1 2929 46 GENES AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ALTHOUGH MUCH REMAINS TO BE DONE, RECENT ADVANCES AND THE ADVENT OF NEW METHODOLOGIES ARE PROMISING AND SHOULD YIELD INCREASED UNDERSTANDING OF THE GENETIC AND EPIGENETIC MECHANISMS INFLUENCING THE PATHOGENESIS OF COPD, BOTH RELATED AND UNRELATED TO SEVERE AAT DEFICIENCY. SUCH UNDERSTANDING SHOULD ULTIMATELY BE TRANSLATED INTO NOVEL APPROACHES TO PREVENT, DIAGNOSE, AND TREAT COPD. 2012 2 1031 13 CIRCULATING TUMOR DNA DETECTION AND ITS APPLICATION STATUS IN GASTRIC CANCER: A NARRATIVE REVIEW. CIRCULATING TUMOR DNA (CTDNA) IS THE SMALL GENOMIC FRAGMENT RELEASED BY TUMOR CELLS INTO THE CIRCULATING SYSTEM, WHICH CARRIES THE GENE VARIATION FEATURES, SUCH AS MUTATION, INSERTION, DELETION, REARRANGEMENT, COPY NUMBER VARIATION (CNV) AND METHYLATION, RENDERING IT AN IMPORTANT BIOMARKER. IT CAN BE USED NOT ONLY TO DIAGNOSE CERTAIN TYPES OF SOLID TUMORS, BUT ALSO TO MONITOR THE THERAPEUTIC RESPONSE AND EXPLORE THE MINIMAL RESIDUAL DISEASE (MRD) AND RESISTANT MUTATION OF TARGETED THERAPY. THEREFORE, CTDNA DETECTION MAY BECOME THE PREFERRED NON-INVASIVE TUMOR SCREENING METHOD. FOR PATIENTS WHO CANNOT RECEIVE FURTHER GENE DETECTION DUE TO INSUFFICIENT OR RESTRICTED SAMPLE COLLECTION WITH THE DEFINED PATHOLOGICAL DIAGNOSIS, CTDNA DETECTION CAN BE CARRIED OUT TO DETERMINE THE GENE MUTATION TYPE, WITH NO NEED FOR REPEATED SAMPLING. GASTRIC CANCER (GC) IS A MALIGNANCY WITH EXTREMELY HIGH MORBIDITY AND MORTALITY, AND ITS GENESIS AND DEVELOPMENT ARE THE CONSEQUENCE OF INTERACTIONS OF MULTIPLE FACTORS, INCLUDING ENVIRONMENT, DIET, HEREDITY, HELICOBACTER PYLORI INFECTION, CHRONIC INFLAMMATORY INFILTRATION, AND PRECANCEROUS LESION. AS THE RESEARCH ON GC MOVES FORWARD, THE EXISTING RESEARCH MAINLY FOCUSES ON GENETIC AND EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA CHANGES, GENE MUTATION, GENE HETEROZYGOSITY LOSS AND MICROSATELLITE INSTABILITY. THIS PAPER AIMED TO SUMMARIZE THE CONTENTS OF CTDNA DETECTION, ITS APPLICATION STATUS IN GC AND CLINICAL SIGNIFICANCE. 2021 3 4816 12 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 4 638 24 BIOMARKERS ASSOCIATED WITH MIGRAINE AND THEIR POTENTIAL ROLE IN MIGRAINE MANAGEMENT. OBJECTIVE: THE FOCUS OF THIS REVIEW IS TO REVIEW POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKERS ASSOCIATED WITH MIGRAINE. BACKGROUND: MIGRAINE HEADACHE IS A COMMON DISEASE THAT AFFECTS MILLIONS OF INDIVIDUALS WORLDWIDE. ALTHOUGH WELL-ACCEPTED DIAGNOSTIC CRITERIA EXIST FOR MIGRAINE, IT IS STILL A COMPLEX DISORDER THAT REMAINS BOTH UNDERDIAGNOSED AND MISDIAGNOSED. THE CAUSES OF MIGRAINE ARE LIKELY A MIX OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT, TOGETHER WITH THE INDIVIDUAL'S LIFE HISTORY, TRANSLATE INTO THE OBSERVED CLINICAL HETEROGENEITY. INHERENT CLINICAL HETEROGENEITY IS AN OBSTACLE IN DEVELOPING MORE EFFECTIVE TREATMENTS. THE LACK OF APPROPRIATE BIOMARKERS IS ALSO AN IMPEDIMENT TO DEVELOPING MORE EFFECTIVE THERAPEUTIC/PREVENTIVE APPROACHES. ULTIMATELY, BIOMARKERS MAY FACILITATE THE GOAL OF INDIVIDUALIZED MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER TYPES OF HEADACHE. METHODS: A COMPREHENSIVE REVIEW WAS CONDUCTED OF PUBMED CITATIONS CONTAINING THE KEY WORD "MARKER" OR "BIOMARKER" COMBINED WITH "MIGRAINE" OR "HEADACHE." OTHER KEY WORDS INCLUDED "SERUM," "SALIVA," "CEREBROSPINAL FLUID," "GENES," "BLOOD," AND "INFLAMMATION." THE ONLY RESTRICTION WAS ENGLISH-LANGUAGE PUBLICATION. THE ABSTRACTS OF ALL ARTICLES MEETING THESE CRITERIA WERE REVIEWED, AND FULL TEXT WAS RETRIEVED AND EXAMINED FOR RELEVANT REFERENCES. RESULTS: DATA FROM HUMAN STUDIES HAVE BEGUN TO IDENTIFY GENETIC MUTATIONS/POLYMORPHISMS AND ALTERED LEVELS OF SPECIFIC PROINFLAMMATORY AND NEUROMODULATORY MOLECULES THAT STRONGLY CORRELATE WITH MIGRAINE AS WELL AS SYMPTOM SEVERITY. RESULTS FROM A SMALLER NUMBER OF STUDIES HAVE IDENTIFIED PARAMETERS, SUCH AS THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP), WHICH ARE SIGNIFICANTLY ASSOCIATED WITH RESPONSE TO SPECIFIC TREATMENTS FOR ACUTE MIGRAINE ATTACKS AND PROPHYLAXIS. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MIGRAINE, AND UNDERSTANDING ENVIRONMENTALLY INDUCED GENETIC CHANGES ASSOCIATED WITH THIS DISEASE MAY EVENTUALLY GUIDE THE DEVELOPMENT OF THERAPIES CAPABLE OF REVERSING THESE PATHOPHYSIOLOGICAL CHANGES IN GENE FUNCTION. CONCLUSIONS: THE UNDERSTANDING OF THE ETIOLOGY OF MIGRAINE IS INCOMPLETE. ALTHOUGH THE IDENTIFICATION AND VALIDATION OF BIOMARKERS HAS GREATLY ADVANCED DIAGNOSTIC PRECISION AND MEASURES OF THERAPEUTIC EFFICACY IN OTHER DISEASES, THERE ARE NO CURRENTLY ACCEPTED BIOMARKERS FOR CHRONIC OR EPISODIC MIGRAINE. HOWEVER, THE CONTINUED INVESTIGATION AND IDENTIFICATION OF GENETIC, EPIGENETIC, AND MOLECULAR BIOMARKERS IS LIKELY TO FACILITATE THE GOAL OF INDIVIDUALIZING MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER HEADACHE DISORDERS. 2013 5 6355 20 THE ROLE OF HERPESVIRUS 6A AND 6B IN MULTIPLE SCLEROSIS AND EPILEPSY. HUMAN HERPESVIRUS 6A (HHV-6A) AND 6B (HHV-6B) ARE TWO CLOSELY RELATED VIRUSES THAT CAN INFECT CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). THE SIMILARITIES BETWEEN THESE VIRUSES HAVE MADE IT DIFFICULT TO SEPARATE THEM ON SEROLOGICAL LEVEL. THE BROAD TERM HHV-6 REMAINS WHEN REFERRING TO STUDIES WHERE THE TWO SPECIES WERE NOT DISTINGUISHED, AND AS SUCH, THE SEROPREVALENCE IS OVER 90% IN THE ADULT POPULATION. HHV-6B HAS BEEN DETECTED IN UP TO 100% OF INFANTS WITH THE PRIMARY INFECTION ROSEOLA INFANTUM, BUT LESS IS KNOWN ABOUT THE PRIMARY INFECTION OF HHV-6A. BOTH VIRUSES ARE NEUROTROPIC AND HAVE CAPACITY TO ESTABLISH LIFELONG LATENCY IN CELLS OF THE CENTRAL NERVOUS SYSTEM, WITH POTENTIAL TO REACTIVATE AND CAUSE COMPLICATIONS LATER IN LIFE. HHV-6A INFECTION HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF MULTIPLE SCLEROSIS (MS), WHEREAS HHV-6B IS INDICATED TO BE INVOLVED IN PATHOGENESIS OF EPILEPSY. THESE TWO ASSOCIATIONS SHOW HOW NEUROLOGICAL DISEASES MIGHT BE CAUSED BY VIRAL INFECTIONS, BUT AS SUGGESTED HERE, THROUGH COMPLETELY DIFFERENT MOLECULAR MECHANISMS, IN AN AUTOIMMUNE DISEASE, SUCH AS MS, BY TRIGGERING AN OVERREACTION OF THE IMMUNE SYSTEM AND IN EPILEPSY BY HAMPERING INTERNAL CELLULAR FUNCTIONS WHEN THE IMMUNE SYSTEM FAILS TO ELIMINATE THE VIRUS. UNDERSTANDING THE VIRAL MECHANISMS OF PRIMARY INFECTION AND REACTIVATION AND THEIR SPECTRUM OF ASSOCIATED SYMPTOMS WILL AID OUR ABILITY TO DIAGNOSE, TREAT AND PREVENT THESE SEVERE AND CHRONIC DISEASES. THIS REVIEW EXPLORES THE ROLE OF HHV-6A AND HHV-6B SPECIFICALLY IN MS AND EPILEPSY, THE EVIDENCE TO DATE AND THE FUTURE DIRECTIONS OF THIS FIELD. 2020 6 3900 22 LATEST INSIGHTS INTO PATHOGENESIS OF MYCOSIS FUNGOIDES AND CUTANEOUS T-CELL LYMPHOMA. CUTANEOUS T-CELL LYMPHOMA (CTCL) IS A RARE BUT INCREASING MALIGNANCY WHOSE PROTEAN MANIFESTATIONS NECESSARILY PRESENT IN THE INTEGUMENT, BUT CAN ALSO SPREAD TO INVOLVE BLOOD, LYMPH NODES AND INTERNAL ORGANS. WE HAVE DEVELOPED EFFICACIOUS AND VARIED THERAPIES TO TREAT EARLY AND ADVANCED STAGE DISEASE, BUT THERE ARE STILL MANY WHO SUFFER TREMENDOUSLY FROM THIS ILLNESS. ALTHOUGH THE PATHOGENESIS OF THIS CANCER REMAINS FRUSTRATINGLY ELUSIVE, OVER THE LAST 200 YEARS WE HAVE GENERATED A ROBUST BODY OF EVIDENCE THAT POINTS TOWARD POSSIBLE SINGULAR AS WELL AS MULTIFACTORIAL ETIOLOGIES. COMBINING THE HISTORICAL HYPOTHESES WHICH HAVE FOCUSED UPON THE CONCEPT OF INFECTIOUS CAUSES, INCLUDING CARCINOGENIC GENOMIC VIRAL INTEGRATION AND BACTERIAL SUPERANTIGENIC CHRONIC STIMULATION AS WELL AS INDUSTRIAL/OCCUPATIONAL EXPOSURE, ALONG WITH THE MORE RECENT REVELATIONS OF BOTH GENETIC AND EPIGENETIC ALTERATION AND IMMUNE DYSREGULATION, WE ARE CLOSER THAN EVER TO UNDERSTANDING THE ETIOLOGY OF CTCL. IT IS THROUGH THIS KNOWLEDGE AND CONTINUED RESEARCH EFFORTS THAT WE WILL BE ABLE TO BETTER DIAGNOSE, TREAT, AND POTENTIALLY PREVENT OR CURE CTCL. 2017 7 6847 15 [MOLECULAR DIAGNOSIS OF CHRONIC MYELOPROLIFERATIVE DISEASES AND MYELODYSPLASTIC SYNDROMES]. HISTOMORPHOLOGICAL EVALUATION OF BONE MARROW TREPHINES AND SMEARS REPRESENTS THE MAJOR APPROACH TO DIAGNOSE THE CHRONIC MYELOPROLIFERATIVE DISEASES (CMPD) AND THE MYELODYSPLASTIC SYNDROMES (MDS). HOWEVER, RISING INSIGHTS INTO MOLECULAR PATHOGENESIS OF HUMAN DISEASES STRENGTHEN THE ATTEMPT OF PATHOLOGISTS TO DEFINE AND TO DETECT UNDERLYING DEFECTS BEYOND THE MICROSCOPE. SINCE DISCOVERY OF THE PHILADELPHIA CHROMOSOME IN CHRONIC MYELOID LEUKEMIA AS THE FIRST SPECIFIC MOLECULAR ABNORMALITY EVER DETECTED IN A HUMAN NEOPLASIA THE GAIN OF KNOWLEDGE OF MOLECULAR PATHOMECHANISMS IN PHILADELPHIA CHROMOSOME NEGATIVE (PH-) CMPD WAS RATHER SPARSE. A DECISIVE BREAKTHROUGH IN PH CMPD WAS THE FINDING OF JAK2 (V617F) DERIVED FROM A SOMATIC POINT MUTATION IN THE MAJORITY OF PATIENTS WITH POLYCYTHEMIA VERA (P.VERA) AND HALF OF PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF). IT THEREFORE CAN NOT BE OVERESTIMATED THAT DETECTION OF JAK2 (V617F) IN A SUSPECTIVE MYELOPROLIFERATION NOW ENABLES A CLEARCUT DISCRIMINATION OF A TRUE PH CMPD FROM A REACTIVE STATE, E.G. P.VERA FROM REACTIVE ERYTHROCYTOSIS. INTERESTINGLY, A BASIC PRINCIPLE OF MOLECULAR DEFECTS DEMONSTRABLE IN CMPD AND RELATED DISORDERS SEEMS TO BE THE INVOLVEMENT OF GENES WITH KINASE ACTIVITIES. SOME OF THOSE GENES WILL BE DISCUSSED IN MORE DETAIL. IN PRIMARY MDS, KARYOTYPING VIA CLASSICAL CYTOGENETICS IS THE PREDOMINANT MOLECULAR APPROACH TO ESTIMATE PROGNOSIS, E.G. -Y, DEL(5Q) AND DEL(20Q) REPRESENT FAVOURABLE ANOMALIES. INDEED, IN 5Q- SYNDROMES KARYOTYPING ENABLES DEFINITE SUBTYPING AND ALLOWS CLINICIANS AND PATIENTS TO EXPECT A GOOD PROGNOSIS. UNTIL NOW, DOZENS OF MOLECULAR ABNORMALITIES SUCH AS MUTATIONS IN AML1, FLT3 AND RAS AS WELL AS EPIGENETIC ALTERATIONS OF GENES HAVE BEEN IDENTIFIED TO VARIOUS DEGREES IN MDS SUBTYPES. SOME OF THEM SEEM TO BE INVOLVED IN DISEASE INITIATION ("MASTER EVENT") AND OTHERS MIGHT INDICATE DISEASE PROGRESSION. HOWEVER, EVEN THOUGH USEFUL FOR FURTHER DISSECTION OF MOLECULAR PATHOMECHANISMS THE MAJORITY OF ABERRATIONS CURRENTLY DOES NOT SERVE AS POTENT MARKERS IN THE DAILY ROUTINE. NEVERTHELESS, IN CMPD AND MDS THE IMPORTANCE OF MOLECULAR ANALYSES FOR DIAGNOSIS, ESTIMATION OF PROGNOSIS, AND DISEASE MONITORING WILL FURTHER INCREASE IN A FORESEEABLE PERIOD OF TIME. 2007 8 2474 20 EPIGENETIC UNDERPINNINGS OF INFLAMMATION: CONNECTING THE DOTS BETWEEN PULMONARY DISEASES, LUNG CANCER AND COVID-19. INFLAMMATION IS AN ESSENTIAL COMPONENT OF SEVERAL RESPIRATORY DISEASES, SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA AND ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). IT IS CENTRAL TO LUNG CANCER, THE LEADING CANCER IN TERMS OF ASSOCIATED MORTALITY THAT HAS AFFECTED MILLIONS OF INDIVIDUALS WORLDWIDE. INFLAMMATION AND PULMONARY MANIFESTATIONS ARE ALSO THE MAJOR CAUSES OF COVID-19 RELATED DEATHS. ACUTE HYPERINFLAMMATION PLAYS AN IMPORTANT ROLE IN THE COVID-19 DISEASE PROGRESSION AND SEVERITY, AND DEVELOPMENT OF PROTECTIVE IMMUNITY AGAINST THE VIRUS IS GREATLY SOUGHT. FURTHER, THE SEVERITY OF COVID-19 IS GREATLY ENHANCED IN LUNG CANCER PATIENTS, PROBABLY DUE TO THE GENES SUCH AS ACE2, TMPRSS2, PAI-1 AND FURIN THAT ARE COMMONLY INVOLVED IN CANCER PROGRESSION AS WELL AS SAR-COV-2 INFECTION. THE IMPORTANCE OF INFLAMMATION IN PULMONARY MANIFESTATIONS, CANCER AND COVID-19 CALLS FOR A CLOSER LOOK AT THE UNDERLYING PROCESSES, PARTICULARLY THE ASSOCIATED INCREASE IN IL-6 AND OTHER CYTOKINES, THE DYSREGULATION OF IMMUNE CELLS AND THE COAGULATION PATHWAY. TOWARDS THIS END, SEVERAL REPORTS HAVE IDENTIFIED EPIGENETIC REGULATION OF INFLAMMATION AT DIFFERENT LEVELS. EXPRESSION OF SEVERAL KEY INFLAMMATION-RELATED CYTOKINES, CHEMOKINES AND OTHER GENES IS AFFECTED BY METHYLATION AND ACETYLATION WHILE NON-CODING RNAS, INCLUDING MICRORNAS AS WELL AS LONG NON-CODING RNAS, ALSO AFFECT THE OVERALL INFLAMMATORY RESPONSES. SELECT MIRNAS CAN REGULATE INFLAMMATION IN COVID-19 INFECTION, LUNG CANCER AS WELL AS OTHER INFLAMMATORY LUNG DISEASES, AND CAN SERVE AS EPIGENETIC LINKS THAT CAN BE THERAPEUTICALLY TARGETED. FURTHERMORE, EPIGENETIC CHANGES ALSO MEDIATE THE ENVIRONMENTAL FACTORS-INDUCED INFLAMMATION. THEREFORE, A BETTER UNDERSTANDING OF EPIGENETIC REGULATION OF INFLAMMATION CAN POTENTIALLY HELP DEVELOP NOVEL STRATEGIES TO PREVENT, DIAGNOSE AND TREAT CHRONIC PULMONARY DISEASES, LUNG CANCER AND COVID-19. 2022 9 778 15 CELL-FREE DNA METHYLATION: THE NEW FRONTIERS OF PANCREATIC CANCER BIOMARKERS' DISCOVERY. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS AMONG THE MOST LETHAL CANCER TYPES WORLD-WIDE. ITS HIGH MORTALITY IS RELATED TO THE DIFFICULTY IN THE DIAGNOSIS, WHICH OFTEN OCCURS WHEN THE DISEASE IS ALREADY ADVANCED. AS OF TODAY, NO EARLY DIAGNOSTIC TESTS ARE AVAILABLE, WHILE ONLY A LIMITED NUMBER OF PROGNOSTIC TESTS HAVE REACHED CLINICAL PRACTICE. THE MAIN REASON IS THE LACK OF RELIABLE BIOMARKERS THAT ARE ABLE TO CAPTURE THE EARLY DEVELOPMENT OR THE PROGRESSION OF THE DISEASE. HENCE, THE DISCOVERY OF BIOMARKERS FOR EARLY DIAGNOSIS OR PROGNOSIS OF PDAC REMAINS, DE FACTO, AN UNMET NEED. AN INCREASING NUMBER OF STUDIES HAS SHOWN THAT CELL-FREE DNA (CFDNA) METHYLATION ANALYSIS REPRESENTS A PROMISING NON-INVASIVE APPROACH FOR THE DISCOVERY OF BIOMARKERS WITH DIAGNOSTIC OR PROGNOSTIC POTENTIAL. IN PARTICULAR, CFDNA METHYLATION COULD BE UTILIZED FOR THE IDENTIFICATION OF DISEASE-SPECIFIC SIGNATURES IN PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS (CP), REPRESENTING A SENSITIVE AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PDAC. IN THIS REVIEW, WE WILL DISCUSS THE ADVANTAGES AND PITFALLS OF CFDNA METHYLATION STUDIES. FURTHER, WE WILL PRESENT THE CURRENT ADVANCES IN THE DISCOVERY OF PANCREATIC CANCER BIOMARKERS WITH EARLY DIAGNOSTIC OR PROGNOSTIC POTENTIAL, FOCUSING ON PANCREAS-SPECIFIC (E.G., CUX2 OR REG1A) OR ABNORMAL (E.G., ADAMTS1 OR BNC1) CFDNA METHYLATION SIGNATURES IN HIGH RISK PRE-NEOPLASTIC CONDITIONS AND PDAC. 2019 10 2076 15 EPIGENETIC DIFFERENCES OF CHRONIC HEPATITIS B IN DIFFERENT TCM SYNDROMES: PROTOCOL FOR A CASE-CONTROL, NON-INTERVENTIONAL, OBSERVATIONAL CLINICAL STUDY. INTRODUCTION: CHRONIC HEPATITIS B IS A SERIOUS DISEASE CAUSING SERIOUS HARM TO THE HUMAN HEALTH. CHINESE MEDICINE HAS ITS UNIQUE ADVANTAGES IN THE CLINICAL PREVENTION AND TREATMENT, WHILE THE SYNDROME OF CHINESE MEDICINE LACKS THE UNDERSTANDING AT THE MICRO LEVEL. THERE ARE SOME THEORETICAL COMMONALITIES BETWEEN THE EPIGENETICS AND TRADITIONAL CHINESE MEDICINE (TCM) SYNDROMES. THE BIOLOGICAL BASIS OF CHRONIC HEPATITIS B (CHB) SYNDROME DIFFERENTIATION FROM THE PERSPECTIVE OF EPIGENETICS IS OF GREAT SIGNIFICANCE TO DIAGNOSE AND PREVENT THE DISEASES. METHODS: THIS PROTOCOL IS A CASE-CONTROL, NONINTERVENTIONAL, OBSERVATIONAL CLINICAL STUDY. PATIENTS WITH CHB FOR SPLEEN-STOMACH DAMP HEAT AND LIVER DEPRESSION AND SPLEEN DEFICIENCY, WITH 12 EACH AND 11 HEALTHY VOLUNTEERS WERE RECRUITED. PERIPHERAL VENOUS BLOOD WAS COLLECTED FROM THE PARTICIPANTS. DNA METHYLATED TRANSFERASE, GENOMIC DNA METHYLATED SPECTRUM, METHYLATED DNA BINDING PROTEIN MECP2, CHRONIC INFECTION OF HEPATITIS B VIRUS WITH METHYLATED RELATED PROTEINS, AND MIRNA TARGET GENES WERE ANALYZED. OBJECTIVES: FROM THE PERSPECTIVE OF DNA METHYLATION EPIGENETICS, "DNA METHYLATION-MIRNA-TARGET GENE" IS THE MAIN LINE, WHICH FURTHER REVEALS THE ESSENCE OF TCM SYNDROME. TO IMPROVE THE LEVEL OF TCM CLINICAL SYNDROME DIFFERENTIATION AND THE CLINICAL EFFICACY OF TCM, ESPECIALLY IN THE STUDY OF TCM SYNDROMES OF CHB, DISCOVERING ITS UNDERLYING BIOLOGICAL SIGNATURE IS NECESSARY. TRIAL REGISTRATION: CLINICAL TRIALS REGISTRATION: CHICTR1800017365, REGISTERED 26 JULY 2018. 2018 11 3265 16 HEPATOCARCINOMA: GENETIC AND EPIGENETIC FEATURES. HCC IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE, ACCOUNTING FOR ABOUT 1 MILLION DEATHS ANNUALLY. THE INCIDENCE OF HCC IS HIGHEST IN ASIA AND AFRICA, WHERE THE ENDEMIC HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C STRONGLY PREDISPOSES TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE AND SUBSEQUENT DEVELOPMENT OF HCC. PATIENTS WITH HCC GENERALLY PRESENT AT AN ADVANCED STAGE DUE TO COMPENSATED CIRRHOSIS DEFINED BY THE ABSENCE OF PATHOGNOMONIC SYMPTOMS, RESULTING IN DEATH WITHIN 6 TO 20 MONTHS, SUGGESTING AN URGENT NEED IN TREATMENT MODALITIES THAT WILL DRAMATICALLY DECREASE THE MORTALITY RATE OF HCC. THE MOLECULAR HEPATOCARCINOGENESIS IS, HOWEVER, A GRADUAL PROCESS DURING WHICH GENETIC ALTERATIONS PROGRESSIVELY ACCUMULATE AND LEAD TO HCC THROUGH INTERMEDIATE PRENEOPLASTIC STAGES. WITH THE ADVENT OF WHOLE GENOME SEQUENCING TOOLS, VARIOUS MUTATIONS ASSOCIATED WITH HCC HAVE BEEN IDENTI FI ED, WHICH HAVE ADVANCED OUR MOLECULAR UNDERSTANDING OF HCC. HOWEVER, THE FREQUENCY OF THESE MUTATIONS IS RARE, AND THESE GENETIC MUTATIONS ONLY PARTLY EXPLAIN THE ETIOLOGY OF THE DISEASE. BETTER UNDERSTANDING AND CHARACTERIZATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS, WHICH ARE IMPORTANT TO HEPATOCARCINOGENESIS, MAY HELP UNDERSTAND THE MOLECULAR PATHOGENESIS OF HCC, AS WELL AS PROVIDING NOVEL THERAPEUTIC TARGETS FOR HCC TREATMENT. FURTHER CONSIDERATION SHOULD BE GIVEN TO DEVELOPING MORE EFFECTIVE MOLECULAR DIAGNOSTIC MARKERS AND TARGETED DRUG THERAPY. 2018 12 5406 15 REGULATING THE REGULATORS: MICRORNA AND ASTHMA. ONE OBSTACLE TO DEVELOPING AN EFFECTIVE THERAPEUTIC STRATEGY TO TREAT OR PREVENT ASTHMA IS THAT THE FUNDAMENTAL CAUSES OF ASTHMA ARE NOT TOTALLY UNDERSTOOD. ASTHMA IS THOUGHT TO BE A CHRONIC TH2 IMMUNE-MEDIATED INFLAMMATORY DISEASE. EPIGENETIC CHANGES ARE RECOGNIZED TO PLAY A ROLE IN THE INITIATION AND MAINTENANCE OF A TH2 RESPONSE. MICRORNAS (MIRNAS) ARE KEY EPIGENETIC REGULATORS OF GENE EXPRESSION, AND THEIR EXPRESSION IS HIGHLY REGULATED, THEREFORE, DEREGULATION OF MIRNAS MAY PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ASTHMA. PROFILING CIRCULATING MIRNA MIGHT PROVIDE THE HIGHEST SPECIFICITY AND SENSITIVITY TO DIAGNOSE ASTHMA; SIMILARLY, CORRECTING POTENTIAL DEFECTS IN THE MIRNA REGULATION NETWORK MAY LEAD TO NEW THERAPEUTIC MODALITIES TO TREAT THIS DISEASE. 2011 13 5787 16 SPUTUM ANALYSIS: NON-INVASIVE EARLY LUNG CANCER DETECTION. LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED DEATHS OVER THE WORLD, CHARACTERIZED BY A VERY HIGH MORTALITY RATE. MOLECULAR TECHNIQUE DEVELOPMENT TRIES TO FOCUS ON EARLY DETECTION OF CANCERS BY STUDYING MOLECULAR ALTERATIONS THAT CHARACTERIZE CANCER CELLS. WORLDWIDE LUNG CANCER RESEARCH HAS FOCUSED ON AN EVER-INCREASING NUMBER OF MOLECULAR ELEMENTS OF CARCINOGENESIS AT GENETIC, EPIGENETIC AND PROTEIN LEVELS. THE NON-INVASIVENESS IS THE CHARACTERISTIC THAT ALL CLINICAL TRIALS ON CANCER DETECTION SHOULD HAVE. ABNORMAL CHEST IMAGING AND/OR NON-SPECIFIC SYMPTOMS ARE INITIAL SIGNALS OF LUNG CANCER THAT APPEAR IN AN ADVANCED STAGE OF DISEASE. THIS FACT REPRESENTS THE CAUSE OF THE LOW 5-YEAR SURVIVAL RATE: OVER 90% OF PATIENTS DYING WITHIN 5 YEARS OF DIAGNOSIS. SINCE SMOKERS HAVE HIGHER QUANTITY OF SPUTUM CONTAINING EXFOLIATED CELLS FROM THE BRONCHIAL TREE, AND THE SPUTUM REPRESENTS THE MOST EASILY ACCESSIBLE BIOLOGICAL FLUID AND ITS COLLECTION IS NON-INVASIVE, ANALYSIS OF THIS SAMPLE REPRESENTS A GOOD AREA OF RESEARCH IN EARLY LUNG CANCER DIAGNOSIS. CONTINUED CIGARETTE SMOKING IS THE CAUSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), WITH AN ESTIMATED ATTRIBUTABLE RISK FACTOR EXCEEDING 80% IN SMOKING AFFECTED INDIVIDUALS. LUNG CANCER IS FOUND IN 40-70% OF PATIENTS WITH COPD, PARTICULARLY IN SEVERE DISEASE, AND IT IS A COMMON CAUSE OF DEATH IN THESE PATIENTS. A LARGE PROSPECTIVE TRIAL OF ALMOST HALF A MILLION NON-SMOKERS SHOWED AS LUNG CANCER IS ALSO COMMON IN PATIENTS WITH COPD WHO HAVE NEVER SMOKED. THIS REVIEW DESCRIBES ISSUES RELATED TO EARLY LUNG CANCER SCREENING USING NON-INVASIVE METHODS. 2013 14 2720 17 EXOSOMAL MIRNAS IN HEPATITIS B VIRUS RELATED LIVER DISEASE: A NEW HOPE FOR BIOMARKER. THE WORLD HEALTH ORGANISATION, IN ITS 2019 PROGRESS REPORT ON HIV, VIRAL HEPATITIS AND STDS INDICATES THAT 257 MILLION PEOPLE ARE AFFLICTED WITH CHRONIC HBV INFECTIONS, OF WHICH, 1 MILLION PATIENTS LOSE THEIR LIVES EVERY YEAR DUE TO HBV RELATED CHRONIC LIVER DISEASES INCLUDING SERIOUS COMPLICATIONS SUCH AS LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. THE COURSE OF HBV INFECTION AND ASSOCIATED LIVER INJURY DEPEND ON SEVERAL HOST FACTORS, GENETIC VARIABILITY OF THE VIRUS, AND THE HOST VIRAL INTERPLAY. THE CHALLENGE OF MEDICAL SCIENCE IS THE EARLY DIAGNOSIS/IDENTIFICATION OF THE POTENTIAL FOR DEVELOPMENT OF FATAL COMPLICATIONS LIKE LIVER CIRRHOSIS AND HCC SO THAT TIMELY MEDICAL INTERVENTION CAN IMPROVE THE CHANCES OF SURVIVAL. CURRENTLY, NEITHER THE VACCINATION REGIME NOR THE DIAGNOSTIC METHODS ARE COMPLETELY EFFECTIVE AS REFLECTED IN THE HIGH NUMBER OF ANNUAL DEATHS. IT IS EVIDENT FROM NUMEROUS PUBLICATIONS THAT MICRORNAS (MIRNAS) ARE THE CRITICAL REGULATORS OF GENE EXPRESSION AND VARIOUS CELLULAR PROCESSES LIKE PROLIFERATION, DEVELOPMENT, DIFFERENTIATION, APOPTOSIS AND TUMORIGENESIS. EXPRESSIONS OF THESE DIMINUTIVE RNAS ARE SIGNIFICANTLY AFFECTED IN CANCEROUS TISSUES AS A RESULT OF NUMEROUS GENOMIC AND EPIGENETIC MODIFICATIONS. EXOSOMES ARE MEMBRANE-DERIVED VESICLES (30-100 NM) SECRETED BY NORMAL AS WELL AS MALIGNANT CELLS, AND ARE PRESENT IN ALL BODY FLUIDS. THEY ARE RECOGNIZED AS CRITICAL MOLECULES IN INTERCELLULAR COMMUNICATION BETWEEN CELLS THROUGH HORIZONTAL TRANSFER OF INFORMATION VIA THEIR CARGO, WHICH INCLUDES SELECTIVE PROTEINS, MRNAS AND MIRNAS. EXOSOMAL MIRNAS ARE TRANSFERRED TO RECIPIENT CELLS WHERE THEY CAN REGULATE TARGET GENE EXPRESSION. THIS PROVIDES AN INSIGHT INTO THE ELEMENTARY BIOLOGY OF CANCER PROGRESSION AND THEREFORE THE DEVELOPMENT OF THERAPEUTIC APPROACHES. THIS CONCISE REVIEW OUTLINES VARIOUS ON-GOING RESEARCH ON MIRNA MEDIATED REGULATION OF HBV PATHOGENESIS WITH SPECIAL EMPHASIS ON ASSOCIATION OF EXOSOMAL MIRNA IN ADVANCED STAGE LIVER DISEASE LIKE HEPATOCELLULAR CARCINOMA. THIS REVIEW ALSO DISCUSSES THE POSSIBLE USE OF EXOSOMAL MIRNAS AS BIOMARKERS IN THE EARLY DETECTION OF HCC AND LIVER CIRRHOSIS. 2020 15 4316 16 MICRORNAS AS NON-INVASIVE DIAGNOSTIC BIOMARKERS FOR GASTRIC CANCER: CURRENT INSIGHTS AND FUTURE PERSPECTIVES. NON-INVASIVE DIAGNOSTIC BIOMARKERS MAY CONTRIBUTE TO AN EARLY IDENTIFICATION OF GASTRIC CANCER (GC) AND IMPROVE THE CLINICAL MANAGEMENT. UNFORTUNATELY, NO SENSITIVE AND SPECIFIC SCREENING BIOMARKERS ARE AVAILABLE YET AND THE CURRENTLY AVAILABLE APPROACHES ARE LIMITED BY THE NATURE OF THE DISEASE. GC IS A HETEROGENIC DISEASE WITH VARIOUS DISTINCT GENETIC AND EPIGENETIC EVENTS THAT OCCUR DURING THE MULTIFACTORIAL CASCADE OF CARCINOGENESIS. MICRORNAS (MIRNAS) ARE COMMONLY DEREGULATED IN GASTRIC MUCOSA DURING THE HELICOBACTER PYLORI INFECTION AND IN STEPWISE MANNER FROM CHRONIC GASTRITIS, THROUGH PRENEOPLASTIC CONDITIONS SUCH AS ATROPHIC GASTRITIS AND INTESTINAL METAPLASIA, TO EARLY DYSPLASIA AND INVASIVE CANCER. IDENTIFICATION OF MIRNAS IN BLOOD IN 2008 LED TO A GREAT INTEREST ON MIRNA-BASED DIAGNOSTIC, PROGNOSTIC BIOMARKERS IN GC. IN THIS REVIEW, WE PROVIDE THE MOST RECENT SYSTEMATIC REVIEW ON THE EXISTING STUDIES RELATED TO MIRNAS AS DIAGNOSTIC BIOMARKERS FOR GC. HERE, WE SYSTEMATICALLY EVALUATE 75 STUDIES RELATED TO DIFFERENTIAL EXPRESSION OF CIRCULATING MIRNAS IN GC PATIENTS AND PROVIDE NOVEL VIEW ON VARIOUS HETEROGENIC ASPECTS OF THE EXISTING DATA AND SUMMARIZE THE METHODOLOGICAL DIFFERENCES. FINALLY, WE HIGHLIGHT SEVERAL IMPORTANT ASPECTS CRUCIAL TO IMPROVE THE FUTURE TRANSLATIONAL AND CLINICAL RESEARCH IN THE FIELD. 2018 16 3925 10 LIQUID BIOPSIES BASED ON DNA METHYLATION AS BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG CANCER. LUNG CANCER (LC) IS THE MAIN CAUSE OF CANCER-RELATED MORTALITY. MOST LC PATIENTS ARE DIAGNOSED IN AN ADVANCED STAGE WHEN THE SYMPTOMS ARE OBVIOUS, AND THE PROGNOSIS IS QUITE POOR. ALTHOUGH LOW-DOSE COMPUTED TOMOGRAPHY (LDCT) IS A ROUTINE CLINICAL EXAMINATION FOR EARLY DETECTION OF LC, THE FALSE-POSITIVE RATE IS OVER 90%. AS ONE OF THE INTENSELY STUDIED EPIGENETIC MODIFICATIONS, DNA METHYLATION PLAYS A KEY ROLE IN VARIOUS DISEASES, INCLUDING CANCER AND OTHER DISEASES. HYPERMETHYLATION IN TUMOR SUPPRESSOR GENES OR HYPOMETHYLATION IN ONCOGENES IS AN IMPORTANT EVENT IN TUMORIGENESIS. REMARKABLY, DNA METHYLATION USUALLY OCCURS IN THE VERY EARLY STAGE OF MALIGNANT TUMORS. THUS, DNA METHYLATION ANALYSIS MAY PROVIDE SOME USEFUL INFORMATION ABOUT THE EARLY DETECTION OF LC. IN RECENT YEARS, LIQUID BIOPSY HAS DEVELOPED RAPIDLY. LIQUID BIOPSY CAN DETECT AND MONITOR BOTH PRIMARY AND METASTATIC MALIGNANT TUMORS AND CAN REFLECT TUMOR HETEROGENEITY. MOREOVER, IT IS A MINIMALLY INVASIVE PROCEDURE, AND IT CAUSES LESS PAIN FOR PATIENTS. THIS REVIEW SUMMARIZED VARIOUS LIQUID BIOPSIES BASED ON DNA METHYLATION FOR LC. AT FIRST, WE BRIEFLY DISCUSSED SOME EMERGING TECHNOLOGIES FOR DNA METHYLATION ANALYSIS. SUBSEQUENTLY, WE OUTLINED CELL-FREE DNA (CFDNA), SPUTUM, BRONCHOALVEOLAR LAVAGE FLUID, BRONCHIAL ASPIRATES, AND BRONCHIAL WASHINGS DNA METHYLATION-BASED LIQUID BIOPSY FOR THE EARLY DETECTION OF LC. FINALLY, THE PROGNOSTIC VALUE OF DNA METHYLATION IN CFDNA AND SPUTUM AND THE DIAGNOSTIC VALUE OF OTHER DNA METHYLATION-BASED LIQUID BIOPSIES FOR LC WERE ALSO ANALYZED. 2022 17 6370 13 THE ROLE OF MICRORNAS IN METAL CARCINOGEN-INDUCED CELL MALIGNANT TRANSFORMATION AND TUMORIGENESIS. MICRORNAS (MIRNAS), AN IMPORTANT COMPONENT OF EPIGENETIC MECHANISMS OF CARCINOGENESIS, HAVE BEEN SHOWN TO PLAY CRUCIAL ROLES IN CANCER INITIATION, METASTASIS, PROGNOSIS AND RESPONSES TO DRUG TREATMENT AND MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS OF CANCER AND TOOLS FOR CANCER THERAPY. METAL CARCINOGENS, SUCH AS ARSENIC, CADMIUM, HEXAVALENT CHROMIUM AND NICKEL, ARE WELL-ESTABLISHED HUMAN CARCINOGENS CAUSING VARIOUS CANCERS UPON LONG TERM EXPOSURE. HOWEVER, THE MECHANISM OF METAL CARCINOGENESIS HAS NOT BEEN WELL UNDERSTOOD, WHICH LIMITS OUR CAPABILITY TO EFFECTIVELY DIAGNOSE AND TREAT HUMAN CANCERS RESULTING FROM CHRONIC METAL CARCINOGEN EXPOSURE. OVER RECENT YEARS, THE ROLE OF MIRNAS IN METAL CARCINOGENESIS HAS BEEN ACTIVELY EXPLORED AND A GROWING BODY OF EVIDENCE INDICATES THE CRITICAL INVOLVEMENT OF MIRNAS IN METAL CARCINOGENESIS. THIS REVIEW AIMS TO DISCUSS RECENT STUDIES SHOWING THAT MIRNAS PLAY IMPORTANT ROLES IN METAL CARCINOGEN-INDUCED CELL MALIGNANT TRANSFORMATION AND TUMORIGENESIS. SOME THOUGHTS FOR FUTURE FURTHER STUDIES IN THIS FIELD ARE ALSO PRESENTED. 2016 18 1858 13 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 19 5233 10 PROFIBROTIC SIGNALING AND HCC RISK DURING CHRONIC VIRAL HEPATITIS: BIOMARKER DEVELOPMENT. DESPITE BREAKTHROUGHS IN ANTIVIRAL THERAPIES, CHRONIC VIRAL HEPATITIS B AND C ARE STILL THE MAJOR CAUSES OF LIVER FIBROSIS AND HEPATOCELLULAR CARCINOMA (HCC). IMPORTANTLY, EVEN IN PATIENTS WITH CONTROLLED INFECTION OR VIRAL CURE, THE CANCER RISK CANNOT BE FULLY ELIMINATED, HIGHLIGHTING A PERSISTING ONCOGENIC PRESSURE IMPOSED BY EPIGENETIC IMPRINTING AND ADVANCED LIVER DISEASE. RELIABLE AND MINIMALLY INVASIVE BIOMARKERS FOR EARLY FIBROSIS AND FOR RESIDUAL HCC RISK IN HCV-CURED PATIENTS ARE URGENTLY NEEDED. CHRONIC INFECTION WITH HBV AND/OR HCV DYSREGULATES ONCOGENIC AND PROFIBROGENIC SIGNALING WITHIN THE HOST, ALSO DISPLAYED IN THE SECRETION OF SOLUBLE FACTORS TO THE BLOOD. THE STUDY OF VIRUS-DYSREGULATED SIGNALING PATHWAYS MAY, THEREFORE, CONTRIBUTE TO THE IDENTIFICATION OF RELIABLE MINIMALLY INVASIVE BIOMARKERS FOR THE DETECTION OF PATIENTS AT EARLY-STAGE LIVER DISEASE POTENTIALLY COMPLEMENTING EXISTING NONINVASIVE METHODS IN CLINICS. WITH A FOCUS ON VIRUS-INDUCED SIGNALING EVENTS, THIS REVIEW PROVIDES AN OVERVIEW OF CANDIDATE BLOOD BIOMARKERS FOR LIVER DISEASE AND HCC RISK ASSOCIATED WITH CHRONIC VIRAL HEPATITIS AND EPIGENETIC VIRAL FOOTPRINTS. 2021 20 3271 12 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