tbuckley/cabot-search huggingface dataset:
Abstract 5463: Free fatty acids augment radiation-induced cytotoxicity in cervical cancer cells via mTOR/Akt//PPARg/p53-mediated pathway
Authors: Naoshad Muhammad, Ramachandran Rashmi, Fiona Ruiz, Michael C. Zahner, Julie K. Schwarz
Journal: Cancer Research (2018)

Abstract Purposes of the study: Our clinical results show that obese patients with cervical cancer who are treated with definitive chemoradiation have favorable outcomes, and this effect is independent of diabetes or metformin use. PI3K/AKT pathway signaling is decreased in cervical tumors from obese hosts, even in the context of genomic mutations that would otherwise activate PI3K signaling, such as PTEN deletion. The objective of the present study is to determine whether other factors related to obesity, such as circulating free fatty acids, influence radiation responses in vitro. Experimental procedures: Radiation sensitivity experiments were performed in cervical cancer cells with and without PI3K pathway mutations (CaSki (mutant), ME180 (mutant), SiHa (WT). To determine whether combination treatment of free fatty acids (palmitic, oleic and linoleic) plus radiation increases cytotoxicity in cervical cells, we performed cell viability assay, long term colony formation assays (CFA) and morphological examination by vertical microscope. To determine whether the addition of free fatty acids to radiation influences cell survival signaling, a series of Western blots were performed. Summary: We observed that combination treatment of free fatty acids and radiation significantly increased cytotoxicity in all the cervical cancer cell lines tested. Mechanistic investigations revealed that free fatty acids induced potentiation of radiation-induced cytotoxicity through downregulation of p-mTOR, p-Akt and PTEN. Furthermore, we observed that this combination regimen upregulates the expression PPARγ and p53. Conclusions: Free fatty acids potentiated the effect of radiation in PI3K-activated cervical cancer cell lines through mTOR/Akt//PPARg/p53 mediated pathway. Future studies will characterize the mechanism of free fatty acid potentiation of radiation-induced tumor cell death in detail, including the potential contribution of lipid peroxidation and alterations in glucose metabolism. Citation Format: Naoshad Muhammad, Ramachandran Rashmi, Fiona Ruiz, Michael C. Zahner, Julie K. Schwarz. Free fatty acids augment radiation-induced cytotoxicity in cervical cancer cells via mTOR/Akt//PPARg/p53-mediated pathway [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 5463.
Severely Impaired Cardiac Autonomic Nervous Activity After the Fontan Operation
Authors: HideoOhuchi, SatoshiHasegawa, KenjiYasuda, OsamuYamada, YasuoOno, ShigeyukiEchigo
Journal: Circulation (2001)

Background Elevated neurohumoral activity and an abnormal cardiopulmonary response to exercise are well-established characteristics in patients after the Fontan operation. However, there have been few studies addressing cardiac autonomic nervous activity (CANA) in these patients. Methods and Results We evaluated CANA in 63 post-Fontan patients and 44 controls. Cardiac parasympathetic nervous activity (PSNA) was estimated by heart rate (HR) changes after cholinergic blockade, HR variability, and arterial baroreflex sensitivity. Cardiac sympathetic nervous activity was estimated by the heart to mediastinum [123I]metaiodobenzylguanidine activity ratio (H/M) and the HR increase (ΔHR) after isoproterenol infusion (β). ΔHR and peak oxygen uptake (Vo2) were measured by exercise test. There was no difference in β between the Fontan group and controls. PSNA and H/M were markedly lower than in controls (P<0.001). PSNA and β were related to ΔHR (P<0.05); however, peak Vo2 was not correlated with ΔHR. Neither PSNA ...
Abstract 15852: PKR-Like Endoplasmic Reticulum Kinase (PERK) and Glycogen Synthase Kinase (GSK)-3α/β Signaling Regulate Atherosclerosis Development
Authors: CameronMcAlpine, GeoffWerstuck
Journal: Circulation (2014)

Background: Recently, a role for endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β has been proposed in atherogenesis; this study sought to delineate the underlying molecular mechanisms. Methods and Results: Cultured THP1-derived macrophages were treated with the ER stress-inducing agents, glucosamine, thapsigargin or palmitate in the presence or absence of inhibitors of the unfolded protein response (UPR) pathways (PERK, IRE, ATF6) or GSK3α/β (CT99021). ER stress enhanced GSK3α/β activity while inhibition of the PERK pathway, but not the IRE or ATF6 pathways, attenuated GSK3α/β activity. GSK3α/β inhibition did not affect adaptive components of the UPR but did repress the expression of factors downstream of PERK (ATF4 and CHOP). ER stress enhanced the mRNA expression of genes controlling lipid biosynthesis and uptake; while GSK3α/β inhibition attenuated this effect. GSK3α/β inhibition blocked ER stress-induced cholesterol accumulation in macrophages. To investigate th...
Dietary Patterns and the Risk of Acute Myocardial Infarction in 52 Countries
Authors: RomainaIqbal, SoniaAnand, StephanieOunpuu, ShofiqulIslam, XiaoheZhang, SumathyRangarajan, JephatChifamba, AliAl-Hinai, MatyasKeltai, SalimYusuf
Journal: Circulation (2008)

Background— Diet is a major modifiable risk factor for cardiovascular disease, but it varies markedly in different regions of the world. The objectives of the present study were to assess the association between dietary patterns and acute myocardial infarction (AMI) globally. Methods and Results— INTERHEART is a standardized case-control study involving participants from 52 countries. The present analysis included 5761 cases and 10 646 control subjects. We identified 3 major dietary patterns using factor analysis: Oriental (high intake of tofu and soy and other sauces), Western (high in fried foods, salty snacks, eggs, and meat), and prudent (high in fruit and vegetables). We observed an inverse association between the prudent pattern and AMI, with higher levels being protective. Compared with the first quartile, the adjusted ORs were 0.78 (95% CI 0.69 to 0.88) for the second quartile, 0.66 (95% CI 0.59 to 0.75) for the third, and 0.70 (95% CI 0.61 to 0.80) for the fourth (P for trend <0.001). The Western...
Thrombomodulin Prolongs Thrombin-Induced Extracellular Signal–Regulated Kinase Phosphorylation and Nuclear Retention in Endothelial Cells
Authors: Jean-MarcOlivot, EvaEstebanell, MoniqueLafay, BrigitteBrohard, MartineAiach, FrancineRendu
Journal: Circulation Research (2001)

Abstract—On endothelial cells, thrombin binds to thrombomodulin (TM), an integral membrane-bound glycoprotein, and to protease-activated receptors (PARs). Thrombin binding to TM modulates endothelial cell and smooth muscle cell proliferation mediated through PAR1. We studied the phosphorylation and nuclear translocation of extracellular signal–regulated kinases (ERKs) 1 and 2 in human umbilical vein endothelial cells activated by thrombin. Thrombin and thrombin receptor–activating peptide (TRAP)-induced DNA synthesis were significantly inhibited by PD98059, an inhibitor of ERK phosphorylation. Immunoblots of phosphorylated ERKs (pERKs) and immunocytochemical studies of pERK localization revealed differences in the signal generated by thrombin and TRAP. After a short activation (15 minutes), the phosphorylation and the intracellular localization of pERKs were the same with the 2 agonists. After 4 hours, however, pERKs were visualized in the nuclei of thrombin-activated cells but barely detectable in TRAP-a...
Abstract 18637: Recurrence Quantification Analysis to Distinguish Active From Passive Mechanisms of CFAEs During Catheter Ablation of Atrial Fibrillation
Authors: Alex Baher, Anil K Gehi, Prabhat Kumar, Eugene Chung, Benjamin H Buck, John P Mounsey, Joe G Akar, James P Hummel
Journal: Circulation (2015)

Background: Ablation of complex fractionated atrial electrograms (CFAEs) is controversial, primarily because of difficulty in visually distinguishing CFAEs representing an active site of driver activity from a passive site of double potentials, wave break, and/or slow conduction. We hypothesized that CFAEs within rotors in atrial fibrillation (AF) would exhibit highly recurrent behavior compared with CFAEs remote from these driver regions. Methods: Active and passive mechanisms of CFAE formation were simulated in several 2D 7.5 x 7.5 cm modified Luo-Rudy 1 models. CFAEs within areas of rotors were considered active, while those caused by wave break, slow conduction or double potentials remote from rotors were considered passive. Clinical signals were also collected during catheter ablation of paroxysmal AF (n=8 patients). An active driver CFAE site was defined by termination of AF with ablation followed by non-inducibility. A passive site was defined as CFAE occurring remotely. Detection of CFAEs was based on mean cycle length (MCL) calculated from 4 second windows using -dV/dt for detection (40ms refractory period/10ms maximum EGM width for simulations; 45ms/15ms respectively for clinical signals). Recurrence quantification analysis (RQA) was performed on discrete time series of simulated and clinical CFAE activations. Results: RQA was performed on 20 simulated EGMs. MCL was similar in both active and passive CFAEs (74±11ms and 78±6ms respectively, p=NS), but recurrence was significantly higher in active compared to passive sites (%recurrence: 61±22% active, 4±6% passive, p&lt;0.01). In patients with AF, the driver sites were all located within the pulmonary vein antra while passive CFAEs were remote. The MCL of CFAEs at active driver sites was similar to that of passive sites (100±13ms active, 98±17ms passive, p=NS), but recurrence was significantly higher in the active driver sites (%recurrence: 18±15% active, 2±1% passive, p=0.02). Conclusion: CFAEs may occur due to either active or passive mechanisms. Sites within rotors or focal drivers of AF are more likely to exhibit recurrent patterns. RQA may be a powerful tool to differentiate driver from bystander CFAEs enabling more efficient targeting for ablation.
Low to Moderate Air Pollutant Exposure and Acute Respiratory Distress Syndrome after Severe Trauma
Authors: John P. Reilly, Zhiguo Zhao, Michael G. S. Shashaty, Tatsuki Koyama, Jason D. Christie, Paul N. Lanken, Chunxue Wang, John R. Balmes, Michael A. Matthay, Carolyn S. Calfee, Lorraine B. Ware
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Exposure to air pollution has molecular and physiologic effects on the lung that may increase the risk of acute respiratory distress syndrome (ARDS) after injury.To determine the association of short- and long-term air pollutant exposures and ARDS risk after severe trauma.We analyzed data from a prospective cohort of 996 critically ill patients presenting with acute trauma and an injury severity score greater than 15. Exposures to ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and particulate matter less than 2.5 μm were assessed by weighted averages of daily levels from all monitors within 50 km of the geocoded location of a patient's residence. Patients were followed for 6 days for the development of ARDS according to Berlin Criteria. The association between each exposure and ARDS was determined via multivariable logistic regression adjusting for potential confounders.ARDS developed in 243 (24%) patients. None of the short-term exposures averaged over the 3 days before presentation was associated with ARDS, except sulfur dioxide, which demonstrated a nonlinear association. Nitrogen dioxide, sulfur dioxide, and particulate matter less than or equal to 2.5 μm in aerodynamic diameter exposure over the 6 weeks before presentation was significantly associated with ARDS (P < 0.05). All long-term exposures (3 yr) were associated with ARDS (P < 0.01) in adjusted models, despite exposure levels largely below U.S. and European Union air quality standards.Long-term low- to moderate-level air pollutant exposure is associated with a greater risk of developing ARDS after severe trauma and represents a novel and potentially modifiable environmental risk factor for ARDS.
Abstract LB-055: Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive, basal-like breast cancer
Authors: Allison P. Drain, Ken Takai, Devon A. Lawson, Laurie E. Littlepage, Marcela Karpuj, Kai Kessenbrock, Annie Le, Kenichi Inoue, Valerie M. Weaver, Zena Werb
Journal: Cancer Research (2018)

Abstract Breast cancer studies implicate the discoidin domain receptor 1 (DDR1) in both pro- and anti-tumor roles. DDR1 is often overexpressed in breast tumors and its activation by collagen promotes tumor cell invasion and potentiates metastatic colonization by cell lines. However, DDR1 transfection into low DDR1 expressing tumor cells hinders cell migration. Moreover, low expression of DDR1 correlates with higher grade human tumors and associates with worse prognosis. To better understand the role of DDR1 in breast tumor progression and metastasis, we established a DDR1 knockout and crossed it into the MMTV-PyMT mouse. DDR1 loss compromised luminal cell adhesion and expanded the basal/myoepithelial population in adult mice. PyMT DDR1-/- tumors grew faster and had increased lung metastasis both in size and number of metastatic colonies. The DDR1-/- tumors broadly exhibited a more basal-like phenotype with enhanced fibrosis and were more hypoxic. Furthermore, these tumors contained more CD90+ CD24+ tumor cells and more K8+ K14+ cells surrounding necrotic regions. Taken together these data suggest DDR1 loss confers a growth advantage favoring basal cell expansion via impaired luminal adhesion and enhanced basal differentiation leading to more aggressive, basal-like disease. Citation Format: Allison P. Drain, Ken Takai, Devon A. Lawson, Laurie E. Littlepage, Marcela Karpuj, Kai Kessenbrock, Annie Le, Kenichi Inoue, Valerie M. Weaver, Zena Werb. Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive, basal-like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-055.
Effects of Probucol on Vascular Remodeling After Coronary Angioplasty
Authors: GillesCôté, Jean-ClaudeTardif, JacquesLespérance, JeanLambert, MartialBourassa, RaoulBonan, GilbertGosselin, MichelJoyal, Jean-FrançoisTanguay, StanleyNattel, RichardGallo, JacquesCrépeau
Journal: Circulation (1999)

Background—We have shown that probucol reduces restenosis after balloon angioplasty. Whether probucol acted via prevention of neointimal formation or improvement in vascular remodeling could not be addressed by angiography and required the use of intravascular ultrasound (IVUS). Methods and Results—Beginning 30 days before angioplasty, 317 patients were randomly assigned to receive probucol, multivitamins, combined treatment, or placebo. Patients were then treated for 6 months after angioplasty. IVUS examination was performed immediately after angioplasty and at follow-up in 94 patients (111 segments). The cross section selected for serial analysis was the one at the angioplasty site with the smallest lumen area at follow-up. In the placebo group, lumen area decreased by −1.21±1.88 mm2 at follow-up, and wall area and external elastic membrane (EEM) area increased by 1.50±2.50 and 0.29±2.93 mm2, respectively. Change in lumen area, however, correlated more strongly with the change in EEM area (r=0.53, P=0.0...
Abstract 5203: Bitter melon extract modulates immune signaling in prevention of tobacco associated carcinogen induced oral carcinogenesis
Authors: Subhayan Sur, Robert Steele, Ratna B. Ray
Journal: Cancer Research (2018)

Abstract Oral squamous cell carcinoma (OSCC) is a complex malignancy and tobacco habit is one of the main etiological factors. Our previous study showed potential chemopreventive effect of bitter melon (Momordica charantia) extract (BME) in different pre-clinical cancer models like head and neck, breast, prostate. The aim of this study is to understand the molecular mechanism of BME in prevention of carcinogen induced in-vivo oral carcinogenesis. For this purpose, we induced oral cancer in immunocompetent mice by using tobacco associated carcinogen 4-nitroquinoline 1-oxide (4-NQO), and treated with BME through their drinking water. We observed that BME feeding significantly reduced the incidence of 4-NQO induced oral cancer. Histological analysis showed moderate dysplasia to invasive squamous cell carcinoma in 4NQO treated mice tongue, whereas no remarkable changes were seen in the BME-fed mice. RNA-seq data showed differential expression of several genes during carcinogenesis and during prevention of the cancer. We previously showed that BME treatment decreases the infiltrating regulatory T (Treg) cells by inhibiting FoxP3+ populations in the tumors and in spleens, suggesting an immunomodulatory role of BME in prevention. Here, we observed elevated expression of pro-inflammatory genes s100a9, IL23a, IL-1β and immune check point gene PDCD1/PD1 of the pathway, during oral cancer development. Interestingly, BME treatment significantly reduced the expression of these molecules. Subsequently, we observed the enhancement of MMP9 during carcinogenesis, which was reduced in BME-fed mouse tongue tissues. Taken together, our observation strongly demonstrated a chemopreventive effect of BME on carcinogen induced oral cancer. Citation Format: Subhayan Sur, Robert Steele, Ratna B. Ray. Bitter melon extract modulates immune signaling in prevention of tobacco associated carcinogen induced oral carcinogenesis [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 5203.
Hepatocyte Growth Factor Suppresses Vascular Medial Hyperplasia and Matrix Accumulation in Advanced Pulmonary Hypertension of Rats
Authors: MasamichiOno, YoshikiSawa, ShinyaMizuno, NorihidaFukushima, HajimeIchikawa, KazuhikoBessho, ToshikazuNakamura, HikaruMatsuda
Journal: Circulation (2004)

Background— Pulmonary hypertension (PH) is a progressive disease characterized by raised pulmonary vascular resistance, thought to be curable only through lung transplantation. Pathophysiologically, proliferation of pulmonary artery smooth muscle cells triggers pulmonary arterial stenosis and/or regurgitation, especially in advanced PH. Methods and Results— Using a rat model of advanced pulmonary vascular disease produced by injecting monocrotaline, we show that hepatocyte growth factor (HGF) targets pulmonary arterioles and blocks the progression of PH. In these rats, endogenous HGF production was dramatically downregulated during developing experimental PH, but c-Met/HGF receptor was abundant in the medial layers of pulmonary arterioles. HGF gene transfection 2 weeks after the monocrotaline injection resulted in milder medial hyperplasia in lung arterioles and inhibited overgrowth of pulmonary artery smooth muscle cells. Notably, exogenous HGF reduced lung expression levels of endothelin-1 and transform...
Ionic Remodeling in the Heart
Authors: StanleyNattel, DanshiLi
Journal: Circulation Research (2000)

Abstract—Heart disease has long been recognized to alter cardiac electrical function. Detailed studies of disease-induced remodeling of ionic transport processes that underlie ventricular electrophysiological alterations have been performed over the past 10 years, but our knowledge of atrial ionic remodeling is more limited and has emerged much more recently. The present review focuses on recent findings regarding ionic remodeling at the atrial level, particularly with respect to two conditions that promote atrial fibrillation (AF) in well-developed clinically relevant animal models: (1) sustained atrial tachycardia and (2) ventricular tachypacing–induced congestive heart failure. Complementary data from experimental models and from observations in atrial tissue samples from patients are examined critically and integrated. Consideration is also given to potential molecular mechanisms underlying remodeling, the relationship between atrial and ventricular ionic remodeling in response to similar stimuli, and...
The red blood cell death receptor and thrombosis
Authors: Nigel Mackman
Journal: Journal of Clinical Investigation (2018)

RBCs are the most abundant circulating cells in humans and typically comprise 35% to 45% of the blood volume (hematocrit). Anemia is associated with an increase in bleeding, and epidemiological studies have shown an association between an elevated hematocrit and thrombosis. RBCs may contribute to hemostasis and thrombosis via mechanisms that include platelet margination leading to an increase in the near-wall platelet concentration, blood viscosity, thrombin generation, and platelet activation. In this issue of the JCI, Klatt et al. report that binding of the Fas ligand FasL on the surface of platelets to its cognate receptor FasR on the surface of RBCs increases thrombin generation in vitro and thrombosis in mouse models. This represents a new mechanism by which RBCs contribute to thrombosis.
Prevention of Iatrogenic Atrial Tachycardia After Ablation of Atrial Fibrillation
Authors: CarloPappone, FrancescoManguso, GabrieleVicedomini, FilippoGugliotta, OrnellaSantinelli, AmedeoFerro, SimoneGulletta, SimoneSala, NicoletaSora, GabrielePaglino, GiuseppeAugello, EustachioAgricola, AlbertoZangrillo, OttavioAlfieri, VincenzoSantinelli
Journal: Circulation (2004)

Background— Circumferential pulmonary vein ablation (CPVA) is effective in curing atrial fibrillation (AF), but new-onset left atrial tachycardia (AT) is a potential complication. We evaluated whether a modified CPVA approach including additional ablation lines on posterior wall and the mitral isthmus would reduce the incidence of AT after PV ablation. Methods and Results— A total of 560 patients (291 men, 52%; age, 56.5±7.3 years) entered the study; 280 were randomized to CPVA alone (group 1) and 280 to modified CPVA (group 2). The primary end point was freedom from AT after the procedure. In group 1, 28 patients (10%) experienced new-onset AT, and 41 (14.3%) experienced recurrent AF. In group 2, 11 patients (3.9%) experienced AT, and 36 (12.9%) had recurrent AF. Group 1 was more likely to experience AT than group 2 (P=0.005). Freedom from AF after ablation was similar in both groups (P=0.57). Among those in group 1, gap-related macroreentrant AT was documented in 23 of the 28 patients (82%), and focal A...