tbuckley/cabot-search huggingface dataset:
Abstract 16303: Tert-Butylhydroquinone Rescues Cyclosporine-A Mediated Impairment in Vascular Function via Augmenting Phosphorylation of the Transcription Factor Nrf2
Authors: ArashGhashghai, HiroyukiKawajiri, LauraTumiati, LizaGrosman-Rimon, ScottHeximer, SteffenBolz, ThomasLindsay, VivekRao
Journal: Circulation (2014)

Background: Oxidative stress mediates cyclosporine-A (CsA) associated vascular injury post-cardiac transplantation. We investigated the effect of CsA on the Nrf2 pathway by examining vascular function, Nrf2 phosphorylation and superoxide dismutase (SOD) activity and the ability of tBHQ to rescue CsA-mediated injury. Methods and Results: Lewis rats received tBHQ (50mg/kg), CsA (5mg/kg) ± tBHQ, or Saline (CON). Thoracic aortic segments were assessed for vascular function as measured by endothelial-dependent (Edep) relaxation (ED50), and sensitivity to endothelin-1 (ET-1) vasoconstriction. We also analyzed Nrf2 protein expression, phospho-Nrf2/Nrf2 ratio, and SOD activity. CsA significantly impaired Edep vasorelaxation (ED50: 3.5x10-8 +/- 0.4M vs CON 1.8x10-8 +/- 0.5M, p<0.001). tBHQ did not affect vasorelaxation compared to CON (2.18x10-8 +/- 0.4M, p=NS). However, tBHQ improved vasorelaxation in CsA-treated rats significantly (ED50: 2.69x10-8 +/- 0.3M vs CsA alone, p<0.001). Compared to CON, CsA exposure de...
Abstract 14328: Comparison of Right and Left Pectoral ICDs with Single and Dual Coil Leads; A Computational Simulation
Authors: Thomas Pilcher, Jess Tate, Elizabeth Saarel, Michael Puchalski, Ahrash Poursaid, Rob MacLeod
Journal: Circulation (2011)

Background: Clinical studies show no difference in single and dual coil defibrillation thresholds for left pectoral (L) ICDs, however, data on right pectoral (R) ICDs is limited. We used full torso...
Exacerbation Rates Among Severe COPD Patients Prescribed Roflumilast In Sweden During Year 2011
Authors: J. M. Khalid, V. Mushnikov, Gunnar Johansson, T. Backström, P. Korhonen, F. Hoti
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Exacerbation Rates Among Severe COPD Patients Prescribed Roflumilast In Sweden During Year 2011
Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling
Authors: AtsushiAnzai, ToshihisaAnzai, ShigenoriNagai, YuichiroMaekawa, KotaroNaito, HidehiroKaneko, YasuoSugano, ToshiyukiTakahashi, HitoshiAbe, SatsukiMochizuki, MotoakiSano, TsutomuYoshikawa, YasunoriOkada, ShigeoKoyasu, SatoshiOgawa, KeiichiFukuda
Journal: Circulation (2012)

Background—Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. Methods and Results—Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow–derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c+ green fluorescent protein–positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanc...
Abstract 15779: Quality of Life in a Cohort of Familial Hypercholesterolemia Patients Undergoing Molecular Cascade Screening in Brazil
Authors: Ana Cristina Souto, Alexandre Pereira, Cinthia E Jannes, Julia Fukushima, Jose E Krieger, Raul D Santos
Journal: Circulation (2015)

Introduction:: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated disease associated with elevated risk of early cardiovascular disease (CVD) and thus can reduce quality of life. The present health related quality of life (HRQL) investigation, evaluated patients personal interpretation of morbidity burden in daily life. Methods: The study included a total of 1,032 adult individuals participating in a FH molecular cascade-screening program. The involved individuals were index cases (IC n=363), with genetic diagnosis or FH and their first-degree relatives (FDR, n=669). All patients were evaluated at the first session of the molecular diagnosis process. HRQL measurements, mental (MCS) and physical (PCS) component scores, was carried out with the Medical Outcomes Study (MOS) 12-Item Short-Form Health Survey (SF-12) questionnaire. Results: IC were older (52±13.1 vs. 46±16.2 years, P&lt;0.05) and presented lower PCS than FDR (44.7±9.3 vs. 49.2±8.4, P&lt;0.05). No differences were seen on the MCS component. Overall, generalized linear models showed that smoking habit (11.9% prevalence, P=0.006), previous diagnosis of hyperlipidemia (78.6%, P=0.020) and depression (13.5% prevalence, P&lt;0.000) were significant predictors of MCS. The presence of heart failure (6.5%, P=0.018), angina pectoris (12.9%, P=0.005), previous myocardial infarction (12.3%, P=0.012), hypertension (33.9%, P=0.018) and obesity (12.8%, P&lt;0.000) were all predictors of PCS. The presence of arrhythmias (10.7% prevalence) predicted both MCS and PCS (P=0.042 and P=0.00, respectively). Male gender (42.4%, P&lt;0.000) and education level (&lt; 9 years of background, 28% P&lt;0.000) were social-demographic aspects predictive of differences in MCS and PCS, respectively. Conclusions: Reductions in the individuals’ reported quality of life were explained by differences in social-demographic characteristics but mainly by inadequate health/disease status, such as risk factors and previous CVD. Active FH genetic cascade diagnosis by promoting early and adequate medical care and thus preventing early CVD, may improve substantially the subjective appraisal of HRQL.
Abstract LB-367: [18F]FAZA PET imaging reveals precise pharmacodynamics in vivo of the novel chemotherapeutic IACS-010759
Authors: Seth T. Gammon, Federica Pisaneschi, Madhavi Bandi, Melinda Smith, Yi Rao, Vashisht G. Yennu Nanda, Yuting Sun, Michael Davies, Emilia Di Francesco, Joseph Marszalek, David Piwnica-Worms
Journal: Cancer Research (2018)

Abstract Genetic deletions and mutations resulting in defects in glycolysis, force these tumors to depend on oxidative phosphorylation (OxPhos) for growth. IACS-010759 is a nanomolar inhibitor of Complex I, and in phase I clinical trials at MD Anderson for both AML and solid tumors. While ex vivo monitoring of inhibition of oxygen consumption in leukocytes was sufficient for AML, non-invasive methods of monitoring target engagement in solid tumors was desired. Tumors, particularly those that rely on oxidative phosphorylation, yield hypoxic and reducing environments. These conditions are ideal for trapping 2-nitroimidazole based imaging agents, such as F18-labeled fluoroazomycin arabinoside ([18F]FAZA). IACS-010759 inhibited oxygen consumption in vitro with IC50 values ranging from 1.3 nM to 6 nM across a variety of cell lines with a diversity of glycolysis defects. In H460 NSLC, SKMEL5 melanoma, A375R melanoma, and D423-Fluc orthotopic GBM in vivo, at the MTD 10 mg/kg, a robust, up to 6 fold, (2 way ANOVA, p&amp;lt;0.0001) decrease in FAZA T/B ratio was observed. A slight, 1.5-fold, but detectable increase in [18F]FDG was also observed at 10mg/kg in A375 and A375R cells (p=0.002), but smaller than the decrease [18F]FAZA retention. Thus neither cell death nor loss of perfusion could explain the reduction in [18F]FAZA retention. To further test the robustness of the mechanism of inhibition, the converse experiment was conducted. Both 2,4-dinitrophenol and pyruvate were utilized to stimulate oxygen consumption in vivo, and as predicted [18F]FAZA retention increases (p&amp;lt;0.05 in both cases). Finally, [18F]FAZA retention by PET yielded the same IC50 for IACS-010759 as by IHC in a dose-dependent manner, with an apparent IC50 of 1.4 mg/kg (95%CI 0.48 to 4.1 mg/kg, n=12 mice) for A375R melanoma tumors. The PET measurement was more precise than an independently scored IHC metric based upon staining for pimonidazole from the same mice. [18F]FAZA can be a powerful PD marker for the complex-I inhibitor IACS-010759 in preclinical models, and is translatable to upcoming clinical trials in patients. Citation Format: Seth T. Gammon, Federica Pisaneschi, Madhavi Bandi, Melinda Smith, Yi Rao, Vashisht G. Yennu Nanda, Yuting Sun, Michael Davies, Emilia Di Francesco, Joseph Marszalek, David Piwnica-Worms. [18F]FAZA PET imaging reveals precise pharmacodynamics in vivo of the novel chemotherapeutic IACS-010759 [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 LB-367.
Abstract 4819: High-throughput screening of glioma stem-like cells (GSCs) identifies synergistic therapeutic combination of FGFR inhibitor and CDK4/6 inhibitor
Authors: Jianwen Dong, Emmanuel Martinez-Ledesma, Nghi Nguyen, Shaofang Wu, Yuji Piao, Ningyi Tiao, Soon Young Park, David Brunell, Clifford Stephan, Roel Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot
Journal: Cancer Research (2018)

Abstract High-grade gliomas are challenging tumors to treat. The lack of efficacy of single-agent therapy emphasizes the importance of developing combination strategies to overcome acquired resistance. Quantitative high-throughput screening (HTS) of 2 and 3 drug combinations at 5 concentrations (maximal concentration of 1 uM) of each agent were evaluated in a panel of GSCs to identify potentially novel combination therapy. Genomic, proteiomic (reverse protein lysate array, RPPA) and GSC subtype were correlated with drug IC50 to find biomarkers of drug sensitivity. GSCs were classified as sensitive (IC50 ≤ 1µM) or resistant (IC50 &amp;gt;1µM) for single-agent screening. The Bliss independence model and combination index (CI) criteria were used to quantify the synergy of compound combinations. Evaluation of drug combination data for synergistic combination identified FGFR inhibitor LY2874455 and CDK4/6 inhibitor LY2835219 as the most effective combinations for multiple drug sets. Abnormal activation of FGFR and alterations in the CDKN2A-CDK4/6-Retinoblastoma 1 (RB1) pathway have been implicated in glioblastoma pathogenesis. We further investigated the in vitro combination efficacy of FGFR inhibitor and CDK4/6 inhibitor. Compared to single agent, combination of FGFR inhibitor and CDK4/6 inhibitor induced prominent cleaved poly ADP ribose polymerase (c-PARP), an index of apoptosis, which was further confirmed by Annexin V staining. Combination therapy significantly inhibited p-RB, p-STAT3, p-Akt, p-Erk and p-c-Jun expression compared to single agent. Genomic data demonstrated that high PDGFRα expression and low methylation correlated to sensitivity to the FGFR and CDK4/6 inhibitor combination. These findings were validated by demonstrating that this synergistic sensitivity was decreased by knocking out PDGFRα by CRISP/Cas9 system with the combination index (CI) at IC50 increased from 0.964 to 2.247. In addition, Western blotting showed that expression of PDGFRα and Notch1 was significantly inhibited by combination treatment. However, this combination failed to show any survival and tumor inhibition benefits in intracranial xenograft mouse models. Citation Format: Jianwen Dong, Emmanuel Martinez-Ledesma, Nghi Nguyen, Shaofang Wu, Yuji Piao, Ningyi Tiao, Soon Young Park, David Brunell, Clifford Stephan, Roel Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. High-throughput screening of glioma stem-like cells (GSCs) identifies synergistic therapeutic combination of FGFR inhibitor and CDK4/6 inhibitor [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 4819.
Abstract 18751: Inhalable Delivery of AAV-based Mrp4/abcc4 Silencing Rna Attenuates Monocrotaline-induced Pulmonary Hypertension
Authors: CarolineClaude, NathalieMougenot, JuliaBechaux, MichelClergue, FabriceAtassi, Anne-MarieLompré, Jean-SebastienHulot
Journal: Circulation (2014)

The ATP-binding cassette transporter MRP4 (encoded by ABCC4) functions as a plasma membrane efflux pump to extrude cyclic nucleotides from various cell types. MRP4 regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells (SMCs). In previous experiments, we have shown that MRP4 silencing inhibits SMCs proliferation in vitro. Concordantly, MRP4/ABCC4 deficient mice display a reduction in SMCs proliferation and a prevention of pulmonary hypertension in response to hypoxia. We here aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery (using a MicroSprayer® Aerosolizer) of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed thirty-five days later. The efficiency of this approach to transduce the lung vas...
Differential Role of KATP Channels Activated by Conjugated Estrogens in the Regulation of Myocardial and Coronary Protective Effects
Authors: Tsung-MingLee, Tsai-FwuChou, Chang-HerTsai
Journal: Circulation (2003)

Background— We have demonstrated that estrogen can reduce myocardial injury in ischemia-reperfusion via activation of ATP-sensitive potassium (KATP) channels. We sought to determine whether the protective effect of estrogen extends to epicardial coronary artery with attenuated vasoconstriction in patients after angioplasty by activation of such channels. Methods and Results— The study was designed to prospectively investigate 41 consecutive patients scheduled for elective coronary angioplasty. Pretreatment with estrogen limited myocardial ischemia during coronary occlusion and attenuated postangioplasty coronary vasoconstriction at the dilated and distal segments. An inhibitor of KATP channels, glibenclamide, did not affect coronary vasomotor response, although it abolished the beneficial effect of estrogen on myocardial ischemia. Patients to whom estrogen was administered after the second balloon deflation experienced a similar magnitude of myocardial ischemia as controls but showed significantly attenua...
A Vascular Abnormality in Hypertension
Authors: Jamesconway
Journal: Circulation (1963)

Forearm blood flow measurements have been made at rest and after 8 to 10 minutes arterial occlusion in 50 normal and 131 untreated hypertensive subjects. The latter group comprised 91 with essential hypertension; 11 with chronic renal disease (nephritis or pyelonephritis); 21 with renovascular disease; and eight with primary aldosteronism. The resting blood flow increased with the rising pressure in patients with mild hypertension but there was a significant increase in the resting resistance in the more severe cases. The average minimal resistance obtained during reactive hyperemia was greater in hypertensive (3.1 SE 1.0 units) than in normal subjects (2.0 SE 0.07 units). This abnormality was related to the level of blood pressure but not to the duration of the disease. Patients with renovascular disease or aldosteronism presented the same vascular fault as the more common causes of hypertension. Evidence is presented to show that the reactive hyperemia produced maximal dilatation of the forearm vasculat...
Process of Progression of Coronary Artery Lesions From Mild or Moderate Stenosis to Moderate or Severe Stenosis
Authors: KoichiYokoya, HisatoTakatsu, TakahikoSuzuki, HiroakiHosokawa, ShinsukeOjio, TetsuoMatsubara, TsutomuTanaka, SachiroWatanabe, NorihikoMorita, KazuhikoNishigaki, GenzouTakemura, ToshiyukiNoda, ShinyaMinatoguchi, HisayoshiFujiwara
Journal: Circulation (1999)

Background—The process of progression in coronary artery disease is unknown. Methods and Results—The subjects were 36 patients with 36 objective vessels with clinically significant progression of coronary artery disease (≥15% per year) in whom 4 serial coronary arteriograms (CAGs) were performed at intervals of ≈4 months in a 1-year period. The degree of progression of percent stenosis between each of 2 serial CAGs was classified as marked (M: ≥15%), slight (S: 5% to 14%), and no progression (N: <5%). From the pattern of progression, the 36 vessels were classified as 14 type 1 vessels with marked progression (N→N→M in 13 vessels and S→S→M in 1 vessel) and 22 type 2 vessels without marked progression (S→S→S in 18 vessels, N→S→S in 4). Percent stenosis at the first, second, third, and final CAGs was 44±14%, 46±13%, 46±13%, and 88±10% (P<0.05 versus first CAG) in type 1 vessels and 44±11%, 50±9%, 59±9%, and 67±9% in type 2 vessels (P<0.05 for second, third, and final CAGs versus first CAG). Type 1 vessels fe...
Abstract 16511: EN-RAGE: A Novel Inflammatory Marker for Coronary Heart Disease
Authors: Symen Ligthart, Sanaz Sedaghat, M A Ikram, Albert Hofman, Oscar H Franco, Abbas Dehghan
Journal: Circulation (2014)

Introduction: Inflammation plays a key role in atherosclerosis. We hypothesized that uninvestigated inflammatory markers may predict the risk of coronary heart disease (CHD). Methods: We investigated the association of 16 inflammatory biomarkers with the risk of CHD in a random subset of 839 CHD free individuals in a prospective population-based cohort study. A Bonferroni corrected p-value of 3.1х10 -3 was used as a threshold of statistical significance. We additionally tested whether the association of any identified marker was independent of traditional CHD risk factors and previously studied inflammatory markers. Results: Mean age at baseline was 72.8 years. During a median follow-up of 10.6 years, 99 cases of incident CHD were observed. Among all novel inflammatory biomarkers, neutrophil derived human s100a12 (EN-RAGE) showed the strongest association with the risk of CHD (p-value 2.0х10 -3 ). In the age and sex adjusted model, each standard deviation increase in the natural log-transformed EN-RAGE was associated with 37% higher risk of incident CHD (Hazard ratio (HR): 1.37; 95% confidence interval (CI) CI: 1.12 - 1.67). After further adjustment for established cardiovascular risk factors, the effect estimates attenuated slightly (HR: 1.30; 95% CI: 1.06 - 1.59). Adjustment for ten previously studied inflammatory markers did not attenuate the association (HR: 1.41; 95% CI: 1.12 - 1.77). Excluding individuals with prevalent type 2 diabetes, impaired kidney function or individuals using antihypertensive medication did not change the effect estimates. Conclusions: Our results highlight EN-RAGE as a novel inflammatory marker for CHD independent of traditional CHD risk factors and inflammatory markers, suggesting a specific inflammatory risk pathway for CHD.
Stent-Induced Expression and Activation of the Leukocyte Integrin Mac-1 Is Associated With Neointimal Thickening and Restenosis
Authors: TeruoInoue, ToshihikoUchida, IsaoYaguchi, YoshihikoSakai, KanTakayanagi, ShigenoriMorooka
Journal: Circulation (2003)

Background— Increased expression of the β2 integrin Mac-1 (CD11b/CD18, αMβ2), which is responsible for firm leukocyte adhesion to platelets and fibrinogen at injured vessels, is found in association with neointimal hyperplasia after coronary interventions. The role of Mac-1 in the pathophysiology of restenosis is incompletely defined. To clarify further the role of Mac-1, we determined whether coronary stenting induced activation of Mac-1, which is required for high-affinity receptor-ligand interactions. Methods and Results— Expression of CD11b (α-subunit of Mac-1) and binding of 8B2 (monoclonal antibody against an activation-dependent neoepitope of Mac-1) on the surface of polymorphonuclear leukocytes were analyzed in 62 patients undergoing coronary stenting using flow cytometric analysis of whole blood obtained from the coronary sinus and femoral vein. Transcardiac CD11b expression increased significantly at 24 hours and maximally at 48 hours after stenting; 8B2 began to increase at 10 minutes and was m...
Abstract 3947: Glutaminolysis inhibitors benzo[d][1,2]selenazol -3(2H)-one dimers completely disrupt mitochondrial function and showed early promise as effective antitumor agents with little general toxicity
Authors: Benfang Helen Ruan, Yan Yu, Zhao Chen, Yanhong Jin, Jinzhang Fang, Han Zhao, Jennifer Ruan
Journal: Cancer Research (2018)

Abstract Targeting glutaminolysis is an emerging approach to solve the imminent problems of drug resistance and drug toxicity in cancer therapeutics. Ebselen was identified in the KGA coupled assay as a potent KGA inhibitor but showed very low potency in inhibiting the growth of glutamine - dependent cancer cells. For rigorous characterization, we developed a direct kinetic binding assay for KGA using Bio-Layer Interferometry (BLI) as the detection method; Ebselen was identified as a GDH inhibitor but not a KGA inhibitor. Proteomic analysis demonstrated that the ebselen derivative could crosslink with KGA protein, but the binding site is at the N-terminal appendix domain outside of the catalytic domain, which might explain why ebselen is not a potent KGA enzyme inhibitor in functional assays. Furthermore, we designed and synthesized several benzo[d][1,2]selenazol -3(2H)-one dimers which were subjected to SAR analysis by several glutaminolysis specific biochemical and cell based assays. Novel dual KGA/GDH inhibitors were discovered from the synthetic compounds; the dual inhibitors completely disrupt mitochondrial function, depleted cellular NAD(P)H levels, induced ROS mediated cell death, and inhibited the growth of various cancer cells but not the normal cells. Importantly, in an aggressive liver cancer mouse model, a KGA/GDH inhibitor reduced the tumor size by 50-60% and lowered plasma lactate dehydrogenase (a biomarker of tumor metastasis) by 2-3 times. Thus, the novel dual-specific KGA/GDH inhibitors showed early promise as effective antitumor agents with little general toxicity. Citation Format: Benfang Helen Ruan, Yan Yu, Zhao Chen, Yanhong Jin, Jinzhang Fang, Han Zhao, Jennifer Ruan. Glutaminolysis inhibitors benzo[d][1,2]selenazol -3(2H)-one dimers completely disrupt mitochondrial function and showed early promise as effective antitumor agents with little general toxicity [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 3947.
l-Arginine Treatment Alters the Kinetics of Nitric Oxide and Superoxide Release and Reduces Ischemia/Reperfusion Injury in Skeletal Muscle
Authors: IgorHuk, JosephNanobashvili, ChristophNeumayer, AndreasPunz, MarkusMueller, KawehAfkhampour, MartinaMittlboeck, UdoLosert, PeterPolterauer, ErichRoth, StephenPatton, TadeuszMalinski
Journal: Circulation (1997)

Background Constitutive nitric oxide synthase (cNOS) may produce species involved in ischemia/reperfusion (I/R) injury: NO in the presence of sufficient l-arginine and superoxide at the diminished local l-arginine concentration accompanying I/R. Methods and Results During hindlimb I/R (2.5 hours/2 hours), in vivo NO was continuously monitored (porphyrinic sensor), and l-arginine (chromatography), superoxide (chemiluminescence), and I/R injury were measured intermittently. Normal rabbits were compared with those infused with l-arginine 4 mg·kg−1·min−1 for 1 hour. In both groups, ≈6 minutes into ischemia, a rapid increase of NO from its basal level of 50±17 to 115±7 nmol/L, P<.005 (microvessels), was observed. In animals not treated with l-arginine, NO dropped below basal to undetectable levels (<1 nmol/L) during reperfusion. In animals treated with l-arginine, the decrease of NO was slower, such that substantial amounts accumulated during reperfusion (25 nmol/L). Decreased NO during I/R was accompanied by ...