tbuckley/cabot-search huggingface dataset:
Abstract 732: The P2Y <sub>2</sub> Receptor Selectively Binds to Filamin A to Regulate Spreading and Migration of Vascular Smooth Muscle Cells
Authors: Ningpu Yu, Gerardo E Fernandez, Gary A Weisman, Cheikh I Seye
Journal: Circulation (2007)

The functional expression of the G protein-coupled P2Y 2 nucleotide receptor has been associated with the development of intimal lesions. Activation of this receptor also stimulates actin cytoskeleton reorganization and migration of vascular smooth muscle cells (SMCs). Since cell migration has been linked to the dynamic reorganization of the actin cytoskeleton, which transmits biochemical signals and forces necessary for cell locomotion, the aim of the present study was to identify cytoskeletal proteins that bind to the P2Y 2 receptor and potentially regulate SMC migration. Using the yeast two-hybrid system, we isolated filamin A, a filamentous actin-cross linking protein that interacts with the C-terminal domain of the P2Y 2 receptor and we used deletion mapping to identify amino acid deletion in the P2Y 2 receptor that led to selective loss of filamin A binding. Ex-vivo treatment of aortic explants with the P2Y 2 receptor agonist UTP (10 μmol/L) significantly promoted migration of SMCs in wild type but not in P2Y 2 receptor −/− mice. Likewise, using a Transwell migration assay we showed that UTP increased migration of SMCs in wild type (3.5 folds, P&lt;0.01 vs. untreated cells) but not P2Y 2 receptor −/− mice (P&lt;0.4 vs. untreated cells). Adenoviral infection of the full length P2Y 2 receptor restored UTP-mediated cell migration in P2Y 2 receptor −/− mice whereas infection of a mutant P2Y 2 receptor that does not bind filamin A did not. UTP-induced migration was preceded by a rapid phosphorylation of filamin A that was not observed either in P2Y 2 receptor −/− SMCs or in P2Y 2 receptor −/− SMCs infected with the mutant P2Y 2 receptor that does not bind filamin A. Treatment of SMCs from wild type mice with UTP (10 μmol/L) caused a 4-fold increase in spreading to collagen I as compared to unstimulated cells. The UTP-mediated increase of SMC spreading was not found in P2Y 2 receptor −/− SMCs but was restored by adenoviral infection of the full length P2Y 2 receptor cDNA into these cells. However, adenoviral delivery of a mutant receptor −/− which does not bind to filamin A did not restore UTP-mediated spreading of P2Y 2 receptor SMCs to collagen. This study demonstrates that P2Y 2 -dependent modulation of the actin cytoskeleton selectively regulates spreading and migration of SMC.
Evaluation of the STOP-BANG questionnaire as a screening tool for sleep apnea in a sleep medicine center
Authors: Ricardo Reis, Maria Fatima Teixeira, Vitoria Martins, Clara Santos, José Moutinho
Journal: European Respiratory Journal (2013)

Introduction The STOP-BANG questionnaire as recently been validated as a screening tool for sleep apnea in surgical patients.

Aims To evaluate the STOP-BANG questionnaire in predicting sleep apnea in patients observed in a sleep medicine center.

Methods During a 2 month period, from December 2012, all patients observed for the first time in our sleep medicine center filled the Epworth Sleepiness Scale (ESS) and STOP-BANG Questionnaire (SB). All patients performed a sleep study. The scores from the ESS and STOP-BANG questionnaire were compared with the apnea/hypopnea or respiratory disturbance index (AHI/RDI) from the ambulatory or laboratory polysomnography, respectively.

Results A total of 216 patients were observed, of which, 156 (72%) had completed the sleep study analysis at the time of submission. Mean age was 53,7±15,6years and 64% were males. Mean neck circumference was 40,9±4,1cm and BMI was 31,6±11,9kg/m2. Mean ESS was 10,35±6,26. Mean SB score was 4,58±1,69, of which “loud snoring” (76%) and BMI>35 (17%) were the most and less frequent positive criteria, respectively, and 86% were classified as high risk (SB Score>3). Mean AHI/RDI was 25,9±22,9/h and sleep apnea (AHI/RDI>5/h) was diagnosed in 82%. For an AHI/RDI>5/h a SB score>3 had a sensitivity, specificity, PPV and NPV of 93,8%, 50,0%, 89,6% and 63,6%, respectively, with an area under the curve of 0,804 (p 9 had a sensitivity and specificity of 60,2% and 60,7%, with an area under the curve of 0,609 (p=0,072).

Conclusions The STOP-BANG questionnaire when performed in a sleep medicine center shows a high sensitivity and PPV for sleep apnea, outperforming the Epworth Sleepiness Scale.
Abstract P116: County Cardiovascular Health is Associated with County-Level Health Care Resources
Authors: Stephanie J Frisbee, Courtney Pilkerton, Thomas K Bias
Journal: Circulation (2014)

Cardiovascular disease (CVD) remains the leading cause of death in the U.S. Reducing the population burden of CVD will require an increased focus on understanding how to promote and support population-level cardiovascular health (CVH), which will include the ability to measure the presence of CVH, not merely the presence or absence of CVD. Recently, the American Heart Association developed a comprehensive metric designed to measure CVH at the population level. The metric includes smoking, body mass index, physical activity, diet, cholesterol, blood pressure, and blood glucose. The purpose of this study was to assess how population-level CVH is related to the availability of health care providers and services within the county. Data from the Behavioral Risk Factor Surveillance System were used to calculate age-adjusted CVH for each county in 2009. Federal Information Processing Standards codes were used to obtain scores for counties with a sample size of 15 or more. Data on county-level health care services and providers were abstracted from the Area Resource File. The main outcomes were age-standardized mean CVH score. In total, 2236 counties were included in the analysis. Mean CVH score was 3.49 (0.39 SD). After adjustment for county population, county-level CVH score was positively correlated to per capita primary care physicians (rho=0.33, p&lt;0.0001) and nurse practitioners (rho=0.106, p&lt;0.0001). County CVH was also positively and significantly correlated to cardiovascular disease specialists (rho=0.220, p&lt;0.0001). The number of per capita physicians assistants and dieticians / nutritionists were also positively associated with county CVH (rho=0.232, p&lt;0.0001; rho=0.112, p=0.003, respectively). In assessing the effect of the availability of health care facilities, county CVH was positively associated with per capita county-level long term hospital beds, nursing home beds, and community mental health centers (rho/p-values respectively: 0.122/&lt;0.0001; 0.062/p=0.003; 0.078/&lt;0.0001) but negatively associated with per capita county-level beds in skilled nursing facilities, home health agencies and federally qualified health centers (rho/p-values respectively: -0.189/&lt;0.0001; -0.086/&lt;0.0001; -0.065/0.002). Further study is needed to understand the marginal impact of health care providers and facilities on county CVH.
Abstract 3722: Deficiency Of Hck And Fgr Src Kinases Leads To Delayed Atherosclerosis In LDLr <sup>−/−</sup> Mice.
Authors: Indira Medina, Erik A. Biessen
Journal: Circulation (2008)

Hck and Fgr are members of the Src family of tyrosine kinases involved in regulation of immune activation and leukocyte function. In macrophages, deficiency of Hck and Fgr leads to impaired integrin signal transduction, altered cytoskeleton and reduced motility, while loss of Hck alone was seen to skew monocyte differentiation towards an M2 macrophage phenotype. In this study we evaluated the involvement of Hck and Fgr in atherosclerosis progression and composition. Female LDLr−/− mice were lethally irradiated and reconstituted one day later with bone marrow from either Hck/Fgr deficient or wild-type mice. After six weeks of recovery, the animals were fed an atherogenic diet during 13 weeks and then sacrificed for lesion analysis and ex-vivo experiments. Blood leukocyte counts were not different between groups. Peritoneal macrophages from the Hck/Fgr deficient mice exhibited a reduced migratory capacity (17 fold decrease compared to control, P=1E10 – 6) with altered formation of phylopodia. In agreement with these findings, reconstitution with Hck/Fgr deficient bone marrow resulted in 36% reduction in lesion size (P=0.02, n=10). Whereas necrotic core size did not differ between groups, fibrous caps and collagen content were markedly smaller in plaques of Fgr/Hck deficient chimeras, both as total area and as percentage of plaque area, suggesting a reduced stability (fibrous cap: −73% P=0.002 (absolute), 13 vs. 30%, P=0.0002 (relative); collagen: −87%, P=0.0001 (absolute); 2 vs. 11% P=0.0005 (relative)). In conclusion, deficiency of Hck and Fgr Src kinases leads to reduced atherosclerosis accompanied by reduced fibrosis and collagen contents, which may be partly attributable to impaired migration of monocytes to the plaque.
Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial
Authors: Jürgen K Rockstroh, Mark Nelson, Christine Katlama, Jay Lalezari, Josep Mallolas, Mark Bloch, Gail V Matthews, Michael S Saag, Philippe J Zamor, Chloe Orkin, Jacqueline Gress, Stephanie Klopfer, Melissa Shaughnessy, Janice Wahl, Bach-Yen T Nguyen, Eliav Barr, Heather L Platt, Michael N Robertson, Mark Sulkowski
Journal: The Lancet HIV (2015)
Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients With Symptomatic Chronic Heart Failure and Iron Deficiency
Authors: Darlington O. Okonko, Agnieszka Grzeslo, Tomasz Witkowski, Amit K.J. Mandal, Robert M. Slater, Michael Roughton, Gabor Foldes, Thomas Thum, Jacek Majda, Waldemar Banasiak, Constantinos G. Missouris, Philip A. Poole-Wilson, Stefan D. Anker, Piotr Ponikowski
Journal: Journal of the American College of Cardiology (2008)
Abstract #5665: Assessing immunologic impact of anti-CTLA-4 therapy on a pre-surgical clinical trial
Authors: Padmanee Sharma, Ashish Kamat, Derek Ng Tang, Hong Chen, Tihui Fu, Jingjing Sun, Patricia Troncoso, Jianda Yuan, Jedd Wolchok, Sergio Quezada, Christopher Logothetis, James Allison
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Antibody mediated blockade of T cell inhibitory signals regulated by CTLA-4 has been shown to enhance anti-tumor responses in both pre-clinical and clinical settings. Over 3700 cancer patients with different malignancies have been treated with anti-CTLA-4 therapy on clinical trials. Published reports document an approximately 10% response rate for anti-CTLA-4 therapy. Why some patients respond to treatment with anti-CTLA-4 antibody while others do not remains unknown. The identification of intermediate biomarkers is essential for us to understand how anti-CTLA-4 antibody affects human immune responses and whether identified immune responses can serve as predictive markers of anti-tumor responses or allow for the selection of appropriate patients for therapy. To date, trials have been conducted in the metastatic disease setting, which allow for correlation of therapy with clinical outcome but do not provide analyses of relevant biomarkers in the systemic circulation that reflect changes within the tumor microenvironment. In an attempt to identify relevant biomarkers within the tumor microenvironment and systemic circulation, we conducted the first pre-surgical clinical trial with anti-CTLA-4 antibody. Patients with localized bladder cancer were given two doses of antibody at 3 mg/kg (N=6) or 10 mg/kg (N=6) prior to undergoing surgery. We found increased ICOS expression on CD4 T cells within tumor tissues and correlated these changes with those that occurred within the systemic circulation. CD4+ICOShi T cells produced IFN\#947; and could recognize the NY-ESO-1 tumor antigen. We extended our findings to the metastatic disease setting of melanoma patients and analyzed blood samples for changes in frequency of CD4+ICOShi T cells. Our preliminary data indicate that anti-CTLA-4 treated patients who have a 2-fold increase in ICOS-expressing CD4 T cells above pre-therapy values have improved clinical responses and survival as compared to patients without similar increases. Furthermore, we are exploring the role of ICOS-expressing T cells in murine models and have preliminary data to indicate that these T cells play an important role in anti-tumor responses mediated by anti-CTLA-4 antibody. Therefore, our pre-surgical clinical trial led to the identification of ICOS-expressing T cells as a potential biomarker for clinical responses in patients treated with anti-CTLA-4.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5665.
Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner
Authors: Weiwei Yi, Xuelian Hu, Zhiyang Chen, Leiming Liu, Yuan Tian, Hui Chen, Yu-sheng Cong, Fan Yang, Lianfeng Zhang, Karl Lenhard Rudolph, Zhixin Zhang, Yong Zhao, Zhenyu Ju
Journal: Blood (2015)
STUDIES ON THE PROPAGATION IN VITRO OF POLIOMYELITIS VIRUSES
Authors: William F. Scherer, Jerome T. Syverton, George O. Gey
Journal: The Journal of Experimental Medicine (1953)

The cells of a human epithelial cancer cultivated en masse have been shown to support the multiplication of all three types of poliomyelitis virus. These cells (strain HeLa of Gey) have been maintained in vitro since their derivation from an epidermoid carcinoma of the cervix in February, 1951. As the virus multiplied it caused in from 12 to 96 hours degeneration and destruction of the cancer cells. The specific destructive effect of the virus was prevented by adding homotypic antibody to the cultures but not by adding heterotypic antibodies. Methods for the preparation of large numbers of replicate cultures with suspensions of strain HeLa cells were described. The cells in suspension were readily quantitated by direct counts in a hemocytometer. A synthetic solution that maintains cellular viability was employed for viral propagation. The experimental results demonstrate the usefulness of strain HeLa cells for (a) the quantitation of poliomyelitis virus, (b) the measurement of poliomyelitis antibodies, and (c) the production of virus.
Abstract 20414: Cardiac Resynchronization Therapy Reduces Septal Contribution to Right Ventricular Work
Authors: Petter Storsten, Espen W Remme, Espen Boe, Morten Eriksen, Erik Kongsgaard, Otto A Smiseth, Helge Skulstad
Journal: Circulation (2014)

Introduction: During left bundle branch block (LBBB) there is abnormal motion of the interventricular septum (IVS) with early systolic beaking into the left ventricle (LV), followed by rebound stretch into the right ventricle (RV). Hypothesis: We hypothesize that septal rebound stretch contributes to RV function, and therefore cardiac resynchronization therapy (CRT) which removes rebound stretch, may have a negative effect on RV systolic performance. Methods: In 6 anesthetized dogs, LBBB was induced by radio frequency ablation. CRT was applied with electrodes on the IVS and the LV lateral wall. RV pressure (RVP) was measured by a micromanometer, and septum-to-RV free wall diameter and RV free wall long axis segment length by sonomicrometry. RV short-axis work was calculated as the area of RVP-diameter loop and long-axis work as area of the RVP-segment length loop. Results: Induction of LBBB increased RV short axis work from 36 ± 20 to 62 ± 18 mmHg*mm (± SD, p&lt;0.05), but decreased RV long-axis work from 40 ± 13 to 30 ± 14 mmHg*mm (p&lt;0.05). With CRT these changes were reversed; RV short-axis work decreased to 35 ± 21 (p&lt;0.05) and long-axis work increased to 41 ± 15 mmHg*mm (p&lt;0.05). This was associated with an increase in RV dP/dt max (p&lt;0.05). Conclusions: Application of CRT during LBBB caused a marked reduction in RV short-axis work, indicating reduced septal contribution to RV work. This was compensated by an increase in RV free wall long-axis work, and RV dP/dt max increased. Thus, a non-failing RV has the ability to compensate and even increase its function during CRT, but emphases the importance of RV function to achieve response of CRT treatment.
Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study
Authors: Morna Cornell, Leigh F Johnson, Michael Schomaker, Frank Tanser, Mhairi Maskew, Robin Wood, Hans Prozesky, Janet Giddy, Kathryn Stinson, Matthias Egger, Andrew Boulle, Landon Myer
Journal: The Lancet HIV (2015)
Abstract P4-06-04: Targeting the PI3K-AKT-mTOR and RAF-MEK-ERK pathways in <i>HER2</i> amplified breast cancer models
Authors: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones
Journal: Cancer Research (2015)

Abstract Background: The PI3K-AKT-mTOR and the RAF-MEK-ERK signaling pathways are critical for normal physiology and also commonly dysregulated in several cancers including breast cancer. Inhibition of one pathway can still result in the maintenance of signaling and tumor progression via the other reciprocal pathway. Here, we hypothesize that due to the existence of such "escape" mechanisms a dual targeting of these pathways may lead to superior therapeutic activity in HER2+ breast tumors. Methodology: This study evaluated the combination of a pan-PI3K inhibitor GDC-0941 and a MEK1/2 inhibitor GDC-0973 in different HER2+ breast cancer cell lines. HER2+/trastuzumab (T)-sensitive (BT474), HER2+/trastuzumab-resistant (BT474HerR) and HER2+/PIK3CA mutated (HCC1954) cells were used for this study. Growth inhibition/survival, apoptosis, signal transduction and antitumor efficacy were examined using 3D-ON-TOP assays, annexinV staining and mouse xenografts respectively, in T-sensitive, T-resistant and HER2+/PIK3CA mutated breast cancer cell lines. Results: 1) treatment with GDC-0941 caused dose dependent inhibition of phosphorylation of AKT (S473, T308), P70S6K, S6RP, and 4EBP1 (T37/46) and the combination of GDC-0941 plus GDC-0973 more effectively blocked p-S6RP and p-4EBP1, especially in BT474HerR and HCC1954 cells, 2) GDC-0973 inhibited activation of ERK and this inhibition was sustained when combined with GDC-0941, 3) all cell lines showed an increase in annexin V positivity (index of apoptosis) following the treatment of GDC-0941 alone and a combination of GDC-0941 plus GDC-0973 more effectively induced apoptosis in HER2+ cell lines, 4) similar to anti-proliferative and pro-apoptotic signals, a combination of GDC-0941 plus GDC-0973 more effectively abrogated anchorage-independent colony formation in 3D-ON-TOP assay and 5) xenograft data exhibited that the combination of T plus GDC-0941 has an enhanced anti-tumor effect in T-sensitive (80%), T-resistant (82%) and PIK3CA mutated models (58%), and most importantly, tumor regression was more pronounced in all three models when mice were treated with T plus GDC-0941 plus GDC-0973. Conclusions: Our findings suggest that simultaneous administration of MEK1/2 inhibitor may enhance the antitumor activity of PI3K targeted drug and may delay the appearance of resistance of HER2-targeted therapy in HER2 amplified breast cancer. Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. Targeting the PI3K-AKT-mTOR and RAF-MEK-ERK pathways in HER2 amplified breast cancer models [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-06-04.
Trial Registration: Ignored to Irresistible
Authors: Ronald Krall, Frank Rockhold
Journal: JAMA (2005)

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Abstract 2449: Clinical Outcomes in Women with Stable Coronary Artery Disease Randomized to Optimal Medical Therapy With or Without PCI: Pre-Specified Subset Analysis of the COURAGE Trial
Authors: William E Boden, Alice K Jacobs, Koon K Teo, Pamela M Hartigan, David J Maron, William J Kostuk, Bernard R Chaitman, John Mancini, Marcin Dada, Eric Bates, David C Booth, William S Weintraub, Robert A O’Rourke
Journal: Circulation (2007)

Background: The main results of the COURAGE Trial showed no significant differences in the primary outcome of all-cause mortality or non-fatal MI, or in major secondary outcomes (the composites of death, MI or stroke, and hospitalization for ACS) in the 2,287 patients with stable coronary artery disease randomized to optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). In a pre-specified subset analysis, women who received an initial strategy of PCI during a median 4.6 year follow-up appeared to benefit for death or MI, but the interaction P value for this comparison (0.03) exceeded the nominal pre-specified value for all trial subgroup interactions (P&lt;0.01) . Methods: We explored various pre-specified clinical endpoints in the 338 women (15%) of the COURAGE cohort who were randomized to PCI + OMT vs. OMT alone. Chi-Square analyses were conducted for the following outcomes between groups (time to first event): death or MI; death; MI; the composite of death, MI or stroke; death, MI or hospitalization (Hosp) for ACS; and Hosp for CHF. Results: There were no significant differences between treatment arms for major pre-specified cardiovascular events in men, but there was apparent benefit for many clinical outcomes in women randomized to PCI + OMT vs. OMT alone, although in all but one comparison (i.e., CHF), the P values exceeded the pre-specified value for interaction (P &lt; 0.01) during long-term follow-up (Table ): Conclusions: Although the primary endpoint and death alone were not significantly different between groups, women randomized to PCI appeared to fare better than those randomized to OMT alone for selected clinical outcomes. However, because women comprised only 15% of the COURAGE population, it is unclear whether these findings indicative true clinical benefit for PCI in women, or alternatively may represent a statistical play of chance or type II error. These important findings may warrant additional investigation and analysis.