PROM1, CXCL8, RUNX1, NAV1 and TP73 genes as independent markers predictive of prognosis or response to treatment in two cohorts of high-grade serous ovarian cancer patients.

Considering the vast biological diversity and high mortality rate in high-grade ovarian cancers, identification of novel biomarkers, enabling precise diagnosis and effective, less aggravating treatment, is of paramount importance. Based on scientific literature data, we selected 80 cancer-related genes and evaluated their mRNA expression in 70 high-grade serous ovarian cancer (HGSOC) samples by Real-Time qPCR. The results were validated in an independent Northern American cohort of 85 HGSOC patients with publicly available NGS RNA-seq data. Detailed statistical analyses of our cohort with multivariate Cox and logistic regression models considering clinico-pathological data and different TP53 mutation statuses, revealed an altered expression of 49 genes to affect the prognosis and/or treatment response. Next, these genes were investigated in the validation cohort, to confirm the clinical significance of their expression alterations, and to identify genetic variants with an expected high or moderate impact on their products. The expression changes of five genes, PROM1, CXCL8, RUNX1, NAV1, TP73, were found to predict prognosis or response to treatment in both cohorts, depending on the TP53 mutation status. In addition, we revealed novel and confirmed known SNPs in these genes, and showed that SNPs in the PROM1 gene correlated with its elevated expression.

Clinical importance of the EMSY gene expression and polymorphisms in ovarian cancer.

EMSY, a BRCA2-associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease-free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well.

The putative oncogene, CRNDE, is a negative prognostic factor in ovarian cancer patients.

The CRNDE gene seems to play an oncogenic role in cancers, though its exact function remains unknown. Here, we tried to assess its usefulness as a molecular prognostic marker in ovarian cancer. Based on results of our microarray studies, CRNDE transcripts were further analyzed by Real-Time qPCR-based profiling of their expression. The qPCR study was conducted with the use of personally designed TaqMan assays on 135 frozen tissue sections of ovarian carcinomas from patients treated with platinum compounds and either cyclophosphamide (PC, N = 32) or taxanes (TP, N = 103). Elevated levels of two different CRNDE transcripts were a negative prognostic factor; they increased the risk of death and recurrence in the group of patients treated with TP, but not PC (DNA-damaging agents only). Higher associations were found for overexpression of the short CRNDE splice variant (FJ466686): HR 6.072, 95% CI 1.814-20.32, p = 0.003 (the risk of death); HR 15.53, 95% CI 3.812-63.28, p < 0.001 (the risk of recurrence). Additionally, accumulation of the TP53 protein correlated with decreased expression of both CRNDE transcripts in tumor cells. Our results depict CRNDE as a potential marker of poor prognosis in women with ovarian carcinomas, and suggest that its significance depends on the therapeutic regimen used.

Early Substance Use and Subsequent DUI in Adolescents.

OBJECTIVE: Little is known about risk factors in early adolescence that lead to driving under the influence (DUI) and riding with a drinking driver (RWDD). In a diverse group of adolescents, we longitudinally explored the influence of alcohol and marijuana (AM) use, AM beliefs, and peer and family factors (including familism) on DUI/RWDD in high school. METHODS: We conducted 3 surveys 2 years apart of 1189 students recruited from 16 middle schools in Southern California. We used multivariable models to evaluate the effects of AM use, AM beliefs, and peer and family factors at ages 12 and 14 on DUI/RWDD at age 16. RESULTS: At age 12, adolescents with more positive beliefs about marijuana (odds ratio [OR] = 1.63, 95% confidence interval [CI]: 1.20-2.20) and more ability to resist marijuana offers (OR = 1.89, 95% CI: 1.22-2.92) had significantly higher risk of DUI/RWDD 4 years later. At age 14, youth with more past month alcohol use (OR = 2.10, 95% CI: 1.07-4.11), positive beliefs about marijuana (OR = 1.67, 95% CI: 1.31-2.13), exposure to peer AM use (alcohol: OR = 1.01, 95% CI: 1.00-1.02; marijuana: OR = 2.41, 95% CI: 1.28-4.53), and family marijuana use (OR = 1.54, 95% CI: 1.12-2.11) had higher risk of DUI/RWDD at age 16. CONCLUSIONS: Findings indicate a need to target adolescents as young as sixth grade at multiple levels to help prevent DUI/RWDD in high school. Given recent changes in legislation in several states, research should begin to focus on the distinction between DUI/RWDD of AM.

The Novel Gene CRNDE Encodes a Nuclear Peptide (CRNDEP) Which Is Overexpressed in Highly Proliferating Tissues.

CRNDE, recently described as the lncRNA-coding gene, is overexpressed at RNA level in human malignancies. Its role in gametogenesis, cellular differentiation and pluripotency has been suggested as well. Herein, we aimed to verify our hypothesis that the CRNDE gene may encode a protein product, CRNDEP. By using bioinformatics methods, we identified the 84-amino acid ORF encoded by one of two CRNDE transcripts, previously described by our research team. This ORF was cloned into two expression vectors, subsequently utilized in localization studies in HeLa cells. We also developed a polyclonal antibody against CRNDEP. Its specificity was confirmed in immunohistochemical, cellular localization, Western blot and immunoprecipitation experiments, as well as by showing a statistically significant decrease of endogenous CRNDEP expression in the cells with transient shRNA-mediated knockdown of CRNDE. Endogenous CRNDEP localizes predominantly to the nucleus and its expression seems to be elevated in highly proliferating tissues, like the parabasal layer of the squamous epithelium, intestinal crypts or spermatocytes. After its artificial overexpression in HeLa cells, in a fusion with either the EGFP or DsRed Monomer fluorescent tag, CRNDEP seems to stimulate the formation of stress granules and localize to them. Although the exact role of CRNDEP is unknown, our preliminary results suggest that it may be involved in the regulation of the cell proliferation. Possibly, CRNDEP also participates in oxygen metabolism, considering our in silico results, and the correlation between its enforced overexpression and the formation of stress granules. This is the first report showing the existence of a peptide encoded by the CRNDE gene.

Take One for the Team? Influence of Team and Individual Sport Participation on High School Athlete Substance Use Patterns.

The current web-based survey investigated the association between team or individual sport participation (or both) and self-reported alcohol and tobacco use among high school athletes (N=1, 275) transitioning to college. Peak Blood Alcohol Concentration, weekly drinking, and alcohol-related problems were significantly lower among athletes in individual sports compared to other groups. Athletes competing in both team and individual sports reported greater lifetime tobacco use and combined alcohol/tobacco use compared to individual or team sports alone. Preventive strategies targeting HS athletes in general and those participating in team sports in particular may be useful in minimizing future alcohol use and related problems.

College student smokers' cognitive appraisal of high-risk activities.

OBJECTIVE: Students who smoke are more likely to engage in risky behaviors such as binge drinking and unprotected sex (Schnieder and Morris, Environ Behav. 1999; 23:575-591). The goals of the present study were to determine whether smokers assess these behaviors as lower risk than nonsmokers, and if smoking rate influences risk perceptions. METHODS: Participants were 303 college students. Cognitive Appraisal of Risky Activities (Fromme et al., Cognit Ther Res. 1997; 21:421-442) and smoking were assessed August-November, 2006. RESULTS: Smokers reported significantly less risk, more benefit, and more involvement in risky behaviors than nonsmokers (p < .01). In hierarchical linear regression, risk perceptions moderated the association between smoking and (a) expected benefit from risky sexual behaviors (beta = -1.121, p < .05); and (b) expected involvement with illicit drugs (beta = -.313, p < .01). CONCLUSIONS: College smokers' assessment of high-risk behaviors influenced their intended involvement. Risk perception change may therefore alter their involvement in high-risk behaviors.

Pre-quit depression level and smoking expectancies for mood management predict the nature of smoking withdrawal symptoms in college women smokers.

We assessed smoking withdrawal symptoms over a six-day period of abstinence among 21 female college students who were daily cigarette smokers [M=20.3 (4.4); cigarettes per day] and were in the preparation stage of change for quitting smoking. We predicted that reported withdrawal symptoms would covary with baseline depression scores and baseline outcome expectancies for cigarette smoking as a mood management tool. Depression scores at baseline significantly predicted mood-related smoking withdrawal symptoms of Depression-Dejection and Vigor from the Profile of Mood States (POMS). Smoking outcome expectancies for relief of negative affect measured at baseline significantly predicted symptoms of Confusion-Bewilderment and Anger-Hostility. Neither baseline depression nor baseline smoking expectancies for mood management predicted smoking withdrawal symptoms measured by the Smoking Withdrawal Questionnaire (SWQ; [Shiffman, S. M., & Jarvik, M. E. (1976). Smoking withdrawal symptoms in two weeks of abstinence. Psychopharmacology, 50, 35-39]). Results imply that women smokers with baseline depressive symptomatology and expectancies for smoking to relieve negative mood endure greater abstinence-induced mood disturbance, but similar levels of other smoking withdrawal symptoms during initial abstinence. These results may inform smoking cessation efforts.