Hepatitis: Chen Z

Chen Z. · Institute of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China. · Zhejiang Da Xue Xue Bao Yi Xue Ban. · Pubmed #15812879 No free full text.

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Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. · National Taiwan University Hospital, Taipei, Taiwan. · Lancet Oncol. · Pubmed #19095497 No free full text.

Abstract: BACKGROUND: Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. METHODS: Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. FINDINGS: 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. INTERPRETATION: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Langevin AM, Bernstein M, Kuhn JG, Blaney SM, Ivy P, Sun J, Chen Z, Adamson PC, Anonymous00055. · University of Texas Health Science Center, San Antonio, Texas, USA. · Pediatr Blood Cancer. · Pubmed #17610262 No free full text.

Abstract: BACKGROUND: Rebeccamycin Analogue (NSC #655649), a chemically synthesized glycosyl-dichloro-indolocarbazole derivative of rebeccamycin with topoisomerase inhibiting activity, has in vitro activity against pediatric tumor cell lines and tumor specimens including rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma and medulloblastoma. PROCEDURE: The primary objective of this trial was to determine the response rate to Rebeccamycin analogue NSC #655649 in children with refractory solid and CNS tumors. Secondary objectives included further evaluation of the toxicity and pharmacokinetic profile of Rebeccamycin analogue in children with relapsed and refractory cancer. A two-stage design was used for this Phase II trial. Rebeccamycin analogue, 650 mg/m(2), was administered every 21 days, and could be escalated to 780 mg/m(2) in subsequent cycles to achieve a maximum plasma drug concentration >5 microg/ml. RESULTS: From July 2000 to October 2004, 72 male and 61 female eligible patients were enrolled. Of 126 evaluable patients for response, only 4 patients had an objective response: 3 patients with rhabdomyosarcoma (1 CR and 2 PR) and 1 patient with neuroblastoma (1 PR). Grade 3 or 4 myelosuppression occurred in 81% (215/265) of patient courses and hepatotoxicity in 14% (37/265) of patient courses. Transient pancreatitis and/or elevation of amylase and lipase occurred in 6 patients. CONCLUSIONS: The 15% response rate to Rebeccamycin analogue observed in patients with rhabdomyosarcoma, while of interest, is associated with significant myelosuppression. With a global response rate of 3% observed in children with relapsed CNS and non-CNS solid tumors, further development of Rebeccamycin analogue in pediatric solid tumors is not recommended.

Zhang P, Chen Z, Chen F, Li MW, Fan J, Zhou HM, Liu JH, Huang Z. · Institute of Infectious Diseases, the First Affiliated Hospital, College of Medical Science, Zhejiang University, Hangzhou 310003, China. · Chin Med J (Engl). · Pubmed #14733779 links to  free full text

Abstract: BACKGROUND: It has been known that intra-cellular immunity is important for defense against viral infections and this function lies with interferon gamma (INF-gamma). Here we evaluated the role of IFN-gamma system in the pathogenesis of chronic hepatitis C (CHC). METHODS: The levels of interferon gamma receptor alpha (IFNGR alpha) on the peripheral lymphocyte membrane were assayed with flow cytometry. The plasma concentrations of the cytokines IFN-gamma and IL-10 in CHC patients and normal controls were assayed by enzyme-linked-immunosorbent assay (ELISA). The samples were collected randomly from Xinjiang Autonomous Region, Zhejiang and the northern regions of Jiangsu Province in China. RESULTS: The levels of IFNGR alpha in CHC patients were significantly lower than that of normal controls (NC), especially among patients during the stable stage (P < 0.001), whereas there were no significant differences between CHC in active and stable stages. Among the patients of the three regions, there were no significant differences between patients from Xinjiang and Zhejiang provinces, but both had statistically significant difference compared with the patients from Jiangsu Province (P < 0.001). Plasma IFN-gamma and IL-10 concentrations in CHC patients decreased significantly, IFN-gamma in particular, but there were no significant differences in these levels between various stages of the disease. The IFN-gamma/IL-10 (Th1/Th2) ratio in patients was reversed. CONCLUSION: There may be defects in the IFN-gamma system in chronic HCV infected subjects and a low immune response, which may play an important role in the persistence of HCV infection.

Xu H, Zhuang G, Wang X, Chen Q, Chen Z. · Department of Epidemiology, Xi'an Medical University, Xi'an 710061, China. · Zhonghua Yu Fang Yi Xue Za Zhi. · Pubmed #11860915 No free full text.

Abstract: OBJECTIVE: To evaluate the long-term efficacy of hepatitis B vaccine 10 years after primary immunization to provide scientific basis for the time of revaccination. METHODS: The study was strictly designed with randomization, double-blinding, and placebo-controlled method to observe the efficacy and immune memory 11 years following hepatitis B vaccination. RESULTS: Immunogenicity and protective rate of vaccine were still kept well 11 years after immunization with a protective rate against HBV infection of 73.5%. But, there was no significant difference in HBV infection rates between vaccine group and placebo-controlled group (7.89% vs. 13.25%, P > 0.1) nine to 11 years following immunization. There still existed immune memory 11 years after immunization, but it was significantly weaker than that within the first 10 years after immunization. CONCLUSION: The efficacy of the vaccine had begun to drop 11 years after immunization, which should be followed up further to reach a clear conclusion.

Shi S, Cheng L, Fu G, Chen H, Chen Z, Yang W, Su J, Huang Y. · Institute of Animal Husbandry and Veterinary Medicine, Fujian Academy of Agricultural Sciences, Fuzhou 350013, China. · Wei Sheng Wu Xue Bao. · Pubmed #19623953 No free full text.

Abstract: OBJECTIVE: A strain of highly pathogenic duck hepatitis virus was isolated in south China from a Pekin duck flock in 1999. No cross reaction with type 1 and 3 duck hepatitis virus was found by serum neutralization. We suggested the strain should be classified as a new serotype of duck hepatitis virus and named it as DHV-N G strain in our previous study. We wanted to reveal the evolution of this virus in molecular level and gene sequence differences between it and DHV-1 strains. METHODS: We used RT-PCR and 5'-/3'-RACE to amplify the complete genome sequence of DHV-N G strain and compared it with other picornaviruses. RESULTS: The genome of DHV-N G consists of 7774 nucleotides excluding a poly (A) tail of 12 nucleotides. It contains a single large open reading frame encoding a polypeptide of 2251 amino acid residues. The length of 3' UTR of DHV-N G is 366 nucleotides, which is 52 nucleotides longer than that of DHV-1 C80 strain. Significant amino acid variation was found in the protein VP1, especially at the position of 140 - 221 comparing with DHV-1. The DHV-N G genome shares 72.8% - 73.4%, 96.3% - 96.5% and 78.3% similarity with DHV-1 strains, Korea's and Taiwanese DHV-N strains, respectively. CONCLUSION: The genome structure of DHV-N G strain is obviously different with that of DHV-1 strains. The homologies of genome among the DHV-N group are variable, therein DHV-N G strain is more homologous with Korea's strains than with Taiwanese.

Zhang Y, Wen T, Yan L, Chen Z, Yang H, Deng X, Liang G, Li G, Zhang X, Ran S, Liao Z. · Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu, China. · Hepatogastroenterology. · Pubmed #19621712 No free full text.

Abstract: BACKGROUND/AIMS: The results of much research on the variation of the hepatic hemodynamic and functional hepatic reserve after splenectomy with periesophagogastric devascularization are very different, some are even converse. The purpose of this study is to observe the variation. METHODOLOGY: From July 2006 to August 2007, thirty patients with portal hypertension caused by hepatitis B cirrhosis underwent splenectomy with periesophagogastric devascularization in our medical group in West China Hospital of Sichuan University. The PVPG (portal venous pressure gradient) was measured by inductor continually during operation. Moreover, the HAF (hepatic artery flow), PVF (portal venous flow) and hepatic arterial RI (resistant index) were measured with Doppler sonography. The EHBF (effective hepatic blood flow) and ICGR15 (indocyanine green retention rate at 15 minutes) were obtained respectively by indocyanine green clearance test before and after the operation. The MELD (model for end stage liver disease) score was calculated at the same time. RESULTS: The four values of PVPG after laparotomy, ligating the splenic artery, splenectomy and periesophagogastric devascularization showed a tendency to decrease progressively. The PVF decreased and HAF increased in compensation after operation. The EHBF increased, and both the ICGR15 and the MELD score decreased postoperatively. CONCLUSIONS: After splenectomy with periesophagogastric devascularization, the functional hepatic reserve increases at least in the short term notwithstanding the PVPG and PVF decrease.

Jin S, Chen Z, Lunan Y, Zeng Y, Wen T, Li B, Zhao J, Wang W, Xu M, Yang J. · Department of Hepato-Bilio-Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China. · Transplant Proc. · Pubmed #19545780 No free full text.

Abstract: In orthotopic liver transplantation, particular emphasis must be placed on the unique physiologic, pathologic, and clinical features in residents living in areas at high vs low altitude. Hypobaric hypoxia, hypothermia, heavy radiation, high wind speed, and superevaporation at high altitudes may lead to various diseases. These features have progressive effects on cardiopulmonary and central nervous system functions. A high concentration of red cells in the circulation is likely to result in an increased incidence of hepatic artery and portal vein thrombosis. The immune system is also affected at high altitudes. Exposure to high altitude, which is associated with decreased oxygen pressure, can result in oxidation-reduction stress, enhanced generation of reactive oxygen and nitrogen species, and related oxidative damage to lipids, proteins, and DNA. Our male patient with liver cirrhosis caused by chronic hepatitis B virus infectionunderwent orthotopic liver transplantation in Tibet with a successful outcome and good long-term survival.

Zhao J, Yan L, Li B, Zeng Y, Wen T, Zhao J, Wang W, Xu M, Yang J, Ma Y, Chen Z, Wu H, Wei Y. · Liver Transplantation Division, Department of Surgery, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan Province, China. · Transplant Proc. · Pubmed #19545722 No free full text.

Abstract: Most reported data on posttransplantation diabetes mellitus (PTDM) are from Western countries with patients who underwent deceased donor liver transplantation. A retrospective study was performed to assess the prevalence and predictive factors of PTDM in the context of living donor liver transplantation (LDLT) in the Chinese population using the definition of PTDM proposed in 2003 by the World Health Organization and the American Diabetes Association. The prevalence of DM after LDLT in our study was 25% (21/84), and the incidence of PTDM was 14.9% (11/74) with 64% of cases diagnosed within 3 months after LDLT; 9.5% were observed to show impaired fasting glucose postoperatively. Multivariate analysis identified body mass index >or= 25 kg/m(2) before LDLT as the only independent risk factor for developing PTDM. Only one patient was operated for hepatitis C virus (HCV) infection. Hepatitis B virus (HBV)-related diseases were common in our study population, accounting for 78.6% of all patients. Both HCV and HBV infection status were not independent risk factors for developing PTDM. In addition, a greater tacrolimus trough blood level in the PTDM group versus no-DM group was observed at 3 months post-LDLT (11.03 ng/mL vs 4.87 ng/mL). The mean tacrolimus dose was not significantly different between the two groups. In conclusion, PTDM was prevalent among Chinese LDLT recipients.

Chen Z, Zhou H, Li S, He E, Hu J, Zhou J, Skog S. · Healthy Centre of the Third XiangYa Hospital, ZhongNan University, ChangSha, PR China. · Anticancer Res. · Pubmed #19192647 No free full text.

Abstract: BACKGROUND: The role of serum tumour markers is to reveal tumours not yet visible by imaging techniques. Here we examine the use of serum thymidine kinase 1 protein (STK1) in health screening. PATIENTS AND METHODS: Persons (n = 11,880) participating in health screening programs in China, during 2005-2007, were tested for STK1. STK1 was measured by a sensitive chemiluminescence dot-blot assay. Medical examination of participants was carried out in parallel. RESULTS: The proportion of STK1-positive (> 2 pM) individuals was 0.5%, corresponding to the cancer incidence rate of China. No malignant cases were found in the STK1-negative group, but two pre-malignant and one malignant case were found in the STK1-positive group. The low frequency of malignancies found was probably due to the relatively young population (mean age 40.4 +/- 13.4 years). In the STK1-positive group, there were 24% of persons with benign diseases (breast, liver, kidney), 37% with proliferative tissues (breast, prostate), 13% with fatty liver, 9% with inflammatory reactions/virus infections (three hepatitis B virus-positive persons) and 17% showed other types of physiological changes not directly related to proliferation. In the STK1-positive group, a significantly (p < 0.001) higher proportion of persons with proliferation of breast and prostate tissues were found (37%), as compared to the STK1-negative group (18%). Furthermore, the mean ages among the groups of persons with STK1-positive values were between 5-8 years higher, as compared to the STK1 negative group, due to higher mean ages of persons with proliferative breast and prostate tissues. Thus, 83% of the STK1-positive persons had diseases (benign, proliferation tissues, fatty liver, helicobacter pylori-positive and hepatitis B virus-positive) related to malignancies. CONCLUSION: STK1-values > 2 pM may indicate an early risk for development of malignancies years later.

Zhang Y, Wen T, Yan L, Chen Z, Li B, Zeng Y. · Liver Transplantation Division, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan, China. · Transplant Proc. · Pubmed #19100502 No free full text.

Abstract: BACKGROUND: There is debate on the dose schedule and pharmacokinetics of daclizumab in liver transplant recipients. METHODS: A four-dose course of daclizumab was administered to a patient with severe renal dysfunction. Calcineurin inhibitor therapy initiation was delayed to 86 days posttransplantation. RESULTS: The patient is well as 480 days after transplantation. No rejection was observed. CONCLUSIONS: The result suggested the efficacy of our dose schedule, but it will be necessary to confirm it with further pharmacokinetic studies and more cases.

Chen X, Fu S, Chen F, Chen H, Chen Z. · Key Laboratory of Health Ministry, Institute of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China. · Oncol Rep. · Pubmed #18813843 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a major cause of death in Asian countries. The false-negative rate with serum alpha-fetaprotein level alone can reach 40% for early stage HCC patients. Due to the lack of sensitive and specific tumor markers for early diagnosis, it is impossible for HCC patients to receive effective therapy. However, tumor antigens can be recognized by immune cells and be rejected in immune responses. In order to identify antigens which may be used as new markers and immunotherapy targets for HCC, a cDNA expression library derived from an HCC sample was constructed, which was screened with mixed autologous and allogenic serum of HCC patients. Seventeen different HCC antigens were obtained, which are classified as tumor-associated antigens. A panel of allogenic sera from patients with chronic hepatitis, liver cirrhosis, HCC and other tumor entities and sera from health volunteers, was used for frequency analysis of antibody responses. Four of 17 antigens, including eukaryotic translation initiation factor 3, subunit I, lactate dehydrogenase 1, A chain, replication factor C2, 40 kDa and mitochondrial carrier triple repeat 1, reacted predominantly with sera from patients with HCC (31.8, 45.5, 27.3 and 50.0% respectively). Patients (81.8%) with HCC had the antibody against at least one of these four antigens, which indicates that disease-specific humoral response against these antigens was induced in HCC patients and the corresponding antibodies may be used as tumor markers for HCC.

Peng GP, Sun W, Wu W, Sun Z, Tan XF, Li SP, Chen Z. · Institute of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China. · Zhejiang Da Xue Xue Bao Yi Xue Ban. · Pubmed #18705009 No free full text.

Abstract: OBJECTIVE: To determine the PD-L1 expression levels in circulating dendritic cells(DCs) of patients with HBeAg positive chronic hepatitis B, and to investigate the effects of anti-PD-L1 antibody on DCs stimulating capacity of allogeneic lymphocytes. METHODS: DCs were separated and induced from 22 HBeAg positive chronic hepatitis B patients (CHB), 8 acute resolved hepatitis B patients (AHB) and 10 healthy blood donors. PD-L1 and PD-L2 expression in DCs were determined using real-time RT-PCR and flow cytometry. The potential of circulating DCs on the proliferation of allogeneic T cells was detected and a specific monoclonal antibody against PD-L1 was used in alternative experiments. Serum HBV-DNA titers were measured using real-time PCR, and HBV markers and liver function were also evaluated. RESULT: The expression of PD-L1 but not PD-L2 was upregulated in circulating DCs of CHB patients, compared to AHB patients and healthy controls (both P<0.01). CHB patients with greater than 106 copies /ml of serum HBV DNA loads had a higher level of PD-L1 in circulating DCs than those with less than 106 copies/ml (P<0.05), and the high expression of PD-L1 in DCs was positively correlated with the plasma viral load. Moreover, the potential of circulating DCs from CHB patients was significantly decreased compared with healthy controls or AHB patients, while the blockade of PD-L1 using anti-PD-L1 monoclonal antibody increased the ability of DCs on the proliferation of allogeneic T cells in vitro. CONCLUSION: High expression of PD-L1 on circulating DCs may be associated with T cell exhaustion and persistent high levels of HBV DNA replication in chronic hepatitis B patients.

Chen Z, Cheng Y, Xu Y, Liao J, Zhang X, Hu Y, Zhang Q, Wang J, Zhang Z, Shen F, Yuan Z. · Research Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China. · Clin Immunol. · Pubmed #18565796 No free full text.

Abstract: Toll-like receptors (TLRs) play a central role in sensing and initiating innate antiviral response. In this study, we first investigated the expression of TLR1-10 mRNA transcripts in peripheral blood mononuclear cells (PBMCs) from chronic HBV-infected (CHB) patients and healthy donors by quantitative real-time PCR. The expression of TLR1, TLR2, TLR4 and TLR6 transcripts was significantly lower in PBMCs from CHB patients, and the down-regulation of TLR2 was related to HBV genotype C. Flow cytometric analysis showed that the expression of TLR2 on PBMCs was significantly decreased in CHB patients. Furthermore, impaired cytokine production was observed in PBMCs from CHB patients after challenged with TLR2 and TLR4 ligands and was correlated with the levels of plasma hepatitis B virus surface antigen (HBsAg). In conclusion, our study reveals a possible interaction between HBsAg, TLR signaling and the innate immune response, which may partially explain the mechanism of HBV infection induced immuno-tolerance.

Yan XB, Mei L, Feng X, Wan MR, Chen Z, Pavio N, Brechot C. · Department of Infectious Diseases, The First Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China. · World J Gastroenterol. · Pubmed #18473414 links to  free full text

Abstract: AIM: To investigate the influence of different quasispecies of hepatitis C virus (HCV) genotype 1b core protein on growth of Chang liver cells. METHODS: Three eukaryotic expression plasmids (pEGFP-N1/core) that contained different quasispecies truncated core proteins of HCV genotype 1b were constructed. These were derived from tumor (T) and non-tumor (NT) tissues of a patient infected with HCV and C191 (HCV-J6). The core protein expression plasmids were transiently transfected into Chang liver cells. At different times, the cell cycle and apoptosis was assayed by flow cytometry, and cell proliferation was assayed by methyl thiazolyl tetrazolium (MTT) assay. RESULTS: The proportion of S-phase Chang liver cells transfected with pEGFP-N1/core was significantly lower than that of cells transfected with blank plasmid at three different times after transfection (all P < 0.05). The proliferation ratio of cells transfected with pEGFP-N1/core was significantly lower than that of cells transfected with blank plasmid. Among three different quasispecies, T, NT and C191 core expression cells, there was no significant difference in the proportion of S- and G0/G1-phase cells. The percentage of apoptotic cells was highest for T (T > NT > C191), and apoptosis was increased in cells transfected with pEGFP-N1/core as the transfection time increased (72 h > 48 h > 24 h). CONCLUSION: These results suggest that HCV genotype 1b core protein induces apoptosis, and inhibits cell-cycle progression and proliferation of Chang liver cells. Different quasispecies core proteins of HCV genotype 1b might have some differences in the pathogenesis of HCV persistent infection and hepatocellular carcinoma.

Bechill J, Chen Z, Brewer JW, Baker SC. · Department of Microbiology and Immunology, Loyola University Medical Center, 2160 South First Ave., Bldg. 105, Rm. 3929, Maywood, IL 60153, USA. · J Virol. · Pubmed #18305036 links to  free full text

Abstract: During coronavirus replication, viral proteins induce the formation of endoplasmic reticulum (ER)-derived double-membrane vesicles for RNA synthesis, and viral structural proteins assemble virions at the ER-Golgi intermediate compartment. We hypothesized that the association and intense utilization of the ER during viral replication would induce the cellular unfolded protein response (UPR), a signal transduction cascade that acts to modulate translation, membrane biosynthesis, and the levels of ER chaperones. Here, we report that infection by the murine coronavirus mouse hepatitis virus (MHV) triggers the proximal UPR transducers, as revealed by monitoring the IRE1-mediated splicing of XBP-1 mRNA and the cleavage of ATF6alpha. However, we detected minimal downstream induction of UPR target genes, including ERdj4, ER degradation-enhancing alpha-mannosidase-like protein, and p58(IPK), or expression of UPR reporter constructs. Translation initiation factor eIF2alpha is highly phosphorylated during MHV infection, and translation of cellular mRNAs is attenuated. Furthermore, we found that the critical homeostasis regulator GADD34, which recruits protein phosphatase 1 to dephosphorylate eIF2alpha during the recovery phase of the UPR, is not expressed during MHV infection. These results suggest that MHV modifies the UPR by impeding the induction of UPR-responsive genes, thereby favoring a sustained shutdown of the synthesis of host cell proteins while the translation of viral proteins escalates. The role of this modified response and its potential relevance to viral mechanisms for the evasion of innate defense signaling pathways during coronavirus replication are discussed.

Xu N, Yao HP, Sun Z, Chen Z. · Key Laboratory of Health Ministry, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310031, China. · Acta Pharmacol Sin. · Pubmed #18215354 links to  free full text

Abstract: AIM: The aim of the present study was to investigate the expression of Toll-like receptors (TLR) 7 and 9 in peripheral blood mononuclear cells (PBMC) of patients with chronic hepatitis B virus (HBV) infection and related hepatocellular carcinoma. METHODS: The study group was comprised of 52 patients: 41 with chronic hepatitis B and 11 healthy controls. The protein and mRNA levels of TLR7 and TLR9 were evaluated using real-time PCR, Western blot analysis, and flow cytometry. We also detected the serum viral load of HBV in the patients and analyzed the correlation between HBV-DNA copies and the TLR expression. RESULTS: Our results demonstrated a lower TLR7 expression in all HBV infection groups compared to the controls. We found that HBV infection led to a decreased expression of TLR9 mRNA, but an increased expression of the TLR9 protein compared to the healthy group. The TLR protein levels are related to serum HBV-DNA (P<0.01). CONCLUSION: There are downregulations of TLR7 expression and TLR9 mRNA in PBMC of HBV-infected patients, but an increased TLR9 expression at the protein level.

He Q, Cheng R, Chen Z, Xiao X, Xiao Z, Li C, Li B, Zhang P, Zheng H, Feng D. · Department of Pathology, Basic Medical College, Central South University, Changsha 410078, China. · Acta Biochim Biophys Sin (Shanghai). · Pubmed #17928924 links to  free full text

Abstract: Persistent hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma. Non-structural protein 3 (NS3), an important part of HCV, has been implicated in the life cycle of the virus and interacts with host cellular proteins. In this study, we investigated the effect of NS3 protein on cell tranformation and related protein alteration in human hepatocyte QSG7701 cells. The results indicated that stable expression of the NS3 protein in QSG7701 cells induced transformed characters with reduced population doubling time, anchorage-independent growth and tumor development. Fifteen differentially-expressed proteins were separated and identified using 2-D electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Western blot analysis confirmed that the increase of phospho-p44/42 and phospho-p38 proteins was associated with transformed cells. These results supported the view that HCV NS3 protein plays a transforming role and provided some clues to elucidate the carcinogenesis mechanism of HCV-related hepatocellular carcinoma.

Peng G, Li S, Wu W, Tan X, Chen Y, Chen Z. · Key Laboratory of Health Ministry, Institute of Infectious Diseases, First Affiliated Hospital, Medical College, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310003, China. · Mol Immunol. · Pubmed #17868872 No free full text.

Abstract: Programmed death-1 (PD-1) is demonstrated to have an increased expression on antigen-specific T cells during chronic virus infections, and the blockage of PD-1/PD-ligand (PD-L1) pathway could restore the function of exhausted T cells. We measured the PD-1 expression levels on HBV-specific CD8 T cells and investigated the role of PD-1/PD-L1 pathway in T-cell responses of patients with different HBV infection statuses. Compared to the patients with convalescent acute hepatitis B, PD-1 expression on total CD8 T cells from chronic hepatitis B (CHB) patients was significantly upregulated, especially on the HBV pentamer-positive CD8 T cells. And PD-L1, but not PD-L2, was also significantly upregulated on PBMC from CHB patients. In CHB patients, HBV-specific T cells and cellular proliferation could be observed under the recombinant HBV-Ag stimulation in vitro, and blockade of PD-1 pathway significantly enhanced the IFN-gamma production and cellular proliferation of PBMC. Furthermore, PD-1 expression level on HBV-pentamers positive CD8 T cells was positively associated with plasma viral load in CHB patients. Thus, PD-1 upregulation on HBV-specific CD8 T cells is engaged in the dysfunction of T cells and high viraemia in CHB patients, and the antiviral T-cell responses could be improved by the blockade of this inhibitory PD-1/PD-L1 pathway.

Peng G, Li S, Wu W, Sun Z, Chen Y, Chen Z. · Key Laboratory of Health Ministry, Institute of Infectious Diseases, First Affiliated Hospital, Medical College, Zhejiang University, Zhejiang, China. · Immunology. · Pubmed #17764450 links to  free full text

Abstract: Circulating CD4+ CD25+ regulatory T cells (Tregs) have been demonstrated to maintain immunotolerance and suppress the antigen-specific or antigen-non-specific T-cell responses, but their role in chronic hepatitis B (CHB) infection in humans has not been well characterized. In this study, we analysed the frequency and phenotypic characteristics of CD4+ CD25+ Tregs in patients of different hepatitis B virus (HBV) infection status, and investigated the effect of Tregs on antiviral immune responses in CHB patients, and the mechanism of this effect. A total of 137 subjects, including 79 CHB patients, 26 asymptomatic HBV carriers (ASCs), 12 acute hepatitis B (AHB) patients and 20 healthy controls, were enrolled in the study. We found that the frequency of CD4+ CD25(high) Tregs in AHB patients was comparable to that in healthy controls, while it was significantly increased in CHB patients. CD4+ CD25+ Tregs produced interleukin (IL)-10 but little or no interferon (IFN)-gamma under anti-CD3 stimulation. In CHB patients, the frequency of CD4+ CD25(high) Tregs positively correlated with serum viral load, and the Tregs were capable of suppressing the proliferation and IFN-gamma production of autologous peripheral blood mononuclear cells (PBMC) mediated by HBV antigen stimulation in vitro. However, combined administration of anti-programmed death-1 (PD-1) and anti-cytotoxic lymphocyte antigen-4 (CTLA-4) monoclonal antibody slightly enhanced the cellular proliferation and significantly increased the IFN-gamma production of PBMC cocultured with Tregs at a ratio of 2:1. Thus, the frequency of circulating CD4+ CD25+ Tregs is increased in patients with CHB, and this may play an important role in viral persistence by modulating virus-specific immune responses.

Laskus T, Wilkinson J, Karim R, Mack W, Radkowski M, deGiacomo M, Nasseri J, Chen Z, Xu J, Kovacs A. · St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. · Hepatology. · Pubmed #17659581 No free full text.

Abstract: Despite the high frequency of HCV and HIV coinfection, little is known about HCV quasispecies in HIV-positive patients. The current analysis included 236 HIV+/anti-HCV+ women enrolled in the Women's Interagency HIV Study (WIHS). Hypervariable region 1 of the second envelope gene was analyzed by single-strand conformation polymorphism (SSCP). The relationship between the HCV quasispecies and clinical and demographic features were analyzed in multivariate models. Age over 40 years and high HCV RNA load were the only factors significantly associated with quasispecies complexity, assessed as the number of SSCP bands. High HIV and HCV plasma loads were associated with quasispecies stability over time, as reflected by stable SSCP band patterns. However, women who were actively injecting drugs were 3 times more likely to experience quasispecies changes than their noninjecting counterparts. No affect on HCV quasispecies dynamics was noted in relation to CD4 count or highly active antiretroviral therapy (HAART). CONCLUSION: among HIV/HCV coinfected patients, HCV quasispecies complexity and dynamics correlate more closely with HIV and HCV plasma loads than with CD4+ cell counts. Active drug use is associated with quasispecies changes probably due to repeated superinfections with new HCV strains. This needs to be considered when planning treatment and prevention strategies for HCV in coinfected individuals.

Chen Z, Earl P, Americo J, Damon I, Smith SK, Yu F, Sebrell A, Emerson S, Cohen G, Eisenberg RJ, Gorshkova I, Schuck P, Satterfield W, Moss B, Purcell R. · Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, 50 South Drive, MSC 8009, Bethesda, MD 20892, USA. · J Virol. · Pubmed #17581986 links to  free full text

Abstract: Three distinct chimpanzee Fabs against the A33 envelope glycoprotein of vaccinia virus were isolated and converted into complete monoclonal antibodies (MAbs) with human gamma 1 heavy-chain constant regions. The three MAbs (6C, 12C, and 12F) displayed high binding affinities to A33 (K(d) of 0.14 nM to 20 nM) and may recognize the same epitope, which was determined to be conformational and located within amino acid residues 99 to 185 at the C terminus of A33. One or more of the MAbs were shown to reduce the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro and to more effectively protect mice when administered before or 2 days after intranasal challenge with virulent vaccinia virus than a previously isolated mouse anti-A33 MAb (1G10) or vaccinia virus immunoglobulin. The protective efficacy afforded by anti-A33 MAb was comparable to that of a previously isolated chimpanzee/human anti-B5 MAb. The combination of anti-A33 MAb and anti-B5 MAb did not synergize the protective efficacy. These chimpanzee/human anti-A33 MAbs may be useful in the prevention and treatment of vaccinia virus-induced complications of vaccination against smallpox and may also be effective in the immunoprophylaxis and immunotherapy of smallpox and other orthopoxvirus diseases.

Chen Z, Rijnbrand R, Jangra RK, Devaraj SG, Qu L, Ma Y, Lemon SM, Li K. · Department of Microbiology and Immunology and the Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019, USA. · Virology. · Pubmed #17531282 links to  free full text

Abstract: The pathogenesis of bovine viral diarrhea virus (BVDV) infections is complex and only partly understood. It remains controversial whether interferon is produced in cells infected with cytopathic(cp) BVDVs which do not persist in vivo. We show here that a cpBVDV (NADL strain) does not induce interferon responses in cell culture and blocks induction of interferon-stimulated genes by a super-infecting paramyxovirus. cpBVDV infection causes a marked loss of interferon regulatory factor 3 (IRF-3), a cellular transcription factor that controls interferon synthesis. This is attributed to expression of Npro, but not its protease activity. Npro interacts with IRF-3, prior to its activation by virus-induced phosphorylation, resulting in polyubiquitination and subsequent proteasomal degradation of IRF-3. Thermal inactivation of the E1 ubiquitin-activating enzyme prevents Npro-induced IRF-3 loss. These data suggest that inhibition of interferon production is a shared feature of both ncp and cpBVDVs and provide new insights regarding IRF-3 regulation in pestivirus pathogenesis.

Wen T, Chen Z, Yan L, Li B, Zeng Y, Wu G, Zheng G. · General Surgery Department, West China Hospital, West China Medical School of Sichuan University, Chengdu, Sichuan Province, China. · Hepatol Res. · Pubmed #17441807 No free full text.

Abstract: Aim: To evaluate the safety of remnant liver in cirrhotic patients who had undergone irregular hepatectomy with continuous normothermic hemihepatic vascular inflow occlusion for over 60 min. Methods: A group of 133 cirrhotic patients who had hepatitis B virus accompanied by hepatocellular carcinoma and had undergone irregular hepatectomy by hemihepatic vascular inflow occlusion was studied. According to the time of hemihepatic vascular inflow occlusion, patients were assigned either to the control group, treatment(60) group, or treatment(90) group. The quantity of blood loss and blood transfusion, routine liver biochemistry and postoperative complications were retrospectively analyzed. Results: The data showed that there were no significant differences in postoperative complications between the three groups. Compared to the preoperative day, the levels of aspartate transaminase (AST), alanine transaminase (ALT), prothrombin time (PT) and serum bilirubin on postoperative days 1 and 3 were significantly increased in all three groups and the levels of albumin and platelet were significantly decreased on postoperative day 1. Duration of hospital stay and the levels of ALT and AST on postoperative days 1, 3 and 7 were higher in the treatment(90) group than in the control group and treatment(60) group (P < 0.05). However, no significant differences were displayed in the length of hospital stay and the levels of AST, ALT, PT, albumin, platelet count and serum bilirubin on postoperative days 1, 3 and 7 between the control group and the treatment(60) group (P > 0.05). Conclusion: Hemihepatic vascular inflow occlusion over 60 min is a possible method for irregular hepatectomy in patients with cirrhosis caused by the hepatitis B virus. However, caution must be exercised in utilizing this method where the time of vascular occlusion is over 90 min.

Yang Y, Liang Y, Qu L, Chen Z, Yi M, Li K, Lemon SM. · Center for Hepatitis Research, Institute for Human Infections and Immunity, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA. · Proc Natl Acad Sci U S A. · Pubmed #17438296 links to  free full text

Abstract: Mitochondrial antiviral signaling protein (MAVS) is an essential component of virus-activated signaling pathways that induce protective IFN responses. Its localization to the outer mitochondrial membrane suggests an important yet unexplained role for mitochondria in innate immunity. Here, we show that hepatitis A virus (HAV), a hepatotropic picornavirus, ablates type 1 IFN responses by targeting the 3ABC precursor of its 3C(pro) cysteine protease to mitochondria where it colocalizes with and cleaves MAVS, thereby disrupting activation of IRF3 through the MDA5 pathway. The 3ABC cleavage of MAVS requires both the protease activity of 3C(pro) and a transmembrane domain in 3A that directs 3ABC to mitochondria. Lacking this domain, mature 3C(pro) protease is incapable of MAVS proteolysis. HAV thus disrupts host signaling by a mechanism that parallels that of the serine NS3/4A protease of hepatitis C virus, but differs in its use of a stable, catalytically active polyprotein processing intermediate. The unique requirement for mitochondrial localization of 3ABC underscores the importance of mitochondria to host control of virus infections within the liver.