Asymptomatic COVID-19 infection in patients with cancer at a cancer-specialized hospital in Wuhan, China - Preliminary results.

OBJECTIVE: Patients with cancer are usually immunosuppressive and susceptible to COVID-19 infection. Asymptomatic COVID-19 cases are infective and cannot be identified by symptom-based screening. There is an urgent need to control virus spread by asymptomatic carriers at cancer centres. We aim to describe the characteristics, screening methods, and outcomes of cancer patients with asymptomatic COVID-19 infection and to further explore anti-tumour treatment for this population. PATIENTS AND METHODS: We reviewed patients with cancer who were admitted to Hubei Cancer Hospital in Wuhan from February 1, 2020, to April 4, 2020. We collected demographic data, laboratory findings, treatment information, nucleic acid and serum test results, chest computed tomography (CT) information and survival status of cancer patients diagnosed with asymptomatic COVID-19 infection. RESULTS: A total of 16 cancer patients with asymptomatic COVID-19 infection were confirmed. The most common cancer type was breast cancer. The blood cell counts of most patients were in the normal range. Lymphocytes of 100% of asymptomatic carriers were in the normal range. Thirteen (81.3%) patients were positive for virus-specific IgM antibodies, and three (18.8%) were positive by PCR; only one (6.3%) patient showed novel coronavirus pneumonia features on CT. Three (18.3%) patients died, and the cause of death was considered malignancy caused by delaying anti-tumour treatment. CONCLUSIONS: Our study shows that the lymphocytes of 100% of asymptomatic carriers were in the normal range. This result indicates that the host immunity of asymptomatic carriers is not significantly disrupted by COVID-19. Single PCR detection is not sufficient to screen among asymptomatic individuals, and a combination of PCR tests, serological tests and CT is of great importance. Unless the tumour is life-threatening or rapidly progressing, we advise restarting active anti-tumour therapy after PCR tests become negative.

Laparoscopic preperitoneal repair for primary falciform ligament herniation.

Epigastric hernia involving the falciform ligament is exceptionally rare. Most reported cases are incisional hernia secondary to prior abdominal surgery. We report a case of primary falciform ligament herniation into the epigastric region repaired by the laparoscopic preperitoneal approach. In this case, an accompanying vessel along the herniated falciform ligament was identified. This finding provides a basis for the hypothesis of a perforating vessel piercing the linea alba and thereby creating a weak point for hernia protrusion (Moschowitz theory). The patient had an uneventful recovery and was discharged home on the postoperative day two. A laparoscopic preperitoneal approach is feasible for the repair of primary falciform ligament herniation. The magnified endoscopic view enables surgeons to achieve definite repair without missing occult defects.

Complications of percutaneous liver biopsy with Klatskin needles: a 36-year single-centre experience.

BACKGROUND: Liver biopsy is the gold standard in evaluating liver diseases but is susceptible to complications. Safety data on aspiration needle biopsies remain limited. AIM: To evaluate the safety of percutaneous liver biopsy performed with Klatskin needle. METHODS: Clinical and biochemical data were retrospectively retrieved from sequential subjects who underwent liver biopsy with Klatskin needle from 1978 to 2015. Subjects with complications underwent thorough chart reviews for hospital course. RESULTS: Of 3357 biopsies performed, complications occurred in 135 (4%) biopsies with 33 (1%) resulting in major complications. Severe pain occurred in 78 (2.3%) subjects and bleeding occurred in 21 (0.6%) subjects. Biliary injury occurred in 8 (0.2%) biopsies. Three subjects died as a result of massive intraperitoneal bleeding. Compared to viral hepatitis, biopsies performed with certain diagnosis had significantly higher odds of major complications: NRH (OR: 17), DILI (OR: 20), GVHD (OR: 32) and HCC (OR: 34). Subjects with major complications had higher pre-biopsy median AP (153 vs. 78 U/L, P < 0.001), ALT (105 vs. 64 U/L, P < 0.05), AST (62 vs. 47 U/L, P < 0.02), along with marginally lower total bilirubin (1.0 vs. 0.7 mg/dL, P < 0.01) and albumin (3.7 vs. 4.0 g/dL, P < 0.001). By multivariate backward logistic regression, platelets ≤100 K/µL and aPTT >35 were independent risk factors of post-biopsy bleeding. CONCLUSION: Klatskin needle liver biopsies are safe with rare procedural morbidity. Our data suggests certain acutely ill subjects and those with systemic illnesses may be at higher risk of major complications. Clinicians should weigh the risks and benefits of liver biopsy in these patients with other alternative approaches.

miR-494 inhibits invasion and proliferation of gastric cancer by targeting IGF-1R.

OBJECTIVE: The aim of this study was to investigate the target gene of miR-494 and its roles in tumor growth of gastric cancer (GC). PATIENTS AND METHODS: Expression of miR-494 was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in gastric cancer tissues and cell lines. Then, luciferase reporter assay was used to elucidate whether insulin-like growth factor 1 receptor (IGF1R) is a target gene of miR-494. Finally, the roles and mechanism of miR-494 in the regulation of tumor invasion were further investigated. RESULTS: Relative miR-494 level was found to be significantly lower in patients with GC than healthy controls (p < 0.01). Over-expression of miR-494 could inhibit gastric cancer cell proliferation, migration, and invasion in vitro. Furthermore, we demonstrated that miR-494 binds to the 3'-untranslated region (UTR) of IGF1R and inhibits the expression of the IGF1R protein. CONCLUSIONS: Our data showed that miR-494 acted as a tumor suppressor in GC.

Long-term therapy of chronic delta hepatitis with peginterferon alfa.

BACKGROUND: Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response. AIM: To examine the efficacy and safety of long-term peginterferon in achieving a durable response. METHODS: Treatment was initiated with 180 µg/week of peginterferon alfa-2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years. RESULTS: Thirteen patients were treated for a median of 140 weeks (6-260) with an average peginterferon dose of 180 µg/week (90-270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 ± 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05). CONCLUSION: Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection.

Long-term outcome of chronic hepatitis C after sustained virological response to interferon-based therapy.

BACKGROUND: Although the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear. AIM: To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post-SVR. METHODS: The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE). RESULTS: Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5 years post therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12 years post SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (152-27 U/L), AST (87-24 U/L), alkaline phosphatase (78-69 U/L), IgG (1463-1113 mg/dL), platelet count (209 000-239 000/µL) and AST to platelet count ratio index (APRI: 1.31-0.33). TE was performed in 69 patients and was normal (<7.0 kPA) in 60%, moderately elevated (7.1-13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (P < 0.001). CONCLUSIONS: In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma.

Activity and radiation protection studies for the W-Ta target of CSNS.

The Chinese government initiated a conceptual design for the project of China Spallation Neutron Source (CSNS), which consists of an H-linear accelerator, a rapid cycling synchrotron accelerating the beam to 1.6 GeV, a target station converting proton beam into lower energy (<1 eV) neutron beam optimised to instruments for neutron scattering applications. The facility operates at 25-Hz repetition rate with an initial beam power of 100 kW. In the target station, the target-moderator-reflector (TMR) components are exposed to the intensive fluxes of high-energy hadrons and become highly radioactive as a result of long-time irradiation. In this paper, the activity of the TMR components are calculated using the Monte Carlo code system LAHET&MCNP4C&CINDER'90. Comparisons of some results with that simulated by FLUKA code are also performed. Detailed analyses of the radionuclides and their characters in the tantalum clad tungsten target (W-Ta target) are important for the radiation protection of the CSNS target station. The shielding design of the service cell for the decay gamma ray induced from the W-Ta target and its vessel shows that the ambient dose rate decreases exponentially with increasing heavy concrete thickness. And 80 cm thickness of heavy concrete for each side of the service cell can satisfy the safety requirement.

Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-alpha-2a is successful in eradicating virus from only 30 to 80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to the therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) ((relative risk) RR=0.80; 95% CI: 0.66-0.98; P=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95% CI: 0.66-0.94; P=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95% CI: 0.66-0.94; P=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% CI: 0.62-1.0; P=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy.

Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH. AIM: To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH. METHODS: Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three-point improvement in the histological NASH activity index. RESULTS: Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement. CONCLUSION: Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss.

Hepatitis C: a clinical review.

Hepatitis C is a major cause of chronic liver disease. It has been recognized as a global health problem because of the progression to cirrhosis and hepatocellular cancer. Chronic hepatitis C is usually asymptomatic but can cause considerable liver damage before its recognition. This review discusses the natural history, clinical features, diagnosis, therapy, treatment responses and the side effects associated with the treatment of hepatitis C.

Sequential analysis of hepatitis B virus core promoter and precore regions in cancer survivor patients with chronic hepatitis B before, during and after interferon treatment.

We analysed the hepatitis B virus (HBV) core-promoter (CP) and precore (PC) regions before, during and after interferon treatment in young Caucasian cancer survivors who had acquired HBV infection during chemotherapy for malignancies. Fourteen patients with chronic hepatitis B [hepatitis B e antigen (HBeAg) /HBV-DNA positive] received alpha-2a interferon (IFN), 5 MU/m2 t.i.w. for 12 months. HBV CP and PC region sequences were analysed following polymerase chain reaction (PCR) amplification. Sera from responders were studied at: T(0) (before starting IFN), T(1) [at alanine aminotransferase (ALT) peak preceding HBeAg seroconversion], T(2) (at ALT normalization), T(3) (at end of IFN) and T(4) (at one year after IFN) and in nonresponders at time points T(0), T(3) and T(4). Amplified HBV-DNA was cloned and sequenced automatically. Six of 14 patients (43%) responded to IFN treatment. Five of the six (83%) responders displayed the double CP mutation A1762T/G1764A always in association with a T1753C change. None of the nonresponders showed these mutations at any time point. The G1896A change creating the PC stop codon mutation was never detected in any of the patients. In our cancer survivors, IFN-induced HBeAg/anti-HBe seroconversion appeared to correlate with CP mutations and was not influenced by previous chemotherapy. These mutations in addition to low HBV DNA levels and elevated ALT can be considered favourable factors of response to IFN-induced anti-HBe seroconversion.

Genetic immunization of wild-type and hepatitis C virus transgenic mice reveals a hierarchy of cellular immune response and tolerance induction against hepatitis C virus structural proteins.

To study the effect of genetic immunization on transgenic expression of hepatitis C virus (HCV) proteins, we evaluated the immunological response of HCV transgenic mice to HCV expression plasmids. FVB/n transgenic mice expressing HCV structural proteins (core, E1, and E2) and wild-type (WT) FVB/n mice were immunized intramuscularly with plasmids expressing core (pHCVcore) or core/E1/E2 (pHCVSt). After immunization, HCV-specific humoral and cellular immune response was studied. Both WT and transgenic mice immunized with either HCV construct produced antibodies and exhibited T-cell proliferative responses against core or envelope. In WT mice immunized with pHCVSt, cytotoxic T-lymphocyte (CTL) activities were detected against E2 but not against core or E1, whereas strong CTL activities against core could be detected in WT mice immunized with pHCVcore. In pHCVSt-immunized, transgenic mice, CTL activities against the core or envelope were completely absent, but core-specific CTL activities could be detected in pHCVcore-immunized transgenic mice. A similar pattern of immune responses was also observed in other mouse strains, including a transgenic line expressing human HLA-A2.1 molecules (AAD mice). Despite the presence of a peripheral cellular immunity against HCV, no liver pathology or lymphocytic infiltrate was observed in these transgenic mice. Our study suggests a hierarchy of CTL response against the HCV structural proteins (E2 > core > E1) in vivo when the proteins are expressed as a polyprotein. The HCV transgenic mice can be induced by DNA immunization to generate anti-HCV antibodies and anticore CTLs. However, they are tolerant at the CTL level against the E2 protein despite DNA immunization.

Additive activation of hepatic NF-kappaB by ethanol and hepatitis B protein X (HBX) or HCV core protein: involvement of TNF-alpha receptor 1-independent and -dependent mechanisms.

Alcohol consumption and viral hepatitis infection synergistically accelerate liver injury, but the underlying mechanism is not fully understood. Here we have examined the effects of ethanol on hepatitis B protein X (HBX)- or hepatitis C core protein (HCV core protein)-mediated activation of NF-kappaB, a critical signal in hepatic injury, regeneration, and tumor transformation. Acute ethanol or acetaldehyde exposure potentiates HBX or HCV core protein activation of NF-kappaB in primary mouse hepatocytes. Such potentiation can be abolished by blocking ethanol metabolism or overexpression of dominant negative NF-kappaB-inducing kinase (NIK), IkappaB kinase (IKK), or IkappaB. Moreover, pertussis toxin attenuates NF-kappaB activation induced by acetaldehyde but not by HBX or HCV core protein, whereas HBX or HCV core protein-mediated activation of NF-kappaB is abolished completely in tumor necrosis factor a receptor 1 (TNFR1) (-/-) hepatocytes. Finally, chronic ethanol consumption induces hepatic CYP2E1 protein expression and potentiates HBX or HCV core protein activation of NF-kappaB in the liver. These findings suggest that ethanol activates hepatic NF-kappaB via its metabolism and that HBX or HCV core protein activates hepatic NF-kappaB via TNFR1. With the essential role of TNFR1 in alcoholic liver injury, targeting TNFR1 by hepatitis viral proteins could contribute to cooperative effects of alcohol consumption and viral hepatitis on liver disease.

Monoclonal antibodies with broad specificity for hepatitis C virus hypervariable region 1 variants can recognize viral particles.

The hypervariable region 1 (HVR1) of the E2 protein of hepatitis C virus (HCV) is a highly heterogeneous sequence that is promiscuously recognized by human sera via binding to amino acid residues with conserved physicochemical properties. We generated a panel of mAbs from mice immunized with HVR1 surrogate peptides (mimotopes) affinity-selected with sera from HCV-infected patients from a phage display library. A high number of specific clones was obtained after immunization with a pool of nine mimotopes, and the resulting mAbs were shown to recognize several 16- and 27-mer peptides derived from natural HVR1 sequences isolated from patients with acute and chronic HCV infection, suggesting that HVR1 mimotopes were efficient antigenic and immunogenic mimics of naturally occurring HCV variants. Moreover, most mAbs were shown to bind HVR1 in the context of a complete soluble form of the E2 glycoprotein, indicating recognition of correctly folded HVR1. In addition, a highly promiscuous mAb was able to specifically capture bona fide viral particles (circulating HCV RNA) as well as rHCV-like particles assembled in insect cells expressing structural viral polypeptides derived from an HCV 1a isolate. These findings demonstrate that it is possible to induce a broadly cross-reactive clonal Ab response to multiple HCV variants. In consideration of the potentially important role of HVR1 in virus binding to cellular receptor(s), such a mechanism could be exploited for induction of neutralizing Abs specific for a large repertoire of viral variants.

Hepatitis C virus-like particles induce virus-specific humoral and cellular immune responses in mice.

We have recently described the production of hepatitis C virus-like particles (HCV-LPs) in insect cells that resemble the putative virions. Here we evaluate the humoral and cellular immunogenicity of the virus-like particles with or without viral p7 protein, a small viral polypeptide that resides between the structural and nonstructural regions of the HCV polyprotein and whose function has not been defined. Immunized BALB/c mice developed high titers of anti-E2 antibodies and virus-specific cellular immune responses including cytotoxic T lymphocytes and T helper responses with gamma interferon production. The virus-like particles without p7 generated a higher cellular immune response with a more T(H)1 profile than the particles with p7. Immunization of heat-denatured particles resulted in substantially lower humoral and cellular responses, suggesting that the immunogenicity is strongly dependent on particle formation. Administration of CpG oligonucleotide or cationic lipid 3beta-[N-(N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol), two potent adjuvants, did not significantly enhance the immunogenicity of HCV-LPs. Our results indicate that HCV-LPs can induce humoral and cellular immune responses and offer a promising approach to vaccine development.

Conditional liver-specific expression of simian virus 40 T antigen leads to regulatable development of hepatic neoplasm in transgenic mice.

Adaptive epigenetic changes and toxicity often accompany constitutive expression of a transgene or knockout of an endogenous gene in mice. These considerations potentially limit the usefulness of transgenic technology in studying the in vivo functions of a gene. Using conditional gene expression technology, it is possible to override such restrictions to achieve temporal and tissue-specific manipulation of gene expression in vivo. Based on the tetracycline regulatory system, we established a binary transgenic model in which the conditional expression of two transgenes, SV40 T antigen (TAg) and lacZ, can be tightly regulated in the liver by administration of tetracycline. The mouse albumin or mouse major urinary protein promoter was used to achieve liver-specific expression of the tetracycline-responsive transcriptional activator (tTA) in one set of transgenic mice. These mice were crossed with transgenic mice carrying either TAg or lacZ under the control of the tTA-regulated promoter. Analyses of mice transgenic for both tTA and TAg (or lacZ) revealed that the liver-specific expression of the transgenes could be suppressed to undetectable levels and regulated in a reversible fashion by tetracycline administration and withdrawal. Mice with tTA and TAg transgenes developed hepatocellular adenomas and hyperplasia that could be prevented by continuous tetracycline administration. Our report demonstrates the value of this binary transgenic model in studying the physiological functions of any potential genes of interest in a liver-specific manner.

Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection.

Synthesis of the hepatitis B virus (HBV) DNA genome occurs within the viral nucleocapsid in a mechanistically ordered fashion. The nucleocapsid contains small pores that permit influx of nucleotide triphosphates and metabolites of nucleoside analogues such as lamivudine for DNA synthesis. Lamivudine is a potent inhibitor of HBV and human immunodeficiency virus (HIV) reverse transcriptases, but substitutions of isoleucine or valine for methionine within the tyrosine-methionine-aspartate-aspartate (YMDD) motif are associated with virologic and clinical resistance to lamivudine therapy. Under lamivudine selection pressure, the high viral production rate and the low fidelity viral polymerase contribute to frequent development of the YMDD mutants. However, the pattern and dynamics of emergence of the mutant viruses over the wild-type virus are determined by multiple factors including replication efficiency, host immune response, and availability of replication space. Structural modeling of HIV reverse transcriptase has permitted key insights into the molecular basis of lamivudine resistance of HBV based on evolutionary relatedness of HIV and HBV. The side groups of isoleucine and valine of the YMDD mutants sterically prevent lamivudine from appropriately configuring into the nucleotide binding site of the reverse transcriptase. Aminotransferase flares are associated with lamivudine therapy and may signify clinical resistance with emergence of YMDD mutants. They may also herald the recovery phase with seroconversion and viral clearance. Reconstitution of the endogenous anti-HBV immune response may be equally important in the control of viral replication by lamivudine and other nucleoside analogues.

Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex.

Hepatitis B virus (HBV) has a unique fourth open reading frame coding for a 16.5-kDa protein known as hepatitis B virus X protein (HBX). The importance of HBX in the life cycle of HBV has been well established, but the underlying molecular function of HBX remains controversial. We previously identified a proteasome subunit PSMA7 that interacts specifically with HBX in the Saccharomyces cerevisiae two-hybrid system. Here we demonstrate that PSMC1, an ATPase-like subunit of the 19 S proteasome component, also interacts with HBX and PSMA7. Analysis of the interacting domains among PSMA7, PSMC1, and HBX by deletion and site-directed mutagenesis suggested a mutually competitive structural relationship among these polypeptides. The competitive nature of these interactions is further demonstrated using a modified yeast two-hybrid dissociator system. The crucial HBX sequences involved in interaction with PSMA7 and PSMC1 are important for its function as a transcriptional coactivator. HBX, while functioning as a coactivator of AP-1 and acidic activator VP-16 in mammalian cells, had no effect on the transactivation function of their functional orthologs GCN4 and Gal4 in yeast. Overexpression of PSMC1 seemed to suppress the expression of various reporters in mammalian cells; this effect, however, was overcome by coexpression of HBX. In addition, HBX expression inhibited the cellular turnover of c-Jun and ubiquitin-Arg-beta-galactosidase, two well known substrates of the ubiquitin-proteasome pathway. Thus, interaction of HBX with the proteasome complex in metazoan cells may underlie the functional basis of proteasome as a cellular target of HBX.

Pathogenesis, natural history, treatment, and prevention of hepatitis C.

Approximately 4 million persons in the United States and probably more than 100 million persons worldwide are infected with hepatitis C virus. The virus has the unique ability to cause persistent infection in susceptible hosts after parenteral or percutaneous transmission, and its underlying mechanisms are not well understood. The immunologic correlates of protection and viral clearance and the pathogenesis of liver injury are yet to be defined, but recent studies suggest the importance of cell-mediated immune responses. Although 70% to 80% of infected persons become chronic carriers, most have relatively mild disease with slow progression. However, chronic and progressive hepatitis C carries significant morbidity and mortality and is a major cause of cirrhosis, end-stage liver disease, and liver cancer. Development of an effective hepatitis C virus vaccine is not imminent, but recent advances in technology and basic knowledge of molecular virology and immunology have engendered novel approaches to the fundamental problems encountered in vaccine development. Current therapy for hepatitis C, although effective in some patients, is problematic and still evolving. Advances in modern biology and immunology promise new therapies for this important disease.