bluuebunny/crossref_metadata_2025_split huggingface dataset:
The social context of smoking cessation in China: an exploratory interview study
Authors: Zhang Jing-Yu , Chan Sophia Siu-Chee , Fong Daniel Yee-Tak , Malone Ruth E , Lam Tai-hing 
Published: April 2011

BackgroundChina has the largest population of smokers in the world. Little previous research has explored the cultural challenges in encouraging smoking cessation in China. This study aimed to explore and generate research questions about culturally distinctive beliefs and barriers to smoking cessation.MethodsA convenience sample of 21 smokers and ex-smokers selected from a Guangzhou hospital smoking cessation clinic and medical ward was interviewed about experiences with quitting smoking. Data were analysed to elucidate culturally distinctive obstacles to cessation that may warrant further study.ResultsThree major obstacles to smoking cessation were identified: family and social influences, the myth that quitting smoking is dangerous to health and misinformation from health professionals.ConclusionsThis study suggests that smoking cessation in China is made more challenging by a social context in which family, friends and even health professionals may discourage it. However, these identified barriers and beliefs about smoking cessation need to be confirmed in larger, more representative studies in the future.
Bortezomib Primes Neuroblastoma Cells for TRAIL-Induced Apoptosis by Linking the Death Receptor to the Mitochondrial Pathway
Authors: Naumann Ivonne , Kappler Roland , von Schweinitz Dietrich , Debatin Klaus-Michael , Fulda Simone 
Published: April 2011

AbstractPurpose: Searching for novel strategies to modulate apoptosis in neuroblastoma, we investigated the potential of the proteasome inhibitor bortezomib.Experimental Design: The effect of bortezomib on TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis signaling pathways was analyzed in neuroblastoma cell lines, primary neuroblastoma cultures, and in an in vivo model.Results: Bortezomib synergistically cooperates with TRAIL to induce apoptosis and to reduce colony formation of neuroblastoma cells (combination index: 0.5). Mechanistic studies reveal that bortezomib profoundly enhances TRAIL-induced cleavage of Bid into tBid, accumulation of tBid in the cytosol, and its insertion into mitochondrial membranes, pointing to a concerted effect on Bid cleavage (TRAIL) and stabilization of tBid (bortezomib), which links the death receptor to the mitochondrial pathway. In addition, bortezomib increases expression of p53 and Noxa. All these changes lead to increased activation of Bax and Bak, loss of the mitochondrial membrane potential, cytochrome c release, caspase activation, and caspase-dependent apoptosis on treatment with bortezomib and TRAIL. Knockdown of Bid, Noxa, or p53 significantly delays the kinetic of bortezomib- and TRAIL-induced apoptosis, whereas it does not confer long-term protection. By comparison, overexpression of Bcl-2, which simultaneously antagonizes tBid and p53, significantly inhibits bortezomib- and TRAIL-induced apoptosis and even rescues clonogenic survival. Importantly, bortezomib and TRAIL act in concert to trigger apoptosis and to suppress tumor growth in patient-derived primary neuroblastoma cells and in an in vivo model of neuroblastoma.Conclusions: Bortezomib represents a promising new approach to prime neuroblastoma cells toward TRAIL, which warrants further investigation. Clin Cancer Res; 17(10); 3204–18. ©2011 AACR.
Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies
Authors: Olmos David , Barker Douglas , Sharma Rohini , Brunetto Andre T. , Yap Timothy A. , Taegtmeyer Anne B. , Barriuso Jorge , Medani Hanine , Degenhardt Yan Y. , Allred Alicia J. , Smith Deborah A. , Murray Sharon C. , Lampkin Thomas A. , Dar Mohammed M. , Wilson Richard , de Bono Johann S. , Blagden Sarah P. 
Published: April 2011

Abstract
Purpose: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.
Experimental Design: GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies.
Results: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3–4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3–4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and Cmax (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies.
Conclusions: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation. Clin Cancer Res; 17(10); 3420–30. ©2011 AACR.
Progesterone Receptor Isoform-Specific Promoter Methylation: Association ofPRAPromoter Methylation with Worse Outcome in Breast Cancer Patients
Authors: Pathiraja Thushangi N. , Shetty Priya B. , Jelinek Jaroslav , He Rong , Hartmaier Ryan , Margossian Astrid L. , Hilsenbeck Susan G. , Issa Jean-Pierre J. , Oesterreich Steffi 
Published: April 2011

AbstractPurpose: ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.Experimental Design: We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.Results: Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.Conclusions: Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer. Clin Cancer Res; 17(12); 4177–86. ©2011 AACR.
Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival
Authors: Dai Wei , Teodoridis Jens M. , Zeller Constanze , Graham Janet , Hersey Jenny , Flanagan James M. , Stronach Euan , Millan David W. , Siddiqui Nadeem , Paul Jim , Brown Robert 
Published: April 2011

Abstract
Purpose: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS).
Experimental Design: Epithelial ovarian tumors (screening study n = 120, validation study n = 61), prospectively collected through a cohort study, were analyzed by differential methylation hybridization at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and PFS was examined by Cox proportional hazards model.
Results: DNA methylation is associated with PFS at 20 of 302 loci (P &lt; 0.05, n = 111), with 5 loci significant at false discovery rate (FDR) less than 10%. A total of 11 of 20 loci retain significance in an independent validation cohort (n = 48, P ≤ 0.05, FDR ≤ 10%), and 7 of these loci, at FZD4, DVL1, NFATC3, ROCK1, LRP5, AXIN1, and NKD1 genes, are independent from clinical parameters (adjusted P &lt; 0.05). Increased methylation at these loci associates with increased hazard of disease progression. A multivariate Cox model incorporates only NKD1 and DVL1, identifying two groups differing in PFS [HR = 2.09; 95% CI (1.39–3.15); permutation test P &lt; 0.005]. Methylation at DVL1 and NFATC3 show significant association with response. Consistent with their epigenetic regulation, reduced expression of FZD4, DVL1, and ROCK1 is an indicator of early-disease relapse in an independent ovarian tumor cohort (n = 311, adjusted P &lt; 0.05).
Conclusion: The data highlight the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identify methylation at NKD1 and DVL1 as independent predictors of PFS. Clin Cancer Res; 17(12); 4052–62. ©2011 AACR.
Urinary Glycoprotein Biomarker Discovery for Bladder Cancer Detection Using LC/MS-MS and Label-Free Quantification
Authors: Yang Na , Feng Shun , Shedden Kerby , Xie Xiaolei , Liu Yashu , Rosser Charles J. , Lubman David M. , Goodison Steven 
Published: April 2011

Abstract
Background: Cancers of the urinary bladder are the fifth most commonly diagnosed malignancy in the United States. Early clinical diagnosis of bladder cancer remains a major challenge, and the development of noninvasive methods for detection and surveillance is desirable for both patients and health care providers.
Approach: To identify urinary proteins with potential clinical utility, we enriched and profiled the glycoprotein component of urine samples by using a dual-lectin affinity chromatography and liquid chromatography/tandem mass spectrometry platform.
Results: From a primary sample set obtained from 54 cancer patients and 46 controls, a total of 265 distinct glycoproteins were identified with high confidence, and changes in glycoprotein abundance between groups were quantified by a label-free spectral counting method. Validation of candidate biomarker alpha-1-antitrypsin (A1AT) for disease association was done on an independent set of 70 samples (35 cancer cases) by using an ELISA. Increased levels of urinary A1AT glycoprotein were indicative of the presence of bladder cancer (P &lt; 0.0001) and augmented voided urine cytology results. A1AT detection classified bladder cancer patients with a sensitivity of 74% and specificity of 80%.
Summary: The described strategy can enable higher resolution profiling of the proteome in biological fluids by reducing complexity. Application of glycoprotein enrichment provided novel candidates for further investigation as biomarkers for the noninvasive detection of bladder cancer. Clin Cancer Res; 17(10); 3349–59. ©2011 AACR.
Hypoxia Induces Genomic DNA Demethylation through the Activation of HIF-1α and Transcriptional Upregulation of MAT2A in Hepatoma Cells
Authors: Liu Quanyan , Liu Li , Zhao Yuhong , Zhang Jin , Wang Dongfeng , Chen Jiwei , He Yueming , Wu Jianguo , Zhang Zhonglin , Liu Zhisu 
Published: April 2011

Abstract
Hypoxia-inducible factor 1 (HIF-1) emerges as a crucial player in tumor progression. However, its role in hepatocellular carcinoma (HCC), especially its relation with global DNA methylation patterns in HCC under hypoxic tumor microenvironment is not completely understood. Methionine adenosyltransferase 2A (MAT2A) maintains the homeostasis of S-adenosylmethionine (SAM), a critical marker of genomic methylation status. In this study, we investigated the link between HIF-1α and MAT2A as a mechanism responsible for the change in genomic DNA methylation patterns in liver cancer under hypoxia conditions. Our results showed that hypoxia induces genomic DNA demethylation in CpG islands by reducing the steady-state SAM level both in vitro and in vivo. In addition, HIF-1α and MAT2A expression is correlated with tumor size and TNM stage of liver cancer tissues. We further showed that hypoxia-induced MAT2A expression is HIF-1α dependent and requires the recruitment of p300 and HDAC1. We also identified an authentic consensus HIF-1α binding site in MAT2A promoter by site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Taken together, we show for the first time that hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells. These findings provide new insights into our understanding of the molecular link between genomic DNA methylation and tumor hypoxia in HCC. Mol Cancer Ther; 10(6); 1113–23. ©2011 AACR.
Functional Analysis of the p53 Pathway in Neuroblastoma Cells Using the Small-Molecule MDM2 Antagonist Nutlin-3
Authors: Van Maerken Tom , Rihani Ali , Dreidax Daniel , De Clercq Sarah , Yigit Nurten , Marine Jean-Christophe , Westermann Frank , De Paepe Anne , Vandesompele Jo , Speleman Frank 
Published: April 2011

Abstract
Suppression of p53 activity is essential for proliferation and survival of tumor cells. A direct p53-activating compound, nutlin-3, was used in this study, together with p53 mutation analysis, to characterize p53 pathway defects in a set of 34 human neuroblastoma cell lines. We identified 9 cell lines (26%) with a p53 loss-of-function mutation, including 6 missense mutations, 1 nonsense mutation, 1 in-frame deletion, and 1 homozygous deletion of the 3′ end of the p53 gene. Sensitivity to nutlin-3 was highly predictive of absence of p53 mutation. Signaling pathways downstream of p53 were functionally intact in 23 of 25 cell lines with wild-type p53. Knockdown and overexpression experiments revealed a potentiating effect of p14ARF expression on the response of neuroblastoma cells to nutlin-3. Our findings shed light on the spectrum of p53 pathway lesions in neuroblastoma cells, indicate that defects in effector molecules downstream of p53 are remarkably rare in neuroblastoma, and identify p14ARF as a determinant of the outcome of the response to MDM2 inhibition. These insights may prove useful for the clinical translation of evolving strategies aimed at p53 reactivation and for the development of new therapeutic approaches. Mol Cancer Ther; 10(6); 983–93. ©2011 AACR.
Preparatory Processes and Compensatory Effort in Older and Younger Participants in a Driving-Like Dual Task
Authors: Wild-Wall Nele , Hahn Melanie , Falkenstein Michael 
Published: April 2011

Objective: The nature of increased-age-related dual-task interference was examined during a driving-like dual task in the laboratory. Background: Previous research revealed age-related deficits in dual tasks especially when cognitive and motor demands are involved. The specific contributions of sensory input, working memory demands, and/or coordination of motor responses to dual-task interference are not clear and should be clarified in the present study. Method: Younger and older participants performed a driving-like tracking task and a visually cued attention task within a dual task. Behavioral and electrophysiological data were recorded during task performance. Results: Overall tracking performance was lower for the older versus younger participants. This age-related decline was particularly pronounced in the time interval after the stimulus when the attention task demanded a motor response. In contrast, older participants tracked relatively better than the younger participants in the time interval preceding the stimulus. In the attention task, the older versus younger participants showed increased responses times and rates of false alarms and misses, suggesting a deficit in retaining the context in the cue-stimulus interval. The electroencephalogram data suggest that the older participants invested more resources than the younger participants in dual-task management during the cue-stimulus interval. Conclusion: Evidence was found for increased motor interference and a deficient context processing as well as for an increased investment of processing resources in the older compared with the younger group. Application: The results suggest that in-vehicle information systems for older drivers should be designed to support cue maintenance and that simultaneous motor demands should not be required.
Effects of Depression and Antidepressant Use on Goal Setting and Barrier Identification Among Patients With Type 2 Diabetes
Authors: Chen Hsiang-Yu , Ruppert Kristine , Charron-Prochownik Denise , Noullet William V. , Zgibor Janice C. 
Published: April 2011

Purpose The purpose of this study was to examine the effects of depression and antidepressant use on goal setting and barrier identification in patients with type 2 diabetes. Methods In a large diabetes education network, 778 patients with type 2 diabetes were enrolled in the American Association of Diabetes Educators (AADE) Outcomes System as part of their routine diabetes education between 2005 and 2008. Self-reported depression, 7 self-identified behavior change goals, and 13 barriers to diabetes self-care were collected from the Diabetes Self-Management Assessment Report Tool (D-SMART®); antidepressant use was documented from the Diabetes Educator Tool (D-ET®). Multiple linear regression was used to evaluate the effects of depression or antidepressant use on the number of goals or the number of barriers while controlling for relevant covariates. Results Among 778 patients (507 nondepressed, 181 depressed with antidepressant use, 90 depressed without antidepressant use), median age was 58, 60.9% were female, and 85.9% were Caucasian. Patients with and without depression had a similar number of self-identified behavior change goals, whereas patients with depression had 1 additional barrier to diabetes self-care compared with those without depression. In the depressed subgroup, antidepressant use had no association with the number of goals that the subjects set or the number of barriers they identified. Conclusions Among patients with type 2 diabetes, depression was associated with a slightly greater number of barriers, which may support the importance of depression screening and depression treatment in patients with diabetes.
Outcomes After a Single-Stage Procedure for Cell-Based Cartilage Repair
Authors: Cole Brian J. , Farr Jack , Winalski C. S. , Hosea Timothy , Richmond John , Mandelbaum Bert , De Deyne Patrick G. 
Published: April 2011

Background: There are currently several approaches being pursued to treat focal defects of articular cartilage, each having specific advantages or challenges. A single-stage procedure that uses autologous cartilage fragments, Cartilage Autograft Implantation System (CAIS), is being evaluated in patients and may offer a clinically effective option. Purpose: To establish the safety of CAIS and to test whether CAIS improves quality of life by using standardized outcomes assessment tools. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Patients (n = 29) were randomized (1:2) with the intent to treat with either a control (microfracture [MFX]) or an experimental (CAIS) procedure. Patients were followed at predetermined time points for 2 years using several standardized outcomes assessment tools (SF-36, International Knee Documentation Committee [IKDC], Knee injury and Osteoarthritis Outcome Score [KOOS]). Magnetic resonance imaging was performed at baseline, 3 weeks, and 6, 12, and 24 months. Results: Lesion size and International Cartilage Repair Society (ICRS) grade were similar in both groups. General outcome measures (eg, physical component score of the SF-36) indicated an overall improvement in both groups, and no differences in the number of adverse effects were noted in comparisons between the CAIS and MFX groups. The IKDC score of the CAIS group was significantly higher (73.9 ± 14.72 at 12 months and 82.95 ± 14.88 at 24 months) compared with the MFX group (57.78 ± 18.31 at 12 months and 59.5 ± 13.44 at 24 months). Select subdomains (4/5) in the KOOS instrument were significantly different at 12 and 18 months, and all subdomains (Symptoms and Stiffness, Pain, Activities of Daily Living, Sports and Recreation, Knee-related Quality of Life) were significantly increased at 24 months in CAIS with scores of 88.47 ± 11.68, 90.64 ± 7.87, 97.29 ± 3.8, 78.16 ± 22.06, and 69 ± 23.15 compared with 75 ± 9.31, 78.94 ± 13.73, 89.46 ± 8.13, 51.67 ± 26.01, and 37.15 ± 21.67 in the MFX group. These significant improvements were maintained at 24 months in both IKDC and KOOS. Qualitative analysis of the imaging data did not note differences between the 2 groups in fill of the graft bed, tissue integration, or presence of subchondral cysts. Patients treated with MFX had a significantly higher incidence of intralesional osteophyte formation (54% and 70% of total number of lesions treated) at 6 and 12 months when compared with CAIS (8% and 25% of total number of lesions treated). Conclusion: The first clinical experience in using CAIS for treating patients with focal chondral defects indicates that it is a safe, feasible, and effective method that may improve long-term clinical outcomes.