tbuckley/cabot-search huggingface dataset:
Abstract 328: ES1 Is A Novel Mitochondrial Protein Protecting The Heart Via Direct Regulation Of Mitochondrial Energy Metabolism
Authors: QinqiangLong, HuanYang, YiqunZhou, AibingWang, LanHe, YuquanLi, TeayounKim, YishuDing, OlgaZhelyabovska, QinglinYang
Journal: Circulation Research (2014)

Defects in the myocardial energy metabolism have been linked to pathological cardiac hypertrophy and congestive heart failure. However, the regulation of myocardial energy metabolism remains obscure. ATP synthase is an enzyme complex in the mitochondria and plays a central role in energy metabolism. In this study, we identified ES1, a mitochondrial protein with unknown function, as a key determinant of myocardial energy metabolism via controlling ATP synthase activities. We uncovered that ES1 interacts with both α and β subunit of ATP synthase, and its expression levels in H9C2 cardiomyocytes were directly correlated to ATP synthesis and inversely to ATP hydrolysis. Cellular energetic analysis revealed that ES1 levels in H9C2 cardiomyocytes were directly correlated with mitochondrial oxidative metabolism. ATP synthase activity assays revealed increased synthesis activities and decreased hydrolysis activities on cardiac mitochondria from a mouse line with Cre-LoxP mediated, tamoxifen inducible, cardiomyocy...
Abstract 4732: Myeloid-derived suppressor cells potentiate colorectal carcinogenesis: Identification of a novel RIPK3-PGE2 circuit in tumor microenvironment
Authors: Yongsheng Li, Guifang Yan, Huakan Zhao, Qi Zhang
Journal: Cancer Research (2018)

Abstract The role of receptor-interacting protein kinase 3 (RIPK3), a central factor mediating necroptosis, in tumor immunity is largely unknown. Here we show the significantly decreased RIPK3 in the tumor microenvironment of colorectal cancer (CRC) correlated with the accumulation of myeloid-derived suppressor cells (MDSCs). Deficiency of RIPK3 boosted the infiltration and immunosuppressive activity of MDSCs in vitro and in vivo. Mechanistically, the reduction of RIPK3 in MDSCs and colorectal cancer cells elicited NF-κB expression in the nuclei and the transcription of COX-2 which catalyses the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs, i.e. increased arginase 1 (Arg-1), blunted CD8+ T cell activation and accelerated tumor growth. Moreover, PGE2 inhibited RIPK3 expression while enhanced the expression of NF-κB and COX-2 in MDSCs and CRC cells. Inhibition of COX-2 or PGE2 receptors significantly reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. The patient databases also delineated the correlation of RIPK3 and COX-2 with CRC survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, and provide potential targets for the immunotherapy of CRC. Citation Format: Yongsheng Li, Guifang Yan, Huakan Zhao, Qi Zhang. Myeloid-derived suppressor cells potentiate colorectal carcinogenesis: Identification of a novel RIPK3-PGE2 circuit in tumor microenvironment [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 4732.
Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation
Authors: Benjamin A. Steinberg, Sunghee Kim, Jonathan P. Piccini, Gregg C. Fonarow, Renato D. Lopes, Laine Thomas, Michael D. Ezekowitz, Jack Ansell, Peter Kowey, Daniel E. Singer, Bernard Gersh, Kenneth W. Mahaffey, Elaine Hylek, Alan S. Go, Paul Chang, Eric D. Peterson
Journal: Circulation (2013)

The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%; P<0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (≥5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20-1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17-1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low.Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC.URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01165710.
Profiling of Aortic Smooth Muscle Cell Gene Expression in Response to Chronic Inhibition of Nitric Oxide Synthase in Rats
Authors: MorganDupuis, FlorentSoubrier, IsabelleBrocheriou, SégolèneRaoux, MounsifHaloui, LilianeLouedec, Jean-BaptisteMichel, SophieNadaud
Journal: Circulation (2004)

Background— Chronic inhibition of nitric oxide (NO) synthesis by Nω-nitro-l-arginine methyl ester (L-NAME) induces hypertension associated with remodeling of the arterial wall. In this study, we aimed at identifying genes and pathways involved in this process in aortic smooth muscle cells from Fischer 344 rats, which exhibit an accelerated hypertension after administration of L-NAME. Methods and Results— We studied the transcriptional profile of aortic media after 15 days (moderate hypertension) and 30 days (accelerated hypertension) of L-NAME administration (50 mg · kg−1 · d−1) by using rat Affymetrix Genechips, and we present a large-scale validation of the DNA chip results by real-time reverse transcription–polymerase chain reaction (RT-PCR). We observed, in aortic media, a progressive increase in the number of modulated genes during L-NAME administration, with 53 genes significantly modulated after 15 days and 147 genes after 30 days. These expression changes were confirmed at 87% by RT-PCR. We found ...
Death Among the Unsheltered Homeless
Authors: Michael Incze, Mitchell H. Katz
Journal: JAMA Internal Medicine (2018)

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Abstract 4266: Computational exploration of mechanistic determinants of ADC pharmacokinetics using QSP modeling strategies
Authors: A. Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, Jennifer Park, John M. Burke, Joshua F. Apgar
Journal: Cancer Research (2018)

Abstract The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules. This discrepancy is often attributed strictly to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. This work employs a computational quantitative systems pharmacology (QSP) approach that generates a hypotheses to better understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Our work establishes the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs to better enable clinical trial design. References: Kamath, A. V., and Iyer, S. (2014). Preclinical Pharmacokinetic Considerations for the Development of Antibody Drug Conjugates. Pharmaceutical Research, 32(11), 3470-3479. Citation Format: A. Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, Jennifer Park, John M. Burke, Joshua F. Apgar. Computational exploration of mechanistic determinants of ADC pharmacokinetics using QSP modeling strategies [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 4266.
Transient Ischemia Reduces Norepinephrine Release During Sustained Ischemia
Authors: MelchiorSeyfarth, GertRichardt, AnnaMizsnyak, ThomasKurz, AlbertSchömig
Journal: Circulation Research (1996)

Abstract Endogenous catecholamine release may play a role in ischemic preconditioning either as a trigger or as a target within the process of myocardial preconditioning. Therefore, we investigated the effect of transient ischemia (TI) on norepinephrine release during sustained ischemia in isolated rat hearts. TI was induced by multiple cycles of global ischemia followed by reperfusion with a duration of 5 minutes each, comparable to ischemic preconditioning protocols. After TI, norepinephrine release was evoked by either sustained global ischemia, anoxia, cyanide intoxication, tyramine, or electrical stimulation. During TI, no washout of norepinephrine was observed, and tissue concentrations of norepinephrine were not changed. TI, however, reduced norepinephrine overflow after 20 minutes of sustained ischemia from 239±26 pmol/g (control) to 79±8 pmol/g (67% reduction, P<.01). A similar reduction of ischemia-induced norepinephrine release from 192±22 pmol/g (control) to 90±15 pmol/g was observed when hear...
Involvement of Endoplasmic Stress Protein C/EBP Homologous Protein in Arteriosclerosis Acceleration With Augmented Biological Stress Responses
Authors: JunhongGao, YasushiIshigaki, TetsuyaYamada, KeiichiKondo, SuguruYamaguchi, JuntaImai, KenjiUno, YutakaHasegawa, ShojiroSawada, HisamitsuIshihara, SeiichiOyadomari, MasatakaMori, YoshitomoOka, HidekiKatagiri
Journal: Circulation (2011)

Background—The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions. Methods and Results—We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury–induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury–induced neointimal formation was markedly inhibited in CHOP−/− mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation–related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E−/− mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transpla...
Abstract 904: The novel C-terminal truncated 90-kDa isoform of topoisomerase IIα, TOP2α/90, is a determinant of etoposide resistance in K562 leukemia cells via heterodimerization with the TOP2α/170 isoform
Authors: Ragu Kanagasabai, Soumendra Karmahapatra, Yang Yu, Victor A. Hernandez, Corey A. Kientz, Evan E. Kania, Terry S. Elton, Jack C. Yalowich
Journal: Cancer Research (2018)

Abstract DNA topoisomerase IIα (170 kDa, TOP2α/170) is essential in proliferating cells since it resolves DNA topologic entanglements during chromosome condensation, replication, and segregation. We previously characterized a C-terminally truncated TOP2α/90 isoform, detectable in human leukemia K562 cells but more abundantly expressed in a clonal subline, K/VP.5, with acquired resistance to the anticancer agent etoposide (J Pharmacol Exp Ther 2017;360:152-63). TOP2α/90 (786 amino acids) is the translation product of a TOP2α mRNA that retains a processed intron 19. TOP2α/90 lacks the active-site tyrosine-805 (Tyr805) required to generate double-strand DNA breaks as well as the nuclear localization signals present in the TOP2α/170 isoform (1531 amino acids). The function of TOP2α/90 is unknown. Here, we found that TOP2α/90, like TOP2α/170, was detectable in the nucleus and cytoplasm of K562 and K/VP.5 cells. Importantly, co-immunoprecipitation of endogenous TOP2α/90 and TOP2α/170 demonstrated heterodimerization of these isoforms. Forced expression of TOP2α/90 in K562 cells suppressed, while siRNA-mediated knockdown of TOP2α/90 in K/VP.5 cells enhanced, etoposide-mediated DNA strand breaks compared with similarly treated K562 or K/VP.5 cells transfected with empty vector or control siRNAs, respectively. In addition, forced expression of TOP2α/90 in K562 cells inhibited etoposide cytotoxicity assessed by soft agar colony formation assays. qPCR and immunoassays demonstrated expression of TOP2α/90 mRNA and protein in normal human tissues/cells and in leukemia cells from patients. Together, results strongly suggest that TOP2α/90 expression decreases drug-induced TOP2α-DNA covalent complexes and is a determinant of chemoresistance through a dominant-negative effect related to heterodimerization with TOP2α/170. Alternative processing of TOP2α pre-mRNA, and subsequent synthesis of TOP2α/90, may be an important mechanism regulating the formation and/or stability of TOP2α/170-DNA covalent complexes in response to TOP2α-targeting agents. Citation Format: Ragu Kanagasabai, Soumendra Karmahapatra, Yang Yu, Victor A. Hernandez, Corey A. Kientz, Evan E. Kania, Terry S. Elton, Jack C. Yalowich. The novel C-terminal truncated 90-kDa isoform of topoisomerase IIα, TOP2α/90, is a determinant of etoposide resistance in K562 leukemia cells via heterodimerization with the TOP2α/170 isoform [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 904.
The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease
Authors: Cameron McDonald-Hyman, James T. Muller, Michael Loschi, Govindarajan Thangavelu, Asim Saha, Sudha Kumari, Dawn K. Reichenbach, Michelle J. Smith, Guoan Zhang, Brent H. Koehn, Jiqiang Lin, Jason S. Mitchell, Brian T. Fife, Angela Panoskaltsis-Mortari, Colby J. Feser, Andrew Kemal Kirchmeier, Mark J. Osborn, Keli L. Hippen, Ameeta Kelekar, Jonathan S. Serody, Laurence A. Turka, David H. Munn, Hongbo Chi, Thomas A. Neubert, Michael L. Dustin, Bruce R. Blazar
Journal: Journal of Clinical Investigation (2018)

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ–deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.
Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy
Authors: ShinichiHirotani, KinyaOtsu, KazuhikoNishida, YoshiharuHiguchi, TakashiMorita, HiroyukiNakayama, OsamuYamaguchi, ToshiakiMano, YasushiMatsumura, HikaruUeno, MichihikoTada, MasatsuguHori
Journal: Circulation (2002)

Background— Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-κB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein–coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes. Methods and Results— Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-κB activation. Antioxidants such as N-acetyl cysteine, N-mercaptopropionyl glycine, and vitamin E attenuated the NF-κB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IκBα led to suppression of the hypertrophic responses. The GPCR agonists rapidly and ...
Clinicopathologic characteristics of triple-negative breast cancer and relationship to basal markers.
Authors: Dimitrios Tryfonopoulos, Georgios Oikonomopoulos, Stamatina Demiri, Lazaros Lekakis, Nikolaos Fragkiskos Pistamaltzian, George Koumakis, Chris G. Panopoulos, Nektarios Koufopoulos, Nikiforos Apostolikas, Ioannis Misitzis, Anna P. Efremidis
Journal: Journal of Clinical Oncology (2012)

e11519 Background: Triple negative breast cancers are immunohistochemical surrogates of basal-like breast cancers. There is no complete overlap between triple negative and basal-like tumors and as gene expression studies evolve, further subclassification bearing clinical relevance is underway. Our purpose was to correlate clinicopathologic characteristics of triple negative breast cancer tumors with expression of basal markers in an effort to define immunohistochemically subgroups of this heterogenous disease Methods: Data were retrieved and analysed using our electronic databank. Patient samples were reviewed by an expert breast cancer pathologist and stained additionally for EGFR and CK 5/6 antibodies. Results: Sixty-five women with triple negative breast cancer were identified. Mean age was 58.3±12.9 years. Most tumors (86%) were of ductal histology, 53% grade 3, 48% having high Ki-67 index (&gt;14%). 10% of patients presented with Stage IV, 25% with Stage III, 38% with stage II and 27% with stage I disease. 63% of patients were postmenopausal. EGFR staining was present in 43% of tumor samples, whereas CK 5/6 in 38.5%. Both EGFR and CK 5/6 expression was found in 18.5%, whereas 37% of tumors expressed neither EGFR or CK 5/6. No difference was observed between tumors expressing any of these 2 basal markers as compared to EGFR and CK 5/6 negative tumors in terms of Ki-67 index, grade, tumor size and nodal involvement. Lymphovascular invasion and non-ductal histology tended to occur more frequently (p=ns) in non-basal tumors. Additionally, patients with expression of any of the basal markers tended to be more obese than the non-basal triple negative breast cancer patients (p=ns). Conclusions: Further immunohistochemical markers apart from EGFR and CK 5/6 are needed in order to further define clinically meaningful subgroups of triple negative breast cancer.
Abstract 13491: Mitral Valve Annular Dilatation & Augmented Valve Closing Force to Tract Papillary Muscle as a Possible Mechanism of Late-systolic Mitral Valve Prolapse: Pre- & Post-operative Echocardiographic Study With Speckle Tracking Analysis
Authors: Shota Fukuda, Jae-Kwan Song, Keitaro Mahara, Yukio Abe, Jeong Yoon Jang, Hiroshi Kuwaki, Atsushi Hayashi, Takeshi Onoue, Soshi Hei, Mai Iwataki, Byung Joo Sun, Yun Jeong Kim, Masaaki Takeuchi, Masataka Eto, Yosuke Nishimura, Yasuyuki Sasaki, Shuichiro Takanashi, Robert A Levine, Yutaka Otsuji
Journal: Circulation (2016)

Introduction: Stable papillary muscle (PM) position and contraction enable constant PM tip distance from mitral valve (MV) annulus, which can contribute to constant MV coaptation height during systole (Figure A). Hypothesis: In patients with late-systolic MV prolapse (L-MVP), superior shift of MV coaptation toward left atrium (LA) during systole may be linked to abnormal PMs superior shift, which can be related to augmented MV closing force by MV annular dilatation. Methods: In 15 controls and 20 with L-MVP, MV coaptation height from its annulus was measured at early- and late-systole by echocardiography to evaluate systolic superior shift of MV coaptation. Distances of PMs tip and MV annulus from external reference point around the apex were monitored by 2 points speckle tracking, and systolic shift of PMs tip toward MV annulus was measured (Figures B and C). MV closing force was calculated as MV annular area х (systolic blood pressure - 10). Echocardiography was repeated after MV plasty in 5 L-MVP patie...