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Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers.
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Proteínas Adaptadoras Transductoras de Señales , Proliferación Celular , Vía de Señalización Hippo , Papillomavirus Humano 18 , Infecciones por Papillomavirus , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Factores de Transcripción , Neoplasias del Cuello Uterino , Proteínas Señalizadoras YAP , Femenino , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/metabolismo , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Transactivadores/metabolismo , Transactivadores/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Proteínas Señalizadoras YAP/metabolismoRESUMEN
INTRODUCTION: Young adults who are sexual and gender minorities (SGM) are at the highest risk for tobacco initiation in young adulthood. Minority stress theory suggests that sexual orientation and gender identity (SOGI)-based discrimination may contribute to nicotine and tobacco use disparities. Our study aimed to quantify the association between SOGI-based distal minority stressors and current tobacco use among SGM young adults living in the United States (US). METHODS: Eligible participants-including young adults (aged 18-35 years old), who identified as SGM, and were currently residing in the US (N=1116) -were recruited via Prolific into an online survey. We applied stepwise binary regressions with backward selection to model the association between average past 30-day distal minority stress and current tobacco use (i.e., combustible cigarettes or e-cigarettes), controlling for perceived stress and sociodemographic covariates. We also tested interactions between minority stress and SGM status. Exploratory analyses assessed associations between minority stress and current tobacco use among YA, stratified by SGM subgroup. RESULTS: A 1-unit increase in experiencing minority stress in the past 30-days was associated with 1.02 greater odds of current tobacco use among SGM young adults. No difference between SGM subgroups in this association was found. Examining stratified SGM subgroups, a 1-unit increase in minority stress was associated with 1.11 greater odds of current tobacco among transgender adults only. CONCLUSION: Distal minority stress is differentially associated with current tobacco use for transgender young adults, which suggests that tobacco prevention and cessation interventions may need tailoring for subgroups. IMPLICATIONS: This study details the influence of minority stress on current tobacco use among sexual and gender minority (SGM) young adults. Findings underscore the need for targeted and tailored approaches to tobacco control, wherein SGM young adults most at-risk are engaged in cessation interventions that address minority stress as a contributing factor to tobacco use and which support their resilience. To promote health equity, tobacco control must address the contexts that engender minority stress. Assessment of policy impacts on SGM tobacco use and the effectiveness of interventions disseminated within SGM-supportive and discriminatory policy environments are important next steps.
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Minorías Sexuales y de Género , Estrés Psicológico , Uso de Tabaco , Humanos , Masculino , Adulto Joven , Minorías Sexuales y de Género/psicología , Femenino , Adulto , Estrés Psicológico/epidemiología , Estrés Psicológico/psicología , Adolescente , Uso de Tabaco/epidemiología , Estados Unidos/epidemiología , Grupos MinoritariosRESUMEN
OBJECTIVE: Transgender and gender diverse (TGD) populations have a higher prevalence of suicide outcomes compared to cisgender peers. Further, among TGD groups, young adults frequently demonstrate a higher risk compared to other age cohorts. While evidence supports sociodemographic differences in suicide risk, these relationships are not well-established for TGD young adults. METHOD: A secondary data analysis of the young adult (18-24 years) subpopulation of the 2015 U.S. Transgender Survey was conducted. Predicted probabilities of 12-month and lifetime suicide outcomes by gender identity, sexual orientation, race/ethnicity, homelessness, and poverty were estimated comparing fully adjusted models. RESULTS: Gender identity, race/ethnicity, and homelessness were significantly associated with all suicide outcomes. Comparisons of gender identities were significant for all outcomes and varied based on the outcome. American Indian/Alaska Native TGD young adults had the highest predicted probabilities compared to other race/ethnicity groups. Further, having a heterosexual/straight sexual identity was among the lowest predicted probabilities for suicide outcomes and significantly differed from several of the other sexual identities. CONCLUSIONS: Findings underscore the importance of heterogeneity among TGD young adults and the need for intersectional research within this population. Elucidating sociodemographic characteristics that contribute to differential suicide risk is necessary for effective intervention strategies and policy advocacy.
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Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ~5% of all human cancers worldwide, including most cervical cancer cases and a growing number of anogenital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited the oncogenic phenotype in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we demonstrate that the LASP1 SH3 domain is essential for LASP1-mediated oncogenicity in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulates LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrate that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival in cervical cancer, thus identifying a potential therapeutic target in these cancers.
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Proteínas Adaptadoras Transductoras de Señales , Proliferación Celular , Proteínas del Citoesqueleto , Proteínas con Dominio LIM , MicroARNs , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , MicroARNs/genética , Humanos , Femenino , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proliferación Celular/genética , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/patología , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Animales , Ratones , Regulación Neoplásica de la Expresión Génica , Línea Celular TumoralRESUMEN
Ethan L. Morgan works on human papillomaviruses (HPVs), with a specific interest in identifying how HPV induces tumor formation. In this mSphere of Influence article, he reflects on how three papers influenced him. "Comprehensive genomic characterization of head and neck squamous cell carcinomas" (The Cancer Genome Atlas Network, Nature 517:576-582, 2015, https://doi.org/10.1038/nature14129) and "Integrated genomic and molecular characterization of cervical cancer" (The Cancer Genome Atlas Network, Nature 543: 378-384, 2017, https://doi.org/10.1038/nature21386) showed him the power behind comprehensive multi-omic analyses to understand disease biology, while "Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response" (J. Sitz et al., Proc Natl Acad Sci U S A 116:19552-19562, 2019, https://doi.org/10.1073/pnas.1906102116) reinforced how this can be used to undercover potential new drug targets in HPV-associated disease.
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Genómica , Humanos , Infecciones por Papillomavirus/virología , Papillomaviridae/genética , Papillomaviridae/patogenicidad , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/genética , Femenino , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , MultiómicaRESUMEN
Although pre-exposure prophylaxis (PrEP) is a highly effective preventive treatment for HIV, anticipated PrEP stigma can hinder uptake. Perceptions of bias in HIV prevention and evaluations (e.g., happiness) tied to social support among Black and Latine/x sexual and gender diverse (SGD) individuals could be important correlates of anticipated PrEP stigma. To further this line of inquiry, a national sample of 872 Black and Latine/x SGD individuals who had and had never taken PrEP (Mage = 25.1, SD = 2.8) reported how they perceived HIV prevention and how happy they were with their social support. Multivariable linear regressions revealed that greater perceptions of bias in HIV prevention services were associated with higher anticipated PrEP stigma among Black and Latine/x SGD individuals who have never taken PrEP. Greater happiness with friend support was associated with lower PrEP stigma, whereas greater happiness with family support was associated with higher PrEP stigma among individuals who have taken PrEP. Findings highlight the need for PrEP and HIV interventions to address the intersectional stigma attached to prevention and for researchers to understand how evaluations of social support may contribute to stigma among Black and Latine/x SGD individuals.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Masculino , Humanos , Adulto , Homosexualidad Masculina , Felicidad , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Estigma Social , Apoyo Social , Fármacos Anti-VIH/uso terapéuticoRESUMEN
INTRODUCTION: A growing body of research has demonstrated extensive mental health disparities affecting sexual minority populations, yet little research has assessed how these disparities may affect cognitive functioning among subgroups of sexual minorities. METHODS: Data come from the 2021 National Health Information Survey (NHIS). Survey-weighted linear regression analyses were used to assess self-reported measures of cognition, stratified by subgroups sexual identity. In particular, we focused on the association between symptoms of depression or anxiety and each of the measures of cognition, adjusting for demographic covariates. RESULTS: Among 31,994 NHIS participants in the 2021 survey, 5,658 (17.7%) reported at least some difficulty in remembering or concentrating. Basic demographic differences existed when assessing any cognitive difficulty, particularly for bisexual participants (aOR = 2.73; 95% CI: 2.07, 3.60) and participants identifying as a different identity (aOR = 4.22; 95% CI: 2.72, 6.56). Depression was significantly associated with cognitive difficulty with the largest relationship observed among gay/lesbian participants (aOR = 1.39; 95% CI: 1.29, 1.49). The association between anxiety and cognitive difficulty was smallest among bisexuals (aOR = 1.13; 95% CI: 1.08, 1.18) and relatively consistent across other subgroups: heterosexuals (aOR = 1.23; 95% CI: 1.22, 1.24), gay/lesbians (aOR = 1.27; 95% CI: 1.19, 1.36), and those with a different identity (aOR = 1.22; 95% CI: 1.10, 1.35). CONCLUSION: There is a clear set of health disparities between sexual minority subgroups and heterosexuals across all cognitive difficulties. Future research should focus on developing a better understanding of differences in cognition based on sexual minority status while also working to ascertain how disparities vary among sexual minorities.
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Depresión , Minorías Sexuales y de Género , Femenino , Humanos , Depresión/epidemiología , Depresión/psicología , Conducta Sexual/psicología , Ansiedad , CogniciónRESUMEN
Human papillomaviruses (HPV) are a major cause of malignancy, contributing to â¼5% of all human cancers worldwide, including most cervical cancer cases and a growing number of ano-genital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited proliferation in vitro , whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we show that the LASP1 SH3 domain is essential for LASP1-mediated proliferation in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulated LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrated that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival role in cervical cancer, thus identifying a potential therapeutic target in these cancers.
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Compared to young heterosexual men, young sexual and gender minorities (YSGM) have elevated systemic inflammation and unique intestinal microbial profiles, influenced by HIV infection and substance use. However, links between cannabis use and microbial dysbiosis in this population have not been well described. In this pilot study, we aimed to characterize the complex interrelationships between cannabis use and microbial community structure in YSGM in relationship to HIV status. Cannabis use was assessed by self-administered Cannabis Use Disorder Identification Test (CUDIT) questionnaires and rectal microbial community alpha-diversity metrics were assessed via 16S ribosomal ribonucleic acid (rRNA) sequencing in a subset of YSGM (n = 42) in the RADAR cohort (aged 16-29) in Chicago. Multivariable regression models were used to assess the relationship between cannabis use and microbiome alpha-diversity metrics, adjusting for HIV status and other risk characteristics, including inflammation, which was evaluated by plasma levels of C-reactive protein (CRP). Problematic cannabis use, but not general use, was significantly inversely associated with microbial community richness (Adj. Beta = -8.13; 95% confidence interval [CI]: -15.68 to -0.59) and Shannon diversity (Adj. Beta = -0.04; 95% CI: -0.07 to 0.009). No significant association was observed between CUDIT score and community evenness, nor was any significant moderation observed by HIV status. We observed that problematic cannabis use was associated with reduced microbial community richness and Shannon diversity, adjusting for within population differences in inflammation and HIV status. Future research should aim to assess how cannabis use contributes to microbiome-related health factors among YSGM and if decreasing cannabis use can restore gut microbial community structure.
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Cannabis , Infecciones por VIH , Minorías Sexuales y de Género , Trastornos Relacionados con Sustancias , Humanos , Masculino , Infecciones por VIH/epidemiología , Cannabis/genética , Proyectos Piloto , Inflamación , ARN Ribosómico 16S/genéticaRESUMEN
Background: Alcohol and illicit substance use remain significant public health issues in the United States. In this analysis, we assessed differences in the use of primary care and emergency departments (EDs) for treatment of substance use among rural and urban sexual minorities (SMs).Methods: Data come from the National Survey on Drug Use and Health (NSDUH, 2015-2019). Survey-weighted multivariable linear and logistic regression analyses were used to assess the relationship between sexual identity and the use of primary care settings or EDs for treatment of substance use, stratified by urbanicity of residence.Results: Among the entire sample, 7.9% reported residing in rural environments with slightly more SMs living in urban (7.3%) relative to rural (5.4%) locales. Both rural (ß=-0.20; 95% CI: -0.29, -0.10) and urban SMs (ß=-0.13; 95% CI: -0.16, -0.11) self-reported worse overall health. Urban SMs, but not rural SMs, had significantly higher odds of reporting use of primary care treatment for substance use (aOR 2.80; 95% CI: 2.13, 3.68). ED treatment for substance use was greater among both rural (aOR = 2.99; 95% CI: 1.01, 8.87) and urban SMs (aOR = 3.02; 95% CI: 2.12, 4.30) as was overall number of ED visits among both rural (ß = 0.48; 95% CI: 0.24, 0.72) and urban SMs (ß = 0.23; 95% CI: 0.19, 0.28) .Conclusion: These findings suggest increased reliance on EDs for treatment of alcohol or substance use among rural SMs. Future research should examine whether increasing culturally competent primary care services for SMs in rural areas may be a key intervention point for reducing health disparities.
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Servicio de Urgencia en Hospital , Trastornos Relacionados con Sustancias , Humanos , Estados Unidos/epidemiología , Identidad de Género , Encuestas y Cuestionarios , Población Rural , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/terapia , Atención Primaria de SaludRESUMEN
BACKGROUND: Syphilis rates in the United States have increased. Few studies have examined syphilis incidence and prevalence prospectively among young sexual and gender minorities (YSGM). METHODS: This study of YSGM assigned male at birth comes from a Chicago-based prospective cohort at 2 visits 6 months apart (N = 882). Syphilis cases were identified through serologic test results and self-reported history. RESULTS: In this sample, 25.1% had a lifetime prevalence, and 3.3% were incident cases with a crude incidence rate of 6.76 per 100 person-years. CONCLUSIONS: Lifetime syphilis and incidence are high in this sample of YSGM relative to general population samples.
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Infecciones por VIH , Minorías Sexuales y de Género , Sífilis , Adulto , Recién Nacido , Humanos , Masculino , Estados Unidos/epidemiología , Sífilis/epidemiología , Incidencia , Estudios Longitudinales , Estudios Prospectivos , Prevalencia , Conducta Sexual , Homosexualidad Masculina , Infecciones por VIH/epidemiologíaRESUMEN
BACKGROUND: Sexual minority populations are at elevated risk for substance use (SU) and substance use disorders (SUD) compared to heterosexual populations. These disparities are theorized to be amplified for rural sexual minority populations due to their increased exposure to minority stress and reduced access to sexual minority communities. However, there is a lack of research examining differences in SU disparities affecting sexual minority populations by urbanicity, and little research has examined differences in SUD treatment utilization by sexual minority status or urbanicity. METHODS: We utilized data from 2015 to 2019 National Survey on Drug Use and Health to examine disparities in SU, SUD, SUD treatment utilization, and unmet SUD treatment need between sexual minority and heterosexual populations and test whether such disparities vary by urbanicity. RESULTS: Results indicate that disparities in SU and SUD affecting sexual minority populations generalize across urbanicities. A subset of disparities differed by urbanicity, and the direction of these differences varied, with some disparities being stronger in urban than rural populations and vice versa. Despite elevated treatment utilization among some sexual minority groups, disparities in unmet SUD treatment need were prevalent across urbanicities and sexual identity groups. CONCLUSIONS: Study findings highlight the ubiquity of disparities in SU, SUD, and unmet SUD treatment need affecting rural and urban sexual minority populations, while also demonstrating nuanced differences in disparities by urbanicity. The persistence of disparities in unmet SUD treatment need emphasizes the need for future research to identify factors contributing to this disparity and for policies that alleviate these disparities.
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Población Rural , Minorías Sexuales y de Género , Trastornos Relacionados con Sustancias , Población Urbana , Humanos , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/terapia , Minorías Sexuales y de Género/estadística & datos numéricos , Masculino , Femenino , Adulto , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Persona de Mediana Edad , Adolescente , Disparidades en Atención de Salud/estadística & datos numéricos , Estados Unidos/epidemiología , Encuestas y Cuestionarios , Grupos Minoritarios/estadística & datos numéricosRESUMEN
Sexual minorities (SMs; e.g., lesbian, gay, bisexual, and other non-heterosexual individuals) are more likely to be current alcohol drinkers than their heterosexual peers while separately experiencing elevated inflammation. Yet, little research has assessed the association between alcohol use and inflammation among subgroups of SMs, let alone potential differences among people with multiple marginal identities (e.g., race/ethnicity and sexual identity). Data came from the National Health and Nutrition Survey 2015-2016. Survey-weighted multivariable linear regression analysis was used to assess the relationship between alcohol use categories, heavy episodic drinking, and log-CRP (C-reactive protein). Models were stratified by sexual identity to determine whether associations between alcohol use and inflammation or between race/ethnicity and inflammation differed by sexual identity. Among 3220 participants, 1000 (36.8%) reported light alcohol use, 870 (32.0%) reported moderate use, and 483 (17.8%) reported heavy use. Mean raw CRP was 4.1 mg/L (SD = 8.1). The association between race/ethnicity and CRP differed in stratified relative to non-stratified models with key differences in CRP among individuals with multiple marginalized identities. We also observed that while the "classic" J-shaped relationship between alcohol use and systemic inflammation persists among heterosexuals in this sample, it does not hold among subgroups of sexual minorities. In particular, bisexuals who report heavy alcohol use, compared to non-users, experience significantly elevated CRP. Finally, we did not observe any association between heavy episodic drinking and CRP among subgroups of sexual minorities. Future studies assessing alcohol and biomarker data need to strive to include subgroups of sexual minorities and people with multiple marginal identities to better target behavioral and biomedical interventions aimed at reducing health disparities.
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Past research has suggested that sexual and gender minorities experience elevated levels of systemic inflammation which in turn has been linked to worse mental health outcomes. Therefore, the goals of this work are to develop a better understanding of the relationship between mental health variables and inflammation among this high-risk population. Data were collected among a sample of young men who have sex with men and transgender women (YMSM/TGW, N=685) aged 16-20 at the time of enrollment. Multiplex plasma cytokine and inflammatory biomarkers were quantified. Mental health variables were self-reported and included perceived stress, depression, and suicidal ideation. Latent profile analyses (i.e., latent class analyses intended for continuous variables) were utilized to identify four unique profiles of individuals with similar inflammatory markers followed by adjusted multinomial logistic regression to estimate the association between inflammatory profiles and mental health variables. Participants experienced moderate levels of perceived stress, normal levels of depression and ten percent reported suicidal ideation in the past six months. Multinomial regression models indicated that being in the highest inflammation profile, compared to the lowest inflammation profile, was significantly associated only with increased perceived stress and suicidal ideation. In sum, we observed significant relationships between inflammation and both perceived stress and suicidal ideation, but not between inflammation and depression. Future research should continue to assess these relationships using longitudinal data as they are intricate and likely bidirectional and may be key to reducing health disparities among this population.
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Human papillomaviruses (HPVs) infect the oral and anogenital mucosa and can cause cancer. The high-risk (HR)-HPV oncoproteins, E6 and E7, hijack cellular factors to promote cell proliferation, delay differentiation and induce genomic instability, thus predisposing infected cells to malignant transformation. cAMP response element (CRE)-binding protein 1 (CREB1) is a master transcription factor that can function as a proto-oncogene, the abnormal activity of which is associated with multiple cancers. However, little is known about the interplay between HPV and CREB1 activity in cervical cancer or the productive HPV lifecycle. We show that CREB is activated in productively infected primary keratinocytes and that CREB1 expression and phosphorylation is associated with the progression of HPV+ cervical disease. The depletion of CREB1 or inhibition of CREB1 activity results in decreased cell proliferation and reduced expression of markers of epithelial to mesenchymal transition, coupled with reduced migration in HPV+ cervical cancer cell lines. CREB1 expression is negatively regulated by the tumor suppressor microRNA, miR-203a, and CREB1 phosphorylation is controlled through the MAPK/MSK pathway. Crucially, CREB1 directly binds the viral promoter to upregulate transcription of the E6/E7 oncogenes, establishing a positive feedback loop between the HPV oncoproteins and CREB1. Our findings demonstrate the oncogenic function of CREB1 in HPV+ cervical cancer and its relationship with the HPV oncogenes.
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Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Virus del Papiloma Humano , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Transición Epitelial-Mesenquimal , Proteínas Represoras/genética , Oncogenes , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genéticaRESUMEN
ABSTRACT: HIV preexposure prophylaxis (PrEP) is a highly effective class of drugs used to prevent the transmission of HIV-1. Despite its high efficacy, the uptake of PrEP has been very low. This project sought to understand the barriers and facilitators to prescribing PrEP in a community health clinic in a Midwestern state.
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Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , Profilaxis Pre-Exposición , Humanos , Fármacos Anti-VIH/uso terapéutico , Atención Primaria de SaludRESUMEN
INTRODUCTION: Past research has demonstrated that, separately, sexual minorities (SMs) and rural-dwelling populations are each at elevated risk for chronic diseases relative to heterosexuals and urban-dwelling populations, respectively. Little research, however, has assessed whether rural SM populations may experience even further chronic disease risk. METHODS: Data come from the US National Survey on Drug Use and Health, 2015-2019. Survey-weighted logistic regression analyses were used to assess the relationship between sexual identity and various health-associated outcomes, stratified by rural/urban status and adjusted for demographic and other risk factors. RESULTS: Urban bisexual and rural lesbian females had significantly decreased odds of having any health insurance and increased odds of asthma, chronic obstructive pulmonary disease, hepatitis, any heart disease, and STIs relative to their heterosexual counterparts, with disparities affecting bisexual women living in rural areas being largest. Urban gay males had increased odds of having health insurance relative to urban heterosexuals. Both urban gay and bisexual males also experienced increased odds for several chronic diseases, however, among rural residents increased risk was only observed for bisexual males with regards to high blood pressure. CONCLUSION: Rural-dwelling bisexual women experience elevated likelihood for physical health conditions compared to urban-dwelling bisexual women, but few other rural populations experience elevated risk. Urban gay men, meanwhile, are more likely to possess insurance but simultaneously experience worse health outcomes across several domains of diseases, suggesting lower utilization of healthcare services. Future research should strive to avoid pooling all SMs into a single risk group as we have clearly demonstrated that strong differences exist based on both sex and rural/urban status.
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Asma , Homosexualidad Femenina , Minorías Sexuales y de Género , Masculino , Femenino , Humanos , Población Rural , Población UrbanaRESUMEN
Over the next two decades, the number of caregivers is expected to climb dramatically alongside a rise in older adults, particularly sexual and gender minority (SGM) older adults, yet little research has assessed differences between SGM and non-SGM care partners. Data for these analyses come from the Columbus Healthy Aging Project (N = 79). This study was designed to assess several domains of health among adults aged ≥50 years in Columbus, Ohio, US. Multivariable regression models were used to examine the likelihood of being a care partner, the SGM identity of the primary care recipient, and caregiver strain. In our sample, 227 (28.6%) participants self-identified as care partners for at least one individual. Compared to heterosexuals, gay/lesbian (aOR = 8.38; 95% CI: 5.29, 13.29) participants were more likely to be care partners but did not experience elevated caregiver strain. Bisexual individuals (aIRR = 1.70, 95% CI: 1.11, 2.61) reported greater caregiver strain, while those identifying as a different sexual identity reported lower caregiver strain (aIRR = 0.46, 95% CI: 0.23, 0.96). In turn, caregiver strain was reduced significantly when the care recipient identified as a member of the SGM community (aIRR = 0.67: 95% CI: 0.55, 0.80). These results suggest that SGM care partners may be at risk of unique stressors which may contribute to extant health disparities.
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The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. Here we present an investigation of AHR activation using a complex mixture of tryptophan metabolites to examine the biological relevance of circulating tryptophan metabolites. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of a cell-based model for rheumatoid arthritis. We present data that reframe AHR biology to include the presence of a mixture of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.
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OBJECTIVE: Sexual minority individuals are at substantially elevated risk for both cannabis use disorder (CUD) and alcohol use disorder (AUD). Although recent increases in the legalization of cannabis have been linked to increases in cannabis use among the general population, few studies have examined if changes in cannabis use and CUD vary by sexual identity. The purpose of the current study was to examine sexual identity differences in trends for CUD and compare them to trends for AUD. METHOD: We used data from 2015-2019 National Survey on Drug Use and Health to examine annual prevalence and year-specific disparities in cannabis use, CUD, heavy episodic drinking, and AUD. We also examined sex-specific sexual identity differences in linear trends for these substance use outcomes over this 5-year period. RESULTS: All groups except lesbian females experienced significant increases in cannabis use rates from 2015 to 2019. Heterosexual males, heterosexual females, and bisexual females also experienced significant increases in CUD rates. In contrast, no group exhibited significant increases in heavy episodic drinking or AUD rates. Bisexual women exhibited some of the largest year-specific disparities in cannabis use and CUD as well as the largest growth in disparities across time. CONCLUSIONS: The few changes in heavy episodic drinking and AUD alongside numerous changes in cannabis use and CUD suggest that changes in cannabis use may be attributable to legalization of cannabis use in many states during this period. Given profound disparities and increasing rates of CUD affecting bisexual females, further research is needed to identify factors that may explain their disproportionate burden.