Zeng Fang, Wen Li, Zhimin He, Shuping Zhong. Phosphorylated histone H3 mediates epigenetic regulation of Brf1 and Pol III genes in alcohol-associated 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 357.
Abstract 19847: Combination of QRS Duration and JT interval is More Prognostic Than the QT interval for Cardiovascular Death in an Ambulatory Population
Authors: DavidPickham, Le DungHa, AbhaKhandelwal, VerdantPargaonkar, VictorFroelicher
Journal: Circulation (2014)

Background: Few studies have compared the prognostic value of the QT interval and the JT interval for cardiovascular death in an ambulatory population. Hypothesis: We tested the null hypothesis that the prognostic value of the QT interval and the JT interval were the same for cardiovascular death in this ambulatory population. Methods: Resting 12-lead ECGs from 20903 ambulatory subjects at the VA Health System were recorded. Rate corrected QT and JT intervals were grouped by percentiles (75th, 90th, 95th, & 99th); the use of population percentiles allows for generalizability. The primary outcome (CV death) was obtained from state and federal databases. Multivariate Cox Regressions were used to study the associations between the QT interval, JT interval, and cardiovascular death. Results: The majority of subjects (n=18941 (91%)) were men (44 ± 8 years of age) and 9% were women 40 ± 10 years of age). Median follow-up time was 17.5 years. CVD occurred in 4% of subjects (n=884). Univariate analysis shows sign...
Abstract 1733: Wnt antagonists synergize with immune checkpoint inhibitors to enhance anti-tumor responses
Authors: Jenny Ross, Timothy Hoey, Ann Kapoun, John Lewicki, Austin Gurney, Christopher L. Murriel
Journal: Cancer Research (2018)

Abstract Aberrant Wnt signaling through overexpression or activating mutations in Wnt pathway proteins is responsible for the initiation and progression of numerous cancers. While enhanced Wnt signaling has been shown to play a major role in cancer stem cell biology, more recent studies have implicated Wnt in the development of resistance to anti-tumor immune responses. Here, we show that in various syngeneic murine tumor models, targeting Wnt signaling using the Fzd receptor monoclonal antagonist antibody, OMP-18R5 (vantictumab) or the pan-Wnt decoy receptor Fc fusion protein OMP-Fzd8-Fc (ipafricept) in combination with immune checkpoint inhibitors anti-CTLA-4 or anti-PD1 induce synergistic anti-tumor responses leading to decreased tumor volume and increased infiltration of activated CD8+ T cells into the tumor microenvironment. In addition, we show that combined Wnt and immune checkpoint inhibition decrease regulatory T cells (Tregs), enhance cytotoxic T cell activity and increase antigen presentation by APCs. More importantly, we demonstrate that anti-PD1 and the Wnt antagonists decrease immune suppressive myeloid cell populations, which may enhance therapeutic efficacy and anti-tumor responses. Therefore, these results suggest that co-targeting Wnt and immune checkpoint proteins may provide valuable opportunities for novel combination strategies for immunotherapeutic clinical development. Citation Format: Jenny Ross, Timothy Hoey, Ann Kapoun, John Lewicki, Austin Gurney, Christopher L. Murriel. Wnt antagonists synergize with immune checkpoint inhibitors to enhance anti-tumor responses [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 1733.
Abstract 15894: Aortic Flow Patterns and Peak Velocity Assessment Using 4D Flow MRI in Dilated Ascending Aorta With and Without Aortic Valve Stenosis and Regurgitation
Authors: Kenichiro Suwa, Ozair A Rahman, Emilie Bollache, Michael J Rose, Amir A Rahsepar, Hideharu Hayashi, James Carr, Jeremy Collins, Alex Barker, Michael Markl
Journal: Circulation (2016)

Introduction: Aortic valve stenosis (AS) and regurgitation (AR) are associated with ascending aortic (AAo) dilatation. However, patients can develop AAo dilatation even with neither AS nor AR (no AS/AR). Purpose: To characterize differences in AAo flow patterns and velocity between patients with AS, AR, and no AS/AR all with dilated AAo, and healthy controls using 4D flow MRI. Methods: Eight patients with moderate to severe AS (72±9 years, 8 men, mid AAo diameter [MAAd]: 41±2mm), 33 patients with moderate to severe AR (62±14 years, 25 men, MAAd: 44±5 mm), 30 patients with no AS/AR (63±9 years, 22 men, MAAd: 42±4 mm) were identified via IRB-approved retrospective chart review. Twenty five healthy controls (57±10 years, 19 men, MAAd: 33±4 mm) were selected from the existing database. All subjects underwent in-vivo 4D flow MRI. AAo flow patterns were visualized with pathlines and were graded for the presence of vortex and helix flow using a 3 point scale (1, no vortex/mild helix [flow rotation < 180°]; 2, 1-...
Registration of Three-Dimensional Left Atrial Computed Tomographic Images With Projection Images Obtained Using Fluoroscopy
Authors: JasbirSra, DavidKrum, AngelaMalloy, MelissaVass, BarryBelanger, ElisabethSoubelet, RegisVaillant, MasoodAkhtar
Journal: Circulation (2005)

Background— Anatomic structures such as the left atrium and the pulmonary veins (PVs) are not delineated by fluoroscopy because there is no contrast differentiation between them and the surrounding anatomy. Representation of an anatomic structure via a 3D model obtained from computed tomography (CT) imaging and subsequent projection of these images over the fluoroscopy system may help in navigation of the mapping and ablation catheter to the appropriate sites during electrophysiology procedures. Methods and Results— In this feasibility study, in vitro experiments were performed with a plastic heart model (phantom) with 2 catheters or radiopaque platinum beads placed in the phantom at the time of CT imaging and fluoroscopy. Subsequently, 20 consecutive patients underwent contrast-enhanced, ECG-gated CT scanning. Left atrial volumes were generated from the reconstructed data at &75% of the R-R interval during the cardiac cycle. Similarly, the superior vena cava and the coronary sinus were also reconstructed...
Abnormal Termination of Ca2+ Release Is a Common Defect of RyR2 Mutations Associated With Cardiomyopathies
Authors: YijunTang, XixiTian, RuiwuWang, MichaelFill, S.R. WayneChen
Journal: Circulation Research (2012)

Rationale:Naturally occurring mutations in the cardiac ryanodine receptor (RyR2) have been associated with both cardiac arrhythmias and cardiomyopathies. It is clear that delayed afterdepolarization resulting from abnormal activation of sarcoplasmic reticulum Ca2+ release is the primary cause of RyR2-associated cardiac arrhythmias. However, the mechanism underlying RyR2-associated cardiomyopathies is completely unknown. Objective:In the present study, we investigate the role of the NH2-terminal region of RyR2 in and the impact of a number of cardiomyopathy-associated RyR2 mutations on the termination of Ca2+ release. Methods and Results:The 35-residue exon-3 region of RyR2 is associated with dilated cardiomyopathy. Single-cell luminal Ca2+ imaging revealed that the deletion of the first 305 NH2-terminal residues encompassing exon-3 or the deletion of exon-3 itself markedly reduced the luminal Ca2+ threshold at which Ca2+ release terminates and increased the fractional Ca2+ release. Single-cell cytosolic C...
Elevated Levels of cAMP Inhibit Protein Kinase C– Independent Mechanisms of Endothelial Platelet-Derived Growth Factor–B Chain and Intercellular Adhesion Molecule-1 Gene Induction by Lysophosphatidylcholine
Authors: HiroshiOchi, NoriakiKume, EiichiroNishi, ToruKita
Journal: Circulation Research (1995)

Abstract Lysophosphatidylcholine (lyso-PC), a polar phospholipid product increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to differentially induce functional intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 and mRNA for platelet-derived growth factor (PDGF)–A and –B chains and heparin-binding epidermal growth factor–like growth factor in various cultured endothelial cells. In this study, we have demonstrated increased expression of cell- and matrix-associated forms of PDGF–B chain (PDGF-B) protein elicited by lyso-PC and further characterized potential signal transduction mechanisms responsible for lyso-PC–induced gene expression, focusing on PDGF-B and ICAM-1 genes in cultured human umbilical vein endothelial cell models. Cycloheximide almost completely inhibited PDGF-B but not ICAM-1 mRNA induction elicited by lyso-PC, suggesting that dependence on de novo protein synthesis for PDGF-B is different from that for ICAM-1. Prolonged exposure t...
Abstract 18758: Hypertrophy of Neonatal Cardiomyocytes in 3D Engineered Cardiac Tissue Induced by Activation of mTOR Signaling
Authors: Christopher Jackman, Nenad Bursac
Journal: Circulation (2015)

Introduction: An in vitro system inducing robust hypertrophy of neonatal cardiomyocytes (CM) is highly useful for studying cardiac development and improving function of engineered cardiac tissues. Our objective was to establish a methodologically simple way to hypertrophy CMs in densely-packed engineered 3D tissues, and to identify signaling pathways involved. Hypothesis: We hypothesized that hypertrophy could be induced by enhancing mass transport of nutrients to CMs in degradable hydrogel, and this effect would act through mTOR signaling pathway. Methods: Neonatal rat CMs were embedded in fibrin-based hydrogel to form cardiac microbundles, which were cultured for 2 weeks on either a static or dynamic platform. Results: Dynamic culture increases the volume occupied by CMs (Fig 1A), quantified as 2.3-fold increase in CM cross-sectional area (Fig 1B). The amount of sarcomeric proteins was increased by 2.4 to 4.6 fold in dynamically cultured tissues (Fig 1C). mTOR phosphorylation was increased by 51% upon transfer to dynamic culture, and decreased by 42% upon transfer to static culture (Fig 1D). Dynamic cultures generated higher contractile force (2.09 +/- 0.10 mN vs. 0.65 +/- 0.11 mN), and inhibition of mTOR with rapamycin attenuated the effect (1.27 +/- 0.07 mN, Fig 1E, n=12). Conduction velocity of action potentials was increased from 38.1 +/- 2.2 cm/s in static cultures to 51.7 +/- 2.8 cm/s in dynamic cultures (n=19). Conclusions: Dynamic culture of 3D cardiac microtissues results in significant mTOR-mediated CM hypertrophy and contractile force increase without the need for biophysical or growth factor stimulation. For the first time, we show optimized cardiac microtissues with diameter and specific contractile forces similar to trabecular muscle of the adult myocardium (~200 um diameter, 61.5 mN/mm2).
Abstract 3003: Loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities
Authors: Caitlin A. Nichols, Brenton R. Paolella, William J. Gibson, Meredith S. Brown, Laura M. Urbanski, Jack A. Kosmicki, John P. Busanovich, Ashton C. Berger, Galen F. Gao, Andrew D. Cherniack, Rameen Beroukhim
Journal: Cancer Research (2018)

Abstract Despite progress in precision cancer drug discovery, few highly selective therapies exist in the clinic, creating the need for additional therapeutic targets. We have shown that copy number alterations (CNAs) in essential genes represent novel non-driver gene vulnerabilities in cancer. Here we interrogate loss of heterozygosity (LOH) of single nucleotide polymorphisms (SNPs) located in essential genes as a novel class of candidate therapeutic targets. We hypothesized that monoallelic inactivation of the single allele retained in tumors can selectively kill cancer cells, while somatic cells, which retain both alleles, will tolerate allele-specific knockout. We identified a list of over 1000 common missense SNPs in at least 1500 essential genes that undergo LOH in cancer and performed proof-of-concept allele-specific gene inactivation in two essential genes (PRIM1 and EXOSC8) using CRISPR-Cas9. We assessed the fidelity of allele-specific gene disruption and its cellular effects on gene expression, cell growth, and cell death in LOH and non-LOH genetic contexts. We determined that allele-specific knockout of PRIM1 and EXOSC8 selectively targets cells harboring only the single targeted allele of that gene. In cells retaining only the sensitive allele, we observed decreased target gene expression and cell viability that did not occur in cells retaining the resistant allele. We conclude that allele-selective inactivation of essential genes in regions of LOH (such as PRIM1 and EXOSC8) represents a novel candidate therapeutic strategy in cancer. The corresponding class of novel non-driver cancer vulnerabilities may provide a rich source of targets for future precision therapeutic development using gene editing, RNAi, or small-molecule approaches. Citation Format: Caitlin A. Nichols, Brenton R. Paolella, William J. Gibson, Meredith S. Brown, Laura M. Urbanski, Jack A. Kosmicki, John P. Busanovich, Ashton C. Berger, Galen F. Gao, Andrew D. Cherniack, Rameen Beroukhim. Loss of heterozygosity of essential genes represents a novel class of cancer vulnerabilities [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 3003.
Abstract 5149: CMTM6 is a potential metastasis regulator of EWS cells
Authors: Yuko Nishiyama, Naofumi Asano, Yuko Fujiwara, Tadashi Kondou, Naoto Tsuchiya
Journal: Cancer Research (2018)

Abstract Ewing's sarcoma (EWS) is a highly aggressive and metastatic malignant tumor of bone and soft tissues, whose incidence is highest in children and young adulthood. Control of metastasis based on the molecular targeting contributes to improve patient prognosis. To this end, we screened expression of microRNAs in clinical samples to identify target molecules, which regulate malignant properties of EWS cells. Microarray analysis indicated that miR-451a is significantly downregulated in the cases with poor prognosis. Although miR-451a did not affect cell proliferation, it strongly repressed migration of EWS cells. Gene expression analysis revealed that miR-451a targeted CMTM6, a chemokine-like membrane protein with unknown function. Depletion of CMTM6 by siRNAs strongly inhibited migration of EWS cells. Our data suggest that at least the expression of miR-451a and CMTM6 is involved in metastasis onset. Citation Format: Yuko Nishiyama, Naofumi Asano, Yuko Fujiwara, Tadashi Kondou, Naoto Tsuchiya. CMTM6 is a potential metastasis regulator of EWS 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 5149.
The Constitutive Function of Native TRPC3 Channels Modulates Vascular Cell Adhesion Molecule-1 Expression in Coronary Endothelial Cells Through Nuclear Factor κB Signaling
Authors: KathrynSmedlund, Jean-YvesTano, GuillermoVazquez
Journal: Circulation Research (2010)

Rationale: Upregulation of endothelial vascular cell adhesion molecule (VCAM)-1 and the subsequent increase in monocyte recruitment constitute critical events in atherogenesis. We have recently shown that in human coronary artery endothelial cells (HCAECs) regulated expression of VCAM-1 depends, to a significant extent, on expression and function of the Ca2+-permeable channel transient receptor potential canonical (TRPC)3, regardless of the ability of the stimulatory signal to induce regulated Ca2+ influx, leading to the hypothesis that TRPC3 constitutive, rather than regulated function, contributes to the underlying signaling mechanism. Objective: The present studies addressed this important question and gathered mechanistic insight on the signaling coupling constitutive TRPC3 function to VCAM-1 expression. Methods and Results: In HCAECs, maneuvers that prevent Ca2+ influx or knockdown of TRPC3 markedly reduced tumor necrosis factor (TNF)α-induced VCAM-1 and monocyte adhesion. TNFα also induced TRPC3 exp...
Abstract 20352: How Durable is Repair of Degenerative Mitral Regurgitation in the Young?
Authors: Vincent Chan, Elsayed Elmistekawy, Marc Ruel, Mark Hynes, Thierry Mesana
Journal: Circulation (2016)

Introduction: The purpose of this study was to determine the performance of mitral repair in young patients with degenerative disease. Some have described a linear rate of valve repair failure, which, if accurate, would predict inevitable valve reoperation for young patients. This study was performed to determine the durability of repair of degenerative MR according to patient age. Hypothesis: Failure of mitral valve repair is non-linear and is not influenced by the age of the patient presenting to surgery. Methods: Between 2001-2016, 894 patients underwent repair of degenerative MR. Of these, 40 were <40 years of age at the time of surgery; 87 were between 40-50 years; 187 were between 51-60 years; 263 were between 61-70 years and 317 were ?70 at the time of surgery. Patients were assessed in a dedicated valve clinic and follow-up was for 5.0±3.8 years (extended to 13.8 years). Results: Perioperative mortality was 0.3%. Younger patients were more likely to present to surgery with bileaflet prolapse compa...
Abstract 870: Effects of epigenetic modifier inhibitors on AML cell sensitivity to differentiation therapy
Authors: Kalsi K. Heimdal, Edjay Ralph A. Hernandez, Heidi J. Gill Super
Journal: Cancer Research (2018)

Abstract Human acute myeloid leukemia (AML), the most common type of acute leukemia, has approximately eight subtypes, many of which have poor prognosis. Most of these subtypes are associated with specific, recurrent chromosome translocations. These translocations result in fusion genes, which encode oncoproteins that block differentiation and promote proliferation of immature cells. The Myeloid Lymphoid Leukemia gene (MLL) is frequently involved in these translocations, and is considered a driver of the AML. Differentiation promoting drugs, such as all-trans-retinoic acid (ATRA) are an attractive alternative to cytotoxic chemotherapy, but few types of AML, other than acute promyelocytic leukemia (APL), respond to ATRA. We hypothesize that specific genes must be activated or inhibited in AML for drugs like ATRA to induce differentiation, and that gene activation or inhibition may be the result of specific epigenetic modification. We also hypothesize that AML with different genetic alterations may respond differently to specific epigenetic inhibitors. Our initial studies have focused on one AML cell line, MV4;11, with alterations in the MLL gene, and one non-MLL related AML cell line, U937. MV4;11 and U937 were treated with specific epigenetic modifiers, including tranylcypromine (TCP), an inhibitor of histone demethylase KMD1A/LSD1, and CI-994, a general histone deacetylase inhibitor. Evidence for differentiation was noted in a variety of assays, including reduced cell proliferation as measured directly and by MTT assay, upregulation of myeloid-specific cell surface markers such as CD11b as measured by fluorescence-activated cell sorting (FACS), and myeloid-related nuclear morphological changes noted with cytospin analysis of cells. Both CI-994 and TCP seemed to sensitize U937 cells to differentiate when treated with ATRA as measured by all indicators of differentiation. MV4;11 cells were sensitized to differentiation by CI-994 with or without ATRA, although there was no indication of CD11b upregulation. However, MV4;11 was not sensitized by TCP to differentiate with ATRA. These experiments suggest epigenetic inhibitors may increase sensitivity to differentiation therapy, but that the response may still be dependent on the specific genetic alteration driving the AML. Our studies suggest that in MLL-driven leukemia, the MLL fusion oncoprotein may override genetic manipulation resulting from treatment with epigenetic inhibitors, preventing differentiation by ATRA. Citation Format: Kalsi K. Heimdal, Edjay Ralph A. Hernandez, Heidi J. Gill Super. Effects of epigenetic modifier inhibitors on AML cell sensitivity to differentiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 870.