Citations

Purpose. This study examined whether brief intervention strategies founded on the Behavior-Image Model and addressing positive images of college and career success could be potentially efficacious in impacting multiple health habits of high-risk adolescents transitioning into adulthood. Design. Participants were stratified by grade level and drug use and individually randomized to one of the three Plan for Success interventions, with baseline and 1 month postintervention data collections. Setting. A large, relatively diverse suburban school in northeast Florida. Subjects. A total of 375 11th and 12th grade students participated during the spring semester 2006. Intervention. Three interventions studied included: (1) Goal Survey, (2) Goal Survey plus Contract, or (3) Goal Survey plus Consult. Measures. Outcome measures included multiple health risk, health promotion, and personal development behaviors, as well as image and belief measures. Analysis. Repeated-measures MANOVAs and ANOVAs were used to examine intervention effects. Results. MANOVAs were significant for alcohol use, F (4,328) = 6.33, p = .001; marijuana use, F (4,317) = 3.72, p = .01; exercise, F (3,299) = 4.28, p = .01; college preparation, F (2,327) = 6.26, p = .001; and career preparation, F (2,329) = 6.17, p = .001, with most behaviors improving over time, whereas group-by-time interaction effects were found for nutrition habits, F (6,652) = 2.60, p = .02; and career preparation, F (4,658) = 3.26, p = .01, favoring the consultation. Conclusion. Brief interventions founded on the Behavior-Image Model may have potential to improve selected health and personal development habits among older adolescents.

Purpose To improve the understanding of the appropriate design of phase II oncology clinical trials, we compared error rates in single-arm, historically controlled and randomized, concurrently controlled designs. Patients and Methods We simulated error rates of both designs separately from individual patient data from a large colorectal cancer phase III trials and statistical models, which take into account random and systematic variation in historical control data. Results In single-arm trials, false-positive error rates (type I error) were 2 to 4 times those projected when modest drift or patient selection effects (eg, 5% absolute shift in control response rate) were included in statistical models. The power of single-arm designs simulated using actual data was highly sensitive to the fraction of patients from treatment centers with high versus low patient volumes, the presence of patient selection effects or temporal drift in response rates, and random small-sample variation in historical controls. Increasing sample size did not correct the over optimism of single-arm studies. Randomized two-arm design conformed to planned error rates. Conclusion Variability in historical control success rates, outcome drifts in patient populations over time, and/or patient selection effects can result in inaccurate false-positive and false-negative error rates in single-arm designs, but leave performance of the randomized two-arm design largely unaffected at the cost of 2 to 4 times the sample size compared with single-arm designs. Given a large enough patient pool, the randomized phase II designs provide a more accurate decision for screening agents before phase III testing.

Abstract Prostate cancer, a complex disease, can be relatively harmless or extremely aggressive. To identify candidate genes involved in causal pathways of aggressive prostate cancer, we implemented a systems biology approach by combining differential expression analysis and coexpression network analysis to evaluate transcriptional profiles using lymphoblastoid cell lines from 62 prostate cancer patients with aggressive phenotype (Gleason grade ≥ 8) and 63 prostate cancer patients with nonaggressive phenotype (Gleason grade ≤ 5). From 13,935 mRNA genes and 273 microRNAs (miRNA) tested, we identified significant differences in 1,100 mRNAs and 7 miRNAs with a false discovery rate (FDR) of <0.01. We also identified a coexpression module demonstrating significant association with the aggressive phenotype of prostate cancer (P = 3.67 × 10−11). The module of interest was characterized by overrepresentation of cell cycle–related genes (FDR = 3.50 × 10−50). From this module, we further defined 20 hub genes that were highly connected to other genes. Interestingly, 5 of the 7 differentially expressed miRNAs have been implicated in cell cycle regulation and 2 (miR-145 and miR-331-3p) are predicted to target 3 of the 20 hub genes. Ectopic expression of these two miRNAs reduced expression of target hub genes and subsequently resulted in cell growth inhibition and apoptosis. These results suggest that cell cycle is likely to be a molecular pathway causing aggressive phenotype of prostate cancer. Further characterization of cell cycle–related genes (particularly, the hub genes) and miRNAs that regulate these hub genes could facilitate identification of candidate genes responsible for the aggressive phenotype and lead to a better understanding of prostate cancer etiology and progression. [Cancer Res 2009;69(24):9490–7]

Background Hepatitis B virus (HBV) genotype B and C seem not to affect the therapeutic response to lamivudine (3TC). Whether a given genotype has an earlier emergence of 3TC resistance remains unclear. We thus conducted this study to elucidate the association of HBV genotype with the emergence of 3TC-resistant strains in Taiwanese patients. Methods Forty chronic hepatitis B patients who developed resistance after 3TC therapy were retrospectively enrolled. HBV genotype, serum alanine aminotransferase (ALT) and HBV DNA levels were determined at baseline. The presence of 3TC-resistant mutations was confirmed by direct sequencing whenever biochemical breakthrough developed. Results The distribution of HBV genotype B and C in 40 patients receiving 3TC therapy were 60% and 40%, respectively. The mean interval to detect 3TC- resistant strain was 19.6 ±1.7 months. By using multivariate analysis, HBV genotype B and higher pre-treatment HBV DNA level were independently associated with earlier detection of 3TC-resistant strains. In addition, genotype B was significantly associated with development of 3TC resistance within the first 12 months of 3TC therapy compared with genotype C (odds ratio 8.27; P=0.004). Conclusions Compared with HBV genotype C, genotype B appears to have an earlier biochemical resistance to 3TC than genotype C. Therefore, more frequent monitoring of viral load or genotypical resistance might be needed for patients with HBV genotype B infection receiving 3TC therapy, especially during the first year.

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

ABSTRACT The accumulation of filamentous a‐synuclein (α‐S) is associated with Parkinson's disease. It remains controversial as to the mode (antiparallel or parallel) of α‐S self‐assembly and whether an exact alignment of the central hydrophobic region is essential. In the present study, we performed in vitro assembly using α‐S with or without the attachment of artificial leucine zippers (Zips) capable of forming either parallel or antiparallel coiled coils and included a spacer in one derivative. Results showed that Zips accelerate filament assembly in both the parallel and antiparallel fashions, that a precise alignment of the central hydrophobic region is not essential, and that the antiparallel pairs displayed the highest thioflavin T signals. More importantly, cells expressing Zip‐fused α‐S, but not α‐S alone, formed α‐S immunopositive and thioflavin S‐positive inclusions in 7 days. The results suggest that α‐S can assemble in both parallel and antiparallel modes but have a higher tendency to assemble in the latter mode and that cells overexpressing Zip‐fused α‐S may be used to screen α‐S assembly inhibitors due to enhanced ability to form inclusions.—Jiang, P., Ko, L., Jansen, K. R., Golde, T. E., Yen, S.‐H. Using leucine zipper to facilitate α‐synuclein assembly. FASEB J. 22, 3165–3174 (2008)