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Detection of HBV DNA integration in plasma cell-free DNA of different HBV diseases utilizing DNA capture strategy

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Virologica Sinica 2024年第4期39卷 655-666页

作者： Zerui Yang Jingyan Zeng Yueyue Chen Mengchun Wang Hongchun Luo Ai-Long Huang Haijun Deng Yuan Hu Key Laboratory of molecular biology on infectious diseases Ministry of EducationChongqing Medical UniversityChongqing400016China Department of infectious diseases The First Affiliated Hospital of Chongqing Medical UniversityChongqing400016China

The landscape of hepatitis B virus(HBV)integration in the plasma cell-free DNA(cfDNA)of HBV-infected patients with different stages of liver diseases[chronic hepatitis B(CHB),liver cirrhosis(LC),and hepatocellular carcinoma(HCC)]remains *** this study,we developed an improved strategy for detecting HBV DNA integration in plasma cfDNA,based on DNA probe capture and next-generation *** this optimized strategy,we successfully detected HBV integration events in chimeric artificial DNA samples and HBV-infected HepG2-NTCP cells at day one post infection,with high sensitivity and *** characteristics of HBV integration events in the HBV-infected HepG2-NTCP cells and plasma cfDNA from HBV-infected individuals(CHB,LC,and HCC)were further investigated.A total of 112 and 333 integration breakpoints were detected in the HepG2-NTCP cells and 22 out of 25(88%)clinical HBV-infected samples,*** vivo analysis showed that the normalized number of support unique sequences(nnsus)in HCC was significantly higher than in CHB or LC patients(P values<0.05).All integration breakpoints are randomly distributed on human chromosomes and are enriched in the HBV genome around nt *** majority of integration breakpoints(61.86%)are located in the gene-coding *** non-homologous end-joining(NHEJ)and microhomology-mediated end-joining(MMEJ)interactions occurred during HBV integration across the three different stages of liver *** study provides evidence that HBV DNA integration can be detected in the plasma cfDNA of HBV-infected patients,including those with CHB,LC,or HCC,using this optimized strategy.

关键词： Hepatitis B virus(HBV) DNA integration Cell-free DNA(cfDNA) DNA capture

The antiviral treatment should be initiated before the development of cirrhosis

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Hepatobiliary Surgery and Nutrition 2024年第1期13卷 136-138页

作者： Qiao Tang Peng Hu Department of infectious diseases Institute for Viral HepatitisThe Key Laboratory of Molecular Biology for Infectious DiseasesChinese Ministry of EducationThe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Hepatitis B virus(HBV)infection increases the risk of liver fibrosis,cirrhosis and hepatocellular carcinoma(HCC)(1).International guidelines recommend antiviral treatment for eligible patients to prevent the development of HCC and the progression of liver ***,there is discrepancy in these guidelines regarding treatment recommendations for patients with compensated cirrhosis and low-level viremia(LLV),defined as serum HBV-DNA level of 20-2,000 IU/mL(2-4).And data on the natural history of untreated compensated cirrhotic patients with LLV is limited.

关键词： Low-level viraemia maintained virological response(MVR) untreated hepatocellular carcinoma(HCC) decompensated cirrhosis

Safety and Immunogenicity After Primary and Booster Inactivated SARS-Cov-2 Vaccination in Patients with Autoimmune Liver diseases

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Journal of Clinical and Translational Hepatology 2024年第2期12卷 162-171页

作者： Zhiwei Chen Yuting Wang Taiyu He Hu Li Ling Ao Qingbo Pan Yingzhi Zhou Qian Zhu Dejuan Xiang Gaoli Zhang Ning Ling Min Chen Peng Hu Mingli Peng Dachuan Cai Dazhi Zhang Hong Ren Department of infectious diseases the Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina Key Laboratory of molecular biology for infectious diseases(Ministry of Education) Institute for Viral Hepatitisthe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Background and Aims:SARS-CoV-2 vaccines-associated autoimmune liver diseases have been reported in several case ***,the safety and immunogenicity after primary and booster inactivated SARS-CoV-2 vaccination in patients with autoimmune liver diseases(AILD)is still ***:Eighty-four patients with AILD were prospectively followed up after the second dose(primary)of inactivated SARS-CoV-2 *** of them received the third dose(booster)of inactivated *** events(AEs),autoimmune activation,and liver inflammation exacerbation after primary and booster vaccination were ***,dynamics of antireceptor-binding-domain IgG(anti-RBD-IgG),neutralizing antibodies(NAbs)and RBD-specific B cells responses were ***:The overall AEs in AILD patients after primary and booster vaccination were 26.2%and 13.3%,*** decrease of C3 level and increase of immunoglobulin light chain K andλlevels were observed in AILD patients after primary vaccination,however,liver inflammation was not exacerbated,even after booster *** the seroprevalence and titers of anti-RBD-IgG and NAbs were decreased over time in AILD patients after primary ***,the antibody titers were significantly elevated after booster vaccination(10-fold in anti-RBD-IgG and 7.4-fold in NAbs,respectively),which was as high as in healthy ***,the inferior antibody response was not enhanced after booster vaccination in patients with *** of atypical memory B cells were inversely related to antibody levels,which indicate that the impaired immune memory was partially restored partly by the booster ***:The well tolerability and enhanced humoral immune response of inactivated vaccine supports an additional booster vaccination in AILD patients without immunosuppressants.

关键词： SARS-CoV-2 Autoimmune liver disease Inactivated SARS-CoV-2 vaccine Safety Antibody responses Memory B cells

Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling

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Genes & diseases 2024年第5期11卷 470-483页

作者： Zhirong Zhang Jiayao Yang Rui Liu Jing Ma Kai Wang Xiaojun Wang Ni Tang Key Laboratory of molecular biology for infectious diseases(Ministry of Education) Institute for Viral HepatitisDepartment of Infectious DiseasesThe Second Affiliated HospitalChongqing Medical UniversityChongqing 400016China Institute of Hepatobiliary Surgery Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China

Cancer stem cells(CSCs)play a crucial role in tumor initiation,recurrence,metastasis,and drug ***,the current understanding of CSCs in hepatocellular carcinoma(HCC)remains *** a comprehensive analysis of the database,it has been observed that 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMGCR),a critical enzyme involved in cholesterol synthesis,is up-regulated in HCC tissues and liver ***,high expression of HMGCR is associated with a poor prognosis in patients with ***,HMGCR promotes the stemness and metastasis of HCC both in vitro and in *** screening various signaling pathway inhibitors,we have determined that HMGCR regulates stemness and metastasis by activating the Hedgehog signaling in ***,HMGCR positively correlates with the expression of the Smoothened receptor and facilitates the nuclear translocation of the transcriptional activator GLI family zinc finger *** of the Hedgehog pathway can reverse the stimulatory effects of HMGCR on stemness and metastasis in ***,simvastatin,an FDA-approved cholesterol-lowering drug,has been shown to inhibit stemness and metastasis of HCC by targeting *** together,our findings suggest that HMGCR promotes the regeneration and metastasis of HCC through the activation of Hedgehog signaling,and simvastatin holds the potential for clinical suppression of HCC metastasis.

关键词： Cancer stem cells Hedgehog Hepatocellular carcinoma Metastasis Statin

Mesenchymal Stem Cells Alleviate Acute Liver Failure through Regulating Hepatocyte Apoptosis and Macrophage Polarization

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Journal of Clinical and Translational Hepatology 2024年第6期12卷 571-580页

作者： Yachao Tao Yonghong Wang Menglan Wang Hong Tang Enqiang Chen Center of infectious diseases West China HospitalSichuan UniversityChengduSichuanChina division of infectious diseases State Key Laboratory of BiotherapySichuan UniversityChengduSichuanChina

Background and Aims:Acute liver failure(ALF)is a life-threatening clinical problem with limited treatment *** of human umbilical cord mesenchymal stem cells(hUC-MSCs)may be a promising approach for *** study aimed to explore the role of hUC-MSCs in the treat-ment of ALF and the underlying ***:A mouse model of ALF was induced by lipopolysaccharide and d-galactosamine *** therapeutic effects of hUC-MSCs were evaluated by assessing serum enzyme activity,histological appearance,and cell apoptosis in liver *** apoptosis rate was analyzed in AML12 *** levels of inflammatory cytokines and the phenotype of RAW264.7 cells co-cultured with hUC-MSCs were *** C-Jun N-terminal kinase/nuclear factor-kappa B signal-ing pathway was ***:The hUC-MSCstreatment decreased the levels of serum alanine aminotransferase and aspartate aminotransferase,reduced pathological damage,alleviated hepatocyte apoptosis,and reduced mortality in *** hUC-MSCs co-culture reduced the apoptosis rate of AML12 cells in ***,lipopolysaccharide-stimulated RAW264.7 cells had higher levels of tumor necrosis factor-α,interleukin-6,and interleukin-1β and showed more CD86-positive cells,whereas the hUC-MSCs co-culture reduced the levels of the three inflammatory cytokines and increased the ratio of CD206-positive *** hUC-MSCs treatment inhibited the activation of phosphorylated(p)-C-Jun N-terminal kinase and p-nuclear factor-kappa B not only in liver tissues but also in AML12and RAW264.7 cells co-cultured with ***:hUC-MSCs could alleviate ALF by regulating hepatocyte apoptosis and macrophage polarization,thus hUC-MSC-based cell therapy may be an alternative option for patients with ALF.

关键词： Human umbilical cord mesenchymal stem cells Acute liver failure Hepatocyte apoptosis Hepatitis Macrophage polarization LPS/D-GalN

Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease

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Science China(Life Sciences) 2024年第6期67卷 1183-1198页

作者： Shiman Jiang Lvwan Xu Yanfei Chen Zheyue Shu Longxian Lv Yuxi Zhao Kefan Bi Sisi Yang Qiangqiang Wang Lanjuan Li State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Liver disease,a major health concern worldwide,is a serious and progressive ***,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut *** liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse *** metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC *** abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in *** on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were *** increased abundance of *** and depletion of *** may be hallmarks of the progression of liver cirrhosis to early ***,the administration of *** and *** in the LC-HCC progression could accelerate or retard the progression of ***,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

关键词： gut mycobiome liver disease longitudinal studies hepatocarcinogenesis fungal biomarker

Interconnection of cellular autophagy and endosomal vesicle trafficking and its role in hepatitis B virus replication and release

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Virologica Sinica 2024年第1期39卷 24-30页

作者： Jia Li Yong Lin Xueyu Wang Mengji Lu Institute for Virology University Hospital EssenUniversity of Duisburg-EssenEssen45122Germany Key Laboratory of molecular biology of infectious diseases(Chinese Ministry of Education) Chongqing Medical UniversityChongqing400016China The Key Laboratory for Diagnosis and Treatment of infectious diseases The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou310000China

Hepatitis B virus(HBV)produces and releases various particle types,including complete virions,subviral particles with envelope proteins,and naked *** studies demonstrate that HBV exploits distinct intracellular membrane trafficking pathways,including the endosomal vesicle trafficking and autophagy pathway,to assemble and release viral and subviral ***,we summarize the findings about the distinct roles of autophagy and endosomal membrane trafficking and the interaction of both pathways in HBV replication,assembly,and release.

关键词： Amphisome Autophagy Endosomal vesicle Hepatitis B virus(HBV)

Immune landscape and response to oncolytic virus-based immunotherapy

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Frontiers of Medicine 2024年第3期18卷 411-429页

作者： Chaolong Lin Wenzhong Teng Yang Tian Shaopeng Li Ningshao Xia Chenghao Huang State Key Laboratory of Vaccines for infectious diseases Xiang An Biomedicine LaboratoryDepartment of Laboratory MedicineSchool of Public HealthXiamen UniversityXiamen361102China National Institute of Diagnostics and Vaccine Development in infectious diseases State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsXiamen UniversityXiamen361102China

Oncolytic virus(OV)-based immunotherapy has emerged as a promising strategy for cancer treatment,offering a unique potential to selectively target malignant cells while sparing normal ***,the immunosuppressive nature of tumor microenvironment(TME)poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents,as it restricts the activation and recruitment of immune *** review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune *** examine the role of OVs in targeting specific immune cell populations,including dendritic cells,T cells,natural killer cells,and macrophages,and their ability to alter the TME by inhibiting angiogenesis and reducing tumor ***,we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated *** conclusion,this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy,underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

关键词： oncolytic virus immunotherapy immunotherapeutic agents immune landscape

The immune response to SARS-CoV-2 in people with HIV

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Cellular & molecular Immunology 2024年第2期21卷 184-196页

作者： Maxine A.Höft Wendy A.Burgers Catherine Riou Institute of infectious Disease and molecular Medicine University of Cape TownCape TownSouth Africa division of Medical Virology Department of PathologyUniversity of Cape TownCape TownSouth Africa Wellcome Centre for infectious diseases Research in Africa University of Cape TownCape TownSouth Africa

This review examines the intersection of the HIV and SARS-CoV-2 *** with HIV(PWH)are a heterogeneous group that differ in their degree of immune suppression,immune reconstitution,and viral *** COVID-19 in those with wellcontrolled HIV infection poses no greater risk than that for HIV-uninfected individuals,people with advanced HIV disease are more vulnerable to poor COVID-19 ***-19 vaccines are effective and well tolerated in the majority of PWH,though reduced vaccine efficacy,breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in *** is likely a result of suboptimal humoral and cellular immune responses after *** with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants,but initiation or resumption of antiretroviral therapy(ART)can effectively clear persistent ***-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely *** recommend continued research and monitoring of PWH with SARS-CoV-2 infection,especially in areas with a high HIV burden.

关键词： SARS-CoV-2 HIV Immune dysfunction Vaccine efficacy Prolonged infection Immunogenicity