1 3928 97 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 2 251 33 ADVANCED THERAPEUTIC MODALITIES IN HEPATOCELLULAR CARCINOMA: NOVEL INSIGHTS. HEPATOCELLULAR CARCINOMA (HCC), THE MOST COMMON TYPE OF LIVER CANCER, IS USUALLY A LATENT AND ASYMPTOMATIC MALIGNANCY CAUSED BY DIFFERENT AETIOLOGIES, WHICH IS A RESULT OF VARIOUS ABERRANT MOLECULAR HETEROGENEITY AND OFTEN DIAGNOSED AT ADVANCED STAGES. THE INCIDENCE AND PREVALENCE HAVE SIGNIFICANTLY INCREASED BECAUSE OF SEDENTARY LIFESTYLE, DIABETES, CHRONIC INFECTION WITH HEPATOTROPIC VIRUSES AND EXPOSURE TO AFLATOXINS. DUE TO ADVANCED INTRA- OR EXTRAHEPATIC METASTASIS, RECURRENCE IS VERY COMMON EVEN AFTER RADICAL RESECTION. IN THIS PAPER, WE HIGHLIGHTED NOVEL THERAPEUTIC MODALITIES, SUCH AS MOLECULAR-TARGETED THERAPIES, TARGETED RADIONUCLIDE THERAPIES AND EPIGENETIC MODIFICATION-BASED THERAPIES. THESE TOPICS ARE TRENDING HEADLINES AND THEIR COMBINATION WITH CELL-BASED IMMUNOTHERAPIES, AND GENE THERAPY HAS PROVIDED PROMISING PROSPECTS FOR THE FUTURE OF HCC TREATMENT. MOREOVER, A COMPREHENSIVE OVERVIEW OF CURRENT AND ADVANCED THERAPEUTIC APPROACHES IS DISCUSSED AND THE ADVANTAGES AND LIMITATIONS OF EACH STRATEGY ARE DESCRIBED. FINALLY, VERY RECENT AND APPROVED NOVEL COMBINED THERAPIES AND THEIR PROMISING RESULTS IN HCC TREATMENT HAVE BEEN INTRODUCED. 2021 3 3103 25 GENOMIC LANDSCAPE OF HCC. INTRODUCTION: HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER RELATED MORTALITY IN THE WORLD AND IT HAS LIMITED TREATMENT OPTIONS. UNDERSTANDING THE MOLECULAR DRIVERS OF HCC IS IMPORTANT TO DEVELOP NOVEL BIOMARKERS AND THERAPEUTICS. PURPOSE OF REVIEW: HCC ARISES IN A COMPLEX BACKGROUND OF CHRONIC HEPATITIS, FIBROSIS AND LIVER REGENERATION WHICH LEAD TO GENOMIC CHANGES. HERE, WE SUMMARIZE STUDIES THAT HAVE EXPANDED OUR UNDERSTANDING OF THE MOLECULAR LANDSCAPE OF HCC. RECENT FINDINGS: RECENT TECHNOLOGICAL ADVANCES IN NEXT GENERATION SEQUENCING (NGS) HAVE ELUCIDATED SPECIFIC GENETIC AND MOLECULAR PROGRAMS INVOLVED IN HEPATOCARCINOGENESIS. WE SUMMARIZE THE MAJOR SOMATIC MUTATIONS AND EPIGENETIC CHANGES HAVE BEEN IDENTIFIED IN NGS-BASED STUDIES. WE ALSO DESCRIBE PROMISING MOLECULAR THERAPIES AND IMMUNOTHERAPIES WHICH TARGET SPECIFIC GENETIC AND EPIGENETIC MOLECULAR EVENTS. SUMMARY: THE GENOMIC LANDSCAPE OF HCC IS INCREDIBLY COMPLEX AND HETEROGENEOUS. PROMISING NEW DEVELOPMENTS ARE HELPING US DECIPHER THE MOLECULAR DRIVERS OF HCC AND LEADING TO NEW THERAPIES. 2020 4 2502 24 EPIGENETICS AND LIVER FIBROSIS. LIVER FIBROSIS ARISES BECAUSE PROLONGED INJURY COMBINED WITH EXCESSIVE SCAR DEPOSITION WITHIN HEPATIC PARENCHYMA ARISING FROM OVERACTIVE WOUND HEALING RESPONSE MEDIATED BY ACTIVATED MYOFIBROBLASTS. FIBROSIS IS THE COMMON END POINT FOR ANY TYPE OF CHRONIC LIVER INJURY INCLUDING ALCOHOLIC LIVER DISEASE, NONALCOHOLIC FATTY LIVER DISEASE, VIRAL HEPATITIS, AND CHOLESTATIC LIVER DISEASES. ALTHOUGH GENETIC INFLUENCES ARE IMPORTANT, IT IS EPIGENETIC MECHANISMS THAT HAVE BEEN SHOWN TO ORCHESTRATE MANY ASPECTS OF FIBROGENESIS IN THE LIVER. NEW DISCOVERIES IN THE FIELD ARE LEADING TOWARD THE DEVELOPMENT OF EPIGENETIC BIOMARKERS AND TARGETED THERAPIES. THIS REVIEW CONSIDERS EPIGENETIC MECHANISMS AS WELL AS RECENT ADVANCES IN EPIGENETIC PROGRAMMING IN THE CONTEXT OF HEPATIC FIBROSIS. 2017 5 3742 19 INSIGHTS FOR HEPATITIS C VIRUS RELATED HEPATOCELLULAR CARCINOMA GENETIC BIOMARKERS: EARLY DIAGNOSIS AND THERAPEUTIC INTERVENTION. THE CURRENT REVIEW EXPLORES THE ROLE OF EMERGING MOLECULAR CONTRIBUTING FACTORS IN LIVER CARCINOGENESIS ON TOP OF HEPATITIS C VIRUS (HCV). HERE WE WILL TRY TO DISCUSS THE ROLE GENETIC AND EPIGENETIC FACTORS IN PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE ROLE OF THESE FACTORS WILL HELP IN DISCOVERING THE MYSTERY OF LIVER CARCINOGENESIS ON TOP OF CHRONIC HCV INFECTION. MOREOVER, USE OF THE STUDIED MOLECULAR FACTORS WILL PROVIDE THE HEPATOLOGISTS WITH TAILORED DIAGNOSTIC PROMISING BIOMARKERS AND FLATTEN THE WAY FOR ESTABLISHMENT OF EMERGING MOLECULAR TREATMENT BASED ON EXPLORING THE MOLECULAR SUBSCRIPTION OF THIS AGGRESSIVE LIVER CANCER. 2016 6 6882 16 [RESEARCH PROGRESS ON NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. PRIMARY LIVER CANCER ARISES FROM CHRONIC LIVER DISEASE, AND CIRRHOTIC LIVER GRADUALLY DEVELOPS INTO DYSPLASTIC NODULES THAT EVENTUALLY FORM MALIGNANT TUMORS. IN RECENT YEARS, MOLECULAR BIOTECHNOLOGY DEVELOPMENT HAS DEEPENED PEOPLE'S UNDERSTANDING ON THE PATHOGENESIS OF LIVER CANCER. EPIGENETIC MODIFICATIONS PLAY A SIGNIFICANT ROLE IN DNA METHYLATION, NON-CODING RNAS, CHROMATIN REMODELING, AND HISTONE MODIFICATION. THIS REVIEW FOCUSES ON THE PROGRESS OF CURRENTLY IMPLICATED NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA, AND ITS POTENTIAL APPLICATION IN IMPROVING THE DIAGNOSIS AND TREATMENT. 2018 7 3365 33 HISTONE METHYLATION IN PRE-CANCEROUS LIVER DISEASES AND HEPATOCELLULAR CARCINOMA: RECENT OVERVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE PREVALENT FORM OF LIVER CANCER IN ADULTS AND THE FOURTH MOST COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. HCC PREDOMINANTLY ARISES IN THE CONTEXT OF CIRRHOSIS AS A RESULT OF CHRONIC LIVER DISEASE, INJURY AND INFLAMMATION. FULL-BLOWN HCC HAS POOR PROGNOSIS BECAUSE IT IS HIGHLY AGGRESSIVE AND RESISTANT TO THERAPY. CONSEQUENTLY, INTERVENTIONS THAT CAN PREVENT OR RESTRAIN HCC EMERGENCE FROM PRE-CANCEROUS DISEASED LIVER ARE A DESIRABLE STRATEGY. HISTONE METHYLATION IS A DYNAMIC, REVERSIBLE EPIGENETIC MODIFICATION INVOLVING THE ADDITION OR REMOVAL OF METHYL GROUPS FROM LYSINE, ARGININE OR GLUTAMINE RESIDUES. ABERRANT ACTIVITY OF HISTONE METHYLATION WRITERS, ERASES AND READERS HAS BEEN IMPLICATED IN SEVERAL CANCER TYPES, INCLUDING HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RESEARCH ON THE ROLE OF HISTONE METHYLATION IN PRE-CANCEROUS AND CANCEROUS HCC PUBLISHED OVER THE LAST 5 YEARS. IN PARTICULAR, WE PRESENT THE EVIDENCE LINKING ENVIRONMENTAL FACTORS SUCH AS DIET, VIRAL INFECTIONS AND CARCINOGENIC AGENTS WITH DYSREGULATION OF HISTONE METHYLATION DURING LIVER CANCER PROGRESSION WITH THE AIM TO HIGHLIGHT FUTURE THERAPEUTIC POSSIBILITIES. 2023 8 3270 28 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 9 3266 28 HEPATOCELLULAR CANCER AND GUT MICROBIOME: TIME TO UNTIE GORDIAN'S KNOT. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE LEADING CAUSES OF CANCER DEATH WORLDWIDE AND THE INCIDENCE IS GROWING ON A GLOBAL SCALE. ABOUT 90% OF CASES DEVELOP ON THE CIRRHOTIC LIVER AND THE ETIOLOGY IS MULTIFACTORIAL. INCREASING NUMBER OF STUDIES SUGGEST THAT GUT MICROBIOTA INFLUENCES THE DEVELOPMENT AND PROGRESSION OF LIVER DISEASES, INCLUDING CHRONIC HEPATIC INFLAMMATION, FIBROSIS, CIRRHOSIS, AND HCC. THE KEY ROLE OF GUT MICROBIOTA IN CARCINOGENESIS SEEMS TO BE ASSOCIATED WITH GENOMIC INSTABILITY OF HOST CELLS AND IMMUNE DYSREGULATION. RECENT CLINICAL STUDIES SHOWED THAT A STABLE AND HEALTHY MICROBIOTA INITIALLY COULD HAVE THE ABILITY TO RESIST THE EMERGENCE OF CHRONIC INFLAMMATION AND, THEREFORE, PREVENT THE INDUCTION OF CARCINOGENIC CELLS IN VARIOUS ORGANS SUCH AS THE ESOPHAGUS, STOMACH, COLON, AND LIVER. THE PROGRESSION FROM INFLAMMATION TO CANCER IS A STEPWISE PROCESS OCCURRING BY THE CONCERTED ACTION OF SEVERAL FACTORS SUCH AS DYSBIOSIS, INCREASED GUT PERMEABILITY, DIET, METABOLOMIC, GENETIC, AND EPIGENETIC CHANGES. IN THIS ARTICLE, WE AIMED TO REVIEW THE POSSIBLE ROLE OF GUT MICROBIOTA IN THE DEVELOPMENT, PROGRESSION, AND TREATMENT OF HCC. 2021 10 3269 35 HEPATOCELLULAR CARCINOMA IN ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER DISEASE-ONE OF A KIND OR TWO DIFFERENT ENEMIES? HEPATOCELLULAR CANCER (HCC) IS A CANCER WITH AN OVERALL POOR PROGNOSIS AND AN ALARMING GLOBALLY RISING INCIDENCE. WHILE VIRAL ETIOLOGY OF CHRONIC LIVER DISEASE AND HCC IS DOWN-TRENDING, ALCOHOL AND EXCESS CALORIE INTAKE HAVE EMERGED AS MAJOR CULPRITS. ALCOHOL RELATED LIVER DISEASE (ALD) AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) SHARE SIMILAR PATHOGENETIC MECHANISM OF HEPATIC INJURY AND IN PROMOTING DEVELOPMENT OF HCC; YET SOME GENETIC AND EPIGENETIC FEATURES ARE DISTINCT AND MAY PROMISE CLINICAL UTILITY. POPULATION BASED INTERVENTION ARE URGENTLY NEEDED TO REDUCE ALCOHOL USE AND IMPROVE METABOLIC FACTORS SUCH AS OBESITY AND DIABETES. THE GOAL IS TO IDENTIFY AT-RISK PATIENTS, TO LINK THESE PATIENTS TO CARE AND TO PROVIDE EFFECTIVE MANAGEMENT OF CHRONIC LIVER DISEASE AND HCC. THIS REVIEW FOCUSES ON THE EPIDEMIOLOGY, PATHOPHYSIOLOGY INCLUDING GENETIC AND EPIGENETIC ALTERCATION AS WELL AS CLINICAL ASPECTS OF ALD AND NAFLD ASSOCIATED HCC. 2019 11 5211 31 PRENEOPLASTIC LESIONS IN HUMAN HEPATOCARCINOGENESIS. THE EARLY STAGES OF HEPATOCARCINOGENESIS IN HUMAN CHRONIC LIVER DISEASES ARE CHARACTERIZED BY THE EMERGENCE OF PRENEOPLASTIC LESIONS OF WHICH SOME WILL EVENTUALLY DEVELOP INTO HEPATOCELLULAR CARCINOMA (HCC). BASIC STUDIES ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THESE PRENEOPLASTIC LESIONS MAY EVENTUALLY LEAD TO NEW THERAPEUTIC STRATEGIES. CLINICOPATHOLOGICAL STUDIES ARE ALSO IMPORTANT IN ORDER TO DETERMINE OPTIMAL MANAGEMENT OF PATIENTS WITH A PRENEOPLASTIC LESION. THIS ARTICLE AIMS TO PROVIDE A COMPREHENSIVE REVIEW OF THE CURRENT CONCEPTS OF PRENEOPLASTIC LESION IN CHRONIC LIVER DISEASES. THE MICROSCOPICAL SMALL-CELL DYSPLASTIC FOCUS IS THE SMALLEST MORPHOLOGICALLY RECOGNIZABLE PRECURSOR LESION OF HCC AND THEREFORE IS A LOGICAL TARGET OF STUDY TO ELUCIDATE THE EARLIEST EVENTS IN HEPATOCARCINOGENESIS. IN CONTRAST, LARGE-CELL DYSPLASIA IS NOT A PRECURSOR LESION, BUT APPEARS TO BE OF CLINICAL VALUE BECAUSE OF ITS GOOD PREDICTIVE VALUE FOR DEVELOPMENT OF HCC. DYSPLASTIC NODULES (DNS) ARE MACROSCOPICALLY RECOGNIZABLE PRECURSOR LESIONS OF HCC AND HIGH-GRADE DNS (HGDNS) HAVE A RISK OF MALIGNANT TRANSFORMATION. DETECTION OF DNS AND CORRECT DIFFERENTIATION FROM SMALL HCC (<2 CM) IS SOMETIMES DIFFICULT, ESPECIALLY WHEN ONLY IMAGING TECHNIQUES ARE USED. ADDITIONAL CLINICOPATHOLOGICAL STUDIES ON IDENTIFICATION AND OPTIMAL TREATMENT OF DNS ARE NECESSARY. MOLECULAR STUDIES ON HGDNS AND SMALL HCCS MAY YIELD MUCH INFORMATION ON THE GENETIC MECHANISMS INVOLVED IN THE TRANSITION FROM SEVERE DYSPLASIA TO EARLY MALIGNANCY. IN CONTRAST, CURRENTLY AVAILABLE DATA INDICATE THAT (LARGE) REGENERATIVE NODULES DO NOT REPRESENT A DISTINCT STEP IN HEPATOCARCINOGENESIS. ANIMAL MODELS WILL BE HELPFUL IN THE FURTHER UNRAVELLING OF HUMAN HCC DEVELOPMENT, PROVIDED THAT STUDIES ARE PERFORMED ON MODELS THAT ARE GOOD REPRESENTATIVES OF HUMAN HEPATOCARCINOGENESIS. WE PROPOSE THREE CRITERIA BY WHICH GOOD MIMICKERS CAN BE IDENTIFIED. 2005 12 3278 27 HEPATOEPIGENETIC ALTERATIONS IN VIRAL AND NONVIRAL-INDUCED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR PUBLIC HEALTH CONCERN AND ONE OF THE LEADING CAUSES OF TUMOUR-RELATED DEATHS WORLDWIDE. EXTENSIVE EVIDENCE ENDORSES THAT HCC IS A MULTIFACTORIAL DISEASE CHARACTERISED BY HEPATIC CIRRHOSIS MOSTLY ASSOCIATED WITH CHRONIC INFLAMMATION AND HEPATITIS B/C VIRAL INFECTIONS. INTERACTION OF VIRAL PRODUCTS WITH THE HOST CELL MACHINERY MAY LEAD TO INCREASED FREQUENCY OF GENETIC AND EPIGENETIC ABERRATIONS THAT CAUSE HARMFUL ALTERATIONS IN GENE TRANSCRIPTION. THIS MAY PROVIDE A PROGRESSIVE SELECTIVE ADVANTAGE FOR NEOPLASTIC TRANSFORMATION OF HEPATOCYTES ASSOCIATED WITH PHENOTYPIC HETEROGENEITY OF INTRATUMOUR HCC CELLS, THUS POSING EVEN MORE CHALLENGES IN HCC TREATMENT DEVELOPMENT. EPIGENETIC ABERRATIONS INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING MIRNA DYSREGULATION HAVE BEEN SHOWN TO BE INTIMATELY LINKED WITH AND PLAY A CRITICAL ROLE IN TUMOUR INITIATION, PROGRESSION, AND METASTASES. THE CURRENT REVIEW FOCUSES ON THE ABERRANT HEPATOEPIGENETICS EVENTS THAT PLAY IMPORTANT ROLES IN HEPATOCARCINOGENESIS AND THEIR UTILITIES IN THE DEVELOPMENT OF HCC THERAPY. 2016 13 1042 29 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 14 3263 31 HEPATITIS VIRUS AND HEPATOCELLULAR CARCINOMA: RECENT ADVANCES. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL HEALTH CHALLENGE, CAUSING 600,000 DEATHS EACH YEAR. INFECTIOUS FACTORS, INCLUDING HEPATITIS B VIRUS (HBV), HEPATITIS C VIRUS (HCV) AND HEPATITIS D VIRUS (HDV), HAVE LONG BEEN CONSIDERED THE MAJOR RISK FACTORS FOR THE DEVELOPMENT AND PROGRESSION OF HCC. THESE PATHOGENS INDUCE HEPATOCYTE TRANSFORMATION THROUGH A VARIETY OF MECHANISMS, INCLUDING INSERTIONAL MUTATIONS CAUSED BY VIRAL GENE INTEGRATION, EPIGENETIC CHANGES, AND THE INDUCTION OF LONG-TERM IMMUNE DYSFUNCTION. THE DISCOVERY OF THESE MECHANISMS, WHILE ADVANCING OUR UNDERSTANDING OF THE DISEASE, ALSO PROVIDES TARGETS FOR NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. IN ADDITION, THE DISCOVERY AND RESEARCH OF CHRONIC HEV INFECTION OVER THE PAST DECADE INDICATE THAT THIS COMMON HEPATITIS VIRUS ALSO SEEMS TO HAVE THE POTENTIAL TO INDUCE HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT STUDIES ON THE LINK BETWEEN HEPATITIS VIRUS AND HCC, AS WELL AS NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES TO HCC BASED ON THESE FINDINGS. FINALLY, WE ALSO DISCUSS THE POTENTIAL RELATIONSHIP BETWEEN HEV AND HCC. IN CONCLUSION, THESE ASSOCIATIONS WILL FURTHER OPTIMIZE THE DIAGNOSIS AND TREATMENT OF INFECTION-ASSOCIATED HCC AND CALL FOR BETTER MANAGEMENT POLICIES. 2023 15 5903 33 T3/TRS AXIS IN HEPATOCELLULAR CARCINOMA: NEW CONCEPTS FOR AN OLD PAIR. HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE, AND ITS BURDEN IS EXPECTED TO FURTHER INCREASE IN THE NEXT YEARS. CHRONIC INFLAMMATION, INDUCED BY MULTIPLE VIRUSES OR METABOLIC ALTERATIONS, AND EPIGENETIC AND GENETIC MODIFICATIONS, COOPERATE IN CANCER DEVELOPMENT VIA A COMBINATION OF COMMON AND DISTINCT AETIOLOGY-SPECIFIC PATHWAYS. IN SPITE OF THE ADVANCES OF CLASSICAL THERAPIES, THE PROGNOSIS OF THIS NEOPLASM HAS NOT CONSIDERABLY IMPROVED OVER THE PAST FEW YEARS. THE ADVENT OF TARGETED THERAPIES AND THE APPROVAL OF THE SYSTEMIC TREATMENT OF ADVANCED HCC WITH THE KINASE INHIBITOR SORAFENIB HAVE PROVIDED SOME HOPE FOR THE FUTURE. HOWEVER, THE BENEFITS OBTAINED FROM THIS TREATMENT ARE STILL DISAPPOINTING, AS IT EXTENDS THE MEDIAN LIFE EXPECTANCY OF PATIENTS BY ONLY FEW MONTHS. IT IS THUS MANDATORY TO FIND ALTERNATIVE EFFECTIVE TREATMENTS. ALTHOUGH THE ROLE PLAYED BY THYROID HORMONES (THS) AND THEIR NUCLEAR RECEPTORS (TRS) IN HUMAN CANCER IS STILL UNCLEAR, MOUNTING EVIDENCE INDICATES THAT THEY BEHAVE AS ONCOSUPPRESSORS IN HCC. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH THEY EXERT THIS EFFECT AND THE CONSEQUENCE OF THEIR ACTIVATION FOLLOWING LIGAND BINDING ON HCC PROGRESSION REMAIN ELUSIVE. IN THIS REVIEW, WE RE-EVALUATE THE EXISTING EVIDENCE OF THE ROLE OF TH/TRS IN HCC DEVELOPMENT; WE WILL ALSO DISCUSS HOW TR ALTERATIONS COULD AFFECT FUNDAMENTAL BIOLOGICAL PROCESSES, SUCH AS HEPATOCYTE PROLIFERATION AND DIFFERENTIATION, AND CONSEQUENTLY HCC PROGRESSION. FINALLY, WE WILL DISCUSS IF AND HOW TRS CAN BE FORESEEN AS THERAPEUTIC TARGETS IN HCC AND WHETHER SELECTIVE TR MODULATION BY TH ANALOGUES MAY HOLD PROMISE FOR HCC TREATMENT. 2016 16 3811 14 INTRATUMORAL HETEROGENEITY: CLONAL COOPERATION IN EPITHELIAL-TO-MESENCHYMAL TRANSITION AND METASTASIS. ALTHOUGH PHENOTYPIC INTRATUMORAL HETEROGENEITY WAS FIRST DESCRIBED MANY DECADES AGO, THE ADVENT OF NEXT-GENERATION SEQUENCING HAS PROVIDED CONCLUSIVE EVIDENCE THAT IN ADDITION TO PHENOTYPIC DIVERSITY, SIGNIFICANT GENOTYPIC DIVERSITY EXISTS WITHIN TUMORS. TUMOR HETEROGENEITY LIKELY ARISES BOTH FROM CLONAL EXPANSIONS, AS WELL AS FROM DIFFERENTIATION HIERARCHIES EXISTENT IN THE TUMOR, SUCH AS THAT ESTABLISHED BY CANCER STEM CELLS (CSCS) AND NON-CSCS. THESE DIFFERENTIATION HIERARCHIES MAY ARISE DUE TO GENETIC MUTATIONS, EPIGENETIC ALTERATIONS, OR MICROENVIRONMENTAL INFLUENCES. AN ADDITIONAL DIFFERENTIATION HIERARCHY WITHIN EPITHELIAL TUMORS MAY ARISE WHEN ONLY A FEW TUMOR CELLS TRANS-DIFFERENTIATE INTO MESENCHYMAL-LIKE CELLS, A PROCESS KNOWN AS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). AGAIN, THIS PROCESS CAN BE INFLUENCED BY BOTH GENETIC AND NON-GENETIC FACTORS. IN THIS REVIEW WE DISCUSS THE EVIDENCE FOR CLONAL INTERACTION AND COOPERATION FOR TUMOR MAINTENANCE AND PROGRESSION, PARTICULARLY WITH RESPECT TO EMT, AND FURTHER ADDRESS THE FAR-REACHING EFFECTS THAT TUMOR HETEROGENEITY MAY HAVE ON CANCER THERAPY. 2015 17 2538 24 EPIGENETICS IN HEPATOCELLULAR CARCINOMA: AN UPDATE AND FUTURE THERAPY PERSPECTIVES. HEPATOCELLULAR CARCINOMA (HCC), THE PREDOMINANT FORM OF ADULT LIVER MALIGNANCIES, IS A GLOBAL HEALTH CONCERN. ITS DISMAL PROGNOSIS HAS PROMPTED RECENT SIGNIFICANT ADVANCES IN THE UNDERSTANDING OF ITS ETIOLOGY AND PATHOGENESIS. THE DEREGULATION OF EPIGENETIC MECHANISMS, WHICH MAINTAIN HERITABLE GENE EXPRESSION CHANGES AND CHROMATIN ORGANIZATION, IS IMPLICATED IN THE DEVELOPMENT OF MULTIPLE CANCERS, INCLUDING HCC. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF HCC, WITH AN EMPHASIS ON HCC MEDIATED BY CHRONIC HEPATITIS B VIRUS INFECTION. THIS REVIEW ALSO DISCUSSES THE ENCOURAGING OUTCOMES AND LESSONS LEARNT FROM EPIGENETIC THERAPIES FOR HEMATOLOGICAL AND OTHER SOLID CANCERS, AND HIGHLIGHTS THE FUTURE POTENTIAL OF SIMILAR THERAPIES IN THE TREATMENT OF HCC. 2014 18 4666 25 NEW INSIGHTS AND OPTIONS INTO THE MECHANISMS AND EFFECTS OF COMBINED TARGETED THERAPY AND IMMUNOTHERAPY IN PROSTATE CANCER. CHRONIC INFLAMMATION IS BELIEVED TO DRIVE PROSTATE CARCINOGENESIS BY PRODUCING REACTIVE OXYGEN SPECIES OR REACTIVE NITROGEN SPECIES TO INDUCE DNA DAMAGE. THIS EFFECT MIGHT SUBSEQUENTLY CAUSE EPIGENETIC AND GENOMIC ALTERATIONS, LEADING TO MALIGNANT TRANSFORMATION. ALTHOUGH ESTABLISHED THERAPEUTIC ADVANCES HAVE EXTENDED OVERALL SURVIVAL, TUMORS IN PATIENTS WITH ADVANCED PROSTATE CANCER ARE PRONE TO METASTASIS, TRANSFORMATION INTO METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, AND THERAPEUTIC RESISTANCE. THE TUMOR MICROENVIRONMENT (TME) OF PROSTATE CANCER IS INVOLVED IN CARCINOGENESIS, INVASION AND DRUG RESISTANCE. A PLETHORA OF PRECLINICAL STUDIES HAVE FOCUSED ON IMMUNE-BASED THERAPIES. UNDERSTANDING THE INTRICATE TME SYSTEM IN PROSTATE CANCER MAY HOLD MUCH PROMISE FOR DEVELOPING NOVEL THERAPIES, DESIGNING COMBINATIONAL THERAPEUTIC STRATEGIES, AND FURTHER OVERCOMING RESISTANCE TO ESTABLISHED TREATMENTS TO IMPROVE THE LIVES OF PROSTATE CANCER PATIENTS. IN THIS REVIEW, WE DISCUSS NONIMMUNE COMPONENTS AND VARIOUS IMMUNE CELLS WITHIN THE TME AND THEIR PUTATIVE ROLES DURING PROSTATE CANCER INITIATION, PROGRESSION, AND METASTASIS. WE ALSO OUTLINE THE UPDATED FUNDAMENTAL RESEARCH FOCUSING ON THERAPEUTIC ADVANCES OF TARGETED THERAPY AS WELL AS COMBINATIONAL OPTIONS FOR PROSTATE CANCER. 2023 19 4712 22 NON-ALCOHOLIC FATTY LIVER DISEASE: METABOLIC, GENETIC, EPIGENETIC AND ENVIRONMENTAL RISK FACTORS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST FREQUENT CAUSES OF CHRONIC LIVER DISEASE IN THE WESTERN WORLD, PROBABLY DUE TO THE GROWING PREVALENCE OF OBESITY, METABOLIC DISEASES, AND EXPOSURE TO SOME ENVIRONMENTAL AGENTS. IN CERTAIN PATIENTS, SIMPLE HEPATIC STEATOSIS CAN PROGRESS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH), WHICH CAN SOMETIMES LEAD TO LIVER CIRRHOSIS AND ITS COMPLICATIONS INCLUDING HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE MECHANISMS THAT CAUSE THE PROGRESSION OF NAFLD TO NASH IS CRUCIAL TO BE ABLE TO CONTROL THE ADVANCEMENT OF THE DISEASE. THE MAIN HYPOTHESIS CONSIDERS THAT IT IS DUE TO MULTIPLE FACTORS THAT ACT TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO SUFFER FROM NAFLD INCLUDING INSULIN RESISTANCE, NUTRITIONAL FACTORS, GUT MICROBIOTA, AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE WILL DISCUSS THE EPIDEMIOLOGY OF NAFLD, AND WE OVERVIEW SEVERAL TOPICS THAT INFLUENCE THE DEVELOPMENT OF THE DISEASE FROM SIMPLE STEATOSIS TO LIVER CIRRHOSIS AND ITS POSSIBLE COMPLICATIONS. 2021 20 4859 22 ORAL SQUAMOUS CELL CARCINOMA: DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS. OSCC IS THE MOST FREQUENT MALIGNANT TUMOUR OF THE ORAL CAVITY, ACCOUNTING FOR MORE THAN 90% OF MALIGNANT TUMOURS OF THIS ANATOMIC REGION AND IT OFTEN ARISES FROM PRECURSOR LESIONS. ASIDE FROM TOBACCO AND ALCOHOL CONSUMPTION, FURTHER DETERMINANTS HAVE BEEN CONSIDERED TO INCREASE THE RISK OF OSCC DEVELOPMENT, SUCH AS MICRONUTRIENT DEFICIENCIES, CHRONIC TRAUMATISM, POOR ORAL HYGIENE AND VIRUSES. RECURRENCE, SURVIVAL AND CONVERSELY, MORTALITY DEPENDS ON NUMEROUS AND DIFFERENT BIOLOGICAL, HISTOLOGICAL, MACROSCOPIC AND MICROSCOPIC FACTORS THAT HAVE BEEN INVESTIGATED IN ORDER TO DEFINE CAUSES, TO HELP DIAGNOSIS AND TO REFINE APPROPRIATE TREATMENTS THAT PERFECTLY FIT WITH THE DIFFERENT FEATURES OF OSCCS. FOR THIS PURPOSE, DURING THE LAST DECADES, THE IMPROVEMENT OF SCIENTIFIC TECHNOLOGIES AND MOLECULAR ANALYSES HAVE ALLOWED TO INVESTIGATE MARKERS AND GENETIC AND EPIGENETIC FACTORS, IN ORDER TO CLARIFY THEIR RESPONSIBILITIES RELATED TO EARLY DIAGNOSIS AND OSCC PROGRESSION AND PROGNOSIS IN ORDER TO ADDRESS THEM AS TARGETS IN FUTURE SELECTIVE AND INDIVIDUALLY-SHAPED THERAPIES. THIS REVIEW WILL FOCUS ON THE ETIOLOGY, ADVANCES IN DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS FOR ORAL CANCERS. 2016