1 4707 129 NMR PLASMA METABOLOMICS STUDY OF PATIENTS OVERCOMING ACUTE MYOCARDIAL INFARCTION: IN THE FIRST 12 H AFTER ONSET OF CHEST PAIN WITH STATISTICAL DISCRIMINATION TOWARDS METABOLOMIC BIOMARKERS. ACUTE MYOCARDIAL INFARCTION (AMI) IS ONE OF THE LEADING CAUSES OF DEATH AMONG ADULTS IN OLDER AGE. UNDERSTANDING MECHANISMS HOW ORGANISM RESPONDS TO ISCHEMIA IS ESSENTIAL FOR THE ISCHEMIC PATIENT'S PREVENTION AND TREATMENT. DESPITE THE GREAT PREVALENCE AND INCIDENCE ONLY A SMALL NUMBER OF STUDIES UTILIZE A METABOLOMIC APPROACH TO DESCRIBE AMI CONDITION. RECENT STUDIES HAVE SHOWN THE IMPACT OF METABOLITES ON EPIGENETIC CHANGES, IN THESE STUDIES PLASMA METABOLITES WERE RELATED TO NEUROLOGICAL OUTCOME OF THE PATIENTS MAKING METABOLOMIC STUDIES INCREASINGLY INTERESTING. THE AIM OF THIS STUDY WAS TO DESCRIBE METABOLOMIC RESPONSE OF AN ORGANISM TO ISCHEMIC STRESS THROUGH THE CHANGES IN ENERGETIC METABOLITES AND AMINOACIDS IN BLOOD PLASMA IN PATIENTS OVERCOMING ACUTE MYOCARDIAL INFARCTION. BLOOD PLASMA FROM PATIENTS IN THE FIRST 12 H AFTER ONSET OF CHEST PAIN WAS COLLECTED AND COMPARED WITH VOLUNTEERS WITHOUT ANY HISTORY OF ISCHEMIC DISEASES VIA NMR SPECTROSCOPY. LOWERED PLASMA LEVELS OF PYRUVATE, ALANINE, GLUTAMINE AND NEUROTRANSMITTER PRECURSORS TYROSINE AND TRYPTOPHAN WERE FOUND. FURTHER, WE OBSERVED INCREASED PLASMA LEVELS OF 3-HYDROXYBUTYRATE AND ACETOACETATE IN BALANCE WITH DECREASED LEVEL OF LIPOPROTEINS FRACTION, SUGGESTING THE ONGOING KETONIC STATE OF AN ORGANISM. DISCRIMINATORY ANALYSIS SHOWED VERY PROMISING PERFORMANCE WHERE COMPOUNDS: LIPOPROTEINS, ALANINE, PYRUVATE, GLUTAMINE, TRYPTOPHAN AND 3-HYDROXYBUTYRATE WERE OF THE HIGHEST DISCRIMINATORY POWER WITH FEASIBILITY OF SUCCESSFUL STATISTICAL DISCRIMINATION. 2020 2 3608 29 IN SEARCH FOR GENES RELATED TO ATHEROSCLEROSIS AND DYSLIPIDEMIA USING ANIMAL MODELS. ATHEROSCLEROSIS IS A MULTIFACTORIAL CHRONIC DISEASE THAT AFFECTS LARGE ARTERIES AND MAY LEAD TO FATAL CONSEQUENCES. ACCORDING TO CURRENT UNDERSTANDING, INFLAMMATION AND LIPID ACCUMULATION ARE THE TWO KEY MECHANISMS OF ATHEROSCLEROSIS DEVELOPMENT. ANIMAL MODELS BASED ON GENETICALLY MODIFIED MICE HAVE BEEN DEVELOPED TO INVESTIGATE THESE ASPECTS. ONE SUCH MODEL IS LOW-DENSITY LIPOPROTEIN (LDL) RECEPTOR KNOCKOUT (KO) MICE (LDLR(-/-)), WHICH ARE CHARACTERIZED BY A MODERATE INCREASE OF PLASMA LDL CHOLESTEROL LEVELS. ANOTHER WIDELY USED GENETICALLY MODIFIED MOUSE STRAIN IS APOLIPOPROTEIN-E KO MICE (APOE(-/-)) THAT LACKS THE PRIMARY LIPOPROTEIN REQUIRED FOR THE UPTAKE OF LIPOPROTEINS THROUGH THE HEPATIC RECEPTORS, LEADING TO EVEN GREATER PLASMA CHOLESTEROL INCREASE THAN IN LDLR(-/-) MICE. THESE AND OTHER ANIMAL MODELS ALLOWED FOR CONDUCTING GENETIC STUDIES, SUCH AS GENOME-WIDE ASSOCIATION STUDIES, MICROARRAYS, AND GENOTYPING METHODS, WHICH HELPED IDENTIFYING MORE THAN 100 MUTATIONS THAT CONTRIBUTE TO ATHEROSCLEROSIS DEVELOPMENT. HOWEVER, TRANSLATION OF THE RESULTS OBTAINED IN ANIMAL MODELS FOR HUMAN SITUATIONS WAS SLOW AND CHALLENGING. AT THE SAME TIME, GENETIC STUDIES CONDUCTED IN HUMANS WERE LIMITED BY LOW SAMPLE SIZES AND HIGH HETEROGENEITY IN PREDICTIVE SUBCLINICAL PHENOTYPES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE ON THE USE OF KO MICE FOR IDENTIFICATION OF GENES IMPLICATED IN ATHEROSCLEROSIS AND PROVIDE A LIST OF GENES INVOLVED IN ATHEROSCLEROSIS-ASSOCIATED INFLAMMATORY PATHWAYS AND THEIR BRIEF CHARACTERISTICS. MOREOVER, WE DISCUSS THE APPROACHES FOR CANDIDATE GENE SEARCH IN ANIMALS AND HUMANS AND DISCUSS THE PROGRESS MADE IN THE FIELD OF EPIGENETIC STUDIES THAT APPEAR TO BE PROMISING FOR IDENTIFICATION OF NOVEL BIOMARKERS AND THERAPEUTIC TARGETS. 2020 3 250 33 ADVANCED GLYCATION END PRODUCTS (AGES): BIOCHEMISTRY, SIGNALING, ANALYTICAL METHODS, AND EPIGENETIC EFFECTS. THE ADVANCED GLYCATION END PRODUCTS (AGES) ARE ORGANIC MOLECULES FORMED IN ANY LIVING ORGANISMS WITH A GREAT VARIETY OF STRUCTURAL AND FUNCTIONAL PROPERTIES. THEY ARE CONSIDERED ORGANIC MARKERS OF THE GLYCATION PROCESS. DUE TO THEIR GREAT HETEROGENEITY, THERE IS NO SPECIFIC TEST FOR THEIR OPERATIONAL MEASUREMENT. IN THIS REVIEW, WE HAVE UPDATED THE MOST COMMON CHROMATOGRAPHIC, COLORIMETRIC, SPECTROSCOPIC, MASS SPECTROMETRIC, AND SEROLOGICAL METHODS, TYPICALLY USED FOR THE DETERMINATION OF AGES IN BIOLOGICAL SAMPLES. WE HAVE DESCRIBED THEIR SIGNALING AND SIGNAL TRANSDUCTION MECHANISMS AND CELL EPIGENETIC EFFECTS. ALTHOUGH MASS SPECTROMETRIC ANALYSIS IS NOT WIDESPREAD IN THE DETECTION OF AGES AT THE CLINICAL LEVEL, THIS TECHNIQUE IS HIGHLY PROMISING FOR THE EARLY DIAGNOSIS AND THERAPEUTICS OF DISEASES CAUSED BY AGES. PROTOCOLS ARE AVAILABLE FOR HIGH-RESOLUTION MASS SPECTROMETRY OF GLYCATED PROTEINS ALTHOUGH THEY ARE CHARACTERIZED BY COMPLEX MACHINE MANAGEMENT. SIMPLER PROCEDURES ARE AVAILABLE ALTHOUGH MUCH LESS PRECISE THAN MASS SPECTROMETRY. AMONG THEM, IMMUNOCHEMICAL TESTS ARE VERY COMMON SINCE THEY ARE ABLE TO DETECT AGES IN A SIMPLE AND IMMEDIATE WAY. IN THESE YEARS, NEW METHODOLOGIES HAVE BEEN DEVELOPED USING AN IN VIVO NOVEL AND NONINVASIVE SPECTROSCOPIC METHODS. THESE METHODS ARE BASED ON THE MEASUREMENT OF AUTOFLUORESCENCE OF AGES. ANOTHER METHOD CONSISTS OF DETECTING AGES IN THE HUMAN SKIN TO DETECT CHRONIC EXPOSURE, WITHOUT THE INCONVENIENCE OF INVASIVE METHODS. THE AIM OF THIS REVIEW IS TO COMPARE THE DIFFERENT APPROACHES OF MEASURING AGES AT A CLINICAL PERSPECTIVE DUE TO THEIR STRICT ASSOCIATION WITH OXIDATIVE STRESS AND INFLAMMATION. 2020 4 6159 30 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 5 6013 30 THE APPLICATIONS OF DNA METHYLATION AS A BIOMARKER IN KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW. BACKGROUND: ALTHOUGH KIDNEY TRANSPLANTATION IMPROVES PATIENT SURVIVAL AND QUALITY OF LIFE, LONG-TERM RESULTS ARE HAMPERED BY BOTH IMMUNE- AND NON-IMMUNE-MEDIATED COMPLICATIONS. CURRENT BIOMARKERS OF POST-TRANSPLANT COMPLICATIONS, SUCH AS ALLOGRAFT REJECTION, CHRONIC RENAL ALLOGRAFT DYSFUNCTION, AND CUTANEOUS SQUAMOUS CELL CARCINOMA, HAVE A SUBOPTIMAL PREDICTIVE VALUE. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT DIRECTLY AFFECTS GENE EXPRESSION AND PLAYS AN IMPORTANT ROLE IN PROCESSES SUCH AS ISCHEMIA/REPERFUSION INJURY, FIBROSIS, AND ALLOREACTIVE IMMUNE RESPONSE. NOVEL TECHNIQUES CAN QUICKLY ASSESS THE DNA METHYLATION STATUS OF MULTIPLE LOCI IN DIFFERENT CELL TYPES, ALLOWING A DEEP AND INTERESTING STUDY OF CELLS' ACTIVITY AND FUNCTION. THEREFORE, DNA METHYLATION HAS THE POTENTIAL TO BECOME AN IMPORTANT BIOMARKER FOR PREDICTION AND MONITORING IN KIDNEY TRANSPLANTATION. PURPOSE OF THE STUDY: THE AIM OF THIS STUDY WAS TO EVALUATE THE ROLE OF DNA METHYLATION AS A POTENTIAL BIOMARKER OF GRAFT SURVIVAL AND COMPLICATIONS DEVELOPMENT IN KIDNEY TRANSPLANTATION. MATERIAL AND METHODS: A SYSTEMATIC REVIEW OF SEVERAL DATABASES HAS BEEN CONDUCTED. THE NEWCASTLE-OTTAWA SCALE AND THE JADAD SCALE HAVE BEEN USED TO ASSESS THE RISK OF BIAS FOR OBSERVATIONAL AND RANDOMIZED STUDIES, RESPECTIVELY. RESULTS: TWENTY ARTICLES REPORTING ON DNA METHYLATION AS A BIOMARKER FOR KIDNEY TRANSPLANTATION WERE INCLUDED, ALL USING DNA METHYLATION FOR PREDICTION AND MONITORING. DNA METHYLATION PATTERN ALTERATIONS IN CELLS ISOLATED FROM DIFFERENT TISSUES, SUCH AS KIDNEY BIOPSIES, URINE, AND BLOOD, HAVE BEEN ASSOCIATED WITH ISCHEMIA-REPERFUSION INJURY AND CHRONIC RENAL ALLOGRAFT DYSFUNCTION. THESE ALTERATIONS OCCURRED IN DIFFERENT AND SPECIFIC LOCI. DNA METHYLATION STATUS HAS ALSO PROVED TO BE IMPORTANT FOR IMMUNE RESPONSE MODULATION, HAVING A CRUCIAL ROLE IN REGULATORY T CELL DEFINITION AND ACTIVITY. RESEARCH ALSO FOCUSED ON A BETTER UNDERSTANDING OF THE ROLE OF THIS EPIGENETIC MODIFICATION ASSESSMENT FOR REGULATORY T CELLS ISOLATION AND EXPANSION FOR FUTURE TOLERANCE INDUCTION-ORIENTED THERAPIES. CONCLUSIONS: STUDIES INCLUDED IN THIS REVIEW ARE HETEROGENEOUS IN STUDY DESIGN, BIOLOGICAL SAMPLES, AND OUTCOME. MORE COORDINATED INVESTIGATIONS ARE NEEDED TO AFFIRM DNA METHYLATION AS A CLINICALLY RELEVANT BIOMARKER IMPORTANT FOR PREVENTION, MONITORING, AND INTERVENTION. 2022 6 5303 27 PROTEOME DATA OF SERUM SAMPLES FROM PATIENTS WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A COMPLEX CHRONIC DISEASE. THE MOLECULAR DETERMINANTS AND NEUROPATHOLOGY OF SCHIZOPHRENIA ARE MULTIFACETED; AN IMPORTANT ROLE IN THE PATHOGENESIS IS PLAYED BY THE DYSREGULATION OF MOLECULAR AND EPIGENETIC MECHANISMS. HOWEVER, THE MOLECULAR MECHANISMS OF THE DEVELOPMENT OF THE DISEASE HAVE NOT YET BEEN STUDIED. AN IMPORTANT TASK IS THE ACCUMULATION AND SYSTEMATIZATION OF "OMICS"-KNOWLEDGE OF THE MOLECULAR PROFILES (TRANSCRIPTOME, PROTEOME, METABOLOME) OF BLOOD SPECIFIC TO PATHOLOGY. THEREBY THE DEVELOPMENT AND IMPROVEMENT OF MASS SPECTROMETRIC METHODS FOR THE DETECTION OF BIOLOGICAL MOLECULES HAS BECOME INCREASINGLY IMPORTANT IN BIOMEDICAL RESEARCH. IN THE FIELD OF APPLIED PROBLEMS IN BIOMEDICAL RESEARCH, THE MOST PREVALENT ISSUE INVOLVES THE IDENTIFICATION OF SEROLOGICAL PROTEIN MARKERS ASSOCIATED WITH THE DEVELOPMENT OF SCHIZOPHRENIA, WHICH ACCOUNT FOR THE DISEASES THAT CAUSE THE A LIFE-SHORTENING ILLNESS, DISABILITY, DECREASED OF FUNCTIONING AND QUALITY OF LIFE AND WELLBEING OR HEALTH STATUS. OMICS APPROACHES ARE DESIGNED TO DETECT GENES (GENOMICS), MRNA (TRANSCRIPTOMICS), PROTEINS (PROTEOMICS) AND METABOLITES (METABOLOMICS) IN A SPECIFIC BIOLOGICAL SAMPLE. WE REPORT THE PROTEOMIC DATASETS ON THE SERUM SAMPLES FROM PATIENTS WITH SCHIZOPHRENIA (SERIES "SCZ") AND HEALTHY VOLUNTEERS (SERIES "CNT"). DATA WERE ACQUIRED USING SHOTGUN ULTRA-HIGH RESOLUTION MASS SPECTROMETRY. 2020 7 1844 32 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016 8 3994 31 LONGITUDINAL PROFILING IN PATIENTS UNDERGOING CARDIAC SURGERY REVEALS POSTOPERATIVE CHANGES IN DNA METHYLATION. BACKGROUND: CARDIAC SURGERY AND CARDIOPULMONARY BYPASS INDUCE A SUBSTANTIAL IMMUNE AND INFLAMMATORY RESPONSE, THE OVERACTIVATION OF WHICH IS ASSOCIATED WITH SIGNIFICANT PULMONARY, CARDIOVASCULAR, AND NEUROLOGIC COMPLICATIONS. COMMENSURATE WITH THE IMMUNE AND INFLAMMATORY RESPONSE ARE CHANGES IN THE HEART AND VASCULATURE ITSELF, WHICH TOGETHER DRIVE POSTOPERATIVE COMPLICATIONS THROUGH MECHANISMS THAT ARE POORLY UNDERSTOOD. LONGITUDINAL DNA METHYLATION PROFILING HAS THE POTENTIAL TO IDENTIFY CHANGES IN GENE REGULATORY MECHANISMS THAT ARE SECONDARY TO SURGERY AND TO IDENTIFY MOLECULAR PROCESSES THAT PREDICT AND/OR CAUSE POSTOPERATIVE COMPLICATIONS. IN THIS STUDY, WE MEASURE DNA METHYLATION IN PREOPERATIVE AND POSTOPERATIVE WHOLE BLOOD SAMPLES FROM 96 PATIENTS UNDERGOING CARDIAC SURGERY ON CARDIOPULMONARY BYPASS. RESULTS: WHILE THE VAST MAJORITY OF DNA METHYLATION IS UNCHANGED BY SURGERY AFTER ACCOUNTING FOR CHANGES IN CELL-TYPE COMPOSITION, WE IDENTIFY SEVERAL LOCI WITH STATISTICALLY SIGNIFICANT POSTOPERATIVE CHANGES IN METHYLATION. ADDITIONALLY, TWO OF THESE LOCI ARE ASSOCIATED WITH NEW-ONSET POSTOPERATIVE ATRIAL FIBRILLATION, A SIGNIFICANT COMPLICATION AFTER CARDIAC SURGERY. PAIRED STATISTICAL ANALYSIS, USE OF FACS DATA TO SUPPORT SUFFICIENT CONTROL OF CELL-TYPE HETEROGENEITY, AND MEASUREMENT OF IL6 LEVELS IN A SUBSET OF PATIENTS ADD RIGOR TO THIS ANALYSIS, ALLOWING US TO DISTINGUISH CELL-TYPE VARIABILITY FROM ACTUAL CHANGES IN METHYLATION. CONCLUSIONS: THIS STUDY IDENTIFIES SIGNIFICANT CHANGES IN DNA METHYLATION THAT OCCUR IMMEDIATELY AFTER CARDIAC SURGERY AND DEMONSTRATES THAT THESE ACUTE ALTERATIONS IN DNA METHYLATION HAVE THE GRANULARITY TO IDENTIFY PROCESSES ASSOCIATED WITH MAJOR POSTOPERATIVE COMPLICATIONS. THIS RESEARCH ALSO ESTABLISHES METHODS FOR CONTROLLING FOR CELL-TYPE VARIABILITY IN A LARGE HUMAN COHORT THAT MAY BE USEFUL TO DEPLOY IN OTHER LONGITUDINAL STUDIES OF EPIGENETIC MARKS IN THE SETTING OF ACUTE AND CHRONIC DISEASE. 2022 9 5618 24 SARS-COV-2 INTERACTION WITH HUMAN DNA METHYL TRANSFERASE 1: A POTENTIAL RISK FOR INCREASING THE INCIDENCE OF LATER CHRONIC DISEASES IN THE SURVIVED PATIENTS. CURRENTLY, THE COVID-19 PANDEMIC IS THE MOST DISCUSSED SUBJECT IN MEDICAL RESEARCHES WORLDWIDE. AS THE KNOWLEDGE IS EXPANDED ABOUT THE DISEASE, MORE HYPOTHESES BECOME CREATED. A RECENT STUDY ON THE VIRAL PROTEIN INTERACTION MAP REVEALED THAT SARS-COV-2 OPEN READING FRAME 8 (ORF8) INTERACTS WITH HUMAN DNA METHYL TRANSFERASE1 (DNMT1), AN ACTIVE EPIGENETIC AGENT IN DNA METHYLATION. MOREOVER, DNMT1 IS A CONTRIBUTOR TO A VARIETY OF CHRONIC DISEASES WHICH COULD CAUSE SOME EPIGENETIC DYSREGULATION IN INFECTED CELLS, ESPECIALLY LEUKOCYTES, PANCREATIC BETA, AND ENDOTHELIAL CELLS. REGARDING THE FACT THAT EPIGENETIC ALTERATIONS HAVE A PARTIAL, BUT NOT COMPLETELY REVERSIBLE PHENOMENA, IT RAISES THE QUESTION THAT IF THIS INTERACTION MAY CAUSE LONG-TERM COMPLICATIONS SUCH AS DIABETES, ATHEROSCLEROSIS, CANCER, AND AUTOIMMUNE DISEASES. ACCORDINGLY, LONG FOLLOW-UP STUDIES ON THE RECOVERED PATIENTS FROM COVID-19 ARE RECOMMENDED. 2022 10 822 23 CHARACTERIZATION OF BLOOD SURROGATE IMMUNE-METHYLATION BIOMARKERS FOR IMMUNE CELL INFILTRATION IN CHRONIC INFLAMMAGING DISORDERS. ALZHEIMER'S DISEASE (AD) AND ATHEROSCLEROSIS ARE BOTH CHRONIC AGE- AND INFLAMMATION-DEPENDENT DISEASES. IN ADDITION, ATHEROSCLEROSIS IS FREQUENTLY OBSERVED IN AD PATIENTS INDICATING COMMON INVOLVEMENT OF VASCULAR COMPONENTS IN BOTH DISEASE ETIOLOGIES. RECENTLY, EPIGENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED EPIGENETIC ALTERATIONS, AND IN PARTICULARLY DNA METHYLATION CHANGES FOR BOTH DISORDERS. WE HYPOTHESIZED THE EXISTENCE OF A COMMON DNA METHYLATION PROFILE IN ATHEROSCLEROSIS AND AD WHICH MAY BE VALUABLE AS A BLOOD-BASED DNA METHYLATION INFLAMMAGING BIOMARKER. USING PUBLICLY AVAILABLE 450K ILLUMINA METHYLATION DATASETS, WE IDENTIFIED A CO-METHYLATION NETWORK ASSOCIATED WITH BOTH ATHEROSCLEROSIS AND AD IN WHOLE BLOOD SAMPLES. THIS METHYLATION PROFILE APPEARED TO INDICATE SHIFTS IN BLOOD IMMUNE CELL TYPE DISTRIBUTION. REMARKABLY, SIMILAR METHYLATION CHANGES WERE ALSO DETECTED IN DISEASE TISSUES, INCLUDING AD BRAIN TISSUES, ATHEROSCLEROTIC PLAQUES, AND TUMORS AND WERE FOUND TO CORRELATE WITH IMMUNE CELL INFILTRATION. IN ADDITION, THIS IMMUNE-RELATED METHYLATION PROFILE COULD ALSO BE DETECTED IN OTHER INFLAMMAGING DISEASES, INCLUDING PARKINSON'S DISEASE AND OBESITY, BUT NOT IN MULTIPLE SCLEROSIS, SCHIZOPHRENIA, AND OSTEOPOROSIS. IN CONCLUSION, WE IDENTIFIED A BLOOD-BASED IMMUNE-RELATED DNA METHYLATION SIGNATURE IN MULTIPLE INFLAMMAGING DISEASES ASSOCIATED WITH CHANGES IN BLOOD IMMUNE CELL COUNTS AND PREDICTIVE FOR IMMUNE CELL INFILTRATION IN DISEASED TISSUES. IN ADDITION TO EPIGENETIC CLOCK MEASUREMENTS, THIS IMMUNE-METHYLATION SIGNATURE MAY BECOME A VALUABLE BLOOD-BASED BIOMARKER TO PREVENT CHRONIC INFLAMMATORY DISEASE DEVELOPMENT OR MONITOR LIFESTYLE INTERVENTION STRATEGIES WHICH PROMOTE HEALTHY AGING. 2019 11 1599 31 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 12 5894 32 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 13 728 30 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 14 2507 26 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 15 2093 27 EPIGENETIC EFFECTS FOLLOWING ACUTE AND CHRONIC EXERCISE IN CARDIOVASCULAR DISEASE: A SYSTEMATIC REVIEW. INTRODUCTION: ACUTE EXERCISE AND EXERCISE TRAINING MAY CONFER EPIGENETIC MODIFICATIONS IN HEALTHY SUBJECTS. EPIGENETIC EFFECTS AFTER EXERCISE HAVE BEEN SHOWED IN PATIENTS WITH CARDIOVASCULAR DISEASE. THE AIM OF THIS SYSTEMATIC REVIEW WAS TO SUMMARIZE THE EVIDENCE FROM AVAILABLE CLINICAL TRIALS THAT STUDY EPIGENETIC ADAPTATIONS AFTER EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. METHODS: THE SEARCH STRATEGY WAS PERFORMED IN PUBMED AND CENTRAL DATABASES ON ARTICLES PUBLISHED UNTIL SEPTEMBER 2020. STUDIES WITH TITLES AND ABSTRACTS RELEVANT TO EXERCISE EPIGENETIC MODIFICATION APPLIED TO CARDIOVASCULAR PATIENTS WERE FULLY EXAMINED. INCLUSION AND EXCLUSION CRITERIA WERE UTILIZED FOR STUDIES SCREENING. QUALITY ASSESSMENT WITH PEDRO SCALE AND EVALUATION BY TWO INDEPENDENT REVIEWERS WAS PERFORMED. RESULTS: OF THE 1714 ARTICLES RETRIEVED, 88 ARTICLES WERE ASSESSED FOR ELIGIBILITY CRITERIA AND 8 ARTICLES MATCHED OUR SEARCH CRITERIA AND FINALLY INCLUDED IN THE SYSTEMATIC ANALYSIS. THE ACUTE EXERCISE EPIGENETIC (MIRNAS) EFFECTS WERE ASSESSED IN THREE STUDIES AND THE CHRONIC EXERCISE TRAINING EFFECTS (MIRNAS AND DNA METHYLATION) IN SIX STUDIES. THE RESULTS HAVE SHOWN THAT THERE IS POSSIBLY AN ACUTE SIGNIFICANT EXERCISE EFFECT ON EPIGENETIC TARGETS WHICH IS MORE EVIDENT AFTER CHRONIC EXERCISE TRAINING. CONCLUSIONS: BY THE PRESENT SYSTEMATIC REVIEW, WE PROVIDE PRELIMINARY EVIDENCE OF BENEFICIAL EPIGENETIC ADAPTATIONS FOLLOWING ACUTE AND CHRONIC EXERCISE IN PATIENTS WITH CARDIOVASCULAR DISEASE. MORE CONTROLLED STUDIES ARE NEEDED TO CONFIRM SUCH EVIDENCE. 2021 16 5847 25 SUBCLINICAL ATHEROSCLEROSIS AND ACCELERATED EPIGENETIC AGE MEDIATED BY INFLAMMATION: A MULTI-OMICS STUDY. AIMS: EPIGENETIC AGE IS EMERGING AS A PERSONALIZED AND ACCURATE PREDICTOR OF BIOLOGICAL AGE. THE AIM OF THIS ARTICLE IS TO ASSESS THE ASSOCIATION OF SUBCLINICAL ATHEROSCLEROSIS WITH ACCELERATED EPIGENETIC AGE AND TO INVESTIGATE THE UNDERLYING MECHANISMS MEDIATING THIS ASSOCIATION. METHODS AND RESULTS: WHOLE BLOOD METHYLOMICS, TRANSCRIPTOMICS, AND PLASMA PROTEOMICS WERE OBTAINED FOR 391 PARTICIPANTS OF THE PROGRESSION OF EARLY SUBCLINICAL ATHEROSCLEROSIS STUDY. EPIGENETIC AGE WAS CALCULATED FROM METHYLOMICS DATA FOR EACH PARTICIPANT. ITS DIVERGENCE FROM CHRONOLOGICAL AGE IS TERMED EPIGENETIC AGE ACCELERATION. SUBCLINICAL ATHEROSCLEROSIS BURDEN WAS ESTIMATED BY MULTI-TERRITORY 2D/3D VASCULAR ULTRASOUND AND BY CORONARY ARTERY CALCIFICATION. IN HEALTHY INDIVIDUALS, THE PRESENCE, EXTENSION, AND PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS WERE ASSOCIATED WITH A SIGNIFICANT ACCELERATION OF THE GRIM EPIGENETIC AGE, A PREDICTOR OF HEALTH AND LIFESPAN, REGARDLESS OF TRADITIONAL CARDIOVASCULAR RISK FACTORS. INDIVIDUALS WITH AN ACCELERATED GRIM EPIGENETIC AGE WERE CHARACTERIZED BY AN INCREASED SYSTEMIC INFLAMMATION AND ASSOCIATED WITH A SCORE OF LOW-GRADE, CHRONIC INFLAMMATION. MEDIATION ANALYSIS USING TRANSCRIPTOMICS AND PROTEOMICS DATA REVEALED KEY PRO-INFLAMMATORY PATHWAYS (IL6, INFLAMMASOME, AND IL10) AND GENES (IL1B, OSM, TLR5, AND CD14) MEDIATING THE ASSOCIATION BETWEEN SUBCLINICAL ATHEROSCLEROSIS AND EPIGENETIC AGE ACCELERATION. CONCLUSION: THE PRESENCE, EXTENSION, AND PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS IN MIDDLE-AGED ASYMPTOMATIC INDIVIDUALS ARE ASSOCIATED WITH AN ACCELERATION IN THE GRIM EPIGENETIC AGE. MEDIATION ANALYSIS USING TRANSCRIPTOMICS AND PROTEOMICS DATA SUGGESTS A KEY ROLE OF SYSTEMIC INFLAMMATION IN THIS ASSOCIATION, REINFORCING THE RELEVANCE OF INTERVENTIONS ON INFLAMMATION TO PREVENT CARDIOVASCULAR DISEASE. 2023 17 246 32 ADULT STEM CELL THERAPY FOR CARDIAC REPAIR IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION LEADING TO ISCHEMIC HEART FAILURE: AN OVERVIEW OF EVIDENCE FROM THE RECENT CLINICAL TRIALS. BACKGROUND: CARDIOVASCULAR DISEASES (CVD) STILL REPRESENT THE LEADING CAUSE OF MORTALITY WORLDWIDE, DESPITE THE REMARKABLE ADVANCES IN INTERVENTIONAL CARDIOLOGY, CARDIAC SURGERY, AND MODERN PHARMACOTHERAPY, PARTICULARLY IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION (AMI), CHRONIC ISCHEMIC HEART FAILURE (HF), CARDIOMYOPATHY (CM), AND THE ASSOCIATED LEFT VENTRICULAR (LV) DYSFUNCTION. A SIGNIFICANT LOSS OF CARDIOMYOCYTES THAT UNDERLIES ALL OF THESE CONDITIONS WAS PREVIOUSLY CONSIDERED IRREVERSIBLE. HOWEVER, CURRENT EVIDENCE INDICATES THAT THE HUMAN HEART HAS SOME POTENTIAL FOR REPAIR, AND OVER THE PAST DECADE, MANY RESEARCH STUDIES HAVE BEEN EXPLORING THE USE OF STEM CELLS (SCS) TO FACILITATE RESTORATION OF MYOCARDIUM. CONSEQUENTLY, THE SAFETY, FEASIBILITY, AND EFFECTIVENESS OF SC THERAPY HAVE BEEN REPORTED IN MANY RANDOMIZED CLINICAL TRIALS (RCTS), USING DIFFERENT LINEAGES OF ADULT SCS. NEVERTHELESS, THE CLINICAL BENEFITS OF SC THERAPY ARE NOT YET WELL ESTABLISHED. IN THE NEAR FUTURE, UNDERSTANDING OF THE COMPLEX INTERRELATIONS BETWEEN SCS, PARACRINE FACTORS, GENETIC OR EPIGENETIC PREDISPOSITIONS, AND MYOCARDIAL MICROENVIRONMENT, IN THE CONTEXT OF AN INDIVIDUAL PATIENT, WILL BE CRUCIAL FOR TRANSLATION OF THIS KNOWLEDGE INTO PRACTICAL DEVELOPMENT OF SUCCESSFUL, LONG-TERM REGENERATIVE SC THERAPEUTIC APPLICATIONS, IN A GROWING POPULATION OF PATIENTS SUFFERING FROM PREVIOUS MYOCARDIAL INFARCTION (MI) LEADING TO CHRONIC ISCHEMIC CARDIOMYOPATHY. CONCLUSION: THIS OVERVIEW HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF ADULT SCS IN TERMS OF THEIR POSSIBLE REGENERATIVE CAPACITY, SAFETY, AND CLINICAL OUTCOMES, IN PATIENTS WITH AMI, AND/OR SUBSEQUENT HF (DUE TO CHRONIC ISCHEMIC CARDIOMYOPATHY). THIS REVIEW WAS BASED UPON PUBMED DATABASE SEARCH FOR TRIALS ON SC THERAPY, IN PATIENTS WITH AMI AND HF, AND THE MAIN TIMEFRAME WAS SET FROM 2006 TO 2016. 2017 18 948 20 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 19 3502 39 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277. 2020 20 3936 28 LIVING IN ENDEMIC AREA FOR INFECTIOUS DISEASES ACCELERATES EPIGENETIC AGE. INFLAMMAGING IS A LOW-GRADE INFLAMMATORY STATE GENERATED BY THE AGING PROCESS THAT CAN CONTRIBUTE TO FRAILTY AND AGE-RELATED DISEASES IN THE ELDERLY. HOWEVER, IT CAN HAVE DISTINCT EFFECTS IN THE ELDERLY LIVING IN ENDEMIC AREAS FOR INFECTIOUS DISEASES. AN INCREASED INFLAMMATORY RESPONSE MAY CONFER PROTECTION AGAINST INFECTIOUS AGENTS IN THESE AREAS, ALTHOUGH THIS ADVANTAGE CAN CAUSE ACCELERATING EPIGENETIC AGING. IN THIS STUDY, WE EVALUATED THE INFLAMMATORY PROFILE AND THE EPIGENETIC AGE OF INFECTED AND NONINFECTED INDIVIDUALS FROM AN ENDEMIC AREA IN BRAZIL. THE PROFILE OF CYTOKINES, CHEMOKINES AND GROWTH FACTORS ANALYZED IN THE SERA OF THE TWO GROUPS OF INDIVIDUALS SHOWED SIMILARITIES, ALTHOUGH INFECTED INDIVIDUALS HAD A HIGHER CONCENTRATION OF THESE MEDIATORS. A SIGNIFICANT INCREASE IN IL-1RA, CXCL8, CCL2, CCL3 AND CCL4 PRODUCTION WAS ASSOCIATED WITH LEPROSY INFECTION. NOTABLY, ELDERLY INDIVIDUALS DISPLAYED DISTINCT IMMUNE RESPONSES ASSOCIATED WITH THEIR INFECTION STATUS WHEN COMPARED TO ADULTS SUGGESTING AN ADAPTIVE REMODELLING OF THEIR IMMUNE RESPONSES. EPIGENETIC ANALYSIS ALSO SHOWED THAT THERE WAS NO DIFFERENCE IN EPIGENETIC AGE BETWEEN THE TWO GROUPS OF INDIVIDUALS. HOWEVER, INDIVIDUALS FROM THE ENDEMIC AREA HAD A SIGNIFICANT ACCELERATED AGING WHEN COMPARED TO INDIVIDUALS FROM SAO PAULO, A NON-ENDEMIC AREA IN BRAZIL. MOREOVER, THE LATTER COHORT WAS ALSO EPIGENETICALLY AGED IN RELATION TO AN ITALIAN COHORT. OUR DATA SHOWS THAT LIVING IN ENDEMIC AREAS FOR CHRONIC INFECTIOUS DISEASES RESULTS IN REMODELLING OF INFLAMMAGING AND ACCELERATION OF EPIGENETIC AGING IN INDIVIDUALS REGARDLESS OF THEIR INFECTIOUS STATUS. IT ALSO HIGHLIGHTS THAT GEOGRAPHICAL, GENETIC AND ENVIRONMENTAL FACTORS INFLUENCE AGING AND IMMUNOSENESCENCE IN THEIR PACE AND PROFILE. 2022