tbuckley/cabot-search huggingface dataset:
Abstract 2000: The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like cells
Authors: Weijie Gao, Dinglan Wu, Yuliang Wang, Zhu Wang, Taiyang Ma, Franky Leung Chan
Journal: Cancer Research (2018)

Abstract Cumulative studies indicate that there is a small subpopulation of cancer cells present in cancers or solid tumors referred as cancer stem-like cells (CSCs) as they share some common characteristics with stem cells, particularly self-renewal and multipotency, and these CSCs may contribute to the tumor initiation, treatment resistance and relapse. Recent advances also indicate that prostate cancer stem-like cells (PCSCs) may play a critical role in the development of castration-resistant prostate cancer (CRPC) and also its metastasis. Here, we demonstrated using an established CRPC xenograft model (VCaP-CRPC) that both the xenograft tumors and a xenograft-derived cell line contained more PCSC population, which showed higher expression levels of endothelial nitric oxide synthase (eNOS) and elevated intracellular NO production. PCSCs, isolated from prostaspheres derived from prostate cancer cell lines (DU145, LNCaP and VCaP) using a newly developed agar-based non-attachment 3D-culture method, exhibited up-regulation of eNOS and increased intracellular NO levels. Interruption of eNOS signaling by NOS inhibitors and shRNA-knockdown could significantly suppress the sphere formation capability of prostate cancer cells. Exogenous overexpression of eNOS could promote the tumor growth capacity of prostate cancer cells and their metastasis in vivo, while knockdown of eNOS could prevent the tumor growth and metastasis. Combined transcriptome-sequencing analysis and qPCR validation of prostaspheres upon eNOS-knockdown identified some potential targets of eNOS/NO signaling in the PCSC-enriched prostaspheres. In summary, our results suggest that eNOS/NO signaling may play a positive role in the growth regulation of PCSCs and eNOS might be a potential target for advanced prostate cancer. This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (project code 14107617) and an Innovation and Technology Fund (GHP/003/16GD) from the Innovation and Technology Commission of Hong Kong. Citation Format: Weijie Gao, Dinglan Wu, Yuliang Wang, Zhu Wang, Taiyang Ma, Franky Leung Chan. The regulatory role of endothelial nitric oxide synthase signaling in the growth of prostate cancer stem-like 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 2000.
Vascular Cell Senescence
Authors: TohruMinamino, IsseiKomuro
Journal: Circulation Research (2007)

Cardiologists and most physicians believe that aging is an independent risk factor for human atherosclerosis, whereas atherosclerosis is thought to be a characteristic feature of aging in humans by many gerontologists. Because atherosclerosis is among the age-associated changes that almost always escape the influence of natural selection in humans, it might be reasonable to regard atherosclerosis as a feature of aging. Accordingly, when we investigate the pathogenesis of human atherosclerosis, it may be more important to answer the question of how we age than what specifically promotes atherosclerosis. Recently, genetic analyses using various animal models have identified molecules that are crucial for aging. These include components of the DNA-repair system, the tumor suppressor pathway, the telomere maintenance system, the insulin/Akt pathway, and other metabolic pathways. Interestingly, most of the molecules that influence the phenotypic changes of aging also regulate cellular senescence, suggesting a ...
Abstract 13496: Exercise Blood Pressure as a Predictor of Future Hypertension: Evaluation Using Receiver Operating Characteristic
Authors: Sae YoungJae, MercedesCarnethon, JinaChoo, Yoon-HoChoi, BoFernhall
Journal: Circulation (2014)

The meaningful cutoff values for exaggerated blood pressure (EBP) response to exercise are inconsistent and arbitrarily defined, and confounding variables in the association between EBP and future hypertension are often not adequately accounted for. The purpose of this study is 1) to evaluate receiver operating characteristic curve to identify optimal cutoffs of EBP using both a maximal systolic blood pressure (SBP) and a relative SBP as predictors of future hypertension, and 2) to analyze the validity of 210 mmHg of the EBP cutoff value suggested in previous studies for men. Study participants were 3,742 men who participated in two health examinations during 1998-2009. All the participants were free of cardiovascular diseases and hypertension at baseline examination. The relative SBP were calculated as the difference between the resting SBP before and the maximal SBP during exercise testing. Hypertension was defined as systolic or diastolic blood pressure ≥140/90mmHg. During 5 years of follow-up, 364 (9....
Abstract 5073: Involvement of TGFa-EGFR-Akt axis on enhanced proinflammatory chemokines in triple-negative breast cancer cells
Authors: Rosa Mistica Coles Ignacio, Carla Gibbs, Eunsook Lee, Deok-Soo Son
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is aggressive, leading to poorer outcomes. Chemokines have chemoattractive potential for cancer metastasis. We investigated the signature of chemokine network between TNBC and non-TNBC cells followed by underlining mechanisms on enhanced proinflammatory chemokines in TNBC. Analysis from microarray dataset revealed that basal-like BC subtype representing TNBC expressed dominantly proinflammatory chemokines, such as CXCL1 and 8, compared to non-TNBC. Chemokine PCR array confirmed the dominant proinflammatory chemokines in TNBC cells. As a driving factor for proinflammatory chemokines in TNBC cells, we checked expression profiles for epidermal growth factor receptor (EGFR) family and its downstream signaling. TNBC cells showed higher expression levels of EGFR and phosphorylated Akt compared to non-TNBC cells. In addition, EGF enhanced the proinflammatory chemokines in TNBC cells. Knockdown of Akt reduced the CXCL2 promoter activity, while overexpression of Akt enhanced the activity. MKK2206, an Akt inhibitor, abrogated the CXCL2 promoter activity, but targeting Erk using inhibitor and knockdown did not reduce the activity. As a driving factor for EGFR-mediated Akt activation in TNBC cells, we found transforming growth factor alpha (TGFα) among ligands of EGFR family. MK2206 decreased the TGFα promoter activity, while overexpression of Akt significantly increased the activity in TNBC cells. MK2206 abrogated TGFα protein released by TNBC cells. MK2206 downregulated CXCL2 mRNA, while TGFα upregulated the CXCL2 expression. Taken together, higher expression of proinflammatory chemokines in TNBC involves TGFα-EGFR-Akt axis, probably contributing to the inflammatory burden followed by promoted cancer progression and higher mortality in TNBC. Citation Format: Rosa Mistica Coles Ignacio, Carla Gibbs, Eunsook Lee, Deok-Soo Son. Involvement of TGFa-EGFR-Akt axis on enhanced proinflammatory chemokines in triple-negative breast 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 5073.
Myocardial Perfusion Patterns Related to Thrombolysis in Myocardial Infarction Perfusion Grades After Coronary Angioplasty in Patients With Acute Anterior Wall Myocardial Infarction
Authors: HiroshiIto, AtsunoriOkamura, KatsuomiIwakura, TohruMasuyama, MasatsuguHori, ShinTakiuchi, ShinjiNegoro, YoshiakiNakatsuchi, YoshiakiTaniyama, YorihikoHigashino, KenshiFujii, TakazoMinamino
Journal: Circulation (1996)

Background Epicardial coronary flow is occasionally reduced even after coronary intervention despite the absence of vessel obstruction in patients with acute myocardial infarction. Our aim was to clarify the cause and outcomes of radiocontrast slow filling in patients with reperfused acute anterior myocardial infarction by assessing microvascular damage with the use of myocardial contrast echocardiography (MCE) and functional outcomes. Methods and Results We carefully reviewed the cineangiograms of 86 patients who achieved coronary revascularization within 12 hours of the onset and underwent MCE before and soon after recanalization with the intracoronary injection of sonicated microbubbles. Antegrade coronary flow after recanalization was graded by two observers based on Thrombolysis in Myocardial Infarction (TIMI) trial flow grades. Left ventricular ejection fraction was measured on the day of infarction and 1 month later. TIMI grade 2 was observed in 18 patients (21%), and the other 68 patients manifest...
Asymmetrical Hypertrophic Cardiomyopathy Simulating Mitral Stenosis
Authors: Ralphshabetai, Sidneydavidson
Journal: Circulation (1972)

Hypertrophic cardiomyopathy usually involves the left ventricle more severely than the right, and when asymmetrical may produce the syndrome of idiopathic subaortic stenosis. Less commonly, clinical manifestations of inflow-tract obstruction predominate and produce a syndrome that may be mistaken for mitral stenosis, principally because of an apical diastolic rumbling murmur. The probability of this diagnostic error and the risk of a consequent unnecessary operation can be reduced by appreciating the significance of the clues to left ventricular disease revealed by the electrocardiogram and the chest roentgenogram. Furthermore, proper timing of the heart sounds differentiates the protodiastolic filling sound of cardiomyopathy from the opening snap of mitral stenosis. The correct diagnosis is established following ventriculographic and hemodynamic studies.
Platelet Function During and After Thrombolytic Therapy for Acute Myocardial Infarction With Reteplase, Alteplase, or Streptokinase
Authors: MartinMoser, ThomasNordt, KarlheinzPeter, JohannesRuef, BenediktKohler, MarcSchmittner, RichardSmalling, WolfgangKübler, ChristophBode
Journal: Circulation (1999)

Background—Changes in platelet aggregation (PA) and platelet surface receptor expression induced by thrombolytic therapy for acute myocardial infarction may influence the rate of initial reperfusion and early reocclusion. Methods and Results—In the RAPID-1 (Reteplase Angiographic Phase II International Dose-finding study), RAPID-2 (Reteplase vs Alteplase Patency Investigation During myocardial infarction), INJECT (INternational Joint Efficacy Comparison of Thrombolytics), and GUSTO-3 (Global Use of Strategies To Open occluded coronary arteries) trials, 126 patients were enrolled in a single center. Patients were treated with either conventional alteplase (100 mg/180 min; n=15), accelerated alteplase (100 mg/90 min; n=21), reteplase 10+10-U double bolus (n=50), reteplase 10+5-U double bolus (n=15), reteplase 15-U single bolus (n=15), or streptokinase (1.5 MU/60 min; n=10). PA (after stimulation with ADP), P-selectin expression and fibrinogen binding to glycoprotein (GP) IIb/IIIa (determined by flow cytomet...
Mortality Among Unsheltered Homeless Adults in Boston, Massachusetts, 2000-2009
Authors: Jill S. Roncarati, Travis P. Baggett, James J. O’Connell, Stephen W. Hwang, E. Francis Cook, Nancy Krieger, Glorian Sorensen
Journal: JAMA Internal Medicine (2018)

<h3>Importance</h3> Previous studies have shown high mortality rates among homeless people in general, but little is known about the patterns of mortality among "rough sleepers," the subgroup of unsheltered urban homeless people who avoid emergency shelters and primarily sleep outside. <h3>Objectives</h3> To assess the mortality rates and causes of death for a cohort of unsheltered homeless adults from Boston, Massachusetts. <h3>Design, Setting, and Participants</h3> A 10-year prospective cohort study (2000-2009) of 445 unsheltered homeless adults in Boston, Massachusetts, who were seen during daytime street and overnight van clinical visits performed by the Boston Health Care for the Homeless Program's Street Team during 2000. Data used to describe the unsheltered homeless cohort and to document causes of death were gathered from clinical encounters, medical records, the National Death Index, and the Massachusetts Department of Public Health death occurrence files. The study data set was linked to the death occurrence files by using a probabilistic record linkage program to confirm the deaths. Data analysis was performed from May 1, 2015, to September 6, 2016. <h3>Exposure</h3> Being unsheltered in an urban setting. <h3>Main Outcomes and Measures</h3> Age-standardized all-cause and cause-specific mortality rates and age-stratified incident rate ratios that were calculated for the unsheltered adult cohort using 2 comparison groups: the nonhomeless Massachusetts adult population and an adult homeless cohort from Boston who slept primarily in shelters. <h3>Results</h3> Of 445 unsheltered adults in the study cohort, the mean (SD) age at enrollment was 44 (11.4) years, 299 participants (67.2%) were non-Hispanic white, and 72.4% were men. Among the 134 individuals who died, the mean (SD) age at death was 53 (11.4) years. The all-cause mortality rate for the unsheltered cohort was almost 10 times higher than that of the Massachusetts population (standardized mortality rate, 9.8; 95% CI, 8.2-11.5) and nearly 3 times higher than that of the adult homeless cohort (standardized mortality rate, 2.7; 95% CI, 2.3-3.2). Non-Hispanic black individuals had more than half the rate of death compared with non-Hispanic white individuals, with a rate ratio of 0.4 (95% CI, 0.2-0.7;<i>P</i> &lt; .001). The most common causes of death were noncommunicable diseases (eg, cancer and heart disease), alcohol use disorder, and chronic liver disease. <h3>Conclusions and Relevance</h3> Mortality rates for unsheltered homeless adults in this study were higher than those for the Massachusetts adult population and a sheltered adult homeless cohort with equivalent services. This study suggests that this distinct subpopulation of homeless people merits special attention to meet their unique clinical and psychosocial needs.
Abstract 203: Glucose Stimulated Endothelial Microparticles Increase Endothelial Cell Apoptotic Susceptibility
Authors: Tyler Bammert, Jamie Hijmans, Whitney Reiakvam, Ma’ayan Levy, Kelly Stockelman, Lillian Bruster, Zoë Goldthwaite, Jared Greiner, Christopher DeSouza
Journal: Circulation Research (2017)

Clinical interest in endothelial cell-derived microparticles (EMPs) has increased due to their role in the pathogenesis of vascular disease. Although released by the endothelium, EMPs have autocrine properties that can significantly impact endovascular health. Hyperglycemic conditions, such as diabetes, are known to stimulate EMP release; however, the effects of these glucose-related microparticles on endothelial cell function are not well understood. High glucose concentrations induce endothelial cell apoptosis through a caspase-3-dependent mechanism. The aim of this study was to determine the effect of EMPs derived from a hyperglycemic condition on endothelial cell susceptibility to apoptosis. Human umbilical vein endothelial cells (HUVECs) were cultured (3 rd passage) and plated in 6-well plates at a density of 5.0 x 10 5 cell/condition. Cells were incubated with RPMI 1640 media containing 25mM D-glucose (concentration representing a diabetic glycemic state) or 5mM D-glucose (control, normoglycemic, condition) for 48 h to generate EMPs. EMPs derived from both conditions were pelleted by centrifugation and resuspended in culture media. EMP identification (CD144 + expression) and number was determined by flow cytometry. HUVECs (2 x10 6 cells/condition) were treated with EMPs (2:1 ratio) generated from either the hyperglycemic or normoglycemic conditions for 24 h. Thereafter, cells were treated with staurosporine (1μmol/L) for 3 h at 37°C and biotin-ZVKD-fmk inhibitor for 1 h at 37°C. Intracellular concentration of active caspase-3 was determined by enzyme immune assay. Cellular expression of miR-Let7a, an anti-apoptotic microRNA, was determined by RT-PCR using the ΔΔCT normalized to RNU6. Hyperglycemic EMPs resulted in significant increase in basal (1.5 + 0.1 vs 1.0 + 0.1 ng/mL) and staurosporine-stimulated (2.2 + 0.2 vs 1.4 + 0.1 ng/mL) caspase-3 activity compared with normoglycemic EMPs. Additional, the expression of miR-Let7a was markedly reduced (~140%) in response to hyperglycemic EMPs (0.43 + 0.17 fold vs control). These results demonstrate that hyperglycemic-induced EMPs increase endothelial cell apoptotic susceptibility. This apoptotic effect may be mediated, at least in part, by a reduction in miR-Let7a expression.
Revised Version of Research Letter by Nikpay et al and Associated Changes for Accompanying Commentary
Authors: Allan J. Coukell, Sean Dickson
Journal: JAMA Internal Medicine (2018)

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Angiotensin Blockade Inhibits Activation of Mitogen-Activated Protein Kinases in Rat Balloon-Injured Artery
Authors: ShokeiKim, YasukatsuIzumi, MasahikoYano, AkinoriHamaguchi, KatsuyukiMiura, ShinyaYamanaka, HitoshiMiyazaki, HiroshiIwao
Journal: Circulation (1998)

Background—The effect of balloon injury on the arterial signal transduction pathway has not been examined. In vitro studies show that extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), belonging to the mitogen-activated protein kinase (MAPK) family, play a critical role in the activation of transcription factor activator protein-1 (AP-1) and cell proliferation or apoptosis. However, the activation and role of MAPKs in vascular diseases in vivo remain to be determined. Therefore, we examined the effect of balloon injury on arterial MAPKs and the possible role of angiotensin II. Methods and Results—Arterial JNK and ERK activities were measured by in-gel kinase assay. AP-1 DNA binding activity was determined by gel mobility shift analysis. After balloon injury of rat carotid artery, JNK (p46JNK and p55JNK) and ERK (p44ERK and p42ERK) activities were increased as early as 2 minutes, reached their peak (6- to 18-fold) at 5 minutes, and thereafter rapidly declined to control le...
Erratum: Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo (Nature Immunology (2007) 10.1038/ni1522)
Authors: Shalin H. Naik, Priyanka Sathe, Hae Young Park, Donald Metcalf, Anna I Proietto, Aleksander Dakic, Sebastian Carotta, Meredith O'Keeffe, Melanie Bahlo, Anthony Papenfuss, Jong Young Kwak, Li Wu, Ken Shortman
Journal: Nature Immunology (2007)
Abstract 17949: Molecular Imaging of Regulation of mTORC1-S6K Signal Pathway of Mesenchymal Stem Cells in Alleviating Mice Cardiac Dysfunction Induced from Sepsis
Authors: WeiHuang
Journal: Circulation (2014)

Objective: Sepsis remains a major cause of morbidity and mortality in the patient suffered from severe trauma. Recent animal studies revealed that mesenchymal stem cells (MSCs) may be useful therapeutic adjuncts for tissue repairing. This study was designed to evaluate therapeutic efficacy and mechanism of mesenchymal stem cells in sepsis induced mice cardiac dysfunction(SICD). Methods: Mesenchymal stem cells (MSCs) stably expressing firefly luciferase (Fluc) were isolated from s-actin-Fluc transgenic FVB mice. Eight week-old wild type mice (WT) of cardiac-specific Raptor knockout mice were subjected to administration of LPS (20mg/kg) and inoculated intraperitoneally with MSCs (1х106). Cell survival and proliferation were assessed by bioluminescent imaging (BLI). Echocardiogram was performed for analysis of cardiac function. H9C2 Cells were exposed to LPS(10-4mol/L)for 24 hours and co-cultured with or without MSCs. Apoptosis was evaluated by TUNEL staining. The expressions of mTOR, p-mTOR, Raptor, Rictor,...
Abstract 2907: Targeting the epigenetic regulator KAT2a in cancer
Authors: Andrea Gunnell, Jessica Downs, Lewis Pennicott, Kay Osborn, Darren Le Grand, Katie Duffell, Hitesh Patel, Jessica Hudson, Jessica R. Booth, Simon Ward
Journal: Cancer Research (2018)

Abstract Gene expression frequently requires the dynamic remodelling of the chromatin architecture to orchestrate the assembly of transcriptional protein complexes at the promoter sites of DNA. Chromatin remodelling complexes are multicomponent proteins that facilitate reorganisation of chromatin structure using the energy derived from ATP hydrolysis, and as a result play a pivotal role in controlling gene expression. Mammalian SWI/SNF complexes are examples of chromatin remodelling complexes with multiple roles in maintaining genome stability. It is estimated that 19.6% of all human tumours have mutations in SWI/SNF complexes, leading to the deregulation of gene expression as an early driver of carcinogenesis. Our interest in developing novel treatments for renal cancer focused on the role of the chromatin remodelling complex, PBAF. The BAF180 component of PBAF is mutated in 40 % of clear cell renal carcinomas and its loss is an early event in renal cell tumorigenesis. We performed an siRNA based high throughput screen to identify genes associated with genome stability that were synthetically lethal with the loss of BAF180 and identified KAT2a as a potential druggable target. KAT2a is a protein that also functions in the regulation of gene expression as a component of the SAGA histone modifying complex. It is a multifunctional protein that can both ‘read' and ‘write' acetylation marks on histone proteins through its bromodomain and a histone acetyltransferase domain respectively. We will describe our efforts to establish suitable assays to support the discovery of selective inhibitors of the bromodomain of KAT2a. The work will include the establishment of a high throughput assay to measure compound binding, crystallographic characterisation of small molecule inhibitors of the bromodomain, and our initial studies towards the target validation of the bromodomain to recapitulate the synthetic lethality observed with depletion of BAF180. Citation Format: Andrea Gunnell, Jessica Downs, Lewis Pennicott, Kay Osborn, Darren Le Grand, Katie Duffell, Hitesh Patel, Jessica Hudson, Jessica R. Booth, Simon Ward. Targeting the epigenetic regulator KAT2a in 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 2907.