Hepatitis: Yang Y

Liu PY, Yang Y, Shi ZY. · Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · Jpn J Infect Dis. · Pubmed #19168962 links to  free full text

Abstract: Cryptococcus neoformans usually involves the central nervous system and the respiratory tract. We report a case of disseminated cryptococcosis with a liver abscess and meningoencephalitis in a patient with myelodysplastic syndrome. Computed tomography of the abdomen showed a 3-cm low-attenuated lesion in the left lobe of liver. Cultures from specimens of blood, the liver abscess, and the cerebrospinal fluid all yielded C. neoformans. The cryptococcal antigen titers for the serum and cerebral fluid were both 1:32. The patient was successfully treated with 1,335 mg of amphotericin-B followed by fluconazole. Most cryptococcal liver infections present as hepatitis, cholangitis, or microabscesses.

Blomme EA, Yang Y, Waring JF. · Department of Cellular, Molecular and Exploratory Toxicology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA. · Toxicol Lett. · Pubmed #18996174 No free full text.

Abstract: Hepatotoxicity is a common cause of failure in drug discovery and development and is also frequently the source of adverse drug reactions. Therefore, a better prediction, characterization and understanding of drug-induced hepatotoxicity could result in safer drugs and a more efficient drug discovery and development process. Among the 'omics technologies, toxicogenomics (or the use of gene expression profiling in toxicology) represents an attractive approach to predict toxicity and to gain a mechanistic understanding of toxic changes. In this review, we illustrate, using selected examples, how toxicogenomics can be applied to investigate drug-induced hepatotoxicity in animal models and in vitro systems. In general, this technology can not only improve the discipline of toxicology and risk assessment but also represent an extremely effective, hypothesis-generating alternative to rapidly understand mechanisms of hepatotoxicity.

Clifford DB, Yang Y, Evans S. · Washington University School of Medicine, St.Louis, MI 63110, USA. · J Neurovirol. · Pubmed #16540458 No free full text.

Abstract: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share overlapping, large worldwide distribution. The implications of coinfection are being explored because of the importance of these viruses and demographic factors that favor coinfection. The nervous system is affected by HIV in a variety of ways resulting in significant disease of all levels of the nervous system. Emerging evidence that HCV can also impact the nervous system raises concerns that detrimental interactions might occur. Several reports addressing the manifestations of coinfection support independent contributions for both HIV and HCV on central nervous system performance, but not on distal sensory neuropathy. Neuropsychological testing reveals independent contributions resulting in poorer performance in coinfection in several drug-abusing cohorts. Motor physiologic testing substantiates performance deficits from HCV in coinfected subjects as does testing in treatment naive coinfected subjects. Although ongoing deficits attributed to HCV may be seen during HIV treatment, these deficits may be less apparent in advanced HIV disease. Current evidence supports independent contributions of HCV and HIV to neurological impairment. Preliminary evidence suggests that coinfection-related impairment does not appear to accelerate HIV-1-associated cognitive disease.

Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, Li MX, Lu YB, Ushikai M, Tabata A, Moriyama M, Hsiao KJ, Yang Y. · Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. · Mol Genet Metab. · Pubmed #15050970 No free full text.

Abstract: Citrin is a mitochondrial aspartate glutamate carrier primarily expressed in the liver, heart, and kidney. We found that adult-onset type II citrullinemia is caused by mutations in the SLC25A13 gene that encodes for citrin. In this report, we describe the frequency of SLC25A13 mutations, the roles of citrin as a member of the urea cycle and as a member of the malate-aspartate shuttle, the relationship between its functions and symptoms of citrin deficiency, and therapeutic issues.

He Q, Chen SC, Wang S, Jiang XL, Xu C, Zhang B, Li LX, Tang H, Yang Y, Wang WY, Zhao LS. · East Lake Hospital of Shenzhen, Shenzhen 518020, China. · Zhonghua Gan Zang Bing Za Zhi. · Pubmed #12716519 No free full text.

Abstract: OBJECTIVE: To summarize the clinical changing characters of the clinical markers after interferon treatment in chronic hepatitis B (CHB) and make out practical indexes to predict the effect. METHODS: 150 CHB patients were randomly divided into two groups: therapeutic group (90) and control group (60) in the prospective controlled trial. The levels of endogenous interferon before treatment, interferon antibody at the end of the second month and fourth month after treatment, alanine aminotransferase (ALT) and HBV DNA in the serum were detected. Then the data was analysed to find out indexes for predicting the effect. RESULTS: (1) The clearance rate of HBeAg had no significant difference in age except for 20 - 30 and 30 - 40 (t > 2.331 2, P < 0.01). (2) It was more effective if ALT level was higher than 400 U/L before treatment and it decreased more than 50% two months after treatment. (3) The patients whose HBV DNA was negative (dot hybridization) or less than 10(6) copies/ml before treatment had higher rate of HBeAg clearance. (4) There was no effect on patients whose interferon antibody turned positive at the end of the second month. (5)A predictive method of comprehensive factors was made out, whose sensitivity, specificity, and accuracy were 80%, 100% and 90%, respectively. CONCLUSION: The clinical characters of these Chinese patients are different from those of the westerners and the effects of interferon have close relation to the levels of ALT, HBV DNA and interferon antibody.

Yang Y, Song B, Wu B, Lei XZ. · Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China. · Zhongguo Yi Xue Ke Xue Yuan Xue Bao. · Pubmed #19507592 No free full text.

Abstract: OBJECTIVE: To investigate the diagnostic value of magnetic resonance diffusion-weighted imaging (DWI) technique in assessing the disease activity and liver fibrosis of chronic viral hepatitis. METHODS: A total of 49 patients with chronic viral hepatitis who received liver biopsy and 10 healthy volunteers were included in this study. All of them underwent DWI on a 3.0 T magnetic resonance imaging system. When the gradient factor b value was set at 100, 200, 400, 600, and 800 s/mm2, the apparent diffusion coefficient (ADC) of the liver was measured respectively. Biopsy specimens were scored for necroinflammation and liver fibrosis according to the Knodell histological activity index. RESULTS: The ADC values of the right lobe in both controls and patients were lower than those of the left lobe. When the b value was set at 400, 600, and 800 s/mm2, the differences of the ADC values between the fibrosis group (n = 36) and the non-fibrosis group (n = 23, including 10 cases of normal subjects) were statistically significant (P < 0.01). When the b value was set at 800 s/mm2, the ADC values among the different degrees of necroinflammation and grades of liver fibrosis were also significantly different (P < 0.05, P < 0.01). CONCLUSION: DWI is a valuable method for in vivo and noninvasive assessment of the disease activity and liver fibrosis of chronic viral hepatitis.

Jiang N, Li H, Wang GS, Zhang J, Zhang JF, Yi SH, Yang Y, Cai CJ, Lu MQ, Chen GH. · Liver Transplant Center, Third Affiliated Hospital of Sun Yat-sen University, Transplantation Research Institute of Sun Yat-sen University, NO.600 TianHe Road, TianHe District, Guangzhou 510630, Guangdong Province, PR China. · Leuk Res. · Pubmed #19446880 No free full text.

Abstract: Little information is available about the risk factors and means to improve the survival rate of acute leukemia in a rare but often fatal complication after liver transplantation (LT). We report the development of AML-M2 in one of the 764 patients who underwent liver transplantation at our center, and review the literature on similar cases. The patient, a 42-year-old man who developed acute leukemia 38 months after liver transplantation, was successfully treated with chemotherapy and has subsequently been in remission. With appropriate adjustment of immunosuppressive agents, he was able to safely benefit from chemotherapy. Only 16 patients with acute leukemia after liver transplantation have been reported, and the mortality rate is extraordinarily high (52.94%, 9/17). More cases of acute leukemia will emerge as the rate of survival after liver transplantation increases. The patient's chromosomal mutation profile, the choice of immunosuppressive agent, and infection by hepatitis virus may be the risk factors for the development of acute leukemia after LT. Our experience suggests that clinicians should adjust the immunosuppressive agents according to the immunosuppressive state of the patient and explore the option of reducing or stopping the medication as long as liver function remains stable. These measures could help reduce the high mortality rate among these patients.

Campbell RV, Yang Y, Wang T, Rachamallu A, Li Y, Watowich SJ, Weinman SA. · Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA. · Methods Enzymol. · Pubmed #19348899 No free full text.

Abstract: Viral infections frequently alter mitochondrial function with suppression or induction of apoptosis and enhanced generation of reactive oxygen species. The mechanisms of these effects are varied, and mitochondria are affected by both direct interactions with viral proteins and by secondary effects of viral-activated signaling cascades. This chapter describes methods used in our laboratory to assess the effects of the hepatitis C virus core protein on mitochondrial ROS production, electron transport, and Ca(2+) uptake. These include measurements of the effects of in vitro incubation of liver mitochondria with purified core protein and assessment of the function of mitochondria in cells and tissues expressing core and other viral proteins. These methods are generally applicable to the study of viral-mitochondrial interactions.

Qiu S, Zhang J, Tian Y, Yang Y, Huang H, Yang D, Lu M, Xu Y. · Department of Microbiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. · Intervirology. · Pubmed #19258718 No free full text.

Abstract: BACKGROUND: Substitutions at amino acid residue 126 of hepatitis B surface antigen (HBsAg) occur frequently in hepatitis B virus (HBV) isolates from patients with chronic HBV infection. These substitutions occur naturally, but their significance for viral persistence is unclear and requires further investigation. METHODS: We amplified coding regions of HBsAg by PCR using sera from 1 patient chronically infected with HBV. Three representative clones of HBsAg with amino acid residues 126Ile (I), 126Thr (T) and 126Ser (S) were selected from sequenced clones. HBsAg 126Ala (A) mutants of subtype C/adr and D/adw were generated by site-directed mutagenesis. The HBsAg expression vectors were constructed and transiently transfected into HepG2 cells. The binding reactivity of HBsAg to anti-HBs antibodies was tested by chemiluminescent microparticle immunoassay and by immunofluorescence staining with polyclonal and monoclonal anti-HBs antibodies. RESULTS: Diverse HBsAg variants with substitutions at amino acid residue 126 co-existed in a chronically infected HBV patient. HBsAg with the substitution 126S showed a significantly low antigenicity, while the binding reactivity to anti-HBs of other HBsAg with 126I, 126T and 126A were comparable. CONCLUSION: HBsAg with the 126S substitution has a reduced antigenicity, which may contribute to immune escape in chronic HBV infection.

Hang JQ, Yang Y, Harris SF, Leveque V, Whittington HJ, Rajyaguru S, Ao-Ieong G, McCown MF, Wong A, Giannetti AM, Le Pogam S, Talamás F, Cammack N, Nájera I, Klumpp K. · Roche Palo Alto LLC, Palo Alto, California 94304, USA. · J Biol Chem. · Pubmed #19246450 No free full text.

Abstract: The binding affinity of four palm and thumb site representative non-nucleoside inhibitors (NNIs) of HCV polymerase NS5B to wild-type and resistant NS5B polymerase proteins was determined, and the influence of RNA binding on NNI binding affinity was investigated. NNIs with high binding affinity potently inhibited HCV RNA polymerase activity and replicon replication. Among the compounds tested, HCV-796 showed slow binding kinetics to NS5B. The binding affinity of HCV-796 to NS5B increased 27-fold over a 3-h incubation period with an equilibrium Kd of 71 +/- 2 nm. Slow binding kinetics of HCV-796 was driven by slow dissociation from NS5B with a k(off) of 4.9 +/- 0.5 x 10(-4) s(-1). NS5B bound a long, 378-nucleotide HCV RNA oligonucleotide with high affinity (Kd = 6.9 +/- 0.3 nm), whereas the binding affinity was significantly lower for a short, 21-nucleotide RNA (Kd = 155.1 +/- 16.2 nm). The formation of the NS5B-HCV RNA complex did not affect the slow binding kinetics profile and only slightly reduced NS5B binding affinity of HCV-796. The magnitude of reduction of NNI binding affinity for the NS5B proteins with various resistance mutations in the palm and thumb binding sites correlated well with resistance -fold shifts in NS5B polymerase activity and replicon assays. Co-crystal structures of NS5B-Con1 and NS5B-BK with HCV-796 revealed a deep hydrophobic binding pocket at the palm region of NS5B. HCV-796 interaction with the induced binding pocket on NS5B is consistent with slow binding kinetics and loss of binding affinity with mutations at amino acid position 316.

Warter L, Cohen L, Benureau Y, Chavez D, Yang Y, Bodola F, Lemon SM, Traboni C, Lanford RE, Martin A. · Institut Pasteur, Unité de Génétique Moléculaire des Virus à ARN, CNRS URA 3015, Université Paris Diderot - Paris 7 EA 302, Paris, France. · PLoS One. · Pubmed #19204793 links to  free full text

Abstract: GB virus B (GBV-B) is closely related to hepatitis C virus (HCV), infects small non-human primates, and is thus a valuable surrogate for studying HCV. Despite significant differences, the 5' nontranslated RNAs (NTRs) of these viruses fold into four similar structured domains (I-IV), with domains II-III-IV comprising the viral internal ribosomal entry site (IRES). We previously reported the in vivo rescue of a chimeric GBV-B (vGB/III(HC)) containing HCV sequence in domain III, an essential segment of the IRES. We show here that three mutations identified within the vGB/III(HC) genome (within the 3'NTR, upstream of the poly(U) tract, and NS5A coding sequence) are necessary and sufficient for production of this chimeric virus following intrahepatic inoculation of synthetic RNA in tamarins, and thus apparently compensate for the presence of HCV sequence in domain III. To assess the mechanism(s) underlying these compensatory mutations, and to determine whether 5'NTR subdomains participating in genome replication do so in a virus-specific fashion, we constructed and evaluated a series of chimeric subgenomic GBV-B replicons in which various 5'NTR subdomains were substituted with their HCV homologs. Domains I and II of the GBV-B 5'NTR could not be replaced with HCV sequence, indicating that they contain essential, virus-specific RNA replication elements. In contrast, domain III could be swapped with minimal loss of genome replication capacity in cell culture. The 3'NTR and NS5A mutations required for rescue of the related chimeric virus in vivo had no effect on replication of the subgenomic GBneoD/III(HC) RNA in vitro. The data suggest that in vivo fitness of the domain III chimeric virus is dependent on a cooperative interaction between the 5'NTR, 3'NTR and NS5A at a step in the viral life cycle subsequent to genome replication, most likely during particle assembly. Such a mechanism may be common to all hepaciviruses.

Yang Y, Zhang J, Zhang YC, Cai CJ, Lu MQ, Xu C, Li H, Wang GS, Yi SH, Zhang JF, Yi HM, Jiang N, Jiang H, Chen GH. · Liver Transplant Center, Third Affiliated Hospital of Sun Yat-sen University, Transplantation Research Institute of Sun Yat-sen University, Guangzhou 510630, China. · Zhonghua Yi Xue Za Zhi. · Pubmed #19159597 No free full text.

Abstract: OBJECTIVE: To evaluate the long-term survival rates of the adults with benign end-stage liver disease (BELD) after liver transplantation (LT) and the causes of death. METHODS: The common causes of late death (after more than 1 year) after LT were retrospectively analyzed in 203 consecutive patients with BELD who underwent LT from Oct. 2003 to May.2006. RESULTS: The 1, 2 and 3-year survival rates were 88.7%, 85.5%, and 81.2% respectively. The 2-year and 3-year survival rates of the patients with HBV-related liver disease were 88.4% and 84.5% respectively, not significantly different from those of patients with non-HBV-related liver disease (75.6% and 64.0% respectively, P = 0.144). 165 recipients survived for more than 1 year and 21 recipients died during the period between 12 and 48 months after LT with a mean of (22.7 +/- 6.6) months. The common causes of late death included related to infectious complications (4.8%, 8/165), biliary tract complications (3.6%, 6/165), HBV re-infection (1.8%, 3/165), chronic rejection (1.2%, 2/165), renal functional lesion (0.6%, 1/165), and hepatic arterial complication (0.6%1/165). CONCLUSION: Satisfactory long-term survival can be achieved in most adult recipients with BELD after LT and the major causes that influence the long-term survival are infectious complications, biliary tract complications, and HBV re-infection. Prevention of these complications, rational use of immunosuppressant, and regular follow-up are essential to improve long-term survival.

Santodomingo-Garzon T, Han J, Le T, Yang Y, Swain MG. · From the Immunology Research Group, University of Calgary, Calgary, Alberta, Canada. · Hepatology. · Pubmed #19140218 No free full text.

Abstract: Natural killer T (NKT) cells and regulatory T cells (Tregs) are both found within the liver and are known to exhibit immune regulatory functions. Hepatic NKT cells are activated early during inflammatory responses and release cytokines, including interferon gamma (IFN-gamma), which we speculated could regulate Treg recruitment to the liver. To examine this, we treated C57BL/6 mice with a specific NKT cell activating ligand alpha galactosyl-C18-ceramide (alphaGal-C18-Cer) and examined the hepatic recruitment of Tregs. We found a time-dependant increase in the hepatic recruitment of Tregs after NKT cell activation, which was absent in NKT cell-deficient mice. Most recruited Tregs expressed interleukin (IL) 10, and to a lesser extent transforming growth factor beta (TGF-beta). Because IFN-gamma induces the production of chemokine (C-X-C motif) ligand 10 (CXCL10), and Tregs can express the cognate receptor for CXCL10 (that is, CXCR3), we considered that CXCL10 might mediate the hepatic recruitment of Tregs after NKT cell activation. Hepatic CXCL10 levels were markedly increased after alphaGal-C18-Cer administration in wild-type but not in NKT cell-deficient mice. Moreover, approximately 50% of Tregs recruited to the liver after alphaGal-C18-Cer administration expressed CXCR3 and CXCR3+ Treg recruitment into the liver was significantly inhibited in IFN-gamma KO mice, and after CXCL10 neutralization. In addition, prevention of CXCR3+ Treg recruitment into the liver enhanced inflammatory effector cell recruitment into the liver after alphaGal-C18-Cer treatment. CONCLUSION: These results show that activated NKT cells can induce the hepatic recruitment of Tregs through a cytokine-to-chemokine pathway, which could be relevant in the development of chemokine blocking or NKT cell activating strategies to treat liver diseases.

Liu J, Li Y, Chen T, Yang Y, Wang K, He Y, Yang Q, Ye F, Jin Y, Qiu T, Lin S, Liu M, Zhao Y. · Department of Infectious Diseases, The First Affiliated Hospital of Xi'an JiaoTong University School of Medicine, 710061, Xi'an, Shaanxi Province, China. · Arch Virol. · Pubmed #18982245 No free full text.

Abstract: Using a nested-PCR genotyping system, we analyzed the viral genotypes in HBV-infected patients from HBV clustering infection families (CIFs), as compared with HBV infected patients without familial infection history. The patients in the CIF group showed significantly increased prevalence of genotype C infection, while genotype B was absent. Additionally, in the genotype C carriers younger than 50 years old, the prevalence of HCC and LC were significantly increased in CIF compared to the control. We found that HBeAg-positive HBV genotype C carriers are prone to develop end-stage liver diseases earlier than those infected by genotype B.

Yang Y, Yang Y, Zhang J, Yi HM, Lu MQ, Cai CJ, Li X, Jiang N, Xu C, Li H, Wang GS, Yi SH, Zhang JF, Jiang H, Yang Q, Chen GH. · Liver Transplantation Center, Third Affiliated Hospital/Institute of Organ Transplantation, Sun Yat-sen University, Guangzhou 510630, China. · Nan Fang Yi Ke Da Xue Xue Bao. · Pubmed #18971179 links to  free full text

Abstract: OBJECTIVE: To evaluate the prophylactic efficacy of adefovir dipivoxil (ADV) for post-transplant recurrence of hepatitis B virus (HBV) with lamivudine-resistant YMDD mutation in liver recipients. METHODS: From March 2004 to May 2006, 20 patients with chronic hepatitis B associated with YMDD mutant HBV prior to liver transplantation received treatment with ADV and additional intramuscular hepatitis B immunoglobulin (HBIG) for prevention of post-transplant graft reinfection. The liver function, serum HBsAg, anti-HBs (HBIG), HBeAg, anti-HBc, anti-HBe, HBV DNA and creatinine were examined in all the patients before and after the transplantation. RESULTS: The median follow-up duration of these patients after the transplantation was 33.5 months. Nineteen patients survived and one patient died of recurrent hepatocellular carcinoma. There was significant difference in YMDD mutation rate between the patients with HBV-DNA over 10(6) copies/ml and those with HBV-DNA less than 10(6) copies/ml (12.4% vs 2.5%, P < 0.05). HBV-DNA was undetectable at 4 weeks after the transplantation in 95.0% of the patients (19/20) and at 6 months in one case. No recurrence of hepatitis B was detected by long-term regular testing of HBsAg, HBeAg and HBV-DNA. Serum creatinine increased in 1 case 1 year after the use of ADV. CONCLUSION: ADV offers protection against recurrence of HBV with YMDD mutation after liver transplantation with only mild nephrotoxicity, but renal function monitoring during the use of ADV is still necessary.

Yang Y, Yang Y, Zhang J, Yi HM, Lu MQ, Cai CJ, Li X, Jiang N, Xu C, Li H, Wang GS, Yi SH, Zhang JF, Jiang H, Yang Q, Chen GH. · Liver Transplantation Center, Third Affiliated Hospital/Institute of Organ Transplantation, Sun Yat-sen University, Guangzhou 510630, China. · Nan Fang Yi Ke Da Xue Xue Bao. · Pubmed #18971179 links to  free full text

Abstract: OBJECTIVE: To evaluate the prophylactic efficacy of adefovir dipivoxil (ADV) for post-transplant recurrence of hepatitis B virus (HBV) with lamivudine-resistant YMDD mutation in liver recipients. METHODS: From March 2004 to May 2006, 20 patients with chronic hepatitis B associated with YMDD mutant HBV prior to liver transplantation received treatment with ADV and additional intramuscular hepatitis B immunoglobulin (HBIG) for prevention of post-transplant graft reinfection. The liver function, serum HBsAg, anti-HBs (HBIG), HBeAg, anti-HBc, anti-HBe, HBV DNA and creatinine were examined in all the patients before and after the transplantation. RESULTS: The median follow-up duration of these patients after the transplantation was 33.5 months. Nineteen patients survived and one patient died of recurrent hepatocellular carcinoma. There was significant difference in YMDD mutation rate between the patients with HBV-DNA over 10(6) copies/ml and those with HBV-DNA less than 10(6) copies/ml (12.4% vs 2.5%, P < 0.05). HBV-DNA was undetectable at 4 weeks after the transplantation in 95.0% of the patients (19/20) and at 6 months in one case. No recurrence of hepatitis B was detected by long-term regular testing of HBsAg, HBeAg and HBV-DNA. Serum creatinine increased in 1 case 1 year after the use of ADV. CONCLUSION: ADV offers protection against recurrence of HBV with YMDD mutation after liver transplantation with only mild nephrotoxicity, but renal function monitoring during the use of ADV is still necessary.

Wu C, Wang Z, Liu L, Zhao P, Wang W, Yao D, Shi B, Lu J, Liao P, Yang Y, Zhu L. · Department of Gastroenterology, Changzheng Hospital, Shanghai 200003, China. · J Gastroenterol Hepatol. · Pubmed #18823443 No free full text.

Abstract: BACKGROUND AND AIM: To screen for serum biomarkers of HBV-related hepatocellular carcinoma (HCC) and HBV-related liver cirrhosis (LC) in an attempt to seek a new method for differential diagnosis of HCC and LC using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) techniques. METHODS: Using SELDI-TOF-MS, serum proteins/peptide profiles on the immobilized metal ion affinity capture (IMAC) protein chips were obtained from 29 HCC patients and 30 LC patients. Discriminant analysis was carried out to establish new diagnostic methods using protein/peptide peaks with or without alpha-fetoprotein (AFP). RESULTS: Forty-five protein/peptide peaks changed much more in the HCC group than they did in the LC group. Discriminant analysis using the Wilcoxon rank-sum test showed high sensitivity and specificity in distinguishing HCC from LC. The most significantly differentiating peak, 3892, offered 69.0% sensitivity, 83.3% specificity and 80% positive predictive value in distinguishing HCC and LC. Interestingly, six HCC patients with negative serum AFP were confirmed by peak 3892. The combination of multi-protein peaks (m/z = 9297, 29 941) with AFP offered an 82.8% sensitivity, 93.3% specificity and 92.3% positive predictive value, which was much better than AFP alone (P = 0.013). CONCLUSIONS: Special proteins/peptides of serum may differentiate HBV-related HCC and HBV-related LC, indicating that SELDI-TOF-MS may be useful to distinguish HCC from LC with the proper discriminant analytical method. SELDI peak 3892 may be a complementary diagnostic marker to positive AFP for HCC and a potential marker for the diagnosis of AFP-negative HCC as well.

Miao X, Liu G, Xu X, Xie C, Sun F, Yang Y, Zhang T, Hua S, Fan W, Li Q, Huang S, Wang Q, Liu G, Zhong D. · Department of Surgery, Xiangya 2nd Hospital, Central South University, Renmin Zhong Road 139, Changsha City, Hunan Province, China. · Cancer Genet Cytogenet. · Pubmed #18786439 No free full text.

Abstract: The vanilloid receptor-1 (VR1) is a ligand-gated, nonselective cation channel expressed predominantly by sensory neurons, but is also involved in carcinogenesis. To elucidate its role in hepatocarcinogenesis, we analyzed the expression of VR1 receptor in tumor and nontumor tissues from human hepatocellular carcinoma (HCC) samples. In situ hybridization analysis showed overexpression of VR1 mRNAs in 9/15 (60.0%) noncancer and 6/15 (40.0%) HCC samples. Immunohistochemistry of 62 HCC samples showed the expression of VR1 increased from normal liver or chronic hepatitis to cirrhosis. Marked expression of VR1 was noted in the majority [31/38 (81.6%)] of cirrhotic liver samples. In HCC, high expression of VR1 was observed in 30/62 (48.4%) cases. Clinicopathologic evaluation indicated a significant correlation between VR1 expression and histopathologic differentiation (P=0.001). Univariate analysis indicated that disease-free survival was significantly better in HCC patients with high versus those with low VR1 expression levels (P= 0.021). Our results indicate that VR1 has anti-HCC progression effects and can be potentially used as a prognostic indicator of HCC. The results suggest the potential beneficiary effects of VR1 expression on the prognosis of patients with HCC.

Yang Y, Yi M, Evans DJ, Simmonds P, Lemon SM. · Center for Hepatitis Research, 4.104 Blocker Medical Research Bldg., University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1073, USA. · J Virol. · Pubmed #18684812 links to  free full text

Abstract: Internally located, cis-acting RNA replication elements (cre) have been identified within the genomes of viruses representing each of the major picornavirus genera (Enterovirus, Rhinovirus, Aphthovirus, and Cardiovirus) except Hepatovirus. Previous efforts to identify a stem-loop structure with cre function in hepatitis A virus (HAV), the type species of this genus, by phylogenetic analyses or thermodynamic predictions have not succeeded. However, a region of markedly suppressed synonymous codon variability was identified in alignments of HAV sequences near the 5' end of the 3D(pol)-coding sequence of HAV, consistent with noncoding constraints imposed by an underlying RNA secondary structure. Subsequent MFOLD predictions identified a 110-nucleotide (nt) complex stem-loop in this region with a typical AAACA/G cre motif in its top loop. A potentially homologous RNA structure was identified in this region of the avian encephalitis virus genome, despite little nucleotide sequence relatedness between it and HAV. Mutations that disrupted secondary RNA structure or the AAACA/G motif, without altering the amino acid sequence of 3D(pol), ablated replication of a subgenomic HAV replicon in transfected human hepatoma cells. Replication competence could be rescued by reinsertion of the native 110-nt stem-loop structure (but not an abbreviated 45-nt stem-loop) upstream of the HAV coding sequence in the replicon. These results suggest that this stem-loop is functionally similar to cre elements of other picornaviruses and likely involved in templating VPg uridylylation as in other picornaviruses, despite its significantly larger size and lower free folding energy.

Zou Z, Li B, Xu D, Zhang Z, Zhao JM, Zhou G, Sun Y, Huang L, Fu J, Yang Y, Jin L, Zhang W, Zhao J, Sun Y, Xin S, Wang FS. · Department of Severe Liver Diseases, Beijing 302 Hospital, Beijing Institute of Infectious Diseases, Beijing, China. · J Clin Gastroenterol. · Pubmed #18633332 No free full text.

Abstract: GOALS: This study attempts to determine expressions of intrahepatic proinflammatory and anti-inflammatory cytokines and their secreting immunocytes to evaluate their roles in the pathogenesis of acute-on-chronic liver failure (ACLF) in chronically hepatitis B virus (HBV)-infected patients. BACKGROUND: ACLF generally affects patients with established, compensated chronic liver diseases who develop an acute deterioration in liver function. In China, HBV-associated ACLF patients account for more than 80% of ACLF patients owing to a high prevalence of chronic HBV infection. Clinical observation showed that the deterioration of this disease may correlate with host immune responses, but related underlying mechanism remains largely unknown. STUDY: In situ expressions of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and their secreting CD4, CD8 T cells, and Kupffer cells (KCs) were analyzed in the livers of patients with ACLF, chronic hepatitis B (CHB), and normal controls (NC) using immunohistochemistry. RESULTS: Intrahepatic proinflammatory IFN-gamma and TNF-alpha expressions were markedly up-regulated in ACLF compared with CHB and NC. However, similar anti-inflammatory IL-10 expressions were observed in ACLF and CHB. IFN-gamma overexpression correlated significantly with increased CD4 and CD8 T-cell accumulation. TNF-alpha up-regulation also correlated significantly with increased KCs. CONCLUSIONS: The imbalanced expression of proinflammatory and anti-inflammatory cytokines and increased accumulation of CD4, CD8 T cells, and KCs may contribute to immunopathogenesis in HBV-infected ACLF.

Chen GH, Fu BS, Cai CJ, Lu MQ, Yang Y, Yi SH, Xu C, Li H, Wang GS, Zhang T. · Liver Transplantation Center, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China. · Transplant Proc. · Pubmed #18589134 No free full text.

Abstract: With the accumulation of orthotopic liver transplantation (OLT) recipients, an increased number of patients with graft failure need retransplantation (re-OLT). This study was undertaken to examine our clinical experience of re-OLT for patients with poor graft function after primary transplantation at a single center. We analyzed retrospectively, the clinical data of 32 re-OLTs in 31 patients at our center from January 2004 to February 2007, including indications and causes of death, timing of retransplantation, and surgical techniques. The indications included bile leak (2 cases), biliary stricture (16 cases), recurrence of hepatocellular carcinoma (HCC) (5 cases), hepatic artery stenosis (4 cases), hepatic artery thrombosis (HAT) (2 cases), and hepatitis B recurrence (3 cases). The rate of re-OLT was 4.29%. All patients underwent modified piggyback liver transplantations with cadaveric allografts. No intraoperative mortality and acute rejection occurred. Overall, 17 of 31 patients (54.8%) died after re-OLT with survival times ranging from 2 weeks to 28 months. Another 14 patients were cured with survival times of 4 to 32 months. The perioperative mortality rate of patients who underwent re-OLT between 8 and 30 days after their initial transplantation was highest (66.7%). The most common cause of death after re-OLT was sepsis (47.1%), multiple-organ failure (17.6%), and recurrence of HCC (17.6%), whereas the majority of deaths posttransplantation were sepsis-related (54%) within 1 year. Re-OLT is the only therapeutic option for a failing liver graft. Proper indications and optimal operative time, advanced surgical procedures, reasonable individual immunosuppression regimens, and effective perioperative anti-infection treatments contribute to the improved survival of patients after re-OLT.

Yang Y, Wu Y, Zhang WL, Yu B, Huang AL. · Institute for Viral Hepatitis, Key Laboratory of Molecular Biology of Infectious Diseases of the Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China. · Zhonghua Gan Zang Bing Za Zhi. · Pubmed #18171521 No free full text.

Abstract: OBJECTIVE: To learn the effect of hepatitis B virus (HBV) sequence nt250-453 on the HBV X promoter. METHODS: A plasmid pNRE-XP which contains the NRE and the HBV X promoter was constructed to co-transfect HepG2 cell line with plasmid RL-TK. The firefly luciferase activity and mRNA expression of the firefly luciferase gene were both detected. Then, nt250-453 of HBV was removed from LJ196, which contained HBV full genes. The mutated plasmid LJ196 and plasmid LJ96 which provided core protein and the viral DNA polymerase were used to co-transfect HepG2 cell line. Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the X gene mRNA level. RESULTS: The activity of firefly luciferase and the expression of firefly luciferase gene mRNA were both down-regulated in the presence of the NRE, while the HBV X gene mRNA expression increased as it was removed from the HBV genes. CONCLUSION: This study demonstrates that nt250-453 of HBV acts as a novel negative regulatory element which could suppress the HBV X promoter activity.

Yang F, Yan S, He Y, Wang F, Song S, Guo Y, Zhou Q, Wang Y, Lin Z, Yang Y, Zhang W, Sun S. · Department of Medical Genetics, Second Military Medical University, Shanghai, PR China. · J Hepatol. · Pubmed #18037187 No free full text.

Abstract: BACKGROUND/AIMS: Hepatitis B virus transgenic mice (HBV-Tg mice) have been widely used as animal models in the study of pathogenesis and control of hepatitis B. It is important for the evaluation of such animal models to define the physiological differences between HBV-Tg and wild-type mice. The aim of this research was to investigate whether the integrated system biology approach that combines proteomics and metabonomics describes the physiological changes and provides new insights into the pathogenesis of the early stages of HBV infection. METHODS: In this study the protein and metabolite profiles of the liver were established based on two-dimensional electrophoresis and HPLC/MS analysis. RESULTS: Several protein molecules, whose expression was altered in HBV-Tg mouse liver, were identified including protective enzymes against oxidative stress and regulatory proteins related to lipid metabolism. Metabonomics confirmed the potential derangement of lipid metabolism by discovering the intermediate and the final products of lipid metabolism that were markedly changed in transgenic mice. CONCLUSIONS: This study demonstrated that HBV antigens could impair host cell lipid metabolism and induce modest oxidative stress in vivo.

Yang Y, Huang H, Zhang Z, Wang B, Tian Y, Lu M, Yang D. · Center of Experimental Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · J Huazhong Univ Sci Technolog Med Sci. · Pubmed #17828498 No free full text.

Abstract: The objective of this study is to express the carbohydrate recognition domain (CRD) of the asialoglycoprotein receptor (ASGPR) H1 and H2 subunits of Marmota himalayan in vitro, and develop polyclonal antibodies against the recombinant proteins. RT-PCR was used to amplify ASGPR CRDH1 and CRDH2 from the liver tissue of Marmota himalayan. The products of amplification were subcloned into prokaryotic expression vector pRSET-B, and expressed in E.coli BL21(DE3)plysS. The recombinant proteins were purified using Ni-NTA spin column. The purified proteins were inoculated into BALB/c mice to develop polyclonal antibodies. The sensitivity and specificity of antibodies were evaluated by enzyme-linked immunosorbent assay (ELISA), Western blotting and immunohistochemical staining (IHC). The polyclonal antibodies showed high sensitivity and specificity against both denaturated and native ASGPR proteins. We successfully amplified and expressed the ASGPR CRDs of Marmota himalayan. The nucleic sequences of ASGPR CRDH1 and CRDH2 of Marmota himalayan have been submitted to Genbank and the sequence ID are DQ 845465 and DQ845466, respectively. The proteins and antibodies prepared can be used for targeting gene therapy in a new animal model-Marmota Himalayan-for the research of infectious diseases of hepatitis viruses and liver cancer treatment.

Yang Y, Zhang Q, Cai CJ, Lu MQ, Li X, Jiang N, Jiang H, Xu C, Li H, Wang GS, Yi SH, Zhang J, Zhang JF, Yi HM, Zhang YC, Chen GH. · Liver Transplant Center, Third Affiliated Hospital of Sun Yat-sen University, Transplantation Research Institute of Sun Yat-sen University, Guangzhou 510630, China. · Chin Med J (Engl). · Pubmed #17825167 links to  free full text

Abstract: BACKGROUND: The most frequently used therapy for post-transplantation recurrence of hepatitis B virus (HBV) infection is lamivudine, but this drug is associated with a high resistance rate due to YMDD mutant. In preliminary reports, adefovir dipivoxil (ADV) has been shown to have activity against lamivudine-resistant strains of HBV. However, clinical experience in treatment of HBV infection after liver transplantation (LT) is still not entirely clear. This study was aimed to evaluate the prophylactic efficacy of ADV plus hepatitis B immunoglobulin (HBIG) in patients with YMDD mutant before LT. METHODS: From March 2004 to March 2006, 16 patients with chronic hepatitis B had lamivudine-resistant YMDD mutants detected prior to liver transplantation and received treatment with ADV plus additional intramuscular HBIG after LT as prophylaxis against graft reinfection. Tests for liver function, serum HBsAg, anti-HBs (HBIG), HBeAg, anti-HBc, anti-HBe, HBV-DNA, and creatinine were assessed pre- or post-liver transplantation. RESULTS: The median follow-up of these patients post-liver transplantation was 19.4 months. Fifteen patients survived and one patient died of recurrence of hepatocellular carcinoma (HCC). There was significant difference (10.98% vs. 2.26%, P < 0.05) in YMDD mutant rate between the patients with HBV-DNA over 10(6) copies/ml and those with HBV-DNA less than 10(6) copies/ml. Fifteen patients (93.8%) had undetectable HBV-DNA at 4 weeks and 1 (6.3%) at 6 months after LT. No hepatitis B recurrence was detected by persistent testing of HBsAg, HBeAg, and HBV-DNA and no increase of serum creatinine level associated with ADV was observed in any of the patients. CONCLUSION: ADV combined with intramuscular HBIG can effectively prevent patients with pre-transplantation YMDD mutant from HBV recurrence after LT.