A Stochastic Model to Assess the Epidemiological Impact of Vaccine Booster Doses on COVID-19 and Viral Hepatitis B Co-Dynamics with Real Data

A patient co-infected with COVID-19 and viral hepatitis B can be atmore risk of severe complications than the one infected with a single infection.This study develops a comprehensive stochastic model to assess the epidemiological impact of vaccine booster doses on the co-dynamics of viral hepatitis B and COVID-19.The model is fitted to real COVID-19 data from Pakistan.The proposed model incorporates logistic growth and saturated incidence functions.Rigorous analyses using the tools of stochastic calculus,are performed to study appropriate conditions for the existence of unique global solutions,stationary distribution in the sense of ergodicity and disease extinction.The stochastic threshold estimated from the data fitting is given by:R_(0)^(S)=3.0651.Numerical assessments are implemented to illustrate the impact of double-dose vaccination and saturated incidence functions on the dynamics of both diseases.The effects of stochastic white noise intensities are also highlighted.

Effect of viral hepatitis on type 2 diabetes:A Mendelian randomization study

BACKGROUND The effects of viral hepatitis(VH)on type 2 diabetes(T2D)remain controversial.AIM To analyze the causal correlation between different types of VH and T2D using Mendelian randomization(MR).METHODS Single nucleotide polymorphisms of VH,chronic hepatitis B(CHB),chronic hepatitis C(CHC)and T2D were obtained from the BioBank Japan Project,European Bioinformatics Institute,and FinnGen.Inverse variance weighted,MREgger,and weighted median were used to test exposure-outcome associations.The MR-Egger intercept analysis and Cochran’s Q test were used to assess horizontal pleiotropy and heterogeneity,respectively.Leave-one-out sensitivity analysis was used to evaluate the robustness of the MR analysis results.RESULTS The MR analysis showed no significant causal relationship between VH and T2D in Europeans[odds ratio(OR)=1.028;95%confidence interval(CI):0.995-1.062,P=0.101].There was a negative causal association between CHB and T2D among East Asians(OR=0.949;95%CI:0.931-0.968,P<0.001),while there was no significant causal association between CHC and T2D among East Asians(OR=1.018;95%CI:0.959-1.081,P=0.551).Intercept analysis and Cochran’s Q test showed no horizontal pleiotropy or heterogeneity(P>0.05).Sensitivity analysis showed that the results were robust.CONCLUSION Among East Asians,CHB is associated with a reduced T2D risk,but this association is limited by HBV load and cirrhosis.Although VH among Europeans and CHC among East Asians are not associated with the risk of T2D,focusing on blood glucose in patients with CHC is still relevant for the early detection of T2D induced by CHCmediated pathways of hepatic steatosis,liver fibrosis,and cirrhosis.

Prevalence of Children Vaccinated against Viral Hepatitis B in Brazzaville

Introduction: Viral hepatitis B (VHL) is a public health problem, particularly in sub-Sahara Africa. The aim of this study was to assess vaccination coverage against HBV in children in Brazzaville. Patients and Methods: This was a cross-sectional analytical study conducted in Brazzaville health centres from January to September 2019. It involved children aged between six months and six years who received a vaccination against HBV. Sampling was exhaustive and based on stratified sampling. Results: The overall prevalence of children vaccinated against HBV in Brazzaville was 96.2%. It was insufficient in the Talangai health district (79%). The pentavalent vaccine was administered to 97.7% of children, 85% of whom had received all three doses. The reasons for incomplete vaccination were parents’ ignorance of HVB (85.6%) and of vaccination (14.3%). Conclusion: Although the prevalence of vaccinated children is high in Brazzaville, it is still insufficient in some health districts, particularly Talangai, because parents are unaware of the disease and of vaccination. Pentavalent is the only vaccine available in the national vaccination programme, which is why an effective national vaccination policy needs to be put in place. .

Plant-based vaccines against viral hepatitis: A panoptic review

The traditional vaccines against hepatitis have been instrumental in reducing the incidence of some types of viral hepatitis;however,the need for cost-effective,easily distributable,and needle-free vaccine alternatives has led to the exploration of plant-based vaccines.Plant-based techniques offer a promising avenue for producing viral hepatitis vaccines due to their low-cost cultivation,scalability,and the potential for oral administration.This review highlights the successful expression of hepatitis B surface antigens in plants and the subsequent formation of virus-like particles,which have shown immunogenicity in preclinical and clinical trials.The challenges such as achieving sufficient antigen expression levels,ensuring consistent dosing,and navigating regulatory frameworks,are addressed.The review considers the potential of plant-based vaccines to meet the demands of rapid vaccine deployment in response to outbreaks and their role in global immunization strategies,particularly in resource-limited settings.This review underscores the significant strides made in plant molecular farming and the potential of plant-based vaccines to complement existing immunization methods against viral hepatitis.

Evaluation of the diagnostic efficacy of noninvasive diagnosis in patients with chronic viral hepatitis B complicated with nonalcoholic fatty liver disease and significant liver fibrosis

Objective:To evaluate the diagnostic efficacy of chronic viral hepatitis B(CHB)with significant liver fibrosis(S2)in patients with nonalcoholic fatty liver disease(NAFLD)by using noninvasive diagnosis and their combined models,and to explore their clinical features.Methods:A total of 104 inpatients with CHB diagnosed and complicated with NAFLD(hepatic steatosis suggested by liver biopsy)were retrospectively collected from January 2018 to January 2023 in the Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University.Liver biopsy was performed in all patients.General data,laboratory test results,liver hardness(LSM),FIB-4,APRI,GGT/PLT,AST/PLT and other results of patients were collected and grouped according to different fibrosis stages(S)to explore the clinical and pathological characteristics of patients with<S2 and S2 stages.Receiver operating characteristic curve was used to evaluate the diagnostic value of LSM,FIB-4,APRI,GGT/PLT,AST/PLT and their combined models in patients with significant liver fibrosis in CHB patients with NAFLD.Results:Among the 104 patients,there were 55 patients had S1 fibrosis,32 patients had S2 fibrosis,11 patients had S3 fibrosis and 6 patients had S4 fibrosis.Patients had<S2 fibrosis,ALT 33.75±17.15 U/L,AST 24.00(19.77,29.00)U/L,inflammation above G2 stage accounted for 92.72%,GGT/PLT 0.07(0.10,0.15),AST/PLT 0.09(0.10,0.15),LSM 8.70(6.80,10.10)kPa,FIB-41.07±0.51,APRI 0.26(0.22,0.28).In patients S2 fibrosis,ALT 42.14±21.39 U/L,AST 29.04(24.00,40.32)U/L,inflammation above G2 stage accounted for 97.95%,GGT/PLT 0.15(0.10,0.28),AST/PLT 0.14(0.10,0.26),GGT/PLT 0.15(0.10,0.28),AST/PLT 0.14(0.10,0.26).LSM 11.80(8.50,16.65)kPa,FIB-41.39±0.72,APRI 0.35(0.26,0.66),the difference between the two groups was statistically significant(P<0.05).The area under the receiver operator characteristic curves of the subjects of LSM,FIB-4,APRI,GGT/PLT and AST/PLT were 0.716,0.623,0.669,0.644 and 0.669(P<0.05),respectively.In the combined model,the area under the receiver operator characteristic curves of LSM combined with FIB-4,LSM combined with APRI,LSM combined with GGT/PLT and LSM combined with AST/PLT were 0.712,0.719,0.715 and 0.719,respectively(P<0.05).Conclusion:Although the currently commonly used Noninvasive diagnosis of liver fibrosis has certain diagnostic efficacy for significant liver fibrosis in CHB complicated with NAFLD,it cannot replace liver biopsy.Noninvasive Diagnosis can be used as an auxiliary method for regular clinical evaluation of liver biopsy.

Factors Associated with Hepatic Steatosis in Black African Subjects with Chronic Viral Hepatitis B in Côte d’Ivoire

Context/Objectives: With the progression of the global epidemic of obesity and metabolic syndrome, the coexistence of hepatic steatosis in patients with chronic viral hepatitis B (VHB) is becoming significant. The aim of this work was to determine the factors associated with hepatic steatosis assessed by a Fibroscan with Controlled Attenuation Parameter (CAP) in patients with chronic viral hepatitis B in Côte d’Ivoire. Methods: This was a cross-sectional and analytical study. Data was collected from February 15 to July 31, 2020 in a private hospital structure in the city of Abidjan in Côte d’Ivoire. We included 83 patients with chronic viral hepatitis B. These were black patients, having performed a Fibroscan/CAP during the recruitment period and consenting to participate in the study. Patients with significant alcohol consumption, a secondary cause of hepatic steatosis, or other liver disease regardless of the etiology associated with hepatitis B were not included. Results: The frequency of hepatic steatosis in chronic VHB carriers assessed by the CAP in our study population was 48.19% including 24.10% severe steatosis. Obesity and high LDL cholesterol were statistically correlated with the presence of steatosis in our patients. Patients who had steatosis on ultrasound were 5 times more likely to have steatosis on CAP. Significant fibrosis was not significantly associated with steatosis. Conclusion: Obesity and LDL hypercholesterolemia are the main factors associated with hepatic steatosis detected by Fibroscan/CAP in patients with chronic viral hepatitis B.

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis,cancer,and liver failure.Liver cancer is the third leading cause of cancer-associated mortality,of which hepatocellular carcinoma(HCC)represents 90%of all primary liver cancers.Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management.Chronic infection with hepatitis B virus(HBV),hepatitis delta virus(HDV),and hepatitis C virus(HCV)are the greatest etiological risk factors for HCC.Due to the significant role of chronic viral infection in HCC development,it is important to investigate direct(viral associated)and indirect(immune-associated)mechanisms involved in the pathogenesis of HCC.Common mechanisms used by HBV,HCV,and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response,immune and viral protein-mediated oxidative stress,and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection,and metabolic reprogramming leading to steatosis is driven by HCV infection.The current review aims to provide a brief overview of HBV,HCV and HDV molecular biology,and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC,and current as well as emerging treatments for HCC.

Fibrinogen-like protein 2 fibroleukin expression and its correlation with disease progression in murine hepatitis virus type 3-induced fulminant hepatitis and in patients with severe viral hepatitis B

AIM： To evaluate the expression of fibrinogenlike protein 2 （fgl2） and its correlation with disease progression in both mice and patients with severe viral hepatitis. METHODS： Balb/cJ or A/J mice were infected intraperitoneally （ip） with 100 PFU of murine hepatitis virus type 3 （MHV-3）, liver and serum were harvested at 24, 48, and 72 h post infection for further use. Liver tissues were obtained from 23 patients with severe acute chronic （AOC） hepatitis B and 13 patients with mild chronic hepatitis B. Fourteen patients with mild chronic hepatitis B with cirrhosis and 4 liver donors served as normal controls. In addition, peripheral blood mononuciear cells （PBMC） were isolated from 30 patients （unpaired） with severe AOC hepatitis B and 10 healthy volunteers as controls. Procoagulant activity representing functional prothrombinase activity in PBMC and white blood cells was also assayed. A polyclonal antibody against fgl2 was used to detect the expression of both mouse and human fgl2 protein in liver samples as well as in PBMC by immunohistochemistry staining in a separate set of studies. Alanine aminotransferase （ALT） and total bilirubin （TBil） in serum were measured to assess the severity of liver injury.RESULTS： Histological changes were found in liver sections 12-24 h post MHV-3 infection in Balb/cJ mice. In association with changes in liver histology, marked elevations in serum ALT and TBil were observed. House fgl2 （mfgl2） protein was detected in the endothelium of intrahepatic veins and hepatic sinusoids within the liver 24 h after MHV-3 infection. Liver tissues from the patients with severe AOC hepatitis B had classical pathological features of acute necroinflammation. Human fgl2 （hfgl2） was detected in 21 of 23 patients （91.30%） with severe AOC hepatitis B, while only 1 of 13 patients （7.69%） with mild chronic hepatitis B and cirrhosis had hfgl2 mRNA or protein expression. Twenty-eight of thirty patients （93.33%） with severe AOC hepatitis B and 1 of 10 with mild chronic hepatitis B had detectable hfgl2 expression in PBMC. No hfgl2 expression was found either in the liver tissue or in the PBMC from normal donors. There was a positive correlation between hfgl2 expression and the severity of the liver disease as indicated by the levels of TBil. PCA significantly increased in PBMC in patients with severe AOC hepatitis B. CONCLUSION： The molecular and cellular results reported here in both mice and patients with severe viral hepatitis suggest that virus-induced hfgl2 prothrombinase/fibroleukin expression and the coagulation activity associated with the encoded fgl2 protein play a pivotal role in initiating severe hepatitis. The measurement of hfgl2/fibroleukin expression in PBMC may serve as a useful marker to monitor the severity of AOC hepatitis B and a target for therapeutic intervention.

Viral hepatitis update: Progress and perspectives

Viral hepatitis,secondary to infection with hepatitis A,B,C,D,and E viruses,are a major public health problem and an important cause of morbidity and mortality.Despite the huge medical advances achieved in recent years,there are still points of conflict concerning the pathogenesis,immune response,development of new and more effective vaccines,therapies,and treatment.This review focuses on the most important research topics that deal with issues that are currently being solved,those that remain to be solved,and future research directions.For hepatitis A virus we will address epidemiology,molecular surveillance,new susceptible populations as well as environmental and food detections.In the case of hepatitis B virus,we will discuss host factors related to disease,diagnosis,therapy,and vaccine improvement.On hepatitis C virus,we will focus on pathogenesis,immune response,direct action antivirals treatment in the context of solid organ transplantation,issues related to hepatocellular carcinoma development,direct action antivirals resistance due to selection of resistanceassociated variants,and vaccination.Regarding hepatitis D virus,we describe diagnostic methodology,pathogenesis,and therapy.Finally,for hepatitis E virus,we will address epidemiology(including new emerging species),diagnosis,clinical aspects,treatment,the development of a vaccine,and environmental surveillance.

Specific CD8^+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

Regulatory T cells in viral hepatitis

The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.

Viral hepatitis:Past,present,and future

Each hepatitis virus—Hepatitis A,B,C,D,E,and G—poses a distinct scenario to the patient and clinician alike.Since the discovery of each virus,extensive knowledge regarding epidemiology,virologic properties,and the natural clinical and immunologic history of acute and chronic infections has been generated.Basic discoveries about host immunologic responses to acute and chronic viral infections,combined with virologic data,has led to vaccines to prevent Hepatitis A,B,and E and highly efficacious antivirals for Hepatitis B and C.These therapeutic breakthroughs are transforming the fields of hepatology,transplant medicine in general,and public and global health.Most notably,there is even an ambitious global effort to eliminate chronic viral hepatitis within the next decade.While attainable,there are many barriers to this goal that are being actively investigated in basic and clinical labs on the local,national,and international scales.Herein,we discuss pertinent clinical information and recent organizational guidelines for each of the individual hepatitis viruses while also synthesizing this information with the latest research to focus on exciting future directions for each virus.

Viral hepatitis:Milestones,unresolved issues,and future goals

In this review the current overall knowledge on hepatitis A,B,C,D,and E will be discussed.These diseases are all characterized by liver inflammation but have significant differences in distribution,transmission routes,and outcomes.Hepatitis B virus and hepatitis C virus are transmitted by exposure to infected blood,and in addition to acute infection,they can cause chronic hepatitis,which in turn can evolve into cirrhosis.It is estimated that more than 300 million people suffer from chronic hepatitis B or C worldwide.Hepatitis D virus,which is also transmitted by blood,only affects hepatitis B virus infected people,and this dual infection results in worse liver-related outcomes.Hepatitis A and E spread via the fecal-oral route,which corresponds mainly to the ingestion of food or water contaminated with infected stools.However,in developed countries hepatitis E is predominantly a zoonosis.Although hepatitis A virus and hepatitis E virus are usually responsible for a self-limiting hepatitis,a serious,rarely fatal illness is also possible,and in immunosuppressed patients,such as organ transplant recipients,hepatitis E virus infection can become chronic.The description of goals achieved,unresolved issues,and the latest research on this topic may make it possible to speculate on future scenarios in the world of viral hepatitis.

Viral hepatitis:Innovations and expectations

Viral hepatitis is a significant health problem worldwide,associated with morbidity and mortality.Hepatitis B,C,D,and occasionally E viruses(HBV,HCV,HDV,and HEV)can evolve in chronic infections,whereas hepatitis A virus(HAV)frequently produces acute self-limiting hepatitis.In the last years,different studies have been performed to introduce new antiviral therapies.The most important goal in the treatment of viral hepatitis is to avoid chronic liver disease and complications.This review analyzes currently available therapies,in particular for viruses associated with chronic liver disease.The focus is especially on HBV and HCV therapies,investigating new drugs already introduced in clinical practice and clinical trials.We also describe new entry inhibitors,developed for the treatment of chronic HDV and HBV and currently available treatments for HEV.The last drugs introduced have shown important efficacy in HCV,with achievable target HCV elimination by 2030.Concurrently,renewed interest in curative HBV therapies has been registered;current nucleotide/nucleoside analogs positively impact liver-related complications,ensuring high safety and tolerability.Novel approaches to HBV cure are based on new antivirals,targeting different steps of the HBV life cycle and immune modulators.The improved knowledge of the HDV life cycle has facilitated the development of some direct-acting agents,as bulevirtide,the first drug conditionally approved in Europe for HDV associated compensated liver disease.Further studies are required to identify a new therapeutic approach in hepatitis E,especially in immunosuppressed patients.

Linker phosphorylation of Smad3 promotes fibro-carcinogenesis in chronic viral hepatitis of hepatocellular carcinoma

Epidemiological and clinical data point to a close association between chronic hepatitis B virus infection or chronic hepatitis C virus infection and development of hepatocellular carcinoma (HCC). HCC develops over several decades and is associated with fibrosis. This sequence suggests that persistent viral infection and chronic inflammation can synergistically induce liver fibrosis and hepatocarcinogenesis. The transforming growth factor-&#x003b2; (TGF-&#x003b2;) signaling pathway plays a pivotal role in diverse cellular processes and contributes to hepatic fibro-carcinogenesis under inflammatory microenvironments during chronic liver diseases. The biological activities of TGF-&#x003b2; are initiated by the binding of the ligand to TGF-&#x003b2; receptors, which phosphorylate Smad proteins. TGF-&#x003b2; type&#x02005;I&#x02005;receptor activates Smad3 to create COOH-terminally phosphorylated Smad3 (pSmad3C), while pro-inflammatory cytokine-activated kinases phosphorylates Smad3 to create the linker phosphorylated Smad3 (pSmad3L). During chronic liver disease progression, virus components, together with pro-inflammatory cytokines and somatic mutations, convert the Smad3 signal from tumor-suppressive pSmad3C to fibro-carcinogenic pSmad3L pathways, accelerating liver fibrosis and increasing the risk of HCC. The understanding of Smad3 phosphorylation profiles may provide new opportunities for effective chemoprevention and personalized therapy for patients with hepatitis virus-related HCC in the future.

Analysis of prognosis on patients with severe viral hepatitis using the model for end-stage liver disease

AIM: To study the practical use of the model for endstage liver disease (MELD) on clinic and assess its validity by the concordance (C)-statistic in predicting the prognosis of the patient with severe viral hepatitis.METHODS: One hundred and twenty-one patients were divided into plasma exchange group and non-plasma exchange group, and were graded with MELD formula.The death rate was observed within 3 mo.RESULTS: Eighty-one patients died within 3 mo (35 cases in PE group, 46 cases in non-PE group). The mortality of patients in PE group whose MELD score between 20-30and 30-40 were 31.6% and 57.7%, respectively, but in non-PE cases they were 67.6%, 81.3% respectively.There was significant difference between PE group and non-PE group (P＜0.05). However, the mortality of patients whose MELD score higher than 40 were 93.3% in PE group and 100% in non-PE group and there was no significant difference between the two groups (P= 0.65＞0.05). The optimal cut-off values of MELD to predict the prognosis of patients were 30 in PE group whose sensitivity, specificity and C-statistic were 80.0%, 52.0% and 0.777, but in non-PE group they were 25, 82.6%, 86.7% and 0.869, respectively.CONCLUSION: The MELD score can act as a disease severity index for patients with severe viral hepatitis, and the mortality of the patient increases with the increase of the MELD score. The MELD can accurately predict the short-term prognosis of patients with severe viral hepatitis.

Update on the management and treatment of viral hepatitis

This review aims to summarize the current evidence on the treatment of viral hepatitis,focusing on its clinical management.Also,future treatment options and areas of potential research interest are detailed.PubMed and Scopus databases were searched for primary studies published within the last ten years.Keywords included hepatitis A virus,hepatitis B virus(HBV),hepatitis C virus,hepatitis D virus(HDV),hepatitis E virus,and treatment.Outcomes reported in the studies were summarized,tabulated,and synthesized.Significant advances in viral hepatitis treatment were accomplished,such as the advent of curative therapies for hepatitis C and the development and improvement of hepatitis A,hepatitis B,and hepatitis E vaccination.Drugs that cure hepatitis B,going beyond viral suppression,are so far unavailable;however,targeted antiviral drugs against HBV(immunomodulatory therapies and gene silencing technologies)are promising approaches to eradicating the virus.Ultimately,high vaccination coverage and large-scale test-and-treat programmes with high screening rates may eliminate viral hepatitis and mitigate their burden on health systems.The development of curative hepatitis C treatment renewed the enthusiasm for curing hepatitis B,albeit further investigation is required.Novel therapeutic options targeting HDV life cycle are currently under clinical investigation.

Hepatitis B virus infection and hepatocellular carcinoma in sub- Saharan Africa: Implications for elimination of viral hepatitis by 2030?

Elimination of viral hepatitis in sub-Saharan Africa by 2030 is an ambitious feat.However,as stated by the World Health Organization,there are unprecedented opportunities to act and make significant contributions to the elimination target.With 60 million people chronically infected with hepatitis B virus(HBV)of whom 38800 are at risk of developing highly fatal hepatocellular carcinoma(HCC)every year,sub-Saharan Africa faces one of the greatest battles towards elimination of viral hepatitis.There is a need to examine progress in controlling the disproportionate burden of HBV-associated HCC in sub-Saharan Africa within the context of this elimination target.By scaling-up coverage of hepatitis B birth dose and early childhood vaccination,we can significantly reduce new cases of HCC by as much as 50%within the next three to five decades.Given the substantial reservoir of chronic HBV carriers however,projections show that HCC incidence and mortality rates in sub-Saharan Africa will double by 2040.This warrants urgent public health attention.The trends in the burden of HCC over the next two decades,will be determined to a large extent by progress in achieving early diagnosis and appropriate linkage to care for high-risk chronic HBV infected persons.

γδ T Cells Contribute to the Outcome of Murine Fulminant Viral Hepatitis via Effector Cytokines TNF-α and IFN-γ

The mechanisms involved in virus-induced severe hepatitis have not been fully elucidated. In this study, we investigated the role of gamma delta T cell receptors （γδ） T cells in the pathogenesis of fulminant viral hepatitis （FVH） induced by murine hepatitis virus strain 3 （MHV-3）. The model of FVH was established by intraperitoneal injection of MHV-3 into Balb/cJ mice. The survival days of mice, and the serum levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were examined. The proportions of γδ T cells in blood, spleen and liver, and cytokines secreted by hepatic γδ T cells were analyzed by flow cytometry. The function of hepatic γδ T cells was examined by cytotoxicity assay. Balb/cJ mice died in 3 to 6 days post MHV-3 infection, with severe hepatic necrosis and significant augmentation of serum ALT and AST levels. The proportions of γδ T cells in blood, spleen and liver were significantly increased post MHV-3 infection, while those of the early activating molecule CD69-expressing γδ T cells and productions of cytokines tumor necrosis factor-alpha （TNF-α） and interferon-y （IFN-3,） increased remarkably in the liver. These highly activated liver γδ T cells were cytotoxic to MHV-3-infected hepatocytes in vitro and this effect of liver γδ T cells against hepatocytes might involve the TNF-α and IFN-γ pathway. These results demonstrated that γδ T cells might contribute to the pathogenesis of MHV-3-induced FVH through the effector cytokines TNF-α and IFN-γ. Key words： fulminant viral hepatitis; murine hepatitis virus strain 3; gamma delta T cell receptors T cells; tumor necrosis factor-a; interferon-α

Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update

Hepatocellular carcinoma(HCC)is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancerrelated deaths worldwide.In recent years,uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets.Despite the vast amount of data on this topic,HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile.Therefore,the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase.In this context,the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior.In line with these efforts,this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus(HBV)and hepatitis C virus(HCV)participate in oncogenesis and tumor progression in HCC and summarize new findings.Cumulative evidence indicates that HBV DNA integration promotes genomic instability,resulting in the overexpression of genes related to cancer development,metastasis,and angiogenesis or inactivation of tumor suppressor genes.In addition,genetic variations in HBV itself,especially preS2 deletions,may play a role in malignant transformation.Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs.Similarly,viral proteins of both HBV and HCV can affect pathways that are important anticancer targets.The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated.Additional,comprehensive studies are also needed to determine these viruses'interaction with integrins,farnesoid X,and the apelin system in malignant transformation and tumor progression.Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined,further studies are warranted to decipher the relationship among inflam masomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.