RESUMO
In previous studies we have demonstrated that the p53 response to DNA damage in preneoplastic liver lesions, referred to as enzyme-altered foci (EAF), is attenuated. In the present investigation comparative quantitative RT-PCR revealed no major difference in the p53 mRNA levels in EAF and non-EAF tissue. When CoCl(2) was employed to induce hypoxia-inducible factor (HIF-1alpha), both non-EAF and EAF hepatocytes readily accumulated p53, whereas EAF hepatocytes did not accumulate p53 upon treatment with diethylnitrosamine (DEN). The p53 response was also induced in EAF hepatocytes by the inhibitor of nuclear export, leptomycin B. An inhibitor of DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM), wortmannin, blocked the DEN-induced p53 response in non-EAF hepatocytes. Assay of kinase activity in immunoprecipitated material from EAF and non-EAF tissue revealed attenuated ATM activity in EAF. Immunohistological and western blot analysis of the level of ATM protein was in agreement with the activity measurements and no phosphorylation of Ser15 in p53 was detected in EAF tissue 24 h after a challenging dose of DEN. Taken together with previously published data, these data indicate selective attenuation of the DNA damage pathway in EAF hepatocytes. Down-regulation of DNA damage-induced and ATM-mediated phosphorylation of p53 may confer a growth advantage on EAF hepatocytes.
Assuntos
Carcinógenos/farmacologia , Dano ao DNA/efeitos dos fármacos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Lesões Pré-Cancerosas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Androstadienos/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Western Blotting , Cafeína/farmacologia , Proteínas de Ciclo Celular , Cobalto/farmacologia , Dano ao DNA/genética , Proteínas de Ligação a DNA , Dietilnitrosamina/farmacologia , Ácidos Graxos Insaturados/farmacologia , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor , WortmaninaRESUMO
Knowledge of the correlates of human papillomavirus (HPV) seropositivity is of interest for planning of preventive measures and for evaluation of possible confounding in epidemiological studies. The epidemiological determinants for seropositivity for oncogenic and benign HPV types were assessed using a serosurvey of 275 healthy Swedish women, stratified by age and lifetime number of sexual partners. Seroprevalences were compared with 17 behavioral variables obtained by interview and 3 laboratory-diagnosed microbiological exposures. In univariate analysis, history of gonorrhea and condylomatosis, human herpesvirus type 8 and herpes simplex virus 2 seropositivities, lifetime number of sexual partners, and current partner's lifetime number of sexual partners were associated with oncogenic HPV seropositivity. Noteworthy lack of correlations included smoking habits and oral contraceptive use. In multivariate analysis, only the number of lifetime sexual partners [odds ratio (OR), 8.7; 95% confidence interval (CI), 3.3-22.6] and seropositivity for benign HPV types remained significant (OR, 2.9; 95% CI, 1.6-5.3). Seropositivity for benign HPV was primarily associated with condyloma history (OR, 3.6; 95% CI, 1.2-10.8) and seropositivity for oncogenic HPV (OR, 2.9; 95% CI, 1.6-5.2). An association with sexual history lost significance in the multivariate model. In conclusion, lifetime number of sexual partners is the major determinant of acquisition of oncogenic HPV. By contrast, benign HPV infection associates more strongly with condyloma history than with sexual history per se.
Assuntos
Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/transmissão , Parceiros Sexuais , Infecções Tumorais por Vírus/transmissão , Doenças do Colo do Útero/epidemiologia , Adolescente , Adulto , Análise de Variância , Anticorpos Antivirais/sangue , Transmissão de Doença Infecciosa , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/epidemiologia , Estudos Soroepidemiológicos , Inquéritos e Questionários , Suécia/epidemiologia , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/epidemiologia , Doenças do Colo do Útero/sangueRESUMO
The mode of transmission of human herpesvirus 8 (HHV8) was investigated in two seroepidemiological studies of Swedish women who completed a questionnaire about sexual behavior. Seropositivity for HHV8 antibodies, measured using an indirect immunofluorescence assay, was linked to a high number (>10) of sexual partners (P < 0.004). It also correlated strongly with a history of other sexually transmitted diseases (STD; P < 0.0001), in particular with a history of Chlamydia trachomatis infection and condyloma acuminata. There was appreciable HHV8 seropositivity already among virginal or monogamous women (9%). In summary, HHV8 transmission to women in Sweden may occur nonsexually. When sexual transmission occurs, it appears to be associated with high risk-taking sexual behavior.