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Novel Approaches to Inhibition of HBsAg Expression from cccDNA and Chromosomal Integrants:A Review

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Journal of Clinical and Translational Hepatology 2023年第7期11卷 1485-1497页

作者： Ahmed H.Abdelwahed Brent D.Heineman George Y.Wu department of medicine Division of Gastroenterology-HepatologyUniversity of Connecticut Health CenterFarmingtonCTUSA

Hepatitis B virus(HBV)is a widely prevalent liver infection that can cause acute or chronic *** current treatment modalities are highly effective in the suppression of viral levels,they cannot eliminate the virus or achieve definitive *** is a consequence of the complex nature of HBV-host *** challenges to achieving sustained viral suppression include the presence of a high viral burden from the HBV DNA and hepatitis B surface antigen(HBsAg),the presence of reservoirs for HBV replication and antigen production,and the HBV-impaired innate and adaptive immune response of the *** therapeutic methods include cell entry inhibitors,HBsAg inhibitors,gene editing approaches,immune-targeting therapies and direct inhibitors of covalently closed circular DNA(cccDNA).Novel approaches that target these key mechanisms are now being studied in preclinical and clinical *** this review article,we provide a comprehensive review on mechanisms by which HBV escapes elimination from current treatments,and highlight new agents to achieve a definitive HBV cure.

关键词： Hepatitis B Viruses Liver disease Hepatocytes Gene editing

Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

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The Journal of Biomedical Research 2024年第1期38卷 37-50页

作者： Sumeng Wang Silu Chen Huiqin Li Shuai Ben Tingyu Zhao Rui Zheng Meilin Wang Dongying Gu Lingxiang Liu department of Oncology the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China department of Genetic Toxicology the Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China department of Biostatistics Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China department of Oncology Nanjing First HospitalNanjing Medical UniversityNanjingJiangsu 210006China.

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is *** address this gap,we conducted a study aiming to investigate this association and identify relevant *** analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune ***,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)*** employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune *** findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal ***,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA *** conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

关键词： trans-omics DNA replication tumor immune microenvironment causal mediation colorectal tumorigenesis

Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma

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World Journal of gastroenterology 2016年第37期22卷 8271-8282页

作者： Stijn Van Hees Peter Michielsen Thomas Vanwolleghem department of gastroenterology and Hepatology Antwerp University Hospital Laboratory of Experimental medicine and Pediatrics University of Antwerp

Chronic hepatitis B virus(HBV) infected patients have an almost 100-fold increased risk to develop hepatocellular carcinoma(HCC). HCC is the fifth most common and third most deadly cancer worldwide. Up to 50% of newly diagnosed HCC cases are attributed to HBV infection. Early detection improves survival and can be achieved through regular screening. Six-monthly abdominal ultrasound, either alone or in combination with alphafetoprotein serum levels, has been widely endorsed for this purpose. Both techniques however yield limited diagnostic accuracy, which is not improved when they are combined. Alternative circulating or histological markers to predict or diagnose HCC are therefore urgently needed. Recent advances in systems biology technologies have enabled the identification of several new putative circulating biomarkers. Although results from studies assessing combinations of these biomarkers are promising, evidence for their clinical utility remains low. In addition, most of the studies conducted so far show limitations in design. Attention must be paid for instance to different ethnicities and different etiologies when studying biomarkers for hepatocellular carcinoma. This review provides an overview on the current understandings and recent progress in the field of diagnostic and predictive circulating biomarkers for hepatocellular carcinoma in chronically infected HBV patients and discusses the future prospects.

关键词： Hepatocellular carcinoma Hepatitis B virus infection Biomarkers Predictive Diagnostic Alphafetoprotein Validation Limitations MicroR NA

Portal vein thrombosis in cirrhosis: Why a well-known complication is still matter of debate

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World Journal of gastroenterology 2019年第31期25卷 4437-4451页

作者： Mariella Faccia Maria Elena Ainora Francesca Romana Ponziani Laura Riccardi Matteo Garcovich Antonio Gasbarrini Maurizio Pompili Maria Assunta Zocco department of Internal medicine and gastroenterology Fondazione Policlinico Universitario A.Gemelli IRCCSCatholic University

Portal vein thrombosis(PVT)represents a well-known complication during the natural course of liver cirrhosis(LC),ranging from asymptomatic cases to lifethreating conditions related to portal hypertension and hepatic *** flow stasis,complex acquired hypercoagulable disorders and exogenous factors leading to endothelial dysfunction have emerged as key factors for PVT ***,PVT occurrence remains unpredictable and many issues regarding its natural history,prognostic significance and treatment are still *** particular although spontaneous resolution or disease stability occur in most cases of PVT,factors predisposing to disease progression or recurrence after spontaneous recanalization are not clarified as ***,PVT impact on LC outcome is still debated,as PVT may represent itself a consequence of liver fibrosis and hepatic dysfunction *** and transjugular intrahepatic portosystemic shunt are considered safe and effective in this setting and are recommended in selected cases,even if the safer therapeutic option and the optimal therapy duration are still ***,their impact on mortality rates should be addressed more *** this review we present the most debated questions regarding PVT,whose answers should come from prospective cohort studies and large sample-size randomized trials.

关键词： Portal vein thrombosis Liver cirrhosis Hypercoagulability Anticoagulation Direct oral anticoagulants

Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis

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Chinese Medical Journal 2024年第2期137卷 181-189页

作者： Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang department of Physiology State Key Laboratory of Common Mechanism Research for Major DiseasesHaihe Laboratory of Cell EcosystemInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China department of Physiology Institute of Basic Medical Sciences and School of Basic MedicineGraduate School of Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China department of Physiology School of Life ScienceChina Medical UniversityShenyangLiaoning 110122China School of Life Sciences Westlake UniversityHangzhouZhejiang 310024China Key Laboratory of Pediatric Hematology and Oncology Ministry of HealthInstitute of Pediatric Translational MedicineShanghai Children’s Medical CenterShanghai Jiao Tong School of MedicineShanghai 200127China

Background:Liver cancer is largely resistant to *** study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic ***:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type *** metabolomics was carried out to examine the alterations of metabolites in nucleotide *** efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in ***-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver ***:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated *** nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of ***,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver ***:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver *** repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关键词： Liver cancer β-catenin Methotrexate Nucleotide synthesis Chemotherapy

Non-invasive diagnosis of liver fibrosis in chronic hepatitis C

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World Journal of gastroenterology 2014年第11期20卷 2854-2866页

作者： Leonardo de Lucca Schiavon Janaína Luz Narciso-Schiavon Roberto José de Carvalho-Filho gastroenterology Division Department of Internal MedicineFederal University of Santa CatarinaFlorianópolisSC 88040-900Brazil gastroenterology Division Department of MedicineFederal University of Sao PauloSao PauloSP 04023-900Brazil

Assessment of liver fibrosis in chronic hepatitis C virus(HCV)infection is considered a relevant part of patient care and key for decision *** liver biopsy has been considered the gold standard for staging liver fibrosis,it is an invasive technique and subject to sampling errors and significant intra-and inter-observer *** the last decade,several noninvasive markers were proposed for liver fibrosis diagnosis in chronic HCV infection,with variable *** the clear advantage of being noninvasive,a more objective interpretation of test results may overcome the mentioned intra-and inter-observer variability of liver *** addition,these tests can theoretically offer a more accurate view of fibrogenic events occurring in the entire liver with the advantage of providing frequent fibrosis evaluation without additional ***,in general,these tests show low accuracy in discriminating between intermediate stages of fibrosis and may be influenced by several hepatic and extrahepatic *** methods are either serum markers(usually combined in a mathematical model)or imaging modalities that can be used separately or combined in algorithms to improve *** this review we will discuss the different noninvasive methods that are currently available for the evaluation of liver fibrosis in chronic hepatitis C,their advantages,limitations and application in clinical practice.

关键词： Liver fibrosis Liver cirrhosis Hepatitis C Diagnosis Elasticity imaging techniques

Risk prediction rule for advanced neoplasia on screening colonoscopy for average-risk individuals

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World Journal of gastroenterology 2020年第37期26卷 5705-5717页

作者： Ala I Sharara Ali El Mokahal Ali H Harb Natalia Khalaf Fayez S Sarkis Mustapha M El-Halabi Nabil M Mansour Ahmad Malli Robert Habib Division of gastroenterology Department of Internal MedicineAmerican University of Beirut Medical CenterBeirut 11072020Lebanon Digestive and Liver Diseases Division University of Texas-SouthwesternDallasTX 75390United States Division of gastroenterology Department of Internal MedicineBaylor College of MedicineHoustonTX 77030United States Division of gastroenterology and Hepatology University of Kansas Medical CenterKansas CityMO 66160United States Division of gastroenterology St Elizabeth HealthcareCrestview HillsKY 41017United States department of Internal medicine Section of Gastroenterology and HepatologyBaylor College of MedicineHoustonTX 77030United States gastroenterology Hennepin HealthcareMinneapolisMN 55404United States department of Internal medicine American University of BeirutBeirut 11072020Lebanon

BACKGROUND In resource-limited countries,risk stratification can be used to optimize colorectal cancer *** prospective risk prediction models exist for advanced neoplasia(AN)in true average-risk *** To create and internally validate a risk prediction model for detection of AN in METHODS Prospective study of asymptomatic individuals undergoing first screening *** characteristics including diet,exercise and medications were *** logistic regression was used to elucidate risk factors for AN(adenoma≥1 cm,villous histology,high-grade dysplasia or carcinoma).The model was validated through bootstrapping,and discrimination and calibration of the model were *** 980 consecutive individuals(51%F;49%M)were *** and AN detection rates were 36.6%(F 29%:M 45%;P<0.001)and 5.1%(F 3.8%;M 6.5%)*** multivariate analysis,predictors of AN[OR(95%CI)]were age[1.036(1.00-1.07);P=0.048],BMI[overweight 2.21(0.98-5.00);obese 3.54(1.48-8.50);P=0.018],smoking[<40 pack-years 2.01(1.01-4.01);≥40 pack-years 3.96(1.86-8.42);P=0.002],and daily red meat consumption[2.02(0.92-4.42)P=0.079].Nomograms of AN risk were developed in terms of risk factors and age separately for normal,overweight and obese *** model had good discrimination and *** The prevalence of adenoma and AN in average-risk Lebanese individuals is similar to the ***,smoking,and BMI are important predictors of AN,with obesity being particularly *** external validation is needed,this model provides an important platform for improved risk-stratification for screening programs in regions where universal screening is not currently employed.

关键词： Colon Adenoma Cancer Risk factors

Transforming growth factor-β1 induces intestinal myofibroblast differentiation and modulates their migration

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World Journal of gastroenterology 2009年第12期15卷 1431-1442页

作者： Julia Brenmoehl Sandra Nicole Miller Claudia Hofmann Daniela Vogl Werner Falk Jrgen Schlmerich Gerhard Rogler department of Internal medicine Ⅰ University of Regensburg93055 Regensburg Germany department of Internal medicine Ⅱ University of Jena07747 Jena Germany Clinic of gastroenterology and Hepatology Department of Internal MedicineUniversity Hospital of Zurich8091 ZurichSwitzerland

AIM： To investigate the effects of transforming growth factor β1 （TGF-β1） on the differentiation of colonic lamina propria fibroblasts （CLPF） into myofibroblasts in vitro.METHODS： Primary CLPF cultures were incubated with TGF-β1 and analyzed for production of m-smooth muscle actin （α-SMA）, fibronectin （FN） and FN isoforms. Migration assays were performed in a modified 48-well Boyden chamber. Levels of total and phosphorylated focal adhesion kinase （FAK） in CLPF were analyzed after induction of *** not change α-SMA levels, while TGF-β1 treatment for 6 d significantly increased α-SIVlA production. Short term incubation （6 h） with TGF-β1 enhanced CLPF migration, while long term treatment （6 d） of CLPF with TGF-β1 reduced migration to 15%-37% compared to untreated cells. FN and FN isoform mRNA expression were increased after short term incubation with TGF-β1 （2 d） in contrast to long term incubation with TGF-β1 for 6 d. After induction of migration, TGF-β1-preincubated CLPF showed higher amounts of FN and its isoforms and lower levels of total and phosphorylated FAK than untreated cells.CONCLUSION： Long term incubation of CLPF with TGF-β1 induced differentiation into myofibroblasts with enhanced α-SMA, reduced migratory potential and FAK phosphorylation, and increased FN production. In contrast, short term contact （6 h） of fibroblasts with TGF-β1 induced a dose-dependent increase of cell migration and FAK phosphorylation without induction of α-SMA production.

关键词： Transforming growth factor β1 Colonicfibroblasts Myofibroblasts Migration Fibronectin

Two-week bismuth-containing quadruple therapy and concomitant therapy are effective first-line treatments for Helicobacter pylori eradication: A prospective open-label randomized trial

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World Journal of gastroenterology 2019年第46期25卷 6790-6798页

作者： So Jeong Kim Jun-Won Chung Hyun Sun Woo Su Young Kim Jung Ho Kim Yoon Jae Kim Kyoung Oh Kim Kwang An Kwon Dong Kyun Park College of medicine Gachon University Graduate School of MedicineIncheon 21936South Korea Division of gastroenterology Department of Internal MedicineGachon University Gil Medical CenterIncheon 21565South Korea Division of gastroenterology Department of Internal MedicineYonsei University Wonju College of MedicineWonju 26426South Korea

BACKGROUND Increasing levels of antibiotic resistance have reduced the Helicobacter pylori(***)eradication rates afforded by the standard triple ***,2-wk firstline four-drug regimens must be *** To analyze the eradication rates of modified bismuth-containing quadruple therapy(mBCQT)and concomitant therapy(CT),the associated adverse events,and *** Patients infected with *** were prospectively randomized to receive mBCQT or CT for 2 *** featured a proton pump inhibitor(PPI),bismuth,metronidazole,and tetracycline,taken twice *** included a PPI,clarithromycin,metronidazole,and amoxicillin,taken twice *** 13C-urea breath test was performed no earlier than 4 wk after therapy concluded to confirm *** either the histological or rapid urease test was positive,*** infection was *** The demographic characteristics of 68 patients who received mBCQT and 68 who received CT did not differ *** intention-to-treat analysis,the eradication rate was 88.2%(60/68)in the mBCQT group and 79.4%(54/68)in the CT group(P=0.162).By per-protocol analysis,the respective eradication rates were 98.4%(60/61)and 93.1%(54/58)(P=0.199).More CT than mBCQT patients experienced adverse events[33.8%(23/68)mBCQT vs 51.5%(35/58)CT patients,respectively,P=0.037].All patients showed good compliance[85.3%(58/68)mBCQT vs 82.4%(56/68)CT patients,P=0.641].CONCLUSION The *** eradication rates of the 2-wk mBCQT and CT regimens are *** patients show good compliance,and more CT than mBCQT patients experience adverse events.

关键词： Helicobacter pylori Therapy Bismuth-containing quadruple therapy Concomitant therapy