Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state.

Oestrogen receptor-alpha (ERalpha)-regulated transcription in breast cancer cells involves protein co-factors that contribute to the regulation of chromatin structure. These include co-factors with the potential to regulate histone modifications such as acetylation or methylation, and therefore the transcriptional state of target genes. Although much of the information regarding the interaction of specific co-factors with ER has been generated by studying specific promoter regions, we now have an improved understanding of the nature of these interactions and are better placed to relate these with ER activity and potentially with the activity of breast cancer drugs, including tamoxifen.

Regulation of the response to Nodal-mediated mesoderm induction by Xrel3.

The Xenopus egg has a yolk-laden vegetal hemisphere juxtaposed to a darkly pigmented animal hemisphere. Mesoderm is derived from the marginal zone, located at the interface between the two hemispheres. The vegetal-most cells become endoderm and release TGF-beta-related factors, including the Xenopus Nodal related (Xnr) proteins, which diffuse to induce the marginal zone to form mesoderm. The remaining animal cells become ectoderm, but our understanding of the mechanisms that limit the response to induction is incomplete. In this study, we provide evidence to suggest that Xrel3, a member of the Rel/NF-kappaB family, plays a role in defining the boundary separating induced from uninduced cells by regulating Xnr-responsive gene transcription. Ectopic Xrel3 expressed in prospective mesoderm caused repression of mesoderm-specific genes resulting in loss-of-function phenotypes that were rescued by co-expression of Xnr2. Depletion of Xrel3 from embryos with antisense morpholinos increased Xnr-dependent transcription, broadened expression of the pan-mesoderm marker Xbra and sensitized animal cells to mesoderm induction by Xnr2. We propose that an additional component to the mechanism that differentiates the ectoderm from the mesoderm involves regulation of nodal-dependent gene transcription by Xrel3.

Seroconcordant sexual partnerings of HIV-seropositive men who have sex with men.

OBJECTIVES: To describe the sexual behaviors of HIV-positive men with their seroconcordant partners and to determine the factors associated with unprotected anal intercourse (UAI) in these sexual partnerings. METHODS: The data were drawn from the baseline assessment of a randomized controlled intervention study of 1168 HIV-positive men who have sex with men recruited from mainstream gay venues, AIDS service organizations, and public/commercial sex environments. RESULTS: Of the 1168 men, 596 engaged in sexual experiences with other HIV-positive men, and 371 of the 596 (62%) practised UAI with their seroconcordant partners. Those who engaged in UAI expressed less self-evaluation with regard to their unsafe sexual practices, had higher levels of hedonism associated with unsafe sex, and were more likely both to inject recreation drugs and use methamphetamine in particular. Furthermore, these participants expressed less concern with regard to HIV re-infection, infection with other sexually transmitted infections, and the transmission of pathogens causing opportunistic infections. CONCLUSION: Our findings suggest that at least three sets of factors predispose HIV-positive men to engage in unsafe anal sexual behaviors with their concordant partners: a decreased belief that infection with other pathogens or re-infection with HIV present health problems; less evaluation of sexual activities and behaviors; more hedonistic expectations of sex and higher levels of sexual compulsivity, as well as recreational drug use with and without sex.

Sex with older partners is associated with primary HIV infection among men who have sex with men in North Carolina.

BACKGROUND: Studies from the 1990s suggested sex with older partners was associated with HIV infection. We evaluated the hypothesized association between primary HIV infection (PHI) and having older sexual partners among men who have sex with men (MSM). METHODS: MSM with PHI and HIV-uninfected MSM completed audio computer-assisted self-interviews exploring behaviors involving their 3 most recent sexual partners before enrollment (if uninfected) or diagnosis (if PHI). RESULTS: Of 74 men reporting any lifetime sex with men, 20 had PHI (27%). Demographics (including age) were similar between groups; 39% were non-white and 74% identified as gay. The mean age of sex partners differed significantly: men with PHI had partners on average 6 years older than themselves, whereas uninfected men's partners were 4 months their junior (P < 0.001). After adjusting for race, sex while intoxicated, and having a serodiscordant/serostatus unknown partner, a participant had twice the odds of PHI if his sex partner was 5 years his senior (odds ratio 2.0, 95% confidence interval: 1.2 to 3.3). CONCLUSIONS: Among a sample of young MSM, the odds of HIV infection increased significantly as the age of sexual partners increased. These findings can inform behavioral interventions in communities of at-risk MSM and secondary prevention efforts among those already living with HIV.

Sildenafil (Viagra) and club drug use in gay and bisexual men: the role of drug combinations and context.

Data ascertained in a study of club drug use among 450 gay and bisexual men indicate that at least one class of PDE-5 (phosphodiesterase type 5 inhibitor, sildenafil [Viagra]) is used frequently in combination with club drugs such as methamphetamine, MDMA (3,4 methylenedioxymethamphetamine [ecstasy]), ketamine, cocaine, and GHB (gamma hydroxy butyrate). Patterns of sildenafil use in combination with each of the club drugs differ among key demographics including race and age. Multivariate models, controlling for demographic factors, suggest that contextual factors are key to understanding why men mix sildenafil with club drugs, although age may still be an important issue to consider. Of particular importance is the fact that use of club drugs in combination with sildenafil is strongly associated with circuit and sex parties, where a centerpiece of these environments focuses on sexual exchange. These models imply interplay between person-level and contextual factors in explaining drug use patterns and further indicate that interventions aimed at addressing illicit substance use must carefully consider the role of environmental factors in explaining behavior.

Longitudinal investigation of methamphetamine use among gay and bisexual men in New York City: findings from Project BUMPS.

In recent years, methamphetamine has become a drug more commonly used among gay and bisexual men in New York City. Part of a longitudinal investigation of drug abuse in this population involved assessing the patterns and context of methamphetamine use during the course of 1 year. Findings indicate that among self-identified club-drug-using men, methamphetamine is widely used by men across age groups, educational level, race/ethnicity, and HIV status. Participants reported use of methamphetamine in combination with numerous other illicit and prescribed substances and in a variety of contexts outside the "club scene." Reasons for and contexts of use are related to HIV status, with HIV-positive men indicating a greater likelihood of use to avoid conflict, unpleasant emotions, and social pressures, and reporting higher levels of use in environments such as bathhouses and "sex parties." These patterns and relationships are consistent across time and suggest a complex interaction between person level factors, environmental factors, and HIV. Findings indicate that treatment of methamphetamine addiction among gay and bisexual men must take into account the complex interrelationships between mental health, drug use, sexual risk taking, and HIV.