1   811 104 CHANGES IN DNA METHYLATION OF TANDEM DNA REPEATS ARE DIFFERENT FROM INTERSPERSED REPEATS IN CANCER. HYPOMETHYLATION OF DNA REPETITIVE ELEMENTS IS A COMMON FINDING IN CANCER, BUT VERY LITTLE IS KNOWN ABOUT THE DNA METHYLATION CHANGES OF DIFFERENT TYPES OF DNA REPETITIVE ELEMENTS, SUCH AS INTERSPERSED REPEATS (LINE1 AND ALU YB8) AND TANDEM REPEATS (SAT-ALPHA, NBL-2 AND D4Z4). WE USED BISULFITE-PCR PYROSEQUENCING TO QUANTITATIVELY MEASURE THE DNA METHYLATION OF FIVE DIFFERENT DNA REPETITIVE ELEMENTS IN NORMAL TISSUE AND CANCER. IN ALL WE STUDIED 10 DIFFERENT TISSUES FROM FOUR INDIVIDUALS UNDERGOING AUTOPSY, 34 PAIRED NORMAL AND TUMOR TISSUES FROM PATIENTS WITH BLADDER CANCER, 58 PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA AND 23 PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA. WE FOUND THAT THE DNA METHYLATION OF INTERSPERSED REPEATS (LINE1 AND ALU YB8) WAS VERY CONSISTENT FROM PERSON TO PERSON AND TISSUE TO TISSUE WHILE TANDEM DNA REPEATS APPEARED MORE VARIABLE IN NORMAL TISSUES. IN BLADDER CANCER WE FOUND CLEAR HYPOMETHYLATION OF LINE1, ALU YB8, SAT-ALPHA AND NBL-2. CONVERSELY, WE FOUND AN INCREASE IN THE DNA METHYLATION LEVELS OF D4Z4 FROM NORMAL TO CANCER. IN CONTRAST LEUKEMIA SHOWED NO SIGNIFICANT CHANGES IN THE DNA METHYLATION OF LINE1 AND ALU YB8, BUT DNA METHYLATION INCREASES IN NBL-2 AND D4Z4 TANDEM REPEATS. OUR FINDINGS SHOW THAT THE CHANGES IN DNA METHYLATION LEVELS OF INDIVIDUAL DNA REPETITIVE ELEMENTS ARE UNIQUE FOR EACH REPETITIVE ELEMENT, WHICH MAY REFLECT DISTINCT EPIGENETIC FACTORS AND MAY HAVE IMPORTANT IMPLICATIONS IN THE USE OF DNA METHYLATION OF REPETITIVE ELEMENTS AS GLOBAL DNA METHYLATION BIOMARKERS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2   512  29 ASSOCIATION OF SAT-A AND ALU METHYLATION STATUS WITH HCV-INDUCED CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. BACKGROUND: THE COMBINATION OF EPIGENETIC AND GENETIC ABNORMALITIES CONTRIBUTES TOGETHER TO THE DEVELOPMENT OF LIVER CANCER. THE METHYLATION STATUS OF THE REPETITIVE ELEMENTS (RES) IN DNA HAS BEEN INVESTIGATED IN A VARIETY OF HUMAN ILLNESSES. HOWEVER, THE METHYLATION PATTERNS OF SAT-ALPHA AND ALU RES IN CHRONIC LIVER DISEASE (CLD) AND HEPATOCELLULAR CARCINOMA (HCC) CAUSED BY HEPATITIS C VIRUS (HCV) HAVE NEVER BEEN STUDIED BEFORE. METHODOLOGY: IN THIS STUDY, 3 GROUPS OF PARTICIPANTS INCLUDING 50 PATIENTS HAVING HCV-INDUCED CLD, 50 PATIENTS HAVING HCV-INDUCED HCC, AND 46 HEALTHY SUBJECTS WERE SUBJECTED TO MEASUREMENT OF SAT-ALPHA AND ALU METHYLATION USING THE QUANTITATIVE METHYLIGHT ASSAY. RESULTS: SAT-ALPHA AND ALU METHYLATION PERCENTAGES DECREASED SIGNIFICANTLY IN BOTH CLD AND HCC, COMPARED TO CONTROL. ALSO, A SIGNIFICANT SAT-ALPHA HYPOMETHYLATION WAS DETECTED IN HCC, COMPARED TO CLD. IN ADDITION, SAT-ALPHA AND ALU METHYLATION SHOWED A SIGNIFICANT DECLINE AS LESION SIZE GREW. HOWEVER, ONLY SAT-ALPHA HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN ASSOCIATION WITH PORTAL VEIN THROMBOSIS AND THE MELD SCORE. SAT-ALPHA METHYLATION PERCENTAGE HAD THE HIGHEST SENSITIVITY AND SPECIFICITY FOR DIAGNOSING HCC (100% AND 84.4%) FOLLOWED BY ALPHA-FETOPROTEIN (80% AND 84.4%) AND ALU METHYLATION (66% AND 61.5%). FURTHERMORE, THERE WAS A STRONG POSITIVE CORRELATION BETWEEN SAT-ALPHA AND ALU METHYLATION. CONCLUSIONS: MEASURING SAT-ALPHA AND ALU METHYLATION PROVIDES US WITH A NEW TOOL FOR EARLY DETECTING HCV-INDUCED CLD AND HEPATOCARCINOGENESIS. SAT-ALPHA HAS THE POTENTIAL TO BE UTILIZED AS AN INDEPENDENT PREDICTIVE PARAMETER FOR HCC DEVELOPMENT AND PROGRESSION BECAUSE OF ITS ABILITY TO DISTINGUISH BETWEEN CLD AND HCC WITH THEIR DIFFERENT MELD SCORES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3  4092  24 MATERNAL REPETITIVE HYPOXIA PRIOR TO MATING CONFERS EPIGENETIC RESILIENCE TO MEMORY IMPAIRMENT IN MALE PROGENY. WE SHOWED PREVIOUSLY IN A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA INVOLVING CHRONIC CEREBRAL HYPOPERFUSION (CCH) THAT REPETITIVE HYPOXIC CONDITIONING (RHC) OF BOTH PARENTS RESULTS IN THE EPIGENETIC, INTERGENERATIONAL TRANSMISSION OF RESILIENCE TO RECOGNITION MEMORY LOSS IN ADULT PROGENY, AS ASSESSED BY THE NOVEL OBJECT RECOGNITION TEST. THE PRESENT STUDY WAS UNDERTAKEN IN THE SAME MODEL TO DETERMINE WHETHER RHC TREATMENT OF ONE OR BOTH PARENTS IS REQUIRED TO CONFER DEMENTIA RESILIENCE INTERGENERATIONALLY. WE FOUND INHERITED RESILIENCE TO 3 MONTHS OF CCH IN MALES IS MATERNALLY MEDIATED (P = .006). STATISTICALLY, WE OBSERVED A STRONG TREND FOR THE PATERNAL GERMLINE TO CONTRIBUTE AS WELL (P = .052). WE ALSO FOUND THAT, IN CONTRAST TO WHAT IS WIDELY OBSERVED IN MALES, FEMALES DISPLAY INTACT RECOGNITION MEMORY (P = .001) AFTER 3 MONTHS OF CCH, REVEALING A HERETOFORE UNIDENTIFIED SEXUAL DIMORPHISM WITH RESPECT TO COGNITIVE IMPACT DURING DISEASE PROGRESSION. OVERALL, RESULTS OF OUR STUDY STRONGLY IMPLICATE EPIGENETIC CHANGES IN MATERNAL GERM CELLS, INDUCED BY OUR REPETITIVE SYSTEMIC HYPOXIC STIMULUS, CONTRIBUTING TO A MODIFIED DIFFERENTIATION PROGRAM CAPABLE OF ESTABLISHING A DEMENTIA-RESILIENT PHENOTYPE IN ADULT MALE FIRST-GENERATION PROGENY. (PSYCINFO DATABASE RECORD (C) 2023 APA, ALL RIGHTS RESERVED).	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  1781  29 EFFECT OF 1 YEAR B AND D VITAMIN SUPPLEMENTATION ON LINE-1 REPETITIVE ELEMENT METHYLATION IN OLDER SUBJECTS. BACKGROUND: DISTURBED DNA METHYLATION IS CAUSALLY RELATED TO CHRONIC DISEASES LIKE CANCER AND ATHEROSCLEROSIS. B VITAMINS ARE COFACTORS REQUIRED FOR METHYL GROUP SYNTHESIS AND MAY THEREFORE AFFECT DNA METHYLATION. VITAMIN D HAS EPIGENETIC EFFECTS. WE TESTED IF B AND D VITAMIN SUPPLEMENTATION HAS AN EFFECT ON GENOMIC LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION AND THE METABOLITES S-ADENOSYLMETHIONINE (SAM) AND S-ADENOSYLHOMOCYSTEINE (SAH). METHODS: FIFTY SUBJECTS (MEDIAN AGE 68.0 YEARS) WERE SUPPLEMENTED WITH A DAILY ORAL DOSE OF B VITAMINS (500 MICROG FOLIC ACID, 500 MICROG VITAMIN B12 AND 50 MG VITAMIN B6), 1200 IU VITAMIN D AND 456 MG CALCIUM. FASTING BLOOD SAMPLES WERE COLLECTED BEFORE AND AFTER 1 YEAR OF SUPPLEMENTATION. LINE-1 METHYLATION WAS DETERMINED IN GENOMIC DNA FROM BLOOD CELLS AS A SURROGATE FOR WHOLE GENOME METHYLATION. IN ADDITION, SAM, SAH AND TOTAL HOMOCYSTEINE (THCY) WERE MEASURED IN PLASMA SAMPLES. RESULTS: PLASMA HOMOCYSTEINE DECREASED SIGNIFICANTLY AFTER SUPPLEMENTATION (12.8 VS. 9.1 MICROMOL/L; P<0.05), WHEREAS SAM, SAH, THE SAM/SAH RATIO AND LINE-1 METHYLATION DID NOT CHANGE SIGNIFICANTLY. LINE-1 METHYLATION WAS NOT SIGNIFICANTLY CORRELATED WITH SAH, HOMOCYSTEINE OR B VITAMINS. CONCLUSIONS: LONG-TERM VITAMIN B SUPPLEMENTATION HAD NO EFFECT ON LINE-1 METHYLATION IN BLOOD CELLS NOR ON PLASMA LEVELS OF SAM AND SAH. VITAMIN B AND D SUPPLEMENTATION SEEMS TO HAVE NO EFFECT ON DNA METHYLATION, ESPECIALLY IN CASES WHERE NO SEVERE DEFICIENCY EXISTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  2682  36 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6   649  35 BIRTHWEIGHT, MATERNAL WEIGHT TRAJECTORIES AND GLOBAL DNA METHYLATION OF LINE-1 REPETITIVE ELEMENTS. LOW BIRTHWEIGHT, PREMATURE BIRTH, INTRAUTERINE GROWTH RETARDATION, AND MATERNAL MALNUTRITION HAVE BEEN RELATED TO AN INCREASED RISK OF CARDIOVASCULAR DISEASE, TYPE 2 DIABETES MELLITUS, OBESITY, AND NEUROPSYCHIATRIC DISORDERS LATER IN LIFE. CONVERSELY, HIGH BIRTHWEIGHT HAS BEEN LINKED TO FUTURE RISK OF CANCER. GLOBAL DNA METHYLATION ESTIMATED BY THE METHYLATION OF REPETITIVE SEQUENCES IN THE GENOME IS AN INDICATOR OF SUSCEPTIBILITY TO CHRONIC DISEASES. WE USED DATA AND BIOSPECIMENS FROM AN EPIGENETIC BIRTH COHORT TO EXPLORE THE ASSOCIATION BETWEEN TRAJECTORIES OF FETAL AND MATERNAL WEIGHT AND LINE-1 METHYLATION IN 319 MOTHER-CHILD DYADS. NEWBORNS WITH LOW OR HIGH BIRTHWEIGHT HAD SIGNIFICANTLY LOWER LINE-1 METHYLATION LEVELS IN THEIR CORD BLOOD COMPARED TO NORMAL WEIGHT INFANTS AFTER ADJUSTING FOR GESTATIONAL AGE, SEX OF THE CHILD, MATERNAL AGE AT DELIVERY, AND MATERNAL SMOKING DURING PREGNANCY (P = 0.007 AND P = 0.036, RESPECTIVELY), BUT THE MAGNITUDE OF THE DIFFERENCE WAS SMALL. INFANTS BORN PREMATURELY ALSO HAD LOWER LINE-1 METHYLATION LEVELS IN CORD BLOOD COMPARED TO TERM INFANTS, AND THIS DIFFERENCE, THOUGH SMALL, WAS STATISTICALLY SIGNIFICANT (P = 0.004). WE DID NOT FIND IMPORTANT ASSOCIATIONS BETWEEN MATERNAL PREPREGNANCY BMI OR GESTATIONAL WEIGHT GAIN AND GLOBAL METHYLATION OF THE CORD BLOOD OR FETAL PLACENTAL TISSUE. IN CONCLUSION, WE FOUND SIGNIFICANT DIFFERENCES IN CORD BLOOD LINE-1 METHYLATION AMONG NEWBORNS WITH LOW AND HIGH BIRTHWEIGHT AS WELL AS AMONG PREMATURELY BORN INFANTS. FUTURE STUDIES MAY ELUCIDATE WHETHER CHROMOSOMAL INSTABILITIES OR OTHER FUNCTIONAL CONSEQUENCES OF THESE CHANGES CONTRIBUTE TO THE INCREASED RISK OF CHRONIC DISEASES AMONG INDIVIDUALS WITH THESE CHARACTERISTICS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  5957  22 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8  5683  28 SHORTER TELOMERE LENGTH IN PERIPHERAL BLOOD LYMPHOCYTES OF WORKERS EXPOSED TO POLYCYCLIC AROMATIC HYDROCARBONS. SHORTER TELOMERE LENGTH (TL) IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) IS PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS THAT CAUSE CHROMOSOME INSTABILITY. WHETHER PAH EXPOSURE AND ITS MOLECULAR EFFECTS ARE LINKED WITH SHORTER TL HAS NEVER BEEN EVALUATED. IN THE PRESENT STUDY, WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON TL MEASURED IN PBLS OF POLISH MALE NON-CURRENT SMOKING COKEOVEN WORKERS AND MATCHED CONTROLS. PAH EXPOSURE AND MOLECULAR EFFECTS WERE CHARACTERIZED USING MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), EFFECTIVE DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI, MN) AND DNA METHYLATION [P53 PROMOTER AND ALU AND LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS, AS SURROGATE MEASURES OF GLOBAL METHYLATION] IN PBLS. TL WAS MEASURED BY REAL-TIME POLYMERASE CHAIN REACTION. COKEOVEN WORKERS WERE HEAVILY EXPOSED TO PAHS (79% EXCEEDED THE URINARY 1-PYRENOL BIOLOGICAL EXPOSURE INDEX) AND EXHIBITED LOWER TL (P = 0.038) THAN CONTROLS, AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL ALTERATIONS [I.E. ANTI-BPDE-DNA ADDUCT AND MN (P < 0.0001)] AND EPIGENETIC CHANGES [I.E. P53 GENE-SPECIFIC PROMOTER AND GLOBAL METHYLATION (P <OR= 0.001)]. TL DECREASED WITH LONGER DURATION OF WORK AS COKEOVEN WORKER (P = 0.039) AND IN ALL SUBJECTS WITH HIGHER LEVELS OF ANTI-BPDE-DNA ADDUCT (P = 0.042), P53 HYPOMETHYLATION (P = 0.005) AND MN (P = 0.009). IN MULTIVARIATE ANALYSIS, YEARS OF WORK IN COKERY (P = 0.008) AND P53 HYPOMETHYLATION (P = 0.001) WERE THE PRINCIPAL DETERMINANTS OF SHORTER TL. OUR RESULTS INDICATE THAT SHORTER TL IS ASSOCIATED WITH CHRONIC PAH EXPOSURE. THE INTERRELATIONS WITH OTHER GENETIC AND EPIGENETIC MECHANISMS IN OUR DATA SUGGEST THAT SHORTER TL COULD BE A CENTRAL EVENT IN PAH CARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  5628  23 SEMEN ABNORMALITIES, SPERM DNA DAMAGE AND GLOBAL HYPERMETHYLATION IN HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION. BACKGROUND: CYTOGENETIC STUDIES HAVE DEMONSTRATED THAT LOW LEVELS OF CHRONIC RADIATION EXPOSURE CAN POTENTIALLY INCREASE THE FREQUENCY OF CHROMOSOMAL ABERRATIONS AND ANEUPLOIDY IN SOMATIC CELLS. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION BEAR AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES. OBJECTIVES: TO FIND THE INFLUENCE OF OCCUPATIONAL RADIATION EXPOSURE ON SEMEN CHARACTERISTICS, INCLUDING GENETIC AND EPIGENETIC INTEGRITY OF SPERMATOZOA IN A CHRONICALLY EXPOSED POPULATION. METHODS: THIS CROSS SECTIONAL STUDY INCLUDED 134 MALE VOLUNTEERS OF WHICH 83 WERE OCCUPATIONALLY EXPOSED TO IONIZING RADIATION AND 51 WERE NON-EXPOSED CONTROL SUBJECTS. SEMEN CHARACTERISTICS, SPERM DNA FRAGMENTATION, ANEUPLOIDY AND INCIDENCE OF GLOBAL HYPERMETHYLATION IN THE SPERMATOZOA WERE DETERMINED AND COMPARED BETWEEN THE NON-EXPOSED AND THE EXPOSED GROUP. RESULTS: DIRECT COMPARISON OF THE SEMEN CHARACTERISTICS BETWEEN THE NON-EXPOSED AND THE EXPOSED POPULATION REVEALED SIGNIFICANT DIFFERENCES IN MOTILITY CHARACTERISTICS, VIABILITY, AND MORPHOLOGICAL ABNORMALITIES (P<0.05-0.0001). ALTHOUGH, THE LEVEL OF SPERM DNA FRAGMENTATION WAS SIGNIFICANTLY HIGHER IN THE EXPOSED GROUP AS COMPARED TO THE NON-EXPOSED GROUP (P<0.05-0.0001), THE INCIDENCE OF SPERM ANEUPLOIDY WAS NOT STATISTICALLY DIFFERENT BETWEEN THE TWO GROUPS. HOWEVER, A SIGNIFICANT NUMBER OF HYPERMETHYLATED SPERMATOZOA WERE OBSERVED IN THE EXPOSED GROUP IN COMPARISON TO NON-EXPOSED GROUP (P<0.05). CONCLUSIONS: WE PROVIDE THE FIRST EVIDENCE ON THE DETRIMENTAL EFFECTS OF OCCUPATIONAL RADIATION EXPOSURE ON FUNCTIONAL, GENETIC AND EPIGENETIC INTEGRITY OF SPERM IN HEALTH WORKERS. HOWEVER, FURTHER STUDIES ARE REQUIRED TO CONFIRM THE POTENTIAL DETRIMENTAL EFFECTS OF IONIZING RADIATION IN THESE SUBJECTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10   524  24 ASSOCIATIONS OF BDNF GENOTYPE AND PROMOTER METHYLATION WITH ACUTE AND LONG-TERM STROKE OUTCOMES IN AN EAST ASIAN COHORT. BACKGROUND: BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN POSTSTROKE RECOVERY. BDNF SECRETION IS INFLUENCED BY GENETIC AND EPIGENETIC PROFILES. THIS STUDY AIMED TO INVESTIGATE WHETHER BDNF VAL66MET POLYMORPHISM AND PROMOTER METHYLATION STATUS WERE ASSOCIATED WITH OUTCOMES AT TWO WEEKS AND ONE YEAR AFTER STROKE. METHODS AND FINDINGS: A TOTAL OF 286 PATIENTS WERE EVALUATED AT THE TIME OF ADMISSION AND TWO WEEKS AFTER STROKE, AND 222 (78%) WERE FOLLOWED ONE YEAR LATER IN ORDER TO EVALUATE CONSEQUENCES OF STROKE AT BOTH ACUTE AND CHRONIC STAGES. STROKE OUTCOMES WERE DICHOTOMISED INTO GOOD AND POOR BY THE MODIFIED RANKIN SCALE. STROKE SEVERITY (NATIONAL INSTITUTES OF HEALTH STROKE SCALE), PHYSICAL DISABILITY (BARTHEL INDEX), AND COGNITIVE FUNCTION (MINI-MENTAL STATE EXAMINATION) WERE MEASURED. ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION STATUS ON STROKE OUTCOMES AND ASSESSMENT SCALE SCORES WERE INVESTIGATED USING LOGISTIC REGRESSION, REPEATED MEASURES ANOVA AND PARTIAL CORRELATION TESTS. BDNF VAL66MET POLYMORPHISM WAS INDEPENDENTLY ASSOCIATED WITH POOR OUTCOME AT 2 WEEKS AND AT 1 YEAR, AND WITH WORSENING PHYSICAL DISABILITY AND COGNITIVE FUNCTION OVER THAT PERIOD. HIGHER BDNF PROMOTER METHYLATION STATUS WAS INDEPENDENTLY ASSOCIATED WITH WORSE OUTCOMES AT 1 YEAR, AND WITH THE WORSENING OF PHYSICAL DISABILITY AND COGNITIVE FUNCTION. NO SIGNIFICANT GENOTYPE-METHYLATION INTERACTIONS WERE FOUND. CONCLUSIONS: A ROLE FOR BDNF IN POSTSTROKE RECOVERY WAS SUPPORTED, AND CLINICAL UTILITY OF BDNF GENETIC AND EPIGENETIC PROFILE AS PROGNOSTIC BIOMARKERS AND A TARGET FOR DRUG DEVELOPMENT WAS SUGGESTED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  1132  33 COMPREHENSIVE DNA METHYLATION ANALYSIS USING A METHYL-CPG-BINDING DOMAIN CAPTURE-BASED METHOD IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. THE ROLE OF LONG NONCODING RNAS (LNCRNAS) IN CANCER IS COMING TO THE FOREFRONT DUE TO GROWING INTEREST IN UNDERSTANDING THEIR MECHANISTIC FUNCTIONS DURING CANCER DEVELOPMENT AND PROGRESSION. DESPITE THIS, THE GLOBAL EPIGENETIC REGULATION OF LNCRNAS AND REPETITIVE SEQUENCES IN CANCER HAS NOT BEEN WELL INVESTIGATED, PARTICULARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THIS STUDY FOCUSES ON A UNIQUE APPROACH: THE IMMUNOPRECIPITATION-BASED CAPTURE OF DOUBLE-STRANDED, METHYLATED DNA FRAGMENTS USING METHYL-BINDING DOMAIN (MBD) PROTEINS, FOLLOWED BY NEXT-GENERATION SEQUENCING (MBD-SEQ). CLL PATIENT SAMPLES BELONGING TO TWO PROGNOSTIC SUBGROUPS (5 IGVH MUTATED SAMPLES + 5 IGVH UNMUTATED SAMPLES) WERE USED IN THIS STUDY. ANALYSIS REVEALED 5,800 HYPERMETHYLATED AND 12,570 HYPOMETHYLATED CLL-SPECIFIC DIFFERENTIALLY METHYLATED GENES (CLLDMGS) COMPARED TO NORMAL HEALTHY CONTROLS. IMPORTANTLY, THESE RESULTS IDENTIFIED SEVERAL CLL-SPECIFIC, DIFFERENTIALLY METHYLATED LNCRNAS, REPETITIVE ELEMENTS, AND PROTEIN-CODING GENES WITH POTENTIAL PROGNOSTIC VALUE. THIS WORK OUTLINES A DETAILED PROTOCOL FOR AN MBD-SEQ AND BIOINFORMATICS PIPELINE DEVELOPED FOR THE COMPREHENSIVE ANALYSIS OF GLOBAL METHYLATION PROFILES IN HIGHLY CPG-RICH REGIONS USING CLL PATIENT SAMPLES. FINALLY, A PROTEIN-CODING GENE AND AN LNCRNA WERE VALIDATED USING PYROSEQUENCING, WHICH IS A HIGHLY QUANTITATIVE METHOD TO ANALYZE CPG METHYLATION LEVELS TO FURTHER CORROBORATE THE FINDINGS FROM THE MBD-SEQ PROTOCOL.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12   509  28 ASSOCIATION OF NUTRACEUTICAL SUPPLEMENTS WITH LONGER TELOMERE LENGTH. TELOMERES ARE NUCLEOTIDE TANDEM REPEATS LOCATED AT THE TIP OF EUKARYOTIC CHROMOSOMES THAT MAINTAIN GENOMIC INTEGRITY. THE GRADUAL SHORTENING OF TELOMERES LEADS TO CELLULAR SENESCENCE AND APOPTOSIS, A KEY MECHANISM OF AGING AND AGE?RELATED CHRONIC DISEASES. EPIGENETIC FACTORS, SUCH AS NUTRITION, EXERCISE AND TOBACCO CAN AFFECT THE RATE AT WHICH TELOMERES SHORTEN AND CAN MODIFY THE RISK OF DEVELOPING CHRONIC DISEASES. IN THIS STUDY, WE EVALUATED THE EFFECTS OF A COMBINATION OF NUTRACEUTICAL SUPPLEMENTS (NS) ON TELOMERE LENGTH (TL) IN HEALTHY VOLUNTEERS WITH NO MEDICAL HISTORY OF ANY DISEASE. PARTICIPANTS (N=47) WERE SELECTED FROM HEALTHY OUTPATIENTS VISITING A PRIVATE CLINIC AND WERE DIVIDED INTO THE EXPERIMENTAL GROUP (N=16), THAT RECEIVED THE NS AND THE CONTROL GROUP (N=31). WE ESTIMATED THE LENGTH OF SINGLE TELOMERES IN METAPHASE SPREAD LEUKOCYTES, ISOLATED FROM PERIPHERAL BLOOD, USING QUANTITATIVE?FLUORESCENT IN SITU HYBRIDIZATION (Q?FISH) ANALYSIS. THE LENGTH OF THE WHOLE TELOMERE GENOME WAS SIGNIFICANTLY INCREASED (P<0.05) FOR THE MEAN, 1ST QUARTILE AND MEDIAN MEASUREMENTS IN THE EXPERIMENTAL GROUP. SIMILAR FINDINGS WERE OBSERVED FOR SHORT TL (20TH PERCENTILE) (P<0.05) FOR THE MEDIAN AND 3RD QUARTILE MEASUREMENTS IN THE NS GROUP, COMPARED TO THE CONTROL GROUP. THE BENEFICIAL EFFECTS OF THE SUPPLEMENTS ON THE LENGTH OF SHORT TELOMERES REMAINED SIGNIFICANT (P<0.05) FOLLOWING ADJUSTMENT FOR AGE AND SEX. TELOMERES WERE MODERATELY LONGER IN FEMALE PATIENTS COMPARED TO THE MALE PATIENTS. ON THE WHOLE, THE FINDINGS OF THIS STUDY SUGGEST THAT THE ADMINISTRATION OF NS MAY BE LINKED TO SUSTAINING THE TL.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  5498  32 REVIEW: DNA METHYLATION AND ALCOHOL USE DISORDERS: PROGRESS AND CHALLENGES. BACKGROUND AND OBJECTIVES: RISK FOR ALCOHOL USE DISORDERS (AUDS) IS INFLUENCED BY GENE-ENVIRONMENT INTERACTIONS. ENVIRONMENTAL FACTORS CAN AFFECT GENE EXPRESSION THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION. THIS REVIEW OUTLINES THE FINDINGS REGARDING THE ASSOCIATION OF DNA METHYLATION AND AUDS. METHODS: WE SEARCHED PUBMED (BY APRIL 2016) AND IDENTIFIED 29 STUDIES THAT EXAMINED THE ASSOCIATION OF DNA METHYLATION AND AUDS. WE ALSO EVALUATED THE METHODS USED IN THESE STUDIES. RESULTS: TWO STUDIES DEMONSTRATED ELEVATED GLOBAL (REPETITIVE ELEMENT) DNA METHYLATION LEVELS IN AUD SUBJECTS. FIFTEEN CANDIDATE GENE STUDIES SHOWED HYPERMETHYLATION OF PROMOTER REGIONS OF SIX GENES (AVP, DNMT3B, HERP, HTR3A, OPRM1, AND SNCA) OR HYPOMETHYLATION OF THE GDAP1 PROMOTER REGION IN AUD SUBJECTS. FIVE GENOME-WIDE DNA METHYLATION STUDIES DEMONSTRATED WIDESPREAD DNA METHYLATION CHANGES ACROSS THE GENOME IN AUD SUBJECTS. SIX STUDIES SHOWED SIGNIFICANT CORRELATIONS OF DNA METHYLATION WITH GENE EXPRESSION IN AUD SUBJECTS. THREE STUDIES REVEALED INTERACTIVE EFFECTS OF GENETIC VARIATION AND DNA METHYLATION ON SUSCEPTIBILITY TO AUDS. MOST STUDIES ANALYZED AUD-ASSOCIATED DNA METHYLATION CHANGES IN THE PERIPHERAL BLOOD; A FEW STUDIES EXAMINED DNA METHYLATION CHANGES IN POSTMORTEM BRAINS OF AUD SUBJECTS. DISCUSSION AND CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION MAY RESULT IN DNA METHYLATION CHANGES, LEADING TO NEUROADAPTATIONS THAT MAY UNDERLIE SOME OF THE MECHANISMS OF AUD RISK AND PERSISTENCE. FUTURE STUDIES ARE NEEDED TO CONFIRM THE FEW EXISTING RESULTS, AND THEN TO ELUCIDATE WHETHER DNA METHYLATION CHANGES ARE THE CAUSE OR CONSEQUENCE OF AUDS. SCIENTIFIC SIGNIFICANCE: DNA METHYLATION PROFILES MAY BE USED TO ASSESS AUD STATUS OR MONITOR AUD TREATMENT RESPONSE. (AM J ADDICT 2017;26:502-515).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  4242  33 METHYLATION STATUS OF ALU AND LINE-1 INTERSPERSED REPETITIVE SEQUENCES IN BEHCET'S DISEASE PATIENTS. BEHCET'S DISEASE (BD) IS A MULTISYSTEM CHRONIC INFLAMMATORY DISEASE. THE PATHOLOGY IS BELIEVED TO INVOLVE BOTH GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL FACTORS. HYPOMETHYLATION LEADING TO ACTIVATION OF INTERSPERSED REPETITIVE SEQUENCES (IRSS) SUCH AS LINE-1 AND ALU CONTRIBUTES TO THE PATHOLOGIES OF AUTOIMMUNE DISEASES AND CANCER. HEREIN, THE EPIGENETIC CHANGES OF IRSS IN BD WERE EVALUATED USING COMBINED BISULFITE RESTRICTION ANALYSIS-INTERSPERSED REPETITIVE SEQUENCES (COBRA-IRS). DNA FROM NEUTROPHILS AND PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF BD PATIENTS WITH OCULAR INVOLVEMENT THAT WERE IN ACTIVE OR INACTIVE STATES AND HEALTHY CONTROLS WERE USED TO ANALYZE LINE-1 AND ALU METHYLATION LEVELS. FOR ALU SEQUENCES, SIGNIFICANT DIFFERENCES WERE OBSERVED IN THE FREQUENCY OF (U)C(U)C ALLELES BETWEEN PBMCS OF PATIENTS AND CONTROLS (P = 0.03), AND BETWEEN INACTIVE PATIENTS AND CONTROLS (P = 0.03). FOR NEUTROPHILS, THE FREQUENCY OF (U)C(U)C WAS SIGNIFICANTLY HIGHER BETWEEN PATIENTS AND CONTROLS (P = 0.006) AND BETWEEN INACTIVE PATIENTS AND CONTROLS (P = 0.002). THE PARTIAL METHYLATION ((U)C(M)C + (M)C(U)C) FREQUENCIES OF ALU BETWEEN INACTIVE PATIENTS AND CONTROL SAMPLES ALSO DIFFERED (P = 0.02). NO STATISTICALLY SIGNIFICANT DIFFERENCES FOR LINE-1 WERE DETECTED. THUS, CHANGES IN THE METHYLATION LEVEL OF IRS ELEMENTS MIGHT CONTRIBUTE TO THE PATHOGENESIS OF BD. THE ROLE OF ALU TRANSCRIPTS IN BD SHOULD BE INVESTIGATED FURTHER.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  5960  27 TELOMERE LENGTH IN HEPATOCELLULAR CARCINOMA AND PAIRED ADJACENT NON-TUMOR TISSUES BY QUANTITATIVE PCR. TELOMERE SHORTENING LIMITS THE PROLIFERATIVE CAPACITY OF HUMAN CELLS, RESTRAINS THE REGENERATIVE CAPACITY OF ORGAN SYSTEMS DURING CHRONIC DISEASES AND AGING AND ALSO INDUCES CHROMOSOMAL INSTABILITY AS WELL AS INITIATION OF CANCER. PREVIOUS STUDIES DEMONSTRATED THAT TELOMERES ARE OFTEN SIGNIFICANTLY SHORTER IN TUMOR TISSUE, INCLUDING HEPATOCELLULAR CARCINOMA (HCC), COMPARED TO THE SURROUNDING TISSUE, BUT TELOMERE LENGTH IN HCC TISSUES WAS NOT CORRELATED WITH SEVERAL CLINICAL PARAMETERS, SUCH AS AGE, SEX, HBV OR HCV INFECTIONS AND TUMOR SIZE. IN THE PRESENT STUDY, THE TELOMERE LENGTH RATIO OF 36 PAIRED HCC, AND THEIR ADJACENT NON-TUMOR TISSUES WAS MEASURED BY QUANTITATIVE PCR (Q-PCR). THE MEAN TELOMERE LENGTHS (SD) FOR HCC AND ADJACENT NON-TUMOR TISSUES WERE 0.26 (0.10) AND 0.47 (0.20) RESPECTIVELY (T = 6.22, P < 0.0001). THERE WAS A LARGE DIFFERENCE IN THE DISTRIBUTION OF SUBJECTS BASED ON TELOMERE LENGTH IN TUMOR AND ADJACENT NON-TUMOR TISSUES. THE NUMBER OF TUMORS WITH TELOMERE LENGTH SHORTER THAN 0.50 WAS MUCH HIGHER THAN THAT OF ADJACENT NON-TUMOR TISSUES; MORE THAN 90% OF THE TISSUES WITH TELOMERE LENGTH > OR = 0.50 WERE ADJACENT NON-TUMOR TISSUES. THE CORRELATIONS BETWEEN TELOMERE LENGTH AND AFLATOXIN B1- AND POLYCYCLIC AROMATIC HYDROCARBON-DNA ADDUCTS LEVEL, P53 MUTATIONS AND P16 HYPERMETHYLATION STATUS WERE ALSO TESTED, BUT NO SIGNIFICANT ASSOCIATIONS WERE FOUND. THE RELATIONSHIP BETWEEN TELOMERE LENGTH SHORTENING, CHEMICAL CARCINOGEN EXPOSURE, AND GENETIC AND EPIGENETIC CHANGES IN HEPATOCARCINOGENESIS NEEDS FURTHER INVESTIGATION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  2051  19 EPIGENETIC CONDITIONING INDUCES INTERGENERATIONAL RESILIENCE TO DEMENTIA IN A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT. INTRODUCTION: EPIGENETIC STIMULI INDUCE BENEFICIAL OR DETRIMENTAL CHANGES IN GENE EXPRESSION, AND CONSEQUENTLY, PHENOTYPE. SOME OF THESE PHENOTYPES CAN MANIFEST ACROSS THE LIFESPAN-AND EVEN IN SUBSEQUENT GENERATIONS. HERE, WE USED A MOUSE MODEL OF VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA (VCID) TO DETERMINE WHETHER EPIGENETICALLY INDUCED RESILIENCE TO SPECIFIC DEMENTIA-RELATED PHENOTYPES IS HERITABLE BY FIRST-GENERATION PROGENY. METHODS: OUR SYSTEMIC EPIGENETIC THERAPY CONSISTED OF 2 MONTHS OF REPETITIVE HYPOXIC "CONDITIONING" (RHC) PRIOR TO CHRONIC CEREBRAL HYPOPERFUSION IN ADULT C57BL/6J MICE. RESULTANT CHANGES IN OBJECT RECOGNITION MEMORY AND HIPPOCAMPAL LONG-TERM POTENTIATION (LTP) WERE ASSESSED 3 AND 4 MONTHS LATER, RESPECTIVELY. RESULTS: HYPOPERFUSION-INDUCED MEMORY/PLASTICITY DEFICITS WERE ABROGATED BY RHC. MOREOVER, SIMILARLY ROBUST DEMENTIA RESILIENCE WAS DOCUMENTED IN UNTREATED CEREBRAL HYPOPERFUSED ANIMALS DERIVED FROM RHC-TREATED PARENTS. CONCLUSIONS: OUR RESULTS IN EXPERIMENTAL VCID UNDERSCORE THE EFFICACY OF EPIGENETICS-BASED TREATMENTS TO PREVENT MEMORY LOSS, AND DEMONSTRATE FOR THE FIRST TIME THE HERITABILITY OF AN INDUCED RESILIENCE TO DEMENTIA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  2031  26 EPIGENETIC CHANGES IN LYMPHOCYTES OF SOLVENT-EXPOSED INDIVIDUALS. AIM: WE INVESTIGATED GLOBAL DNA METHYLATION ALTERATIONS IN LYMPHOCYTES OF SOLVENT WORKERS AND CHRONIC TOXIC ENCEPHALOPATHY (CTE) PATIENTS AND EXPLORED POTENTIAL GENE-ENVIRONMENT INTERACTIONS FOR GST. POPULATION & METHODS: A CROSS-SECTIONAL STUDY WAS SET UP IN 41 REFERENTS, 128 SOLVENT WORKERS AND 23 CTE PATIENTS. RESULTS: WE FOUND A GLOBAL DNA HYPERMETHYLATION IN THE SOLVENT-EXPOSED POPULATION COMPARED WITH THE REFERENTS (P = 0.001, R = -0.544). GLOBAL DNA METHYLATION WAS NEGATIVELY ASSOCIATED WITH EXPOSURE. FURTHERMORE, GSTP1 GENOTYPIC POLYMORPHISM WAS FOUND TO BE SIGNIFICANTLY ASSOCIATED (P = 0.033) WITH GLOBAL DNA HYPOMETHYLATION, WHICH INDICATES A POTENTIAL ROLE FOR GENE-ENVIRONMENT INTERACTION IN THE ETIOLOGY OF SOLVENT-INDUCED NEUROBEHAVIORAL DISORDERS. CONCLUSION: THIS STUDY INDICATES THAT SOLVENT-INDUCED DNA METHYLATION ALTERATIONS HAVE AN IMPACT ON NEUROTOXICITY AND DEVELOPMENT OF CTE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  5486  36 REVERSE INFLAMMAGING: LONG-TERM EFFECTS OF HCV CURE ON BIOLOGICAL AGE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION CAN BE CURED WITH DIRECT-ACTING ANTIVIRALS (DAAS). HOWEVER, NOT ALL SEQUELAE OF CHRONIC HEPATITIS C APPEAR TO BE COMPLETELY REVERSIBLE AFTER SUSTAINED VIROLOGIC RESPONSE (SVR). RECENTLY, CHRONIC VIRAL INFECTIONS HAVE BEEN SHOWN TO BE ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION DEFINED BY THE EPIGENETIC CLOCK. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER CHRONIC HCV INFECTION IS ASSOCIATED WITH EPIGENETIC CHANGES AND BIOLOGICAL AGE ACCELERATION AND WHETHER THIS IS REVERSIBLE AFTER SVR. METHODS: WE INCLUDED 54 WELL-CHARACTERIZED INDIVIDUALS WITH CHRONIC HEPATITIS C WHO ACHIEVED SVR AFTER DAA THERAPY AT THREE TIME POINTS: DAA TREATMENT INITIATION, END OF TREATMENT, AND LONG-TERM FOLLOW-UP (MEDIAN 96 WEEKS AFTER END OF TREATMENT). GENOME-WIDE DNA METHYLATION STATUS WAS DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND USED TO CALCULATE EPIGENETIC AGE ACCELERATION (EAA) USING HORVATH'S CLOCK. RESULTS: INDIVIDUALS WITH HCV HAD AN OVERALL SIGNIFICANT EAA OF 3.12 YEARS AT BASELINE COMPARED WITH -2.61 YEARS IN THE AGE- AND SEX-MATCHED REFERENCE GROUP (P <0.00003). HCV ELIMINATION RESULTED IN A SIGNIFICANT LONG-TERM INCREASE IN DNA METHYLATION DOMINATED BY HYPERMETHYLATED CPGS IN ALL PATIENT GROUPS. ACCORDINGLY, EAA DECREASED TO 1.37 YEARS AT LONG-TERM FOLLOW-UP. THE DECREASE IN EAA WAS SIGNIFICANT ONLY BETWEEN THE END OF TREATMENT AND FOLLOW-UP (P = 0.01). INTERESTINGLY, EIGHT INDIVIDUALS WHO DEVELOPED HEPATOCELLULAR CARCINOMA AFTER SVR HAD THE HIGHEST EAA AND SHOWED NO EVIDENCE OF REVERSAL AFTER SVR. CONCLUSIONS: OUR DATA CONTRIBUTE TO THE UNDERSTANDING OF THE BIOLOGICAL IMPACT OF HCV ELIMINATION AFTER DAA THERAPY AND DEMONSTRATE THAT HCV ELIMINATION CAN LEAD TO "REVERSE INFLAMMAGING". IN ADDITION, OUR DATA SUPPORT THE POTENTIAL USE OF BIOLOGICAL AGE AS A BIOMARKER FOR HCV SEQUELAE AFTER SVR. IMPACT AND IMPLICATIONS: CHRONIC HEPATITIS C VIRUS INFECTION IS NOW CURABLE WITH DIRECT-ACTING ANTIVIRALS, BUT IT REMAINS UNCLEAR WHETHER HEPATITIS C SEQUELAE ARE FULLY REVERSIBLE AFTER VIRAL ELIMINATION. OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OR ACCELERATION OF BIOLOGICAL AGE ARE REVERSIBLE IN PRINCIPLE, BUT THIS REQUIRES TIME, WHILE A LACK OF REVERSIBILITY APPEARS TO BE ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. WHILE MOST CLINICAL RISK SCORES NOW TAKE CHRONOLOGICAL AGE INTO ACCOUNT, IT MAY BE WORTHWHILE TO EXPLORE HOW BIOLOGICAL AGE MIGHT IMPROVE THESE SCORES IN THE FUTURE. BIOLOGICAL AGE MAY BE A CORNERSTONE FOR THE INDIVIDUALIZED CLINICAL ASSESSMENT OF PATIENTS IN THE FUTURE, AS IT BETTER REFLECTS PATIENTS' LIFESTYLE AND ENVIRONMENTAL EXPOSURES OVER DECADES.	2023	

19  5682  28 SHORT-TERM CHANGES IN GLOBAL METHYLATION AND HYDROXYMETHYLATION DURING ALCOHOL DETOXIFICATION. ALCOHOL DEPENDENCE IS A COMMON PUBLIC HEALTH PROBLEM AND EPIGENETICS MAY OFFER NEW ASPECTS IN UNDERSTANDING THE BIOLOGICAL AND GENETIC UNDERPINNINGS AND IMPROVE TREATMENT OF THIS COMPLEX DISEASE. SUPPOSEDLY, METHYLATION AND HYDROXYMETHYLATION ARE ALTERED IN BRAIN TISSUES AND IN SYNAPSE-RELATED GENES DUE TO CHRONIC ALCOHOL INTAKE AND DURING WITHDRAWAL. TO ASSESS POTENTIAL EPIGENETIC CHANGES AFTER CESSATION OF CHRONIC ALCOHOL INTAKE, WE COMPARED 23 ALCOHOL-DEPENDENT INDIVIDUALS DURING INPATIENT ALCOHOL DETOXIFICATION WITH 13 CAREFULLY MATCHED CONTROLS. BLOOD SAMPLES WERE TAKEN ON THE DAY OF ADMISSION, AFTER ONE AND AFTER TWO WEEKS AT THE END OF INPATIENT TREATMENT. GENOME-WIDE GLOBAL METHYLATION AND GLOBAL DNA HYDROXYMETHYLATION WERE COMPARED ACROSS GROUPS. THERE WERE SIGNIFICANT DIFFERENCES IN GLOBAL METHYLATION ACROSS TIME FROM ADMISSION TO ONE AND TWO WEEKS OF INPATIENT WITHDRAWAL (P < 0.001). THESE FINDINGS WERE PARALLELED TO CHANGES IN GLOBAL DNA HYDROXYMETHYLATION ACROSS TIME WHEN AGE WAS EMPLOYED AS A COFACTOR (P < 0.001). SEVERAL POTENTIALLY INFLUENCING VARIABLES LIKE SEVERITY OF WITHDRAWAL, DOSE OF WITHDRAWAL MEDICATION AND ALCOHOL INTAKE BEFORE ADMISSION DID NOT YIELD SIGNIFICANT INFLUENCE ON EPIGENETIC CHANGES. THE RESULTS CONFIRM PREVIOUS FINDINGS OF SIGNIFICANT ALTERATIONS OF EPIGENETIC PATTERNS DURING ALCOHOL INTOXICATION AND PRESENT FOR THE FIRST TIME HYDROXYMETHYLATION CHANGES IN THESE INDIVIDUALS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3136  30 GLOBAL DNA METHYLATION LEVELS IN WHITE BLOOD CELLS OF PATIENTS WITH CHRONIC HEROIN USE DISORDER. A PROSPECTIVE STUDY. BACKGROUND: INCREASING SCIENTIFIC EVIDENCE SHOWS THE SIGNIFICANT ROLE OF EPIGENETIC MECHANISMS IN DRUG USE DISORDER, ABSTINENCE AND RELAPSE. STUDIES ON HUMAN SUBJECTS ARE LIMITED COMPARED TO THOSE ON ANIMALS, FOR VARIOUS REASONS SUCH AS POLY-SUBSTANCE ABUSE, HIGH DROP-OUT RATE AND TECHNICAL DIFFICULTIES. OBJECTIVES: OUR GOAL WAS TO EVALUATE WHETHER A MONITORED ABSTINENCE PERIOD OF 21 DAYS COULD INDUCE CHANGES IN GLOBAL DNA METHYLATION IN CHRONIC HEROIN USERS. METHOD: IN THE CURRENT STUDY, WE PRESENT DATA ON GLOBAL DNA METHYLATION ON A SET OF 18 MALE PATIENTS WITH CHRONIC HEROIN USE DISORDER, CAREFULLY SELECTED BASED ON INCLUSION AND EXCLUSION CRITERIA, WHO WERE HOSPITALIZED AND CLOSELY MONITORED DURING A 21-DAY DETOXIFICATION PROGRAM, ONE OF THE FEW WHERE NO OPIOID AGONIST IS ADMINISTERED. THE PARTICIPANTS WERE SAMPLED TWICE, ONCE UPON ENROLMENT TO THE PROGRAM AND ONCE UPON COMPLETION. RESULTS: ACCORDING TO OUR RESULTS, NO DIFFERENCE IN GLOBAL DNA METHYLATION WAS DETECTED BETWEEN SAMPLES COLLECTED UPON ENROLMENT AND SAMPLES COLLECTED UPON COMPLETION OF THE PROGRAM. CONCLUSION: THE FINDINGS OF THIS STUDY DO NOT RULE OUT THE POSSIBILITY THAT THE 21-DAY ABSTINENCE PERIOD WAS NOT LONG ENOUGH TO OBSERVE CHANGES IN GLOBAL DNA METHYLATION, OR THAT ABSTINENCE INDUCED SITE-SPECIFIC METHYLATION CHANGES (BUT NOT GLOBAL CHANGES), THAT CERTAINLY MERIT FURTHER EVALUATION.	2021