1  3380 143 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY.	2023	
                                                                                                                                                                                                                                                                                                                 
2  3438  27 HYPERHOMOCYSTEINEMIA IN UREMIA--A RED FLAG IN A DISRUPTED CIRCUIT. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ACCORDING TO MOST OBSERVATIONAL STUDIES AND TO STUDIES USING THE MENDELIAN RANDOMIZATION APPROACH, UTILIZING THE COMMON POLYMORPHISM C677T OF METHYLENE TETRAHYDROFOLATE REDUCTASE. IN CONTRAST, THE MOST RECENT SECONDARY PREVENTIVE INTERVENTION STUDIES, IN THE GENERAL POPULATION AND IN CHRONIC KIDNEY DISEASE (CKD) AND UREMIA, WHICH ARE ALL NEGATIVE (WITH THE POSSIBLE NOTABLE EXCEPTION OF STROKE), POINT TO OTHER DIRECTIONS. HOWEVER, ALL TRIALS USE FOLIC ACID IN VARIOUS DOSAGES AS A MEANS TO REDUCE HOMOCYSTEINE LEVELS, WITH THE ADDITION OF VITAMINS B6 AND B12. IT IS POSSIBLE THAT FOLIC ACID HAS NEGATIVE EFFECTS, WHICH OFFSET THE BENEFITS; ALTERNATIVELY, HOMOCYSTEINE COULD BE AN INNOCENT BY-STANDER, OR A SURROGATE OF THE REAL CULPRIT. THE LATTER POSSIBILITY LEADS US TO THE SEARCH FOR POTENTIAL CANDIDATES. FIRST, THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH BY ITSELF IS CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, SHOW. IN CKD AND IN UREMIA, HYPERHOMOCYSTEINEMIA AND HIGH INTRACELLULAR ADOHCY ARE PRESENT AND ARE ASSOCIATED WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION, SUCH AS IMPRINTED GENES, AND PSEUDOAUTOSOMAL GENES, THUS POINTING TO EPIGENETIC DYSREGULATION. THESE ALTERATIONS ARE SUSCEPTIBLE TO REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. SECOND, IT HAS TO BE KEPT IN MIND THAT HOMOCYSTEINE IS MAINLY PROTEIN-BOUND, AND ITS EFFECTS COULD BE LINKED THEREFORE TO PROTEIN HOMOCYSTEINYLATION. IN THIS RESPECT, INCREASED PROTEIN HOMOCYSTEINYLATION HAS BEEN FOUND IN UREMIA, LEADING TO ALTERATIONS IN PROTEIN FUNCTION.	2009	
                                                                                                                                                                                            
3   852  30 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	

4  5702  29 SINGLE-CELL GENOMICS FOR INVESTIGATING PATHOGENESIS OF INFLAMMATORY DISEASES. RECENT TECHNICAL ADVANCES HAVE ENABLED UNBIASED TRANSCRIPTOMIC AND EPIGENETIC ANALYSIS OF EACH CELL, KNOWN AS "SINGLE-CELL ANALYSIS". SINGLE-CELL ANALYSIS HAS A VARIETY OF TECHNICAL APPROACHES TO INVESTIGATE THE STATE OF EACH CELL, INCLUDING MRNA LEVELS (TRANSCRIPTOME), THE IMMUNE REPERTOIRE (IMMUNE REPERTOIRE ANALYSIS), CELL SURFACE PROTEINS (SURFACE PROTEOME ANALYSIS), CHROMATIN ACCESSIBILITY (EPIGENOME), AND ACCORDANCE WITH GENOME VARIANTS (EQTLS; EXPRESSION QUANTITATIVE TRAIT LOCI). AS AN EFFECTIVE TOOL FOR INVESTIGATING ROBUST IMMUNE RESPONSES IN CORONAVIRUS DISEASE 2019 (COVID-19), MANY RESEARCHERS PERFORMED SINGLE-CELL ANALYSIS TO CAPTURE THE DIVERSE, UNBIASED IMMUNE CELL ACTIVATION AND DIFFERENTIATION. DESPITE CHALLENGES ELUCIDATING THE COMPLICATED IMMUNE MICROENVIRONMENTS OF CHRONIC INFLAMMATORY DISEASES USING EXISTING EXPERIMENTAL METHODS, IT IS NOW POSSIBLE TO CAPTURE THE SIMULTANEOUS IMMUNE FEATURES OF DIFFERENT CELL TYPES ACROSS INFLAMED TISSUES USING VARIOUS SINGLE-CELL TOOLS. IN THIS REVIEW, WE INTRODUCE PATIENT-BASED AND EXPERIMENTAL MOUSE MODEL RESEARCH UTILIZING SINGLE-CELL ANALYSES IN THE FIELD OF CHRONIC INFLAMMATORY DISEASES, AS WELL AS MULTI-ORGAN ATLAS TARGETING IMMUNE CELLS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  2539  30 EPIGENETICS IN HYPERHOMOCYSTEINEMIC STATES. A SPECIAL FOCUS ON UREMIA. AIM OF THIS ARTICLE IS TO REVIEW THE TOPIC OF EPIGENETIC CONTROL OF GENE EXPRESSION, ESPECIALLY REGARDING DNA METHYLATION, IN CHRONIC KIDNEY DISEASE AND UREMIA. HYPERHOMOCYSTEINEMIA IS CONSIDERED AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ALTHOUGH THE MOST RECENT INTERVENTION STUDIES UTILIZING FOLIC ACID ARE NEGATIVE. THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH IS ITSELF CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. THE EXTENT OF METHYLATION INHIBITION OF EACH INDIVIDUAL METHYLTRANSFERASE DEPENDS ON THE METHYL DONOR S-ADENOSYLMETHIONINE (ADOMET) AVAILABILITY, ON THE [ADOMET]/[ADOHCY] RATIO, AND ON THE INDIVIDUAL KM VALUE FOR ADOMET AND KI FOR ADOHCY. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, ALMOST UNEQUIVOCALLY SHOW. IN VIVO, DNA METHYLATION MAY BE ALSO INFLUENCED BY VARIOUS FACTORS IN DIFFERENT TISSUES, FOR EXAMPLE BY RATE OF CELL GROWTH, FOLATE STATUS, ETC. AND IMPORTANTLY INFLAMMATION. IN CHRONIC KIDNEY DISEASE AND IN UREMIA, HYPERHOMOCYSTEINEMIA IS COMMONLY SEEN, AND CAN BE ASSOCIATED WITH GLOBAL DNA HYPOMETHYLATION, AND WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION. THIS ALTERATION IS SUSCEPTIBLE OF REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. IF THIS ABNORMALITY WILL TRANSLATE ITSELF IN ALTERATIONS OF EXPRESSION OF GENES RELEVANT TO THE PATHOGENESIS OF THIS DISEASE STILL REMAINS TO BE ESTABLISHED. IN ADDITION, THESE RESULTS ESTABLISH A LINK BETWEEN THE EPIGENETIC CONTROL OF GENE EXPRESSION AND XENOBIOTIC INFLUENCES, SUCH AS FOLATE THERAPY.	2009	
                                                                                                                                                                                                                                                                                                                                                                
6  5144  25 POTENTIAL ROLE OF LNCRNA-TSIX, MIR-548-A-3P, AND SOGA1 MRNA IN THE DIAGNOSIS OF HEPATOCELLULAR CARCINOMA. RECENT TRENDS ARE MOVING TOWARDS THE USE OF THE CIRCULATING TRANSCRIPTOME AS A POTENTIAL DIAGNOSTIC AND THERAPEUTIC TOOL FOR HEPATOCELLULAR CARCINOMA (HCC). THE AIM OF THIS STUDY IS TO IDENTIFY CIRCULATORY RNA BASED BIOMARKER PANEL, IN ADDITION TO THEIR RELATIONSHIP TO THE OUTCOME IN HCC. FIRST, UTILIZING BIOINFORMATICS TOOLS, WE SELECTED AN HCC-SPECIFIC RNA-BASED BIOMARKER PANEL THAT DEPENDED ON THE INTEGRATION OF SUPPRESSOR OF GLUCOSE AUTOPHAGY-ASSOCIATED (SOGA1) GENE EXPRESSION WITH THE CHOSEN PANEL OF EPIGENETIC REGULATORS OF THIS GENE [LONG NON-CODING RNA ANTISENSE FOR X-INACTIVE-SPECIFIC TRANSCRIPT (LNCRNA-TSIX) AND MICRORNA-548-A-3P (MIR-548-A-3P)]. SECOND, WE ATTEMPTED TO VALIDATE THESE BIOMARKERS USING THE SERA OF 65 PATIENTS WITH HCC, 34 PATIENTS WITH CHRONIC HEPATITIS C VIRUS (CHC) INFECTION AND 32 HEALTHY VOLUNTEERS. FINALLY, THE EXPRESSION LEVELS OF THE CHOSEN RNA-BASED BIOMARKER PANEL WERE ASSESSED IN THE SERUM SAMPLES USING QRT-PCR ASSAYS. THE PANEL OF 3 RNA-BASED BIOMARKERS (LNCRNA-TSIX, MIR-548-A-3P, AND SOGA1) EXHIBITED HIGH SENSITIVITY AND SPECIFICITY IN DIFFERENTIATING HCC PATIENTS FROM CHC PATIENTS AND HEALTHY CONTROLS. AMONG THESE 3 RNAS, SERUM LNCRNA-TSIX AND SOGA1 WERE INDEPENDENT PROGNOSTIC FACTOR. THE CHOSEN CIRCULATORY RNA-BASED BIOMARKER PANEL MAY SERVE AS A DIAGNOSTIC AND PROGNOSTIC BIOMARKER FOR HCC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  1623  35 DNA MODIFICATIONS IN MODELS OF ALCOHOL USE DISORDERS. CHRONIC ALCOHOL USE AND ABUSE RESULT IN WIDESPREAD CHANGES TO GENE EXPRESSION, SOME OF WHICH CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-USE DISORDERS (AUD). GENE EXPRESSION IS CONTROLLED, IN PART, BY A GROUP OF REGULATORY SYSTEMS OFTEN REFERRED TO AS EPIGENETIC FACTORS, WHICH INCLUDES, AMONG OTHER MECHANISMS, CHEMICAL MARKS MADE ON THE HISTONE PROTEINS AROUND WHICH GENOMIC DNA IS WOUND TO FORM CHROMATIN, AND ON NUCLEOTIDES OF THE DNA ITSELF. IN PARTICULAR, ALCOHOL HAS BEEN SHOWN TO PERTURB THE EPIGENETIC MACHINERY, LEADING TO CHANGES IN GENE EXPRESSION AND CELLULAR FUNCTIONS CHARACTERISTIC OF AUD AND, ULTIMATELY, TO ALTERED BEHAVIOR. DNA MODIFICATIONS IN PARTICULAR ARE SEEING INCREASING RESEARCH IN THE CONTEXT OF ALCOHOL USE AND ABUSE. TO DATE, STUDIES OF DNA MODIFICATIONS IN AUD HAVE PRIMARILY LOOKED AT GLOBAL METHYLATION PROFILES IN HUMAN BRAIN AND BLOOD, GENE-SPECIFIC METHYLATION PROFILES IN ANIMAL MODELS, METHYLATION CHANGES ASSOCIATED WITH PRENATAL ETHANOL EXPOSURE, AND THE POTENTIAL THERAPEUTIC ABILITIES OF DNA METHYLTRANSFERASE INHIBITORS. FUTURE STUDIES MAY BE AIMED AT IDENTIFYING CHANGES TO MORE RECENTLY DISCOVERED DNA MODIFICATIONS, UTILIZING NEW METHODS TO DISCRIMINATE METHYLATION PROFILES BETWEEN CELL TYPES, THUS CLARIFYING HOW ALCOHOL INFLUENCES THE METHYLOMES OF CELL-TYPE POPULATIONS AND HOW THIS MAY AFFECT DOWNSTREAM PROCESSES. THESE STUDIES AND MORE IN-DEPTH PROBING OF DNA METHYLATION WILL BE KEY TO DETERMINING WHETHER DNA-LEVEL EPIGENETIC REGULATION PLAYS A CAUSATIVE ROLE IN AUD AND CAN THUS BE TARGETED FOR TREATMENT OF THE DISORDER.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8   311  31 ALCOHOL AND THE METHYLOME: DESIGN AND ANALYSIS CONSIDERATIONS FOR RESEARCH USING HUMAN SAMPLES. BACKGROUND: A GROWING NUMBER OF STUDIES IN HUMAN SAMPLES HAVE SOUGHT TO DETERMINE WHETHER CHRONIC ALCOHOL USE AND ALCOHOL USE DISORDERS (AUDS) MAY BE ASSOCIATED WITH EPIGENETIC FACTORS, SUCH AS DNA METHYLATION. WE REVIEW THE EXTANT LITERATURE IN LIGHT OF SOME OF THE CHALLENGES THAT CURRENTLY AFFECT THE DESIGN AND INTERPRETATION OF EPIGENETIC RESEARCH IN HUMAN SAMPLES. METHOD: A LITERATURE SEARCH WAS USED TO IDENTIFY STUDIES THAT HAVE EXAMINED DNA METHYLATION IN RELATION TO ALCOHOL USE OR AUDS IN HUMAN SAMPLES (THROUGH JULY 2013). A TOTAL OF 22 STUDIES WERE IDENTIFIED. RESULTS: ASSOCIATIONS WITH QUANTITATIVE OR DIAGNOSTIC PHENOTYPES OF ALCOHOL USE OR AUDS HAVE BEEN REPORTED FOR SEVERAL GENES. HOWEVER, ALL STUDIES TO DATE HAVE RELIED ON RELATIVELY SMALL SAMPLES AND CROSS-SECTIONAL STUDY DESIGNS. ADDITIONALLY, ATTEMPTS TO REPLICATE RESULTS HAVE BEEN RARE. MORE GENERALLY, RESEARCH PROGRESS IS HAMPERED BY SEVERAL ISSUES, INCLUDING LIMITATIONS OF THE TECHNOLOGIES USED TO ASSESS DNA METHYLATION, TISSUE- AND CELL-SPECIFICITY OF METHYLATION PATTERNS, THE DIFFICULTIES OF RELATING OBSERVED METHYLATION DIFFERENCES AT A GIVEN LOCUS TO A FUNCTIONAL EFFECT, AND LIMITED KNOWLEDGE ABOUT THE MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF ALCOHOL ON DNA METHYLATION. CONCLUSIONS: ALTHOUGH WE SHARE THE OPTIMISM THAT EPIGENETICS MAY LEAD TO NEW INSIGHTS INTO THE ETIOLOGY AND PATHOPHYSIOLOGY OF AUDS, THE METHODOLOGICAL AND SCIENTIFIC CHALLENGES ASSOCIATED WITH CONDUCTING METHYLOMIC RESEARCH IN HUMAN SAMPLES NEED TO BE CAREFULLY CONSIDERED WHEN DESIGNING AND EVALUATING SUCH STUDIES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  6712  35 VIRUS-HOST INTERPLAY IN HEPATITIS B VIRUS INFECTION AND EPIGENETIC TREATMENT STRATEGIES. WORLDWIDE, CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A MAJOR HEALTH PROBLEM AND NO CURE EXISTS. IMPORTANTLY, HEPATOCYTE INTRUSION BY HBV PARTICLES RESULTS IN A COMPLEX DEREGULATION OF BOTH VIRAL AND HOST CELLULAR GENETIC AND EPIGENETIC PROCESSES. AMONG THE ATTEMPTS TO DEVELOP NOVEL THERAPEUTIC APPROACHES AGAINST HBV INFECTION, SEVERAL OPTIONS TARGETING THE EPIGENOMIC REGULATION OF HBV REPLICATION ARE GAINING ATTENTION. THESE INCLUDE THE EXPERIMENTAL TREATMENT WITH 'EPIDRUGS'. MOREOVER, AS A TARGETED APPROACH, THE PRINCIPLE OF 'EPIGENETIC EDITING' RECENTLY IS BEING EXPLOITED TO CONTROL VIRAL REPLICATION. SILENCING OF HBV BY SPECIFIC REWRITING OF EPIGENETIC MARKS MIGHT DIMINISH VIRAL REPLICATION, VIREMIA, AND INFECTIVITY, EVENTUALLY CONTROLLING THE DISEASE AND ITS COMPLICATIONS. ADDITIONALLY, EPIGENETIC EDITING CAN BE USED AS AN EXPERIMENTAL TOOL TO INCREASE OUR LIMITED UNDERSTANDING REGARDING THE ROLE OF EPIGENETIC MODIFICATIONS IN VIRAL INFECTIONS. AIMING FOR PERMANENT EPIGENETIC REPROGRAMMING OF THE VIRAL GENOME WITHOUT UNSPECIFIC SIDE EFFECTS, THIS BREAKTHROUGH MAY PAVE THE ROADS FOR AN AMBITIOUS TECHNOLOGICAL PURSUIT: TO START DESIGNING A CURATIVE APPROACH UTILIZING MANIPULATIVE MOLECULAR THERAPIES FOR VIRAL INFECTIONS IN VIVO.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  5699  38 SIMULTANEOUS DETECTION OF DNA VARIATION AND METHYLATION AT HLA CLASS II LOCUS AND IMMUNE GENE PROMOTERS USING TARGETED SURESELECT METHYL-SEQUENCING. THE HUMAN LEUKOCYTE ANTIGEN (HLA) LOCUS ASSOCIATES WITH A VARIETY OF COMPLEX DISEASES, PARTICULARLY AUTOIMMUNE AND INFLAMMATORY CONDITIONS. THE HLA-DR15 HAPLOTYPE, FOR EXAMPLE, CONFERS THE MAJOR RISK FOR DEVELOPING MULTIPLE SCLEROSIS IN CAUCASIANS, PINPOINTING AN IMPORTANT ROLE IN THE ETIOLOGY OF THIS CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM. IN ADDITION TO THE PROTEIN-CODING VARIANTS THAT SHAPE THE FUNCTIONAL HLA-ANTIGEN-T CELL INTERACTION, RECENT STUDIES SUGGEST THAT THE LEVELS OF HLA MOLECULE EXPRESSION, THAT ARE EPIGENETICALLY CONTROLLED, ALSO PLAY A ROLE IN DISEASE DEVELOPMENT. HOWEVER, DECIPHERING THE EXACT MOLECULAR MECHANISMS OF THE HLA ASSOCIATION HAS BEEN HAMPERED BY THE TREMENDOUS GENETIC COMPLEXITY OF THE LOCUS AND A LACK OF ROBUST APPROACHES TO INVESTIGATE IT. HERE, WE DEVELOPED A METHOD TO SPECIFICALLY ENRICH THE GENOMIC DNA FROM THE HLA CLASS II LOCUS (CHR6:32,426,802-34,167,129) AND PROXIMAL PROMOTERS OF 2,157 IMMUNE-RELEVANT GENES, UTILIZING THE AGILENT RNA-BASED SURESELECT METHYL-SEQ CAPTURE RELATED METHOD, FOLLOWED BY SEQUENCING TO DETECT GENETIC AND EPIGENETIC VARIATION. WE DEMONSTRATED SUCCESSFUL SIMULTANEOUS DETECTION OF THE GENETIC VARIATION AND QUANTIFICATION OF DNA METHYLATION LEVELS IN HLA LOCUS. MOREOVER, BY THE DETECTION OF DIFFERENTIALLY METHYLATED POSITIONS IN PROMOTERS OF IMMUNE-RELATED GENES, WE IDENTIFIED RELEVANT PATHWAYS FOLLOWING STIMULATION OF CELLS. TAKEN TOGETHER, WE PRESENT A METHOD THAT CAN BE UTILIZED TO STUDY THE INTERPLAY BETWEEN GENETIC VARIANCE AND EPIGENETIC REGULATION IN THE HLA CLASS II REGION, POTENTIALLY, IN A WIDE DISEASE CONTEXT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  3996  35 LOOKING FORWARD: NOVEL THERAPEUTIC APPROACHES IN CHRONIC AND ADVANCED PHASES OF MYELOFIBROSIS. MYELOFIBROSIS (MF) IS COMPLEX AT THE PATHOBIOLOGIC LEVEL AND HETEROGENEOUS AT THE CLINICAL LEVEL. THE ADVANCES IN MOLECULAR CHARACTERIZATION OF MF PROVIDE IMPORTANT INSIGHT INTO THE MECHANISMS DRIVING THIS CHRONIC MYELOID MALIGNANCY, REFINE RISK STRATIFICATION, OFFER NOVEL THERAPEUTIC TARGETS, AND SERVE TO MEASURE THERAPEUTIC RESPONSE. ALTHOUGH JAK2 INHIBITION HAS BEEN THE FOCUS OF LABORATORY AND CLINICAL EFFORTS OVER THE LAST DECADE, CURRENT EXPERIMENTAL THERAPEUTIC APPROACHES HAVE BROADENED TO INCLUDE INHIBITORS OF KEY ALTERNATIVE SIGNALING PATHWAYS, EPIGENETIC MODULATORS, ANTI-FIBROTICS, AND IMMUNOTHERAPIES. BASED ON COMPELLING PRECLINICAL RATIONALE, A NUMBER OF JAK2 INHIBITOR BASED COMBINATION THERAPIES ARE NOW ACTIVELY BEING EVALUATED IN THE CLINIC WITH THE GOAL OF DISEASE COURSE MODIFICATION. THE ROLE AND TIMING OF HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) FOR MF HAS BEEN CHALLENGED WITH THE AVAILABILITY OF COMMERCIAL RUXOLITINIB AND THE PLETHORA OF EXPERIMENTAL TREATMENT OPTIONS THAT EXIST. INTEGRATION OF PRECONDITIONING JAK2 INHIBITION, REDUCED INTENSITY CONDITIONING REGIMENS, AND ALTERNATIVE DONOR SOURCES ARE ALL BEING EXPLORED IN AN ATTEMPT TO OPTIMIZE THIS POTENTIALLY CURATIVE MODALITY. THIS REVIEW WILL SUMMARIZE MODERN MF RISK STRATIFICATION, CURRENT CLINICAL RESEARCH APPROACHES TO CHRONIC AND ADVANCE PHASE MF FOCUSING ON NOVEL AGENTS ALONE AND IN COMBINATION, AND UPDATE THE READER ON NEW DIRECTIONS IN HSCT.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  5039  28 PHARMACOGENETICS OF CHRONIC PAIN MANAGEMENT. OBJECTIVE: THE EXPERIENCE OF CHRONIC PAIN IS ONE OF THE COMMONEST REASONS INDIVIDUALS SEEK MEDICAL ATTENTION, MAKING THE MANAGEMENT OF CHRONIC PAIN A MAJOR ISSUE IN CLINICAL PRACTICE. DRUG METABOLISM AND RESPONSES ARE AFFECTED BY MANY FACTORS, WITH GENETIC VARIATIONS OFFERING ONLY A PARTIAL EXPLANATION OF AN INDIVIDUAL'S RESPONSE. THERE IS A PAUCITY OF EVIDENCE FOR THE BENEFITS OF PHARMACOGENETIC TESTING IN THE CONTEXT OF PAIN MANAGEMENT. DESIGN AND METHODS: WE REVIEWED THE LITERATURE BETWEEN 2000 AND 2013, AND REFERENCES CITED THEREIN, USING VARIOUS KEYWORDS RELATED TO PAIN MANAGEMENT, PHARMACOLOGY AND PHARMACOGENETICS. RESULTS: OPIOIDS CONTINUE TO BE THE MAINSTAY OF CHRONIC PAIN MANAGEMENT. SEVERAL NON-OPIOID BASED THERAPIES, SUCH AS TREATMENT WITH CANNABINOIDS, GENE THERAPY AND EPIGENETIC-BASED APPROACHES ARE NOW AVAILABLE FOR THESE PATIENTS. ADJUVANT THERAPIES WITH ANTIDEPRESSANTS, BENZODIAZEPINES OR ANTICONVULSANTS CAN ALSO BE USEFUL IN MANAGING PAIN. CURRENTLY, LABORATORY MONITORING OF PAIN MANAGEMENT PATIENTS, IF PERFORMED, IS LARGELY THROUGH URINE DRUG MEASUREMENTS. CONCLUSIONS: DRUG HALF-LIFE CALCULATIONS CAN BE USED AS FUNCTIONAL MARKERS OF THE CUMULATIVE EFFECT OF PHARMACOGENETICS AND DRUG-DRUG INTERACTIONS. ASSESSMENT OF HALF-LIFE AND THERAPEUTIC EFFECTS MAY BE MORE USEFUL THAN GENETIC TESTING IN PREVENTING ADVERSE DRUG REACTIONS TO PAIN MEDICATIONS, WHILE ENSURING EFFECTIVE ANALGESIA. DEFINITIVE, MASS SPECTROMETRY-BASED METHODS, CAPABLE OF MEASURING PARENT DRUG AND METABOLITE LEVELS, ARE THE MOST USEFUL ASSAYS FOR THIS PURPOSE. URINE DRUG MEASUREMENTS DO NOT NECESSARILY CORRELATE WITH SERUM DRUG CONCENTRATIONS OR THERAPEUTIC EFFECTS. THEREFORE, THEY ARE LIMITED IN THEIR USE IN MONITORING EFFICACY AND TOXICITY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                    
13   391  37 AN INTRODUCTION TO THE MATHEMATICAL MODELING IN THE STUDY OF CANCER SYSTEMS BIOLOGY. BACKGROUND: FREQUENTLY OCCURRING IN CANCER ARE THE ABERRANT ALTERATIONS OF REGULATORY ONCO-METABOLITES, VARIOUS ONCOGENES/EPIGENETIC STOCHASTICITY, AND SUPPRESSOR GENES, AS WELL AS THE DEFICIENT MISMATCH REPAIR MECHANISM, CHRONIC INFLAMMATION, OR THOSE DEVIATIONS BELONGING TO THE OTHER CANCER CHARACTERISTICS. HOW THESE ABERRATIONS THAT EVOLVE OVERTIME DETERMINE THE GLOBAL PHENOTYPE OF MALIGNANT TUMORS REMAINS TO BE COMPLETELY UNDERSTOOD. DYNAMIC ANALYSIS MAY HAVE POTENTIAL TO REVEAL THE MECHANISM OF CARCINOGENESIS AND CAN OFFER NEW THERAPEUTIC INTERVENTION. AIMS: WE INTRODUCE SIMPLIFIED MATHEMATICAL TOOLS TO MODEL SERIAL QUANTITATIVE DATA OF CANCER BIOMARKERS. WE ALSO HIGHLIGHT AN INTRODUCTORY OVERVIEW OF MATHEMATICAL TOOLS AND MODELS AS THEY APPLY FROM THE VIEWPOINT OF KNOWN CANCER FEATURES. METHODS: MATHEMATICAL MODELING OF POTENTIALLY ACTIONABLE GENOMIC PRODUCTS AND HOW THEY PROCEED OVERTIME DURING TUMORIGENESIS ARE EXPLORED. THIS REPORT IS INTENDED TO BE INSTINCTIVE WITHOUT BEING OVERLY TECHNICAL. RESULTS: TO DATE, MANY MATHEMATICAL MODELS OF THE COMMON FEATURES OF CANCER HAVE BEEN DEVELOPED. HOWEVER, THE DYNAMIC OF INTEGRATED HETEROGENEOUS PROCESSES AND THEIR CROSS TALKS RELATED TO CARCINOGENESIS REMAINS TO BE RESOLVED. CONCLUSIONS: IN CANCER RESEARCH, OUTLINING MATHEMATICAL MODELING OF EXPERIMENTALLY OBTAINED DATA SNAPSHOTS OF MOLECULAR SPECIES MAY PROVIDE INSIGHTS INTO A BETTER UNDERSTANDING OF THE MULTIPLE BIOCHEMICAL CIRCUITS. RECENT DISCOVERIES HAVE PROVIDED SUPPORT FOR THE EXISTENCE OF COMPLEX CANCER PROGRESSION IN DYNAMICS THAT SPAN FROM A SIMPLE 1-DIMENSIONAL DETERMINISTIC SYSTEM TO A STOCHASTIC (IE, PROBABILISTIC) OR TO AN OSCILLATORY AND MULTISTABLE NETWORKS. FURTHER RESEARCH IN MATHEMATICAL MODELING OF CANCER PROGRESSION, BASED ON THE EVOLVING MOLECULAR KINETICS (TIME SERIES), COULD INFORM A SPECIFIC AND A PREDICTIVE BEHAVIOR ABOUT THE GLOBAL SYSTEMS BIOLOGY OF VULNERABLE TUMOR CELLS IN THEIR EARLIER STAGES OF ONCOGENESIS. ON THIS FOOTING, NEW PREVENTIVE MEASURES AND ANTICANCER THERAPY COULD THEN BE CONSTRUCTED.	2018	
                                                     
14  5770  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  2192  26 EPIGENETIC METHODS AND TWIN STUDIES. GENOMIC PREDISPOSITION FAILS TO FULLY EXPLAIN THE ONSET OF COMPLEX DISEASES, WHICH IS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELING, AND NON-CODING RNA, ARE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. AUTOIMMUNE DISEASES NOW INCLUDE ALMOST 100 CONDITIONS AND ARE ESTIMATED TO CUMULATIVELY AFFECT UP TO 5% OF THE WORLD POPULATION WITH A HEALTHCARE EXPENDITURE SUPERIOR TO CANCER WORLDWIDE. MANY ADVANCES IN MEDICINE HAVE BEEN MADE TO TREAT THESE CONDITIONS BUT THERE ARE STILL GAPS, AND AN INNOVATIVE AND EFFICIENT THERAPY IS NEEDED. SYSTEMIC AUTOIMMUNE DISEASES INCLUDE RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, SJOGREN SYNDROME, POLYMYOSITIS, AND DERMATOMYOSITIS. MONOZYGOTIC TWINS DISCORDANT FOR ANY DISEASE OFFER AN IDEAL STUDY DESIGN AS THEY ARE MATCHED FOR MANY FACTORS, INCLUDING GENETIC VARIATION AND THIS IS A REAL ADVANTAGE FOR EPIGENETICS STUDY. WE WILL HEREIN DISCUSS THE AVAILABLE DATA IN THE EPIGENETIC DIFFERENCES LEADING TO DISEASE DISCORDANCE IN MZ TWINS FOR SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AND SYSTEMIC SCLEROSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  4495  24 MORE GAIN, LESS PAIN: HOW RESISTANCE TRAINING AFFECTS IMMUNE SYSTEM FUNCTIONING IN MULTIPLE SCLEROSIS PATIENTS: A REVIEW. MULTIPLE SCLEROSIS (MS) IS CHARACTERIZED BY A COMPLEX ETIOLOGY THAT IS MIRRORED BY THE PERPLEXING AND INCONSISTENT TREATMENT RESPONSES OBSERVED ACROSS DIFFERENT PATIENTS. ALTHOUGH EPIGENETIC RESEARCH HAS GARNERED RIGHTFUL INTEREST IN ITS EFFORTS TOWARDS DEMYSTIFYING AND UNDERSTANDING ABERRANT RESPONSES TO TREATMENT, THE INTERIM UNDOUBTEDLY REQUIRES ALTERNATIVE NON-PHARMACOLOGICAL APPROACHES TOWARDS ATTAINING MORE EFFECTIVE MANAGEMENT STRATEGIES. OF PARTICULAR INTEREST IN THIS REVIEW IS RESISTANCE TRAINING (RT) AS A NON-PHARMACOLOGICAL EXERCISE-BASED INTERVENTIONAL STRATEGY AND ITS POTENTIAL ROLE AS A DISEASE-MODIFYING TOOL. RT HAS BEEN REPORTED ACROSS LITERATURE TO POSITIVELY INFLUENCE NUMEROUS ASPECTS IN THE QUALITY OF LIFE (QOL) AND FUNCTIONAL CAPACITY OF MS PATIENTS, AND ONE OF THE ATTRIBUTES OF THESE BENEFITS MAY BE A SHIFT IN THE IMMUNE SYSTEM OF THESE INDIVIDUALS. RT HAS ALSO BEEN PROVEN TO AFFECT DIFFERENT IMMUNE SYSTEM KEY PLAYERS ASSOCIATED WITH MS PATHOLOGY. ULTIMATELY, THIS BRIEF REVIEW AIMS TO PROVIDE A POTENTIAL YET CRUCIAL LINK BETWEEN RT, ALTERATIONS IN THE EXPRESSION PROFILE OF THE IMMUNE SYSTEM, AND FINALLY AN IMMINENT IMPROVEMENT IN THE OVERALL WELL-BEING AND QOL OF MS PATIENTS, SUGGESTING THAT UTILIZING RT AS AN INTERVENTIONAL EXERCISE MODALITY MAY BE AN EFFECTIVE STRATEGY THAT WOULD AID IN MANAGING SUCH A COMPLEX AND DEBILITATING DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17  1041  32 CLINICAL AND MOLECULAR ASPECTS OF LEAD TOXICITY: AN UPDATE. LEAD TOXICITY IS A MAJOR PUBLIC HEALTH ISSUE IN DEVELOPED AND DEVELOPING COUNTRIES. BOTH ACUTE AND CHRONIC LEAD EXPOSURE HAS THE POTENTIAL TO CAUSE MANY DELETERIOUS SYSTEMATIC EFFECTS INCLUDING HYPERTENSION, FRANK ANEMIA, COGNITIVE DEFICITS, INFERTILITY, IMMUNE IMBALANCES, DELAYED SKELETAL AND DECIDUOUS DENTAL DEVELOPMENT, VITAMIN D DEFICIENCY, AND GASTROINTESTINAL EFFECTS. THE UNDERLYING MECHANISMS FOR ALL THESE SYSTEMIC EFFECTS HAVE NOT BEEN ELUCIDATED COMPLETELY. HOWEVER, THE MOST PLAUSIBLE CAUSE IS FREE RADICAL DAMAGE. IN ADDITION TO THIS, LEAD BEING A DIVALENT CATION CAN SURROGATE FOR CALCIUM AT MULTIPLE LEVELS AFFECTING VARIOUS CELL SIGNALING PATHWAYS. THE MOLECULAR BASIS OF LEAD EXPOSURE RESULTING IN VARIOUS SYSTEMIC EFFECTS IS BEING EXTENSIVELY EXPLORED. THE REPORTS INCLUDE SINGLE NUCLEOTIDE POLYMORPHISMS, EPIGENETIC MODIFICATIONS IN SUSCEPTIBLE INDIVIDUALS, AND THE MOST RECENT REPORTS ALSO FEATURE REGULATORY RNA MOLECULES - MIRNAS. HOWEVER, MANY GENETIC TARGETS ARE IDENTIFIED, BUT THEIR POSSIBLE MECHANISMS ARE STILL AN AREA TO BE EXPLORED. ADDITIONAL STUDIES ARE NEEDED IN DIFFERENT POPULATION GROUPS TO VALIDATE THE EXISTING FINDINGS, AS WELL AS TO FIND NEWER TARGETS THAT MAY HELP IN BETTER UNDERSTANDING THE MOLECULAR MECHANISMS CONTRIBUTING TO LEAD TOXICITY. FURTHERMORE, NEWER STRATEGIES FOR LEAD RISK ASSESSMENT BECOMES NECESSARY AS THE PREVIOUSLY RECOGNIZED "SAFE" LEVEL OF LEAD IS ALSO BEING FOUND TO BE ASSOCIATED WITH NEGATIVE HEALTH OUTCOMES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  3621  27 IN VIVO AND IN VITRO MODELS OF HEPATOCELLULAR CARCINOMA: CURRENT STRATEGIES FOR TRANSLATIONAL MODELING. HEPATOCELLULAR CARCINOMA (HCC) IS THE SIXTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH GLOBALLY. HCC IS A COMPLEX MULTISTEP DISEASE AND USUALLY EMERGES IN THE SETTING OF CHRONIC LIVER DISEASES. THE MOLECULAR PATHOGENESIS OF HCC VARIES ACCORDING TO THE ETIOLOGY, MAINLY CAUSED BY CHRONIC HEPATITIS B AND C VIRUS INFECTIONS, CHRONIC ALCOHOL CONSUMPTION, AFLATOXIN-CONTAMINATED FOOD, AND NON-ALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH METABOLIC SYNDROME OR DIABETES MELLITUS. THE ESTABLISHMENT OF HCC MODELS HAS BECOME ESSENTIAL FOR BOTH BASIC AND TRANSLATIONAL RESEARCH TO IMPROVE OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY AND UNRAVEL NEW MOLECULAR DRIVERS OF THIS DISEASE. THE IDEAL MODEL SHOULD RECAPITULATE KEY EVENTS OBSERVED DURING HEPATOCARCINOGENESIS AND HCC PROGRESSION IN VIEW OF ESTABLISHING EFFECTIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO BE TRANSLATED INTO CLINICAL PRACTICE. DESPITE CONSIDERABLE EFFORTS CURRENTLY DEVOTED TO LIVER CANCER RESEARCH, ONLY A FEW ANTI-HCC DRUGS ARE AVAILABLE, AND PATIENT PROGNOSIS AND SURVIVAL ARE STILL POOR. THE PRESENT PAPER PROVIDES A STATE-OF-THE-ART OVERVIEW OF IN VIVO AND IN VITRO MODELS USED FOR TRANSLATIONAL MODELING OF HCC WITH A SPECIFIC FOCUS ON THEIR KEY MOLECULAR HALLMARKS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  1516  24 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL.	2018	
                                                                                                                                                                                                    
20   250  36 ADVANCED GLYCATION END PRODUCTS (AGES): BIOCHEMISTRY, SIGNALING, ANALYTICAL METHODS, AND EPIGENETIC EFFECTS. THE ADVANCED GLYCATION END PRODUCTS (AGES) ARE ORGANIC MOLECULES FORMED IN ANY LIVING ORGANISMS WITH A GREAT VARIETY OF STRUCTURAL AND FUNCTIONAL PROPERTIES. THEY ARE CONSIDERED ORGANIC MARKERS OF THE GLYCATION PROCESS. DUE TO THEIR GREAT HETEROGENEITY, THERE IS NO SPECIFIC TEST FOR THEIR OPERATIONAL MEASUREMENT. IN THIS REVIEW, WE HAVE UPDATED THE MOST COMMON CHROMATOGRAPHIC, COLORIMETRIC, SPECTROSCOPIC, MASS SPECTROMETRIC, AND SEROLOGICAL METHODS, TYPICALLY USED FOR THE DETERMINATION OF AGES IN BIOLOGICAL SAMPLES. WE HAVE DESCRIBED THEIR SIGNALING AND SIGNAL TRANSDUCTION MECHANISMS AND CELL EPIGENETIC EFFECTS. ALTHOUGH MASS SPECTROMETRIC ANALYSIS IS NOT WIDESPREAD IN THE DETECTION OF AGES AT THE CLINICAL LEVEL, THIS TECHNIQUE IS HIGHLY PROMISING FOR THE EARLY DIAGNOSIS AND THERAPEUTICS OF DISEASES CAUSED BY AGES. PROTOCOLS ARE AVAILABLE FOR HIGH-RESOLUTION MASS SPECTROMETRY OF GLYCATED PROTEINS ALTHOUGH THEY ARE CHARACTERIZED BY COMPLEX MACHINE MANAGEMENT. SIMPLER PROCEDURES ARE AVAILABLE ALTHOUGH MUCH LESS PRECISE THAN MASS SPECTROMETRY. AMONG THEM, IMMUNOCHEMICAL TESTS ARE VERY COMMON SINCE THEY ARE ABLE TO DETECT AGES IN A SIMPLE AND IMMEDIATE WAY. IN THESE YEARS, NEW METHODOLOGIES HAVE BEEN DEVELOPED USING AN IN VIVO NOVEL AND NONINVASIVE SPECTROSCOPIC METHODS. THESE METHODS ARE BASED ON THE MEASUREMENT OF AUTOFLUORESCENCE OF AGES. ANOTHER METHOD CONSISTS OF DETECTING AGES IN THE HUMAN SKIN TO DETECT CHRONIC EXPOSURE, WITHOUT THE INCONVENIENCE OF INVASIVE METHODS. THE AIM OF THIS REVIEW IS TO COMPARE THE DIFFERENT APPROACHES OF MEASURING AGES AT A CLINICAL PERSPECTIVE DUE TO THEIR STRICT ASSOCIATION WITH OXIDATIVE STRESS AND INFLAMMATION.	2020