tbuckley/cabot-search huggingface dataset:
Inhibition of azoxymethane-induced colonic aberrant crypt foci formation by silibinin in male Fisher 344 rats
Authors: Velmurugan Balaiya, Rana Singh, Alpna Tyagi, Rajesh Agarwal
Journal: Cancer Research (2007)

4975   Colon cancer is one of the major causes of cancer mortality in the United States of America. Early detection and prevention are the important alternative approaches to control colon cancer. Recently, substantial attention has been focused on identifying naturally occurring chemopreventive compounds capable of inhibiting early events involved in malignant transformation. Of late, laboratory studies have demonstrated that silibinin exhibits various biological activities and significantly inhibits tumorigenesis at various organ sites in several rodent models. The present study is an attempt to investigate the dose-dependent effect of dietary silibinin on azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation in Fisher 344 male rats. In addition, we analyzed the effect of silibinin on cell proliferation and the induction of apoptosis by immunohistochemical staining during AOM-induced ACF formation. Five-week-old male F344 rats were randomly divided into 12 groups and fed AIN-76A control diet (group 1) or diet supplemented with 0.033, 0.1, 0.33 or 1% (w/w) silibinin (groups 3-6) till the end of the study. Two weeks later, rats in groups 2-11 were given s.c. injection of AOM once a week for 2 weeks at a concentration of 15 mg/kg body weight. Two weeks after the last AOM injection, rats in groups 7-11 were fed with diet containing 0.033, 0.1, 0.33 or 1% silibinin or 0.032% sulindac. Rats in group 12 were fed with diet containing 1% silibinin alone throughout the study. At 16 weeks of age, the rats were sacrificed, and their colons were evaluated for ACF. The results of this study revealed that silibinin significantly (P
Abstract 123: Cardiac Beta-arrestin2 Promotes Contractility by Enhancing SERCA2a SUMOylation and Activity
Authors: Anastasios Lymperopoulos, Malika Jafferjee, Thairy Reyes Valero, Christine Marrero, Katie A McCrink, Ava Brill, Erhe Gao, Walter J Koch
Journal: Circulation Research (2015)

Heart failure (HF) is the number one killer disease in the western world and new and innovative treatments are needed. Sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA)-2a is a crucial, for contractile function, calcium-handling protein expressed in the mammalian myocardium and its downregulation is one of the molecular hallmarks of chronic HF. Its activation is part of the signaling mechanism by which the β 1 -adrenergic receptors (ARs) increase cardiac contractility. Agonist-bound β 1 ARs however, like most G protein-coupled receptors (GPCRs), undergo functional desensitization/internalization due to the actions of βarrestin1 or -2. These two arrestins are universal GPCR adapter proteins, mediating G protein-independent signaling via multi-protein scaffolding, and, among the cellular processes they can regulate, is protein SUMO (small ubiquitin-like modifier)-ylation, which generally increases protein stability/levels. In the heart, βarrestin1 appears detrimental, whereas βarrestin2 beneficial, for structure and function post-myocardial infarction (MI). Post-MI βarrestin1 knockout mice also display elevated SERCA2a activity and better contractility than post-MI wild type mice. In addition, reduced cardiac SERCA2a SUMOylation is known to underlie its downregulation in HF, decreasing cardiac contractility. Thus, in the present study, we sought to investigate a potential involvement of cardiac β 1 AR-activated βarrestins in regulation of SERCA2a SUMOylation and activity. By studying individual βarrestin knockout heart extracts, we found that βarrestin2, but not βarrestin1, interacts with SERCA2a in the mouse heart in vivo, promoting the latter`s SUMOylation and activity. This interaction is direct, as indicated by pull-down and FRET experiments. Finally, via in vitro studies in the cardiomyocyte-like cell line H9c2, we found that this interaction is both β 1 AR-, and beta-agonist-specific, and leads to increased Ubc9-dependent SERCA2a SUMOylation, which, in turn, acutely enhances SERCA2a activity in H9c2 cells. These results suggest that βarrestin2, presumed to also decrease cardiac function by desensitizing βARs, may actually (directly) enhance cardiac contractility, thereby opposing βarrestin1 in that regard.
Abstract P038: Cardiomyocyte Proliferating Chemicals: Activation of Proliferation of ESC/iPSC-Derived Cardiomyocytes
Authors: Hideki Uosaki, Jun K Yamashita
Journal: Circulation Research (2011)

Cardiomyocytes derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising cell sources for cardiac regeneration. Previously, we established a novel systematic cardiovascular cell induction system with mouse ESCs and iPSCs. ESC/iPSC-derived cardiomyocytes rarely proliferate after differentiation, similar to neonatal and adult cardiomyocytes. Cardiomyocyte proliferation is highly restricted and the regulating machineries of proliferation and growth arrest of cardiomyocytes are long-standing mysteries of cell biology. In order to establish cardiac regenerative medicine, it is critical to dissect and manipulate the machineries involved. Here we devised a novel approach using small molecules in an attempt to unravel the mystery and to manipulate ESC/iPSC-derived cardiomyocyte proliferation. We screened a chemical library containing well-established kinase inhibitors with high content screen to enhance mouse ESC-derived cardiomyocyte proliferation, and identified two novel chemical groups, extracellular signal-regulated kinase activators and Ca2+/calmodulin-dependent protein kinase II inhibitors, and two previously reported chemical groups, glycogen synthase kinase-3 inhibitors and a p38 mitogen-activated protein kinase inhibitior. Each chemical increased actual cardiomyocyte cell numbers two- to three-fold compared to control. An optimal combination of these chemicals strongly enhanced proliferation of ESC-derived cardiomyocytes and ESCM number was reached up to 14-fold. Expanded cells retained various functional and structural features of cardiomyocytes. These chemicals are robustly effective on cardiomyocytes from various sources including human iPSCs. Efficient combination of stem cell and chemical biology demonstrated a novel molecular mechanism of cardiomyocyte proliferation and offered a critical technological basis for cardiac regeneration.
天然細胞外マトリックス配位子ヘパラン硫酸へのケモカインCXCL12の結合は筋芽細胞接着を可能にし,細胞運動性を促進する【Powered by NICT】
Authors: Thakar Dhruv, Dalonneau Fabien, Migliorini Elisa, Lortat-Jacob Hugues, Boturyn Didier, Albiges-Rizo Corinne, Coche-Guerente Liliane, Picart Catherine, P Richter Ralf
Journal: Biomaterials (2017)
幹細胞リプログラミング組合せ療法のためのハイスループットmechanopharmacologicalスクリーニングプラットフォームとしての生体力学的感作された肝しゅようアレイ【Powered by NICT】
Authors: Zhu Lu, Fan Xingliang, Wang Bingjie, Liu Longwei, Yan Xiaojun, Zhou Lyu, Zeng Yang, C Poznansky Mark, Wang Lili, Chen Huabiao, Du Yanan
Journal: Biomaterials (2017)
Response to Laser Treatment of Café au Lait Macules Based on Morphologic Features
Authors: Daniel A. Belkin, Julia P. Neckman, Hana Jeon, Paul Friedman, Roy G. Geronemus
Journal: JAMA Dermatology (2017)

Response to laser treatment for café au lait macules (CALMs) is inconsistent and difficult to predict.To test the hypothesis that irregularly bordered CALMs of the "coast of Maine" subtype respond better to treatment than those of the smooth-bordered "coast of California" subtype.This retrospective case series included patients from 2 multiple-clinician US practices treated from 2005 through 2016. All patients had a clinical diagnosis of CALM and were treated with a Q-switched or picosecond laser. A total of 51 consecutive patients were eligible, 6 of whom were excluded owing to ambiguous lesion subtype. Observers were blinded to final patient groupings.Treatment with 755-nm alexandrite picosecond laser, Q-switched ruby laser, Q-switched alexandrite laser, or Q-switched 1064-nm Nd:YAG laser.Main outcome was grade in a visual analog scale (VAS) consisting of 4 levels of treatment response: poor (grade 1, 0%-25% improvement), fair (grade 2, 26%-50% improvement), good (grade 3, 51%-75% improvement), and excellent (grade 4, 76%-100% improvement).Forty-five patients were included in the series, 19 with smooth-bordered lesions and 26 with irregularly bordered lesions. Thirty-four (76%) of the participants were female; 33 (73%) were white; and the mean age at the time of laser treatment was 14.5 years (range, 0-44 years). Smooth-bordered lesions received a mean VAS score of 1.76, corresponding to a fair response on average (26%-50% pigmentary clearance). Irregularly bordered lesions received a mean VAS score of 3.67, corresponding to an excellent response on average (76%-100% clearance) (P < .001).CALMs with jagged or ill-defined borders of the coast of Maine subtype tend to respond well to laser treatment, whereas those with smooth and well-defined borders of the coast of California subtype tend to have poor response. Clinicians using Q-switched or picosecond lasers to treat CALMs can use morphologic characteristics to help predict response and more effectively manage patient expectations.
The effectiveness of influenza vaccination in preventing hospitalisations of elderly individuals in two influenza seasons: a multicentre case–control study, Spain, 2013/14 and 2014/15
Authors: Angela Domínguez, Núria Soldevila, Diana Toledo, Pere Godoy, Elena Espejo, Maria Amelia Fernandez, José María Mayoral, Jesús Castilla, Mikel Egurrola, Sonia Tamames, Jenaro Astray, María Morales-Suárez-Varela
Journal: Eurosurveillance (2017)

Influenza vaccination may limit the impact of influenza in the community. The aim of this study was to assess the effectiveness of influenza vaccination in preventing hospitalisation in individuals aged ≥ 65 years in Spain. A multicentre case–control study was conducted in 20 Spanish hospitals during 2013/14 and 2014/15. Patients aged ≥ 65 years who were hospitalised with laboratory-confirmed influenza were matched with controls according to sex, age and date of hospitalisation. Adjusted vaccine effectiveness (VE) was calculated by multivariate conditional logistic regression. A total of 728 cases and 1,826 matched controls were included in the study. Overall VE was 36% (95% confidence interval (CI): 22–47). VE was 51% (95% CI: 15–71) in patients without high-risk medical conditions and 30% (95% CI: 14–44) in patients with them. VE was 39% (95% CI: 20–53) in patients aged 65–79 years and 34% (95% CI: 11–51) in patients aged ≥ 80 years, and was greater against the influenza A(H1N1)pdm09 subtype than the A(H3N2) subtype. Influenza vaccination was effective in preventing hospitalisations of elderly individuals.
The impact of body mass index dynamics on survival of patients with advanced pancreatic cancer receiving chemotherapy.
Authors: Younak Choi, Do-Youn Oh, Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2013)

e15066 Background: The obesity is increasing worldwide. High body mass index (BMI) is linked with an increased risk of developing pancreatic cancer (PC). However, in patients with advanced PC (APC), especially those are receiving palliative chemotherapy (the majority of all PC patients), the impact of BMI and its change during disease course on survival has not been fully investigated. Methods: Consecutive patients with APC were enrolled during years 2003-2010, all treated with palliative chemotherapy. The BMI measured at the point of starting the first cycle of palliative chemotherapy was called as “BMI at diagnosis”. “Pre-cancer weight” which means the weight in good health was the sum of “weight at diagnosis” and “weight loss at diagnosis” that the patients’ self- reported at the first visit. “Pre-cancer BMI” was calculated using pre-cancer weight. We got weight data measured at every visit during chemotherapy to investigate BMI change during chemotherapy period. Clinical characteristics and outcomes were analyzed. Results: A total of 425 patients were enrolled (median age, 60.1 years). At diagnosis of APC, the BMI distribution of patients was as follows: &lt;18.5 (45, 10.6%); 18.5-19.9 (67, 15.8%); 20.0-22.4 (156, 36.7%); 22.5-24.9 (107, 25.2%); 25.0-29.9 (49, 11.5%); and ≥30.0 (1, 0.2%). Clinical characteristics were balanced across BMI groups. Median overall survival (OS) was 8.1 months (95% CI, 7.2-9.1). Pre-cancer BMI and BMI at diagnosis had no impact on OS (p = 0.488, p = 0.348, respectively), although patients at BMI range of 22.5-24.9 achieved the longest OS (9.9 months; 95% CI, 8.5-11.3). BMI loss at diagnosis (pre-cancer BMI minus BMI at the diagnosis) and BMI loss during chemotherapy (both stipulated as BMI change ≥1) were associated with shortened OS (HR, 1.300; p = 0.012 and HR, 1.367; p= 0.010, respectively). Conclusions: In patients with APC undergoing palliative chemotherapy, both declines in BMI at diagnosis of APC and during chemotherapy are more hazardous for OS than pre-cancer BMI or BMI at diagnosis itself as absolute values. Further research evaluating strategies to maintain BMI during chemotherapy in this setting is thus warranted.
Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity
Authors: Deepika Polineni, Hong Dang, Paul J. Gallins, Lisa C. Jones, Rhonda G. Pace, Jaclyn R. Stonebraker, Leah A. Commander, Jeanne E. Krenicky, Yi-Hui Zhou, Harriet Corvol, Garry R. Cutting, Mitchell L. Drumm, Lisa J. Strug, Michael P. Boyle, Peter R. Durie, James F. Chmiel, Fei Zou, Fred A. Wright, Wanda K. O’Neal, Michael R. Knowles
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known.Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data.Methods: Nasal mucosal RNA from 134 patients with CF was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess the concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested.Measurements and Main Results: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA (human leukocyte antigen) genes. Ion transport and CFTR processing pathways, as well as HLA genes, were identified across differential gene expression and GWAS signals.Conclusions: Transcriptomic analyses of CF airway epithelia, coupled to genomic (GWAS) analyses, highlight the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health.
SAT0689 Prevalence of and temporal trends in hyperuricaemia among adult patients with chronic kidney disease in ireland
Authors: F Adeeb, AA Udayakumar, D Ryan, X Li, AD Fraser, AG Stack
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> An increasing body of evidence links hyperuricaemia with the development of several metabolic disorders and major cardiovascular outcomes. A better understanding of the burden and variation of hyperuricemia within the health system is important in order to identify high-risk groups and facilitate early intervention with effective management strategies. <h3>Objectives</h3> The aim of this study was to describe the prevalence of hyperuricaemia, and period trends within the Irish Health System among patients with chronic kidney disease (CKD). <h3>Methods</h3> 136,325 adult CKD patients aged 18 and above with valid measurements of serum uric acid and creatinine levels were identified between 2006 and 2014 from the laboratory systems within the Irish health system. Hyperuricaemia was defined as serum uric acid ≥420μmol/L in men and ≥360μmol/L in women. Estimated glomerular filtration rates were determined using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation and patients were classified by CKD stage according to the Kidney Disease Improving Global Outcomes (KDIGO) staging system. Age- and sex-specific prevalence of hyperuricemia estimates with 95% confidence intervals were determined for each group and across calendar years. Comparisons among groups and across years were conducted using chi-square and multivariate logistic regression was used to explore associations using adjusted odds ratios (AOR) and 95% Confidence Intervals (CI). <h3>Results</h3> Patients with hyperuricaemia were noted to be older [58.2 (18.5) vs. 51.2 (17.4) years]. The prevalence of hyperuricaemia increased progressively between 2006 and 2014 from 20.3% (19.5, 21.0) to 26.5% (25.8, 27.2%) in men and from 17.9% (17.2, 18.6) to 20.4% (19.8, 21.0) in women, p&lt;0.001. Age-specific prevalence increased significantly over time for all age groups (18–39, 40–59, 60–79, and ≥80 years) for men and women, p&lt;0.001. Prevalence was significantly higher with more advanced CKD stage: 15.1% (14.5, 15.6) in Stage 1 CKD compared to 43.0% (34.8, 51.1) in Stage 5 CKD, p&lt;0.001. However, rates fell significantly for those Stage 4 and 5 CKD respectively (Figure1). In multi-variable models, the adjusted likelihood of hyperuricaemia increased with each successive year (Figure 2). <h3>Conclusions</h3> The prevalence of hyperuricaemia is substantial in the Irish health system and has increased in frequency over the past decade. Although the burden was highest among patients with more advanced CKD, an encouraging decline in prevalence was observed in recent years. Greater management of gout and hyperuricaemia from increasing utilization of urate-lowering therapies may be responsible for this trend. <h3>Disclosure of Interest</h3> None declared
Gene Expression Profile of Circulating Myeloma Cells Reveals CD44 and CD97 (ADGRE5) Overexpression
Authors: Tereza Sevcikova, Fedor Kryukov, Lucie Brozova, Jana Filipova, Zuzana Kufova, Katerina Growkova, Renata Bezdekova, Pavel Nemec, Lucie Rihova, Jiri Jarkovsky, Roman Hajek
Journal: Blood (2016)
Medication and Cognitive Behavioral Therapy for Pediatric Anxiety Disorders
Authors: Joan Rosenbaum Asarnow, Michelle S. Rozenman, Gabrielle A. Carlson
Journal: JAMA Pediatrics (2017)

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Abstract P076: Essential Role of Neuronal Nitric Oxide Synthase in Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase II Activation in Cardiac Myocytes During β-Adrenergic Stimulation
Authors: Lifei Tang, Steve Roof, Mark Ziolo
Journal: Circulation Research (2011)

RATIONALE: Stimulation of the beta-adrenergic (beta-AR) pathway leads to positive inotropy, and is the major regulator of heart function. In addition to the traditional PKA pathway, activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and neuronal nitric oxide synthase (NOS1) signaling also play important roles in the positive inotropy by modulating ryanodine receptor (RyR) activity. OBJECTIVE: The upstream activators of CaMKII during beta-AR stimulation are not well defined. The purpose of this study is to investigate if there is any cross-talk between the CaMKII and NOS1 signaling pathways. METHODS AND RESULTS: Myocytes were isolated from wildtype (WT, C57Bl/6) and NOS1 −/− mice. Ca 2+ transients (Fluo-4) and cell shortening (edge detection) were simultaneously measured. RyR activity was measured using the SR Ca 2+ leak/load relationship. CaMKII was acutely inhibited by KN93. In WT myocytes, KN93 decreased beta-AR stimulated contraction (Ca2+ transients (Fluo-4) and cell shortening). In NOS1 −/− myocytes, beta-AR stimulated contraction was blunted compared to WT, and KN93 had no further effect on contraction. Furthermore, beta-AR stimulated RyR activity was blunted in NOS1 −/− compared to WT myocytes. As with contraction, KN93 decreased beta-AR stimulated RyR activity in WT myocytes, but had no effect in NOS1 −/− myocytes. CONCLUSION: These data suggest that NOS1 is required for CaMKII-mediated RyR activation which contributes to positive inotropy during beta-AR stimulation. Further study of this pathway is warranted since CAMKII expression and activity are increased in cardiac hypertrophy and heart failure. A better understanding of the NOS1/CaMKII pathway during beta-AR stimulation has beneficial therapeutic potential for heart diseases.