A prospect for pharmacogenomics in the interferon therapy of chronic viral hepatitis.
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Confidence Intervals↗
Biomedical subjects
Ding-Shinn Chen
Publications and source records attributed to Ding-Shinn Chen.
Concurrent delivery of GM-CSF and endostatin genes by a single adenoviral vector provides a synergistic effect on the treatment of orthotopic liver tumors.
BACKGROUND: The immune resistance of large tumors represents a major problem for cancer immunotherapy, whereas the need for repeated injections of high doses of recombinant anti-angiogenic proteins represents a similar problem for anti-angiogenic therapy. To test whether antitumor activity could be increased by combining the above two mechanisms, this study examined the therapeutic effect of combination gene therapy using a murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) gene and a human endostatin (hED) gene on a rat orthotopic liver tumor model. METHODS: An adenoviral vector was constructed that simultaneously carried two transcriptional cassettes, for the expression of mGM-CSF and hED, respectively, or that carried a single cassette of either gene. The adenoviruses were intratumorally administered to 3-day-old or 7-day-old tumors. Moreover, the antitumor effects of the combination therapy and monotherapy were assessed and compared. RESULTS: The double-gene-containing adenoviral vector expressed transgenes as efficiently as the single-gene-containing vector. Moreover, the adenovirally expressed endostatin was biologically active, as demonstrated in vitro and in vivo. Results from animal experiments demonstrated a synergistic antitumor effect induced by the combined mGM-CSF and hED therapy. The combination of hED with mGM-CSF enhanced tumor-specific CTL activity, but did not interfere with the infiltration of cellular effectors in the tumor regions. The blood vessel density of the liver tumors markedly reduced as a result of hED expression in both monotherapy and combination therapy. Furthermore, combination therapy significantly increased the number of apoptotic cells in the tumor regions. CONCLUSIONS: The experimental results suggest that the combined gene therapy against tumor cells and the tumor vascular system using antitumor immune mechanisms and anti-angiogenic mechanisms holds promise as a strategy for treating cancers.
Adenoviridae↗
Secular trend of age-specific prevalence of hepatitis B surface and e antigenemia in pregnant women in Taiwan.
To elucidate the impact of aging of hepatitis B carrier women on their viral replicative markers in a hepatitis B endemic area, all the parturients admitted to the Hospital were studied from 1985 to 2000. Serum hepatitis B surface (HBsAg) and hepatitis B e antigen (HBeAg) were tested by radioimmunoassay. Mann-Whitney U and Student's t-tests were used for statistical analysis. The results showed the yearly prevalence rate of HBsAg in pregnant women seemed stable with a mean of 12.0 +/- 1.1% during the period. The yearly positive rate of HBeAg among HBsAg-positive pregnant women varied between 30.4% and 42.6% from 1985 to 1992 and declined from 29.6% in 1993 to 18.1% in 2000. The mean ratio of HBeAg/HBsAg in carrier parturients was 24.7% [intraquantile range (IQR) 20.5-28.4] from 1993 to 2000, which was significantly lower than that of 32.4% (IQR 31.0-39.0) from 1985 to 1992 (P < 0.0001). The mean age of HBeAg-positive primiparas from 1993 to 2000 was 29.1 +/- 3.9 years and significantly higher than that of 28.0 +/- 3.7 years from 1985 to 1993 (P < 0.001), as well as in secundiparas 31.2 +/- 3.8 years vs. 30.1 +/- 3.4 years (P < 0.001) and in total parturients 30.3 +/- 4.2 years vs. 29.3 +/- 3.8 years (P < 0.001). Thus, no significant decrease of HBsAg carriage was observed in the past 16 years, whereas a decreased ratio of HBeAg/HBsAg was noted in carrier parturients in the past 8 years and the elderly HBeAg-positive parturients from 1993 to 2000 may be the cause.
Adolescent↗
Dynamics of plasma hepatitis B virus levels after highly active antiretroviral therapy in patients with HIV infection.
BACKGROUND/AIMS: The optimal strategy to prescribe highly active antiretroviral therapy (HAART) in patients infected with both hepatitis B virus (HBV) and human immunodeficiency virus (HIV) remains unsettled. This study aimed to compare the HBV dynamics between HBeAg-positive and HBeAg-negative coinfected patients treated with lamivudine-containing HAART. METHODS: We retrospectively analyzed the serial changes of plasma HBV DNA levels in 24 HBsAg-positive HIV-infected patients who entered the HAART program. A polymerase chain reaction-based assay, capable of quantifying as few as 400 HBV copies/ml, was used. The median follow-up time was 18 months. RESULTS: HAART containing lamivudine 300 mg/day effectively suppressed plasma HBV-DNA to 10(-3)-10(-5)-fold of the baseline levels, but a multi-phasic decay of HBV DNA was observed. The later phases became flat, as a persistent residual HBV viremia, in eight of the studied 10 HBeAg-positive patients; in contrast, residual HBV viremia was not observed in the 10 HBeAg-negative patients studied (8/10 vs. 0/10, P=0.0007, Fisher's exact test). HAART without lamivudine did not suppress plasma HBV DNA levels in the remaining four patients. CONCLUSIONS: HAART containing lamivudine 300 mg/day effectively suppress HBV replication in HBeAg-negative HIV/HBV-coinfected patients. Nevertheless, residual HBV replication persisted in most HBeAg-positive coinfected patients.
Adult↗
Clinical aspects and outcomes of volunteer blood donors testing positive for hepatitis-C virus infection in Taiwan: a prospective study.
BACKGROUND/AIM: The natural history of hepatitis-C virus (HCV) infection has been explored in volunteer blood donors, but not yet in hepatitis-B endemic areas. Whether previous or concurrent hepatitis-B virus (HBV) infection influences the natural history of HCV infection remains unknown. Thus, we followed the anti-HCV-positive blood donors who had past or concurrent HBV infection in Taiwan. METHODS: From 1992 to 1993, 1588 anti-HCV reactive volunteer blood donors were referred to us from the Taipei Blood Center and 879 (55%) repeatedly reactive for anti-HCV were enrolled. Two hundred and forty-three donors (HCV RNA seropositive rate 49% by polymerase chain reaction (PCR)) received regular follow-ups (mean period: 4.9 years) with their liver disease status determined mainly by clinical and biochemical parameters, serum alpha-fetoprotein level and imaging studies. Hepatitis-C virus genotype and occult HBV infection were determined by PCR-based assays. RESULTS: Of the initial 879 subjects, 250 (28%) had chronic hepatitis, nine (1%) had liver cirrhosis (LC) and two (0.2%) had hepatocellular carcinoma (HCC) already. In the 243 regularly followed donors, 30% had repeatedly normal serum alanine aminotransferase (ALT) and 70% had more than once elevated ALT. Cirrhosis developed in four (1.6%; follow-up period range: 2-6 years) and HCC in two (0.8%; follow-up period: 3 and 4 years, respectively). Distribution of HCV genotype and hepatitis-B surface antigen (HBsAg) did not differ between those with and those without elevation of ALT. Of the 15 donors with LC and/or HCC, only 1(7%) was positive for both HBsAg and HBV DNA and the other 14 were negative for both HBsAg and serum HBV DNA. CONCLUSIONS: Incidentally detected hepatitis-C was progressive in a small proportion of anti-HCV-positive volunteer blood donors in Taiwan. Occult HBV infection played a minimal role in the development of LC in this donor population.
Adult↗
A prospective study characterizing full-length hepatitis B virus genomes during acute exacerbation.
BACKGROUND & AIMS: Hepatitis B virus (HBV) evolves rapidly in patients with chronic hepatitis B, and HBV variation may trigger acute exacerbation. To study this relationship, we investigated full-length viral sequences before, during, and after exacerbation. METHODS: We prospectively studied 14 patients with exacerbation of hepatitis B, either spontaneously (n = 4) or after receiving various medical interventions (n = 10), and measured their serum alanine aminotransferase (ALT) and HBV DNA levels monthly. Full-length HBV genomes at baseline, at the peak of serum viral load, at ALT peak, and after ALT peak were obtained by polymerase chain reaction, sequenced, and compared. Replication activities of serial HBV variants were assayed by in vitro transfection. RESULTS: Serum viral load was increased in all exacerbations. Viral peak preceded ALT peak in 13 (93%) of the 14 patients. At virologic peak, 12 patients (86%) harbored viral genome identical to the corresponding baseline genome. At and after ALT peak, 9 (64%) and 7 (50%) of the viral genomes remained identical to baseline, respectively. Mean nucleotide change per genome was 0.2 at virologic peak but increased to 4.4 and 8.1 at and after ALT peak, respectively. The replication potential of the viral variant that emerged during or after exacerbation was equivalent to that at baseline. CONCLUSIONS: Most exacerbations were preceded by an upsurge of serum HBV identical to the preexisting HBV strain. After exacerbation, about half of the patients were repopulated by a different viral variant, which was likely a result of immune selection.
Adult↗
Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.
BACKGROUND & AIMS: Hepatitis B viral (HBV) genotype C is associated with the development of hepatocellular carcinoma (HCC) compared with genotype B; however, the virologic factors contributing to the pathogenic differences remain unknown. We investigated the prevalence of T1762/A1764 basal core promoter mutant in a cohort of 250 genotype B- or C-infected HBV carriers with different stages of liver disease to clarify a possible role for this mutant in hepatocarcinogenesis. METHODS: The sequences of basal core promoter of HBV genome were determined in 60 inactive HBV carriers and 190 patients with histologically verified chronic liver disease and HCC. RESULTS: Genotype C has a higher prevalence of T1762/A1764 mutation than genotype B (odds ratio, 5.18; 95% confidence interval [CI], 2.59-10.37; P < 0.001). The likelihood of T1762/A1764 mutation parallels the progression of liver disease, from 3% in inactive carriers to 64% in HCC patients (odds ratio, 20.04; 95% CI, 7.25-55.41; P < 0.001). By multiple logistic regression analysis, patients with T1762/A1764 mutation were significantly associated with the development of HCC than those without (odds ratio, 10.60; 95% CI, 4.92-22.86; P < 0.001), and the risk was observed for both genotypes B and C. In addition, the prevalence of T1762/A1764 mutation in younger HCC patients was comparable with older HCC patients but was significantly higher than that in age-matched inactive carriers, irrespective of genotypes. CONCLUSIONS: Our data suggest that HBV carriers with T1762/A1764 basal core promoter mutant are at increased risk for HCC and that this mutant may contribute to the pathogenesis of HBV infection.
Adult↗
Clinical relevance of hepatitis B virus genotypes Ba and Bj in Taiwan.
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Carcinoma, Hepatocellular↗
Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients.
Ribavirin and interferon (IFN) are an effective treatment in 30% to 60% of patients with chronic hepatitis C. Whether they are also effective in dually infected patients with hepatitis B and C is unknown. Twenty-four patients with chronic hepatitis seropositive for both hepatitis B surface antigen and antibody to HCV received ribavirin 1,200 mg daily for 6 months, together with 6 million units (MU) IFN-alpha 2a thrice weekly for 12 weeks and then 3 MU for another 12 weeks. Serum HCV RNA was positive in 21 patients (group I, serum HBV DNA positive in 17 patients) and negative in 3 patients (group II, all HBV DNA positive) by Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ). Serum alanine aminotransferase (ALT), HCV RNA, and hepatitis B virus (HBV) DNA were monitored regularly for 12 months. Another 30 patients with chronic hepatitis C alone receiving the same regimen, served as controls. The serum HCV clearance rate in group I patients (43%) was comparable with that in controls (60%, P =.63) 24 weeks posttreatment. The serum ALT normalization rate in group I and group II patients was 43% and 0%, respectively, 24 weeks posttreatment. After treatment, resurgence of HBV and HCV was encountered in 4 group I patients and 1 group II patient, respectively. In conclusion, in hepatitis B and C dually infected patients, combination of IFN with ribavirin can achieve a sustained HCV clearance rate comparable with hepatitis C alone. In dually infected patients, the treatment may alter the dominant, ruling hepatitis virus.
Adult↗
Molecular assays for hepatitis B virus infection.
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DNA, Viral↗
Mutations in the NS5A and E2-PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin.
BACKGROUND/AIMS: Combination therapy with interferon (IFN) and ribavirin is the current standard treatment for chronic hepatitis C, but the efficacy is still not satisfactory, especially for genotype 1b. NS5A and E2 proteins of hepatitis C virus (HCV) may repress the IFN-induced RNA-dependent protein kinase (PKR), and thus have the potential to influence the response of HCV to IFN therapy; however, this issue remains controversial. METHODS: Nucleotide sequences of the PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) and PKR-binding domain (NS5A-PKR bd) of the HCV genome were analyzed by amplification and direct sequencing in 30 HCV genotype 1b patients who had been treated with IFN and ribavirin. RESULTS: Nine (30%) patients achieved a sustained virological response (SVR) to combination therapy. Pretreatment variables and amino acid substitutions were compared between responders and non-responders. The responders were younger than non-responders (37.2 +/- 10.4 vs. 45.4 +/- 9.5 years, P = 0.017), whereas no significant statistical differences were found in the number of amino acid substitutions in NS5A and E2-PePHD regions between the two groups. CONCLUSIONS: Genetic heterogeneity in NS5A and E2-PePHD regions of the HCV genome may not serve as a predictor for treatment outcome with combination therapy in Taiwanese patients with chronic HCV genotype 1b infection.
Adult↗
An oath for bioscientists.
In this paper, by examining the idea of a 'Hippocratic Oath for scientists', promoted by Sir Joseph Rotblat, oaths for medical professionals and scientists and the definitions and relationships of different moral norms such as oaths, codes and guidelines, we propose an oath for bioscientists with justifications based on professional and organizational ethics.
Codes of Ethics↗
Three-dimensional power Doppler ultrasonography for demonstrating associated arteries of hepatocellular carcinoma.
BACKGROUND AND PURPOSE: Although 2-dimensional (2D) ultrasonography (US) with conventional color and power Doppler US has been applied widely in the differential diagnosis of hepatic tumors and in the follow-up of treatment of hepatocellular carcinomas (HCCs), it has limited capabilities for demonstrating associated arteries of HCCs. Three-dimensional (3D) US can provide more accurate depiction of stereotypic vascular patterns than 2D US. This study investigated the efficacy of 3D power Doppler US versus angiography for demonstrating associated arteries of HCCs. METHODS: A total of 24 HCCs with surrounding or intratumoral arteries detected by 2D power Doppler US were studied using a US machine equipped with power Doppler software and a built-in stereo image processing workstation. Serial 2D images were reconstructed into 3D images to analyze the distribution and routes of arteries associated with HCCs. These results were compared with angiographic findings. RESULTS: Three-dimensional US imaging of vasculature associated with HCCs in the 24 patients was categorized into 3 patterns: peripheral arteries around the tumor (pattern I, n = 9); no more than 4 intratumoral arteries with or without originating peripheral arteries (pattern II, n = 9); and prominent (more than 4) intratumoral arteries (pattern III, n = 6). Most feeding arteries shown in angiograms that could be demonstrated by 3D power Doppler US were in HCCs with pattern I and II vasculature. In HCCs with pattern III, the basket vascular pattern shown on angiograms could also be demonstrated on 3D power Doppler US. The vascular proficiency, including major feeding arteries and branches of feeding arteries,could be shown to significantly increase from pattern I to III on 3D power Doppler, but this method had a lower detection rate of smaller branches and neovascularization than angiographic study. CONCLUSION: Three-dimensional power Doppler US can effectively depict the associated arteries of HCCs, especially the major feeding arteries. Three vascularization patterns of HCCs were categorized in 3D images. There is a good correlation of the findings of 3D power Doppler US with angiographic study. These findings demonstrate the usefulness of 3D power Doppler as a non-invasive alternative to angiographic examination.
Adult↗
SEN virus infection in patients with chronic hepatitis C: preferential coinfection with hepatitis C genotype 2a and no effect on response to therapy with interferon plus ribavirin.
To clarify the influence that a recently identified SEN virus (SENV) has on hepatitis C virus (HCV) response to therapy with interferon plus ribavirin, 2 SENV variants, SENV-D and SENV-H, were studied in 100 patients with chronic hepatitis C; 57 of these patients were positive for SENV-D/H DNA, and there were no differences, in clinicopathological features, between patients with and without SENV coinfection. However, patients with SENV coinfection had a higher prevalence of HCV genotype 2a than did those without it. The sustained HCV response rate after combination therapy was comparable between patients with and without SENV coinfection. Of the 57 patients with SENV coinfection, 18 (32%) had a sustained SENV response to combination therapy, and SENV-D had a higher sustained response rate than did SENV-H. These results suggest that SENV has a specific link to HCV genotype 2a and that SENV infection has no apparent effect on coexisting chronic hepatitis C.
Adult↗
Long-term immunogenicity and efficacy of universal hepatitis B virus vaccination in Taiwan.
The long-term immunogenicity of universal hepatitis B virus (HBV) vaccine is seldom studied in large-scale prospective community-based populations, especially in adolescents. This study enrolled 1200 children aged 7 years with complete HBV immunization in infancy and determined HBV surface antigen (HBsAg), its antibody (anti-HBs), and HBV core antibody (anti-HBc) annually until the children were aged 14 years. Eleven children had new HBV infections with anti-HBc positivity as the only marker. None became positive for HBsAg or had detectable HBV DNA by polymerase chain reaction. The percentage of protective anti-HBs in 951 children without booster vaccination gradually decreased from 71.1% at age 7 years to 37.4% at age 12 years. Only 1 of the 200 children in the booster group and 2 of the 258 children in the nonbooster group developed new anti-HBc positivity. The results suggest that routine booster vaccination may not be required to provide protection against chronic HBV infection before age 15 years.
Adolescent↗
Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis.
The CAG polymorphism in exon 1 of the androgen receptor (AR) gene has been shown associated with the development of human male hepatocellular carcinoma (HCC) with the shorter AR alleles conferring a higher risk. However, the significance of AR-CAG repeats in female hepatocarcinogenesis remains to be addressed. In this study, seventy-six pairs of female HCCs and corresponding nontumorous tissues were collected, and 180 cirrhotic nodules were microdissected from 7 cirrhotic livers. The clonality status, functional AR alleles, and CAG repeat number of each sample were determined by AR methylation analysis. In a total of 44 monoclonal HCCs, the mean of CAG repeats in the active alleles was significantly longer than that in the inactive alleles (22.0 +/- 2.8 versus 20.7 +/- 3.6; P = 0.047). When we divided HCCs into hepatitis B virus-positive [HBV(+)] and HBV(-) subgroups, the long AR allele dominance was found only in HBV(+) ones (P = 0.006 versus P = 0.923). Notably, the preference of long CAG repeat has also been found in the 100 monoclonal nodules (P = 0.013). For comparison of monoclonal nodules obtained from the same individual, a dominant long AR allele was found in 6 patients. The proportion of monoclonal cirrhotic nodules and HCCs expressing longer AR allele, 69 and 68%, are both significantly higher than 50%, the assumed value in normal liver (P < 0.001 for cirrhotic nodules and P = 0.005 for HCC). The dominance is again only prominent in HBV-infected HCCs [85% for HBV(+) HCC; P < 0.001 but 54% for HBV(-) HCC; P = 0.27]. The results indicated that in female hepatocarcinogenesis, hepatocytes expressing the longer AR allele seem to be favorably selected for autonomous growth and transformation, especially in synergy with HBV infection.
Adult↗
Hepatitis B e antigen and the risk of hepatocellular carcinoma.
BACKGROUND: The presence of hepatitis B e antigen (HBeAg) in serum indicates active viral replication in hepatocytes. HBeAg is thus a surrogate marker for the presence of hepatitis B virus DNA. We conducted a prospective study to determine the relation between positivity for hepatitis B surface antigen (HBsAg) and HBeAg and the development of hepatocellular carcinoma. METHODS: In 1991 and 1992, we enrolled 11,893 men without evidence of hepatocellular carcinoma (age range, 30 to 65 years) from seven townships in Taiwan. Serum samples obtained at the time of enrollment were tested for HBsAg and HBeAg by radioimmunoassay. The diagnosis of hepatocellular carcinoma was ascertained through data linkage with the computerized National Cancer Registry in Taiwan and with death certificates. We performed a multiple regression analysis to determine the relative risk of hepatocellular carcinoma among men who were positive for HBsAg alone or for HBsAg and HBeAg, as compared with those who were negative for both. RESULTS: There were 111 cases of newly diagnosed hepatocellular carcinoma during 92,359 person-years of follow-up. The incidence rate of hepatocellular carcinoma was 1169 cases per 100,000 person-years among men who were positive for both HBsAg and HBeAg, 324 per 100,000 person-years for those who were positive for HBsAg only, and 39 per 100,000 person-years for those who were negative for both. After adjustment for age, sex, the presence or absence of antibodies against hepatitis C virus, cigarette-smoking status, and use or nonuse of alcohol, the relative risk of hepatocellular carcinoma was 9.6 (95 percent confidence interval, 6.0 to 15.2) among men who were positive for HBsAg alone and 60.2 (95 percent confidence interval, 35.5 to 102.1) among those who were positive for both HBsAg and HBeAg, as compared with men who were negative for both. CONCLUSIONS: Positivity for HBeAg is associated with an increased risk of hepatocellular carcinoma.
Adult↗
The double-stranded RNA-activated kinase, PKR, can phosphorylate hepatitis D virus small delta antigen at functional serine and threonine residues.
Hepatitis D virus (HDV) encodes two proteins, the 24-kDa small delta antigen (S-HDAg) and 27-kDa large delta antigen (L-HDAg) in its single open reading frame. Both of them had been identified as nuclear phosphoproteins. Moreover, the phosphorylated form of S-HDAg was shown to be important for HDV replication. However, the kinase responsible for S-HDAg phosphorylation remains unknown. Therefore, we employed an in-gel kinase assay to search candidate kinases and indeed identified a kinase with a molecular mass of about 68 kDa. Much evidence demonstrated this kinase to be the double-stranded RNA-activated kinase, PKR. The immunoprecipitated endogenous PKR was sufficient to catalyze S-HDAg phosphorylation, and the kinase activity disappeared in the PKR-depleted cell lysate. The S-HDAg and PKR could be co-immunoprecipitated together, and both of them co-located in the nucleolus. The LC/MS/MS analysis revealed that the serine 177, serine 180, and threonine 182 of S-HDAg were phosphorylated by PKR in vitro. This result was consistent with previous phosphoamino acid analysis indicating that serine and threonine were phosphorylation targets in S-HDAg. Furthermore, serine 177 was also shown to be the predominant phosphorylation site for S-HDAg purified the from cell line. In dominant negative PKR-transfected cells, the level of phosphorylated S-HDAg was suppressed, but replication of HDV was enhanced. Other than human immunodeficiency virus type 1 trans-activating protein (Tat), S-HDAg is another viral protein phosphorylated by PKR that may regulates HDV replication and viral response to interferon therapy.
Cell Line↗