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.

Relationship between Provider Stigma and Predictors of Staff Turnover among Addiction Treatment Providers.

To further our knowledge about feasible targets for improving quality of addiction treatment services, the current study provides preliminary assessment of the relationship between provider stigma and indicators of staff turnover. As predicted, results suggest that higher provider stigma was significantly related to lower ratings of job satisfaction and workplace climate. However, provider stigma was not significantly related to burnout. Our preliminary findings, if replicated, suggest the importance of considering provider stigma as a risk factor for future staff turnover and job dissatisfaction. Promising provider stigma interventions do exist and offer viable opportunity for improving quality of addiction treatment.

Internalized stigma as an independent risk factor for substance use problems among primary care patients: Rationale and preliminary support.

BACKGROUND: Little is known about internalized stigma among primary care patients, and whether the presence of internalized stigma is related to the severity of substance use problems independent of substance use-related variables. We sought to examine the relationship between internalized stigma and substance use problems among primary care patients with opioid or alcohol use disorders (OAUDs). METHODS: We present baseline data from 393 primary care patients who were enrolled in a study of collaborative care for OAUDs. Regression analyses examined the relationship between internalized stigma and substance use problems, controlling for demographics, psychiatric comorbidity, and quantity/frequency of use. RESULTS: The majority of participants reported thinking, at least sometimes, that they "have permanently screwed up" their lives (60%), and felt "ashamed" (60%), and "out of place in the world" (51%) as a result of their opioid or alcohol use. Higher internalized stigma was significantly related to more substance use problems (ß=2.68, p<0.01), even after the effects of covariates were accounted for. Stigma added 22%, out of 51% total variance explained, leading to a significant improvement in prediction of substance use problems. CONCLUSIONS: Among this group of primary care patients with OAUDs, rates of internalized stigma were comparable to those reported in specialty substance use treatment settings. Consistent with extant specialty care literature, our results suggest that internalized stigma may be a unique contributor that is associated with treatment outcomes, such as substance use problems, among primary care patients with OAUDs.

Bringing alcohol treatment to driving under the influence programs: Perceptions from first-time offenders.

Alcohol use disorders (AUDs) are common among first-time driving under the influence (DUI) offenders. Individuals with a DUI arrest may attend a DUI alcohol education program for license reinstatement. We evaluated the acceptability of cognitive behavioral treatment (CBT) for AUDs adapted for DUI programs. Participants (N=35) were enrolled in one of two DUI programs in Los Angeles and were an average of 34.5 (SD=11.9) years old; 66% male; 37.1% African American, 34.2% Hispanic/Latino(a), and 20% non-Hispanic White. We analyzed data from ten focus groups and 35 self-report surveys that evaluated the nine-session CBT group protocol. Overall, participants stated that the CBT philosophy was acceptable and helpful in thinking about how to prevent future DUIs. They also found the coping skills in the sessions relevant to other life events and decisions. Participants valued the personal disclosure and interactive role-play and group exercises embedded within each session stating that these exercises helped with group cohesion and self-disclosure. Data from satisfaction surveys showed that participants reported high satisfaction ratings on the overall session, session content, and session facilitator. Future studies are needed to evaluate whether evidence-based treatment within DUI programs may increase access to evidence-base care among at-risk individuals who may not otherwise seek treatment for their AUDs.

Developing a research agenda for understanding the stigma of addictions Part I: Lessons from the Mental Health Stigma Literature.

BACKGROUND AND OBJECTIVES: Although advocates and providers identify stigma as a major factor in confounding the recovery of people with SUDs, research on addiction stigma is lacking, especially when compared to the substantive literature examining the stigma of mental illness. METHODS: A review of key studies from the stigma literature that yielded empirically supported concepts and methods from the mental health arena was contrasted with the much smaller and mostly descriptive findings from the addiction field. RESULTS: Integration of this information led to Part I of this two part paper, development of a research paradigm seeking to understand phenomena of addiction stigma (eg, stereotypes, prejudice, and discrimination) and its different types (public, self, and label avoidance). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In Part II paper (American Journal of Addictions, Vol 26, pages 67-74, this issue), we address how this literature informs a research program meant to develop and evaluate and stigma strategies (eg, education, contact, and protest). Both papers end with recommendations for next steps to jumpstart the addiction stigma portfolio. Here in Part I, we offer one possible list of key research issues for studies attempting to describe or explain addiction stigma. (Am J Addict 2017;26:59-66).

Developing a research agenda for reducing the stigma of addictions, part II: Lessons from the mental health stigma literature.

BACKGROUND AND OBJECTIVES: Although advocates and providers identify stigma as a major factor in confounding the recovery of people with SUDs, research on addiction stigma is lacking, especially when compared to the substantive literature examining the stigma of mental illness. METHODS: A comprehensive review of the stigma literature that yielded empirically supported concepts and methods from the mental health arena was contrasted with the much smaller and mostly descriptive findings from the addiction field. In Part I of this two part paper (American Journal of Addictions, Vol 26, pages 59-66, this issue), constructs and methods from the mental health stigma literature were used to summarize research that seeks to understand the phenomena of addiction stigma. RESULTS: In Paper II, we use this summary, as well as the extensive literature on mental illness stigma change, to outline a research program to develop and evaluate strategies meant to diminish impact on public and self-stigma (eg, education and contact). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The paper ends with recommendations for next steps in addiction stigma research. (Am J Addict 2017;26:67-74).

Towards greater understanding of addiction stigma: Intersectionality with race/ethnicity and gender.

BACKGROUND: In spite of the significant burden associated with substance use disorders, especially among persons who inject drugs (PWIDs), most affected individuals do not engage with any type of formal or informal treatment. Addiction stigma, which is represented by negative social attitudes toward individuals who use alcohol and/or other drugs, is one of the barriers to care that is poorly understood. The current study: a) assessed implicit (indirect and difficult to consciously control) and explicit (consciously controlled) beliefs about PWIDs among visitors to a public web site; and b) experimentally investigated the effects of ethnicity/race and gender on those implicit and explicit beliefs. METHODS: N=899 predominantly White (70%) and women (62%) were randomly assigned to one of six target PWIDs conditions: gender (man/woman) x race/ethnicity (White, Black, Latino/a). Participants completed an Implicit Association Test and explicit assessment of addiction stigma. RESULTS: Participants implicitly associated PWIDs (especially Latino/a vs. White PWIDs) with deserving punishment as opposed to help (p=0.003, d=0.31), indicating presence of addiction stigma-related implicit beliefs. However, this bias was not evident on the explicit measure (p=0.89). Gender did not predict differential implicit or explicit addiction stigma (p=0.18). CONCLUSIONS: Contrary to explicit egalitarian views towards PWIDs, participants' implicit beliefs were more in line with addiction stigma. If replicated and clearer ties to behavior are established, results suggest the potential importance of identifying conditions under which implicit bias might influence behavior (even despite explicit egalitarian views) and increase the likelihood of discrimination towards PWIDs.

Study design to evaluate cognitive behavioral therapy among a diverse sample of adults with a first-time DUI offense.

BACKGROUND: Driving under the influence (DUI) of alcohol is a major public health concern, and many individuals continue to drink and drive even after being convicted of a DUI offense. Latinos, in particular, are disproportionately likely to be arrested for a DUI, have higher rates of recidivism, and are more likely to die in alcohol-related accidents than non-Latino Whites. Latinos also experience significant disparities in accessing alcohol-related treatment. METHODS/DESIGN: This study protocol paper describes a randomized trial of cognitive behavioral therapy (CBT) compared to usual care in DUI programs for individuals with a first-time offense and at-risk drinking. We will utilize a two-group randomized design where individuals enrolled in a DUI program with a first-time conviction will be randomized to CBT (n = 150) or usual care (n = 150). Participants will be assessed at baseline, immediately post-treatment, and 6-months post-treatment. Recidivism data will be collected using administrative data within 2 years post-treatment. DISCUSSION: This project has the potential to benefit a large population of vulnerable individuals who are at risk of DUI recidivism. It also develops a new model of care by providing treatment in DUI programs to reduce disparities associated with poor treatment access. Trial registration NCT02588703.

Reviewing and interpreting the effects of brief alcohol interventions: comment on a Cochrane review about motivational interviewing for young adults.

BACKGROUND: Cochrane recently published a systematic review on motivational interviewing (MI) for alcohol misuse in young adults. The review authors concluded that 'there are no substantive, meaningful benefits of MI interventions for the prevention of alcohol misuse' (p. 2), as effect sizes were 'small and unlikely to be of any meaningful benefit in practice' (p. 27). As most of these interventions were quite brief, we wish to open a dialogue about interpreting effect sizes in this review and of (brief) alcohol interventions more generally. ANALYSIS: We analyze four methodological aspects of the review that likely influenced the author's conclusions about intervention effects: (1) risk of bias assessments, (2) search strategies, (3) assessing the quality of the body of evidence and (4) definitions of sustainability and clinical significance. CONCLUSIONS: We interpret the effect sizes found in this review to indicate modest yet beneficial and potentially meaningful effects of these interventions, given their brevity and low cost. This interpretation is consistent with other reviews on brief, MI-based interventions and brief interventions more generally. We therefore encourage the field to re-open dialogue about the clinical importance of the effects of MI on alcohol misuse by young adults. Rather than dismissing interventions with small effects, we believe a more fruitful way forward for the field would be to catalogue effect sizes for various alcohol interventions. Such a catalogue would help stakeholders themselves to choose which interventions meet their minimum desired impact, and thus may be suitable given their targeted populations, setting and resources.

Help-Seeking Stigma and Mental Health Treatment Seeking Among Young Adult Veterans.

Veterans underutilize mental health services. We investigated the association between treatment seeking stigma and utilization of mental health services in a sample of 812 young adult veterans. Higher perceived public stigma of treatment seeking was significantly related to lower treatment utilization. Although many veterans were concerned about negative perceptions if they were to seek treatment, a much smaller number of them endorsed that they would judge a fellow veteran negatively in similar situation. Targeting perceived public stigma of treatment seeking, through perceived norms interventions, might help in narrowing the gap between the need and receipt of help among veterans.

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.

Moderated mediation analysis: An illustration using the association of gender with delinquency and mental health.

PURPOSE: When researchers find an association between two variables, it is useful to evaluate the role of other constructs in this association. While assessing these mediation effects, it is important to determine if results are equal for different groups. It is possible that the strength of a mediation effect may differ for males and females, for example - such an effect is known as moderated mediation. DESIGN: Participants were 2532 adolescents from diverse ethnic/racial backgrounds and equally distributed across gender. The goal of this study was to investigate parental respect as a potential mediator of the relationship between gender and delinquency and mental health, and to determine whether observed mediation is moderated by gender. FINDINGS: Parental respect mediated the association between gender and both delinquency and mental health. Specifically, parental respect was a protective factor against delinquency and mental health problems for both females and males. PRACTICAL IMPLICATIONS: Demonstrated the process of estimating models in Lavaan, using two approaches (i.e. single group regression and multiple group regression model), and including covariates in both models.

Correlates of public support toward federal funding for harm reduction strategies.

BACKGROUND: Historically, US federal policy has not supported harm reduction interventions, such as safe injection facilities (SIFs) and needle and syringe programs (NSPs), which can reduce the burden associated with injection drug use. Given recent increases in abuse of both legal and illegal opioids, there has been a renewed debate about effective ways to address this problem. The current study (1) assessed participants' support for SIFs and NSPs, and (2) evaluated several demographic factors (e.g., age, gender, race, education, political ideology, and religiosity) and individual differences in stigmatizing beliefs about people who inject drugs (PWID) that might relate to support for these interventions. METHODS: U.S. adults (N = 899) completed a web-based study that assessed self-reported support for NSPs and SIFs, and stigma about PWID. RESULTS: The majority of participants were at least somewhat supportive of both NSPs and SIFs. Regression analyses indicated greater support for NSPs and SIFs was predicted by more liberal political ideology, more agreement that PWID deserve help rather than punishment, older age, and male gender. Also, participants who endorsed lower stigma about PWID were more supportive of NSPs and SIFs. Race, religiosity, and education did not predict support for NSPs and SIFs. CONCLUSIONS: Most participants tended to report support for harm reduction strategies. Age, political ideology, and individual differences in stigmatizing beliefs about PWID were significantly associated with support. Given the potential malleability of stigmatizing beliefs, efforts that seek to shift stigma about PWID could have important implications for public policy towards harm reduction strategies for PWID.

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.

COPING AS A MEDIATOR OF INTERNALIZED HOMOPHOBIA AND PSYCHOLOGICAL DISTRESS AMONG YOUNG ADULT SEXUAL MINORITY WOMEN.

Sexual minorities have higher rates of depression and anxiety than their heterosexual counterparts. This elevated risk of psychological distress has generally been hypothesized to be a result of the effects of discrimination including internalized negative beliefs about sexual minorities. However, little research has examined the role of various types of coping in mediating between internalized homophobia and mental health. We tested the direct relationship between internalized homophobia and psychological distress and evaluated general and sexual minority-specific coping strategies as potential mediators using structural equation modeling. Data are from a national sample of 1,099 young adult sexual minority women who were on average 20.86 (SD= 2.12) years old, participating in a study on mental health and substance use. The model demonstrated acceptable fit, χ2 (83) = 402.9, p <.001, CFI=.94, TLI=.92, SRMR= .07, and RMSEA=.06, accounting for 73% of variance in psychological distress. Greater use of maladaptive coping and less use of sexual minority-specific coping were associated with higher psychological distress. Although maladaptive coping mediated the relationship between internalized homophobia and psychological distress, sexual minority-specific coping did not. Our findings support previous studies that have demonstrated the impact of internalized homophobia on psychological distress as well as the role of coping as a protective/risk factor in this relationship.

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.

Do positive alcohol expectancies have a critical developmental period in pre-adolescents?

OBJECTIVE: Positive outcome expectancies have been shown to predict initiation of alcohol use in children and to mediate and moderate the relationship between dispositional variables and drinking behavior. Negative outcome expectancies for alcohol appear to weaken as children progress to middle adolescence, but positive expectancies tend to increase during this time. Positive alcohol expectancies have been found to increase in children in third and fourth grades, indicating what some investigators have termed a possible critical period for the development of positive expectancies. METHOD: In the present study, we assessed alcohol expectancies at baseline, 6, 12, and 18 months in 277 second-through sixth-grade students. Children completed the Alcohol Expectancy Questionnaire-Adolescent. Univariate analyses of covariance were conducted. RESULTS: There were significant main effects for grade on positive alcohol-expectancy change for Global Positive Transformations at 12 and 18 months, Social Behavior Enhancement or Impediment at 6 and 12 months, and Relaxation/Tension Reduction at 6 and 18 months, whereby a consistent pattern emerged in that lower grades did not differ from each other, but they differed significantly from the higher grades. CONCLUSIONS: Data support a critical developmental period for positive alcohol expectancies, with the greatest change observed between third and fourth grade and between fourth and fifth grade, and only in those expectancies clearly describing positive outcomes (e.g., Relaxation/Tension Reduction) via positive or negative reinforcement versus those with either combined or ambiguous outcomes (e.g., Social Behavior Enhancement or Impediment).