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Chang-hua, Taiwan

Yeh C.-T.,Liver Research Center | Yeh C.-T.,Chang Gung University | Chen T.,New York University | Hsu C.-W.,Liver Research Center | And 4 more authors.
BMC Cancer | Year: 2011

Background: Development of the hepatitis B virus (HBV) rtA181T/sW172* mutant could occur during prolonged lamivudine (LAM) therapy, conferring cross resistance to adefovir. Recent studies demonstrated an increased oncogenic potential of this mutant in NIH3T3 cells. In this study, we aimed to investigate the clinical significance of this finding.Methods: Serum samples from 123 LAM-resistant chronic hepatitis B patients were submitted for virological assays. A highly sensitive amplification created restriction enzyme site (ACRES) method was devised to detect small amounts of the rtA181T mutant in the serum. Virological factors including HBV-DNA level, genotype, precore G1896A, BCP A1762T/G1764A, rtM204I/V, rtA181T and pre-S internal deletion mutations as well as clinical variables including subsequent use of rescue drugs were submitted for outcome analysis.Results: By use of the highly sensitive ACRES method, the rtA181T mutant was detectable in 10 of the 123 LAM-resistant patients. During the mean follow-up period of 26.2 ± 16.4 months (range 2 to 108 months), 3 of the 10 (30.0%) rtA181T-positive patients and 2 of the 113 (1.8%) rtA181T-negative patients developed hepatocellular carcinoma (HCC). Kaplan-Meier analysis indicated that the presence of rtA181T mutation (P < 0.001), age > 50 years (P = 0.001), and liver cirrhosis (P < 0.001) were significantly associated with subsequent occurrence of HCC. All 5 HCC patients belonged to the older age and cirrhosis groups.Conclusions: Emergence of the rtA181T/sW172* mutant in LAM-resistant patients increased the risk of HCC development in the subsequent courses of antiviral therapy. © 2011 Yeh et al; licensee BioMed Central Ltd.


Huang T.-P.,Center for Traditional Chinese Medicine | Huang T.-P.,Chang Gung University | Chang Y.-H.,Center for Traditional Chinese Medicine | Chang Y.-H.,Chang Gung University | And 7 more authors.
Complementary Therapies in Medicine | Year: 2013

Objective: Presentation of a case illustrating the benefits of traditional Chinese herbal granules for treatment of immune thrombocytopenic purpura in children. Clinical features: A 4-year-old girl presented with persistent immune thrombocytopenic purpura refractory to the first-line conventional treatment of steroids and intravenous immunoglobulin over 7 months. She was brought to the traditional Chinese medical clinic at the Chang Gung Memorial Hospital in 2011 for alternative therapy. She received a modified Chinese herbal formula, Zi-Ying-Jiang-Huo-Tang (Phellodendri Combination), for 6 months and was followed clinically by both a pediatrician and a traditional Chinese medical doctor. The patient had a dramatic improvement in platelet count and entered complete remission after treatment with the traditional Chinese medicine. There was no recurrence of disease or side effects of treatment noted during the 12-month follow-up period. Conclusions: Our case report suggests that collaborative monitoring of treatments with traditional Chinese medicine may prove beneficial in the management of childhood persistent immune thrombocytopenic purpura. A larger clinical study is warranted for further evaluation of the role of Zi-Ying-Jiang-Huo-Tang in treating immune thrombocytopenic purpura. © 2013 Elsevier Ltd.


Huang Y.-H.,Liver Research Center | Lin K.-H.,Chang Gung University | Liao C.-H.,Chang Gung University | Lai M.-W.,Chang Gung Children Hospital | And 3 more authors.
PLoS ONE | Year: 2012

Furin is a member of the pro-protein convertase family. It processes several growth regulatory proteins into their active forms, which are critical to tumor progression, metastasis, and angiogenesis. Furin over-expression could occur in liver cancer and a previous study showed that over-expression of furin promoted HepG2 cell invasion in tail vein xenograft models. However, the clinical relevance of furin expression in hepatocellular carcinoma (HCC) remained unknown. Surprisingly, in a postoperative survival analysis for HCC patients, it was found that the tumor/non-tumor (T/N) ratio of furin expression ≥ 3.5 in HCC tissues predicted a better postoperative disease-free survival (DFS) (P = 0.010; log-rank test). Furthermore, subcutaneous xenograft experiments demonstrated a significant suppression effect of tumor growth in the furin-overexpressed xenografts (Huh7-Furin) compared to the mock control. Administration of a synthetic furin inhibitor for inhibition of the pro-protein convertase activity, decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decRVKR-CMK), to the Huh7-Furin xenograft bearing mice restored the repression effect of tumor growth. In contrast, administration of decRVKR-CMK to the mock Huh7 xenograft bearing mice showed no change in growth rate. In conclusion, furin overexpression inhibited HCC tumor growth in a subcutaneous xenograft model and predicted a better postoperative DFS in clinical analysis. © 2012 Huang et al.


Huang Y.-H.,Liver Research Center | Lin K.-H.,Chang Gung University | Chen H.-C.,Chang Gung University | Chang M.-L.,Liver Research Center | And 7 more authors.
PLoS ONE | Year: 2012

Comparison of microRNA (miRNA) expression profiles in the noncancerous liver tissues adjacent to hepatocelluar carcinomas (HCCs) was a strategy to identify postoperative prognostic predictors in this study. Expression profiles of 270 miRNAs were determined in the paraneoplastic liver tissues of 12 HCC patients with known postoperative prognosis. A panel of candidate miRNA predictors was identified. The prognostic predictive value of these candidate miRNAs was then verified in 216 postoperative HCC patients. Univariate analysis identified 8 and 3 miRNA predictors for recurrence-free (RFS) and overall (OS) survivals, respectively. Multivariate analysis revealed high expression levels of miR-155 (HR, 2.002 [1.324-3.027]; P =. 001), miR-15a (HR, 0.478 [0.248-0.920]; P =. 027), miR-432 (HR, 1.816 [1.203-2.740]; P =. 015), miR-486-3p (HR, 0.543 [0.330-0.893]; P =. 016), miR-15b (HR, 1.074 [1.002-1.152]; P =. 043) and miR-30b (HR, 1.102 [1.025-1.185]; P =. 009) were significantly associated with RFS. When clinicopathological predictors were included, multivariate analysis revealed that tumor number and miR-432, miR-486-3p, and miR-30b expression levels remained significant as independent predictors for RFS. Additionally, expression knockdown of miR-155 in J7 and Mahlavu hepatoma cells resulted in decreased cell growth and enhanced cell death in xenograft tumors, suggesting an oncogenic effect of miR-155. In conclusion, significant prognostic miRNA predictors were identified through examination of miRNA expression levels in paraneoplastic liver tissues. Functional analysis of a miRNA predictor, miR-155, suggested that the prognostic miRNA predictors identified under this strategy could serve as potential molecular targets for anticancer therapy. © 2012 Huang et al.


Wu-Chou Y.-H.,Chang Gung University | Yeh T.-H.,Chang Gung University | Wang C.-Y.,Chang Gung Children Hospital | Lin J.-J.,Chushang Show Chwan Hospital | And 7 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2010

Large deletions in the GCH1 gene have been reported in a minority of cases of dopa-responsive dystonia (DRD). In this study, we performed an extensive clinical and genetic investigation of 22 affected members in eight families. Sequence analysis revealed five different mutations in five families (n = 10); Ser81-Pro (novel), Ser76X, Gly203Arg, 249del A, and IVS5 + 3insT. Applying multiple ligation-dependent probe amplification analysis, we detected a large heterozygous deletion of exons 1-3 in the remaining three families (n = 12), which was verified by quantitative real-timePCRanalysis. Therefore, the large deletion accounted for 37.5% of the total families and 55% of our DRD population. The deletion appeared to have high penetrance and was associated with multifocal dystonia and adult onset in males. Adult-onset patients were commonly presenting with resting tremor, rigidity, and bradykinesia, indistinguishable fromthose in Parkinson's disease. In conclusion, a high frequency of multi-exonic deletion of GCH1 was identified in the Taiwanese DRD population. By dosage analysis, we were able to detect a mutation in all patients. Our study demonstrates that dosage analysis is necessary for molecular diagnostics in DRD patients of Han Chinese ethnicity. © 2010 Wiley-Liss, Inc.

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