tbuckley/cabot-search huggingface dataset:
Abstract 14876: Prognostic Impact of Cardio-renal-anemia Syndrome in Patients at Risk for Heart Failure
Authors: Masatoshi Minamisawa, Takashi Miura, Hirohiko Motoki, Yasushi Ueki, Hitoshi Nishimura, Wataru Shoin, Tomoaki Mochidome, Keisuke Senda, Yasutaka Oguchi, Tatsuya Saigusa, Soichiro Ebisawa, Koichiro Kuwahara
Journal: Circulation (2017)

Introduction: Cardio-renal-anemia (CRA) syndrome has begun to gather attention as a vicious circle since chronic heart failure (CHF), chronic kidney disease (CKD), and anemia are able to be caused ...
Contribution of Adventitial Fibroblasts to Neointima Formation and Vascular Remodeling
Authors: SaverioSartore, AngelaChiavegato, ElisabettaFaggin, RafaellaFranch, MassimoPuato, SimonettaAusoni, PaoloPauletto
Journal: Circulation Research (2001)

The adventitial layer surrounding the blood vessels has long been exclusively considered a supporting tissue the main function of which is to provide adequate nourishment to the muscle layers of tunica media. Although functionally interconnected, the adventitial and medial layers are structurally interfaced at the external elastic lamina level, clearly distinguishable at the maturational phase of vascular morphogenesis. Over the last few years the “passive” role that the adventitia seemed to play in experimental and spontaneous vascular pathologies involving proliferation, migration, differentiation, and apoptosis of vascular smooth muscle cells (VSMCs) has been questioned. It has been demonstrated that fibroblasts from the adventitia display an important partnership with the resident medial VSMCs in terms of phenotypic conversion, proliferation, apoptotic, and migratory properties the result of which is neointima formation and vascular remodeling. This article is an attempt at reviewing the major themes ...
Sex Differences in Mortality in Children Undergoing Congenital Heart Disease Surgery
Authors: ArianeMarelli, KimberleeGauvreau, MikeLandzberg, KathyJenkins
Journal: Circulation (2010)

Background—The changing demographics of the adult congenital heart disease (CHD) population requires an understanding of the factors that impact patient survival to adulthood. We sought to investigate sex differences in CHD surgical mortality in children. Methods and Results—Children <18 years old hospitalized for CHD surgery were identified using the Kids’ Inpatient Database in 2000, 2003, and 2006. Demographic, diagnostic, and procedural variables were grouped according to RACHS-1 (Risk Adjustment for Congenital Heart Surgery) method. Logistic regression was used to determine the odds ratio of death in females versus males adjusting for RACHS-1 risk category, age, prematurity, major noncardiac anomalies, and multiple procedures. Analyses were stratified by RACHS-1 risk categories and age. Of 33 848 hospitalizations for CHD surgery, 54.7% were in males. Males were more likely than females to have CHD surgery in infancy, high-risk CHD surgery, and multiple CHD procedures. Females had more major noncardiac...
Intra-Arrest Transnasal Evaporative Cooling
Authors: MaaretCastrén, PerNordberg, LeifSvensson, FabioTaccone, Jean-LouiseVincent, DidierDesruelles, FrankEichwede, PierreMols, TilmannSchwab, MichelVergnion, ChristianStorm, AntonioPesenti, JanPachl, FabienGuérisse, ThomasElste, MarkusRoessler, HaraldFritz, PieterjanDurnez, Hans-JörgBusch, BeckyInderbitzen, DeniseBarbut
Journal: Circulation (2010)

Background— Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge. Methods and Results— Witnessed cardiac arrest patients with a treatment interval ≤20 minutes were randomized to intra-arrest cooling with a RhinoChill device (treatment group, n=96) versus standard care (control group, n=104). The final analysis included 93 versus 101 patients, respectively. Both groups were cooled after hospital arrival. The patients had similar demographics, initial rhythms, rates of bystander cardiopulmonary resuscitation, and intervals to cardiopulmonary resuscitation and arrival of advanced life support personnel. Eighteen device-related adverse events (1 periorbital emphysema, 3 epistaxis, 1 perioral bleed, and 13 nasal discolor...
Abstract 5501: The role of G-protein coupled receptor 64 (GPR64) as a tumor suppressor in endometrial cancer
Authors: Jung-Yoon Yoo, Jong Il Ahn, Tae Hoon Kim, Russell R. Broaddus, Jeong Mook Lim, Ho-Geun Yoon, Jae-Wook Jeong
Journal: Cancer Research (2018)

Abstract Endometrial cancer is the most common gynecologic cancer. G-protein coupled receptor 64 (GPR64) belongs to a family of adhesion GPCRs and plays an important role for male fertility. However, GPR64 function has not been reported in endometrial cancer. Our objective is to investigate the role of GPR64 in endometrial cancer. We examined the levels of GPR64 in human endometrial cancer tissue by immunohistochemistry analysis. GPR64 levels were significantly lower in 10 of 21 (47.62%) of endometrial carcinoma samples compared to control. To test whether GPR64 has a role of tumor suppressor in endometrial cancer, we used an siRNA loss-of-function approach in human endometrial adenocarcinoma cell lines. Depletion of GPR64 by siRNA transfection in Ishikawa and HEC1A cells showed an increase of colony formation ability and cell proliferation. Depletion of GPR64 also significantly increased the migration and invasion activity of Ishikawa and HEC1A cells. Furthermore, the phosphorylation of AMP-activated protein kinase (AMPK) and expression of Connexin 43 (Cx43), a member of the large family of gap junction proteins, were regulated in GPR64-deficient Ishikawa cells. These results suggest that GPR64 plays an important role for cell proliferation, migration, and invasion as a tumor suppressor in endometrial cancer. Citation Format: Jung-Yoon Yoo, Jong Il Ahn, Tae Hoon Kim, Russell R. Broaddus, Jeong Mook Lim, Ho-Geun Yoon, Jae-Wook Jeong. The role of G-protein coupled receptor 64 (GPR64) as a tumor suppressor in endometrial 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 5501.
Perioperative Dexmedetomidine Improves Outcomes of Cardiac Surgery
Authors: FuhaiJi, ZhongminLi, HungNguyen, NilasYoung, PengcaiShi, NealFleming, HongLiu
Journal: Circulation (2013)

Background—Cardiac surgery is associated with a high risk of cardiovascular and other complications that translate into increased mortality and healthcare costs. This retrospective study was designed to determine whether the perioperative use of dexmedetomidine could reduce the incidence of complications and mortality after cardiac surgery. Methods and Results—A total of 1134 patients who underwent coronary artery bypass surgery and coronary artery bypass surgery plus valvular or other procedures were included. Of them, 568 received intravenous dexmedetomidine infusion and 566 did not. Data were adjusted with propensity scores, and multivariate logistic regression was used. The primary outcomes measured included mortality and postoperative major adverse cardiocerebral events (stroke, coma, perioperative myocardial infarction, heart block, or cardiac arrest). Secondary outcomes included renal failure, sepsis, delirium, postoperative ventilation hours, length of hospital stay, and 30-day readmission. Dexmed...
Structure-Related Initiation of Reentry by Rapid Pacing in Monolayers of Cardiac Cells
Authors: WeiningBian, LeslieTung
Journal: Circulation Research (2006)

This study examines how a zigzag pattern of conduction, a form of structural heterogeneity frequently found in old or diseased hearts, affects the vulnerability to reentry during rapid pacing. A central rectangular island (8×4 mm) containing a predefined zigzag pattern was created in cultured isotropic monolayers of neonatal rat ventricular myocytes. Impulse propagation was optically mapped from 253 sites using voltage-sensitive dye and was anisotropic within the zigzag island. With increasing interval between neighboring transverse connections (a), relative to the distance between longitudinal strands (b), transverse conduction velocity (CV) decreased to 66±6%, 20±2%, and 15±2% of CV in the surrounding isotropic region, whereas longitudinal CV increased to 102±8%, 113±12%, and 131±23% for a:b ratios of 1:1, 1:5, and 1:9, respectively. During rapid pacing, propagation distal to the island was steered from the side of the island with more transverse connections (“dominant” side) toward the side with fewer ...
Left Ventricular Hypertrophy Demonstrated by Four-Dimensional Myocardiography by Helical Computed Tomography
Authors: YasushiKoyama, HiroshiMatsuoka, HiroshiHigashino, TeruhitoMochizuki, HideoKawakami, KatsujiInoue, IchirouSogabe, KazuhisaNishimura, ShigeruNakata, MasayaDoi, MasatoImai, HisashiShinohara, TaketoshiIto
Journal: Circulation (2001)
Prolonged Endoplasmic Reticulum Stress in Hypertrophic and Failing Heart After Aortic Constriction
Authors: Ken-ichiroOkada, TetsuoMinamino, YoshitaneTsukamoto, YulinLiao, OsamuTsukamoto, SeijiTakashima, AkioHirata, MasashiFujita, YokoNagamachi, TakeshiNakatani, ChikaoYutani, KentaroOzawa, SatoshiOgawa, HitonobuTomoike, MasatsuguHori, MasafumiKitakaze
Journal: Circulation (2004)

Background— The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear. Methods and Results— Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. O...
Abstract 4368: PAK4-NAMPT dual inhibition as a feasible strategy for treatment of resistant pancreatic neuroendocrine tumors
Authors: Gabriel Mpilla, Irfana Muqbil, Amro Aboukameel, Philip A. Philip, William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad, Asfar S. Azmi
Journal: Cancer Research (2018)

Abstract Our studies in pancreatic neuroendocrine tumor (pNET) cell lines demonstrate hyper-activation of the Rho GTPase effector p21 activated kinase 4 (PAK4) and the nicotinamide adenine dinucleotide (NAD) salvage pathway rate limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). The PAK4 protein is known to regulate a myriad of signaling proteins in the mTOR pathway including mTORC1, mTORC2, PI3K, and IGF-1. Similarly, NAMPT is recognized to regulate mTOR through energy sensor protein, AMPK. In this study, pNET cell lines QGP-1 and Bon-1 were subjected to either PAK4 RNA interference (RNAi), PAK4-NAMPT dual inhibitors (the clinical compound KPT-9274 or an analog KPT-7523) or the PAK4 specific inhibitor, PF-3738309 and NAMPT specific inhibitor FK866 in the presence or absence of mTOR inhibitors (everolimus or INK128). Gene expression profiling and phospho-proteomic analyses were performed to capture molecular changes post single or combination treatments. The anti-tumor activity of KPT-9274-everolimus was evaluated in a subcutaneous xenograft mouse model derived from QGP-1 and Bon-1 cells. PAK4 RNAi suppressed proliferation and restored everolimus sensitivity in pNET cell lines. The dual inhibitors were effective in reducing proliferation and inducing apoptosis. KPT-9274 or KPT-7523 could synergistically enhance the anti-tumor activity of everolimus or INK128 in pNET cell lines [CI &amp;lt;1]. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers such as mTORC1, mTORC2, PI3K, ERK, FAK, RICTOR, β-catenin and IGF-1. In addition, KPT-9274 and analogs suppressed the steady state level of NAD and ATP. Importantly, KPT-9274 given i.v. or orally at the maximum tolerated dose (140 mg/kg, once/day for 5 days/week for 4 weeks) dramatically inhibited the growth of QGP-1 and Bon-1 tumors. This is the first study demonstrating the role of PAK4 and NAMPT in pNETs. KPT-9274 is currently in a Phase I trial of patients with advance solid malignancies or NHL (NCT02702492). Our pre-clinical work establishes a solid rationale for a Phase II clinical study of KPT-9274 and an mTOR inhibitor combination for the treatment of difficult to treat pNETs. Citation Format: Gabriel Mpilla, Irfana Muqbil, Amro Aboukameel, Philip A. Philip, William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad, Asfar S. Azmi. PAK4-NAMPT dual inhibition as a feasible strategy for treatment of resistant pancreatic neuroendocrine tumors [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 4368.
Inhibition of TRPC6 Channel Activity Contributes to the Antihypertrophic Effects of Natriuretic Peptides-Guanylyl Cyclase-A Signaling in the Heart
Authors: HideyukiKinoshita, KoichiroKuwahara, MotohiroNishida, ZhongJian, XiangluRong, ShigekiKiyonaka, YoshihiroKuwabara, HitoshiKurose, RyujiInoue, YasuoMori, YuhaoLi, YasuakiNakagawa, SatoruUsami, MasatakaFujiwara, YukoYamada, TakeyaMinami, KenjiUeshima, KazuwaNakao
Journal: Circulation Research (2010)

Rationale: Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. Objective: We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca2+ channel known to positively regulate prohypertrophic calcineurin–nuclear factor of activated T cells (NFAT) signaling. Methods and Results: In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca2+ influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specif...
Abstract P182: Low Diastolic Blood Pressure is Associated With Subclinical Myocardial Disease and Cardiac Events in Patients With Coronary Artery Disease
Authors: Matthew L Topel, Pratik B Sandesara, Eric P Stahl, Yi-An Ko, Ayman S Tahhan, Salim S Hayek, Arshed A Quyyumi
Journal: Circulation (2018)

Introduction: Clinical trials have shown increased survival at lower blood pressures, but low diastolic blood pressure (DBP) is associated with increased cardiovascular (CV) events and mortality. The suggested mechanism in patients with coronary artery disease (CAD) is limitation in coronary blood flow; however, evidence is lacking. We investigated the association between DBP, biomarkers of myocardial injury, and incident events in patients with CAD. Methods: We assessed 2448 individuals (aged 65±12 years, 68% male, median follow-up 4.5 years) with stable CAD undergoing cardiac catheterization. Those with acute coronary syndromes or heart failure with reduced ejection fraction were excluded. DBP was categorized into 10 mm Hg increments. Biomarkers of myocardial damage (high sensitivity cardiac troponin-I [hs-cTnI] and soluble urokinase plasminogen activating receptor [suPAR]) were dichotomized at their median values. DBP 80-89 mmHg was used as the referent group and individuals were followed for MACE (CV death or non-fatal myocardial infarction) and all-cause mortality. Results: After adjusting for relevant demographic and clinical covariates, individuals with DBP &lt; 60 mm Hg had increased odds of elevated hs-cTnI (OR = 1.75; 95% CI = 1.05, 2.90) and suPAR (OR = 1.73; 95% CI = 1.09, 2.76) compared to the referent group. Additionally, DBP &lt; 60 mm Hg was associated with increased risk of MACE (HR = 2.01; 95% CI = 1.24, 3.25) and all-cause mortality (HR = 2.18; 95% CI = 1.50, 3.19). Adding hs-cTnI and suPAR into the Cox proportional hazards model attenuated the association between DBP &lt; 60 mmHg and MACE (HR =1.63, 95% CI 0.91, 2.91), but not all-cause mortality (HR = 1.67, 95% CI = 1.06, 2.63). Conclusion: In patients with CAD, low DBP is associated with biomarkers of myocardial injury and incident events. Aggressive blood pressure control may be harmful in these patients, and further investigation is warranted to determine appropriate blood pressure targets in patients with CAD.
Abstract 831: Reproducible, mechanism of action-reflecting reporter based bioassays to enable drug development of biosimilars and biobetters
Authors: Richard L. Somberg, Rich Moravec, Dun Li, Aileen Paguio, Mei Cong
Journal: Cancer Research (2018)

Abstract The demand for biosimilars and bioassays for biosimilars are increasing as the patent cliff approaches for many blockbuster biologics. Recently, the expanded approval of Actemra (Tocilizumab) to treat CAR T-cell-induced cytokine release syndrome (CRS) demonstrated the role of anti-IL-6 blocking drugs as critical for the treatment of serious diseases such as cancer and autoimmune diseases. Here we describe a portfolio of luciferase reporter-based bioassays to support the development and potency determination of biosimilar drugs targeting cytokines such as IL-2, IL-6, IL-12, IL-15, IL-12/23, IL-17, VEGF, RANK, Epo, IFNs, etc. The availability of quantitative, functional bioassays in Thaw-and-Use format provides the benefit of convenience, reproducibility, and transferability. We demonstrate these assays are able to measure relative potency for antibody biologics and detect potency changes for stressed antibody samples. In summary, the reporter-based bioassay portfolio for biosimilars provides a valuable tool for the development, stability testing, and potency determination in manufacture of biosimilars and biobetters. Citation Format: Richard L. Somberg, Rich Moravec, Dun Li, Aileen Paguio, Mei Cong. Reproducible, mechanism of action-reflecting reporter based bioassays to enable drug development of biosimilars and biobetters [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 831.
Cytomegalovirus Antigen Expression, Endothelial Cell Proliferation, and Intimal Thickening in Rat Cardiac Allografts After Cytomegalovirus Infection
Authors: KarlLemström, PetriKoskinen, LeenaKrogerus, MatDaemen, CathrienBruggeman, PekkaHäyry
Journal: Circulation (1995)

Background Cardiac allograft arteriosclerosis is the primary cause of late death in heart transplant recipients. Clinical studies have suggested that humoral and cellular immune response, hyperlipidemia, and cytomegalovirus (CMV) infection may amplify the disease. In this study, the role of CMV infection in the development of rat cardiac allograft arteriosclerosis is investigated. Methods and Results Heterotopic rat cardiac allografts were performed from the DA to the WF rat strains. To prevent rejection, the recipients received triple-drug (cyclosporine A 20 mg · kg−1 · d−1, azathioprine 2 mg · kg−1 · d−1, and methylprednisolone 0.5 mg · kg−1 · d−1) immunosuppression postoperatively. Recipient rats were infected intraperitoneally (n=21) with 105 plaque-forming units of rat CMV (RCMV) 1 day after transplantation or were left uninfected and used as controls (n=18). The grafts were removed 7 and 14 days and 1 and 3 months after transplantation. In 42% (9 of 21) of cardiac allografts in RCMV-infected rats, a...
Abstract 2330: CaV1.3 calcium channel expression in prostate cancer cells during androgen-deprivation conditions
Authors: Niamh McKerr, Conor Breen, Kirtiman Srivastava, Ian G. Mills, Karen D. McCloskey
Journal: Cancer Research (2018)

Abstract Background Prostate cancer (PCa) remains one of the most frequently diagnosed cancers in males in the western world. Despite efforts to reduce tumour burden through treatments including androgen-deprivation therapy (ADT), patients often relapse 2 years post-therapy due to emergence of castration-resistant disease. The importance of ion channels including calcium channels in cancer biology is increasingly recognized. CACNA1D encodes the calcium channel, CaV1.3, which is overexpressed in PCa biopsies. In addition to canonical ion transport, the c-terminal region of CaV1.3 may modulate gene expression. The purpose of this study was to elucidate the expression of CaV1.3 during PCa progression and explore the effects of calcium channel blockers. Methods A cell line panel comprising normal prostate epithelium (RWPE-1), androgen-sensitive PCa (LNCaP, VCaP) and castration-resistant PCa (C4-2B, DU145 and PC3) were used. LNCaP were cultured in charcoal-stripped serum-containing media to mimic ADT or with the anti-androgen enzalutamide (10μM) for 4-14 days. qPCR, Western blotting and immunofluorescence imaging were performed. Cell viability assays were performed in the absence/presence of ADT, enzalutamide and the CaV1.3 blocker nifedipine (1μM). Apoptosis was measured with flow cytometry in cells stained with Annexin V/Propidium Iodide (AV/PI). Results CACNA1D mRNA had higher expression in LNCaP, VCaP and C4-2B vs. RWPE-1 (p≤0.05; N=3). Western blotting/densitometry showed higher protein expression of CaV1.3 in LNCaP, VCaP and C4-2B relative to RWPE-1 (P≤0.05; N=3). Immunofluorescence indicated cytoplasmic and perinuclear localisation of CaV1.3 in the majority of cell lines and diffuse cytoplasmic staining in VCaP (N=2). ADT and enzalutamide-treated LNCaP displayed time-dependent increased CACNA1D expression over 14 days however, CaV1.3 protein expression peaked at 4 days (N=3). Cell viability assays of LNCaP treated with ADT or enzalutamide (4 days) showed significant reduction in viability when nifedipine was combined with the treatment (N=3; P≤0.05). Similarly, increased % of apoptotic LNCaP cells were observed when nifedipine was added to treated LNCaP vs. ADT or enzalutamide alone (N=2). Conclusion CaV1.3 expression is differentially expressed in cells lines modelling PCa progression and enhanced during ADT. Blockade of CaV1.3 in combination with ADT treatments further reduced cell viability and increased the apoptotic population. Citation Format: Niamh McKerr, Conor Breen, Kirtiman Srivastava, Ian G. Mills, Karen D. McCloskey. CaV1.3 calcium channel expression in prostate cancer cells during androgen-deprivation conditions [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 2330.