bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and associated factors of smoking in middle and high school students: a school-based cross-sectional study in Zhejiang Province, China
Authors: Wang Meng , Zhong Jie-Ming , Fang Le , Wang Hao 
Published: January 2016

ObjectivesTo determine the prevalence and associated factors of smoking in a Chinese adolescent population.SettingA multistage, stratified cluster sampling technique was used in the present cross-sectional study conducted in Zhejiang Province of China. Based on socioeconomic status, school levels and geographical positions, 253 middle school classes, 122 academic school classes and 115 vocational high school classes located in 12 urban areas and 18 rural areas were chosen.ParticipantsA total of 9617 middle school students, 5495 academic high school students and 4430 vocational high school students were recruited in this survey.Primary and secondary outcome measuresEver, current smoking status and associated factors were collected via a self-administered questionnaire. Logistic regression models were used to examine the associations between current smoking and the associated factors. ORs with their 95% CIs were reported.ResultsOverall, the prevalence of ever-smokers and current smokers was 33.83% and 7.93%, respectively. Focused on current smokers, significantly higher risks of adolescent smoking were observed in an older age group, boys, rural areas and vocational high school. Other significant factors were parents smoking, secondhand smoke exposure, parental divorce or separation, living with family, school performance and belief that smoking is harmful.ConclusionsThe prevalence of smoking was relatively high among Chinese adolescents in Zhejiang Province. Factors related to personal characteristics, family and school were associated with adolescent smoking.
Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials
Authors: Lancaster Lisa , Albera Carlo , Bradford Williamson Z , Costabel Ulrich , du Bois Roland M , Fagan Elizabeth A , Fishman Robert S , Glaspole Ian , Glassberg Marilyn K , King Talmadge E , Lederer David J , Lin Zhengning , Nathan Steven D , Pereira Carlos A , Swigris Jeffrey J , Valeyre Dominique , Noble Paul W 
Published: January 2016

BackgroundPirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF.MethodsAll patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug.ResultsA total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation.ConclusionsA comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated.Trial registration numbersNCT00287716,NCT00287729,NCT00662038,NCT01366209.
How do patients feel about taking part in clinical trials in emergency care?
Authors: Buckley Joseph M , Irving Andy D , Goodacre Steve 
Published: January 2016

BackgroundThere is little in-depth research into how patients feel about emergency medical trials, and what influences these feelings.ObjectivesTo investigate patients’ feelings on taking part in emergency medical research, particularly trials conducted without prospective consent.MethodsSeventeen inpatients, all recently admitted with a medical emergency, were interviewed. Questions focused on feelings on taking part in hypothetical trials, particularly trials conducted with deferred consent.ResultsFive main themes were identified.Level of trust in the medical profession—high levels of trust tended to correlate with willingness to participate in trials. Previous bad healthcare experiences tended to diminish trust.Concerns for personal well-being—patients identified a conflict between aversion to unknown side effects and desire for access to newer and potentially better treatments. Some would be less inclined to participate in research if they were severely unwell, some more so.Altruism—many cited the importance of helping to advance medical knowledge and of ‘giving back to the health service’.Concerns over autonomy—some felt that deferred consent was a violation of personal autonomy.Uncertainty—many patients seemed to struggle to understand the more complex concepts discussed.ConclusionsPatients are broadly trusting, and open to participating in emergency medical trials, but want to be kept as informed as possible throughout the process. Willingness may be improved by providing more complete explanations, although this may be limited by the complexity of relevant concepts. Good communication and improved public understanding of clinical trials would likely increase acceptance of emergency care research.
Adult and adolescent exposure to tobacco and alcohol content in contemporary YouTube music videos in Great Britain: a population estimate
Authors: Cranwell Jo , Opazo-Breton Magdalena , Britton John 
Published: January 2016

BackgroundWe estimate exposure of British adults and adolescents to tobacco and alcohol content from a sample of popular YouTube music videos.MethodsBritish viewing figures were generated from 2 representative online national surveys of adult and adolescent viewing of the 32 most popular videos containing content. 2068 adolescents aged 11–18 years (1010 boys, 1058 girls), and 2232 adults aged 19+years (1052 male, 1180 female) completed the surveys. We used the number of 10 s intervals in the 32 most popular videos containing content to estimate the number of impressions. We extrapolated gross and per capita impressions for the British population from census data and estimated numbers of adults and adolescents who had ever watched the sampled videos.ResultsFrom video release to the point of survey, the videos delivered an estimated 1006 million gross impressions of alcohol (95% CI 748 to 1264 million), and 203 million of tobacco (95% CI 151 to 255 million), to the British population. Per capita exposure was around 5 times higher for alcohol than for tobacco, and nearly 4 times higher in adolescents, who were exposed to an average of 52.1 (95% CI 43.4 to 60.9) and 10.5 (95% CI 8.8 to 12.3) alcohol and tobacco impressions, respectively, than in adults (14.1 (95% CI 10.2 to 18.1) and 2.9 (95% CI 2.1 to 3.6)). Exposure rates were higher in girls than in boys.ConclusionsYouTubemusic videos deliver millions of gross impressions of alcohol and tobacco content. Adolescents are exposed much more than adults. Music videos are a major global medium of exposure to such content.
Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response
Authors: Conery Andrew R. , Centore Richard C. , Spillane Kerry L. , Follmer Nicole E. , Bommi-Reddy Archana , Hatton Charlie , Bryant Barbara M. , Greninger Patricia , Amzallag Arnaud , Benes Cyril H. , Mertz Jennifer A. , Sims Robert J. 
Published: January 2016

Abstract
Small-molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are being tested in clinical trials for a variety of cancers, but patient selection strategies remain limited. This challenge is partly attributed to the heterogeneous responses elicited by BET inhibition (BETi), including cellular differentiation, senescence, and death. In this study, we performed phenotypic and gene-expression analyses of treatment-naive and engineered tolerant cell lines representing human melanoma and leukemia to elucidate the dominant features defining response to BETi. We found that de novo and acquired tolerance to BETi is driven by the robustness of the apoptotic response, and that genetic or pharmacologic manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further reveal that the expression signatures of the apoptotic genes BCL2, BCL2L1, and BAD significantly predict response to BETi. Taken together, our findings highlight the apoptotic program as a determinant of response to BETi, and provide a molecular basis for patient stratification and combination therapy development. Cancer Res; 76(6); 1313–9. ©2016 AACR.
Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin–GUCY2C Paracrine Signaling Axis
Authors: Lin Jieru E. , Colon-Gonzalez Francheska , Blomain Erik , Kim Gilbert W. , Aing Amanda , Stoecker Brian , Rock Justin , Snook Adam E. , Zhan Tingting , Hyslop Terry M. , Tomczak Michal , Blumberg Richard S. , Waldman Scott A. 
Published: January 2016

Abstract
Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin–GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. Cancer Res; 76(2); 339–46. ©2016 AACR.
Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β
Authors: Nakanishi Yoshito , Walter Kimberly , Spoerke Jill M. , O'Brien Carol , Huw Ling Y. , Hampton Garret M. , Lackner Mark R. 
Published: January 2016

Abstract
Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110β D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors. Cancer Res; 76(5); 1193–203. ©2016 AACR.
Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer
Authors: Loibl Sibylle , Darb-Esfahani Silvia , Huober Jens , Klimowicz Alexander , Furlanetto Jenny , Lederer Bianca , Hartmann Arndt , Eidtmann Holger , Pfitzner Berit , Fasching Peter A. , Tiemann Katharina , Jackisch Christian , Mehta Keyur , von Minckwitz Gunter , Untch Michael , Denkert Carsten 
Published: January 2016

AbstractBackground: The PI3K/AKT pathway and phosphatase and tensin homolog (PTEN) aberrations are common in breast cancer. We investigated the correlation between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN, p4EBP1 (phosphorylated E4 binding protein 1), and pathologic complete response (pCR) in patients receiving neoadjuvant therapy.Experimental Design: We retrospectively evaluated PIK3CA, PTEN, and p4EBP1 protein expression in centrally HER2-positive patients (n = 181) who received epirubicin cyclophosphamide/trastuzumab followed by docetaxel/trastuzumab alone or concomitant/followed by capecitabine within the GeparQuattro study. PTEN was assessed using the automated quantitative immunofluorescence analysis and was analyzed as a dichotomic variable. p4EBP1 was assessed by immunohistochemistry and used as a continuous and dichotomic variable.Results: p4EBP1 was available from 137, PTEN from 108, and PIK3CA genotype from 83 patients. Overall, the pCR rate in PTEN-low tumors was 27.6%, and in PTEN-high tumors, it was 57.1% (P = 0.010). pCR rates were not statistically different between PIK3CA wild-type and mutant (35% vs. 22%) or p4EBP1 IRS ≤ 4 and IRS &gt; 4 (39% vs. 33%). pCR rate was 57.1% (8/14) in PTEN-high/PIK3CA wild-type and decreased to 15.4% in PTEN-low/PIK3CA-mutant tumors (P = 0.023). In multivariable analysis adjusted for baseline parameters, PTEN independently predicted pCR in the following cohorts: overall [OR, 7.54; 95% confidence interval (CI), 2.03–28.06; P = 0.003], PIK3CA wild-type (OR, 23.81; 95% CI, 1.75–324.05; P = 0.017), p4EBP1 IRS &gt; 4 (OR, 11.53; 95% CI, 1.84–72.24; P = 0.009), and hormone receptor–positive (OR, 40.91; 95% CI, 2.93–570.44; P = 0.006). p4EBP1 was independently predictive for pCR in PIK3CA wild-type tumors (OR, 0.14; 95% CI, 0.03–0.78; P = 0.025).Conclusions: The study showed the potential role of PIK3CA genotype, PTEN, and p4EBP in predicting pCR after anthracycline–taxane-based chemotherapy and anti-HER2 treatment. Clin Cancer Res; 22(11); 2675–83. ©2016 AACR.
Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial
Authors: Jovelet Cécile , Ileana Ecaterina , Le Deley Marie-Cécile , Motté Nelly , Rosellini Silvia , Romero Alfredo , Lefebvre Celine , Pedrero Marion , Pata-Merci Noémie , Droin Nathalie , Deloger Marc , Massard Christophe , Hollebecque Antoine , Ferté Charles , Boichard Amélie , Postel-Vinay Sophie , Ngo-Camus Maud , De Baere Thierry , Vielh Philippe , Scoazec Jean-Yves , Vassal Gilles , Eggermont Alexander , André Fabrice , Soria Jean-Charles , Lacroix Ludovic 
Published: January 2016

AbstractPurpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019).Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes.Results: Among the 283 patients with tDNA–cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%–61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (≥8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations.Conclusions: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960–8. ©2016 AACR.
Investigating the Nature of the Left Periphery in Peninsular Spanish wh-Question Intonation
Authors: Henriksen Nicholas 
Published: January 2016

AbstractBackground/Aims: In this paper we aim to resolve the phonological status of utterance-initial rises in Spanish wh-questions. Methods/Analysis 1: In analysis 1 we examine the scaling and alignment properties of utterance-initial rises produced by 14 speakers of Peninsular Spanish. Results/Analysis 1: The results provide evidence for a single bitonal pitch accent at the left periphery (L + &lt;H*) despite multiple options at the right periphery. Conclusion/Analysis 1: Our analysis, relying on the notion of sparse tonal specification, helps to explain Sp_ToBI transcribers' past inconsistencies in labeling wh-question initial rises. Methods/Analysis 2: In analysis 2 we tested whether there are scaling differences between the wh-question contours produced in analysis 1 and statement contours produced by the same 14 speakers. Results/Analysis 2: We showed that speakers scale utterance-initial peaks higher in statements, and that they scale utterancefinal peaks higher in wh-questions. Conclusion/Analysis 2: This finding is incompatible with the notion that speakers of Spanish use a higher F0 level from the start of the utterance to distinguish questions from statements.
Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice
Authors: Chu Yi , Lund Donald D. , Doshi Hardik , Keen Henry L. , Knudtson Kevin L. , Funk Nathan D. , Shao Jian Q. , Cheng Justine , Hajj Georges P. , Zimmerman Kathy A. , Davis Melissa K. , Brooks Robert M. , Chapleau Mark W. , Sigmund Curt D. , Weiss Robert M. , Heistad Donald D. 
Published: January 2016

Objective—
Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice.

Approach and Results—

Control, hypertensive, hypercholesterolemic (
Apoe

−/−

), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice.

Conclusions—
Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.
Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-γ and cAMP Pathways in Vascular Cells
Authors: Sanada Fumihiro , Kanbara Yasuhiro , Taniyama Yoshiaki , Otsu Rei , Carracedo Miguel , Ikeda-Iwabu Yuka , Muratsu Jun , Sugimoto Ken , Yamamoto Koichi , Rakugi Hiromi , Morishita Ryuichi 
Published: January 2016

Objective—
Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of intermittent claudication. Cilostazol has been shown to be beneficial for the improvement of pain-free walking distance in patients with intermittent claudication in a series of randomized clinical trials. However, the underlying mechanism how cilostazol improved intermittent claudication symptoms is still unclear.

Approach and Results—
In this study, the effect of cilostazol on ischemic leg was investigated in mouse ischemic hindlimb model. Administration of cilostazol significantly increased the expression of hepatocyte growth factor (HGF), vascular endothelial growth factor, angiopoietin-1, and peroxisome proliferator-activated receptor-γ in vasculature. The capillary density in ischemic leg was also significantly increased in cilostazol treatment group when compared with control and aspirin treatment group. However, an increase in capillary density and the expression of growth factors was almost completely abolished by coadministration of HGF-neutralizing antibody, suggesting that cilostazol enhanced angiogenesis mainly through HGF. In vitro experiment revealed that cilostazol treatment increased HGF production in vascular smooth muscle cells via 2 major pathways: peroxisome proliferator-activated receptor-γ and cAMP pathways.

Conclusions—
Our data suggest that the favorable effects of cilostazol on ischemic leg might be through the angiogenesis through the induction of HGF via peroxisome proliferator-activated receptor-γ and cAMP pathways.