1 3257 130 HEPATITIS B X ANTIGEN (HBX) IS AN IMPORTANT THERAPEUTIC TARGET IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) IS A HUMAN PATHOGEN THAT HAS INFECTED AN ESTIMATED TWO BILLION PEOPLE WORLDWIDE. DESPITE THE AVAILABILITY OF HIGHLY EFFICACIOUS VACCINES, UNIVERSAL SCREENING OF THE BLOOD SUPPLY FOR VIRUS, AND POTENT DIRECT ACTING ANTI-VIRAL DRUGS, THERE ARE MORE THAN 250 MILLION CARRIERS OF HBV WHO ARE AT RISK FOR THE SEQUENTIAL DEVELOPMENT OF HEPATITIS, FIBROSIS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). MORE THAN 800,000 DEATHS PER YEAR ARE ATTRIBUTED TO CHRONIC HEPATITIS B. MANY DIFFERENT THERAPEUTIC APPROACHES HAVE BEEN DEVELOPED TO BLOCK VIRUS REPLICATION, AND ALTHOUGH EFFECTIVE, NONE ARE CURATIVE. THESE TREATMENTS HAVE LITTLE OR NO IMPACT UPON THE PORTIONS OF INTEGRATED HBV DNA, WHICH OFTEN ENCODE THE VIRUS REGULATORY PROTEIN, HBX. ALTHOUGH GIVEN LITTLE ATTENTION, HBX IS AN IMPORTANT THERAPEUTIC TARGET BECAUSE IT CONTRIBUTES IMPORTANTLY TO (A) HBV REPLICATION, (B) IN PROTECTING INFECTED CELLS FROM IMMUNE MEDIATED DESTRUCTION DURING CHRONIC INFECTION, AND (C) IN THE DEVELOPMENT OF HCC. THUS, THE DEVELOPMENT OF THERAPIES TARGETING HBX, COMBINED WITH OTHER ESTABLISHED THERAPIES, WILL PROVIDE A FUNCTIONAL CURE THAT WILL TARGET VIRUS REPLICATION AND FURTHER REDUCE OR ELIMINATE BOTH THE MORBIDITY AND MORTALITY ASSOCIATED WITH CHRONIC LIVER DISEASE AND HCC. SIMULTANEOUS TARGETING OF ALL THESE CHARACTERISTICS UNDERSCORES THE IMPORTANCE OF DEVELOPING THERAPIES AGAINST HBX. 2021 2 3394 44 HOST EPIGENETIC ALTERATIONS AND HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST FREQUENT PRIMARY MALIGNANCY OF THE LIVER AND A LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ALTHOUGH MUCH PROGRESS HAS BEEN MADE IN HCC DRUG DEVELOPMENT IN RECENT YEARS, TREATMENT OPTIONS REMAIN LIMITED. THE MAJOR CAUSE OF HCC IS CHRONIC HEPATITIS B VIRUS (HBV) INFECTION. DESPITE THE EXISTENCE OF A VACCINE, MORE THAN 250 MILLION INDIVIDUALS ARE CHRONICALLY INFECTED BY HBV. CURRENT ANTIVIRAL THERAPIES CAN REPRESS VIRAL REPLICATION BUT TO DATE THERE IS NO CURE FOR CHRONIC HEPATITIS B. OF NOTE, INHIBITION OF VIRAL REPLICATION REDUCES BUT DOES NOT ELIMINATE THE RISK OF HCC DEVELOPMENT. HBV CONTRIBUTES TO LIVER CARCINOGENESIS BY DIRECT AND INDIRECT EFFECTS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF HBV-INDUCED HOST EPIGENETIC ALTERATIONS AND THEIR ASSOCIATION WITH HCC, WITH AN EMPHASIS ON THE INTERACTIONS BETWEEN HBV PROTEINS AND THE HOST CELL EPIGENETIC MACHINERY LEADING TO MODULATION OF GENE EXPRESSION. 2021 3 5365 38 RECENT ADVANCES IN HEPATITIS B TREATMENT. HEPATITIS B VIRUS INFECTION AFFECTS OVER 250 MILLION CHRONIC CARRIERS, CAUSING MORE THAN 800,000 DEATHS ANNUALLY, ALTHOUGH A SAFE AND EFFECTIVE VACCINE IS AVAILABLE. CURRENTLY USED ANTIVIRAL AGENTS, PEGYLATED INTERFERON AND NUCLEOS(T)IDE ANALOGUES, HAVE MAJOR DRAWBACKS AND FAIL TO COMPLETELY ERADICATE THE VIRUS FROM INFECTED CELLS. THUS, ACHIEVING A "FUNCTIONAL CURE" OF THE INFECTION REMAINS A REAL CHALLENGE. RECENT FINDINGS CONCERNING THE VIRAL REPLICATION CYCLE HAVE LED TO DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES INCLUDING VIRAL ENTRY INHIBITORS, EPIGENETIC CONTROL OF CCCDNA, IMMUNE MODULATORS, RNA INTERFERENCE TECHNIQUES, RIBONUCLEASE H INHIBITORS, AND CAPSID ASSEMBLY MODULATORS. PROMISING PRECLINICAL RESULTS HAVE BEEN OBTAINED, AND THE LEADING MOLECULES UNDER DEVELOPMENT HAVE ENTERED CLINICAL EVALUATION. THIS REVIEW SUMMARIZES THE KEY STEPS OF THE HBV LIFE CYCLE, EXAMINES THE CURRENTLY APPROVED ANTI-HBV DRUGS, AND ANALYZES NOVEL HBV TREATMENT REGIMENS. 2021 4 3928 29 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 5 3265 43 HEPATOCARCINOMA: GENETIC AND EPIGENETIC FEATURES. HCC IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE, ACCOUNTING FOR ABOUT 1 MILLION DEATHS ANNUALLY. THE INCIDENCE OF HCC IS HIGHEST IN ASIA AND AFRICA, WHERE THE ENDEMIC HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C STRONGLY PREDISPOSES TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE AND SUBSEQUENT DEVELOPMENT OF HCC. PATIENTS WITH HCC GENERALLY PRESENT AT AN ADVANCED STAGE DUE TO COMPENSATED CIRRHOSIS DEFINED BY THE ABSENCE OF PATHOGNOMONIC SYMPTOMS, RESULTING IN DEATH WITHIN 6 TO 20 MONTHS, SUGGESTING AN URGENT NEED IN TREATMENT MODALITIES THAT WILL DRAMATICALLY DECREASE THE MORTALITY RATE OF HCC. THE MOLECULAR HEPATOCARCINOGENESIS IS, HOWEVER, A GRADUAL PROCESS DURING WHICH GENETIC ALTERATIONS PROGRESSIVELY ACCUMULATE AND LEAD TO HCC THROUGH INTERMEDIATE PRENEOPLASTIC STAGES. WITH THE ADVENT OF WHOLE GENOME SEQUENCING TOOLS, VARIOUS MUTATIONS ASSOCIATED WITH HCC HAVE BEEN IDENTI FI ED, WHICH HAVE ADVANCED OUR MOLECULAR UNDERSTANDING OF HCC. HOWEVER, THE FREQUENCY OF THESE MUTATIONS IS RARE, AND THESE GENETIC MUTATIONS ONLY PARTLY EXPLAIN THE ETIOLOGY OF THE DISEASE. BETTER UNDERSTANDING AND CHARACTERIZATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS, WHICH ARE IMPORTANT TO HEPATOCARCINOGENESIS, MAY HELP UNDERSTAND THE MOLECULAR PATHOGENESIS OF HCC, AS WELL AS PROVIDING NOVEL THERAPEUTIC TARGETS FOR HCC TREATMENT. FURTHER CONSIDERATION SHOULD BE GIVEN TO DEVELOPING MORE EFFECTIVE MOLECULAR DIAGNOSTIC MARKERS AND TARGETED DRUG THERAPY. 2018 6 4133 30 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 7 3270 24 HEPATOCELLULAR CARCINOMA IN THE CONTEXT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH): RECENT ADVANCES IN THE PATHOGENIC MECHANISMS. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER. HCC IS PARTICULARLY AGGRESSIVE AND IS ONE OF THE LEADING CAUSES OF CANCER MORTALITY. IN RECENT DECADES, THE EPIDEMIOLOGICAL LANDSCAPE OF HCC HAS UNDERGONE SIGNIFICANT CHANGES. WHILE CHRONIC VIRAL HEPATITIS AND EXCESSIVE ALCOHOL CONSUMPTION HAVE LONG BEEN IDENTIFIED AS THE MAIN RISK FACTORS FOR HCC, NON-ALCOHOLIC STEATOHEPATITIS (NASH), PARALLELING THE WORLDWIDE EPIDEMIC OF OBESITY AND TYPE 2 DIABETES, HAS BECOME A GROWING CAUSE OF HCC IN THE US AND EUROPE. HERE, WE REVIEW THE RECENT ADVANCES IN EPIDEMIOLOGICAL, GENETIC, EPIGENETIC AND PATHOGENIC MECHANISMS AS WELL AS EXPERIMENTAL MOUSE MODELS THAT HAVE IMPROVED THE UNDERSTANDING OF NASH PROGRESSION TOWARD HCC. WE ALSO DISCUSS THE CLINICAL MANAGEMENT OF PATIENTS WITH NASH-RELATED HCC AND POSSIBLE THERAPEUTIC APPROACHES. 2020 8 3271 44 HEPATOCELLULAR CARCINOMA RISK AFTER VIRAL RESPONSE IN HEPATITIS C VIRUS-ADVANCED FIBROSIS: WHO TO SCREEN AND FOR HOW LONG? HEPATITIS C VIRUS (HCV) CHRONIC INFECTION IS ASSOCIATED WITH FIBROSIS PROGRESSION, END-STAGE LIVER COMPLICATIONS AND HCC. NOT SURPRISINGLY, HCV INFECTION IS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY WORLDWIDE. AFTER SUSTAINED VIROLOGICAL RESPONSE (SVR), THE RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IS NOT COMPLETELY ELIMINATED IN PATIENTS WITH ESTABLISHED CIRRHOSIS OR WITH ADVANCED FIBROSIS. THEREFORE, LIFELONG SURVEILLANCE IS CURRENTLY RECOMMENDED. THIS STRATEGY IS LIKELY NOT UNIVERSALLY COST-EFFECTIVE AND HARMLESS, CONSIDERING THAT NOT ALL PATIENTS WITH ADVANCED FIBROSIS HAVE THE SAME RISK OF DEVELOPING HCC. FACTORS RELATED TO THE SEVERITY OF LIVER DISEASE AND ITS POTENTIAL TO IMPROVE AFTER SVR, THE MOLECULAR AND EPIGENETIC CHANGES THAT OCCUR DURING INFECTION AND OTHER ASSOCIATED COMORBIDITIES MIGHT ACCOUNT FOR DIFFERENT RISK LEVELS AND ARE LIKELY ESSENTIAL FOR IDENTIFYING PATIENTS WHO WOULD BENEFIT FROM SCREENING PROGRAMS AFTER SVR. EFFORTS TO DEVELOP PREDICTIVE MODELS AND RISK CALCULATORS, BIOMARKERS AND GENETIC PANELS AND EVEN DEEP LEARNING MODELS TO ESTIMATE THE INDIVIDUAL RISK OF HCC HAVE BEEN MADE IN THE DIRECT-ACTING ANTIVIRAL AGENTS ERA, WHEN THOUSANDS OF PATIENTS WITH ADVANCED FIBROSIS AND CIRRHOSIS HAVE REACHED SVR. THESE TOOLS COULD HELP TO IDENTIFY PATIENTS WITH VERY LOW HCC RISK IN WHOM SURVEILLANCE MIGHT NOT BE JUSTIFIED. IN THIS REVIEW, FACTORS AFFECTING THE PROBABILITY OF HCC DEVELOPMENT AFTER SVR, THE BENEFITS AND RISKS OF SURVEILLANCE, SUGGESTED STRATEGIES TO ESTIMATE INDIVIDUALIZED HCC RISK AND THE CURRENT EVIDENCE TO RECOMMEND LIFELONG SURVEILLANCE ARE DISCUSSED. 2021 9 1942 43 EPIDEMIOLOGY OF LIVER CANCER IN AFRICA: CURRENT AND FUTURE TRENDS. HEPATOCELLULAR CARCINOMA (HCC) IS A DISEASE OF GLOBAL PUBLIC HEALTH SIGNIFICANCE WITH MORTALITY ON THE RISE, DESPITE THE PREVENTABLE NATURE OF ITS RISK FACTORS ESPECIALLY IN AFRICA. IT IS NOW THE SIXTH MOST COMMON CANCER WORLDWIDE, FIFTH IN MALES, AND NINTH IN FEMALES. HCC INCIDENCE AND MORTALITY ARE PREDICTED TO INCREASE IN AFRICAN COUNTRIES CONSTRAINED BY LIMITED RESOURCES TO COMBAT ENDEMIC LEVELS OF VIRAL INFECTION AND SYNERGISTIC ENVIRONMENTAL RISK FACTORS. THE CHANGING NATURE OF HCC ETIOLOGY IS PARTICULARLY ILLUSTRATED HERE WITH THE TRADITIONAL RISK FACTORS LIKE VIRAL HEPATITIS COEXISTING ALONGSIDE HIGH HUMAN IMMUNODEFICIENCY VIRUS (HIV) PREVALENCE AND RAPIDLY INCREASING URBANIZATION THAT HAVE PROMOTED A SHARP INCREASE IN ADDITIONAL RISK FACTORS LIKE COINFECTION, TYPE 2 DIABETES MELLITUS, AND OBESITY. ALTHOUGH THERE ARE SOME DIFFERENCES IN ETIOLOGY BETWEEN NORTH AFRICA AND SUB-SAHARAN AFRICA, RISK FACTORS LIKE CHRONIC VIRAL HEPATITIS B AND C, AFLATOXIN EXPOSURE, AND IRON OVERLOAD PREDOMINATE. AGGRESSIVE HEPATITIS B GENOTYPES, COMBINED WITH HEPATITIS B VIRUS/HEPATITIS C VIRUS/HIV COINFECTIONS AND AFLATOXIN EXPOSURE, PROMOTE A MORE AGGRESSIVE MOLECULAR PHENOTYPE. IN PARALLEL TO A BETTER UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF HCC, POLICY AND PLANNING INITIATIVES TO ADDRESS THE BURDEN OF HCC MUST BE ANCHORED WITHIN THE REALITY OF THE LIMITED RESOURCES AVAILABLE. ESTABLISHMENT AND COORDINATION OF CANCER REGISTRIES ACROSS AFRICA IS NEEDED TO IMPROVE THE QUALITY OF DATA NECESSARY TO GALVANIZE ACTION. PREVENTIVE MEASURES INCLUDING HEPATITIS B VACCINATION PROGRAMS, MEASURES TO PREVENT MATERNAL-TO-CHILD AND CHILD-TO-CHILD TRANSMISSION, DELIVERY OF UNIVERSALLY ACCESSIBLE ANTIRETROVIRAL AND ANTIVIRAL TREATMENTS, AND REDUCTION OF DIETARY AFLATOXIN EXPOSURE CAN CONTRIBUTE MARKEDLY TO REDUCE HCC INCIDENCE. FINALLY, THE DEVELOPMENT OF BIOMARKERS AND NEW THERAPEUTIC INTERVENTIONS WILL NEED A BETTER UNDERSTANDING OF THE UNIQUE GENETIC AND EPIGENETIC CHARACTERISTICS OF HCC ON THE CONTINENT. WE PRESENT A NARRATIVE REVIEW OF HCC IN AFRICA, DISCUSSING PRESENT AND FUTURE TRENDS. 2020 10 5772 35 SPECTRUM, SCREENING, AND DIAGNOSIS OF ALCOHOL-RELATED LIVER DISEASE. ALCOHOL-RELATED LIVER DISEASE (ALD) REPRESENTS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASE AND IS A MAJOR CAUSE OF LIVER-RELATED DEATHS WORLDWIDE. ALD ENCOMPASSES A RANGE OF DISORDERS INCLUDING SIMPLE STEATOSIS, ALCOHOLIC STEATOHEPATITIS, FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. PATIENTS WITH UNDERLYING ALD AND CONTINUED HEAVY ALCOHOL CONSUMPTION CAN ALSO DEVELOP AN EPISODE OF ACUTE-ON-CHRONIC LIVER INJURY CALLED ALCOHOL-ASSOCIATED HEPATITIS, THE MOST SEVERE FORM OF THE DISEASE, WHICH PORTENDS A POOR PROGNOSIS. THE MOST IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF ALD IS THE AMOUNT OF ALCOHOL CONSUMED. INDIVIDUAL SUSCEPTIBILITY TO PROGRESSION TO ADVANCED FIBROSIS AMONG HEAVY DRINKERS IS LIKELY DETERMINED BY A COMBINATION OF BEHAVIORAL, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS, BUT THE MECHANISMS ARE LARGELY UNKNOWN. THE ONLY EFFECTIVE THERAPY FOR ALD IS PROLONGED ALCOHOL ABSTINENCE. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. IN CLINICAL PRACTICE, THE HISTOLOGICAL ASSESSMENT FOR ALD DIAGNOSIS IS UNCOMMON, AND IT IS USUALLY BASED ON THE MEDICAL HISTORY, CLINICAL MANIFESTATIONS, AND LABORATORY AND IMAGING TESTS. SEVERAL PROMISING BIOMARKERS THAT CAN HAVE BOTH DIAGNOSTIC AND PROGNOSTIC VALUE IN PATIENTS WITH ALD HAVE BEEN IDENTIFIED IN RECENT YEARS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CLINICAL SPECTRUM OF ALD, THE DIAGNOSTIC APPROACH OF THE DISEASE FROM DIFFERENT PERSPECTIVES AS WELL AS CURRENT DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. 2023 11 3621 34 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 12 4929 30 PAST, PRESENT, AND FUTURE OF CHEMICALLY INDUCED HEPATOCARCINOGENESIS RODENT MODELS: PERSPECTIVES CONCERNING CLASSIC AND NEW CANCER HALLMARKS. HEPATOCELLULAR CARCINOMA (HCC), THE MAIN PRIMARY LIVER CANCER, ACCOUNTS FOR 5 % OF ALL INCIDENT CASES AND 8.4 % OF ALL CANCER-RELATED DEATHS WORLDWIDE. HCC DISPLAYS A SPECTRUM OF ENVIRONMENTAL RISK FACTORS (VIRAL CHRONIC INFECTIONS, AFLATOXIN EXPOSURE, ALCOHOLIC- AND NONALCOHOLIC FATTY LIVER DISEASES) THAT RESULT IN MOLECULAR COMPLEXITY AND HETEROGENEITY, CONTRIBUTING TO A RISING EPIDEMIOLOGICAL BURDEN, POOR PROGNOSIS, AND NON-SATISFACTORY TREATMENT OPTIONS. THE EMERGENCE OF HCC (I.E., HEPATOCARCINOGENESIS) IS A MULTISTEP AND COMPLEX PROCESS THAT ADDRESSES MANY (EPI)GENETIC ALTERATIONS AND PHENOTYPIC TRAITS, THE SO-CALLED CANCER HALLMARKS. "POLYMORPHIC MICROBIOMES", "EPIGENETIC REPROGRAMMING", "SENESCENT CELLS" AND "UNLOCKING PHENOTYPIC PLASTICITY" ARE TRENDING HALLMARKS/ENABLING FEATURES IN CANCER BIOLOGY. AS THE MAIN MOLECULAR DRIVERS OF HCC ARE STILL UNDRUGGABLE, CHEMICALLY INDUCED IN VIVO MODELS OF HEPATOCARCINOGENESIS ARE USEFUL TOOLS IN PRECLINICAL RESEARCH. THUS, THIS NARRATIVE REVIEW AIMED AT RECAPITULATING THE BASIC FEATURES OF CHEMICALLY INDUCED RODENT MODELS OF HEPATOCARCINOGENESIS, ELICITING THEIR PERMANENT TRANSLATIONAL VALUE REGARDING THE "CLASSIC" AND THE "NEW" CANCER HALLMARKS/ENABLING FEATURES. WE GATHERED STATE-OF-ART PRECLINICAL EVIDENCE ON NON-CIRRHOTIC, INFLAMMATION-, ALCOHOLIC LIVER DISEASE- AND NONALCOHOLIC FATTY LIVER-ASSOCIATED HCC MODELS, DEMONSTRATING THAT THESE BIOASSAYS INDEED EXPRESS THE RECENTLY ADDED HALLMARKS, AS WELL AS REFLECT THE INTERPLAY BETWEEN CLASSICAL AND NEW CANCER TRAITS. OUR REVIEW DEMONSTRATED THAT THESE PROTOCOLS REMAIN VALUABLE FOR TRANSLATIONAL PRECLINICAL APPLICATION, AS THEY RECAPITULATE TRENDING FEATURES OF CANCER SCIENCE. FURTHER "OMICS-BASED" APPROACHES ARE WARRANTED WHILE MULTIMODEL INVESTIGATIONS ARE ENCOURAGED IN ORDER TO AVOID "MODEL-BIASED" RESPONSES. 2023 13 2720 45 EXOSOMAL MIRNAS IN HEPATITIS B VIRUS RELATED LIVER DISEASE: A NEW HOPE FOR BIOMARKER. THE WORLD HEALTH ORGANISATION, IN ITS 2019 PROGRESS REPORT ON HIV, VIRAL HEPATITIS AND STDS INDICATES THAT 257 MILLION PEOPLE ARE AFFLICTED WITH CHRONIC HBV INFECTIONS, OF WHICH, 1 MILLION PATIENTS LOSE THEIR LIVES EVERY YEAR DUE TO HBV RELATED CHRONIC LIVER DISEASES INCLUDING SERIOUS COMPLICATIONS SUCH AS LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. THE COURSE OF HBV INFECTION AND ASSOCIATED LIVER INJURY DEPEND ON SEVERAL HOST FACTORS, GENETIC VARIABILITY OF THE VIRUS, AND THE HOST VIRAL INTERPLAY. THE CHALLENGE OF MEDICAL SCIENCE IS THE EARLY DIAGNOSIS/IDENTIFICATION OF THE POTENTIAL FOR DEVELOPMENT OF FATAL COMPLICATIONS LIKE LIVER CIRRHOSIS AND HCC SO THAT TIMELY MEDICAL INTERVENTION CAN IMPROVE THE CHANCES OF SURVIVAL. CURRENTLY, NEITHER THE VACCINATION REGIME NOR THE DIAGNOSTIC METHODS ARE COMPLETELY EFFECTIVE AS REFLECTED IN THE HIGH NUMBER OF ANNUAL DEATHS. IT IS EVIDENT FROM NUMEROUS PUBLICATIONS THAT MICRORNAS (MIRNAS) ARE THE CRITICAL REGULATORS OF GENE EXPRESSION AND VARIOUS CELLULAR PROCESSES LIKE PROLIFERATION, DEVELOPMENT, DIFFERENTIATION, APOPTOSIS AND TUMORIGENESIS. EXPRESSIONS OF THESE DIMINUTIVE RNAS ARE SIGNIFICANTLY AFFECTED IN CANCEROUS TISSUES AS A RESULT OF NUMEROUS GENOMIC AND EPIGENETIC MODIFICATIONS. EXOSOMES ARE MEMBRANE-DERIVED VESICLES (30-100 NM) SECRETED BY NORMAL AS WELL AS MALIGNANT CELLS, AND ARE PRESENT IN ALL BODY FLUIDS. THEY ARE RECOGNIZED AS CRITICAL MOLECULES IN INTERCELLULAR COMMUNICATION BETWEEN CELLS THROUGH HORIZONTAL TRANSFER OF INFORMATION VIA THEIR CARGO, WHICH INCLUDES SELECTIVE PROTEINS, MRNAS AND MIRNAS. EXOSOMAL MIRNAS ARE TRANSFERRED TO RECIPIENT CELLS WHERE THEY CAN REGULATE TARGET GENE EXPRESSION. THIS PROVIDES AN INSIGHT INTO THE ELEMENTARY BIOLOGY OF CANCER PROGRESSION AND THEREFORE THE DEVELOPMENT OF THERAPEUTIC APPROACHES. THIS CONCISE REVIEW OUTLINES VARIOUS ON-GOING RESEARCH ON MIRNA MEDIATED REGULATION OF HBV PATHOGENESIS WITH SPECIAL EMPHASIS ON ASSOCIATION OF EXOSOMAL MIRNA IN ADVANCED STAGE LIVER DISEASE LIKE HEPATOCELLULAR CARCINOMA. THIS REVIEW ALSO DISCUSSES THE POSSIBLE USE OF EXOSOMAL MIRNAS AS BIOMARKERS IN THE EARLY DETECTION OF HCC AND LIVER CIRRHOSIS. 2020 14 6797 39 [EPIDEMIOLOGY, NATURAL HISTORY AND PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE MAIN TYPE OF PRIMARY LIVER CANCERS AND THE THIRD MOST COMMON CAUSE OF CANCER MORTALITY WORLDWIDE. IN FRANCE, RISING NUMBER BETWEEN 5000 AND 6000 CASES ARE DIAGNOSED EACH YEAR. THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA IS CHRONIC HEPATITIS: VIRAL HEPATITIS B, VIRAL HEPATITIS C, CONSUMPTION OF ALCOHOL, HEMOCHROMATOSIS. HEPATOCELLULAR CARCINOMA IS CLOSELY ASSOCIATED TO LIVER CIRRHOSIS, WHICH IS A TRUE PRECANCEROUS STATE. BECAUSE HEPATOCARCINOGENESIS IS A LONG AND HETEROGENEOUS PROCESS, THERE IS STILL MUCH TO UNDERSTAND. MANY GENETIC AND EPIGENETIC ALTERATIONS ARE DESCRIBED LEADING TO CHANGES IN CELLULAR SIGNALLING CASCADES INVOLVED IN REGULATION OF GROWTH, DIFFERENTIATION, APOPTOSIS, MOTILITY. HEPATITIS VIRUSES PLAY A DIRECT ONCOGENIC ROLE THROUGH THE INTERACTION BETWEEN VIRAL AND CELLULAR PROTEINS, WHICH CONTROL CELL HOMEOSTASIS, OR BY THE INTEGRATION OF HEPATITIS B VIRUS GENOME INTO THE HOST GENOME. FURTHERMORE, HEPATITIS VIRUSES PLAY AN INDIRECT ONCOGENIC ROLE BY CAUSING CHRONIC INFLAMMATION AND HEPATOCYTE REGENERATION RELATED TO VIRAL HEPATOPATHY. IN EXPECTATION OF A BETTER UNDERSTANDING OF HEPATOCARCINOGENESIS AND NEW TREATMENTS, PREVENTION FROM RISK FACTORS AND ULTRASONOGRAPHIC SCREENING OF PATIENTS WITH CIRRHOSIS SHOULD INCREASE PROGNOSIS. 2011 15 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 16 1478 31 DIVERSE ROLES OF HEPATITIS B VIRUS IN LIVER CANCER. HEPATITIS B VIRUS (HBV) IS A WIDESPREAD HUMAN PATHOGEN RESPONSIBLE FOR ACUTE AND CHRONIC LIVER DISEASES. THE HEPATITIS B BURDEN IS PARTICULARLY HEAVY IN ENDEMIC COUNTRIES, WHERE LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA ARE LEADING CAUSES OF DEATH. HOWEVER, THE ONCOGENIC ROLE OF HBV REMAINS ENIGMATIC. AS THE VIRUS HAS NO CYTOPATHIC EFFECT, LIVER DAMAGE IS ATTRIBUTED TO IMMUNE RESPONSES THAT INDUCE INFLAMMATION, APOPTOSIS AND REGENERATION, FOSTERING THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN A MORE DIRECT ACTION, FREQUENT INTEGRATION OF HBV DNA INTO HOST CHROMOSOMES MAY LEAD TO INSERTIONAL MUTAGENESIS OF CANCER-RELATED GENES AND CHROMOSOMAL INSTABILITY. HBV PROTEINS, NOTABLY THE HBX TRANSACTIVATOR, PARTICIPATE AS CO-FACTORS IN ONCOGENESIS. BETTER UNDERSTANDING OF HEPATITIS B PATHOGENESIS IS MANDATORY FOR IMPROVING DISEASE MANAGEMENT. 2012 17 319 35 ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS THE MOST PREVALENT TYPE OF CHRONIC LIVER DISEASE WORLDWIDE. ALD CAN PROGRESS FROM ALCOHOLIC FATTY LIVER (AFL) TO ALCOHOLIC STEATOHEPATITIS (ASH), WHICH IS CHARACTERIZED BY HEPATIC INFLAMMATION. CHRONIC ASH CAN EVENTUALLY LEAD TO FIBROSIS AND CIRRHOSIS AND IN SOME CASES HEPATOCELLULAR CANCER (HCC). IN ADDITION, SEVERE ASH (WITH OR WITHOUT CIRRHOSIS) CAN LEAD TO ALCOHOLIC HEPATITIS, WHICH IS AN ACUTE CLINICAL PRESENTATION OF ALD THAT IS ASSOCIATED WITH LIVER FAILURE AND HIGH MORTALITY. MOST INDIVIDUALS CONSUMING >40 G OF ALCOHOL PER DAY DEVELOP AFL; HOWEVER, ONLY A SUBSET OF INDIVIDUALS WILL DEVELOP MORE ADVANCED DISEASE. GENETIC, EPIGENETIC AND NON-GENETIC FACTORS MIGHT EXPLAIN THE CONSIDERABLE INTERINDIVIDUAL VARIATION IN ALD PHENOTYPE. THE PATHOGENESIS OF ALD INCLUDES HEPATIC STEATOSIS, OXIDATIVE STRESS, ACETALDEHYDE-MEDIATED TOXICITY AND CYTOKINE AND CHEMOKINE-INDUCED INFLAMMATION. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. THE DEGREE OF AFL AND LIVER FIBROSIS CAN BE DETERMINED BY ULTRASONOGRAPHY, TRANSIENT ELASTOGRAPHY, MRI, MEASUREMENT OF SERUM BIOMARKERS AND LIVER BIOPSY HISTOLOGY. ALCOHOL ABSTINENCE ACHIEVED BY PSYCHOSOMATIC INTERVENTION IS THE BEST TREATMENT FOR ALL STAGES OF ALD. IN THE CASE OF ADVANCED DISEASE SUCH AS CIRRHOSIS OR HCC, LIVER TRANSPLANTATION MAY BE REQUIRED. THUS, NEW THERAPIES ARE URGENTLY NEEDED. 2018 18 4326 39 MICRORNAS IN THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), OR, MORE ACCURATELY, METABOLIC ASSOCIATED FATTY LIVER DISEASE, ACCOUNTS FOR A LARGE PROPORTION OF CHRONIC LIVER DISORDERS WORLDWIDE AND IS CLOSELY ASSOCIATED WITH OTHER CONDITIONS SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND TYPE 2 DIABETES MELLITUS. NAFLD RANGES FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH) AND CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, ALSO HEPATOCELLULAR CARCINOMA. THE MORBIDITY AND MORTALITY ASSOCIATED WITH NAFLD ARE INCREASING RAPIDLY YEAR ON YEAR. CONSEQUENTLY, THERE IS AN URGENT NEED TO UNDERSTAND THE ETIOLOGY AND PATHOGENESIS OF NAFLD AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. MICRORNAS (MIRNAS), IMPORTANT EPIGENETIC FACTORS, HAVE RECENTLY BEEN PROPOSED TO PARTICIPATE IN NAFLD PATHOGENESIS. HERE, WE REVIEW THE ROLES OF MIRNAS IN LIPID METABOLISM, INFLAMMATION, APOPTOSIS, FIBROSIS, HEPATIC STELLATE CELL ACTIVATION, INSULIN RESISTANCE, AND OXIDATIVE STRESS, KEY FACTORS THAT CONTRIBUTE TO THE OCCURRENCE AND PROGRESSION OF NAFLD. ADDITIONALLY, WE SUMMARIZE THE ROLE OF MIRNA-ENRICHED EXTRACELLULAR VESICLES IN NAFLD. THESE MIRNAS MAY COMPRISE SUITABLE THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS CONDITION. 2021 19 6850 32 [MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER DEATH WORLDWIDE. HCC NEARLY ALMOST ALWAYS DEVELOPS IN CONNECTION WITH CHRONIC HEPATITIS OR LIVER CIRRHOSIS, MAINLY DUE TO HEPATITIS B VIRUS OR HEPATITIS C VIRUS INFECTION. SEVERAL FACTORS ARE SUPPOSED TO PLAY KEY ROLES IN THE DEVELOPMENT OF HCC, SUCH AS ABERRANT VIRAL PROTEIN EXPRESSION, GENOMIC INSTABILITY WITH/WITHOUT INSERTIONS OF VIRAL DNAS, GENE MUTATIONS, EPIGENETIC GENE MODIFICATION, OXIDATIVE STRESS, AND ALTERATION OF THE MICROENVIRONMENT INCLUDING INFLAMMATION, FIBROSIS, AND EMERGENCE OF STEM/PROGENITOR CELLS AS A RESULT OF REPEATED NECROSIS AND REGENERATION OF HEPATOCYTES. THE ELUCIDATION OF MOLECULAR MECHANISMS OF HEPATOCARCINOGENESIS HAS SUCCESSFULLY PROVIDED SMALL MOLECULE INHIBITORS TARGETING ABERRANTLY ACTIVATED SIGNALING IN HCC. DEVELOPMENT OF NOVEL CLASSIFICATION SYSTEMS BASED ON THE MOLECULAR PROFILES AND DRUG SENSITIVITIES AGAINST MOLECULARLY TARGETED COMPOUNDS IS CURRENTLY UNDERWAY TO FACILITATE NOVEL STRATEGIES FOR EFFECTIVE ERADICATION OF HCC. 2010 20 1042 24 CLINICAL AND MOLECULAR BASIS OF HEPATOCELLULAR CARCINOMA AFTER HEPATITIS C VIRUS ERADICATION. HEPATOCELLULAR CARCINOMA (HCC) ARISES IN THE BACKGROUND OF CHRONIC LIVER DISEASES, INCLUDING HEPATITIS AND LIVER CIRRHOSIS CAUSED BY HEPATITIS C VIRUS (HCV) INFECTION. IT IS WELL KNOWN THAT HCV ERADICATION USING ANTIVIRAL DRUGS CAN EFFICIENTLY INHIBIT HEPATOCARCINOGENESIS. RECENT ADVANCES IN AND DEVELOPMENT OF DIRECT-ACTING ANTIVIRAL (DAA) DRUGS HAS REVOLUTIONIZED THE TREATMENT OF HCV INFECTION, AND THE VAST MAJORITY OF HCV PATIENTS CAN ACHIEVE HCV ERADICATION USING DAAS. HOWEVER, MOUNTING EVIDENCE CLEARLY INDICATES THAT HCC INEVITABLY OCCURS IN A SUBSET OF PATIENTS AFTER SUCCESSFUL VIRAL ERADICATION USING DAA THERAPY. CANCER IS A GENETIC DISEASE, AND THE ACCUMULATION OF GENETIC AND EPIGENETIC ABERRATIONS MAY CAUSE HEPATOCARCINOGENESIS IN CHRONICALLY DAMAGED LIVER, EVEN AFTER VIRUS ELIMINATION. IN THIS REVIEW, WE HIGHLIGHT HCC DEVELOPMENT AFTER HCV ERADICATION AND DISCUSS THE CURRENT UNDERSTANDING OF THE MOLECULAR MECHANISMS OF TUMORIGENESIS AFTER VIRUS ELIMINATION, FOCUSING ON THE GENETIC AND EPIGENETIC BACKGROUND OF CHRONICALLY DAMAGED LIVER TISSUES. 2022