RESUMO
The Human Papillomavirus type-16 (HPV-16) E6 and E7 oncogenes are selectively retained and expressed in cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize human cervical epithelial cells. Expression of the epidermal growth factor receptor (EGFR) is often increased in cervical dysplasia and carcinoma, and HPV oncoproteins stimulate cell growth via the EGFR pathway. We found that erlotinib, a specific inhibitor of EGFR tyrosine kinase activity, prevented immortalization of cultured human cervical epithelial cells by the complete HPV-16 genome or the E6/E7 oncogenes. Erlotinib stimulated apoptosis in cells that expressed HPV-16 E6/E7 proteins and induced senescence in a subpopulation of cells that did not undergo apoptosis. Since immortalization by HPV E6/E7 is an important early event in cervical carcinogenesis, the EGFR is a potential target for chemoprevention or therapy in women who have a high risk for cervical cancer.
Assuntos
Transformação Celular Viral/efeitos dos fármacos , Regulação para Baixo , Receptores ErbB/genética , Papillomavirus Humano 16/fisiologia , Infecções por Papillomavirus/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Neoplasias do Colo do Útero/genética , Apoptose/efeitos dos fármacos , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Colo do Útero/virologia , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Feminino , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Papillomavirus Humano 16/efeitos dos fármacos , Papillomavirus Humano 16/genética , Humanos , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologiaRESUMO
BACKGROUND: Current data suggest that mortality after noncardiac surgery may be associated with persistent hypotension and the cumulative duration of low processed electroencephalogram-based bispectral index (BIS). This study assessed the relationships among cumulative duration of low BIS (BIS < 45), intermediate-term mortality, and anesthetic dose after cardiac surgery. METHODS: The authors studied 460 patients (mean age, 63.0 +/- 13.1 yr; 287 men) who underwent cardiac surgery between September 2005 and October 2006 at Washington University Medical Center, St Louis, Missouri. By using multivariable Cox regression analysis, perioperative factors were evaluated for their potential association with intermediate-term all-cause mortality. RESULTS: A total of 82 patients (17.8%) died during a median follow-up of 3 yr (interquartile range, 2.7-3.3 yr). Comparing patients who died with those who survived, there was no statistically significant difference in the relationship between end-tidal anesthetic gas concentrations during the anesthetic maintenance phase and the BIS. Cumulative duration of low BIS was independently associated with intermediate-term mortality. The 1.29 adjusted hazard ratio (95% CI, 1.12-1.49) for intermediate-term mortality with cumulative duration of low BIS translated into a 29% increased risk of death for every cumulative hour spent with a BIS less than 45. The final multivariable Cox regression model showed a good discriminative ability (c-index of 0.78). CONCLUSIONS: This study found an association between cumulative duration of low BIS and mortality in the setting of cardiac surgery. Notably, this association was independent of both volatile anesthetic concentration and duration of anesthesia, suggesting that intermediate-term mortality after cardiac surgery was not causally related to excessive anesthetic dose.
