tbuckley/cabot-search huggingface dataset:
Abstract 18208: Vasomera™, a Novel VPAC2-selective Vasoactive Intestinal Peptide Agonist, Triggers Sustained Blood Pressure Control in Telemetered Spontaneously Hypertensive Rats: Additive Effects to Atenolol, Amlodipine, and Ramipril
Authors: Carlos L del Rio, Lynne Georgopoulos, Sue Arnold, Steve T Yeh, Travis Brown, Andrew Pavlina, Jeff Wallery, Robert L Hamlin
Journal: Circulation (2011)

The natural vasoactive intestinal peptide (VIP) triggers potent vasodilatation by activating the G-protein-coupled VPAC1 and VPAC2 receptors; however, VIP's clinical utility is limited due to its short half-life and VPAC1-mediated side-effects. Vasomera™ is a novel long-acting biopolymer-based selective VPAC2-receptor agonist. Here, the hemodynamic effects of Vasomera when given as a single-dose SQ bolus to conscious spontaneously hypertensive rats (SHR) pretreated with three common anti-hypertensives were tested. SHR rats (351 ± 4 g, n = 8) were instrumented for telemetric blood pressure and ECG monitoring. First, Vasomera (9 mg [177nmol]/kg, SQ) and placebo (VEH) were assayed in untreated animals. Then, the effects of Vasomera were tested during concomitant oral β-AR blockade (+BB, atenolol 20 mg/kg/day), calcium-channel blockade (+CCB, amlodipine 5 mg/kg/day) and ACE-inhibition (+ACE, ramipril 1 mg/kg/day). Mean pressure (MAP) and heart rate (HR) were measured/averaged over 24hrs both pre and post-dosing. Vasomera induced blood pressure decreases that were sustained for up to 12hrs post-dosing (see Fig. A). On average, Vasomera lowered MAP by 9 ± 1 % (188 ± 6 to 171 ± 5 mmHg, P &lt; 0.05). Vasomera's vaso-relaxation was preserved/enhanced in rats pre-treated with either atenolol (-14 ± 1%, P &lt; 0.05), amlodipine (-13 ± 2%, P &lt; 0.05), and/or ramipril (-9 ± 2%, P &lt; 0.05) (see Fig. B). Vasomera triggered moderate cardio-acceleration in untreated rats (+8 ± 1%, 355 ± 6 to 384 ± 8 bpm, P &lt; 0.05); such chronotropy was blunted under β-AR blockade (+6 ± 1%, 278 ± 2 to 294 ± 2 bpm), but was unaffected by amlodipine or ramipril (see Fig. C). In all cases, heart rates were lower than in controls, and no adverse clinical effects were noted. Vasomera, a novel VPAC2 agonist, can provide long-acting blood pressure control synergistically with concomitant anti-hypertensive therapies (e.g., β-AR blockade) and may represent a novel adjunct therapy for resistant/uncontrolled hypertension.
Abstract 4124: Polymorphisms can Predict Appropriate Therapies in Patients with Heart Failure and Implantable Cardioverter Defibrillators
Authors: Diego Chemello, Luis E Rohde, Leandro Zimerman, Mauricio Pimentel, Lais P Abreu, Vinicius Gonzalez, Priscila R Rosa, Eliza Dalsasso, Nadine Clausell
Journal: Circulation (2008)

Introduction: The use of implantable cardioverter defibrillators (ICD) reduces mortality in patients with heart failure (HF). However, given its elevated cost, an adequate selection of individuals with higher risk is warranted. Yet, known predictors of risk of sudden cardiac death have shown limited value to select use of ICD. More recently, genetic polymorphisms have been considered as potentially interesting tools to guide therapeutic strategies. Objective: To study the role of three genetic polymorphisms (β1 Arg389Gly, GNB3 C825T and GP IIb/IIIa Pl A1 /Pl A2 ) as predictors of appropriate ICD therapies in patients with heart failure (HF) who received an ICD implant for primary or secondary prevention. Patients and Methods: Retrospective cohort study of patients with ICD use during at least 6 months for primary and secondary prevention, followed at our HF outpatient clinic. Clinical data were registered and ICD analyses were made by telemetry. ICD therapies were defined as appropriate or inappropriate by a cardiac electrophysiologist. Twenty mL of blood were collected for polymorphism analysis by the PCR-RFLP technique. For univariate analysis, Student’s t-test and the χ 2 (chi-square) test were used; logistic regression was used for multivariate analysis. Results: The sample included 73 patients (75% male, 89% white and 56% ischemic etiology). The mean ejection fraction was 34.9 ± 9.8%. Individually, the Arg389 allele of the β1 Arg389Gly polymorphism, the T825 allele of the GNB3 C825T polymorphism, and the Pl A2 allele of the GP IIb/IIIa Pl A1 /Pl A2 polymorphism were not associated with appropriate ICD therapy. Nevertheless, the combined presence of these alleles identified patients with higher risk for appropriate shocks (p=0.03). Survival rate free of appropriate shocks was significantly lower in patients with 2 or 3 risk genotypes when compared with others (p=0.03). Conclusions: When analyzed in combination, the presence of the β1 Arg389Gly, GNB3 C825T, and GP IIb/IIIa Pl A1 /Pl A2 polymorphisms possibly act as predictors of appropriate therapies in ICD recipients with HF. Further studies are needed to determine the clinical applicability of these genetic markers.
Abstract 15260: Traumatic Brain Injury, Coronary Atherosclerosis, and Cardiovascular Mortality
Authors: Naser Ahmadi, Fereshteh Hajsadeghi, Hormoz Babaei, Rachel Yehuda, David Garfield, Ramin Ebrahimi
Journal: Circulation (2012)

Background: Traumatic brain injury(TBI) is a devastating condition resulted in cerebral edema and ischemia. This study investigates the association of TBI to subclinical-atherosclerosis and cardiov...
Abstract 15833: Shear Stress Modulates the Expression of the Vasoprotective Protein Cx37 in Endothelial Cells
Authors: Anna Pfenniger, Katia Galan, Cindy Wong, Simon Cuhlmann, Paul C Evans, Fran cois Mach, Rob Krams, Brenda R Kwak
Journal: Circulation (2010)

Connexin37 (Cx37) is a gap junction protein essential for cell-cell communication in the vasculature. Endothelial cells (ECs) of healthy arteries express high levels of Cx37, but this expression is lost in ECs overlying atherosclerotic plaques. The deletion of Cx37 in ApoE−/− mice increases their susceptibility to atherosclerosis, which suggests that Cx37 has anti-atherogenic properties. High laminar shear stress is known to be vasculoprotective partly through the induction of KLF2. As the promoter region of the Cx37 gene contains KLF consensus binding sites, we hypothesize that shear stress, through the modulation of KLF2, may affect Cx37 expression in ECs. We observed that Cx37 is highly expressed in the straight region of the common carotid artery of ApoE−/− mice, whereas it was reduced at carotid bifurcation. Shear stress-modifying vascular casts were placed around the right common carotid artery of ApoE−/− mice and Cx37 expression in response to flow was assessed by en face immunofluorescence. We found that Cx37 expression is downregulated in regions of altered flow (either low laminar or oscillatory shear stress), but is conserved in regions of high laminar flow. To further study the mechanisms involved, the mouse endothelial cell line bEnd.3 was exposed to shear stress in vitro. After 24hrs of high laminar shear stress (30 dynes/cm2) Cx37 and KLF2 expression were increased when compared to static condition. Alternatively, bEnd.3 cells were exposed to simvastatin, which is known to mimic the effects of high laminar flow on KLF2. Simvastatin simultaneously increased the expression of Cx37 and KLF2. Interestingly, Cx37 expression was reduced after effective silencing of KLF2 by transfection with siRNA, suggesting that KLF2 acts as a transcription factor for this gap junction protein. In conclusion, high laminar shear stress in vivo or in vitro as well as exposure to simvastatin, upregulate the expression of KLF2 and of the anti-atherogenic protein Cx37. Therefore, this effect of shear stress on Cx37 expression may participate in the overall protective effect of high laminar flow on the endothelium.
Abstract 16250: Comparison of Risk Models to Predict In-Hospital Mortality for Patients With Acute Coronary Syndrome in India: The CSI-Kerala Risk Score
Authors: Mark D Huffman, Rony Mathew, S. Harikrishnan, M.N. Krishan, Geevar Zachriah, Jhony Joseph, Dorairaj Prabhakaran, Ali Faizal, P.B. Jayagopal, P.K. Varghese, Asokan Nambiar, P.P. Mohanan, Kerala Acs Registry Investigators
Journal: Circulation (2011)

Introduction: Acute coronary syndrome (ACS) risk models such as the Global Registry of Acute Coronary Events (GRACE) risk score are commonly used to predict in-hospital death. However, no India-spe...
ERCP and reprocessing in focus: what can we do to prevent or manage infection outbreaks?
Authors: Ulrike Beilenhoff
Journal: Endoscopy (2015)

Since the late 1970s, there have been sporadic reports of endoscopic transmission of exogenous infections in gastrointestinal endoscopy. The majority of documented cases were the result of noncompliance with national and international guidelines, including [1]:
Abstract 8741: Depressive Symptoms and Medication Adherence have a Synergistic Effect on Cardiac Event-Free Survival in Patients with Heart Failure
Authors: Jia-Rong Wu, Terry Lennie, Rebecca Dekker, Misook Chung, Debra K Moseer
Journal: Circulation (2011)

Background: Depressive symptoms and medication nonadherence predict hospitalization and death in patients with heart failure (HF). Patients with depressive symptoms have lower medication adherence. However, the combined effects of depressive symptoms and medication nonadherence on hospitalization and death have not been investigated in patients with HF. Objective: To explore the combined effect of depressive symptoms and medication adherence on cardiac event-free survival in patients with HF. Method: This was a longitudinal study of 218 patients with HF (male 65%, age 60±12 years, NYHA class III/IV 56%). Medication adherence was assessed using a valid and objective measure, the Medication Event Monitoring System (MEMS). Depressive symptoms were measured using the Patient Health Questionnaire (PHQ). Patients were followed for up to 4 years to collect data on cardiac event-free survival (i.e., cardiac emergency department visit, hospitalization, and death). Patients were grouped using an evidence-based cutpoint of 88% on medication adherence from the MEMS data and a score 10 on the PHQ. Kaplan-Meier, log-rank tests and Cox regressions were used to compare cardiac event-free survival among groups. Results: Depressive symptoms and medication adherence were independent predictors of cardiac event-free survival ( p &lt; .001 and = .006, respectively, Figure 1). Patients who had depressive symptoms and were nonadherent had a 4.95 times higher risk of cardiac events than those who had no depressive symptoms and were adherent (Figure 2). Conclusion: Depressive symptoms and medication nonadherence work synergistically to reduce cardiac event-free survival in patients with HF.
Abstract 16192: Persistently Reduced Exercise Capacity After Cardiac Rehabilitation in Patients With Right Ventricular Infarction; Evidence of Impaired Right Ventricular Contribution
Authors: Eriko Hisamatsu, Masashi Fujino, Reon Kumasaka, Tetsuo Arakawa, Michio Nakanishi, Teruo Noguchi, Reiko Fujiwara, Takahiro Ohara, Shigefumi Fukui, Masanobu Yanase, Hiroshi Takaki, Masaharu Ishihara, Satoshi Yasuda, Yoichi Goto
Journal: Circulation (2013)

Background: It has been reported that exercise capacity is reduced in patients with right ventricular (RV) dysfunction but preserved left ventricular function early after acute myocardial infarctio...
Aggressive Primary Chemotherapy Plus Autologous Stem Cell Transplantation Improves Outcome for Peripheral T Cell Lymphomas Compared with CHOP-Like Regimens.
Authors: Michal Sieniawski, James Lennard, Christopher Millar, Simon Lyons, Philip Mounter, Zor Maung, Stephen J. Proctor, Anne L. Lennard
Journal: Blood (2009)
Abstract 4303: Heme Oxygenase 1 Expression in Dendritic Cells Drives Cd4+ T Cell Activation in Transplantation Atherosclerosis
Authors: Annemarie M Noordeloos, C Cheng, E van Deel, D Tempel, M L Simoons, B Lambrecht, D J Duncker, H J Duckers
Journal: Circulation (2008)

Although over-expression of heme oxygenase-1 (HO-1) attenuates transplantation arteriosclerosis, the mechanism by which HO-1 exerts its protective effect remains unclear. In order to investigate the effect of HO-1 expression specifically in the dendritic cell (DC) in the context of transplantation atherosclerosis, we studied the effect of HO1-deficient versus wildtype (WT) DCs on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. At day 0 C57bl6 mice received either WT (N=7) or HO1-knockout DCs (N=7) pre-sensitized with Balb/c splenocytes lysate. At day 10 an allogenic aorta segment derived from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice. 14 days post transplantation, the grafts were harvested and analyzed by imumnohistology. Adoptive transfer of HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 versus 38428 μm2 P&lt;0.05). HO-1 deficient DCs also increased medial thickeness (15936 versus 12034 μm2 P&lt;0.05), reduced intimal VSMCs content (46 versus 75% P&lt;0.05) and resulted in more prominent medial cell infiltration (461 versus 232 μm2 P&lt;0.05). In the transplanted aorta of the with HO-1 nullizygous DCs treated recipient group, an increase in CD4+ T-cell infiltration (9.5 versus 0.2% in WT P&lt;0.05) and IgG deposition, concomitant to a decrease of CD8+ T cell infiltration (8.1 versus 14.3%, P&lt;0.05) was observed. In line with these observations, in vitro analysis of HO-1 deficiency in DC function showed an increased priming potential for CD4+ T cells, thereby increasing the CD4+/CD8+ T cell ratio. Increased efficiency in CD4+ T cell priming by HO-1 deficient DCs was facilitated by a higher cell surface level of MHC II. Further studies indicated that HO-1 deficiency increased STAT1 phosphorylation, thereby enhancing CIITA gene expression that lead to increased MHC II levels on the DCs cell surface. HO-1 deficiency in dendritic cells increases vascular cell infiltration with a higher CD4+/CD8 T-cell ratio in vascular allografts resulting in an augmented form of transplantation arteriosclerosis. This effect is facilitated by a STAT1-CIITA-MHCII dependent intracellular pathway.
Pulmonary artery sarcoma: an insidious tumor still diagnosed too late. Analysis of the literature and report of a case.
Authors: A Coli, P Parente, G Bigotti
Journal: Journal of experimental & clinical cancer research (2007)

Pulmonary artery sarcoma is an exceptionally rare tumor which must be considered in the differential diagnosis of pulmonary thromboembolism. We report the case of a 36-year-old woman and review 100 cases published in the literature between 1988 and 2005. The patient presented with a history of dyspnea, fatigue, fever, night sweats and anemia that did not respond to antibiotic therapy. She also had hemoptysis. Transvenous catheter biopsy was indicative of sarcoma. A left pneumonectomy was performed, followed by five cycles of chemotherapy. Histological and immunohistochemical studies documented an intimal sarcoma with myofibroblastic differentiation. The patient is alive and well 20 months after surgery. The clinico-pathological features of pulmonary artery sarcoma are described.
Abstract 12369: The Degree of Baseline Radial Dyssynchrony Predicts Long-Term Survival Following Cardiac Resynchronization Therapy
Authors: Phillip J Habib, Olusegun Oyenuga, Stephanie C Haberman, Hidekazu Tanaka, Evan Adelstein, Tetsuari Onishi, John Gorcsan
Journal: Circulation (2010)

Introduction: The significance of echocardiographic dyssynchrony in patients undergoing cardiac resynchronization therapy (CRT) is unclear. Methods: To test the hypothesis that the degree of radial...
Biomarker identification for AT9283 a multi-targeted kinase inhibitor with Aurora A and B activities from pre-clinical models to clinical trials.
Authors: John Lyons, Matt Squires, Murray Yule, Victoria Lock, Jayne Curry, Matthias Reule, Neil Thompson
Journal: Clinical Cancer Research (2008)

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA

B15 

AT9283 is a potent inhibitor of several tyrosine and serine/threonine mitotic kinases including Aurora kinases A and B as well as JAK2, c-ABL and ABL mutants. Treatment of a range of solid tumour and leukemia cell lines has demonstrated the ability of AT9283 to inhibit the growth and survival of tumor cells.    Growth inhibition by AT9283 in vitro is consistent with inhibition of the Aurora kinases and results in mitotic exit without cell division resulting in polyploidy. Aurora kinase A can phosphorylate p53 at Ser315, leading to its ubiquitination by Mdm2 and proteolysis. P53 is not degraded in the presence of inactive aurora kinase A or ubiquitination-defective Mdm2. Silencing of Aurora kinase A via AT9283 inhibition can also result in reduced phosphorylation of p53 at Ser315, greater stability of p53 and cell-cycle arrest with 4N DNA. Aurora-B overexpression contributes to chromosome number instability by phosphorylation of Histone H3 on serine 10 and hence, chromosome condensation and the subsequent segregation of chromosomes    AT9283 was profiled in a series of tumor cell lines in vitro using a colony forming assay. Mechanistic studies confirmed inhibition of phosphorylation of an Aurora B direct downstream substrate Histone H3 on serine 10.    The compound was then profiled in xenograft models following repeated intraperitoneal dosing, including HCT 116 colorectal and A2780 ovarian carcinoma models where evidence of growth inhibition was observed. Tumour samples from treated animals revealed evidence of p53 stabilisation and serine 10 phospho-Histone H3 knockdown. Enlarged multinucleated cells were also observed.    Identical assays were performed on the proliferating layer of the basal epidermis both pre-treatment and during a 72 hour intravenous infusion of AT9283 in patients with refractory solid tumours during a dose escalation study. Increased levels of p53 and a reduction in phosphorylated Histone H3 occurred in a dose dependent manner. Immunohistochemical staining of PCNA and Ki67 was also reduced at higher dose levels. Similar changes in phospho-Histone H3 have also been detected in leukemic blasts from patients receiving high dose AT9283.    Reduction in phospho-Histone H3 levels, and to a lesser extent stabilisation of p53 amongst surrogate tissues are valid biomarkers for patients receiving treatment with Aurora kinase inhibitors.
Abstract 18279: Contemporary Trends of Optimal Evidence-Based Medical Therapy at Discharge for Patients Surviving Acute Myocardial Infarction From Korea Acute Myocardial Infarction Registry
Authors: Jang Hoon Lee, Jae Hee Kim, Se Yong Jang, Sun Hee Park, Myung Hwan Bae, Dong Heon Yang, Hun Sik Park, Yongkeun Cho, Shung Chull Chae
Journal: Circulation (2013)

Background: Most published studies about the contemporary trends in optimal medical therapy (OMT) were conducted more than 5 years ago. Furthermore, In Asia, only limited data are available for the recent trend of OMT at discharge after acute myocardial infarction (AMI). The aims of this study is (1) to describe the contemporary, as well as changing, prescribing of 4 effective cardiac medications in post-MI hospital survivors and (2) to determine whether use of 4 effective cardiac medications at the time of hospital discharge differ on the basis of age or gender. Methods: The Korea AMI Registry (November 2005-June 2011) were multicenter observational study. We examined the discharge medications among 22,646 post-MI survivors who did not have any documented contraindications to anti-platelet drugs, beta-blockers (BBs), angiotensin converting enzyme inhibitors (ACE-I)/ angiotensin II receptor blockers (ARBs) or statins in 6 periods by 12-month interval. OMT was defined as the use of all 4 indicated medications. Results: Particularly marked relative increase from period 1 to period 6 were observed in the use of BBs (from 70.3% to 84.5%) and statins (from 77.4% to 83.2%), whereas less dramatic increases were noted in the use of ACE-I/ARBs. Among ACE-Is/ARBs users, marked increases in the use of ARBs (from 17.4% to 32.2%) and declines in the use of ACE-Is (65.7% to 49.3%) were observed over time. Consistent with these trends, there were also marked increases in the use of OMT (from 48.9% to 62.3%). The odds ratios of the use of OMT from period 1 to period 6 were as follows: 1, 1.11 (p=0.034), 1.18 (p=0.001), 1.32 (p &lt;0.001), 1.41 (p &lt;0.001), and 1.57 (p &lt;0.001), respectively, in overall. The use of OMT was significantly higher in men than women over time (p &lt;0.05). Among patients aged 65 years or less, the use of OMT was significantly higher in men than women, whereas there was no significant difference between men and women over time among patients aged 65 to 75 years. Among patients aged more than 75 years, the use of OMT was significantly higher in women than men over time. Conclusions: National health improvement program implemented from 2007 markedly increased the use of all 4 effective cardiac medications, particularly in elderly women who were no more undertreated in our study.
STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch
Authors: Miho Shiratori-Hayashi, Keisuke Koga, Hidetoshi Tozaki-Saitoh, Yuta Kohro, Honami Toyonaga, Chiharu Yamaguchi, Ayumi Hasegawa, Takeshi Nakahara, Junichi Hachisuka, Shizuo Akira, Hideyuki Okano, Masutaka Furue, Kazuhide Inoue, Makoto Tsuda
Journal: Nature Medicine (2015)
Abstract 9021: Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A Administration. A Pharmacological Reprogrammation of Cellular Defects in Diseased Aorta.
Authors: Allaire Eric, Dai Jianping, Michineau Stephanie, Desgranges Pascal, Becquemin Jean-Pierre
Journal: Circulation (2010)

Once they have formed, abdominal aortic aneurysms (AAAs) tend to expand inexorably as a consequence of aortic destruction/reconstruction unbalance and smooth muscle cell (VSMC) depletion. Pharmacological approaches have consisted so far in permanent drug administration to block tissue destruction. Cyclosporine A (CsA), a member of the calcineurin inhibitor family, induces Transforming Growth Factor-beta 1 (TGF-beta1) and promotes tissue accumulation including in the vasculature, a structural aim to compensate for AAA wall atrophy. We tested the hypothesis that a short course of CsA administration could trigger aortic reconstruction and durably stabilize AAAs, beyond drug interruption.   Methods and results:  CsA induced TGF-beta1 and decreased matrix metalloprotease-9 expression dose-dependently in fragments of human AAAs  in vitro , and in two animal models of AAA  in vivo . CsA prevented AAA formation in the calcium chloride mouse model (14 day diameters: CsA: 0.72+/−0.06 mm; vehicle: 1.10+/−0.05 mm, P=0.008), decreased inflammation and preserved wall elastin and VSMCs. A seven day administration of CsA prevented further expansion of already formed AAAs in a xenograft model in rats, up to seven weeks after drug withdrawal (diameter increase: CsA: 11.8+/−6.0 %; vehicle: 45.2+/−6.1%, P=0.017), down-regulated wall inflammation, and increased alpha-SMA positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, alpha-SMA positive cell accumulation and diameter stabilization in expanding AAAs, demonstrating that the pleiotropic activity of TGF-beta is required for CsA to restore the capability of the diseased aneurysm wall to withstand arterial pressure without dilating further.   Conclusion:  Pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the destructive/reconstructive balance towards healing. We provide a model of pharmacological induction of a cytokine and aortic wall cellular repair as an alternative to gene or cell therapy. Short duration of CsA administration may obviate systemic side effects and allow for a local, high dose delivery from an endovascular plate-form.