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Biomedical subjects

Ding-Shinn Chen

Publications and source records attributed to Ding-Shinn Chen.

At least 55 records · Page 3Linked to original sources
PubMed2005

Serum adiponectin correlates with viral characteristics but not histologic features in patients with chronic hepatitis C.

BACKGROUND/AIMS: Adiponectin induces insulin sensitivity and modulates inflammatory responses. We thus studied the implications of adiponectin in patients with chronic hepatitis C virus (HCV) infection inherently linked to insulin resistance. METHODS: We analyzed the association of serum adiponectin levels with clinical, virologic, and histologic findings in 95 naive Taiwanese patients with chronic hepatitis C before and after antiviral therapy. RESULTS: At baseline, 14 (15%) of the 95 patients were obese and 26 (27%) had type 2 diabetes mellitus. Fifty-seven patients were infected with HCV genotype 1 and 38 with genotype 2. Steatosis and periportal fibrosis was present in 44 (46%) and 69 (73%), respectively. In multivariate analysis, male gender, insulin resistance, high HCV load and genotype 2 were significantly associated with a lower serum adiponectin level. In contrast, intrahepatic gene expression of adiponectin receptors was higher in genotype 2 compared with genotype 1. Serum adiponectin level did not correlate with other clinical or histologic parameters. After treatment, change of steatosis also did not correlate with the change of adiponectin level (P=0.61). CONCLUSIONS: Adiponectin correlated with hepatitis C viral factors at both serum and liver tissue levels. The interactions among adiponectin, insulin resistance and chronic HCV infection merit further studies.

Adiponectin↗
PubMed2005

RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant.

BACKGROUND & AIMS: Present therapy for chronic hepatitis B attains control only in limited proportions. Small interfering RNA (siRNA) offers a new tool with potential therapeutic applications for hepatitis B virus (HBV). Given the importance of sequence identity in the effectiveness of siRNA and the heterogeneity of HBV sequences among different isolates, a short hairpin RNA (shRNA)-expressing plasmid, pSuper/HBVS1, was developed to target a region conserved among major HBV genotypes and assess its effectiveness control of HBV. METHODS: HBV replication-competent plasmid was cotransfected with pSuper/HBVS1 to HuH-7 cells or to mice. The levels of viral proteins, RNA, and DNA were examined in transfected cells and animals. The effects of pSuper/HBVS1 on clinical isolates with genotypes B and C were also determined. RESULTS: pSuper/HBVS1 significantly decreased levels of viral proteins, RNA, and DNA for HBV genotype A in cell culture and in mice. Comparable suppressive effects were observed on clinical isolates of genotypes B and C. A clone with a silent mutation in the target region was identified from a patient with genotype C. This mutant revealed diminished sensitivity to pSuper/HBVS1 and could be selected out in the presence of pSuper/HBVS1 in cell culture. CONCLUSIONS: These findings indicated that shRNA could suppress HBV expression and replication for genotypes A, B, and C, promising an advance in treatment of HBV. However, the emergence of resistant mutants in HBV quasispecies should be considered.

Animals↗
PubMed2005

Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study.

OBJECTIVE: To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study. METHODS: A total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency. RESULTS: Follow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival. CONCLUSIONS: Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.

Administration, Cutaneous↗
PubMed2005

Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND/AIMS: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan. METHODS: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease. RESULTS: HBV carriers with older age (> 50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22-25, P < 0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.41-12.03, P = 0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.30-14.52, P = 0.02). CONCLUSIONS: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.

Adult↗
PubMed2005

Prevalence and clinical implications of HFE gene mutations (C282Y and H63D) in patients with chronic hepatitis B and C in Taiwan.

BACKGROUND/AIMS: The implication of hemochromatosis (HFE) gene mutations in chronic viral hepatitis remains controversial. We therefore studied the prevalence of HFE mutations and their impact on the progression of chronic viral hepatitis in Taiwan. PATIENTS & METHODS: H63D and C282Y mutations were screened by using polymerase chain reaction followed by restriction fragment length polymorphism in 152 chronic hepatitis B patients with various stages of liver disease, 87 chronic hepatitis C patients with various stages of liver disease, and 49 healthy controls. The distribution of each allele frequency was then compared among different groups of patients and in various stages of liver disease. RESULTS: All three groups of patients were C282Y wild type and the majority of H63D mutations were heterozygotes. Although statistically not significant, allele frequencies of H63D mutation in hepatitis B-related liver cirrhosis (6%) and hepatitis C-related liver cirrhosis (9.1%) were higher than those in healthy control (2%). After adjustment for age and sex, hepatitis B patients with H63D heterozygosity had a higher likelihood of cirrhosis than those with H63D wild type (odds ratios (OR): 3.2, confidence interval (CI): 0.49-20.5, P = 0.22). Similarly, hepatitis C patients with H63D homozygosity had a higher likelihood of cirrhosis compared with those with H63D wild type (OR: 2.35, CI : 0.19-28.5, P = 0.52). CONCLUSIONS: Almost all Taiwanese are C282Y wild type. H63D heterozygote and homozygote, occurring in less than 5% of the subjects, tended to be associated with the development of liver cirrhosis, irrespective of viral etiology. Screening for H63D mutation might be considered in patients with chronic viral hepatitis in Taiwan.

Adult↗
PubMed2005

Changing disease burden of hepatocellular carcinoma in the Far East and Southeast Asia.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and has a marked difference in geographic distribution. More than 80% of HCC cases occur in developing countries, especially the Far East and Southeast Asia. Although immunization has been successful against hepatitis B virus (HBV), a changing disease burden of HCC has been observed in many parts of the world because of the increasing prevalence and duration of hepatitis C virus (HCV) infection in these countries. In addition, the age-specific incidence of HCC has progressively shifted toward younger people. Hepatitis B genotypes B and C are prevalent in the Far East and Southeast Asia, and the clinical relevance of HBV genotypes has become increasingly recognized. Compared with genotype C, genotype B is associated with earlier hepatitis B e antigen seroconversion, slower progression to cirrhosis and less frequent development of HCC. By using periodic examinations of serum alfa-fetoprotein levels and abdominal ultrasonography, small HCC can be detected and treated earlier. However, prevention of HBV and HCV infections as well as effective treatment of the chronic viral infections with timely interventions are still needed for the global control of HCC, particularly in the Far East and Southeast Asia.

Asia, Southeastern↗
PubMed2005

Therapeutic implications of hepatitis B virus genotypes.

BACKGROUND/AIMS: Hepatitis B virus (HBV) is a global health problem. In addition to the implementation of universal hepatitis B vaccination, effective and individualized treatment of chronic hepatitis B to prevent progression into end-stage liver diseases and hepatocellular carcinoma is still needed. HBV has been designated eight genotypes (A-H) based on genome sequence divergence. The epidemiology of HBV genotypes and their implications on the responses to antiviral therapy have become increasingly recognized in both Asian and Western countries. METHODS: Published data are thus reviewed. RESULTS: Each genotype has its distinct geographical and ethnic distribution. Genotypes A and D occur frequently in Africa, Europe, and India, while genotypes B and C are prevalent in Asia. Genotype E is restricted to West Africa, and genotype F is found in Central and South America. The distribution of genotypes G and H is less clear. Accumulating evidence indicates a better sustained response to conventional interferon in patients with genotype B than those with C, and in patients with genotype A than those with D. In contrast, conflicting results exist regarding the response to pegylated interferon. On the other hand, the therapeutic responses to nucleoside/nucleotide analogues are comparable among patients with different HBV genotypes. The impact of HBV subgenotypes, mixed genotype infections, and recombinants of different genotypes on the response to antiviral treatments awaits further examinations. CONCLUSION: Remarkable clinical and pathogenic differences do exist among HBV genotypes; however, researches on molecular and virologic mechanisms underlying the clinical phenotypes of different HBV genotypes are urgently needed.

Antiviral Agents↗
PubMed2005

Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C.

BACKGROUND/AIMS: The prevalence and clinical implications of non-alcoholic fatty liver disease in patients with chronic hepatitis C remain unknown in Taiwan. METHODS: We addressed the relevant issues by analysing 95 naive Taiwanese patients infected with either hepatitis C virus (HCV) genotype 1 (n = 57) or 2 (n = 38), receiving interferon alone (n = 41) or in combination with ribavirin (n=54) therapy. A single pathologist scored steatosis and steatohepatitis at baseline and 24 weeks after antiviral treatment. RESULTS: At baseline, steatosis and steatohepatitis were present in 44 (46%) and four (4%) patients, respectively. Variables associated with steatosis in logistical regression were hyperglycaemia (P = 0.01), hypertriglyceridaemia (P = 004) and body mass index > or = 27 (P = 0.009), but not HCV genotype or viral load. The grade of steatosis correlated well with the number of metabolic syndrome parameters (P = 0.018). Interferon monotherapy, advanced age and HCV genotype 1, but not steatosis, correlated with lower sustained response rate. After treatment, steatosis improved in 19 and worsened in nine, which also did not correlate with HCV genotype (P = 0.850) or sustained response to antiviral therapy (P = 0.246). CONCLUSIONS: Hepatic steatosis in Taiwanese patients with chronic hepatitis C was associated with features of the metabolic syndrome, but did not correlate with HCV genotype, advanced fibrosis or the response to antiviral therapy.

Adult↗
PubMed2005

Successful treatment with peginterferon and ribavirin in a patient with acute hepatitis C evolving into chronicity.

Acute hepatitis C has a high frequency of chronic evolution, which may progress to cirrhosis and hepatocellular carcinoma. However, only a small proportion of acute hepatitis C patients are incidentally identified and then treated. Controversial issues regarding treatment of acute hepatitis C include optimal time of treatment initiation, best treatment regimen and appropriate duration of treatment. We report a symptomatic acute hepatitis C patient in the late acute phase evolving into chronicity successfully treated by peginterferon and ribavirin combination therapy for 6 months at late acute phase, with sustained virologic response for up to 18 months. Our findings indicate that combination peginterferon and ribavirin therapy may be as effective in treating acute hepatitis C as it is in chronic hepatitis C.

Acute Disease↗
PubMed2005

Natural course and treatment of dual hepatitis B virus and hepatitis C virus infections.

In areas where hepatitis B virus (HBV) infection is endemic such as Southeast Asia, the Far East and southern Europe, a substantial number of patients are infected with both hepatitis C and B. Moreover, patients who are dually infected with hepatitis C virus (HCV) and HBV have been reported to carry a significantly higher risk of developing fulminant hepatic failure, liver cirrhosis and hepatocellular carcinoma than those with HCV or HBV infection alone. Such dually infected patients need careful medical attention and effective treatment. Dually infected hepatitis patients can be classified into 2 groups according to the dominant viral activity: the first in which hepatitis C dominates over hepatitis B (hepatitis C/B) and the second in which hepatitis B dominates over hepatitis C (hepatitis B/C). Their natural histories may differ and require distinct treatments. For hepatitis C/B, conventional interferon (IFN) alone has not been shown to be effective in the clearance of HCV RNA. IFN in combination with ribavirin for 6 months has been used to treat hepatitis C/B patients in a few pilot studies and a sustained HCV clearance rate could be achieved to an extent comparable to that in simple hepatitis C. Nevertheless, the treatment outcomes in those infected with HCV genotype 1 remain unsatisfactory. Systematic trials of treatment for hepatitis B/C patients have not yet been reported. In this article, we review recent updates in the natural history and treatment of dual HBV and HCV infections, and draw attention to several unresolved issues requiring further study. These efforts may culminate in better treatment for patients co-infected with HCV and HBV.

Antiviral Agents↗
PubMed2004

End-of-treatment virologic response does not predict relapse after lamivudine treatment for chronic hepatitis B.

AIM: Attaining hepatitis B e antigen (HBeAg) seroconversion during lamivudine treatment is associated with fewer relapses in HBeAg-positive patients. In HBeAg-negative patients, predictors for post-treatment relapse remain largely unknown. We therefore studied whether end-of-treatment virologic response correlated with relapse after lamivudine treatment. METHODS: We prospectively analyzed 12 HBeAg-negative patients and 14 HBeAg-positive patients with chronic hepatitis B, who received at least 9 mo of lamivudine treatment and were followed up for 12 mo post-treatment. Relapse of hepatitis B activity was defined by an elevation of serum ALT level above twice the upper limit of normal as well as reappearance of serum HBV DNA by the branched DNA assay or HBeAg during the follow-up period. The serum viral loads during and at the end of treatment were further determined by a quantitative real-time polymerase chain reaction assay. RESULTS: Relapse occurred in 6 (50.0%) HBeAg-negative patients within 12 mo post-treatment. Two relapsers had end-of-treatment serum viral load <1 000 copies/mL, the proportion was not significantly different from that in the 6 non-relapsers (33.3% vs 16.7%; P = 1.00). Hepatitis B virus (HBV) DNA levels did not correlate with post-treatment relapse in HBeAg-positive patients either. However, genotype C patients tended to have a lower relapse rate than genotype B patients (14.3% vs 57.9%, P = 0.08). CONCLUSION: Our results suggest that end-of-treatment virologic response cannot predict post-treatment relapse in patients with HBeAg-negative or -positive chronic hepatitis B. The impact of HBV genotype on the response to lamivudine treatment awaits further studies.

Adult↗
PubMed2004

Clustering of minimal deleted regions reveals distinct genetic pathways of human hepatocellular carcinoma.

Systematic scan and statistical analysis of loss of heterozygosity (LOH) has been widely used to define chromosomal aberrations in various cancers for cloning of tumor suppressor genes and for development of prognostic markers. However, the establishment of novel strategies is needed, so that the nonrandom but heterogeneous chromosomal aberration data could provide significant insights into our understanding of molecular pathogenesis of cancers. After comprehensive allelotyping of recurrent allelic losses with 441 highly informative microsatellite markers and overlapping LOH regions on human hepatocellular carcinoma (HCC) chromosomes, 33 minimal deleted regions (MDRs) were revealed. Five and 15 of the 33 MDRs have physical intervals in less than 5 and 10 Mb, respectively, with the smallest MDR9p1 of 2.2 Mb located at 9p21.3-p21.2. Statistical and Kaplan-Meier survival analysis revealed a significant association between the loss of MDR15q1 (15q21.1-q22.2) and the HCC patient survival (adjusted P = 0.033). After cluster analysis of 33 MDRs that represented LOH profiles of each HCC tissue based on clinicopathological features and p53 mutations, two major genetic pathways, low-stage and advanced-stage HCC, were uncovered based on high concordance of MDR clusters. We propose that the definition of genome-wide MDRs on the cancer genome not only narrows down the location of existing tumor suppressor genes to facilitate positional candidate cloning and develop potential prognostic markers after statistical association of MDRs with clinicopathological features but also dissects genetic interactions and pathways of chromosomal aberrations in tumorigenesis.

Carcinoma, Hepatocellular↗
PubMed2004

Hepatitis C virus NS3 RNA helicase activity is modulated by the two domains of NS3 and NS4A.

To determine whether the two domains of hepatitis C virus (HCV) NS3 and the NS4A interact with each other to regulate the RNA unwinding activity, this study compares the RNA unwinding, ATPase and RNA binding activities of three forms of NS3 proteins--the NS3H protein, containing only the helicase domain, the full-length NS3 protein, and the NS3-NS4A complex. The results revealed that NS3 displayed the weakest RNA helicase activity, not because it had lower ATPase or RNA binding activity than did NS3H or NS3-NS4A, but because it had the lowest RNA unwinding processivity. A mutant protein, R1487Q, which contained a mutation in the helicase domain, displayed a reduced protease activity as compared to the wild-type NS3-NS4A. Together, these results suggest the existence of interactions between the two domains of NS3 and the NS4A, which regulates the HCV NS3 protease and RNA helicase activities.

Adenosine Triphosphatases↗
PubMed2004

Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma.

For isolation of novel cellular transforming genes that potentially participated in hepatocarcinogenesis, we conducted anchorage-independent growth (AIG) assays on 10 human liver cancer cell lines and observed strong AIG capabilities in PLC5 and Huh7 but negligible in Tong cells. After cloning of genes by differential subtractive chain reactions (DSC) from strong AIG to AIG negative cells, we sequenced 2304 clones and identified 245 genes. After four stringent criteria for selection of transforming genes among DSC clones, our results of quantitative RT-PCR analysis indicated that six genes, DDX3, EIF3S2, CLIC1, HDGF, GPC3, and HSPCA were overexpressed in 64%, 62%, 60%, 58%, 49%, and 47%, respectively, of 45 hepatocellular carcinoma (HCC) tissues. The results of cellular transformation capability by AIG assays indicated that the transfectants of EIF3S2 showed the strongest (> 100-fold), DDX3 and CLIC1 were moderate, GPC3 and HSPCA were weak, and HDGF was none in forming colonies in soft agar. Together, our results suggested that Tong is a suitable human cell line for screening of overexpressed and/or cellular transforming genes. In addition, our results suggested that diverse functions of cellular transforming genes in various biological pathways could transform human Tong cells and potentially reveal new targets for drug development of HCC.

Blotting, Northern↗
PubMed2004

Characterization of severe acute respiratory syndrome coronavirus genomes in Taiwan: molecular epidemiology and genome evolution.

Since early March 2003, the severe acute respiratory syndrome (SARS) coronavirus (CoV) infection has claimed 346 cases and 37 deaths in Taiwan. The epidemic occurred in two stages. The first stage caused limited familial or hospital infections and lasted from early March to mid-April. All cases had clear contact histories, primarily from Guangdong or Hong Kong. The second stage resulted in a large outbreak in a municipal hospital, and quickly spread to northern and southern Taiwan from late April to mid-June. During this stage, there were some sporadic cases with untraceable contact histories. To investigate the origin and transmission route of SARS-CoV in Taiwan's epidemic, we conducted a systematic viral lineage study by sequencing the entire viral genome from ten SARS patients. SARS-CoV viruses isolated from Taiwan were found closely related to those from Guangdong and Hong Kong. In addition, all cases from the second stage belonged to the same lineage after the municipal hospital outbreak, including the patients without an apparent contact history. Analyses of these full-length sequences showed a positive selection occurring during SARS-CoV virus evolution. The mismatch distribution indicated that SARS viral genomes did not reach equilibrium and suggested a recent introduction of the viruses into human populations. The estimated genome mutation rate was approximately 0.1 per genome, demonstrating possibly one of the lowest rates among known RNA viruses.

Base Pairing↗
PubMed2004

The small delta antigen of hepatitis delta virus is an acetylated protein and acetylation of lysine 72 may influence its cellular localization and viral RNA synthesis.

Hepatitis delta virus (HDV) is a single-stranded RNA virus that encodes two viral nucleocapsid proteins named small and large form hepatitis delta antigen (S-HDAg and L-HDAg). The S-HDAg is essential for viral RNA replication while the L-HDAg is required for viral assembly. In this study, we demonstrated that HDAg are acetylated proteins. Metabolic labeling with [(3)H]acetate revealed that both forms of HDAg could be acetylated in vivo. The histone acetyltransferase (HAT) domain of cellular acetyltransferase p300 could acetylate the full-length and the N-terminal 88 amino acids of S-HDAg in vitro. By mass spectrometric analysis of the modified protein, Lys-72 of S-HDAg was identified as one of the acetylation sites. Substitution of Lys-72 to Arg caused the mutant S-HDAg to redistribute from the nucleus to the cytoplasm. The mutant reduced viral RNA accumulation and resulted in the earlier appearance of L-HDAg. These results demonstrated that HDAg is an acetylated protein and mutation of HDAg at Lys-72 modulates HDAg subcellular localization and may participate in viral RNA nucleocytoplasmic shuttling and replication.

Acetylation↗
PubMed2004

Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination.

To investigate the role of hepatitis B virus (HBV) infection in pediatric fulminant hepatic failure (FHF) after the launch of universal HBV vaccination, the authors analyzed the data from patients with FHF collected from a nationwide collaborative study group. Children aged 1 month to 15 years who were diagnosed with FHF (62 males and 33 females) between 1985-1999 were included. HBV infection (hepatitis B surface antigen [HBsAg] and/or immunoglobulin M hepatitis B core antibody [IgM anti-HBc] seropositive) accounted for 46% (43 of 95 cases) of all the cases of FHF. The average annual incidence of FHF in the time period 1985-1999 was 0.053/100,000 in the group of patients ages 1-15 years and 1.29/100,000 in those patients age < 1 year. Approximately 61% (58 of 95 cases) of all FHF cases were infants. The percentage of HBV infection was found to be higher in infants (57%) compared with children ages 1-15 years (27%) (P = 0.004). The incidence rate ratio of those patients age < 1 year to those ages 1-15 years was 54.2 for HBV-positive FHF and 15.2 for HBV-negative FHF. Maternal HBsAg was found to be positive in 97% of the infants with HBV-positive FHF, and hepatitis B e antigen (HBeAg) was found to be negative in 84% of these infants. Approximately 74% of all HBV-positive FHF patients and 81% of the infantile HBV-positive patients had been vaccinated. In conclusion, within the first 15 years of universal vaccination, HBV was found to rarely cause FHF in children age > 1 year but remained a significant cause of FHF in infants. HBV-positive FHF was prone to develop in infants born to HBeAg-negative, HBsAg-carrier mothers; these infants had not received hepatitis B immunoglobulin according to the vaccination program in place.

Adolescent↗