1 778 116 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 2 4566 20 MYELOID SOMATIC MUTATION PANEL TESTING IN MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS ARE CHARACTERISED BY SOMATIC MUTATIONS IN PATHWAYS THAT REGULATE CELL PROLIFERATION, EPIGENETIC MODIFICATIONS, RNA SPLICING OR DNA REPAIR. ASSESSMENT OF THE MUTATIONAL PROFILE ASSISTS DIAGNOSIS AND CLASSIFICATION, BUT ALSO AIDS ASSESSMENT OF PROGNOSIS, AND MAY GUIDE THE USE OF EMERGING TARGETED THERAPIES. THE MOST PRACTICAL WAY TO PROVIDE INFORMATION ON NUMEROUS GENETIC VARIANTS IS BY USING MASSIVELY PARALLEL SEQUENCING, COMMONLY IN THE FORM OF DISEASE SPECIFIC NEXT GENERATION SEQUENCING (NGS) PANELS. THIS REVIEW SUMMARISES THE DIAGNOSTIC AND PROGNOSTIC VALUE OF SOMATIC MUTATION TESTING IN PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: POLYCYTHAEMIA VERA, ESSENTIAL THROMBOCYTHAEMIA, PRIMARY MYELOFIBROSIS, CHRONIC NEUTROPHILIC LEUKAEMIA, SYSTEMIC MASTOCYTOSIS, AND CHRONIC EOSINOPHILIC LEUKAEMIA. NGS PANEL TESTING IS INCREASING IN ROUTINE PRACTICE AND PROMISES TO IMPROVE THE ACCURACY AND EFFICIENCY OF PATHOLOGICAL DIAGNOSIS AND PROGNOSIS. 2021 3 4884 34 OVERVIEW OF THE PATHOGENESIS, GENETIC, AND NON-INVASIVE CLINICAL, BIOCHEMICAL, AND SCORING METHODS IN THE ASSESSMENT OF NAFLD. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST PREVALENT CHRONIC LIVER DISEASE WORLDWIDE. IT REPRESENTS A RANGE OF DISORDERS, INCLUDING SIMPLE STEATOSIS, NONALCOHOLIC STEATOHEPATITIS (NASH), AND LIVER CIRRHOSIS, AND ITS PREVALENCE CONTINUES TO RISE. IN SOME CASES, HEPATOCELLULAR CARCINOMA (HCC) MAY DEVELOP. THE DEVELOP;MENT OF NON-INVASIVE DIAGNOSTIC AND SCREENING TOOLS IS NEEDED, IN ORDER TO REDUCE THE FREQUENCY OF LIVER BIOPSIES. THE MOST PROMISING METHODS ARE THOSE ABLE TO EXCLUDE ADVANCED FIBROSIS AND QUANTIFY STEATOSIS. IN THIS STUDY, NEW PERSPECTIVE MARKERS FOR INFLAMMATION, OXIDATIVE STRESS, APOPTOSIS, AND FIBROGENESIS; EMERGING SCORING MODELS FOR DETECTING HEPATIC STEATOSIS AND FIBROSIS; AND NEW GENETIC, EPIGENETIC, AND MULTIOMIC STUDIES ARE DISCUSSED. AS ISOLATED BIOCHEMICAL PARAMETERS ARE NOT SPECIFIC OR SENSITIVE ENOUGH TO PREDICT THE PRESENCE OF NASH AND FIBROSIS, THERE IS A TENDENCY TO USE VARIOUS MARKERS AND COMBINE THEM INTO MATHEMATICAL ALGORITHMS. SEVERAL PREDICTIVE MODELS AND SCORING SYSTEMS HAVE BEEN DEVELOPED. CURRENT DATA SUGGESTS THAT PANELS OF MARKERS (NAFLD FIBROSIS SCORE, FIB-4 SCORE, BARD SCORE, AND OTHERS) ARE USEFUL DIAGNOSTIC MODALITIES TO MINIMIZE THE NUMBER OF LIVER BIOPSIES. THE REVIEW UNVEILS PATHOPHYSIOLOGICAL ASPECTS RELATED TO NEW TRENDS IN CURRENT NON-INVASIVE BIOCHEMICAL, GENETIC, AND SCORING METHODS, AND PROVIDES INSIGHT INTO THEIR DIAGNOSTIC ACCURACIES AND SUITABILITY IN CLINICAL PRACTICE. 2019 4 4334 31 MICRORNAS: NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS FOR PANCREATIC DUCTAL ADENOCARCINOMA? PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS KNOWN FOR ITS VERY POOR OVERALL PROGNOSIS, MAKING TOOLS FOR EARLY DIAGNOSIS AND NEW THERAPEUTIC MODALITIES URGENTLY NEEDED. MICRORNAS (MIRNAS), ENDOGENOUS NONCODING RNA MOLECULES OF APPROXIMATELY 22 NT, HAVE GAINED ATTENTION AS AN EPIGENETIC COMPONENT INVOLVED IN THE DEVELOPMENT OF MANY CANCERS, INCLUDING PDAC. MIRNA EXPRESSION PROFILES OF VARYING PANCREATIC TISSUES HAVE IDENTIFIED A NUMBER OF DIFFERENTIALLY EXPRESSED MIRNAS AND SEEM TO BE ABLE TO DIFFERENTIATE BETWEEN THREE TISSUES OF CLINICAL IMPORTANCE: NORMAL PANCREAS, CHRONIC PANCREATITIS, AND PDAC. THIS ARTICLE GATHERS OUR CURRENT KNOWLEDGE OF DIFFERENTIALLY EXPRESSED MIRNAS IN PANCREATIC TISSUES WITH RELEVANCE TO PDAC AND PRESENTS POTENTIAL DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES. 2009 5 1037 18 CLASSIFICATION AND DIAGNOSIS OF TEMPOROMANDIBULAR DISORDERS AND TEMPOROMANDIBULAR DISORDER PAIN. DESIGNING CLASSIFICATION SYSTEMS AND DEVELOPING DIAGNOSTIC CRITERIA FOR TEMPOROMANDIBULAR DISORDERS IS DIFFICULT. AN APPRECIATION OF THE UTILITY AND APPLICABILITY OF THESE ENTITIES REQUIRES AN UNDERSTANDING OF THE IMPORTANCE OF EACH, THE DIFFERENCES BETWEEN THE TWO, AND HOW THEY MAY BE OPTIMALLY OPERATIONALIZED FOR BOTH CLINICAL AND RESEARCH ACTIVITIES IN LIGHT OF THEIR INHERENT ADVANTAGES AND LIMITATIONS. IN ADDITION, CONSIDERATION FOR ADOPTING NEWER APPROACHES, SUCH AS FOLLOWING ONTOLOGICAL AND PRECISION-BASED MEDICINE PRINCIPLES, ACCOUNTING FOR GENETICS/EPIGENETIC AND NEUROBIOLOGICAL FACTORS, AND THE INCLUSION OF BIOMARKERS WILL POTENTIALLY RESULT IN MORE THOROUGH AND COMPREHENSIVE CLASSIFICATION SYSTEMS AND DIAGNOSTIC CRITERIA. 2023 6 4859 30 ORAL SQUAMOUS CELL CARCINOMA: DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS. OSCC IS THE MOST FREQUENT MALIGNANT TUMOUR OF THE ORAL CAVITY, ACCOUNTING FOR MORE THAN 90% OF MALIGNANT TUMOURS OF THIS ANATOMIC REGION AND IT OFTEN ARISES FROM PRECURSOR LESIONS. ASIDE FROM TOBACCO AND ALCOHOL CONSUMPTION, FURTHER DETERMINANTS HAVE BEEN CONSIDERED TO INCREASE THE RISK OF OSCC DEVELOPMENT, SUCH AS MICRONUTRIENT DEFICIENCIES, CHRONIC TRAUMATISM, POOR ORAL HYGIENE AND VIRUSES. RECURRENCE, SURVIVAL AND CONVERSELY, MORTALITY DEPENDS ON NUMEROUS AND DIFFERENT BIOLOGICAL, HISTOLOGICAL, MACROSCOPIC AND MICROSCOPIC FACTORS THAT HAVE BEEN INVESTIGATED IN ORDER TO DEFINE CAUSES, TO HELP DIAGNOSIS AND TO REFINE APPROPRIATE TREATMENTS THAT PERFECTLY FIT WITH THE DIFFERENT FEATURES OF OSCCS. FOR THIS PURPOSE, DURING THE LAST DECADES, THE IMPROVEMENT OF SCIENTIFIC TECHNOLOGIES AND MOLECULAR ANALYSES HAVE ALLOWED TO INVESTIGATE MARKERS AND GENETIC AND EPIGENETIC FACTORS, IN ORDER TO CLARIFY THEIR RESPONSIBILITIES RELATED TO EARLY DIAGNOSIS AND OSCC PROGRESSION AND PROGNOSIS IN ORDER TO ADDRESS THEM AS TARGETS IN FUTURE SELECTIVE AND INDIVIDUALLY-SHAPED THERAPIES. THIS REVIEW WILL FOCUS ON THE ETIOLOGY, ADVANCES IN DIAGNOSTIC MARKERS AND PROGNOSTIC INDICATORS FOR ORAL CANCERS. 2016 7 777 28 CELL-FREE CIRCULATING EPIGENOMIC SIGNATURES: NON-INVASIVE BIOMARKER FOR CARDIOVASCULAR AND OTHER AGE-RELATED CHRONIC DISEASES. THE BURDEN OF CARDIO-VASCULAR AND OTHER AGE-RELATED NON-COMMUNICABLE DISEASES ARE RAPIDLY INCREASING WORLDWIDE. MAJORITY OF THESE CHRONIC AILMENTS ARE CURABLE, IF DIAGNOSED AT EARLY STAGES. CANDIDATE BIOMARKERS OF EARLY DETECTION ARE THEREFORE ESSENTIAL FOR IDENTIFICATION OF HIGH-RISK INDIVIDUALS, PROMPT AND ACCURATE DISEASE DIAGNOSIS, AND TO MONITOR THERAPEUTIC RESPONSE. THE FUNCTIONAL SIGNIFICANCE OF CIRCULATING NUCLEIC ACIDS THAT RECAPITULATE SPECIFIC DISEASE PROFILES IS NOW WELL ESTABLISHED. BUT SUBTLE CHANGES IN DNA SEQUENCE MAY NOT SOLELY REFLECT THE DIFFERENTIATION OF GENE EXPRESSION PATTERNS OBSERVED IN DIVERSE SET OF DISEASES AS EPIGENETIC PHENOMENA PLAY A LARGER ROLE IN AETIOLOGY AND PATHO-PHYSIOLOGY. UNLIKE GENETIC MARKERS, KNOWLEDGE ABOUT THE DIAGNOSTIC UTILITY OF CIRCULATING EPIGENETIC SIGNATURES: METHYLATED DNA; MICRO RNA AND MODIFIED HISTONES ARE DEFICIENT. CHARACTERIZATION OF THESE NOVEL ENTITIES THROUGH OMICS-BASED MOLECULAR TECHNOLOGIES MIGHT PROMPT DEVELOPMENT OF A RANGE OF LABORATORY-BASED STRATEGIES, THEREBY ACCELERATING THEIR BROADER TRANSLATIONAL PURPOSE FOR EARLY DISEASE DIAGNOSIS, MONITORING THERAPEUTIC RESPONSE AND DRUG RESISTANCE. HOWEVER, LARGEST OPPORTUNITY FOR INNOVATION LIES IN DEVELOPING POINT-OF-CARE TESTS WITH ACCURATE DIAGNOSTIC AND HIGHER PROGNOSTIC SCORE THAT IS APPLICABLE FOR SCREENING OF HIGH-RISK POPULATIONS. 2017 8 958 30 CHRONIC MYELOMONOCYTIC LEUKEMIA - A REVIEW. INTRODUCTION: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL MYELOID NEOPLASM, DENOTED BY OVERLAPPING MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES, WITH POOR OVERALL SURVIVAL AND HIGH TRANSFORMATION RATE TO ACUTE MYELOID LEUKEMIA. AREAS COVERED: THIS REVIEW, FOLLOWING A THOROUGH MEDLINE SEARCH OF PERTINENT PUBLISHED LITERATURE, DISCUSSES THE DIAGNOSTIC CRITERIA, THE PATHOGENESIS, AND THE COMPLEX GENETIC LANDSCAPE OF THE DISEASE. PROGNOSTICATION, RESPONSE CRITERIA, THERAPEUTIC MANAGEMENT OF PATIENTS, EFFICACY OF ESTABLISHED AND NOVEL TREATMENT MODALITIES ARE THOROUGHLY REVIEWED. EXPERT OPINION: CYTOGENETIC ABNORMALITIES AND MUTATIONS IN GENES INVOLVED IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION, AND CELL-SIGNALING ARE ABUNDANT IN CMML AND IMPLICATED IN ITS COMPLEX PATHOGENESIS. AS PRESENCE OF THESE MUTATIONS CARRY A PROGNOSTIC IMPACT, THEY ARE INCREASINGLY INCORPORATED IN RISK-STRATIFICATION SCHEMES. NOVEL RESPONSE CRITERIA HAVE BEEN PROPOSED, CONSIDERING THE UNIQUE FEATURES OF THE DISEASE. ALTHOUGH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION REMAINS THE ONLY TREATMENT WITH CURATIVE INTENT, IT IS RESERVED FOR A MINORITY OF PATIENTS; THEREFORE, THERE IS AN UNMET NEED FOR OPTIMIZING TREATMENT MODALITIES, SUCH AS HYPOMETHYLATING AGENTS, AND INTRODUCING NOVEL AGENTS, WHICH COULD SUBSTANTIALLY IMPROVE SURVIVAL AND QUALITY OF LIFE OF CMML PATIENTS. CLINICAL TRIALS DEDICATED SPECIFICALLY TO CMML ARE NEEDED TO EXPLORE THE EFFICACY AND SAFETY OF NOVEL TREATMENT MODALITIES. 2021 9 4316 37 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 10 3925 35 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 11 5787 37 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 12 1055 24 CLINICAL INTEGRATION OF GENOME DIAGNOSTICS FOR CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT. REVOLUTIONS IN GENETICS, EPIGENETICS, AND BIOINFORMATICS ARE CURRENTLY CHANGING THE OUTLINE OF DIAGNOSTICS AND CLINICAL MEDICINE. FROM A NEPHROLOGIST'S PERSPECTIVE, INDIVIDUALS WITH CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) ARE AN IMPORTANT PATIENT CATEGORY: NOT ONLY IS CAKUT THE PREDOMINANT CAUSE OF KIDNEY FAILURE IN CHILDREN AND YOUNG ADULTS, BUT THE STRONG PHENOTYPIC AND GENOTYPIC HETEROGENEITY OF KIDNEY AND URINARY TRACT MALFORMATIONS HAS HAMPERED STANDARDIZATION OF CLINICAL DECISION MAKING UNTIL NOW. HOWEVER, PATIENTS WITH CAKUT MAY BENEFIT FROM PRECISION MEDICINE, INCLUDING AN INTEGRATED DIAGNOSTICS TRAJECTORY, GENETIC COUNSELING, AND PERSONALIZED MANAGEMENT TO IMPROVE CLINICAL OUTCOMES OF DEVELOPMENTAL KIDNEY AND URINARY TRACT DEFECTS. IN THIS REVIEW, WE DISCUSS THE PRESENT UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF CAKUT AND THE CURRENTLY AVAILABLE GENOME DIAGNOSTIC MODALITIES IN THE CLINICAL CARE OF PATIENTS WITH CAKUT. FINALLY, WE DISCUSS HOW CLINICAL INTEGRATION OF FINDINGS FROM LARGE-SCALE GENETIC, EPIGENETIC, AND GENE-ENVIRONMENT INTERACTION STUDIES MAY IMPROVE THE PROGNOSIS OF ALL INDIVIDUALS WITH CAKUT. 2020 13 1280 61 DECIPHERING DNA METHYLATION SIGNATURES OF PANCREATIC CANCER AND PANCREATITIS. BACKGROUND: CHRONIC PANCREATITIS PRESENTS A HIGH RISK OF INFLAMMATION-RELATED PROGRESSION TO PANCREATIC CANCER. PANCREATIC CANCER IS THE FOURTH LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE HIGH MORTALITY RATE IS DIRECTLY RELATED TO THE DIFFICULTY IN PROMPTLY DIAGNOSING THE DISEASE, WHICH OFTEN PRESENTS AS OVERT AND ADVANCED. HENCE, EARLY DIAGNOSIS FOR PANCREATIC CANCER BECOMES CRUCIAL, PROPELLING RESEARCH INTO THE MOLECULAR AND EPIGENETIC LANDSCAPE OF THE DISEASE. MAIN BODY: RECENT STUDIES HAVE SHOWN THAT CELL-FREE DNA METHYLATION PROFILES FROM INFLAMMATORY DISEASES OR CANCER CAN VARY, THUS OPENING A NEW VENUE FOR THE DEVELOPMENT OF BIOMARKERS FOR EARLY DIAGNOSIS. IN PARTICULAR, CELL-FREE DNA METHYLATION COULD BE EMPLOYED IN THE IDENTIFICATION OF PRE-NEOPLASTIC SIGNATURES IN INDIVIDUALS WITH SUSPECTED PANCREATIC CONDITIONS, REPRESENTING A SPECIFIC AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PANCREATIC CANCER. IN THIS REVIEW, WE DESCRIBE THE MOLECULAR DETERMINANTS OF PANCREATIC CANCER AND HOW THESE ARE RELATED TO CHRONIC PANCREATITIS. WE WILL THEN PRESENT AN OVERVIEW OF DIFFERENTIAL METHYLATED GENES IN THE TWO CONDITIONS, HIGHLIGHTING THEIR DIAGNOSTIC OR PROGNOSTIC POTENTIAL. CONCLUSION: EXPLOITING THE RELATION BETWEEN ABNORMALLY METHYLATED CELL-FREE DNA AND PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS MAY BECOME A GAME-CHANGING APPROACH FOR THE DEVELOPMENT OF TOOLS FOR THE EARLY DIAGNOSIS OF PANCREATIC CANCER. 2019 14 6900 32 [THE DIAGNOSTIC IMPORTANCE OF CIRCULATING MICRORNA FOR NON-ALCOHOLIC FATTY LIVER DISEASE (REVIEW OF LITERATURE).]. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASES IN THE WORLD. THE BIOPSY IS REQUIRED TO CONFIRM THE DIAGNOSIS BUT DUE TO ITS INVASIVENESS, THIS PROCEDURE IS NOT SUITABLE FOR THE MASSIVE SCREENING. THERE ARE LABORATORY CRITERIA OF PRIMARY MEDICAL EXAMINATION OF THE PATIENTS WHO ARE SUSPECTED TO HAVE NAFLD THAT ALLOW DIAGNOSING THE PATHOLOGICAL PROCESS, BUT THESE CRITERIA DO NOT COMPLY WITH CLINICIANS' REQUIREMENTS. AT THE SAME TIME, IT IS CRUCIAL TO IDENTIFY THE PATIENTS IN THE INITIAL STAGES OF NAFLD. RECENTLY, THE ATTENTION OF THE SCIENTISTS WAS CONCENTRATED ON THE RESEARCH OF THE MECHANISM OF NAFLD DEVELOPMENT AND NEW DIAGNOSTIC APPROACHES. ACCUMULATING RESULTS OF THIS RESEARCH SHOW THAT NAFLD DEVELOPMENT IS REGULATED WITH EPIGENETIC FACTORS, INCLUDING MICRORNAS FAMILY (MICRORNA, MIR), THAT MAY HAVE HIGH DIAGNOSTIC AND PROGNOSTIC VALUE. IN THIS REVIEW, DATA EXTRACTED FROM PUBMED ARE USED TO DISCUSS THE POTENTIAL ROLE OF MICRORNA IN THE LIVER LIPID METABOLISM AND FATTY LIVER DISEASE. THE POSSIBILITIES OF MICRO RNA (MIR-16, MIR-21, MIR-34A, MIR-103, MIR-122, MIR-145, MIR-192, AND OTHERS) USE AS PROSPECTIVE BIOMARKERS FOR LOW-INVASIVE NAFLD DIAGNOSTIC, EVALUATION OF STEATOSIS ACTIVITY AND FIBROSIS SCORE AND STAGES, AND PROGNOSTIC MARKERS OF THE DISEASE ARE REVIEWED. THIS RESEARCH DISCUSSES THE ANALYTICAL CHARACTERISTICS, BENEFITS AND POSSIBLE LIMITATIONS OF THEIR USE IN THE CLINICAL PRACTICE. THE PRELIMINARY DATA ALLOW CLAIMING THAT SOME MICRORNAS ARE EXTREMELY PERSPECTIVE LOW-INVASIVE DIAGNOSTIC INSTRUMENT AND FURTHER RESEARCH IS REQUIRED TO INVESTIGATE THE IMPACT OF CERTAIN MICRORNAS IN THE PATHOGENETIC MECHANISM OF NAFLD DEVELOPMENT. 2019 15 3575 37 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 16 3265 29 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 17 3022 30 GENETICS AND EPIGENETICS PURPOSE IN NONALCOHOLIC FATTY LIVER DISEASE. INTRODUCTION: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) COMPRISES A BROAD SPECTRUM OF DISEASES, WHICH CAN PROGRESS FROM BENIGN STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE IN DEVELOPED COUNTRIES, AFFECTING APPROXIMATELY 25% OF THE GENERAL POPULATION. INSULIN RESISTANCE, ADIPOSE TISSUE DYSFUNCTION, MITOCHONDRIAL AND ENDOPLASMIC RETICULUM STRESS, CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS ARE NAFLD TRIGGERS THAT CONTROL THE DISEASE SUSCEPTIBILITY AND PROGRESSION. AREAS COVERED: IN RECENT YEARS A LARGE NUMBER OF INVESTIGATIONS HAVE BEEN CARRIED OUT TO ELUCIDATE GENETIC AND EPIGENETIC FACTORS IN THE DISEASE PATHOGENESIS, AS WELL AS THE SEARCH FOR DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS. THIS PAPER OBJECTIVE IS TO REPORT THE MOST STUDIED GENETIC AND EPIGENETIC VARIANTS AROUND NAFLD. EXPERT OPINION: NAFLD LEAD TO VARIOUS COMORBIDITIES, WHICH HAVE A CONSIDERABLE IMPACT ON THE PATIENT WELLNESS AND LIFE QUALITY, AS WELL AS ON THE COSTS THEY GENERATE FOR THE COUNTRY'S HEALTH SERVICES. IT IS ESSENTIAL TO CONTINUE WITH MOLECULAR RESEARCH, SINCE IT COULD BE USED AS A CLINICAL TOOL FOR PROGNOSIS AND DISEASE SEVERITY. SPECIFICALLY, IN THE FIELD OF HEPATOLOGY, PLASMA MIRNAS COULD PROVIDE A NOVEL TOOL IN LIVER DISEASES DIAGNOSIS AND MONITORING, REPRESENTING AN ALTERNATIVE TO INVASIVE DIAGNOSTIC PROCEDURES. 2020 18 2015 40 EPIGENETIC BIOMARKERS IN ESOPHAGEAL CANCER. THE ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES IS WELL DOCUMENTED IN ESOPHAGEAL CANCER, INCLUDING ADENOCARCINOMA (EAC) AND SQUAMOUS CELL CARCINOMA (ESCC) AS WELL AS IN BARRETT'S ESOPHAGUS (BE), A PRE-MALIGNANT CONDITION THAT IS ASSOCIATED WITH CHRONIC ACID REFLUX. BE IS A WELL-RECOGNIZED RISK FACTOR FOR THE DEVELOPMENT OF EAC, AND CONSEQUENTLY THE STANDARD OF CARE IS FOR INDIVIDUALS WITH BE TO BE PLACED IN ENDOSCOPIC SURVEILLANCE PROGRAMS AIMED AT DETECTING EARLY HISTOLOGIC CHANGES THAT ASSOCIATE WITH AN INCREASED RISK OF DEVELOPING EAC. YET BECAUSE THE ABSOLUTE RISK OF EAC IN INDIVIDUALS WITH BE IS MINIMAL, A CLINICAL NEED IN THE MANAGEMENT OF BE IS THE IDENTIFICATION OF ADDITIONAL RISK MARKERS THAT WILL INDICATE INDIVIDUALS WHO ARE AT A SIGNIFICANT ABSOLUTE RISK OF EAC SO THAT THEY MAY BE SUBJECTED TO MORE INTENSIVE SURVEILLANCE. THE BEST CURRENTLY AVAILABLE RISK MARKER IS THE DEGREE OF DYSPLASIA IN ENDOSCOPIC BIOPSIES FROM THE ESOPHAGUS; HOWEVER, THIS MARKER IS SUBOPTIMAL FOR A VARIETY OF REASONS. TO DATE, THERE ARE NO MOLECULAR BIOMARKERS THAT HAVE BEEN TRANSLATED TO WIDESPREAD CLINICAL PRACTICE. THE SEARCH FOR BIOMARKERS, INCLUDING HYPERMETHYLATED GENES, FOR EITHER THE DIAGNOSIS OF BE, EAC, OR ESCC OR FOR RISK STRATIFICATION FOR THE DEVELOPMENT OF EAC IN THOSE WITH BE IS CURRENTLY AN AREA OF ACTIVE RESEARCH. IN THIS REVIEW, WE SUMMARIZE THE STATUS OF IDENTIFIED CANDIDATE EPIGENETIC BIOMARKERS FOR BE, EAC, AND ESCC. MOST OF THESE ABERRANTLY METHYLATED GENES HAVE BEEN DESCRIBED IN THE CONTEXT OF EARLY DETECTION OR DIAGNOSTIC MARKERS; OTHERS MIGHT PROVE USEFUL FOR ESTIMATING PROGNOSIS OR PREDICTING RESPONSE TO TREATMENT. FINALLY, SPECIAL ATTENTION WILL BE PAID TO SOME OF THE CHALLENGES THAT MUST BE OVERCOME IN ORDER TO DEVELOP CLINICALLY USEFUL ESOPHAGEAL CANCER BIOMARKERS. 2014 19 5772 38 SPECTRUM, SCREENING, AND DIAGNOSIS OF ALCOHOL-RELATED LIVER DISEASE. ALCOHOL-RELATED LIVER DISEASE (ALD) REPRESENTS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASE AND IS A MAJOR CAUSE OF LIVER-RELATED DEATHS WORLDWIDE. ALD ENCOMPASSES A RANGE OF DISORDERS INCLUDING SIMPLE STEATOSIS, ALCOHOLIC STEATOHEPATITIS, FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. PATIENTS WITH UNDERLYING ALD AND CONTINUED HEAVY ALCOHOL CONSUMPTION CAN ALSO DEVELOP AN EPISODE OF ACUTE-ON-CHRONIC LIVER INJURY CALLED ALCOHOL-ASSOCIATED HEPATITIS, THE MOST SEVERE FORM OF THE DISEASE, WHICH PORTENDS A POOR PROGNOSIS. THE MOST IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF ALD IS THE AMOUNT OF ALCOHOL CONSUMED. INDIVIDUAL SUSCEPTIBILITY TO PROGRESSION TO ADVANCED FIBROSIS AMONG HEAVY DRINKERS IS LIKELY DETERMINED BY A COMBINATION OF BEHAVIORAL, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS, BUT THE MECHANISMS ARE LARGELY UNKNOWN. THE ONLY EFFECTIVE THERAPY FOR ALD IS PROLONGED ALCOHOL ABSTINENCE. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. IN CLINICAL PRACTICE, THE HISTOLOGICAL ASSESSMENT FOR ALD DIAGNOSIS IS UNCOMMON, AND IT IS USUALLY BASED ON THE MEDICAL HISTORY, CLINICAL MANIFESTATIONS, AND LABORATORY AND IMAGING TESTS. SEVERAL PROMISING BIOMARKERS THAT CAN HAVE BOTH DIAGNOSTIC AND PROGNOSTIC VALUE IN PATIENTS WITH ALD HAVE BEEN IDENTIFIED IN RECENT YEARS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CLINICAL SPECTRUM OF ALD, THE DIAGNOSTIC APPROACH OF THE DISEASE FROM DIFFERENT PERSPECTIVES AS WELL AS CURRENT DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. 2023 20 5025 28 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017