1 3558 139 IMPACT OF CHRONIC BENZENE POISONING ON ABERRANT MITOCHONDRIAL DNA METHYLATION: A PROSPECTIVE OBSERVATIONAL STUDY. BENZENE IS USED AS AN INDUSTRIAL SOLVENT, WHICH MAY RESULT IN CHRONIC BENZENE POISONING (CBP). SEVERAL STUDIES SUGGESTED THAT CBP WAS ASSOCIATED WITH MITOCHONDRIAL EPIGENETIC REGULATION. THIS STUDY AIMED TO EXPLORE THE POTENTIAL RELATION BETWEEN CBP AND MITOCHONDRIAL DNA (MTDNA) METHYLATION. THIS PROSPECTIVE OBSERVATIONAL STUDY ENROLLED CBP PATIENTS ADMITTED TO SHENZHEN PREVENTION AND TREATMENT CENTER FOR OCCUPATIONAL DISEASES HOSPITAL AND HEALTHY INDIVIDUALS BETWEEN 2018 AND 2021. THE WHITE BLOOD CELL (WBC), RED BLOOD CELL (RBC), HEMOGLOBIN (HB), AND PLATELET (PLT) COUNTS AND MTDNA METHYLATION LEVELS WERE MEASURED USING BLOOD FLOW CYTOMETRY AND TARGETED BISULFITE SEQUENCING, RESPECTIVELY. A TOTAL OF 90 PARTICIPANTS WERE RECRUITED, INCLUDING 30 CASES OF CBP (20 FEMALES, MEAN AGE 43.0 +/- 8.0 YEARS) AND 60 HEALTHY INDIVIDUALS (42 FEMALES, MEAN AGE 43.5 +/- 11.5 YEARS). THIS STUDY DETECTED 168 MITOCHONDRIAL METHYLATION SITES >0 IN ALL STUDY SUBJECTS. THE MTDNA METHYLATION LEVELS IN THE CBP CASES WERE LOWER THAN THE HEALTHY INDIVIDUALS [MEDIAN +/- INTERQUARTILE-RANGE (IQR), 25TH PERCENTILE, 75TH PERCENTILE: (1.140 +/- 0.570, 0.965, 1.535)% VS. MEDIAN +/- IQR, 25TH PERCENTILE, 75TH PERCENTILE: (1.705 +/- 0.205,1.240,2.445)%, P < 0.05]. ADDITIONALLY, THE SPEARMAN CORRELATION ANALYSIS SHOWED THAT THE MTDNA METHYLATION LEVELS WERE POSITIVELY CORRELATED WITH THE COUNTS OF CIRCULATING LEUKOCYTES [WBC (R = 0.048, P = 0.036)] AND PLATELETS [PLT (R = 0.129, P < 0.01)]. WE PROVIDED SOLID EVIDENCE OF ASSOCIATION BETWEEN CBP AND ABERRANT MTDNA METHYLATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2 6832  30 [HYPOMETHYLATION OF TNF-ALPHA GENE PROMOTER IN THE PATIENTS WITH ACUTE-ON-CHRONIC HEPATITIS B LIVER FAILURE]. OBJECTIVE: THE PRESENT STUDY WAS DESIGNED TO INVESTIGATE THE POSSIBLE EPIGENETIC ALTERATION IN THE PROMOTER OF TNF-ALPHA IN THE PATIENTS WITH ACUTE-ON-CHRONIC HEPATITIS B LIVER FAILURE (ACHBLF). METHODS: THE METHYLATION OF TNF-ALPHA PROMOTER IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WAS MEASURED BY METHYLATION SPECIFIC PCR (MSP). THE LEVEL OF SERUM TNF-ALPHA WAS DETERMINED BY ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). MODEL FOR END-STAGE LIVER DISEASE (MELD) WAS PERFORMED FOR THE EVALUATION OF LIVER FAILURE. RESULTS: THE SERUM LEVEL OF TNF-ALPHA IN PATIENTS WITH ACHBLF(44.9260 +/- 26.48523) WAS HIGHER THAN THAT IN CHB (18.92505 +/- 9.04461) AND HEALTHY CONTROLS (11.9172 +/- 5.04612) (P < 0.05). MOREOVER, THE SERUM TNF-ALPHA LEVEL WAS SIGNIFICANTLY DECREASED IN METHYLATION GROUP AS COMPARED TO UNMETHYLAITON GROUP IN PATIENTS WITH ACHBLF (P < 0.05). MELD WAS NOT SIGNIFICANTLY DIFFERENT BETWEEN METHYLATED AND UNMETHYLATED GROUP OF ACHBLF PATIENTS (P > 0.05). IN ADDITION, THE SERUM LEVEL OF TNF-ALPHA WAS FOUND TO BE POSITIVELY CORRELATED WITH SERUM TOTAL BILIRUBIN (R = 0.891, P < 0.01) AND MELD SCORE (R = 0.792, P < 0.01), BUT TO BE NEGATIVELY CORRELATED WITH PROTHROMBIN ACTIVITY (R = - 0.511, P < 0.05) IN PATIENTS WITH ACHBLF. CONCLUSION: THE TNF-ALPHA METHYLATION PATTEN IS STABLE FOR THE LIVER FAILURE, SUGGESTING THE EFFECT OF ENVIRONMENT ON METHYLATION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3 1029  35 CIRCULATING PLASMA MICRORNA IN PATIENTS WITH ACTIVE ACROMEGALY. CONTEXT: EXCESSIVE PRODUCTION OF GROWTH HORMONE CAUSES MARKED MULTIORGAN CHANGES IN PATIENTS WITH ACROMEGALY, WHICH MAY INVOLVE EPIGENETIC MECHANISMS. OBJECTIVE: TO EVALUATE DIFFERENCES IN CIRCULATING MICRORNAS (MIRNAS) ASSOCIATED WITH CHRONIC GROWTH HORMONE OVERPRODUCTION IN ADULTS. DESIGN AND SETTING: A CROSS-SECTIONAL CASE-CONTROL STUDY WAS CONDUCTED AT A TERTIARY MEDICAL CENTER. PARTICIPANTS: WE ENROLLED 12 CONSECUTIVE PATIENTS WITH ACROMEGALY ALONG WITH 12 AGE- AND SEX-MATCHED CONTROLS IN THE DISCOVERY PHASE OF THE STUDY AND THEN EXTENDED THIS COHORT TO 47 PATIENTS WITH ACROMEGALY AND 28 HEALTHY CONTROLS FOR THE VALIDATION STUDY. MAIN OUTCOME MEASURES: PLASMA MIRNAS WERE QUANTIFIED BY NEXT-GENERATION SEQUENCING (NGS) IN THE DISCOVERY PHASE. LEVELS OF SELECTED MIRNAS WERE VALIDATED ON EXTENDED COHORTS USING REVERSE TRANSCRIPTION QUANTITATIVE POLYMERASE CHAIN REACTION (RT-QPCR), COMPARED BETWEEN GROUPS, AND CORRELATED WITH CLINICAL PARAMETERS. RESULTS: BASED ON NGS DATA, WE SELECTED 3 PLASMA MIRNAS DOWNREGULATED IN PATIENTS WITH ACROMEGALY COMPARED TO HEALTHY CONTROLS: MIR-4446-3P -1.317 (P = 0.001), MIR-215-5P -3.040 (P = 0.005), AND MIR-342-5P -1.875 (P = 0.013) WITHOUT MULTIPLICITY CORRECTION FOR ALL 3 MIRNAS. THESE RESULTS WERE CONFIRMED BY RT-QPCR IN THE VALIDATION PHASE FOR 2 MIRNAS OUT OF 3: MIR-4446-3P (P < 0.001, PADJUSTED < 0.001), AREA UNDER THE RECEIVER-OPERATOR CURVE (AUC) 0.862 (95% CI 0.723-0.936; P < 0.001) AND MIR-215-5P (P < 0.001, PADJUSTED < 0.001), AUC 0.829 (95% CI 0.698-0.907; P < 0.001) TO DIFFERENTIATE PATIENTS WITH ACROMEGALY FROM HEALTHY CONTROLS. CONCLUSIONS: IN A 2-PHASE EXPERIMENT USING 2 DIFFERENT TECHNIQUES WE FOUND AND VALIDATED THE DOWNREGULATION OF PLASMA MIR-4446-3P AND MIR-215-5P IN PATIENTS WITH ACROMEGALY COMPARED TO HEALTHY SUBJECTS, WHICH MAKES THEM PROMISING BIOMARKERS FOR FURTHER RESEARCH.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  508  33 ASSOCIATION OF LOW-DOSE EXPOSURE TO PERSISTENT ORGANIC POLLUTANTS WITH E-CADHERIN PROMOTER METHYLATION IN HEALTHY KOREANS. BACKGROUND: PERSISTENT ORGANIC POLLUTANTS (POPS), DESPITE THEIR CONSIDERABLY LOW LEVELS IN HUMANS, ARE AN INCREASING CONCERN FOR THE GENERAL POPULATIONS GIVEN THEIR VARIOUS ADVERSE HEALTH PROBLEMS, INCLUDING METABOLIC AND CARCINOGENIC EFFECTS. DNA METHYLATION DEREGULATION IS THOUGHT TO BE A KEY MECHANISM IN THE DEVELOPMENT OF HUMAN CHRONIC DISEASES INCLUDING CANCER. METHODS: IN AN ATTEMPT TO IDENTIFY BIOMARKERS MONITORING LOW-DOSE EXPOSURE AND HAZARD, WE EXPLORED WHETHER ORGANOCHLORINE PESTICIDES (OCPS) AND POLYCHLORINATED BIPHENYLS (PCBS) MAY INFLUENCE THE METHYLATION OF TUMOUR SUPPRESSOR GENE E-CADHERIN (CDH1) USING PERIPHERAL BLOOD CELLS FROM 364 HEALTHY KOREAN SUBJECTS. RESULTS: CDH1 METHYLATION WAS OBSERVED IN 78.3% OF STUDY SUBJECTS. SERUM CONCENTRATIONS OF OCPS OR PCBS COMPOUNDS WERE HIGHER IN CDH1 METHYLATION-POSITIVE SUBJECTS THAN IN METHYLATION-NEGATIVE ONES. AFTER ADJUSTING FOR VARIOUS COVARIATES, THE ODDS RATIO OF CDH1 METHYLATION OF THE SUMMARY MEASURE OF PCBS WERE 1.0, 2.5 (95% CONFIDENCE INTERVAL: 1.2-5.3), 3.6 (1.6-8.1), 3.6 (1.4-8.6), AND 2.5 (1.1-5.7) ACROSS QUINTILES OF PCBS (P(TREND) = 0.01). THE VALUES OF OCPS WERE 1.0, 0.9, 1.2, 2.4 (1.0-5.9), AND 1.7 (P(TREND) = 0.05). CONCLUSIONS: IN THIS EXPLORATORY STUDY WITH A SMALL SAMPLE, CDH1 METHYLATION MIGHT BE SERVED AS THE EPIGENETIC BIOMARKER ASSOCIATED WITH POPS EXPOSURE AND ADVERSE HEALTH EFFECT.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 1786  41 EFFECT OF ARSENIC EXPOSURE ON NRF2-KEAP1 PATHWAY AND EPIGENETIC MODIFICATION. ARSENIC (AS) IS A KNOWN TOXIC ELEMENT AND CARCINOGEN. TRANSCRIPTION FACTOR NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) CONTROLS CELLULAR ADAPTATION TO OXIDANTS AND ELECTROPHILES BY INDUCING ANTIOXIDANT GENES IN RESPONSE TO REDOX STRESS. TO EXPLORE ASSOCIATIONS BETWEEN AS LEVEL AND NRF2-REGULATED CYTOPROTECTIVE GENES EXPRESSION, AN OBSERVATIONAL STUDY WAS CONDUCTED IN A POPULATION OF 61 OCCUPATIONALLY EXPOSED MEN WITH MEDIAN (ME) AGE 50 YEARS (INTERQUARTILE RANGE (IQR) 42-54) AND IN A CONTROL GROUP OF 52 MEN AGED 40 (IQR 31-51.5) WITHOUT OCCUPATIONAL EXPOSURE. NRF2, KEAP1, GSTP1, HMOX1, NQO1, PRDX1, AND TXNRD1 TRANSCRIPT LEVELS WERE DETERMINED BY MEANS OF QUANTITATIVE REAL-TIME PCR ALONG WITH THE GENE EXPRESSION, METHYLATION OF NRF2 AND KEAP1, AS WELL AS GLOBAL DNA METHYLATION WERE ASSESSED. THE MEDIAN URINE AS (TOT.) LEVEL IN THE EXPOSED AND CONTROL GROUP WAS FOUND TO BE 21.8 MUG/G CREAT. (IQR 15.5-39.8 MUG/G CREAT.) AND 3.8 MUG/G CREAT. (IQR 2.5-9.3) (P < 0.001). GLOBAL DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN OCCUPATIONALLY EXPOSED WORKERS THAN IN CONTROLS (ME 14.1 (IQR 9.5-18.1) VS ME 8.5 (IQR 5.9-12.6) P < 0.0001). NRF2 MRNA LEVEL WAS POSITIVELY CORRELATED WITH EXPRESSION OF ALL INVESTIGATED NRF2-TARGET GENES IN BOTH GROUPS (0.37 > R < 0.76, ALL P VALUES < 0.0001). THE MULTIVARIATE LINEAR REGRESSION ADJUSTING FOR GLOBAL METHYLATION SHOWED THAT AS(III) LEVEL WAS SIGNIFICANTLY ASSOCIATED WITH EXPRESSION OF TXNRD1, GSTP1, HMOX1, AND PRDX1. THE RESULTS OF THIS STUDY INDICATE THAT ARSENIC OCCUPATIONAL EXPOSURE IS POSITIVELY ASSOCIATED WITH GLOBAL DNA METHYLATION. THE FINDINGS PROVIDE EVIDENCE FOR RATHER INACTIVATION OF NRF2-KEAP1 PATHWAY IN RESPONSE TO CHRONIC ARSENIC EXPOSURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6 2390  29 EPIGENETIC REPRESSION OF CCDC37 AND MAP1B LINKS CHRONIC OBSTRUCTIVE PULMONARY DISEASE TO LUNG CANCER. INTRODUCTION: LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) SHARE ENVIRONMENTAL RISK FACTORS. COPD ALSO INCREASES THE RISK OF LUNG CANCER; HOWEVER, THE MOLECULAR MECHANISMS ARE UNCLEAR. METHODS: AN EPIGENOME-WIDE ASSOCIATION STUDY OF LUNG TUMORS AND CANCER-FREE LUNG TISSUE (CFLT) PAIRS FROM NON-SMALL-CELL LUNG CANCER CASES WITH (N = 18) OR WITHOUT (N = 17) COPD WAS CONDUCTED USING THE HUMANMETHYLATION450 BEADCHIP (HM450K). COPD-ASSOCIATED METHYLATION OF TOP-RANKED GENES WAS CONFIRMED IN A LARGER SAMPLE SET, INDEPENDENTLY VALIDATED, AND THEIR POTENTIAL AS SPUTUM-BASED BIOMARKERS WAS INVESTIGATED. RESULTS: METHYLATION OF CCDC37 AND MAP1B WAS MORE PREVALENT IN LUNG TUMORS FROM COPD THAN NON-COPD CASES [54 OF 71 (76%) VERSUS 20 OF 46 (43%), P = 0.0013] AND [48 OF 71 (68%) VERSUS 17 OF 46 (37%), P = 0.0035], RESPECTIVELY, AFTER ADJUSTMENT FOR AGE, SEX, SMOKING STATUS, AND TUMOR HISTOLOGY. HM450K PROBES ACROSS CCDC37 AND MAP1B PROMOTERS SHOWED HIGHER METHYLATION IN TUMORS THAN CFLT WITH THE HIGHEST METHYLATION SEEN IN TUMORS FROM COPD CASES (P < 0.05). THESE RESULTS WERE INDEPENDENTLY VALIDATED USING THE CANCER GENOME ATLAS DATA. CCDC37 METHYLATION WAS MORE PREVALENT IN SPUTUM FROM COPD THAN NON-COPD SMOKERS (P < 0.005) FROM TWO COHORTS. CCDC37 AND MAP1B EXPRESSION WAS DRAMATICALLY REPRESSED IN TUMORS AND CFLT FROM COPD THAN NON-COPD CASES, P LESS THAN 0.02. CONCLUSIONS: THE REDUCED EXPRESSION OF CCDC37 AND MAP1B ASSOCIATED WITH COPD LIKELY PREDISPOSES THESE GENES TO METHYLATION THAT IN TURN, MAY CONTRIBUTE TO LUNG CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  659  35 BLOOD GLOBAL DNA METHYLATION IS DECREASED IN NON-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS. BACKGROUND: ALTERATIONS IN GLOBAL DNA METHYLATION HAVE BEEN ASSOCIATED WITH OXIDATIVE STRESS (OS). SINCE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY INCREASED OXIDATIVE STRESS WE AIMED TO EVALUATE THE LEVELS OF GLOBAL DNA METHYLATION IN THIS PATIENT GROUP. METHODS: WE ASSESSED METHYLCYTOSINE (MCYT) LEVELS IN DNA FROM BLOOD COLLECTED IN 43 COPD PATIENTS (29 WITH MILD AND 14 WITH MODERATE DISEASE) AND 43 AGE- AND SEX-MATCHED HEALTHY CONTROLS. RESULTS: DNA METHYLATION WAS SIGNIFICANTLY LOWER IN COPD PATIENTS VS. CONTROLS (4.20 +/- 0.18% MCYT VS. 4.29 +/- 0.18% MCYT, P = 0.02). FURTHERMORE, DNA METHYLATION IN COPD PATIENTS WITH MODERATE DISEASE WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH MILD DISEASE (4.14 +/- 0.15% MCYT VS. 4.23 +/- 0.19% MCYT, P < 0.05). UNIVARIATE LOGISTIC REGRESSION ANALYSIS SHOWED THAT LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH PRESENCE OF COPD (CRUDE OR = 0.06, 95% CI 0.00 TO 0.67, P = 0.023). THIS RELATIONSHIP REMAINED SIGNIFICANT AFTER ADJUSTING FOR SEVERAL CONFOUNDERS (OR 0.03, 95% CI 0.00 TO 0.67; P = 0.028). RECEIVER OPERATING CHARACTERISTICS (ROC) CURVE ANALYSIS DEMONSTRATED THE AREA UNDER THE CURVE OF MCYT WAS 0.646, WITH 46.6% SENSITIVITY AND 79.1% SPECIFICITY FOR PRESENCE OF COPD. CONCLUSIONS: THERE WERE NO SIGNIFICANT CORRELATIONS BETWEEN METHYLATION AND OS INDICES. THE PRESENCE AND SEVERITY OF COPD IS ASSOCIATED WITH PROGRESSIVELY LOWER DNA METHYLATION IN BLOOD. HOWEVER, THIS EPIGENETIC ALTERATION SEEMS INDEPENDENT OF OXIDATIVE STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 6248  33 THE METHYLATION STATUS OF THE DDX43 PROMOTER IN CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION IS A COMMON EPIGENETIC ALTERATION AND AN IMPORTANT FEATURE IN HUMAN CANCERS. THE DEAD BOX POLYPEPTIDE 43 (DDX43) HAS BEEN FOUND TO BE OVEREXPRESSED IN VARIOUS SOLID TUMORS AND SOME HEMATOLOGIC MALIGNANCIES. IN THE PRESENT STUDY, WE INVESTIGATED THE METHYLATION STATUS OF THE DDX43 PROMOTER IN 87 CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) USING REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION AND EXAMINED THE DDX43 TRANSCRIPT IN 35 PATIENTS USING REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION. DDX43 PROMOTER HYPOMETHYLATION WAS OBSERVED IN 22 (25.3%) CML PATIENTS. NO SIGNIFICANT CORRELATION WAS FOUND BETWEEN THE HYPOMETHYLATION OF THE DDX43 PROMOTER WITH THE AGE, SEX, WHITE BLOOD CELL COUNTS, HEMOGLOBIN CONCENTRATION, PLATELET COUNTS, AND CHROMOSOMAL ABNORMALITIES OF CML PATIENTS (P>0.05). THE FREQUENCY OF DDX43 HYPOMETHYLATION IN PATIENTS IN THE CHRONIC PHASE, IN THE ACCELERATED PHASE, AND IN BLAST CRISIS WAS 23.4% (15/64), 25.0% (2/8), AND 33.3% (5/15), RESPECTIVELY (P>0.05). THERE WAS A SIGNIFICANT CORRELATION BETWEEN DDX43 HYPOMETHYLATION AND DDX43 TRANSCRIPT (R=0.469, P=0.004). OUR DATA SUGGEST THAT HYPOMETHYLATION OF THE DDX43 PROMOTER MAY BE AN EARLY AND FREQUENT MOLECULAR EVENT IN THE DEVELOPMENT OF CML IN CHINESE PATIENTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9 2626  34 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10 3310  29 HIGHER ORDER GENES INTERACTION IN DNA REPAIR AND CYTOKINE GENES POLYMORPHISM AND RISK TO LUNG CANCER IN NORTH INDIANS. CONTEXT: LUNG CANCER PATHOLOGICAL PROCESS INVOLVES CUMULATIVE EFFECTS EXERTED BY GENE POLYMORPHISM(S), EPIGENETIC MODIFICATIONS, AND ALTERATIONS IN DNA REPAIR MACHINERY. FURTHER, DNA DAMAGE DUE TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, AND THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS IS ALSO AN ETIOLOGIC MILIEU OF THIS MALIGNANT DISEASE. AIMS: THE PRESENT STUDY AIMS TO ASSESS THE PROGNOSTIC VALUE OF DNA REPAIR, CYTOKINES, AND GST GENE POLYMORPHISM IN LUNG CANCER PATIENTS WHO HAD NOT RECEIVED ANY NEOADJUVANT THERAPY. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, 127 CASES AND 120 CONTROLS WERE ENROLLED. DNA FROM THE BLOOD SAMPLES OF BOTH PATIENTS AND CONTROLS WAS USED TO GENOTYPE XRCC1ARG399GLN, XPDLYS751GLN, AND INTERLEUKIN-1 (IL-1BETA) GENES BY POLYMERASE CHAIN REACTION (PCR)-RESTRICTION FRAGMENT LENGTH POLYMORPHISM METHOD, WHEREAS MULTIPLEX PCR WAS PERFORMED TO GENOTYPE GSTT1 AND GSTM1. RESULTS: BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT XRCC1ARG399GLN-MUTANT GENOTYPE (GLN/GLN, ODDS RATIO [OR] = 4.6, 95% CONFIDENCE INTERVAL [CI]: 2.2-9.6) AND GSTT1 NULL (OR = 2.7, 95% CI: 1.6-4.5) WERE LINKED TO CANCER SUSCEPTIBILITY. GENERALIZED MULTIDIMENSIONAL REDUCTION ANALYSIS OF HIGHER ORDER GENE-GENE INTERACTION USING CROSS-VALIDATION TESTING (CVT) ACCURACY SHOWED THAT GSTT1 (CVT 0.62, P = 0.001), XPD751 AND IL-1BETA (CVT 0.6, P = 0.001), AND XRCC1399, XPD751, AND INTERLEUKIN-1 RECEPTOR ANTAGONISTS (IL-1RN) (CVT 0.98, P = 0.001) WERE SINGLE-, TWO-, AND THREE-FACTOR BEST MODEL PREDICTED, RESPECTIVELY, FOR LUNG CANCER RISK. CLASSIFICATION AND REGRESSION TREE ANALYSIS RESULTS SHOWED THAT TERMINAL NODES WHICH CONTAIN XRCC1399-MUTANT GENOTYPE (AA) HAD INCREASED THE RISK TO LUNG CANCER. CONCLUSION: THE PRESENT STUDY DEMONSTRATED THAT XRCC1399 (GLN/GLN), GSTT1, AND IL-1RN ALLELE I, I/II SERVED AS THE RISK GENOTYPES. THESE GENES COULD SERVE AS THE BIOMARKERS TO PREDICT LUNG CANCER RISK.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  145  37 ABERRANT DNA METHYLATION STATUS AND MRNA EXPRESSION LEVEL OF SMG1 GENE IN CHRONIC MYELOID LEUKEMIA: A CASE-CONTROL STUDY. OOBJECTIVE: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE MALIGNANCY WITH DIFFERENT STAGES. ABERRANT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HAVE BEEN INTRODUCED AS A SIGNATURE FOR DIVERSE CANCERS WHICH ALSO PLAYS A CRUCIAL ROLE IN CML PATHOGENESIS AND DEVELOPMENT. SUPPRESSOR WITH MORPHOGENETIC EFFECT ON GENITALIA (SMG1) GENE RECENTLY HAS BEEN BROUGHT TO THE SPOTLIGHT AS A POTENT TUMOR SUPPRESSOR GENE THAT CAN BE SUPPRESSED BY TUMORS FOR FURTHER PROGRESS. THE PRESENT STUDY AIMS TO INVESTIGATE SMG1 STATUS IN CML PATIENTS. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, PERIPHERAL BLOOD FROM 30 PATIENTS WITH DIFFERENT PHASES OF CML [NEW CASE (N)=10, COMPLETE MOLECULAR REMISSION (CMR)=10, BLASTIC PHASE (BP)=10] AND 10 HEALTHY SUBJECTS WERE COLLECTED. METHYLATION STATUS AND EXPRESSION LEVEL OF SMG1 GENE PROMOTER WAS ASSESSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND QUANTITATIVE REVERSE-TRANSCRIPTION PCR, RESPECTIVELY. RESULTS: MSP RESULTS OF SMG1 GENE PROMOTOR IN THE NEW CASE GROUP WERE METHYLATED (60% METHYLATED, 30% HEMIMETHYLATED AND 10% UNMETHYLATED). ALL CMR AND CONTROL GROUP PATIENTS WERE UNMETHYLATED IN THE SMG1 GENE PROMOTER. IN THE BP GROUP, METHYLATED SMG1 PROMOTER WAS SEEN (50% OF PATIENTS HAD A METHYLATED STATUS AND 50% HAD HEMIMETHYLATED STATUS). IN COMPARISON WITH THE HEALTHY SUBJECTS, EXPRESSION LEVEL OF SMG1 IN THE NEW CASE GROUP WAS DECREASED (P<0.01); IN THE CMR GROUP AND BP-CML GROUPS, IT WAS INCREASED (P<0.05). NO SIGNIFICANT CORRELATION BETWEEN PATIENTS' HEMATOLOGICAL FEATURES AND SMG1 METHYLATION WAS SEEN. CONCLUSION: OUR RESULTS DEMONSTRATED THAT ABERRANT METHYLATION OF SMG1 OCCURRED IN CML PATIENTS AND IT HAD A SIGNIFICANT ASSOCIATION WITH SMG1 EXPRESSION. SMG1 GENE PROMOTER SHOWED DIVERSE METHYLATED STATUS AND SUBSEQUENT EXPRESSION LEVELS IN DIFFERENT PHASES OF CML. THESE FINDINGS SUGGESTED POSSIBLE PARTICIPATION OF SMG1 SUPPRESSION IN THE CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 1529  34 DNA METHYLATION CHANGES IN WHOLE BLOOD AND CD16+ NEUTROPHILS IN RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IN WOMEN OF CHILDBEARING AGE. FOLATE, A WATER-SOLUBLE VITAMIN, IS A KEY SOURCE OF ONE-CARBON GROUPS FOR DNA METHYLATION, BUT STUDIES OF THE DNA METHYLATION RESPONSE TO SUPPLEMENTAL FOLIC ACID YIELD INCONSISTENT RESULTS. THESE STUDIES ARE COMMONLY CONDUCTED USING WHOLE BLOOD, WHICH CONTAINS A MIXED POPULATION OF WHITE BLOOD CELLS THAT HAVE BEEN SHOWN TO CONFOUND RESULTS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE IF CD16+ NEUTROPHILS MAY PROVIDE MORE SPECIFIC DATA THAN WHOLE BLOOD FOR IDENTIFYING DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION. THE STUDY WAS PERFORMED IN NORMAL WEIGHT (BMI 18.5 - 24.9 KG/M2) WOMEN (18 - 35 Y; N = 12), WITH BLOOD SAMPLES TAKEN BEFORE AND AFTER 8 WEEKS OF FOLIC ACID SUPPLEMENTATION AT 800 MUG/DAY. DNA METHYLATION PATTERNS FROM WHOLE BLOOD AND ISOLATED CD16+ NEUTROPHILS WERE MEASURED ACROSS >485,000 CPG SITES THROUGHOUT THE GENOME USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP. OVER THE COURSE OF THE 8-WEEK SUPPLEMENTATION, 6746 AND 7513 CPG SITES CHANGED (P < 0.05) IN WHOLE BLOOD AND CD16+ NEUTROPHILS, RESPECTIVELY. DNA METHYLATION DECREASED IN 68.4% (WHOLE BLOOD) AND 71.8% (CD16+ NEUTROPHILS) OF THESE SITES. THERE WERE ONLY 182 CPG SITES THAT CHANGED IN BOTH THE WHOLE BLOOD AND CD16+ NEUTROPHILS, 139 OF WHICH CHANGED IN THE SAME DIRECTION. THESE RESULTS SUGGEST THAT THE GENOME-WIDE DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IS DIFFERENT BETWEEN WHOLE BLOOD AND CD16+ NEUTROPHILS AND THAT A SINGLE WHITE BLOOD CELL TYPE MAY FUNCTION AS A MORE SPECIFIC EPIGENETIC REPORTER OF FOLATE STATUS THAN WHOLE BLOOD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 5621  29 SCREENING METHYLATION OF DNA REPAIR GENES IN THE ORAL MUCOSA OF CHRONIC SMOKERS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EPIGENETIC CHANGES IN THE PROCESS OF ORAL CARCINOGENESIS BY SCREENING THE METHYLATION OF REPAIR GENES IN CHRONIC SMOKERS. DESIGN: TWO GROUPS WERE FORMED: GROUP 1: 16 SMOKERS WITH CONSUMPTION OF 20 CIGARETTES/DAY FOR AT LEAST 10 YEARS; AND GROUP 2: 10 NON-SMOKING. EXFOLIATIVE CYTOLOGY OF THE TONGUE WAS PERFORMED, AND THE EXTRACTED DNA WAS TREATED BY ENZYMES. THE PCR ARRAY SYSTEM PERFORMED METHYLATION SCREENING TO EVALUATE 22 DNA REPAIR GENES, AND THE RESULTS WERE VALIDATED BY RT-QPCR FOR EACH GENE WITH METHYLATION LEVELS >/=10%. RESULTS: HIGHEST PERCENTAGES OF METHYLATION WERE OBSERVED FOR MLH3 AND XRCC1 GENES (11-20% METHYLATION) AND IN ONE CASE FOR MRE11A AND PMS2 (>50% METHYLATION). STATISTICAL ANALYSIS SHOWED SIGNIFICANT DIFFERENCES IN THE EXPRESSION OF THE GENES MRE11A (P = 0.0002), PMS2(P = 0.0068), XRCC1 (P = 0.0080) AND MLH3 (0.0057) BETWEEN THE TWO GROUPS. CONCLUSION: THE EFFECTS OF CHRONIC SMOKING ON ORAL MUCOSA LED TO THE METHYLATION OF GENES MRE11A PMS2, XRCC1 AND MLH3, BUT RESULTED IN A REDUCTION OF GENE EXPRESSION OF MRE11A AND PMS2, WHICH SHOWED >/=50% METHYLATION. THESE RESULTS PROVIDE EVIDENCE THAT SMOKING CAUSE METHYLATION AND REDUCED EXPRESSION OF REPAIR GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  116  40 A STUDY OF DNA METHYLATION OF BLADDER CANCER BIOMARKERS IN THE URINE OF PATIENTS WITH NEUROGENIC LOWER URINARY TRACT DYSFUNCTION. BACKGROUND: BLADDER CANCER (BCA) IN PATIENTS SUFFERING FROM NEUROGENIC LOWER URINARY TRACT DYSFUNCTION (NLUTD) IS A SIGNIFICANT CONCERN DUE TO ITS ADVANCED STAGE AT DIAGNOSIS AND HIGH MORTALITY RATE. CURRENTLY, THERE IS A SCARCITY OF SPECIFIC GUIDELINES FOR BCA SCREENING IN THESE PATIENTS. THE DEVELOPMENT OF URINE BIOMARKERS FOR BCA SEEMS TO BE AN ATTRACTIVE NON-INVASIVE METHOD OF SCREENING OR RISK STRATIFICATION IN THIS PATIENT POPULATION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION, RESULTING IN THE TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSION GENES, THAT IS FREQUENTLY DETECTED IN THE URINE OF BCA PATIENTS. OBJECTIVES: WE AIMED TO INVESTIGATE DNA HYPERMETHYLATION IN FIVE GENE PROMOTERS, PREVIOUSLY ASSOCIATED WITH BCA, IN THE URINE OF NLUTD PATIENTS, AND IN COMPARISON WITH HEALTHY CONTROLS. DESIGN, SETTING AND PARTICIPANTS: THIS WAS A PROSPECTIVE CASE-CONTROL STUDY THAT RECRUITED NEUROUROLOGY OUTPATIENTS FROM A PUBLIC TEACHING HOSPITAL WHO HAD SUFFERED FROM NLUTD FOR AT LEAST 5 YEARS. THEY ALL UNDERWENT CYSTOSCOPY COMBINED WITH BIOPSY FOR BCA SCREENING FOLLOWING WRITTEN INFORMED CONSENT. DNA WAS EXTRACTED AND DNA METHYLATION WAS ASSESSED FOR THE RASSF1, RARBETA, DAPK, TERT AND APC GENE PROMOTERS VIA QUANTITATIVE METHYLATION-SPECIFIC PCR IN URINE SPECIMENS FROM THE PATIENTS AND CONTROLS. RESULTS: FORTY-ONE PATIENTS OF MIXED NLUTD ETIOLOGY AND 35 CONTROLS WERE ENROLLED. DNA WAS DETECTED IN 36 PATIENTS' URINE SPECIMENS AND IN THOSE OF 22 CONTROLS. IN THE URINE SPECIMENS, DNA WAS HYPERMETHYLATED IN AT LEAST ONE OF FIVE GENE PROMOTERS IN 17/36 PATIENTS AND IN 3/22 CONTROLS (47.22% VS. 13.64%, RESPECTIVELY, P = 0.009). RASSF1 WAS HYPERMETHYLATED IN 10/17 (58.82%) SPECIMENS WITH DETECTED METHYLATION, APC IN 7/17 (41.18%), DAPK IN 4/17 (23.53%), RAR-BETA2 IN 3/17 (17.56%) AND TERT IN NONE. ACCORDING TO A MULTIVARIATE LOGISTIC REGRESSION ANALYSIS, NLUTD AND MALE GENDER WERE SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION (OR = 7.43, P = 0.007 AND OR = 4.21; P = 0.04, RESPECTIVELY). IN THE TISSUE SPECIMENS, HISTOLOGY REVEALED TALG BCA IN TWO PATIENTS AND UROTHELIAL SQUAMOUS METAPLASIA IN FIVE PATIENTS. CHRONIC BLADDER INFLAMMATION WAS PRESENT IN 35/41 BLADDER BIOPSIES. CONCLUSIONS: DNA HYPERMETHYLATION IN A PANEL OF FIVE BCA-ASSOCIATED GENES IN THE URINE WAS SIGNIFICANTLY MORE FREQUENT IN NLUTD PATIENTS THAN IN THE CONTROLS. OUR RESULTS WARRANT FURTHER EVALUATION IN LONGITUDINAL STUDIES ASSESSING THE CLINICAL IMPLICATIONS AND POSSIBLE ASSOCIATIONS BETWEEN DNA HYPERMETHYLATION, CHRONIC INFLAMMATION AND BCA IN THE NLUTD POPULATION.	2023	

15 5070  37 PHYSICAL ACTIVITY, TELEVISION VIEWING TIME, AND DNA METHYLATION IN PERIPHERAL BLOOD. INTRODUCTION: PHYSICAL ACTIVITY MAY AFFECT HEALTH VIA DNA METHYLATION. THE EPIGENETIC INFLUENCES OF SEDENTARY BEHAVIORS SUCH AS TELEVISION VIEWING ARE UNKNOWN. WE PERFORMED A GENOMEWIDE STUDY OF DNA METHYLATION IN PERIPHERAL BLOOD IN RELATION TO PHYSICAL ACTIVITY AND TELEVISION VIEWING TIME. METHODS: DNA METHYLATION WAS MEASURED USING THE ILLUMINA INFINIUM HUMANMETHYLATION450K BEADCHIP ARRAY IN BLOOD SAMPLES COLLECTED AT BASELINE (N = 5513) AND FOLLOW-UP (N = 1249) FROM PARTICIPANTS IN THE MELBOURNE COLLABORATIVE COHORT STUDY. AT BASELINE, TIMES PER WEEK OF LEISURE-TIME PHYSICAL ACTIVITY WERE SELF-REPORTED. AT FOLLOW-UP, THE INTERNATIONAL PHYSICAL ACTIVITY QUESTIONNAIRE WAS USED TO ASSESS MET-HOURS PER WEEK OF TOTAL AND LEISURE-TIME PHYSICAL ACTIVITY AND HOURS PER DAY OF TELEVISION VIEWING TIME. LINEAR MIXED MODELS WERE USED TO ASSESS ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY AND TELEVISION VIEWING MEASURES AND DNA METHYLATION AT INDIVIDUAL CPG SITES, ADJUSTED FOR POTENTIAL CONFOUNDERS AND BATCH EFFECTS. RESULTS: AT FOLLOW-UP, TOTAL PHYSICAL ACTIVITY WAS ASSOCIATED WITH DNA METHYLATION AT CG10266336 (P = 6.0 X 10), ANNOTATED TO THE SAA2 GENE. WEAKER EVIDENCE OF ASSOCIATIONS (P < 1.0 X 10) WERE OBSERVED FOR AN ADDITIONAL 14 CPG SITES WITH TOTAL PHYSICAL ACTIVITY, FOR 7 CPG SITES WITH LEISURE-TIME PHYSICAL ACTIVITY, AND FOR 9 CPG SITES WITH TELEVISION VIEWING TIME. CHANGES IN LEISURE-TIME PHYSICAL ACTIVITY BETWEEN BASELINE AND FOLLOW-UP WERE ASSOCIATED WITH METHYLATION CHANGES (P < 0.05) AT FOUR OF THE SEVEN CPG SITES WITH WEAKER EVIDENCE OF CROSS-SECTIONAL ASSOCIATIONS WITH LEISURE-TIME PHYSICAL ACTIVITY. CONCLUSION: PHYSICAL ACTIVITY AND TELEVISION VIEWING MAY BE ASSOCIATED WITH BLOOD DNA METHYLATION, A POTENTIAL PATHWAY TO CHRONIC DISEASE DEVELOPMENT. FURTHER RESEARCH USING ACCELEROMETER DATA AND LARGER SAMPLE SIZES IS WARRANTED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16 2304  30 EPIGENETIC REGULATION OF CATHEPSIN L EXPRESSION IN CHRONIC MYELOID LEUKAEMIA. THE EXPRESSION AND SIGNIFICANCE OF CATHEPSIN L (CTSL) HAS BEEN EXTENSIVELY STUDIED IN SOLID TUMOURS. HOWEVER NO SUCH INFORMATION IN CHRONIC MYELOID LEUKAEMIA (CML) WAS AVAILABLE. WE INVESTIGATED THE ACTIVITY AND EXPRESSION OF THIS PROTEASE IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF 47 ADULT CML PATIENTS. THIRTY ADULTS SUFFERING FROM SYSTEMIC DISEASES AND 50 HEALTHY VOLUNTEERS SERVED AS CONTROLS. THE MRNA LEVELS OF CTSL, ITS SPECIFIC ENDOGENOUS INHIBITOR CYSTATIN C AND TRANSCRIPTIONAL UP-REGULATOR VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) WERE QUANTITATED BY REAL-TIME QPCR. CTSL PROTEASE ACTIVITY AND ITS MRNA EXPRESSION WERE SIGNIFICANTLY HIGHER IN CML CHRONIC PHASE (CP) PATIENTS COMPARED TO CML ACCELERATED PHASE/BLAST CRISIS (AP/BC) PATIENTS AND CONTROLS (P</= 0.001). VEGF WHOSE EXPRESSION WAS MOST PRONOUNCED IN CP AND DECLINED (P</= 0.001) IN THE ADVANCED PHASES OF THE MALIGNANCY EXHIBITED A STRONG POSITIVE CORRELATION WITH CTSL EXPRESSION (R= 0.97; P</= 0.001). CYSTATIN C EXPRESSION WAS SIGNIFICANTLY LOWER (P</= 0.001) IN CML AND DISPLAYED INVERSE CORRELATION WITH CTSL (R=-0.713; P</= 0.001) ACTIVITY. CTSL PROMOTER WAS SIGNIFICANTLY HYPOMETHYLATED IN CML CP COMPARED TO CML AP/BC PATIENTS AS WELL AS CONTROLS. K562, A BC CML CELL LINE DISPLAYED CTSL ACTIVITY, EXPRESSION AND METHYLATION STATUS OF CTSL PROMOTER THAT WAS COMPARABLE TO CML AP/BC PATIENTS. TREATMENT OF THESE CELLS OR PBMCS ISOLATED FROM CML AP/BC PATIENTS WITH 5'-AZA-CYTIDINE RESULTED IN A DRAMATIC INCREASE IN CSTL ACTIVITY AND/OR EXPRESSION THEREBY DEMONSTRATING THE ROLE OF PROMOTER METHYLATION IN THE STAGE SPECIFIC EXPRESSION OF CTSL IN CML. DIFFERENTIAL EXPRESSION OF CTSL IN CML AT VARIOUS STAGES OF MALIGNANCY MAY PROVE USEFUL IN IDENTIFICATION OF THE HIGH-RISK PATIENTS THEREBY FACILITATING BETTER MANAGEMENT OF DISEASE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17 3907  40 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18 4986  28 PATIENT-REPORTED SYMPTOM OUTCOMES AND MICROSATELLITE INSTABILITY IN PATIENTS WITH METASTATIC COLORECTAL CANCER. BACKGROUND: THE SURVIVAL OF PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IS INFLUENCED BY THE GENETIC AND EPIGENETIC CHANGES THAT MIGHT INFLUENCE THE PATIENT EXPERIENCE OF SYMPTOM BURDEN. UNDERSTANDING THE ASSOCIATION OF MOLECULAR CHANGES WITH THE SYMPTOM BURDEN COULD HELP CLINICIANS GAIN INSIGHT INTO THE MOLECULAR BASIS OF SYMPTOM BURDEN AND IMPROVE TREATMENT TOLERANCE. TO DATE, NO STUDIES HAVE COMPARED THE PATIENT-REPORTED SYMPTOM BURDEN WITH THESE MOLECULAR SUBSETS AMONG PATIENTS WITH MCRC. PATIENTS AND METHODS: WE RECRUITED PATIENTS WITH MCRC THAT WAS REFRACTORY TO >/= 1 LINE OF THERAPY WHO HAD BEEN ENROLLED IN THE ASSESSMENT OF TARGETED THERAPIES AGAINST COLORECTAL CANCER TRIAL AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. ALL PATIENTS COMPLETED A BASELINE GASTROINTESTINAL SYMPTOM INVENTORY (MD ANDERSON SYMPTOM INVENTORY, GASTROINTESTINAL). THE SYMPTOM BURDEN ACROSS KEY DEMOGRAPHIC VARIABLES AND MOLECULAR CHANGES, INCLUDING CRC-ASSOCIATED MUTATIONS, MICROSATELLITE INSTABILITY (MSI) STATUS, AND THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WERE COMPARED USING CHI(2) TESTS. ASSOCIATION OF THE SYMPTOM BURDEN WITH OVERALL SURVIVAL WAS EXAMINED USING COX REGRESSION MODELS. RESULTS: PATIENTS WITH AN MSI-HIGH (MSI-H) PHENOTYPE REPORTED GREATER PAIN (ODDS RATIO [OR], 3.06; 95% CONFIDENCE INTERVAL [CI], 1.61-5.84), FATIGUE (OR, 2.78; 95% CI, 1.41-5.49), SLEEP (OR, 2.52; 95% CI, 1.32-4.08); AND DROWSINESS (OR, 2.51; 95% CI, 1.32-4.78) COMPARED WITH MICROSATELLITE STABLE PATIENTS. PATIENTS WITH AN MSI-H PHENOTYPE ALSO HAD GREATER ODDS OF OVERALL SYMPTOM BURDEN (OR, 2.48; 95% CI, 1.29-4.74) COMPARED WITH MICROSATELLITE STABLE PATIENTS. THE CIMP-HIGH PATIENTS EXPERIENCED GREATER ODDS OF PAIN COMPARED WITH THE CIMP-NEGATIVE PATIENTS (OR, 1.72; 95% CI, 1.06-2.80). A GREATER OVERALL SYMPTOM BURDEN WAS ASSOCIATED WITH POOR OVERALL SURVIVAL (HAZARD RATIO, 1.42; 95% CI, 0.98-2.06]), ALTHOUGH THE DIFFERENCE WAS NOT SIGNIFICANT (P = .06). CONCLUSION: CORRELATION OF MSI-H-ASSOCIATED TUMOR FEATURES WITH THE SYMPTOM BURDEN COULD HELP PROVIDE A BETTER UNDERSTANDING OF UNDERLYING MECHANISMS ASSOCIATED WITH OUR FINDINGS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19 4220  28 METHYLATED CYSTEINE DIOXYGENASE-1 GENE PROMOTER IN THE SERUM IS A POTENTIAL BIOMARKER FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. EPIGENETIC ANALYSIS HAS ATTRACTED INCREASING ATTENTION IN THE MOLECULAR DIAGNOSIS OF HCC. CYSTEINE DIOXYGENASE 1 (CDO1) IS A KEY ENZYME IN THE TAURINE BIOSYNTHETIC PATHWAY AND CONVERTS CYSTEINE TO CYSTEINE SULFINATE. THE CDO1 GENE IS A TUMOR SUPPRESSOR GENE AND IS USUALLY SILENCED BY THE METHYLATION OF ITS PROMOTER IN CARCINOGENESIS. IN THIS STUDY, WE EVALUATED WHETHER THE METHYLATION STATUS OF CDO1 GENE PROMOTER IS OF DIAGNOSTIC VALUE FOR HEPATITIS B VIRUS (HBV)-RELATED HCC. THE CDO1 PROMOTER METHYLATION STATUS WAS DETERMINED IN SERUM SAMPLES USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) IN A COHORT OF 123 PATIENTS WITH HBV-RELATED HCC, 28 WITH LIVER CIRRHOSIS (LC), 29 WITH CHRONIC HEPATITIS B (CHB) AND 20 HEALTHY CONTROLS. THE FREQUENCY OF THE CDO1 PROMOTER METHYLATION IN HBV-RELATED HCC (42.3%) WAS SIGNIFICANTLY HIGHER THAN THAT IN LC (14.3%), CHB (6.9%) AND HEALTHY CONTROLS (0%) (P = 0.006; P < 0.0001; P < 0.0001; RESPECTIVELY). FURTHERMORE, IN HCC PATIENTS, THE FREQUENCY OF CDO1 PROMOTER METHYLATION WAS HIGHER IN ADVANCED STAGES (III-IV) (53%) THAN THE EARLY STAGES (I-II) (20%) (P = 0.001). EVALUATION OF THE CDO1 PROMOTER METHYLATION STATUS IN SERUM, IN COMBINATION WITH AFP (> 20 NG/ML), SIGNIFICANTLY IMPROVED THE DIAGNOSTIC VALUE, WITH SENSITIVITY AND SPECIFICITY OF 82.9% AND 75.4%, RESPECTIVELY IN DISTINGUISHING HCC FROM LC AND CHB. IN CONCLUSION, METHYLATION STATUS OF SERUM CDO1 GENE PROMOTER MAY BE HELPFUL IN THE DIAGNOSIS OF HCC AND THE ESTIMATION OF THE HCC STAGES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20 1990  28 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE.	2021