ErbB4 promotes malignant peripheral nerve sheath tumor pathogenesis via Ras-independent mechanisms

Background We have found that erbB receptor tyrosine kinases drive Ras hyperactivation and growth in NF1-null malignant peripheral nerve sheath tumors (MPNSTs). However, MPNSTs variably express multiple erbB receptors with distinct functional characteristics and it is not clear which of these receptors drive MPNST pathogenesis. Here, we test the hypothesis that altered erbB4 expression promotes MPNST pathogenesis by uniquely activating key cytoplasmic signaling cascades. Methods ErbB4 expression was assessed using immunohistochemistry, immunocytochemistry, immunoblotting and real-time PCR. To define erbB4 functions, we generated mice that develop MPNSTs with floxed Erbb4 alleles (P0-GGFβ3;Trp53+/−;Erbb4flox/flox mice) and ablated Erbb4 in these tumors. MPNST cell proliferation and survival was assessed using 3H-thymidine incorporation, MTT assays, Real-Time Glo and cell count assays. Control and Erbb4-null MPNST cells were orthotopically xenografted in immunodeficient mice and the growth, proliferation (Ki67 labeling), apoptosis (TUNEL labeling) and angiogenesis of these grafts was analyzed. Antibody arrays querying cytoplasmic kinases were used to identify erbB4-responsive kinases. Pharmacologic or genetic inhibition was used to identify erbB4-responsive kinases that drive proliferation. Results Aberrant erbB4 expression was evident in 25/30 surgically resected human MPNSTs and in MPNSTs from genetically engineered mouse models (P0-GGFβ3 and P0-GGFβ3;Trp53+/− mice); multiple erbB4 splice variants that differ in their ability to activate PI3 kinase and nuclear signaling were present in MPNST-derived cell lines. Erbb4-null MPNST cells demonstrated decreased proliferation and survival and altered morphology relative to non-ablated controls. Orthotopic allografts of Erbb4-null cells were significantly smaller than controls, with reduced proliferation, survival and vascularization. ERBB4 knockdown in human MPNST cells similarly inhibited DNA synthesis and viability. Although we have previously shown that broad-spectrum erbB inhibitors inhibit Ras activation, Erbb4 ablation did not affect Ras activation, suggesting that erbB4 drives neoplasia via non-Ras dependent pathways. An analysis of 43 candidate kinases identified multiple NRG1β-responsive and erbB4-dependent signaling cascades including the PI3K, WNK1, STAT3, STAT5 and phospholipase-Cγ pathways. Although WNK1 inhibition did not alter proliferation, inhibition of STAT3, STAT5 and phospholipase-Cγ markedly reduced proliferation. Conclusions ErbB4 promotes MPNST growth by activating key non-Ras dependent signaling cascades including the STAT3, STAT5 and phospholipase-Cγ pathways. ErbB4 and its effector pathways are thus potentially useful therapeutic targets in MPNSTs

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

The additive effects of depressive symptoms and polysubstance use on HIV risk among gay, bisexual, and other men who have sex with men.

IntroductionAmong gay, bisexual, and other men who have sex with men (GBM), collinearity between polysubstance use and mental health concerns has obscured their combined effects on HIV risk with multivariable results often highlighting only one or the other.MethodsWe used mediation and moderation analyses to examine the effects of polysubstance use and depressive symptoms on high-risk sex (i.e., condomless anal sex with serodiscordant/unknown status partner) in a sample of sexually-active GBM, aged ≥16 years, recruited in Metro Vancouver using respondent driven sampling. Hospital Anxiety and Depression Scale scores assessed mental health. Alcohol Use Disorder Identification Test scores assessed alcohol disorders. Poly-use of multiple drug types (e.g., stimulants, sedatives, opiates, hallucinogens) was assessed over the previous six months.ResultsAmong 719 predominantly white (68.0%), gay-identified (80.7%) GBM, alcohol use was not associated with increased prevalence of high-risk sex. Controlling for demographic factors and partner number, an interaction between polysubstance use and depressive symptoms revealed that the combined effects were additively associated with increased odds for high-risk sex. Mediation models showed that polysubstance use partially mediated the relationship between depressive symptoms and high-risk sex.ConclusionAn interaction effect between polysubstance use (defined by using 3 or more substances in the past six months) and depressive symptoms (defined by HADS scores) revealed that the combination of these factors was associated with increased risk for high-risk sex - supporting a syndemic understanding of the production of HIV risk

The additive effects of depressive symptoms and polysubstance use on HIV risk among gay, bisexual, and other men who have sex with men

IntroductionAmong gay, bisexual, and other men who have sex with men (GBM), collinearity between polysubstance use and mental health concerns has obscured their combined effects on HIV risk with multivariable results often highlighting only one or the other.MethodsWe used mediation and moderation analyses to examine the effects of polysubstance use and depressive symptoms on high-risk sex (i.e., condomless anal sex with serodiscordant/unknown status partner) in a sample of sexually-active GBM, aged ≥16 years, recruited in Metro Vancouver using respondent driven sampling. Hospital Anxiety and Depression Scale scores assessed mental health. Alcohol Use Disorder Identification Test scores assessed alcohol disorders. Poly-use of multiple drug types (e.g., stimulants, sedatives, opiates, hallucinogens) was assessed over the previous six months.ResultsAmong 719 predominantly white (68.0%), gay-identified (80.7%) GBM, alcohol use was not associated with increased prevalence of high-risk sex. Controlling for demographic factors and partner number, an interaction between polysubstance use and depressive symptoms revealed that the combined effects were additively associated with increased odds for high-risk sex. Mediation models showed that polysubstance use partially mediated the relationship between depressive symptoms and high-risk sex.ConclusionAn interaction effect between polysubstance use (defined by using 3 or more substances in the past six months) and depressive symptoms (defined by HADS scores) revealed that the combination of these factors was associated with increased risk for high-risk sex – supporting a syndemic understanding of the production of HIV risk

Associations between sexual partner number and HIV risk behaviors: implications for HIV prevention efforts in a Treatment as Prevention (TasP) environment

Previous research indicates that gay and bisexual men (GBM) have significantly more sexual partners than same-aged heterosexual men and women. As a result, some HIV intervention programs have focused on partner reduction. However, new research findings question the relevance of sexual partner number as a sexual risk measure for GBM given Treatment as Prevention (TasP) programs and new seroadaptive strategies which have led to lower GBM community viral load and new HIV prevention behaviors. To assess if sexual partner number continues to remain an important measure of sexual risk for GBM living in a city that actively promotes TasP as provincial policy, we analysed cross-sectional data from 719 GBM recruited through respondent-driven sampling in Vancouver, Canada. Multivariable negative binomial regression analysis showed that partner number was significantly associated with previously identified HIV risk factors including condomless anal intercourse with serodiscordant and/or unknown serostatus partners, using sex toys, attending group sex events, receiving money for sex, and sex drug use. These results indicate that sexual partner number remains an important proximate HIV risk measure. However, more nuanced measures of HIV treatment status and greater understanding of the possible causes of increased partner number among GBM are needed

HIV testing among a representative community sample of gay, bisexual, and other men who have sex with men in Vancouver, Canada

Earlier HIV diagnosis allows for improved treatment outcomes and secondary prevention. It is recommended that all individuals know their HIV status and that those at higher risk test more frequently. Using a representative community sample of gay, bisexual, and other men who have sex with men (GBMSM), we aimed to: (1) determine the proportion of GBMSM who have tested in the past 2 years, (2) determine reasons for testing and never having tested, and (3) explore correlates of testing. Of 535 eligible participants, 80.0% reported having had an HIV test in the past 2 years, most commonly as part of a regular testing schedule. The most common reason for not testing was low perceived HIV risk. Bisexual and older GBMSM, as well as those who lived outside of Vancouver, were less likely to have tested in the past 2 years. Rapid point-of-care testing may help improve testing rates and was shown to effectively engage some hard-to-reach GBMSM (e.g., those who had not tested for other STIs) in this sample

HIV leadership programming attendance is associated with PrEP and PEP awareness among young, gay, bisexual, and other men who have sex with men in Vancouver, Canada

Background: Young gay, bisexual, and other men who have sex with men (YGBM) may have reduced engagement and knowledge of HIV care and biomedical HIV prevention strategies, such as pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and Treatment as Prevention (TasP), compared with adult GBM. We sought to understand differences in HIV prevention awareness, health care access, and service utilization between youth (16–29 years) and adult (≥30 year) GBM, as well as factors associated with attendance in HIV leadership programming among YGBM living in the publicly funded PrEP setting of Vancouver, Canada. Methods: Sexually-active GBM were recruited using respondent-driven sampling (RDS) from February 2012 to February 2015. Participants completed an in-person computer-assisted self-interview every 6 months, up to February 2017, with questions on sociodemographic factors, awareness of biomedical HIV prevention strategies, and an HIV treatment optimism-skepticism scale. Participants were asked if they had ever attended either of two HIV-leadership programs designed for YGBM. Both programs involve multiple GBM-led education and social networking sessions operated by community-based organizations in Vancouver. Multivariable Glimmix confounder models assessed differences between youth and adult GBM. Among younger men, bivariate analyses examined factors associated with HIV-leadership program attendance. Results: Of 698 GBM who enrolled in the longitudinal study, 36.8% were less than 30 years old at the first study visit. After controlling for gender identification, sexual orientation, HIV status, and income in the past 6 months, younger GBM (n = 257/698) had lower awareness of biomedical HIV prevention strategies and less HIV treatment optimism compared with older GBM (n = 441/698). Among younger GBM who attended HIV-leadership programs (n = 50), greater awareness of biomedical HIV prevention strategies and higher HIV treatment optimism were reported, compared with non-attendees. Conclusion: Younger GBM, who are disproportionately affected by the HIV epidemic, are less aware of new prevention technologies than older GBM, but attending peer-based HIV-leadership programs ameliorates age-disparities in HIV-prevention knowledge and treatment optimism.Medicine, Faculty ofOther UBCNon UBCPopulation and Public Health (SPPH), School ofReviewedFacult

Substance use patterns of gay and bisexual men in the Momentum Health Study

Research with male sexual minorities frequently combines gay and bisexual men as Men Who Have Sex with Men or Gay and Bisexual Men. When analyzed separately, bisexual men consistently feature negative health differentials, exemplified by higher substance use levels. This interpretation is not clear-cut because studies may combine bisexual men and women, use different dimensions of sexual orientation to define bisexuality, and/or not consider number of sexual partners as a possible confounding factor. This study conducted separate bivariate and multivariate analyses comparing gay to bisexual Momentum Study participants based on self-identity, sexual attraction, and sexual behavior, while controlling for number of sexual partners and sociodemographic, psychosocial, and sexual behavior measures. The study hypothesized that, regardless of definition, bisexual men feature higher substance use levels compared to gay men. Bivariate analyses revealed significantly higher (p < .05) use among bisexual men for multiple substances in all samples. Nonprescription stimulants and heroin were significant in all multivariate logistic regression models. In contrast, all bisexual samples reported lower use of erectile dysfunction drugs and poppers, substances associated with anal sex among gay men. Subsequent analysis linked these results to lower levels of anal sex in all bisexual samples. Bivariate analyses also revealed that bisexual men featured significantly lower educational levels, annual incomes, and Social Support Scales scores and higher Anxiety and Depression Sub-Scale Scores. In summary, findings revealed bisexual men’s distinctive substance use, sexual behavior, psychosocial, and sociodemographic profiles, and are important for tailoring specific health programs for bisexual men

Trends in awareness and use of HIV PrEP among gay, bisexual, and other men who have sex with men in Vancouver, Canada 2012–2016

Gay, bisexual, and other men who have sex with men (gbMSM) are at the highest risk for HIV infection in British Columbia (BC). Pre-exposure prophylaxis (PrEP) has been recently licensed but is currently not publicly funded in BC. Using respondent-driven sampling, we recruited a cohort of gbMSM to complete a computer-assisted self-interview with follow-up every 6 months. Stratified by HIV status, we examined trends in awareness of PrEP from 11/2012 to 02/2016 and factors associated with PrEP awareness. 732 participants responded to the PrEP awareness question. Awareness of PrEP among HIV-negative men increased from 18 to 80% (p < 0.0001 for trend); among HIV-positive men, awareness increased from 36 to 77% (p < 0.0001). PrEP awareness was associated with factors related to HIV risk including sero-adaptive strategies and sexual sensation seeking. Eight HIV-negative men reported using PrEP. Low PrEP uptake highlights that PrEP access should be expanded for at-risk gbMSM in BC