1  1354 162 DEVELOPMENT AND REGRESSION OF CIRRHOSIS. LIVER CIRRHOSIS IS THE ULTIMATE CONSEQUENCE OF THE WOUND HEALING REACTION SUBSEQUENT TO A CHRONIC INJURY, WHICH LEADS TO A COMPLETE DERANGEMENT OF THE NORMAL HEPATIC LOBULAR AND VASCULAR ARCHITECTURE. CIRRHOSIS IS CHARACTERIZED BY PATTERNS OF EVOLUTION DEPENDING ON THE CAUSATIVE AGENT AND A SERIES OF COMPLEX UNDERLINING MECHANISMS IN WHICH NEO-ANGIOGENESIS AND NECRO-INFLAMMATION PLAY A KEY ROLE. THE IMPORTANCE OF THE DIFFERENT CELL TYPES INVOLVED AND OF THE EXTRACELLULAR MATRIX COMPOSITION AS WELL AS THE ROLE OF INNATE IMMUNITY, BACTERIAL TRANSLOCATION AND OXIDATIVE STRESS ARE ALSO EMERGING. A VARIABLE DEGREE OF REGRESSION OF FIBROSIS AND EVEN CIRRHOSIS HAS BEEN DESCRIBED, IN EXPERIMENTAL MODELS, AFTER SUSPENSION OF THE LIVER DISEASE CAUSATIVE AGENT. AS SOME INDIVIDUAL FEATURES INFLUENCE THE RATE OF FIBROSIS PROGRESSION, GENETIC AND EPIGENETIC FACTORS ARE LIKELY TO INFLUENCE FIBROSIS REGRESSION. KEY MESSAGES: THERE IS INCREASING AWARENESS THAT CIRRHOSIS IS NOT A STATIC CONDITION BUT A DYNAMIC PROCESS. CURRENT SEMI-QUANTITATIVE SCORES AND CLINICAL CLASSIFICATIONS ARE INACCURATE AND UNABLE TO IDENTIFY THE DIFFERENT PHASES OF EVOLUTION OF THE ADVANCED STAGES OF CHRONIC LIVER DISEASES (CLDS). THE INCREASING AVAILABILITY OF EFFECTIVE ETIOLOGY-DRIVEN THERAPEUTIC OPTIONS FOR CLDS MAKES REVERSION OF CIRRHOSIS A MORE POSSIBLE PROSPECTIVE. HOWEVER, THE REMOVAL OF THE CAUSING AGENT, DEPENDING ON THE STAGE OF THE DISEASE, DOES NOT NECESSARILY ELIMINATE THE RISK OF DISEASE PROGRESSION, DECOMPENSATION AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. ALSO, THE NON-INVASIVE MARKERS CURRENTLY VALIDATED FOR THE ASSESSMENT OF FIBROSIS ARE NOT SUITABLE FOR AN EFFECTIVE EVALUATION OF FIBROSIS REGRESSION. CONCLUSIONS: THERE IS A CRITICAL NEED OF A SYSTEM THAT WOULD BE ABLE TO MORE ACCURATELY DESCRIBE THE DYNAMIC DEVELOPMENT OF CIRRHOSIS AND THE IMPACT OF TISSUE FIBROSIS, NEO-ANGIOGENESIS, NECRO-INFLAMMATION AND ATTEMPTED REGENERATION ON ITS EVOLUTION. EFFECTIVE TREATMENT OF CLD CAN LEAD TO A VARIABLE DEGREE OF FIBROSIS REGRESSION. NEW MARKERS ABLE TO EVALUATE THIS PROCESS WILL NEED TO BE DETECTED AND VALIDATED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  3271  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3  3011  33 GENETICS AND EPIGENETICS IN THE FIBROGENIC EVOLUTION OF CHRONIC LIVER DISEASES. RECENT YEARS HAVE SEEN UNPRECEDENTED PROGRESS IN THE IDENTIFICATION AND CHARACTERIZATION OF GENETIC INFORMATION RELATED TO CHRONIC LIVER DISEASES (CLDS). HOWEVER, DESPITE THE CONCEPTUAL BENEFIT IN EARLY RECOGNITION OF AT-RISK POPULATIONS AMENABLE TO PRE-EMPTIVE TREATMENT AND/OR SURVEILLANCE STRATEGIES, RECENT GENOMIC RESEARCH IN THE FIELD HAS PLACED FOCUS ON UNRAVELLING THE GENETIC ARCHITECTURE OF DISEASE SUSCEPTIBILITY, WHILE DATA ON GENETIC MARKERS ANTICIPATING AN ACCELERATED FIBROGENESIS IN AN INDIVIDUAL ARE STILL LIMITED. LIKEWISE, SEQUENCE VARIATION ASSIGNING RAPID FIBROGENIC EVOLUTION COMMON TO CLDS IRRESPECTIVE OF ETIOLOGY ARE POORLY DEFINED ASIDE FROM PNPLA3 (ADIPONUTRIN) AS A PROMINENT EXCEPTION. THE EMERGING FIELD OF EPIGENETICS IN HEPATOLOGY HAS MOSTLY BEEN STUDIED UNDER THE PERSPECTIVE OF GENE REGULATION, LESS SO AS A HERITABLE ALTERATION IN GENE ACTIVITY. IN THIS ARTICLE WE WILL CRITICALLY DISCUSS RECENT FINDINGS IN GENOMIC HEPATOLOGY WITH SPECIAL FOCUS ON THE (EPI)GENETIC CONTRIBUTION TO THE FIBROGENIC EVOLUTION OF CLDS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  2653  41 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5   319  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  5486  39 REVERSE INFLAMMAGING: LONG-TERM EFFECTS OF HCV CURE ON BIOLOGICAL AGE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION CAN BE CURED WITH DIRECT-ACTING ANTIVIRALS (DAAS). HOWEVER, NOT ALL SEQUELAE OF CHRONIC HEPATITIS C APPEAR TO BE COMPLETELY REVERSIBLE AFTER SUSTAINED VIROLOGIC RESPONSE (SVR). RECENTLY, CHRONIC VIRAL INFECTIONS HAVE BEEN SHOWN TO BE ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION DEFINED BY THE EPIGENETIC CLOCK. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER CHRONIC HCV INFECTION IS ASSOCIATED WITH EPIGENETIC CHANGES AND BIOLOGICAL AGE ACCELERATION AND WHETHER THIS IS REVERSIBLE AFTER SVR. METHODS: WE INCLUDED 54 WELL-CHARACTERIZED INDIVIDUALS WITH CHRONIC HEPATITIS C WHO ACHIEVED SVR AFTER DAA THERAPY AT THREE TIME POINTS: DAA TREATMENT INITIATION, END OF TREATMENT, AND LONG-TERM FOLLOW-UP (MEDIAN 96 WEEKS AFTER END OF TREATMENT). GENOME-WIDE DNA METHYLATION STATUS WAS DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND USED TO CALCULATE EPIGENETIC AGE ACCELERATION (EAA) USING HORVATH'S CLOCK. RESULTS: INDIVIDUALS WITH HCV HAD AN OVERALL SIGNIFICANT EAA OF 3.12 YEARS AT BASELINE COMPARED WITH -2.61 YEARS IN THE AGE- AND SEX-MATCHED REFERENCE GROUP (P <0.00003). HCV ELIMINATION RESULTED IN A SIGNIFICANT LONG-TERM INCREASE IN DNA METHYLATION DOMINATED BY HYPERMETHYLATED CPGS IN ALL PATIENT GROUPS. ACCORDINGLY, EAA DECREASED TO 1.37 YEARS AT LONG-TERM FOLLOW-UP. THE DECREASE IN EAA WAS SIGNIFICANT ONLY BETWEEN THE END OF TREATMENT AND FOLLOW-UP (P = 0.01). INTERESTINGLY, EIGHT INDIVIDUALS WHO DEVELOPED HEPATOCELLULAR CARCINOMA AFTER SVR HAD THE HIGHEST EAA AND SHOWED NO EVIDENCE OF REVERSAL AFTER SVR. CONCLUSIONS: OUR DATA CONTRIBUTE TO THE UNDERSTANDING OF THE BIOLOGICAL IMPACT OF HCV ELIMINATION AFTER DAA THERAPY AND DEMONSTRATE THAT HCV ELIMINATION CAN LEAD TO "REVERSE INFLAMMAGING". IN ADDITION, OUR DATA SUPPORT THE POTENTIAL USE OF BIOLOGICAL AGE AS A BIOMARKER FOR HCV SEQUELAE AFTER SVR. IMPACT AND IMPLICATIONS: CHRONIC HEPATITIS C VIRUS INFECTION IS NOW CURABLE WITH DIRECT-ACTING ANTIVIRALS, BUT IT REMAINS UNCLEAR WHETHER HEPATITIS C SEQUELAE ARE FULLY REVERSIBLE AFTER VIRAL ELIMINATION. OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OR ACCELERATION OF BIOLOGICAL AGE ARE REVERSIBLE IN PRINCIPLE, BUT THIS REQUIRES TIME, WHILE A LACK OF REVERSIBILITY APPEARS TO BE ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. WHILE MOST CLINICAL RISK SCORES NOW TAKE CHRONOLOGICAL AGE INTO ACCOUNT, IT MAY BE WORTHWHILE TO EXPLORE HOW BIOLOGICAL AGE MIGHT IMPROVE THESE SCORES IN THE FUTURE. BIOLOGICAL AGE MAY BE A CORNERSTONE FOR THE INDIVIDUALIZED CLINICAL ASSESSMENT OF PATIENTS IN THE FUTURE, AS IT BETTER REFLECTS PATIENTS' LIFESTYLE AND ENVIRONMENTAL EXPOSURES OVER DECADES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  2691  36 EVOLUTION OF HEPATIC FIBROSIS RESEARCH. MOLECULAR ANALYSIS OF HEPATIC FIBROGENESIS HAS PROGRESSED WITH RESPECT TO BOTH FIBROSIS PROGRESSION AND REGRESSION BY USING CELL BIOLOGICAL, MOLECULAR BIOLOGICAL AND (EPI)GENETIC APPROACHES. RECENT RESEARCHES HAVE REVEALED SOURCES OF COLLAGEN-PRODUCING CELLS OTHER THAN HEPATIC STELLATE CELLS IN THE LIVER, AND THE INVOLVEMENT OF THE INNATE IMMUNE SYSTEM AND OXIDATIVE STRESS IN THE FIBROTIC PROCESS HAS ATTRACTED NEW ATTENTION. TOGETHER WITH THESE ADVANCEMENTS IN BASIC KNOWLEDGE ON THE CELLULAR AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS, CLINICAL RESEARCHES HAVE LINKED THE CLARIFICATION OF THE RELATIONSHIP BETWEEN PROGRESSION OF THE FIBROSIS STAGE AND THERAPEUTIC EFFICACY FOR CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS AND VALIDATION OF THE REGRESSION OF ADVANCED FIBROSIS, EVEN CIRRHOSIS, OF APPROPRIATE THERAPIES USING MODERN MEDICINES. FURTHERMORE, NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS USING AN ULTRASOUND-BASED MODALITY HAS BECOME A FOCUS IN THE CLINICAL DIAGNOSIS OF LIVER FIBROSIS INSTEAD OF LIVER BIOPSY. TAKEN TOGETHER, LIVER FIBROSIS RESEARCH HAS BEEN EVOLVING BOTH BASICALLY AND CLINICALLY IN THE PAST THREE DECADES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  1858  43 ELUCIDATING POTENTIAL PROFIBROTIC MECHANISMS OF EMERGING BIOMARKERS FOR EARLY PROGNOSIS OF HEPATIC FIBROSIS. HEPATIC FIBROSIS HAS BEEN ASSOCIATED WITH A SERIES OF PATHOPHYSIOLOGICAL PROCESSES CAUSING EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX PROTEINS. SEVERAL CELLULAR PROCESSES AND MOLECULAR MECHANISMS HAVE BEEN IMPLICATED IN THE DISEASED LIVER THAT AUGMENTS FIBROGENESIS, FIBROGENIC CYTOKINES AND ASSOCIATED LIVER COMPLICATIONS. LIVER BIOPSY REMAINS AN ESSENTIAL DIAGNOSTIC TOOL FOR HISTOLOGICAL EVALUATION OF HEPATIC FIBROSIS TO ESTABLISH A PROGNOSIS. IN ADDITION TO BEING INVASIVE, THIS METHODOLOGY PRESENTS WITH SEVERAL LIMITATIONS INCLUDING POOR COST-EFFECTIVENESS, PROLONGED HOSPITALIZATIONS, AND RISKS OF PERITONEAL BLEEDING, WHILE THE CLINICAL USE OF THIS METHOD DOES NOT REVEAL UNDERLYING PATHOGENIC MECHANISMS. SEVERAL ALTERNATE NONINVASIVE DIAGNOSTIC STRATEGIES HAVE BEEN DEVELOPED, TO DETERMINE THE EXTENT OF HEPATIC FIBROSIS, INCLUDING THE USE OF DIRECT AND INDIRECT BIOMARKERS. IMMEDIATE DIAGNOSIS OF HEPATIC FIBROSIS BY NONINVASIVE MEANS WOULD BE MORE PALATABLE THAN A BIOPSY AND COULD ASSIST CLINICIANS IN TAKING EARLY INTERVENTIONS TIMELY, AVOIDING FATAL COMPLICATIONS, AND IMPROVING PROGNOSIS. THEREFORE, WE SOUGHT TO REVIEW SOME COMMON BIOMARKERS OF LIVER FIBROSIS ALONG WITH SOME EMERGING CANDIDATES, INCLUDING THE OXIDATIVE STRESS-MEDIATED BIOMARKERS, EPIGENETIC AND GENETIC MARKERS, EXOSOMES, AND MIRNAS THAT NEEDS FURTHER EVALUATION AND WOULD HAVE BETTER SENSITIVITY AND SPECIFICITY. WE ALSO AIM TO ELUCIDATE THE POTENTIAL ROLE OF CARDIOTONIC STEROIDS (CTS) AND EVALUATE THE PRO-INFLAMMATORY AND PROFIBROTIC EFFECTS OF CTS IN EXACERBATING HEPATIC FIBROSIS. BY UNDERSTANDING THE UNDERLYING PATHOGENIC PROCESSES, THE EFFICACY OF THESE BIOMARKERS COULD ALLOW FOR EARLY DIAGNOSIS AND TREATMENT OF HEPATIC FIBROSIS IN CHRONIC LIVER DISEASES, ONCE VALIDATED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  5770  35 SPECIFIC MOLECULAR SIGNATURES OF NON-TUMOR LIVER TISSUE MAY PREDICT A RISK OF HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON HUMAN CANCERS AND A MAJOR CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE BLEAK OUTCOMES OF HCC PATIENTS EVEN AFTER CURATIVE TREATMENT HAVE BEEN, AT LEAST PARTIALLY, ATTRIBUTED TO ITS MULTICENTRIC ORIGIN. THEREFORE, IT IS NECESSARY TO EXAMINE NOT ONLY TUMOR TISSUE BUT ALSO NON-TUMOR LIVER TISSUE TO INVESTIGATE THE MOLECULAR MECHANISMS OPERATING DURING HEPATOCARCINOGENESIS BASED ON THE CONCEPT OF "FIELD CANCERIZATION". SEVERAL STUDIES PREVIOUSLY INVESTIGATED THE ASSOCIATION OF MOLECULAR ALTERATIONS IN NON-TUMOR LIVER TISSUE WITH CLINICAL FEATURES AND PROGNOSIS IN HCC PATIENTS ON A GENOME-WIDE SCALE. IN PARTICULAR, SPECIFIC ALTERATIONS OF DNA METHYLATION PROFILES HAVE BEEN CONFIRMED IN NON-TUMOR LIVER TISSUE. THIS REVIEW FOCUSES ON THE POSSIBLE CLINICAL VALUE OF ARRAY-BASED COMPREHENSIVE ANALYSES OF MOLECULAR ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IN NON-TUMOR LIVER TISSUE TO CLARIFY THE RISK OF HEPATOCARCINOGENESIS. CARCINOGENETIC RISK ESTIMATION BASED ON SPECIFIC METHYLATION SIGNATURES MAY BE ADVANTAGEOUS FOR CLOSE FOLLOW-UP OF PATIENTS WHO ARE AT HIGH RISK OF HCC DEVELOPMENT. FURTHERMORE, EPIGENETIC THERAPIES FOR PATIENTS WITH CHRONIC LIVER DISEASES MAY BE HELPFUL TO REDUCE THE RISK OF HCC DEVELOPMENT BECAUSE EPIGENETIC ALTERATIONS ARE POTENTIALLY REVERSIBLE, AND THUS PROVIDE PROMISING MOLECULAR TARGETS FOR THERAPEUTIC INTERVENTION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  5521  44 RISK OF HEPATOCELLULAR CARCINOMA AFTER HCV CLEARANCE BY DIRECT-ACTING ANTIVIRALS TREATMENT PREDICTIVE FACTORS AND ROLE OF EPIGENETICS. DIRECT-ACTING ANTIVIRALS (DAAS) INDUCE A RAPID VIROLOGIC RESPONSE (SVR) IN UP TO 99% OF CHRONIC HEPATITIS C PATIENTS. THE ROLE OF SVR BY DAAS ON THE INCIDENCE OR RECURRENCE OF HEPATOCELLULAR CARCINOMA (HCC) IS STILL A MATTER OF DEBATE, ALTHOUGH IT IS KNOWN THAT SVR DOES NOT ELIMINATE THE RISK OF HCC. IN THIS REVIEW, WE MADE AN UPDATED ANALYSIS OF THE LITERATURE DATA ON THE IMPACT OF SVR BY DAAS ON THE RISK OF HCC AS WELL AS AN ASSESSMENT OF RISK FACTORS AND THE ROLE OF EPIGENETICS. DATA SHOWED THAT SVR HAS NO IMPACT ON THE OCCURRENCE OF HCC IN THE SHORT-MEDIUM TERM BUT REDUCES THE RISK OF HCC IN THE MEDIUM-LONG TERM. A DIRECT ROLE OF DAAS IN THE DEVELOPMENT OF HCC HAS NOT BEEN DEMONSTRATED, WHILE THE HYPOTHESIS OF A REDUCTION IN IMMUNE SURVEILLANCE IN RESPONSE TO THE RAPID CLEARANCE OF HCV AND CHANGES IN THE CYTOKINE PATTERN INFLUENCING EARLY CARCINOGENESIS REMAINS TO BE FURTHER ELUCIDATED. HCV INDUCES EPIGENETIC ALTERATIONS SUCH AS MODIFICATIONS OF THE HISTONE TAIL AND DNA METHYLATION, WHICH ARE RISK FACTORS FOR HCC, AND SUCH CHANGES ARE MAINTAINED AFTER HCV CLEARANCE. FUTURE EPIGENETIC STUDIES COULD LEAD TO IDENTIFY USEFUL BIOMARKERS AND THERAPEUTIC TARGETS. CIRRHOSIS HAS BEEN IDENTIFIED AS A RISK FACTOR FOR HCC, PARTICULARLY IF ASSOCIATED WITH HIGH LIVER STIFFNESS AND ALPHA-FETOPROTEIN VALUES, DIABETES AND THE MALE SEX. CURRENTLY, CONSIDERING THE HIGH NUMBER AND HEALTH COST TO FOLLOW SUBJECTS' POST-HCV CLEARANCE BY DAAS, IT IS MANDATORY TO IDENTIFY THOSE AT HIGH RISK OF HCC TO OPTIMIZE MANAGEMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  2015  40 EPIGENETIC BIOMARKERS IN ESOPHAGEAL CANCER. THE ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES IS WELL DOCUMENTED IN ESOPHAGEAL CANCER, INCLUDING ADENOCARCINOMA (EAC) AND SQUAMOUS CELL CARCINOMA (ESCC) AS WELL AS IN BARRETT'S ESOPHAGUS (BE), A PRE-MALIGNANT CONDITION THAT IS ASSOCIATED WITH CHRONIC ACID REFLUX. BE IS A WELL-RECOGNIZED RISK FACTOR FOR THE DEVELOPMENT OF EAC, AND CONSEQUENTLY THE STANDARD OF CARE IS FOR INDIVIDUALS WITH BE TO BE PLACED IN ENDOSCOPIC SURVEILLANCE PROGRAMS AIMED AT DETECTING EARLY HISTOLOGIC CHANGES THAT ASSOCIATE WITH AN INCREASED RISK OF DEVELOPING EAC. YET BECAUSE THE ABSOLUTE RISK OF EAC IN INDIVIDUALS WITH BE IS MINIMAL, A CLINICAL NEED IN THE MANAGEMENT OF BE IS THE IDENTIFICATION OF ADDITIONAL RISK MARKERS THAT WILL INDICATE INDIVIDUALS WHO ARE AT A SIGNIFICANT ABSOLUTE RISK OF EAC SO THAT THEY MAY BE SUBJECTED TO MORE INTENSIVE SURVEILLANCE. THE BEST CURRENTLY AVAILABLE RISK MARKER IS THE DEGREE OF DYSPLASIA IN ENDOSCOPIC BIOPSIES FROM THE ESOPHAGUS; HOWEVER, THIS MARKER IS SUBOPTIMAL FOR A VARIETY OF REASONS. TO DATE, THERE ARE NO MOLECULAR BIOMARKERS THAT HAVE BEEN TRANSLATED TO WIDESPREAD CLINICAL PRACTICE. THE SEARCH FOR BIOMARKERS, INCLUDING HYPERMETHYLATED GENES, FOR EITHER THE DIAGNOSIS OF BE, EAC, OR ESCC OR FOR RISK STRATIFICATION FOR THE DEVELOPMENT OF EAC IN THOSE WITH BE IS CURRENTLY AN AREA OF ACTIVE RESEARCH. IN THIS REVIEW, WE SUMMARIZE THE STATUS OF IDENTIFIED CANDIDATE EPIGENETIC BIOMARKERS FOR BE, EAC, AND ESCC. MOST OF THESE ABERRANTLY METHYLATED GENES HAVE BEEN DESCRIBED IN THE CONTEXT OF EARLY DETECTION OR DIAGNOSTIC MARKERS; OTHERS MIGHT PROVE USEFUL FOR ESTIMATING PROGNOSIS OR PREDICTING RESPONSE TO TREATMENT. FINALLY, SPECIAL ATTENTION WILL BE PAID TO SOME OF THE CHALLENGES THAT MUST BE OVERCOME IN ORDER TO DEVELOP CLINICALLY USEFUL ESOPHAGEAL CANCER BIOMARKERS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  4815  43 OCCULT HEPATITIS B INFECTION AND HEPATOCELLULAR CARCINOMA: EPIDEMIOLOGY, VIROLOGY, HEPATOCARCINOGENESIS AND CLINICAL SIGNIFICANCE. OCCULT HEPATITIS B INFECTION (OBI) REFERS TO A CONDITION WHERE REPLICATION-COMPETENT HBV DNA IS PRESENT IN THE LIVER, WITH OR WITHOUT HBV DNA IN THE BLOOD, IN INDIVIDUALS WITH SERUM HBSAG NEGATIVITY ASSESSED BY CURRENTLY AVAILABLE ASSAYS. THE EPISOMAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) IN OBI IS IN A LOW REPLICATIVE STATE. VIRAL GENE EXPRESSION IS MEDIATED BY EPIGENETIC CONTROL OF HBV TRANSCRIPTION, INCLUDING THE HBV CPG ISLAND METHYLATION PATHWAY AND POST-TRANSLATIONAL MODIFICATION OF CCCDNA-BOUND HISTONE, WITH A DIFFERENT PATTERN FROM PATIENTS WITH CHRONIC HBV INFECTION. THE PREVALENCE OF OBI VARIES TREMENDOUSLY ACROSS PATIENT POPULATIONS OWING TO NUMEROUS FACTORS, SUCH AS GEOGRAPHIC LOCATION, ASSAY CHARACTERISTICS, HOST IMMUNE RESPONSE, COINFECTION WITH OTHER VIRUSES, AND VACCINATION STATUS. APART FROM THE RISK OF VIRAL REACTIVATION UPON IMMUNOSUPPRESSION AND THE RISK OF TRANSMISSION OF HBV, OBI HAS BEEN IMPLICATED IN HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT IN PATIENTS WITH CHRONIC HCV INFECTION, THOSE WITH CRYPTOGENIC OR KNOWN LIVER DISEASE, AND IN PATIENTS WITH HBSAG SEROCLEARANCE AFTER CHRONIC HBV INFECTION. AN INCREASING NUMBER OF PROSPECTIVE STUDIES AND META-ANALYSES HAVE REPORTED A HIGHER INCIDENCE OF HCC IN PATIENTS WITH HCV AND OBI, AS WELL AS MORE ADVANCED TUMOUR HISTOLOGICAL GRADES AND EARLIER AGE OF HCC DIAGNOSIS, COMPARED WITH PATIENTS WITHOUT OBI. THE PROPOSED PATHOGENETIC MECHANISMS OF OBI-RELATED HCC INCLUDE THE INFLUENCE OF HBV DNA INTEGRATION ON THE HEPATOCYTE CELL CYCLE, THE PRODUCTION OF PRO-ONCOGENIC PROTEINS (HBX PROTEIN AND MUTATED SURFACE PROTEINS), AND PERSISTENT LOW-GRADE NECROINFLAMMATION (CONTRIBUTING TO THE DEVELOPMENT OF FIBROSIS AND CIRRHOSIS). THERE REMAIN UNCERTAINTIES ABOUT EXACTLY HOW, AND IN WHAT ORDER, THESE MECHANISMS DRIVE THE DEVELOPMENT OF TUMOURS IN PATIENTS WITH OBI.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  1942  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14   852  40 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15   512  36 ASSOCIATION OF SAT-A AND ALU METHYLATION STATUS WITH HCV-INDUCED CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. BACKGROUND: THE COMBINATION OF EPIGENETIC AND GENETIC ABNORMALITIES CONTRIBUTES TOGETHER TO THE DEVELOPMENT OF LIVER CANCER. THE METHYLATION STATUS OF THE REPETITIVE ELEMENTS (RES) IN DNA HAS BEEN INVESTIGATED IN A VARIETY OF HUMAN ILLNESSES. HOWEVER, THE METHYLATION PATTERNS OF SAT-ALPHA AND ALU RES IN CHRONIC LIVER DISEASE (CLD) AND HEPATOCELLULAR CARCINOMA (HCC) CAUSED BY HEPATITIS C VIRUS (HCV) HAVE NEVER BEEN STUDIED BEFORE. METHODOLOGY: IN THIS STUDY, 3 GROUPS OF PARTICIPANTS INCLUDING 50 PATIENTS HAVING HCV-INDUCED CLD, 50 PATIENTS HAVING HCV-INDUCED HCC, AND 46 HEALTHY SUBJECTS WERE SUBJECTED TO MEASUREMENT OF SAT-ALPHA AND ALU METHYLATION USING THE QUANTITATIVE METHYLIGHT ASSAY. RESULTS: SAT-ALPHA AND ALU METHYLATION PERCENTAGES DECREASED SIGNIFICANTLY IN BOTH CLD AND HCC, COMPARED TO CONTROL. ALSO, A SIGNIFICANT SAT-ALPHA HYPOMETHYLATION WAS DETECTED IN HCC, COMPARED TO CLD. IN ADDITION, SAT-ALPHA AND ALU METHYLATION SHOWED A SIGNIFICANT DECLINE AS LESION SIZE GREW. HOWEVER, ONLY SAT-ALPHA HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN ASSOCIATION WITH PORTAL VEIN THROMBOSIS AND THE MELD SCORE. SAT-ALPHA METHYLATION PERCENTAGE HAD THE HIGHEST SENSITIVITY AND SPECIFICITY FOR DIAGNOSING HCC (100% AND 84.4%) FOLLOWED BY ALPHA-FETOPROTEIN (80% AND 84.4%) AND ALU METHYLATION (66% AND 61.5%). FURTHERMORE, THERE WAS A STRONG POSITIVE CORRELATION BETWEEN SAT-ALPHA AND ALU METHYLATION. CONCLUSIONS: MEASURING SAT-ALPHA AND ALU METHYLATION PROVIDES US WITH A NEW TOOL FOR EARLY DETECTING HCV-INDUCED CLD AND HEPATOCARCINOGENESIS. SAT-ALPHA HAS THE POTENTIAL TO BE UTILIZED AS AN INDEPENDENT PREDICTIVE PARAMETER FOR HCC DEVELOPMENT AND PROGRESSION BECAUSE OF ITS ABILITY TO DISTINGUISH BETWEEN CLD AND HCC WITH THEIR DIFFERENT MELD SCORES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  5772  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  4816  38 OCCULT HEPATITIS B VIRUS INFECTION: A COMPLEX ENTITY WITH RELEVANT CLINICAL IMPLICATIONS. OCCULT HEPATITIS B VIRUS (HBV) INFECTION IS A WORLD-WIDE ENTITY, FOLLOWING THE GEOGRAPHICAL DISTRIBUTION OF DETECTABLE HEPATITIS B. THIS ENTITY IS DEFINED AS THE PERSISTENCE OF VIRAL GENOMES IN THE LIVER TISSUE AND IN SOME INSTANCES ALSO IN THE SERUM, ASSOCIATED TO NEGATIVE HBV SURFACE ANTIGEN SEROLOGY. THE MOLECULAR BASIS OF THE OCCULT INFECTION IS RELATED TO THE LIFE CYCLE OF HBV, WHICH PRODUCES A COVALENTLY CLOSED CIRCULAR DNA THAT PERSISTS IN THE CELL NUCLEI AS AN EPISOME, AND SERVES AS A TEMPLATE FOR GENE TRANSCRIPTION. THE MECHANISM RESPONSIBLE FOR THE HBSAG NEGATIVE STATUS IN OCCULT HBV CARRIERS IS A STRONG SUPPRESSION OF VIRAL REPLICATION, PROBABLY DUE TO THE HOST'S IMMUNE RESPONSE, CO-INFECTION WITH OTHER INFECTIOUS AGENTS AND EPIGENETIC FACTORS. THERE IS EMERGING EVIDENCE OF THE POTENTIAL CLINICAL RELEVANCE OF OCCULT HBV INFECTION, SINCE THIS COULD BE INVOLVED IN OCCULT HBV TRANSMISSION THROUGH ORTHOTOPIC LIVER TRANSPLANT AND BLOOD TRANSFUSION, REACTIVATION OF HBV INFECTION DURING IMMUNOSUPPRESSION, IMPAIRING CHRONIC LIVER DISEASE OUTCOME AND ACTING AS A RISK FACTOR FOR HEPATOCELLULAR CARCINOMA. THEREFORE IT IS IMPORTANT TO BEAR IN MIND THIS ENTITY IN CRYPTOGENETIC LIVER DISEASES, HEPATITIS C VIRUS/HIV INFECTED PATIENTS AND IMMUNOSUPRESSED INDIVIDUALS. IT IS ALSO NECESSARY TO INCREASE OUR KNOWLEDGE IN THIS FASCINATING FIELD TO DEFINE BETTER STRATEGIES TO DIAGNOSE AND TREAT THIS INFECTION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18    42  30 A COMPREHENSIVE GENOME-WIDE PROFILING COMPARISON BETWEEN HBV AND HCV INFECTED HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS WORLDWIDE, ESPECIALLY IN EAST ASIA. EVEN WITH THE PROGRESS IN THERAPY, 5-YEAR SURVIVAL RATES REMAIN UNSATISFIED. CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) HAS BEEN EPIDEMIOLOGICALLY ASSOCIATED WITH HCC AND IS THE MAJOR ETIOLOGY IN THE EAST ASIAN POPULATION. THE DETAILED MECHANISM, ESPECIALLY THE CHANGES OF DNA METHYLATION AND GENE EXPRESSION BETWEEN THE TWO TYPES OF VIRUS-RELATED HCC, AND THEIR CONTRIBUTIONS TO THE HCC DEVELOPMENT, METASTASIS, AND RECURRENCE REMAIN LARGELY UNKNOWN. METHODS: IN THIS INTEGRATED ANALYSIS, WE CHARACTERIZED GENOME-SCALE PROFILES OF HBV AND HCV INFECTED HCC BY COMPARING THEIR GENE EXPRESSION PATTERN, METHYLATION PROFILES, AND COPY NUMBER VARIATIONS FROM THE PUBLICLY ACCESSIBLE DATA OF THE CANCER GENOME ATLAS PROGRAM (TCGA). RESULTS: THE HLA-A, STAT1, AND OAS2 GENES WERE HIGHLY ENRICHED AND UP-REGULATED DISCOVERED IN THE HCV-INFECTED HCC. HYPOMETHYLATION BUT NOT COPY NUMBER VARIATIONS MIGHT BE THE MAJOR FACTOR FOR THE UP-REGULATION OF THESE IMMUNE-RELATED GENES IN HCV-INFECTED HCC. CONCLUSIONS: THE RESULTS INDICATED THE DIFFERENT EPIGENETIC CHANGES OF HBV/HCV RELATED HEPATOCARCINOGENESIS. THE TOP UP-REGULATED GENES IN HCV GROUP WERE SIGNIFICANTLY CLUSTERED IN THE IMMUNE-RELATED AND DEFENSE RESPONSE PATHWAYS. THESE FINDINGS WILL HELP US TO UNDERSTAND THE PATHOGENESIS OF HBV/HCV ASSOCIATED HEPATOCELLULAR CARCINOMA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  1887  54 ENDOMETRIAL RECEPTIVITY IN WOMEN OF ADVANCED AGE: AN UNDERRATED FACTOR IN INFERTILITY. BACKGROUND: MODERN LIFESTYLE HAS LED TO AN INCREASE IN THE AGE AT CONCEPTION. ADVANCED AGE IS ONE OF THE CRITICAL RISK FACTORS FOR FEMALE-RELATED INFERTILITY. IT IS WELL KNOWN THAT MATERNAL AGE POSITIVELY CORRELATES WITH THE DETERIORATION OF OOCYTE QUALITY AND CHROMOSOMAL ABNORMALITIES IN OOCYTES AND EMBRYOS. THE EFFECT OF AGE ON ENDOMETRIAL FUNCTION MAY BE AN EQUALLY IMPORTANT FACTOR INFLUENCING IMPLANTATION RATE, PREGNANCY RATE, AND OVERALL FEMALE FERTILITY. HOWEVER, THERE ARE ONLY A FEW PUBLISHED STUDIES ON THIS TOPIC, SUGGESTING THAT THIS AREA HAS BEEN UNDER-EXPLORED. IMPROVING OUR KNOWLEDGE OF ENDOMETRIAL AGING FROM THE BIOLOGICAL (CELLULAR, MOLECULAR, HISTOLOGICAL) AND CLINICAL PERSPECTIVES WOULD BROADEN OUR UNDERSTANDING OF THE RISKS OF AGE-RELATED FEMALE INFERTILITY. OBJECTIVE AND RATIONALE: THE OBJECTIVE OF THIS NARRATIVE REVIEW IS TO CRITICALLY EVALUATE THE EXISTING LITERATURE ON ENDOMETRIAL AGING WITH A FOCUS ON SYNTHESIZING THE EVIDENCE FOR THE IMPACT OF ENDOMETRIAL AGING ON CONCEPTION AND PREGNANCY SUCCESS. THIS WOULD PROVIDE INSIGHTS INTO EXISTING GAPS IN THE CLINICAL APPLICATION OF RESEARCH FINDINGS AND PROMOTE THE DEVELOPMENT OF TREATMENT OPTIONS IN THIS FIELD. SEARCH METHODS: THE REVIEW WAS PREPARED USING PUBMED (MEDLINE) UNTIL FEBRUARY 2023 WITH THE KEYWORDS SUCH AS 'ENDOMETRIAL AGING', 'RECEPTIVITY', 'DECIDUALIZATION', 'HORMONE', 'SENESCENCE', 'CELLULAR', 'MOLECULAR', 'METHYLATION', 'BIOLOGICAL AGE', 'EPIGENETIC', 'OOCYTE RECIPIENT', 'OOCYTE DONATION', 'EMBRYO TRANSFER', AND 'PREGNANCY RATE'. ARTICLES IN A LANGUAGE OTHER THAN ENGLISH WERE EXCLUDED. OUTCOMES: IN THE AGING ENDOMETRIUM, ALTERATIONS OCCUR AT THE MOLECULAR, CELLULAR, AND HISTOLOGICAL LEVELS SUGGESTING THAT AGING HAS A NEGATIVE EFFECT ON ENDOMETRIAL BIOLOGY AND MAY IMPAIR ENDOMETRIAL RECEPTIVITY. ADDITIONALLY, ADVANCED AGE INFLUENCES CELLULAR SENESCENCE, WHICH PLAYS AN IMPORTANT ROLE DURING THE INITIAL PHASE OF IMPLANTATION AND IS A MAJOR OBSTACLE IN THE DEVELOPMENT OF SUITABLE SENOLYTIC AGENTS FOR ENDOMETRIAL AGING. AGING IS ALSO ACCOUNTABLE FOR CHRONIC CONDITIONS ASSOCIATED WITH INFLAMMAGING, WHICH EVENTUALLY CAN LEAD TO INCREASED PRO-INFLAMMATION AND TISSUE FIBROSIS. FURTHERMORE, ADVANCED AGE INFLUENCES EPIGENETIC REGULATION IN THE ENDOMETRIUM, THUS ALTERING THE RELATION BETWEEN ITS EPIGENETIC AND CHRONOLOGICAL AGE. THE STUDIES IN OOCYTE DONATION CYCLES TO DETERMINE THE EFFECT OF AGE ON ENDOMETRIAL RECEPTIVITY WITH RESPECT TO THE RATES OF IMPLANTATION, CLINICAL PREGNANCY, MISCARRIAGE, AND LIVE BIRTH HAVE REVEALED CONTRADICTORY INFERENCES INDICATING THE NEED FOR FUTURE RESEARCH ON THE MECHANISMS AND CORRESPONDING CAUSAL EFFECTS OF WOMEN'S AGE ON ENDOMETRIAL RECEPTIVITY. WIDER IMPLICATIONS: INCREASING AGE CAN BE ACCOUNTABLE FOR FEMALE INFERTILITY AND IVF FAILURES. BASED ON THE COMPLIED OBSERVATIONS AND SYNTHESIZED CONCLUSIONS IN THIS REVIEW, ADVANCED AGE HAS BEEN SHOWN TO HAVE A NEGATIVE IMPACT ON ENDOMETRIAL FUNCTIONING. THIS INFORMATION CAN PROVIDE RECOMMENDATIONS FOR FUTURE RESEARCH FOCUSING ON MOLECULAR MECHANISMS OF AGE-RELATED CELLULAR SENESCENCE, CELLULAR COMPOSITION, AND TRANSCRIPTOMIC CHANGES IN RELATION TO ENDOMETRIAL AGING. ADDITIONALLY, FURTHER PROSPECTIVE RESEARCH IS NEEDED TO EXPLORE NEWLY EMERGING THERAPEUTIC OPTIONS, SUCH AS THE SENOLYTIC AGENTS THAT CAN TARGET ENDOMETRIAL AGING WITHOUT AFFECTING DECIDUALIZATION. MOREOVER, CLINICAL TRIAL PROTOCOLS, FOCUSING ON OOCYTE DONATION CYCLES, WOULD BE BENEFICIAL IN UNDERSTANDING THE DIRECT CLINICAL IMPLICATIONS OF ENDOMETRIAL AGING ON PREGNANCY OUTCOMES.	2023	

20  1042  33 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