1 1858 139 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 2 2691 28 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 3 1255 31 CURRENT STATUS OF NOVEL ANTIFIBROTIC THERAPIES IN PATIENTS WITH CHRONIC LIVER DISEASE. FIBROSIS ACCUMULATION IS A DYNAMIC PROCESS RESULTING FROM A WOUND-HEALING RESPONSE TO ACUTE OR CHRONIC LIVER INJURY OF ALL CAUSES. THE CASCADE STARTS WITH HEPATOCYTE NECROSIS AND APOPTOSIS, WHICH INSTIGATE INFLAMMATORY SIGNALING BY CHEMOKINES AND CYTOKINES, RECRUITMENT OF IMMUNE CELL POPULATIONS, AND ACTIVATION OF FIBROGENIC CELLS, CULMINATING IN THE DEPOSITION OF EXTRACELLULAR MATRIX. THESE KEY ELEMENTS, ALONG WITH PATHWAYS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION, REPRESENT FERTILE THERAPEUTIC TARGETS. NEW THERAPIES INCLUDE DRUGS SPECIFICALLY DESIGNED AS ANTIFIBROTICS, AS WELL AS DRUGS ALREADY AVAILABLE WITH WELL-ESTABLISHED SAFETY PROFILES, WHOSE MECHANISM OF ACTION MAY ALSO BE ANTIFIBROTIC. AT THE SAME TIME, THE DEVELOPMENT OF NONINVASIVE FIBROGENIC MARKERS, AND TECHNIQUES (E.G. FIBROSCAN), AS WELL AS COMBINED SCORING SYSTEMS INCORPORATING SERUM AND CLINICAL FEATURES WILL ALLOW IMPROVED ASSESSMENT OF THERAPY RESPONSE. IN AGGREGATE, THE ADVANCES IN THE ELUCIDATION OF THE BIOLOGY OF FIBROSIS, COMBINED WITH IMPROVED TECHNOLOGIES FOR ASSESSMENT WILL PROVIDE A COMPREHENSIVE FRAMEWORK FOR DESIGN OF ANTIFIBROTICS AND THEIR ANALYSIS IN WELL-DESIGNED CLINICAL TRIALS. THESE EFFORTS MAY ULTIMATELY YIELD SUCCESS IN HALTING THE PROGRESSION OF, OR REVERSING, LIVER FIBROSIS. 2011 4 2544 24 EPIGENETICS IN LIVER DISEASE: FROM BIOLOGY TO THERAPEUTICS. KNOWLEDGE OF THE FUNDAMENTAL EPIGENETIC MECHANISMS GOVERNING GENE EXPRESSION AND CELLULAR PHENOTYPE ARE SUFFICIENTLY ADVANCED THAT NOVEL INSIGHTS INTO THE EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE ARE NOW EMERGING. HEPATOLOGISTS ARE IN THE PROCESS OF SHEDDING LIGHT ON THE ROLES PLAYED BY DNA METHYLATION, HISTONE/CHROMATIN MODIFICATIONS AND NON-CODING RNAS IN SPECIFIC LIVER PATHOLOGIES. ALONGSIDE THESE DISCOVERIES ARE ADVANCES IN THE TECHNOLOGIES FOR THE DETECTION AND QUANTIFICATION OF EPIGENETIC BIOMARKERS, EITHER DIRECTLY FROM PATIENT TISSUE OR FROM BODY FLUIDS. THE PREMISE FOR THIS REVIEW IS TO SURVEY THE RECENT ADVANCES IN THE FIELD OF LIVER EPIGENETICS AND TO EXPLORE THEIR POTENTIAL FOR TRANSLATION BY INDUSTRY AND CLINICAL HEPATOLOGISTS FOR THE DESIGN OF NOVEL THERAPEUTICS AND DIAGNOSTIC/PROGNOSTIC BIOMARKERS. IN PARTICULAR, WE PRESENT FINDINGS IN THE CONTEXT OF HEPATOCELLULAR CARCINOMA, FIBROSIS AND NON-ALCOHOLIC FATTY LIVER DISEASE, WHERE THERE IS URGENT UNMET NEED FOR NEW CLINICAL INTERVENTIONS AND BIOMARKERS. 2016 5 5805 40 STRATEGIES TO PREVENT AND REVERSE LIVER FIBROSIS IN HUMANS AND LABORATORY ANIMALS. LIVER FIBROSIS RESULTS FROM CHRONIC DAMAGE TO THE LIVER IN CONJUNCTION WITH VARIOUS PATHWAYS AND IS MEDIATED BY A COMPLEX MICROENVIRONMENT. BASED ON CLINICAL OBSERVATIONS, IT IS NOW EVIDENT THAT FIBROSIS IS A DYNAMIC, BIDIRECTIONAL PROCESS WITH AN INHERENT CAPACITY FOR RECOVERY AND REMODELING. THE MAJOR MECHANISMS INVOLVED IN LIVER FIBROSIS INCLUDE THE REPETITIVE INJURY OF HEPATOCYTES, THE ACTIVATION OF THE INFLAMMATORY RESPONSE AFTER INJURY STIMULATION, AND THE ACTIVATION AND PROLIFERATION OF HEPATIC STELLATE CELLS (HSCS), WHICH REPRESENTS THE MAJOR EXTRACELLULAR MATRIX (ECM)-PRODUCING CELLS, STIMULATED BY HEPATOCYTE INJURY AND INFLAMMATION. THE MICROENVIRONMENT IN THE LIVER IS SYNERGISTICALLY REGULATED ABNORMAL ECM DEPOSITION, SCAR FORMATION, ANGIOGENESIS, AND FIBROGENESIS. MOREOVER, RECENT STUDIES HAVE CLARIFIED NOVEL MECHANISM IN FIBROSIS SUCH AS EPIGENETIC REGULATION OF HSCS, THE LEPTIN AND PPARGAMMA PATHWAYS, THE COAGULATION SYSTEM, AND EVEN AUTOPHAGY. UNCOVERING THE MECHANISMS OF LIVER FIBROGENESIS PROVIDES A BASIS TO DEVELOP POTENTIAL THERAPIES TO REVERSE AND TREAT THE FIBROTIC RESPONSE, THEREBY IMPROVING THE OUTCOMES OF PATIENTS WITH CHRONIC LIVER DISEASE. ALTHOUGH BOTH SCIENTIFIC AND CLINICAL CHALLENGES REMAIN, EMERGING STUDIES ATTEMPT TO REVEAL THE IDEAL ANTI-FIBROTIC DRUG THAT COULD BE EASILY DELIVERED TO THE LIVER WITH HIGH SPECIFICITY AND LOW TOXICITY. THIS REVIEW HIGHLIGHTS THE MECHANISMS, INCLUDING NOVEL PATHWAYS UNDERLYING FIBROGENESIS THAT MAY BE TRANSLATED INTO PREVENTIVE AND TREATMENT STRATEGIES, REVIEWS BOTH CURRENT AND NOVEL AGENTS THAT TARGET SPECIFIC PATHWAYS OR MULTIPLE TARGETS, AND DISCUSSES NOVEL DRUG DELIVERY SYSTEMS SUCH AS NANOTECHNOLOGY THAT CAN BE APPLIED IN THE TREATMENT OF LIVER FIBROSIS. IN ADDITION, WE ALSO DISCUSS SOME CURRENT TREATMENT STRATEGIES THAT ARE BEING APPLIED IN ANIMAL MODELS AND IN CLINICAL TRIALS. 2015 6 3964 37 LONG NONCODING RNAS IN LUNG CANCER. DESPITE GREAT PROGRESS IN RESEARCH AND TREATMENT OPTIONS, LUNG CANCER REMAINS THE LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ONCOGENIC DRIVER MUTATIONS IN PROTEIN-ENCODING GENES WERE DEFINED AND ALLOW FOR PERSONALIZED THERAPIES BASED ON GENETIC DIAGNOSES. NONETHELESS, DIAGNOSIS OF LUNG CANCER MOSTLY OCCURS AT LATE STAGES, AND CHRONIC TREATMENT IS FOLLOWED BY A FAST ONSET OF CHEMORESISTANCE. HENCE, THERE IS AN URGENT NEED FOR RELIABLE BIOMARKERS AND ALTERNATIVE TREATMENT OPTIONS. WITH THE ERA OF WHOLE GENOME AND TRANSCRIPTOME SEQUENCING TECHNOLOGIES, LONG NONCODING RNAS EMERGED AS A NOVEL CLASS OF VERSATILE, FUNCTIONAL RNA MOLECULES. ALTHOUGH FOR MOST OF THEM THE MECHANISM OF ACTION REMAINS TO BE DEFINED, ACCUMULATING EVIDENCE CONFIRMS THEIR INVOLVEMENT IN VARIOUS ASPECTS OF LUNG TUMORIGENESIS. THEY ARE FUNCTIONAL ON THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVEL AND ARE REGULATORS OF PATHOPHYSIOLOGICAL KEY PATHWAYS INCLUDING CELL GROWTH, APOPTOSIS, AND METASTASIS. LONG NONCODING RNAS ARE GAINING INCREASING ATTENTION AS POTENTIAL BIOMARKERS AND A NOVEL CLASS OF DRUGGABLE MOLECULES. IT HAS BECOME CLEAR THAT WE ARE ONLY BEGINNING TO UNDERSTAND THE COMPLEXITY OF TUMORIGENIC PROCESSES. THE CLINICAL INTEGRATION OF LONG NONCODING RNAS IN TERMS OF PROGNOSTIC AND PREDICTIVE BIOMARKER SIGNATURES AND ADDITIONAL CANCER TARGETS COULD PROVIDE A CHANCE TO INCREASE THE THERAPEUTIC BENEFIT. HERE, WE REVIEW THE CURRENT KNOWLEDGE ABOUT THE EXPRESSION, REGULATION, BIOLOGICAL FUNCTION, AND CLINICAL RELEVANCE OF LONG NONCODING RNAS IN LUNG CANCER. 2016 7 1354 43 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 8 1880 40 EMERGING STRATEGIES TO DISRUPT THE CENTRAL TGF-BETA AXIS IN KIDNEY FIBROSIS. CHRONIC KIDNEY DISEASE (CKD) AFFECTS MORE THAN 20 MILLION PEOPLE IN THE UNITED STATES AND THE GLOBAL BURDEN OF THIS DISORDER IS INCREASING. MANY AFFECTED INDIVIDUALS WILL PROGRESS TO END STAGE KIDNEY DISEASE NECESSITATING DIALYSIS OR TRANSPLANTATION. CKD IS ALSO A MAJOR INDEPENDENT CONTRIBUTOR TO THE RISK OF CARDIOVASCULAR MORBIDITY AND MORTALITY. TUBULOINTERSTITIAL FIBROSIS IS A FINAL COMMON PATHWAY FOR MOST CAUSES OF PROGRESSIVE CKD. CURRENTLY, THERE ARE NO CLINICALLY AVAILABLE THERAPIES TARGETING FIBROSIS THAT CAN SLOW THE DECLINE IN KIDNEY FUNCTION. ALTHOUGH IT HAS LONG BEEN KNOWN THAT TGF-BETA SIGNALING IS A CRITICAL MEDIATOR OF KIDNEY FIBROSIS, TRANSLATING THIS KNOWLEDGE TO THE CLINIC HAS BEEN CHALLENGING. IN THIS REVIEW, WE HIGHLIGHT SOME RECENT INSIGHTS INTO THE MECHANISMS OF TGF-BETA SIGNALING THAT TARGET ACTIVATION OF THIS CYTOKINE AT THE SITE OF INJURY OR SELECTIVELY INHIBIT PRO-FIBROTIC GENE EXPRESSION. MOLECULES DIRECTED AT THESE TARGETS HOLD THE PROMISE OF ATTAINING THERAPEUTIC EFFICACY WHILE LIMITING TOXICITY SEEN WITH GLOBAL INHIBITION OF TGF-BETA. KIDNEY INJURY HAS PROFOUND EPIGENETIC EFFECTS LEADING TO ALTERED EXPRESSION OF MORE THAN A THOUSAND GENES. WE DISCUSS HOW DRUGS TARGETING EPIGENETIC MODIFICATIONS, SOME OF WHICH ARE IN USE FOR CANCER THERAPY, HAVE THE POTENTIAL TO REPROGRAM GENE REGULATORY NETWORKS TO FAVOR ADAPTIVE REPAIR AND PREVENT FIBROSIS. THE LACK OF RELIABLE BIOMARKERS OF KIDNEY FIBROSIS IS A MAJOR LIMITATION IN DESIGNING CLINICAL TRIALS FOR TESTING CKD TREATMENTS. WE CONCLUDE BY REVIEWING RECENT ADVANCES IN FIBROSIS BIOMARKER DEVELOPMENT. 2019 9 2394 24 EPIGENETIC REPROGRAMMING IN LIVER FIBROSIS AND CANCER. NOVEL INSIGHTS INTO THE EPIGENETIC CONTROL OF CHRONIC LIVER DISEASES ARE NOW EMERGING. RECENT ADVANCES IN OUR UNDERSTANDING OF THE CRITICAL ROLES OF DNA METHYLATION, HISTONE MODIFICATIONS AND NCRNA MAY NOW BE EXPLOITED TO IMPROVE MANAGEMENT OF FIBROSIS/CIRRHOSIS AND CANCER. FURTHERMORE, IMPROVED TECHNOLOGIES FOR THE DETECTION OF EPIGENETIC MARKERS FROM PATIENTS' BLOOD AND TISSUES WILL VASTLY IMPROVE DIAGNOSIS, TREATMENT OPTIONS AND PROGNOSTIC TRACKING. THE AIM OF THIS REVIEW IS TO PRESENT RECENT FINDINGS FROM THE FIELD OF LIVER EPIGENETICS AND TO EXPLORE THEIR POTENTIAL FOR TRANSLATION INTO THERAPEUTICS TO PREVENT DISEASE PROMOTING EPIGENOME REPROGRAMMING AND REVERSE EPIGENETIC CHANGES. 2017 10 3697 27 INFLAMMATORY MARKERS IN CANCER: POTENTIAL RESOURCES. CANCER IS A LEADING CAUSE OF DEATH WORLDWIDE AND A MAJOR BURDEN ON DEVELOPING AND LESS DEVELOPED COUNTRIES OF THE WORLD WITH LIMITED RESOURCES FOR PREVENTION AND EFFECTIVE TREATMENT OF CANCER. ALTHOUGH CANCER IS MULTIFACTORIAL IN ORIGIN, VARIOUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST THAT CHRONIC INFLAMMATION HAS AN IMPORTANT ROLE IN ALL STAGES OF CANCER, FROM INITIATION TO PROGRESSION AND EVEN SURVIVAL OF THE PATIENT. INFLAMMATORY PRODUCTS LIKE CYTOKINES, CHEMOKINES, LEUCOCYTES, PROSTAGLANDINS, CYCLOOXYGENASE, REACTIVE OXYGEN AND NITROGEN SPECIES, METALLOPROTEINASE INDUCE GENETIC AND EPIGENETIC CHANGES IN NORMAL CELLS DAMAGING ITS DNA, INHIBITING ITS REPAIR, ALTERING TRANSCRIPTION FACTORS, PREVENTING APOPTOSIS, AND STIMULATING ANGIOGENESIS, AND THUS RESULTING IN CARCINOGENESIS. THUS, THESE INFLAMMATORY MEDIATORS HAVE A POTENTIAL ROLE TO BECOME CANCER BIOMARKERS FOR ALL STAGES OF CANCER AS MANY OF THEM CAN BE MEASURED IN A COST-EFFECTIVE MANNER. HOWEVER, LARGE SCALE PROSPECTIVE TRIALS ARE REQUIRED TO VALIDATE THESE POTENTIAL CANCER BIOMARKERS. NONETHELESS, A TRANSITION FROM POTENTIAL TO PRACTICAL UTILIZATION OF THESE MARKERS WILL BE AN EFFECTIVE TOOL FOR THE AMELIORATION OF CANCER BURDEN AND MORTALITY IN A RESOURCE LIMITED SETTING. 2020 11 5622 29 SEARCH FOR USEFUL BIOMARKERS IN HEPATOCELLULAR CARCINOMA, TUMOR FACTORS AND BACKGROUND LIVER FACTORS (REVIEW). HEPATOCARCINOGENESIS IS A COMPLEX AND MULTISTEP PROCESS THAT INVOLVES THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES. TO UNDERSTAND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CURRENT RESEARCH HAS UTILIZED IMPROVED ARRAY TECHNOLOGIES. THE IDENTIFICATION OF CANCER-RELATED MOLECULES COULD LEAD TO THE DEVELOPMENT OF NOVEL MOLECULAR TARGETS FOR TREATMENT AND BIOMARKERS FOR PREDICTING PROGNOSIS. HOWEVER, PROGNOSTIC PREDICTION IS INSUFFICIENT WHEN CONSIDERING ONLY TUMOR FACTORS, SINCE HEPATOCARCINOGENESIS IS ALSO GREATLY INFLUENCED BY THE STATUS OF THE BACKGROUND LIVER. CLINICAL BACKGROUND LIVER FACTORS, SUCH AS THE PRESENCE OF CHRONIC ACTIVE HEPATITIS OR CIRRHOSIS, ARE WELL KNOWN AS RISK FACTORS FOR DEVELOPING HCC. IN CONTRAST, GENETIC OR EPIGENETIC BACKGROUND LIVER FACTORS REMAIN UNKNOWN, ALBEIT THOSE ARE IMPORTANT TO UNDERSTAND THE DEVELOPING PROCESS OF HCC. INVESTIGATING BACKGROUND LIVER FACTORS COULD CONTRIBUTE TO THE DEVELOPMENT OF CARCINOGENIC MARKERS OF HCC AND TO THE PREVENTION OF THE DEVELOPMENT OF HCC. IN THE PRESENT STUDY, WE REVIEW THE CURRENTLY IDENTIFIED TUMOR FACTORS AND BACKGROUND LIVER FACTORS FROM A MOLECULAR BIOLOGICAL VIEWPOINT AND ALSO INTRODUCE OUR COMBINATION ARRAY ANALYSIS. 2017 12 3105 34 GENOMICS AND PROTEOMICS IN LIVER FIBROSIS AND CIRRHOSIS. GENOMICS AND PROTEOMICS HAVE BECOME INCREASINGLY IMPORTANT IN BIOMEDICAL SCIENCE IN THE PAST DECADE, AS THEY PROVIDE AN OPPORTUNITY FOR HYPOTHESIS-FREE EXPERIMENTS THAT CAN YIELD MAJOR INSIGHTS NOT PREVIOUSLY FORESEEN WHEN SCIENTIFIC AND CLINICAL QUESTIONS ARE BASED ONLY ON HYPOTHESIS-DRIVEN APPROACHES. USE OF THESE TOOLS, THEREFORE, OPENS NEW AVENUES FOR UNCOVERING PHYSIOLOGICAL AND PATHOLOGICAL PATHWAYS. LIVER FIBROSIS IS A COMPLEX DISEASE PROVOKED BY A RANGE OF CHRONIC INJURIES TO THE LIVER, AMONG WHICH ARE VIRAL HEPATITIS, (NON-) ALCOHOLIC STEATOHEPATITIS AND AUTOIMMUNE DISORDERS. SOME CHRONIC LIVER PATIENTS WILL NEVER DEVELOP FIBROSIS OR CIRRHOSIS, WHEREAS OTHERS RAPIDLY PROGRESS TOWARDS CIRRHOSIS IN A FEW YEARS. THIS VARIETY CAN BE CAUSED BY DISEASE-RELATED FACTORS (FOR EXAMPLE, VIRAL GENOTYPE) OR HOST-FACTORS (GENETIC/EPIGENETIC). IT IS VITAL TO ESTABLISH ACCURATE TOOLS TO IDENTIFY THOSE PATIENTS AT HIGHEST RISK FOR DISEASE SEVERITY OR PROGRESSION IN ORDER TO DETERMINE WHO ARE IN NEED OF IMMEDIATE THERAPIES. MOREOVER, THERE IS AN URGENT IMPERATIVE TO IDENTIFY NON-INVASIVE MARKERS THAT CAN ACCURATELY DISTINGUISH MILD AND INTERMEDIATE STAGES OF FIBROSIS. IDEALLY, BIOMARKERS CAN BE USED TO PREDICT DISEASE PROGRESSION AND TREATMENT RESPONSE, BUT THESE STUDIES WILL TAKE MANY YEARS DUE TO THE REQUIREMENT FOR LENGTHY FOLLOW-UP PERIODS TO ASSESS OUTCOMES. CURRENT GENOMIC AND PROTEOMIC RESEARCH PROVIDES MANY CANDIDATE BIOMARKERS, BUT INDEPENDENT VALIDATION OF THESE BIOMARKERS IS LACKING, AND REPRODUCIBILITY IS STILL A KEY CONCERN. THUS, GREAT OPPORTUNITIES AND CHALLENGES LIE AHEAD IN THE FIELD OF GENOMICS AND PROTEOMICS, WHICH, IF SUCCESSFUL, COULD TRANSFORM THE DIAGNOSIS AND TREATMENT OF CHRONIC FIBROSING LIVER DISEASES. 2012 13 3958 35 LONG NON-CODING RNAS IN BONE METASTASIS: PROGRESSES AND PERSPECTIVES AS POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN A PRECISION MEDICINE PERSPECTIVE, AMONG THE BIOMARKERS POTENTIALLY USEFUL FOR EARLY DIAGNOSIS OF CANCERS, AS WELL AS TO DEFINE THEIR PROGNOSIS AND EVENTUALLY TO IDENTIFY NOVEL AND MORE EFFECTIVE THERAPEUTIC TARGETS, THERE ARE THE LONG NON-CODING RNAS (LNCRNAS). THE TERM LNCRNA IDENTIFIES A CLASS OF NON-CODING RNA MOLECULES INVOLVED IN THE REGULATION OF GENE EXPRESSION THAT INTERVENE AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVEL. METASTASIS IS A NATURAL EVOLUTION OF SOME MALIGNANT TUMOURS, FREQUENTLY ENCOUNTERED IN PATIENTS WITH ADVANCED CANCERS. ONSET AND DEVELOPMENT OF METASTASIS REPRESENTS A DETRIMENTAL EVENT THAT WORSEN THE PATIENT'S PROGNOSIS BY PROFOUNDLY INFLUENCING THE QUALITY OF LIFE AND IS RESPONSIBLE FOR THE OMINOUS PROGRESSION OF THE DISEASE. DUE TO THE PECULIAR ENVIRONMENT AND THE BIOMECHANICAL PROPERTIES, BONE IS A PREFERENTIAL SITE FOR THE SECONDARY GROWTH OF BREAST, PROSTATE AND LUNG CANCERS. UNFORTUNATELY, ONLY PALLIATIVE AND PAIN THERAPIES ARE CURRENTLY AVAILABLE FOR PATIENTS WITH BONE METASTASES, WHILE NO EFFECTIVE AND DEFINITIVE TREATMENTS ARE AVAILABLE. THE UNDERSTANDING OF PATHOPHYSIOLOGICAL BASIS OF BONE METASTASIS FORMATION AND PROGRESSION, AS WELL AS THE IMPROVEMENT IN THE CLINICAL MANAGEMENT OF THE PATIENT, ARE CENTRAL BUT CHALLENGING TOPICS IN BASIC RESEARCH AND CLINICAL PRACTICE. THE IDENTIFICATION OF NEW MOLECULAR SPECIES THAT MAY HAVE A ROLE AS EARLY HALLMARKS OF THE METASTATIC PROCESS COULD OPEN THE DOOR TO THE DEFINITION OF NEW, AND MORE EFFECTIVE, THERAPEUTIC AND DIAGNOSTIC APPROACHES. NON-CODING RNAS SPECIES AND, PARTICULARLY, LNCRNAS ARE PROMISING COMPOUNDS IN THIS SETTING, AND THEIR STUDY MAY BRING TO THE IDENTIFICATION OF RELEVANT PROCESSES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF LNCRNAS AS EMERGING MOLECULES IN MEDIATING THE FORMATION AND DEVELOPMENT OF BONE METASTASES, AS POSSIBLE BIOMARKERS FOR CANCER DIAGNOSIS AND PROGNOSIS, AND AS THERAPEUTIC TARGETS TO COUNTERACT CANCER SPREAD. 2023 14 4325 34 MICRORNAS IN THE EVALUATION AND POTENTIAL TREATMENT OF LIVER DISEASES. ACUTE AND CHRONIC LIVER DISEASE CONTINUE TO RESULT IN SIGNIFICANT MORBIDITY AND MORTALITY OF PATIENTS, ALONG WITH INCREASING BURDEN ON THEIR FAMILIES, SOCIETY AND THE HEALTH CARE SYSTEM. THIS IN PART IS DUE TO INCREASED INCIDENCE OF LIVER DISEASE ASSOCIATED FACTORS SUCH AS METABOLIC SYNDROME; IMPROVED SURVIVAL OF PATIENTS WITH CHRONIC PREDISPOSING CONDITIONS SUCH AS HIV; AS WELL AS ADVANCES IN THE FIELD OF TRANSPLANTATION AND ASSOCIATED CARE LEADING TO IMPROVED SURVIVAL. THE FACT THAT ONE DISEASE CAN RESULT IN DIFFERENT MANIFESTATIONS AND OUTCOMES HIGHLIGHTS THE NEED FOR IMPROVED UNDERSTANDING OF NOT JUST GENETIC PHENOMENON PREDISPOSING TO A CONDITION, BUT ADDITIONALLY THE ROLE OF EPIGENETIC AND ENVIRONMENTAL FACTORS LEADING TO THE PHENOTYPE OF THE DISEASE. IT IS NOT SURPRISING THAT PROVIDERS CONTINUE TO FACE DAILY CHALLENGES PERTAINING TO DIAGNOSTIC ACCURACY, PROGNOSTICATION OF DISEASE SEVERITY, PROGRESSION, AND RESPONSE TO THERAPIES. A NUMBER OF THESE CHALLENGES CAN BE ADDRESSED BY INCORPORATING A PERSONALIZED APPROACH OF MANAGEMENT TO THE CURRENT PARADIGM OF CARE. RECENT ADVANCES IN THE FIELDS OF MOLECULAR BIOLOGY AND GENETICS HAVE PAVED THE WAY TO MORE ACCURATE, INDIVIDUALIZED AND PRECISE APPROACH TO CARING FOR LIVER DISEASE. THE STUDY OF MICRORNAS AND THEIR ROLE IN BOTH HEALTHY AND DISEASED LIVERS IS ONE EXAMPLE OF SUCH ADVANCES. AS THESE SMALL, NON-CODING RNAS WORK ON FINE-TUNING OF CELLULAR ACTIVITIES AND ORGAN FUNCTION IN A DYNAMIC AND PRECISE FASHION, THEY PROVIDE US A GOLDEN OPPORTUNITY TO ADVANCE THE FIELD OF HEPATOLOGY. THE STUDY OF MICRORNAS IN LIVER DISEASE PROMISES TREMENDOUS IMPROVEMENT IN HEPATOLOGY AND IS LIKELY TO LAY THE FOUNDATION TOWARDS A PERSONALIZED APPROACH IN LIVER DISEASE. 2016 15 5026 40 PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS: FACTS AND PROMISES. PURPOSE OF REVIEW: IN THIS ARTICLE, WE SUMMARIZE AND DISCUSS THE MOST RECENT LITERATURE ON PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS (IPF), A CHRONIC PROGRESSIVE AND ALMOST INVARIABLY LETHAL DISEASE OF UNKNOWN CAUSE. THIS REVIEW IS TIMELY AS MAJOR ADVANCES IN OUR UNDERSTANDING OF DISEASE PATHOBIOLOGY AND IMPROVEMENTS IN MOLECULAR TECHNIQUES HAVE RECENTLY LED TO THE IDENTIFICATION OF POTENTIAL SURROGATES OF DIAGNOSIS, PROGNOSIS AND RESPONSE TO TREATMENT. RECENT FINDINGS: THE MOST PROMISING AND ADVANCED CANDIDATE BIOMARKERS ARE PRESENTED BASED ON THEIR PROPOSED MECHANISTIC PATHWAYS (E.G. ALVEOLAR EPITHELIAL CELL DYSFUNCTION, IMMUNE DYSREGULATION, MICROBIOME, EXTRACELLULAR MATRIX REMODELING AND FIBROPROLIFERATION, EPIGENETIC MARKERS AND METABOLOMICS). RECENT DATA SUGGEST THAT COMPONENTS OF THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE DEVELOPMENT OF IPF. A POTENTIAL ROLE FOR INFECTIONS AS A COFACTOR IN DISEASE DEVELOPMENT AND PROGRESSION OR AS A TRIGGER IN DISEASE EXACERBATION HAS ALSO RECENTLY BEEN PROPOSED. SUMMARY: CLINICAL MANAGEMENT OF IPF IS UNSATISFACTORY BECAUSE OF LIMITED AVAILABILITY OF TRULY EFFECTIVE THERAPIES, LACK OF ACCURATE PREDICTORS OF DISEASE BEHAVIOR AND ABSENCE OF SIMPLE SHORT-TERM MEASURES OF THERAPEUTIC RESPONSE. A NUMBER OF PUTATIVE BIOMARKERS HAVE BEEN IDENTIFIED IN PATIENTS WITH IPF, ALTHOUGH NONE HAS BEEN VALIDATED TO THE STANDARD NECESSARY FOR THEIR USE IN EITHER THERAPEUTIC TRIALS OR CLINICAL PRACTICE. CURRENTLY, ONGOING PROSPECTIVE LONGITUDINAL STUDIES WILL HOPEFULLY PERMIT SUCH VALIDATION. 2015 16 2211 29 EPIGENETIC MODIFICATIONS AND THE DEVELOPMENT OF KIDNEY GRAFT FIBROSIS. PURPOSE OF REVIEW: TO OUTLINE RECENT DISCOVERIES IN EPIGENETIC REGULATORY MECHANISMS THAT HAVE POTENTIAL IMPLICATIONS IN THE DEVELOPMENT OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION. RECENT FINDINGS: THE CHARACTERIZATION OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION HAS SHOWN TGFBETA/SMAD SIGNALING TO PLAY A MAJOR ROLE IN THE PROGRESSION TO CHRONIC ALLOGRAFT DYSFUNCTION. THE ONSET OF UNREGULATED PROINFLAMMATORY PATHWAYS ARE ONLY EXACERBATED BY THE DECLINE IN REGULATORY MECHANISMS LOST WITH PROGRESSIVE PATIENT AGE AND COMORBIDITIES SUCH AS HYPERTENSION AND DIABETES. HOWEVER, SIGNIFICANT DEVELOPMENTS IN THE RECOGNITION OF EPIGENETIC REGULATORY MARKERS UPSTREAM OF ABERRANT TGFBETA-SIGNALING HAS SIGNIFICANT CLINICAL POTENTIAL TO PROVIDE THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL FIBROSIS. IN ADDITION, DISCOVERIES IN EXTRACELLULAR VESICLES AND THE CHARACTERIZATION OF THEIR CARGO HAS LAID NEW FRAMEWORK FOR THE POTENTIAL TO EVALUATE PATIENT OUTCOMES INDEPENDENT OF INVASIVE BIOPSIES. SUMMARY: THE CURRENT REVIEW SUMMARIZES THE MAIN FINDINGS IN EPIGENETIC MACHINERY SPECIFIC TO THE DEVELOPMENT OF RENAL FIBROSIS AND HIGHLIGHTS THERAPEUTIC OPTIONS THAT HAVE SIGNIFICANT POTENTIAL TO TRANSLATE INTO CLINICAL PRACTICE. 2021 17 3038 27 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 18 4043 28 MACROPHAGES IN CHRONIC LIVER FAILURE: DIVERSITY, PLASTICITY AND THERAPEUTIC TARGETING. CHRONIC LIVER INJURY RESULTS IN IMMUNE-DRIVEN PROGRESSIVE FIBROSIS, WITH RISK OF CIRRHOSIS DEVELOPMENT AND IMPACT ON MORBIDITY AND MORTALITY. PERSISTENT LIVER CELL DAMAGE AND DEATH CAUSES IMMUNE CELL ACTIVATION AND INFLAMMATION. PATIENTS WITH ADVANCED CIRRHOSIS ADDITIONALLY EXPERIENCE PATHOLOGICAL BACTERIAL TRANSLOCATION, EXPOSURE TO MICROBIAL PRODUCTS AND CHRONIC ENGAGEMENT OF THE IMMUNE SYSTEM. BACTERIAL INFECTIONS HAVE A HIGH INCIDENCE IN CIRRHOSIS, WITH SPONTANEOUS BACTERIAL PERITONITIS BEING THE MOST COMMON, WHILE THE SUBSEQUENT SYSTEMIC INFLAMMATION, ORGAN FAILURE AND IMMUNE DYSREGULATION INCREASE THE MORTALITY RISK. TISSUE-RESIDENT AND RECRUITED MACROPHAGES PLAY A CENTRAL PART IN THE DEVELOPMENT OF INFLAMMATION AND FIBROSIS PROGRESSION. IN THE LIVER, ADIPOSE TISSUE, PERITONEUM AND INTESTINES, DIVERSE MACROPHAGE POPULATIONS EXHIBIT GREAT PHENOTYPIC AND FUNCTIONAL PLASTICITY DETERMINED BY THEIR ONTOGENY, EPIGENETIC PROGRAMMING AND LOCAL MICROENVIRONMENT. THESE CHANGES CAN, AT DIFFERENT TIMES, PROMOTE OR AMELIORATE DISEASE STATES AND THEREFORE REPRESENT POTENTIAL TARGETS FOR MACROPHAGE-DIRECTED THERAPIES. IN THIS REVIEW, WE DISCUSS THE EVIDENCE FOR MACROPHAGE PHENOTYPIC AND FUNCTIONAL ALTERATIONS IN TISSUE COMPARTMENTS DURING THE DEVELOPMENT AND PROGRESSION OF CHRONIC LIVER FAILURE IN DIFFERENT AETIOLOGIES AND HIGHLIGHT THE POTENTIAL OF MACROPHAGE MODULATION AS A THERAPEUTIC STRATEGY FOR LIVER DISEASE. 2021 19 3621 29 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 20 1522 36 DNA METHYLATION CHANGE PROFILING OF COLORECTAL DISEASE: SCREENING TOWARDS CLINICAL USE. COLON CANCER REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. TRANSFORMATION OF COLON EPITHELIAL CELLS INTO INVASIVE ADENOCARCINOMAS HAS BEEN WELL KNOWN TO BE DUE TO THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC CHANGES. IN THE PAST DECADE, THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) WHICH IS CHARACTERIZED BY CHRONIC INFLAMMATION OF THE INTESTINAL MUCOSA, WAS ONLY PARTIALLY EXPLAINED BY GENETIC STUDIES PROVIDING SUSCEPTIBILITY LOCI, BUT RECENTLY EPIGENETIC STUDIES HAVE PROVIDED CRITICAL EVIDENCES AFFECTING IBD PATHOGENESIS. OVER THE PAST DECADE, A DEEP UNDERSTANDING OF EPIGENETICS ALONG WITH TECHNOLOGICAL ADVANCES HAVE LED TO IDENTIFYING NUMEROUS GENES THAT ARE REGULATED BY PROMOTER DNA HYPERMETHYLATION IN COLORECTAL DISEASES. RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN COLORECTAL DISEASES COULD IMPROVE A MULTITUDE OF POWERFUL DNA METHYLATION-BASED BIOMARKERS, PARTICULARLY FOR USE AS DIAGNOSIS, PROGNOSIS, AND PREDICTION FOR THERAPEUTIC APPROACHES. THIS REVIEW FOCUSES ON THE EMERGING POTENTIAL FOR TRANSLATIONAL RESEARCH OF EPIGENETIC ALTERATIONS INTO CLINICAL UTILITY AS MOLECULAR BIOMARKERS. MOREOVER, THIS REVIEW DISCUSSES RECENT PROGRESS REGARDING THE IDENTIFICATION OF UNKNOWN HYPERMETHYLATED GENES IN COLON CANCERS AND IBD, AS WELL AS THEIR POSSIBLE ROLE IN CLINICAL PRACTICE, WHICH WILL HAVE IMPORTANT CLINICAL SIGNIFICANCE, PARTICULARLY IN THE ERA OF THE PERSONALIZED MEDICINE. 2021