1 427 142 ANTI-HEPATITIS B VIRUS ACTIVITY OF FOOD NUTRIENTS AND POTENTIAL MECHANISMS OF ACTION. HEPATITIS B VIRUS (HBV) IS ENDEMIC IN MANY PARTS OF THE WORLD AND IS A SIGNIFICANT CAUSE OF CHRONIC LIVER DAMAGE AND HEPATOCELLULAR CARCINOMA. HBV THERAPEUTICS VARY ACCORDING TO THE DISEASE STAGE. THE BEST THERAPEUTIC OPTION FOR PATIENTS WITH END-STAGE LIVER DISEASE IS LIVER TRANSPLANTATION, WHILE FOR CHRONIC PATIENTS, HBV INFECTION IS COMMONLY MANAGED USING ANTIVIRALS (NUCLEOS(T)IDES ANALOGS OR INTERFERONS). HOWEVER, DUE TO THE ACCESSIBILITY ISSUES AND THE HIGH COST OF ANTIVIRALS, MOST HBV PATIENTS DO NOT HAVE ACCESS TO TREATMENT. THESE COMPLICATIONS HAVE LED RESEARCHERS TO RECONSIDER TREATMENT APPROACHES, SUCH AS NUTRITIONAL THERAPY. THIS REVIEW SUMMARIZES THE NUTRIENTS REPORTED TO HAVE ANTIVIRAL ACTIVITY AGAINST HBV AND THEIR POSSIBLE MECHANISM OF ACTION. RECENT STUDIES SUGGEST RESVERATROL, VITAMIN E, LACTOFERRIN, SELENIUM, CURCUMIN, LUTEOLIN-7-O-GLUCOSIDE, MORINGA EXTRACTS, CHLOROGENIC ACID, AND EPIGALLOCATECHIN-3-GALLATE MAY BE BENEFICIAL FOR PATIENTS WITH HEPATITIS B. THE ANTI-HBV EFFECT OF MOST OF THESE NUTRIENTS HAS BEEN ANALYZED IN VITRO AND IN ANIMAL MODELS. DIFFERENT ANTIVIRAL AND HEPATOPROTECTIVE MECHANISMS HAVE BEEN PROPOSED FOR THESE NUTRIENTS, SUCH AS THE ACTIVATION OF ANTIOXIDANT AND ANTI-INFLAMMATORY PATHWAYS, REGULATION OF METABOLIC HOMEOSTASIS, EPIGENETIC CONTROL, ACTIVATION OF THE P53 GENE, INHIBITION OF ONCOGENES, INHIBITION OF VIRUS ENTRY, AND INDUCTION OF AUTOPHAGOSOMES. IN CONCLUSION, SCIENTIFIC EVIDENCE INDICATES THAT HBV REPLICATION, TRANSCRIPTION, AND EXPRESSION OF VIRAL ANTIGENS CAN BE AFFECTED DIRECTLY BY NUTRIENTS. IN THE FUTURE, THESE NUTRIENTS MAY BE CONSIDERED TO DEVELOP APPROPRIATE NUTRITIONAL MANAGEMENT FOR PATIENTS WITH HEPATITIS B. 2023 2 3250 46 HEPATITIS B VIRUS INFECTION, MICRORNAS AND LIVER DISEASE. HEPATITIS B VIRUS (HBV) ATTACKS THE LIVER AND CAN CAUSE BOTH ACUTE AS WELL AS CHRONIC LIVER DISEASES WHICH MIGHT LEAD TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. REGARDLESS OF THE AVAILABILITY OF A VACCINE AND NUMEROUS TREATMENT OPTIONS, HBV IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY ACROSS THE WORLD. RECENTLY,MICRORNAS (MIRNAS) HAVE EMERGED AS IMPORTANT MODULATORS OF GENE FUNCTION. STUDIES ON THE ROLE OF MIRNA IN THE REGULATION OF HEPATITIS B VIRUS GENE EXPRESSION HAVE BEEN THE FOCUS OF MODERN ANTIVIRAL RESEARCH. MIRNAS CAN REGULATE VIRAL REPLICATION AND PATHOGENESIS IN A NUMBER OF DIFFERENT WAYS, WHICH INCLUDEFACILITATION, DIRECT OR INDIRECT INHIBITION, ACTIVATION OF IMMUNE RESPONSE, EPIGENETIC MODULATION, ETC. NEVERTHELESS, THESE MECHANISMS CAN APPROPRIATELY BE USED WITH A DIAGNOSTICAND/OR THERAPEUTIC APPROACH. THE PRESENT REVIEW IS AN ATTEMPT TO CLASSIFY SPECIFIC MIRNAS THAT ARE REPORTED TO BE ASSOCIATED WITH VARIOUS ASPECTS OF HEPATITIS B BIOLOGY, IN ORDER TO PRECISELY PRESENT THE PARTICIPATION OF INDIVIDUAL MIRNAS IN MULTIPLE ASPECTS RELATING TO HBV. 2015 3 6754 41 WILL WE NEED NOVEL COMBINATIONS TO CURE HBV INFECTION? CHRONIC HEPATITIS B IS A NUMERICALLY IMPORTANT CAUSE OF CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NUCLEOSIDE ANALOGUE THERAPY MAY MODIFY THE RISK. HOWEVER, MAINTENANCE SUPPRESSIVE THERAPY IS REQUIRED, AS A FUNCTIONAL CURE (GENERALLY DEFINED AS LOSS OF HBSAG OFF TREATMENT) IS AN UNCOMMON OUTCOME OF ANTIVIRAL TREATMENT. CHRONIC HEPATITIS B IS A NUMERICALLY IMPORTANT CAUSE OF CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NUCLEOSIDE ANALOGUE THERAPY MAY MODIFY THE RISK. HOWEVER, MAINTENANCE SUPPRESSIVE THERAPY IS REQUIRED, AS A FUNCTIONAL CURE (GENERALLY DEFINED AS LOSS OF HBSAG OFF TREATMENT) IS AN UNCOMMON OUTCOME OF ANTIVIRAL TREATMENT. CURRENTLY NUMEROUS INVESTIGATIONAL AGENTS BEING DEVELOPED TO EITHER INTERFERE WITH SPECIFIC STEPS IN HBV REPLICATION OR AS HOST CELLULAR TARGETING AGENTS, THAT INHIBIT VIRAL REPLICATION, AND DEPLETE OR INACTIVATE CCCDNA, OR AS IMMUNE MODULATORS. SYNERGISTIC MECHANISMS WILL BE NEEDED TO INCORPORATE A DECREASE IN HBV TRANSCRIPTION, IMPAIRMENT OF TRANSCRIPTION FROM HBV GENOMES, LOSS OF CCCDNA OR ALTERED EPIGENETIC REGULATION OF CCCDNA TRANSCRIPTION, AND IMMUNE MODULATION OR IMMUNOLOGICALLY STIMULATED HEPATOCYTE CELL TURNOVER. NUCLEOSIDE ANALOGUE SUPPRESSED PATIENTS ARE BEING INCLUDED IN MANY CURRENT TRIALS. TRIALS ARE PROGRESSING TO COMBINATION THERAPY AS ADDITIVE OR SYNERGISTIC EFFECTS ARE SOUGHT. THESE TRIALS WILL PROVIDE IMPORTANT INSIGHTS INTO THE BIOLOGY OF HBV AND PERTURBATIONS OF THE IMMUNE RESPONSE, REQUIRED TO EFFECT HBSAG LOSS AT DIFFERENT STAGES OF THE DISEASE. THE PROSPECT OF CURES OF HEPATITIS B WOULD ENSURE THAT A WIDE RANGE OF PATIENTS COULD BE DEEMED CANDIDATES FOR TREATMENT WITH NEW COMPOUNDS IF THESE WERE HIGHLY EFFECTIVE, FINITE AND SAFE. WITHDRAWAL OF THERAPY IN SHORT-TERM TRIALS IS CHALLENGING BECAUSE SHORT-TERM THERAPIES MAY RISK SEVERE HEPATITIS FLARES, AND HEPATIC DECOMPENSATION. THE LIMITED CLINICAL TRIAL DATA TO DATE SUGGEST THAT COMBINATION THERAPY IS INEVITABLE. 2020 4 3401 31 HOW DID HEPATITIS B VIRUS EFFECT THE HOST GENOME IN THE LAST DECADE? THE PRINCIPAL REASON OF CHRONIC LIVER DISEASE, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IS CHRONIC VIRAL HEPATITIS ALL OVER THE WORLD. HEPATITIS B VIRUS (HBV) HAS SOME MUTAGENIC EFFECTS ON THE HOST GENOME. HBV MAY BE EXHIBITING THESE MUTAGENIC EFFECTS THROUGH INTEGRATING INTO THE HOST GENOME, THROUGH ITS VIRAL PROTEINS OR THROUGH SOME EPIGENETIC MECHANISMS RELATED WITH HBV PROTEINS. THIS REVIEW AIMS TO SUMMARIZE THE MOLECULAR MECHANISMS USED BY HBV FOR EFFECTING HOST GENOME DETERMINED IN THE LAST DECADE. THE FOCUS WILL BE ON THE EFFECTS OF INTEGRATION, HBV PROTEINS, ESPECIALLY HBV X PROTEIN AND EPIGENETIC MECHANISMS ON THE HOST GENOME. THESE INTERACTIONS BETWEEN HBV AND THE HOST GENOME ALSO FORMS THE UNDERLYING MECHANISMS OF THE EVOLUTION OF HEPATOCELLULAR CARCINOMA. 2014 5 6016 43 THE ASSOCIATION BETWEEN HEPATOCARCINOGENESIS AND INTRACELLULAR ALTERATIONS DUE TO HEPATITIS B VIRUS INFECTION. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A WORLDWIDE HEALTH PROBLEM LEADING TO SEVERE LIVER DYSFUNCTION, INCLUDING LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. ALTHOUGH CURRENT ANTIVIRAL THERAPIES FOR CHRONIC HBV INFECTION HAVE BEEN IMPROVED AND CAN LEAD TO A STRONG SUPPRESSION OF VIRAL REPLICATION, IT IS DIFFICULT TO COMPLETELY ELIMINATE THE VIRUS WITH THESE THERAPIES ONCE CHRONIC HBV INFECTION IS ESTABLISHED IN THE HOST. FURTHERMORE, CHRONIC HBV INFECTION ALTERS INTRACELLULAR METABOLISM AND SIGNALLING PATHWAYS, RESULTING IN THE ACTIVATION OF CARCINOGENESIS IN THE LIVER. HBV PRODUCES FOUR VIRAL PROTEINS: HEPATITIS B SURFACE-, HEPATITIS B CORE-, HEPATITIS B X PROTEIN, AND POLYMERASE; EACH PLAYS AN IMPORTANT ROLE IN HBV REPLICATION AND THE INTRACELLULAR SIGNALLING PATHWAYS ASSOCIATED WITH HEPATOCARCINOGENESIS. IN VITRO AND IN VIVO EXPERIMENTAL MODELS FOR ANALYZING HBV INFECTION AND REPLICATION HAVE BEEN ESTABLISHED, AND GENE EXPRESSION ANALYSES USING MICROARRAYS OR NEXT-GENERATION SEQUENCING HAVE ALSO BEEN DEVELOPED. THUS, IT IS POSSIBLE TO CLARIFY THE MOLECULAR MECHANISMS FOR INTRACELLULAR ALTERATIONS, SUCH AS ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND EPIGENETIC MODIFICATIONS. IN THIS REVIEW, THE IMPACT OF HBV VIRAL PROTEINS AND INTRACELLULAR ALTERATIONS IN HBV-ASSOCIATED HEPATOCARCINOGENESIS ARE DISCUSSED. 2021 6 915 43 CHRONIC HEPATITIS B VIRUS AND HEPATITIS C VIRUS INFECTIONS AND CANCER: SYNERGY BETWEEN VIRAL AND HOST FACTORS. HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) INFECTIONS REPRESENT MAJOR CAUSES OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. DESPITE INDUCING SHARED PATHOLOGICAL EVENTS LEADING TO ONCOGENIC TRANSFORMATION, THESE TWO VIRUSES PRESENT PROFOUND DIFFERENCES IN THEIR MOLECULAR FEATURES, LIFE CYCLE AND INTERPLAY WITH HOST FACTORS, WHICH SIGNIFICANTLY DIFFERENTIATE THE PROGNOSTIC AND THERAPEUTIC APPROACH TO THE RELATED DISEASES. IN THE PRESENT REVIEW, WE REPORT THE MAIN MECHANISMS INVOLVED IN THE MULTISTEP PROCESS LEADING FROM HCV/HBV INFECTION AND CANCER DEVELOPMENT, DISCUSSING SIDE-BY-SIDE THE ANALOGIES AND DIFFERENCES BETWEEN THE TWO VIRUSES. SUCH EVENTS CAN BE BROADLY CATEGORIZED INTO (A) DIRECT ONCOGENIC EFFECTS, INVOLVING INTEGRATION IN THE HOST GENOME (IN THE CASE OF HBV) AND CHROMOSOMAL INSTABILITY, INTERFERENCE WITH ONCOSUPPRESSOR PATHWAYS, INDUCTION OF OXIDATIVE STRESS, PROMOTION OF ANGIOGENESIS, EPITHELIAL-MESENCHYMAL TRANSITION, ALTERATIONS IN THE EPIGENETIC ASSET AND INTERACTION WITH NON-CODING RNAS; AND (B) INDIRECT ACTIVITIES MOSTLY MEDIATED BY HOST EVENTS, INCLUDING CHRONIC INFLAMMATION SUSTAINED BY PECULIAR CYTOKINE NETWORKS (SUCH AS INTERLEUKIN-6 AND LYMPHOTOXINS), METABOLIC DYSFUNCTIONS PROMOTED BY STEATOHEPATITIS, INTERPLAY WITH GUT MICROBIOTA AND FIBROTIC EVENTS (MAINLY IN HCV INFECTION). THIS SCENARIO SUGGESTS THAT THE INTEGRATED STUDY OF VIRAL AND HOST FACTORS MAY LEAD TO THE SUCCESSFUL DEVELOPMENT OF NOVEL BIOMARKERS AND TARGETS FOR THERAPY. 2015 7 6479 42 TOWARD A NEW ERA OF HEPATITIS B VIRUS THERAPEUTICS: THE PURSUIT OF A FUNCTIONAL CURE. HEPATITIS B VIRUS (HBV) INFECTION, ALTHOUGH PREVENTABLE BY VACCINATION, REMAINS A GLOBAL HEALTH PROBLEM AND A MAJOR CAUSE OF CHRONIC LIVER DISEASE. ALTHOUGH CURRENT TREATMENT STRATEGIES SUPPRESS VIRAL REPLICATION VERY EFFICIENTLY, THE OPTIMAL ENDPOINT OF HEPATITIS B SURFACE ANTIGEN (HBSAG) CLEARANCE IS RARELY ACHIEVED. MOREOVER, THE THORNY PROBLEMS OF PERSISTENT CHROMATIN-LIKE COVALENTLY CLOSED CIRCULAR DNA AND THE PRESENCE OF INTEGRATED HBV DNA IN THE HOST GENOME ARE IGNORED. THEREFORE, THE SCIENTIFIC COMMUNITY HAS FOCUSED ON DEVELOPING INNOVATIVE THERAPEUTIC APPROACHES TO ACHIEVE A FUNCTIONAL CURE OF HBV, DEFINED AS UNDETECTABLE HBV DNA AND HBSAG LOSS OVER A LIMITED TREATMENT PERIOD. A DEEPER UNDERSTANDING OF THE HBV LIFE CYCLE HAS LED TO THE INTRODUCTION OF NOVEL DIRECT-ACTING ANTIVIRALS THAT EXERT THEIR FUNCTION THROUGH MULTIPLE MECHANISMS, INCLUDING INHIBITION OF VIRAL ENTRY, TRANSCRIPTIONAL SILENCING, EPIGENETIC MANIPULATION, INTERFERENCE WITH CAPSID ASSEMBLY, AND DISRUPTION OF HBSAG RELEASE. IN PARALLEL, ANOTHER CATEGORY OF NEW DRUGS AIMS TO RESTORE DYSREGULATED IMMUNE FUNCTION IN CHRONIC HEPATITIS B ACCOMPANIED BY LETHARGIC CELLULAR AND HUMORAL RESPONSES. STIMULATION OF INNATE IMMUNITY BY PATTERN-RECOGNITION RECEPTOR AGONISTS LEADS TO UPREGULATION OF ANTIVIRAL CYTOKINE EXPRESSION AND APPEARS TO CONTRIBUTE TO HBV CONTAINMENT. IMMUNE CHECKPOINT INHIBITORS AND ADOPTIVE TRANSFER OF GENETICALLY ENGINEERED T CELLS ARE BREAKTHROUGH TECHNOLOGIES CURRENTLY BEING EXPLORED THAT MAY ELICIT POTENT HBV-SPECIFIC T-CELL RESPONSES. IN ADDITION, SEVERAL CLINICAL TRIALS ARE ATTEMPTING TO CLARIFY THE ROLE OF THERAPEUTIC VACCINATION IN THIS SETTING. ULTIMATELY, IT IS INCREASINGLY RECOGNIZED THAT ELIMINATION OF HBV REQUIRES A TREATMENT REGIMEN BASED ON A COMBINATION OF MULTIPLE DRUGS. THIS REVIEW DESCRIBES THE RATIONALE FOR PROGRESSIVE THERAPEUTIC INTERVENTIONS AND DISCUSSES THE LATEST FINDINGS IN THE FIELD OF HBV THERAPEUTICS. 2021 8 4687 30 NEW TOOLS FOR MOLECULAR THERAPY OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER, ARISING FROM NEOPLASTIC TRANSFORMATION OF HEPATOCYTES OR LIVER PRECURSOR/STEM CELLS. HCC IS OFTEN ASSOCIATED WITH PRE-EXISTING CHRONIC LIVER PATHOLOGIES OF DIFFERENT ORIGIN (MAINLY SUBSEQUENT TO HBV AND HCV INFECTIONS), SUCH AS FIBROSIS OR CIRRHOSIS. CURRENT THERAPIES ARE ESSENTIALLY STILL INEFFECTIVE, DUE BOTH TO THE TUMOR HETEROGENEITY AND THE FREQUENT LATE DIAGNOSIS, MAKING NECESSARY THE CREATION OF NEW THERAPEUTIC STRATEGIES TO INHIBIT TUMOR ONSET AND PROGRESSION AND IMPROVE THE SURVIVAL OF PATIENTS. A PROMISING STRATEGY FOR TREATMENT OF HCC IS THE TARGETED MOLECULAR THERAPY BASED ON THE RESTORATION OF TUMOR SUPPRESSOR PROTEINS LOST DURING NEOPLASTIC TRANSFORMATION. IN PARTICULAR, THE DELIVERY OF MASTER GENES OF EPITHELIAL/HEPATOCYTE DIFFERENTIATION, ABLE TO TRIGGER AN EXTENSIVE REPROGRAMMING OF GENE EXPRESSION, COULD ALLOW THE INDUCTION OF AN EFFICIENT ANTITUMOR RESPONSE THROUGH THE SIMULTANEOUS ADJUSTMENT OF MULTIPLE GENETIC/EPIGENETIC ALTERATIONS CONTRIBUTING TO TUMOR DEVELOPMENT. HERE, WE REPORT RECENT LITERATURE DATA SUPPORTING THE USE OF MEMBERS OF THE LIVER ENRICHED TRANSCRIPTION FACTOR (LETF) FAMILY, IN PARTICULAR HNF4ALPHA, AS TOOLS FOR GENE THERAPY OF HCC. 2015 9 3268 36 HEPATOCELLULAR CARCINOMA IMMUNOTHERAPY AND THE POTENTIAL INFLUENCE OF GUT MICROBIOME. DISRUPTIONS IN THE HUMAN GUT MICROBIOME HAVE BEEN ASSOCIATED WITH A CYCLE OF HEPATOCYTE INJURY AND REGENERATION CHARACTERISTIC OF CHRONIC LIVER DISEASE. EVIDENCE SUGGESTS THAT THE GUT MICROBIOTA CAN PROMOTE THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA THROUGH THE PERSISTENCE OF THIS INFLAMMATION BY INDUCING GENETIC AND EPIGENETIC CHANGES LEADING TO CANCER. AS THE GUT MICROBIOME IS KNOWN FOR ITS EFFECT ON HOST METABOLISM AND IMMUNE RESPONSE, IT COMES AS NO SURPRISE THAT THE GUT MICROBIOME MAY HAVE A ROLE IN THE RESPONSE TO THERAPEUTIC STRATEGIES SUCH AS IMMUNOTHERAPY AND CHEMOTHERAPY FOR LIVER CANCER. GUT MICROBIOTA MAY INFLUENCE THE EFFICACY OF IMMUNOTHERAPY BY REGULATING THE RESPONSES TO IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. HERE, WE REVIEW THE MECHANISMS BY WHICH GUT MICROBIOTA INFLUENCES HEPATIC CARCINOGENESIS, THE IMMUNE CHECKPOINT INHIBITORS CURRENTLY BEING USED TO TREAT HEPATOCELLULAR CARCINOMA, AS WELL AS SUMMARIZE THE CURRENT FINDINGS TO SUPPORT THE POTENTIAL CRITICAL ROLE OF GUT MICROBIOME IN HEPATOCELLULAR CARCINOMA (HCC) IMMUNOTHERAPY. 2021 10 4127 49 MECHANISMS OF DNA METHYLATION IN VIRUS-HOST INTERACTION IN HEPATITIS B INFECTION: PATHOGENESIS AND ONCOGENETIC PROPERTIES. HEPATITIS B VIRUS (HBV), THE WELL-STUDIED ONCOVIRUS THAT CONTRIBUTES TO THE MAJORITY OF HEPATOCELLULAR CARCINOMAS (HCC) WORLDWIDE, CAN CAUSE A SEVERE INFLAMMATORY MICROENVIRONMENT LEADING TO GENETIC AND EPIGENETIC CHANGES IN HEPATOCYTE CLONES. HBV REPLICATION CONTRIBUTES TO THE REGULATION OF DNA METHYLTRANSFERASE GENE EXPRESSION, PARTICULARLY BY X PROTEIN (HBX), AND SUBSEQUENT METHYLATION CHANGES MAY LEAD TO ABNORMAL TRANSCRIPTION ACTIVATION OF ADJACENT GENES AND GENOMIC INSTABILITY. UNDOUBTEDLY, THE ALTERED EXPRESSION OF THESE GENES HAS BEEN KNOWN TO CAUSE DIVERSE ASPECTS OF INFECTED HEPATOCYTES, INCLUDING APOPTOSIS, PROLIFERATION, REACTIVE OXYGEN SPECIES (ROS) ACCUMULATION, AND IMMUNE RESPONSES. ADDITIONALLY, POLLUTANT-INDUCED DNA METHYLATION CHANGES AND ABERRANT METHYLATION OF IMPRINTED GENES IN HEPATOCYTES ALSO COMPLICATE THE PROCESS OF TUMORIGENESIS. MEANWHILE, HEPATOCYTES ALSO CONTRIBUTE TO EPIGENETIC MODIFICATION OF THE VIRAL GENOME TO AFFECT HBV REPLICATION OR VIRAL PROTEIN PRODUCTION. MEANWHILE, METHYLATION LEVELS OF HBV INTEGRANTS AND SURROUNDING HOST REGIONS ALSO PLAY CRUCIAL ROLES IN THEIR ABILITY TO PRODUCE VIRAL PROTEINS IN AFFECTED HEPATOCYTES. BOTH HOST AND VIRAL CHANGES CAN PROVIDE NOVEL INSIGHTS INTO TUMORIGENESIS, INDIVIDUALIZED RESPONSES TO THERAPEUTIC INTERVENTION, DISEASE PROGRESS, AND EARLY DIAGNOSIS. AS SUCH, DNA METHYLATION-MEDIATED EPIGENETIC SILENCING OF CANCER-RELATED GENES AND VIRAL REPLICATION IS A COMPELLING THERAPEUTIC GOAL TO REDUCE MORBIDITY AND MORTALITY FROM LIVER CANCER CAUSED BY CHRONIC HBV INFECTION. IN THIS REVIEW, WE SUMMARIZE THE MOST RECENT RESEARCH ON ABERRANT DNA METHYLATION ASSOCIATED WITH HBV INFECTION, WHICH IS INVOLVED IN HCC DEVELOPMENT, AND PROVIDE AN OUTLOOK ON THE FUTURE DIRECTION OF THE RESEARCH. 2021 11 4133 34 MECHANISMS OF HEPATITIS B VIRUS-INDUCED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). THERE ARE APPROXIMATELY 250 MILLION PEOPLE IN THE WORLD THAT ARE CHRONICALLY INFECTED BY THIS VIRUS, RESULTING IN NEARLY 1 MILLION DEATHS EVERY YEAR. MANY OF THESE PATIENTS DIE FROM SEVERE LIVER DISEASES, INCLUDING HCC. HBV MAY INDUCE HCC THROUGH THE INDUCTION OF CHRONIC LIVER INFLAMMATION, WHICH CAN CAUSE OXIDATIVE STRESS AND DNA DAMAGE. HOWEVER, MANY STUDIES ALSO INDICATED THAT HBV COULD INDUCE HCC VIA THE ALTERATION OF HEPATOCELLULAR PHYSIOLOGY THAT MAY INVOLVE GENETIC AND EPIGENETIC CHANGES OF THE HOST DNA, THE ALTERATION OF CELLULAR SIGNALING PATHWAYS, AND THE INHIBITION OF DNA REPAIR MECHANISMS. THIS ALTERATION OF CELLULAR PHYSIOLOGY CAN LEAD TO THE ACCUMULATION OF DNA DAMAGES AND THE PROMOTION OF CELL CYCLES AND PREDISPOSE HEPATOCYTES TO ONCOGENIC TRANSFORMATION. 2021 12 5952 43 TARGETING VIRAL CCCDNA FOR CURE OF CHRONIC HEPATITIS B. PURPOSE OF REVIEW: CHRONIC HEPATITIS B (CHB), CAUSED BY HEPATITIS B VIRUS (HBV), IS A MAJOR CAUSE OF ADVANCED LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. HBV REPLICATION IS CHARACTERIZED BY THE SYNTHESIS OF COVALENTLY CLOSED CIRCULAR (CCC) DNA WHICH IS NOT TARGETED BY ANTIVIRAL NUCLEOS(T)IDE ANALOGUES (NUCS) THE KEY MODALITY OF STANDARD OF CARE. WHILE HBV REPLICATION IS SUCCESSFULLY SUPPRESSED IN TREATED PATIENTS, THEY REMAIN AT RISK FOR DEVELOPING HCC. WHILE FUNCTIONAL CURE, CHARACTERIZED BY LOSS OF HBSAG, IS THE FIRST GOAL OF NOVEL ANTIVIRAL THERAPIES, CURATIVE TREATMENTS ELIMINATING CCCDNA REMAIN THE ULTIMATE GOAL. THIS REVIEW SUMMARIZES RECENT ADVANCES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES AND THEIR IMPACT ON CCCDNA BIOLOGY. RECENT FINDINGS: WITHIN THE LAST DECADE, SUBSTANTIAL PROGRESS HAS BEEN MADE IN THE UNDERSTANDING OF CCCDNA BIOLOGY INCLUDING THE DISCOVERY OF HOST DEPENDENCY FACTORS, EPIGENETIC REGULATION OF CCCDNA TRANSCRIPTION AND IMMUNE-MEDIATED DEGRADATION. SEVERAL APPROACHES TARGETING CCCDNA EITHER IN A DIRECT OR INDIRECT MANNER ARE CURRENTLY AT THE STAGE OF DISCOVERY, PRECLINICAL OR EARLY CLINICAL DEVELOPMENT. EXAMPLES INCLUDE GENOME-EDITING APPROACHES, STRATEGIES TARGETING HOST DEPENDENCY FACTORS OR EPIGENETIC GENE REGULATION, NUCLEOCAPSID MODULATORS AND IMMUNE-MEDIATED DEGRADATION. SUMMARY: WHILE DIRECT-TARGETING CCCDNA STRATEGIES ARE STILL LARGELY AT THE PRECLINICAL STAGE OF DEVELOPMENT, CAPSID ASSEMBLY MODULATORS AND IMMUNE-BASED APPROACHES HAVE REACHED THE CLINICAL PHASE. CLINICAL TRIALS ARE ONGOING TO ASSESS THEIR EFFICACY AND SAFETY IN PATIENTS INCLUDING THEIR IMPACT ON VIRAL CCCDNA. COMBINATION THERAPIES PROVIDE ADDITIONAL OPPORTUNITIES TO OVERCOME CURRENT LIMITATIONS OF INDIVIDUAL APPROACHES. 2020 13 2166 44 EPIGENETIC MECHANISMS IN HEPATOCELLULAR CARCINOMA: HOW ENVIRONMENTAL FACTORS INFLUENCE THE EPIGENOME. EPIGENETIC MECHANISMS MAINTAIN HERITABLE CHANGES IN GENE EXPRESSION AND CHROMATIN ORGANIZATION OVER MANY CELL GENERATIONS. IMPORTANTLY, DEREGULATED EPIGENETIC MECHANISMS PLAY A KEY ROLE IN A WIDE RANGE OF HUMAN MALIGNANCIES, INCLUDING LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC), WHICH ORIGINATES FROM THE HEPATOCYTES, IS BY FAR THE MOST COMMON LIVER CANCER, WITH RATES AND AETIOLOGY THAT SHOW CONSIDERABLE GEOGRAPHIC VARIATION. VARIOUS ENVIRONMENTAL AGENTS AND LIFESTYLES KNOWN TO BE RISK FACTORS FOR HCC (SUCH AS INFECTION BY HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), CHRONIC ALCOHOL INTAKE, AND AFLATOXINS) ARE SUSPECTED TO PROMOTE ITS DEVELOPMENT BY ELICITING EPIGENETIC CHANGES, HOWEVER THE PRECISE GENE TARGETS AND UNDERLYING MECHANISMS HAVE NOT BEEN ELUCIDATED. MANY RECENT STUDIES HAVE EXPLOITED CONCEPTUAL AND TECHNOLOGICAL ADVANCES IN EPIGENETICS AND EPIGENOMICS TO INVESTIGATE THE ROLE OF EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN HCC TUMORS AND NON-TUMOR PRECANCEROUS (CIRRHOTIC) LESIONS. THESE STUDIES HAVE IDENTIFIED A LARGE NUMBER OF GENES AND PATHWAYS THAT ARE TARGETED BY EPIGENETIC DEREGULATION (CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-MEDIATED GENE SILENCING) DURING THE DEVELOPMENT AND PROGRESSION OF HCC. FREQUENT IDENTIFICATION OF ABERRANT EPIGENETIC CHANGES IN SPECIFIC GENES IN CIRRHOTIC TISSUE IS CONSISTENT WITH THE NOTION THAT EPIGENETIC DEREGULATION OF SELECTED GENES IN PRE-MALIGNANT LESIONS PRECEDES AND PROMOTES THE DEVELOPMENT OF HCC. IN ADDITION, SEVERAL LINES OF EVIDENCE ARGUE THAT SOME ENVIRONMENTAL FACTORS (SUCH AS HBV VIRUS) MAY ABROGATE CELLULAR DEFENSE SYSTEMS, INDUCE SILENCING OF HOST GENES AND PROMOTE HCC DEVELOPMENT VIA AN "EPIGENETIC STRATEGY". FINALLY, PROFILING STUDIES REVEAL THAT HCC TUMORS AND PRE-CANCEROUS LESIONS MAY EXHIBIT EPIGENETIC SIGNATURES ASSOCIATED WITH SPECIFIC RISK FACTORS AND TUMOR PROGRESSION STAGE. TOGETHER, RECENT EVIDENCE UNDERSCORES THE IMPORTANCE OF ABERRANT EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN LIVER CANCER AND HIGHLIGHTS POTENTIAL TARGETS FOR BIOMARKER DISCOVERY AND FUTURE PREVENTIVE AND THERAPEUTIC STRATEGIES. 2011 14 4920 32 PARALLEL EPIGENETIC AND GENETIC CHANGES IN THE PATHOGENESIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST FREQUENT TUMOR TYPES IN THE WORLD, WITH SHORT SURVIVAL TIMES AND FEW TREATMENT OPTIONS. HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) ARE MAJOR ETIOLOGIC AGENTS OF HCC, ALTHOUGH THE ASSOCIATED MECHANISMS ARE INCOMPLETELY UNDERSTOOD. THE AVAILABLE EVIDENCE SUGGESTS THAT BOTH VIRUSES PROMOTE TUMORIGENESIS BY UP-REGULATING GENES THAT PROMOTE HEPATOCELLULAR GROWTH AND SURVIVAL, AND BY DOWN-REGULATING OTHER GENES THAT ACT AS TUMOR SUPPRESSORS AND NEGATIVE GROWTH REGULATORY MOLECULES. SIGNIFICANTLY, A NUMBER OF THE PATHWAYS THAT ARE ALTERED BY THESE VIRUSES ARE THE SAME ONES THAT ACCUMULATE GENETIC ALTERATIONS DURING TUMOR PROGRESSION. THIS SUGGESTS THAT THE PATHWAYS THAT PROMOTE VIRUS PERSISTENCE AND REPLICATION MAY ALSO PROMOTE CELL GROWTH AND SURVIVAL. FROM THE PERSPECTIVE OF THE VIRUS, THIS PROMOTES CHRONIC INFECTION, WHILE FROM THE PERSPECTIVE OF THE HOST, THIS PROMOTES TUMORIGENESIS. 2006 15 3932 25 LIVER REGENERATION, LIVER CANCERS AND CYCLINS. ACCUMULATING EVIDENCE HAS REVEALED THAT MALIGNANT CELL GROWTH IS REGULATED BY COMPLEX MECHANISMS INVOLVED IN GENETIC AND EPIGENETIC FACTORS. AMONG HUMAN CANCERS, CANCER IN THE LIVER (HEPATOCELLULAR CARCINOMA (HCC)) IS CHARACTERIZED BY THE EVIDENCE THAT IT IS USUALLY BASED ON CHRONIC LIVER DISEASES SUCH AS LIVER CIRRHOSIS OR CHRONIC HEPATITIS, IN WHICH THE LIVER IS PERSISTENTLY REGENERATING FOLLOWING HEPATIC INJURY. THIS RAISES THE POSSIBILITY THAT REPEATED HEPATOCYTE PROLIFERATION MAY CAUSE DISORDER OF GENES THAT ARE REGULATING THE CELL CYCLE IN HEPATOCYTES, THUS CAUSING HCC. IN THIS ARTICLE, RECENT STUDIES FOCUSING ON LIVER REGENERATION AND CANCER ARE REVIEWED FROM THE VIEWPOINT OF THE CELL CYCLE THAT IS REGULATED BY CYCLIN AND THE ASSOCIATED PROTEINS. 1998 16 2165 38 EPIGENETIC MECHANISMS IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC INFECTION OF THE LIVER BY THE HEPATITIS B VIRUS (HBV) IS ASSOCIATED WITH INCREASED RISK FOR DEVELOPING HEPATOCELLULAR CARCINOMA (HCC). A MULTITUDE OF STUDIES HAVE INVESTIGATED THE MECHANISM OF LIVER CANCER PATHOGENESIS DUE TO CHRONIC HBV INFECTION. CHRONIC INFLAMMATION, EXPRESSION OF SPECIFIC VIRAL PROTEINS SUCH AS HBX, THE INTEGRATION SITE OF THE VIRAL GENOME INTO THE HOST GENOME, AND THE VIRAL GENOTYPE, ARE KEY PLAYERS CONTRIBUTING TO HCC PATHOGENESIS. IN ADDITION, THE GENETIC BACKGROUND OF THE HOST AND EXPOSURE TO ENVIRONMENTAL CARCINOGENS ARE ALSO PREDISPOSING PARAMETERS IN HEPATOCARCINOGENESIS. DESPITE THE PLETHORA OF STUDIES, THE MOLECULAR MECHANISM OF HCC PATHOGENESIS REMAINS INCOMPLETELY UNDERSTOOD. IN THIS REVIEW, THE FOCUS IS ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF HBV-ASSOCIATED HCC. EPIGENETIC MECHANISMS ARE DYNAMIC MOLECULAR PROCESSES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE HOST DNA, ACTING BY MODIFYING THE HOST CHROMATIN STRUCTURE VIA COVALENT POST-TRANSLATIONAL HISTONE MODIFICATIONS, CHANGING THE DNA METHYLATION STATUS, EXPRESSION OF NON-CODING RNAS SUCH AS MICRORNAS AND LONG NONCODING RNAS, AND ALTERING THE SPATIAL, 3-D ORGANIZATION OF THE CHROMATIN OF THE VIRUS-INFECTED CELL. HEREIN, STUDIES ARE DESCRIBED THAT PROVIDE EVIDENCE IN SUPPORT OF DEREGULATION OF EPIGENETIC MECHANISMS IN THE HBV-INFECTED/-REPLICATING HEPATOCYTE AND THEIR CONTRIBUTION TO HEPATOCYTE TRANSFORMATION. IN CONTRAST TO GENETIC MUTATIONS WHICH ARE PERMANENT, EPIGENETIC ALTERATIONS ARE DYNAMIC AND REVERSIBLE. ACCORDINGLY, THE IDENTIFICATION OF ESSENTIAL MOLECULAR EPIGENETIC TARGETS INVOLVED IN HBV-MEDIATED HCC PATHOGENESIS OFFERS THE OPPORTUNITY FOR THE DESIGN AND DEVELOPMENT OF NOVEL EPIGENETIC THERAPEUTIC APPROACHES. 2021 17 3621 33 IN VIVO AND IN VITRO MODELS OF HEPATOCELLULAR CARCINOMA: CURRENT STRATEGIES FOR TRANSLATIONAL MODELING. HEPATOCELLULAR CARCINOMA (HCC) IS THE SIXTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH GLOBALLY. HCC IS A COMPLEX MULTISTEP DISEASE AND USUALLY EMERGES IN THE SETTING OF CHRONIC LIVER DISEASES. THE MOLECULAR PATHOGENESIS OF HCC VARIES ACCORDING TO THE ETIOLOGY, MAINLY CAUSED BY CHRONIC HEPATITIS B AND C VIRUS INFECTIONS, CHRONIC ALCOHOL CONSUMPTION, AFLATOXIN-CONTAMINATED FOOD, AND NON-ALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH METABOLIC SYNDROME OR DIABETES MELLITUS. THE ESTABLISHMENT OF HCC MODELS HAS BECOME ESSENTIAL FOR BOTH BASIC AND TRANSLATIONAL RESEARCH TO IMPROVE OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY AND UNRAVEL NEW MOLECULAR DRIVERS OF THIS DISEASE. THE IDEAL MODEL SHOULD RECAPITULATE KEY EVENTS OBSERVED DURING HEPATOCARCINOGENESIS AND HCC PROGRESSION IN VIEW OF ESTABLISHING EFFECTIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO BE TRANSLATED INTO CLINICAL PRACTICE. DESPITE CONSIDERABLE EFFORTS CURRENTLY DEVOTED TO LIVER CANCER RESEARCH, ONLY A FEW ANTI-HCC DRUGS ARE AVAILABLE, AND PATIENT PROGNOSIS AND SURVIVAL ARE STILL POOR. THE PRESENT PAPER PROVIDES A STATE-OF-THE-ART OVERVIEW OF IN VIVO AND IN VITRO MODELS USED FOR TRANSLATIONAL MODELING OF HCC WITH A SPECIFIC FOCUS ON THEIR KEY MOLECULAR HALLMARKS. 2021 18 6640 42 UNRAVELING THE MOLECULAR MECHANISMS INVOLVED IN HCV-INDUCED CARCINOGENESIS. CANCER INDUCED BY A VIRAL INFECTION IS AMONG THE LEADING CAUSES OF CANCER. HEPATITIS C VIRUS (HCV) IS A HEPATOTROPIC ONCOGENIC POSITIVE-SENSE RNA VIRUS THAT LEADS TO CHRONIC INFECTION, EXPOSING THE LIVER TO A CONTINUOUS PROCESS OF DAMAGE AND REGENERATION AND PROMOTING HEPATOCARCINOGENESIS. THE VIRUS PROMOTES THE DEVELOPMENT OF CARCINOGENESIS THROUGH INDIRECT AND DIRECT MOLECULAR MECHANISMS SUCH AS CHRONIC INFLAMMATION, OXIDATIVE STRESS, STEATOSIS, GENETIC ALTERATIONS, EPITHELIAL-MESENCHYMAL TRANSITION, PROLIFERATION, AND APOPTOSIS, AMONG OTHERS. RECENTLY, DIRECT-ACTING ANTIVIRALS (DAAS) SHOWED SUSTAINED VIROLOGIC RESPONSE IN 95% OF CASES. NEVERTHELESS, PATIENTS TREATED WITH DAAS HAVE REPORTED AN UNEXPECTED INCREASE IN THE EARLY INCIDENCE OF HEPATOCELLULAR CARCINOMA (HCC). STUDIES SUGGEST THAT HCV INDUCES EPIGENETIC REGULATION THROUGH NON-CODING RNAS, DNA METHYLATION, AND CHROMATIN REMODELING, WHICH MODIFY GENE EXPRESSIONS AND INDUCE GENOMIC INSTABILITY RELATED TO HCC DEVELOPMENT THAT PERSISTS WITH THE INFECTION'S CLEARANCE. THE NEED FOR A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS ASSOCIATED WITH THE DEVELOPMENT OF CARCINOGENESIS IS EVIDENT. THE AIM OF THIS REVIEW WAS TO UNRAVEL THE MOLECULAR PATHWAYS INVOLVED IN THE DEVELOPMENT OF CARCINOGENESIS BEFORE, DURING, AND AFTER THE VIRAL INFECTION'S RESOLUTION, AND HOW THESE PATHWAYS WERE REGULATED BY THE VIRUS, TO FIND CONTROL POINTS THAT CAN BE USED AS POTENTIAL THERAPEUTIC TARGETS. 2022 19 3273 29 HEPATOCELLULAR CARCINOMA: MOLECULAR PATHWAYS AND NEW THERAPEUTIC TARGETS. HEPATOCELLULAR CARCINOMA IS OFTEN DIAGNOSED AT AN ADVANCED STAGE, WHEN IT IS NOT AMENABLE TO CURATIVE THERAPIES. THERE IS NO EFFECTIVE CHEMOTHERAPY. ADVANCES IN CANCER BIOLOGY SUGGEST THAT A LIMITED NUMBER OF PATHWAYS ARE RESPONSIBLE FOR INITIATING AND MAINTAINING DYSREGULATED CELL PROLIFERATION, WHICH IS THE MAJOR CELLULAR ALTERATION RESPONSIBLE FOR THE CANCER PHENOTYPE. NEW TREATMENTS IN DEVELOPMENT TARGET SEVERAL OF THESE CRITICAL PATHWAYS, INCLUDING AGENTS TARGETING THE RECEPTOR TYROSINE KINASE PATHWAYS, THE WNT/BETA-CATENIN SIGNALING PATHWAY, THE UBIQUITIN/PROTEASOME DEGRADATION PATHWAY, THE EPIGENETIC DNA METHYLATION AND HISTONE DEACETYLATION PATHWAYS, THE PI3 KINASE/AKT/MTOR PATHWAY, ANGIOGENIC PATHWAYS, AND TELOMERASE. SEVERAL OF THESE APPROACHES HOLD SIGNIFICANT PROMISE FOR IMPROVING THE LONG-TERM OUTCOME OF PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA. BECAUSE OF THE HIGH PREVALENCE OF LIVER CIRRHOSIS IN HEPATOCELLULAR CARCINOMA PATIENTS, THESE APPROACHES MUST BE COUPLED WITH NEW STRATEGIES FOR HALTING OR REVERSING THE PROGRESSION OF CHRONIC LIVER DISEASE. 2005 20 3928 27 LIVER CELL CIRCUITS AND THERAPEUTIC DISCOVERY FOR ADVANCED LIVER DISEASE AND CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR GLOBAL HEALTH CHALLENGE WITH RISING INCIDENCE. DESPITE THE PREVIOUS APPROVAL OF SEVERAL NOVEL THERAPEUTIC APPROACHES, HCC REMAINS THE SECOND COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE VAST MAJORITY OF HCCS ARISES IN THE CONTEXT OF CHRONIC FIBROTIC LIVER DISEASES CAUSED BY VIRAL OR METABOLIC ETIOLOGIES. IN PATIENTS WITH ADVANCED LIVER DISEASE THE RISK OF HCC PERSISTS EVEN AFTER VIRAL CURE OR CONTROL OF INFECTION. MOREOVER, GIVEN THE CHANGE IN THE LIFESTYLE AND INCREASE OF OBESITY AND METABOLIC DISORDERS, HCC INCIDENCE IS PREDICTED TO DRASTICALLY AUGMENT IN THE NEXT DECADE. EARLY DETECTION, IMPROVEMENT OF THE SCREENING METHOD IN PATIENT AT-RISK AND DEVELOPMENT OF CHEMOPREVENTIVE STRATEGIES ARE THEREFORE URGENTLY NEEDED TO REDUCE HCC RISK. THIS REVIEW SUMMARIZES THE MAJOR CHALLENGES IN THE IDENTIFICATION OF PATIENT AT RISK FOR HCC AND THE EMERGENT STRATEGIES FOR HCC PREVENTION TO IMPROVE PATIENTS' OUTCOME. 2021