Differential expression of glucose transporters and hexokinases in prostate cancer with a neuroendocrine gene signature: A mechanistic perspective for 18 F-FDG imaging of PSMA-suppressed tumors

Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostatespecific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by 18F-FDG than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and 18F-FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported 18F-FDG avidity of PSMA suppressed tumors. Methods: Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the SLC2A family (encoding GLUT proteins), 4 members of the hexokinase family (genes HK1-HK3 and GCK), and PSMA (FOLH1 gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3. Results: This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of GCK (encoding glucokinase protein) and decreased expression of SLC2A12 correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of GCK and low expression of SLC2A12 correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine- induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. Conclusion: A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of 18F-FDG uptake-associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake

Ecological Barriers to HIV Service Access among Young Men who have Sex with Men and High-Risk Young Women from Low-resourced Urban Communities.

Using an ecological perspective, we sought to elucidate the perceived barriers preventing HIV service access among two groups of U.S. youth (ages 12-24) disproportionately affected by HIV, men who have sex with men and high-risk women. We content analyzed interviews with 318 key informants to identify distinct service barriers. The 29 barriers informants named were organized into six categories (service-seeking demands, stigmas, knowledge and awareness, service quality, powerful opposition, and negative emotions). Findings suggest that barriers impacting access to HIV prevention, testing, and linkage-to-care services are remarkably similar and point to the need for comprehensive approaches to improving youths access services that address both individual-level barriers and extra-individual barriers simultaneously. Findings can be used to guide future research, programming and interventions to reduce the disproportionate spread of HIV among US youth

Examination of Behavioral, Social, and Environmental Contextual Influences on Sexually Transmitted Infections in At Risk, Urban, Adolescents, and Young Adults.

BACKGROUND:Despite the large body of extant literature on sexually transmitted infections (STIs) in adolescents and young adults (AYAs), more research on social and environmental contextual factors is needed. Also, further examination of STI indicators by gender remains a critical area of research focus. METHODS:Anonymous survey data were collected using audio computer-assisted self-interviews in community venues in urban, low-income, STI prevalent, US neighborhoods to reach AYAs, aged 12 to 24 years. Conventional descriptive statistics, bivariate analysis, and multiple logistical regression models were used to assess indicators of a self-reported lifetime prevalence of STIs. RESULTS:Participants (N = 1540) were on average 20.6 years; 57.2% were women, the majority were racial and ethnic minorities (92%), and almost half (49.2%) identified as sexual minorities. Nearly one third (32.%) had 1 or more STIs. As expected, gender differences were identified. For AYA men, being African American/Black, moving residences more than 4 times since kindergarten, and having a history of human immunodeficiency virus testing were each positively associated with STIs. Also, those who strongly disagreed that many young people in their community exchanged sex for money had a significantly lower likelihood of having an STI. For AYA women, exchanging sex for drugs or money, lacking money, which prevented activities, and using marijuana were each associated with STIs. CONCLUSIONS:This research extends our understanding of social and environmental contextual influences on AYAs' risk for STIs. It highlights differences in risk exposures that are distinctly different for AYA women and men, suggesting the need for tailored interventions to address their unique economic needs and social challenges

Examination of Behavioral, Social, and Environmental Contextual Influences on Sexually Transmitted Infections in At Risk, Urban, Adolescents, and Young Adults.

BACKGROUND:Despite the large body of extant literature on sexually transmitted infections (STIs) in adolescents and young adults (AYAs), more research on social and environmental contextual factors is needed. Also, further examination of STI indicators by gender remains a critical area of research focus. METHODS:Anonymous survey data were collected using audio computer-assisted self-interviews in community venues in urban, low-income, STI prevalent, US neighborhoods to reach AYAs, aged 12 to 24 years. Conventional descriptive statistics, bivariate analysis, and multiple logistical regression models were used to assess indicators of a self-reported lifetime prevalence of STIs. RESULTS:Participants (N = 1540) were on average 20.6 years; 57.2% were women, the majority were racial and ethnic minorities (92%), and almost half (49.2%) identified as sexual minorities. Nearly one third (32.%) had 1 or more STIs. As expected, gender differences were identified. For AYA men, being African American/Black, moving residences more than 4 times since kindergarten, and having a history of human immunodeficiency virus testing were each positively associated with STIs. Also, those who strongly disagreed that many young people in their community exchanged sex for money had a significantly lower likelihood of having an STI. For AYA women, exchanging sex for drugs or money, lacking money, which prevented activities, and using marijuana were each associated with STIs. CONCLUSIONS:This research extends our understanding of social and environmental contextual influences on AYAs' risk for STIs. It highlights differences in risk exposures that are distinctly different for AYA women and men, suggesting the need for tailored interventions to address their unique economic needs and social challenges

Efficient and Reproducible Synthesis of an Fmoc-protected Tn Antigen

The total synthesis of the Thomsen-nouveau (Tn) antigen, a tumour-associated O-linked mucin glycopeptide, was achieved through a concise route. The key glycosylation step proved challenging to reproduce from the literature precedents and was most reliably accomplished using a palladium-catalyzed coupling between the glycosyl donor and Fmoc-functionalized serine acceptor to form the target in moderate yields. This is, to the best of our knowledge, the shortest synthesis reported from galactose for preparing this essential building block for large-scale solid phase peptide synthesis

Ecological Barriers to HIV Service Access among Young Men who have Sex with Men and High-Risk Young Women from Low-resourced Urban Communities.

Using an ecological perspective, we sought to elucidate the perceived barriers preventing HIV service access among two groups of U.S. youth (ages 12-24) disproportionately affected by HIV, men who have sex with men and high-risk women. We content analyzed interviews with 318 key informants to identify distinct service barriers. The 29 barriers informants named were organized into six categories (service-seeking demands, stigmas, knowledge and awareness, service quality, powerful opposition, and negative emotions). Findings suggest that barriers impacting access to HIV prevention, testing, and linkage-to-care services are remarkably similar and point to the need for comprehensive approaches to improving youth's access services that address both individual-level barriers and extra-individual barriers simultaneously. Findings can be used to guide future research, programming and interventions to reduce the disproportionate spread of HIV among US youth

Ecological Barriers to HIV Service Access among Young Men who have Sex with Men and High-Risk Young Women from Low-resourced Urban Communities.

Using an ecological perspective, we sought to elucidate the perceived barriers preventing HIV service access among two groups of U.S. youth (ages 12-24) disproportionately affected by HIV, men who have sex with men and high-risk women. We content analyzed interviews with 318 key informants to identify distinct service barriers. The 29 barriers informants named were organized into six categories (service-seeking demands, stigmas, knowledge and awareness, service quality, powerful opposition, and negative emotions). Findings suggest that barriers impacting access to HIV prevention, testing, and linkage-to-care services are remarkably similar and point to the need for comprehensive approaches to improving youth's access services that address both individual-level barriers and extra-individual barriers simultaneously. Findings can be used to guide future research, programming and interventions to reduce the disproportionate spread of HIV among US youth

Efficient and reproducible synthesis of an Fmoc-protected Tn antigen

This concise total synthesis of the Thomsen-Nouveau (Tn) glycoconjugate was accomplished using a palladium-catalyzed coupling between the glycosyl donor and Fmoc-protected serine acceptor. This is, to the best of our knowledge, the shortest synthesis reported from galactose for preparing this essential building block for large-scale solid phase peptide synthesis

Youth health outcomes from the Connect-to-Protect Coalitions to prevent adolescent HIV infections.

We assessed the relationships among HIV-related social and behavioral outcomes resulting from an adolescent-focused HIV structural change initiative in eight urban sites operating Connect to Protect (C2P) coalitions. Over a 4-year period, annual cross-sectional panels of adolescents (N = 2,248) completed an audio-computer-assisted interview, providing data on satisfaction with their communities as adolescent-supportive environments, internalized HIV stigma, lifetime HIV-testing, lifetime sexual risk-taking, and number of sexual partners in the prior year. We used structural equation modeling to estimate hypothesized links between time since coalition mobilization to our social and behavioral outcomes. Over the 4 years, adolescents perceived their communities to become more supportive (p < .05). Positive perceptions of community support were associated with lower lifetime HIV sexual risk (p < .05). The effect of time on risk behavior was mediated by perceptions of community support. Stigma was unchanged over time. Stigma had damaging effects on risk behavior, effects which were also mediated by perceptions of community support. Special efforts are needed to address the deleterious effect of HIV stigma on high-risk urban adolescents

Structural Effects on HIV Risk Among Youth: A Multi-level Analysis.

We proposed a multilevel model of structural influences on HIV-risky sexual partnerships in a diverse sample of 1793 youth residing in 23 states and the District of Columbia. We examined the influence of concentrated disadvantage, HIV stigma, and sexual and gender minority stigma on engagement in HIV risky sexual partnerships and whether youth's participation in opportunity structures, anticipation of HIV stigma, and perceptions of their community as youth-supportive settings mediated structural effects. After controlling for age, HIV status, and race, we found structural HIV stigma had deleterious indirect effects on youth's participation in HIV-risky sexual partnerships. Concentrated disadvantage and structural sexual and gender minority stigma had direct negative effects on youth's perceptions of their communities as supportive and on their participation in prosocial activity. Support perceptions had direct, protective effects on avoidance of HIV-risky sexual partnerships. Structural stigma undermines youth's belief that their communities invest in their safety and well-being