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Ding-Shinn Chen

Publications and source records attributed to Ding-Shinn Chen.

At least 37 records · Page 2Linked to original sources
PubMed2006

High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases.

BACKGROUND & AIMS: The interactions among pre-S deletion, precore (PC) mutation, and basal core promoter (BCP) mutation in various stages of chronic hepatitis B virus (HBV) infection remain unclear and were thus investigated in this study. METHODS: The sequences of the pre-S region and the BCP (A1762T, G1764A) and PC (G1896A) mutations were determined in 46 HBV chronic carriers (CC) and 106 age-matched carriers with different stages of liver diseases, including 38 chronic hepatitis (CH), 18 cirrhosis (LC), and 50 hepatocellular carcinoma (HCC). RESULTS: A higher prevalence of pre-S deletion and BCP and PC mutations was found in carriers with progressive liver diseases compared with the CC group. By logistic regression analysis, patients with pre-S deletion and BCP mutation were significantly associated with the development of progressive liver diseases than those without. Combination of mutations rather than single mutation was associated with the development of progressive liver diseases, especially in combination with pre-S deletion. Sequencing analysis showed that the deleted regions were more often in the 3' terminus of pre-S1 and the 5' terminus of pre-S2. Further mapping of these pre-S deletion sequences found that all the deletion regions encompassed T- and B-cell epitopes, and most of them lost 1 or more functional sites. CONCLUSIONS: Our data indicate that patients with progressive liver diseases have a higher frequency of pre-S deletion.

Adult↗
PubMed2006

Evolution of Hepatitis B virus in an acute hepatitis B patient co-infected with genotypes B and C.

The interactions between different genotypes of Hepatitis B virus (HBV) in co-infected patients remain largely unknown, especially in acute infection. Here, the evolution of HBV strains was studied in an acute, self-limited hepatitis B patient co-infected with genotypes Ba (B2) and C. Virological analyses were performed at four time points after admission: T1 (5 days), T2 (11 days), T3 (22 days) and T4 (260 days). A dominant-genotype change from genotype C to Ba was found after anti-HBV e antigen (anti-HBe) seroconversion. Further clonal and phylogenetic analyses of the pre-S and pre-core/core regions of HBV were carried out to clarify the interactions between genotypes Ba and C. All clones propagated from T1 and T2 were of genotype C. In contrast, clones propagated from T3 (after anti-HBe seroconversion) were of genotype Ba, C and/or recombinant within the pre-S region. At T4, all clones were of genotype Ba with a 123 bp (from nt 3147 of the pre-S1 region to nt 54 of the pre-S2 region) in-frame pre-S deletion and had lost the start codon of the middle envelope protein and the nucleocapsid-binding site. Phylogenetic analysis showed that genetic distance was greater at T3 after seroconversion to anti-HBe. By using SimPlot, the breakpoint of one pre-S recombinant was located at nt 3069-3100 and the other two at nt 49-87. In conclusion, HBV genotype Ba may overtake genotype C as the predominant strain after anti-HBe seroconversion in acute hepatitis B. Recombination within the pre-S region emerged transiently and the pre-S deletion mutant was finally cleared.

Acute Disease↗
PubMed2006

Higher cut-off index value of immunoglobulin M antibody to hepatitis B core antigen in Taiwanese patients with hepatitis B.

BACKGROUND: The cut-off index value of immunoglobulin M (IgM) antibody to hepatitis B core antigen (anti-HBc; AxSYM CORE-M, Abbott) for diagnosing acute hepatitis B is 1.2. A high false-positive rate of IgM anti-HBc was observed in acute flare-ups of chronic hepatitis B in Taiwanese patients. Thus the purpose of the present paper was to study the optimal index value of IgM anti-HBc in Taiwanese subjects. METHODS: The peak index values of 42 IgM anti-HBc-positive patients were collected. There were 20 acute hepatitis B patients and 22 patients with chronic hepatitis B with acute flare. The biochemical, virological, and serological data were obtained. RESULTS: There were significant differences in mean age (36 vs 47 years, P = 0.01), serum alanine aminotransferase level (2042 U/L vs 1193 U/L, P = 0.02) and peak index value of IgM anti-HBc (2.9 vs 1.5, P < 0.01) between patients with acute hepatitis B and those with acute flare of chronic hepatitis B. Eleven (50%) of 22 patients with chronic hepatitis B with acute flare had index value of >1.2. The optimal cut-off index value to differentiate acute hepatitis B from chronic hepatitis B with acute flare was 2.4-2.5, with a sensitivity of 90% and specificity of 90%. CONCLUSIONS: The cut-off index value of IgM anti-HBc to differentiate acute hepatitis B from chronic hepatitis B with acute flare among Taiwanese patients should be set at 2.4-2.5 instead of 0.8-1.2.

Adult↗
PubMed2006

Long-term trends and geographic variations in the survival of patients with hepatocellular carcinoma: analysis of 11,312 patients in Taiwan.

BACKGROUND/AIMS: The survival rates of patients with hepatocellular carcinoma (HCC) were investigated over the past 20 years to clarify the long-term survival trend. METHODS: A total of 11 312 patients with HCC from seven medical centers from 1986 to 2002 were included. Survival was analyzed by correlating data with the national mortality databank. RESULTS: Multivariate analysis showed that the following factors were associated with shorter survival: male sex, younger age, hepatitis B virus, earlier year of diagnosis, alpha fetoprotein higher than 400 ng/mL, alanine aminotransferase (ALT) higher than two times the upper normal limit, higher aspartate aminotransferase (AST)/ALT ratio, central or southern Taiwan residence, and rural areas residence. Patients diagnosed during 1998-2002 showed the highest survival rate, followed by patients diagnosed during 1994-1997, 1990-1993, and 1986-1989, respectively. CONCLUSIONS: There are geographic variations in the survival rates of patients with HCC. Survival has been improving gradually over the past 20 years, probably due to earlier detection of HCC or to improved patient care.

Adult↗
PubMed2006

Do young hepatocellular carcinoma patients have worse prognosis? The paradox of age as a prognostic factor in the survival of hepatocellular carcinoma patients.

BACKGROUND/AIMS: Our previous study showed that male hepatocellular carcinoma (HCC) patients below 40 years of age had the worst survival in the initial several years, but had the best prognosis thereafter. Thus, it seems that age has a paradoxical influence on the prognosis. To further clarify the issue of age on HCC prognosis, we initiated this study. METHODS: A total of 11,312 HCC cases from seven medical centers from 1986 to 2002 were included. We analyzed the 1-year survival and survival after 1 year. RESULTS: Male gender, age younger than 40 years old and hepatitis B virus (HBV) were associated with worse 1-year survival. In contrast, male gender, age younger than 40 years old and HBV were associated with better survival after 1 year. Higher percentage of the young HCC patients had a tumor size larger than 3 cm. 83.7% of HCC patients below 40 years of age were male and 89.8% of them were HBV carriers. CONCLUSIONS: If we encountered a young HCC patient, the patient will probably be a male HBV carrier. He would probably have larger tumor and is more likely to expire within 1 year than the older HCC patients. However, if the young HCC patient can survive for more than 1 year, he would probably have better survival in the following years than the older patients.

Adult↗
PubMed2006

Viral factors correlate with hepatitis B e antigen seroconverson in patients with chronic hepatitis B.

BACKGROUND/AIMS: Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg. METHODS: We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay. RESULTS: We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients. CONCLUSION: Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.

Adolescent↗
PubMed2006

Noninvasive tests for the prediction of significant hepatic fibrosis in hepatitis C virus carriers with persistently normal alanine aminotransferases.

BACKGROUND: The diagnostic value of Doppler and various noninvasive indices in predicting significant hepatic fibrosis in hepatitis C virus (HCV) carriers with persistently normal alanine aminotransferases (PNALT) is unknown. METHODS: Seventy-nine treatment-naïve HCV carriers with PNALT, who received Doppler ultrasonography and percutaneous liver biopsies, were enrolled in the study. Doppler indices, including portal vein velocity (PVV), hepatic arterial resistive index (HARI), hepatic arterial pulsatility index (HAPI), splenic arterial resistive index (SARI), and splenic arterial pulsatility index (SAPI), were compared with known biochemical indices used in HCV carriers with elevated ALT levels, including aspartate aminotransferase (AST) to platelet ratio index (APRI), age-platelet index (API), and AST to ALT ratio (AAR), for the diagnostic accuracy of significant hepatic fibrosis. RESULTS: SAPI was the most discriminatory index among the Doppler indices (P<0.001). By comparing areas under the receiver-operating characteristic (AUROC) of SAPI with various biochemical indices, SAPI was superior to APRI, API, and AAR for predicting significant fibrosis (> or =F2) (0.862 vs. 0.673, 0.639, 0.504). SAPI set at 0.85 and 1.10 had a sensitivity of 96.7% and 66.7%, a specificity of 44.6% and 96.0%, a positive predictive value of 41.4% and 87.1%, and an negative predictive value of 97% and 87.7% in predicting significant fibrosis. CONCLUSIONS: This study indicates that SAPI is the most useful index among Doppler and biochemical indices for the detection of significant hepatic fibrosis in HCV carriers with PNALT levels.

Adult↗
PubMed2006

Genetic predisposition of responsiveness to therapy for chronic hepatitis C.

BACKGROUND: A combination of interferon-alpha (IFN-alpha) and ribavirin has been the choice for treating chronic hepatitis C (CHC) patients. It achieves an overall sustained response rate of approximately 50%; however, the treatment takes 6-12 months and often brings significant adverse reactions to some patients. It would therefore be beneficial to include a pretreatment evaluation in order to maximize the efficacy. In addition to viral genotypes, we hypothesize that patient genotypes might also be useful for the prediction of treatment response. METHODS: We retrospectively analyzed the genetic differences of CHC patients that are associated with IFN/ribavirin responses. The DNA polymorphisms among 195 sustained responders and 122 nonresponders of CHC patients of Taiwanese origin were compared. Statistical and algorithmic methods were used to select the genes associated with drug response and single nucleotide polymorphisms (SNPs) that permitted the construction of a predictive model. RESULTS: Association studies and haplotype reconstruction revealed selection of seven genes: adenosine deaminase, RNA-specific (ADAR), caspase 5, apoptosis-related cysteine peptidase (CASP5), fibroblast growth factor 1 (FGF1), interferon consensus sequence binding protein 1 (ICSBP1), interferon-induced protein 44 (IFI44), transporter 2, ATP-binding cassette, subfamily B (TAP2) and transforming growth factor, beta receptor associated protein 1 (TGFBRAP1) for the responsiveness trait. Based on confirmed linkage disequilibrium block in the population, a minimal set of 26 SNPs in the seven selected genes was inferred. To predict treatment outcome, a multiple logistic regression model was constructed using susceptible genotypes of SNPs. The performance of the resultant model had a sensitivity of 68.2% and specificity of 60.7% on 317 CHC patients treated with IFN-combined therapy. In addition, a prediction model with both the host genetic and viral genotype information was also constructed which enhanced the performance with a sensitivity of 80.7% and specificity of 67.2%. CONCLUSIONS: A genetic model was constructed to predict outcomes of the combination therapy in CHC patients with high sensitivity and specificity. Results also provide a possible process of selecting targets for predicting treatment outcomes and the basis for developing pharmacogenetic tests.

Adult↗
PubMed2005

Epigenetic activation of alpha4, beta2 and beta6 integrins involved in cell migration in trichostatin A-treated Hep3B cells.

The epigenetic modulation by histone deacetylase (HDAC) inhibitors including trichostatin A (TSA) has been known to block cell proliferation, induce apoptosis and inhibit cell migration in human cancer cells that represents the potential therapeutic agents for cancers and fibrosis. However, more than 55% of Hep3B cells remained alive after our initial study of 100 nM TSA treatment. To further study the epigenetic modulation and the biological function of newly activated genes by HDAC inhibitor involved in HCC progression and metastasis, we profiled 23 integrin genes including 15alpha and 8beta in TSA-treated Hep3B cells. Six integrins including three down-regulated alpha6, alpha10, beta8 and three significant up-regulated alpha4, beta2, beta6 integrins were revealed after semi-quantitative RT-PCR. To confirm the epigenetic modulation and explore their biological functions, we selected the three significantly up-regulated integrins for confirmation of protein up-regulation, hyperacetylated-histones by ChIP assays, and functional inhibition by specific neutralizing antibodies of integrins. Our results indicated that epigenetic modulation in TSA-treated Hep3B cells up-regulated new integrins including alpha4, beta2 and beta6 and reduced migration activities by specific neutralizing antibodies to 61.3%, 42.4% and 34.5%, respectively. Our novel findings provided a better understanding of the epigenetic modulation of integrins and suggested that targeting the epigenetic up-regulated integrins to abrogate the migration activity might be a promising strategy to prevent HCC progression.

Base Sequence↗
PubMed2005

Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems.

PURPOSE: In spite of the success of hepatitis B immunization, still a significant proportion of childhood hepatocellular carcinoma (HCC) failed to be prevented by the hepatitis B immunization program. This study is aimed to investigate the problems in the HCC prevention in children. EXPERIMENTAL DESIGN: All HCC children ages 6 to 14 diagnosed between 1981 and 2000 in Taiwan were collected from two national childhood HCC registry systems. We analyzed the causes of HCC prevention failure and the risk ratio of HCC among hepatitis B carriers born before versus after the vaccination program. RESULTS: The incidence of HCC per 100,000 children declined from 0.54 to 0.20 in those born before versus after the vaccination program (risk ratio, 0.36). Vaccine failure (33.3-51.4%) and failure to receive hepatitis B immunoglobulin at birth (42.4-57.5%) were the main causes of HCC prevention failure. Mother-to-child transmission of hepatitis B virus infection is an important risk factor of HCC development. This is evidenced by the very high hepatitis B surface antigen seropositive rate in our HCC children (97%) and their mothers (96%). Hepatitis B carrier children born after the vaccination program had a higher risk of developing HCC than those born before the program (risk ratio, 2.3-4.5). CONCLUSIONS: Vaccine failure and failure to receive hepatitis B immunoglobulin are the main problems preventing eradication of HCC. Hepatitis B carrier children born after the immunization program have a higher risk of developing HCC than those born before.

Adolescent↗
PubMed2005

Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial transmission of hepatitis B virus.

BACKGROUND: Infection with hepatitis B virus (HBV) in early life frequently results in persistent infection, and clustering of the chronic infection within a family is common. However, the relative contribution of perinatal mother-to-infant transmission or early horizontal transmission to the intrafamilial clustering of HBV infection remains unclear. Therefore, we used HBV genotyping and phylogenetic analysis to elucidate the modes of intrafamilial HBV transmission in Taiwan. METHODS: HBV genotypes and serological markers were determined for 103 individuals from 20 families with evidence of clustering HBV infection. RESULTS: Three patterns of intrafamilial clustering of HBV infection were identified. Among the 20 families, 8 included a hepatitis B surface antigen (HBsAg)-positive mother (pattern I), 7 included an HBsAg-positive father (pattern II), and in the remaining 5, both parents were positive for HBsAg (pattern III). The rates of HBsAg positivity for children of the 3 representative groups of families were 85.7%, 65.4%, and 87.5%, respectively (P = .16). The identical genotyping results between index parent and carrier children indicated that pattern I clustering was caused by maternal transmission, whereas pattern II clustering was caused by paternal transmission. In pattern III clustering, a concordant HBV genotype between carrier children and mother or father was found in 3 and 2 families, respectively. The modes of transmission were confirmed by phylogenetic analysis in 1 family of each pattern. CONCLUSIONS: In Taiwan, maternal and paternal transmissions are both important in the intrafamilial spread of HBV infection.

Adult↗
PubMed2005

Transmission of occult hepatitis B virus by transfusion to adult and pediatric recipients in Taiwan.

BACKGROUND/AIMS: The infectivity of occult hepatitis B virus (HBV), defined as HBsAg-negative but HBV DNA-positive, after transfusion has been low but not negligible. To address this, we investigated the incidence of post-transfusion HBV infection after receiving screened blood units in Taiwan. METHODS: Consecutive HBV-naïve (anti-HBc-negative) recipients with normal ALT were followed for HBV DNA and serologic markers before and after transfusion. Among 4448 blood recipients, 467 (10.5%) were anti-HBc-negative. Post-transfusion 6-month follow-up was completed for 327. We identified 5 (1.5%) who developed hepatitis B viremia 1 week after transfusion. Three were children who later seroconverted to anti-HBc but with normal ALT indicating subclinical acute infection, despite all had anti-HBs from previous vaccination. One had transient transfusion-transmitted HBV without seroconversion to anti-HBc and one possibly had occult HBV infection. Our findings suggested the possibility that occult HBV infection was transmissible by transfusion. The incidence of post-transfusion acute HBV infection was 0.9% (100 per million units) in naïve recipients in Taiwan, a figure 7 approximately 40-fold higher than in developed countries. Moreover, some vaccinated children with anti-HBs were still susceptible. CONCLUSIONS: Therefore, despite active immunization, sensitive screening assays for occult HBV infection such as nucleic acid amplification test could be considered in endemic areas.

Adolescent↗
PubMed2005

Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.

BACKGROUND: Although chronic infection with hepatitis B virus (HBV) has been established as a cause of hepatocellular carcinoma (HCC), the roles of viral load and HBV genotype remain unclear. METHODS: From 1988 through 1992, baseline blood samples were collected from 4841 Taiwanese men who were HBV carriers but had not been diagnosed with HCC. We used real-time polymerase chain reaction assays of plasma DNA samples to quantify HBV DNA levels (a measure of viral load) and determine HBV genotypes for 154 case patients who were diagnosed with HCC during 14 years of follow-up and 316 control subjects. Unconditional logistic regression was used to assess odds ratios (ORs) of HCC for HBV-related factors. All statistical tests were two-sided. RESULTS: The risk of HCC increased with increasing HBV viral load (adjusted OR for the highest versus the lowest quintile of HBV DNA copies/mL = 7.26, 95% confidence interval [CI] = 3.54 to 14.89; P(trend)<.001). Genotype C HBV was associated with an increased risk of HCC compared with other HBV genotypes (adjusted OR = 5.11, 95% CI = 3.20 to 8.18). Both viral load and genotype were positively associated with HCC within 10-year age categories among subjects aged 30 years old to older than 60 years. Genotype C HBV was associated with increased viral load, and associations of HBV genotype and viral load with HCC risk were additive. The adjusted OR of HCC for those carrying genotype C HBV and with viral load in the highest quintile was 26.49 (95% CI = 10.41 to 67.42) compared with HBV carriers with other HBV genotypes and viral load in the lowest two quintiles. CONCLUSIONS: Measurements of HBV viral load and genotype may help to define which male HBV carriers aged 30 years or older are at high risk for HCC.

Adult↗
PubMed2005

Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11.

A novel 1-cM (1.8 Mb) homozygous deletion (HD) on 13q12.11 was identified in a human hepatocellular carcinoma (HCC) cell line, SK-Hep-1, after high-density genetic marker scan and Southern blotting analysis. A loss of heterozygosity (LOH) analysis indicated that LOH frequency of the HD region in 48 pairs of HCC tissues was 52%. Interestingly, the occurrence of LOH in the 13q12.11 HD region is significantly associated with early-onset HCC, inferred from Fisher's exact test (P = 0.0047) and Mann-Whitney test (P = 0.023). Since the novel 1-cM (1.8 Mb) HD region is gene-rich with more than 37 predicted transcripts, we used a candidate gene approach by examining down-regulation of known tumor suppressor genes (TSGs), including LATS2, TG737, CRYL1, and GJB2, in HCC tissues. We detected only 14% down-regulation of the LAST2 gene that flanks the outside of the HD, in HCC tissues, by quantitative RT-PCR assays. However, we observed significant down-regulation of the TG737, CRYL1, and GJB2 genes located within the HD in 59, 64, and 71% of HCC tissues, respectively. Together, our results indicated that the identified 13q12.11 HD region contained at least three significant down-regulated TSGs, and preferential LOH in early-onset HCC patients is a putative tumor suppressor locus in HCC.

Aged↗