RESUMEN
BACKGROUND: Acute hepatitis B virus (HBV) infection is followed by high viral replication rates leading to hepatocyte death and ultimately, in some cases, to acute liver failure (ALF) necessitating liver transplantation. Thus, the objective of treating HBV-induced ALF is to eliminate or significantly suppress HBV replication. METHODS/RESULTS: This prospective study (02/2008-02/2009) included 6 patients (1 female and 5 males, median age 35.5 years). HBV DNA and hepatitis B surface antigen (HBsAg) levels were detected, and hepatocyte death was quantified in patients' sera by (a) M65 ELISA and (b) M30 ELISA. All patients received entecavir treatment at 1 mg daily within 1-18 days after admission. Upon treatment, pathologic parameters rapidly decreased and returned to normal values or trace amounts (HBV DNA) within 3 months in all of the cases. A seroconversion to anti-HBsAg was achieved in 5 out of 6 patients; one patient with late onset of treatment did not seroconvert. M65 and the difference of M65-M30 as a marker for cell necrosis dropped significantly within 1 week of treatment. CONCLUSION: This preliminary series of 6 patients reveals that immediate treatment of HBV-induced ALF with entecavir is well tolerated and beneficially affects the course of the disease.
Asunto(s)
Antivirales/uso terapéutico , ADN Viral/sangre , Guanina/análogos & derivados , Hepatitis B/complicaciones , Fallo Hepático Agudo/virología , Adulto , Antivirales/farmacología , Biomarcadores/sangre , Muerte Celular/efectos de los fármacos , Femenino , Guanina/farmacología , Guanina/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Humanos , Fallo Hepático Agudo/sangre , Fallo Hepático Agudo/tratamiento farmacológico , Masculino , Estudios Prospectivos , Replicación Viral/efectos de los fármacos , Adulto JovenRESUMEN
Regulation of chromatin is an important aspect of controlling promoter activity and gene expression. Posttranslational modifications of core histones allow proteins associated with gene transcription to access chromatin. Closely associated with promoters of actively transcribed genes, trimethylation of histone H3 at lysine 4 (H3K4me3) is a core histone mark set by several protein complexes. Some of these protein complexes contain the trithorax protein ASH2 combined with the MLL oncoproteins. We identified human ASH2 in a complex with the oncoprotein MYC. This finding, together with the observation that hASH2 interacts with MLL, led us to test whether hASH2 itself is involved in transformation. We observed that hASH2 cooperates with Ha-RAS to transform primary rat embryo fibroblasts (REF). Furthermore, transformation of REFs by MYC and Ha-RAS required the presence of rAsh2. In an animal model, the hASH2/Ha-RAS-transformed REFs formed rapidly growing tumors characteristic of fibrosarcomas that, compared with tumors derived from MYC/Ha-RAS transformed cells, were poorly differentiated. This finding suggests that ASH2 functions as an oncoprotein. Although hASH2 expression at the mRNA level was generally not deregulated, hASH2 protein expression was increased in most human tumors and tumor cell lines. In addition, knockdown of hASH2 inhibited tumor cell proliferation. Taken together, these observations define hASH2 as a novel oncoprotein.