1   223 143 ACUTE PSYCHOSOCIAL STRESS-MEDIATED CHANGES IN THE EXPRESSION AND METHYLATION OF PERFORIN IN CHRONIC FATIGUE SYNDROME. PERFORIN (PRF1) IS ESSENTIAL FOR IMMUNE SURVEILLANCE AND STUDIES REPORT DECREASED PERFORIN IN CHRONIC FATIGUE SYNDROME (CFS), AN ILLNESS POTENTIALLY ASSOCIATED WITH STRESS AND/OR INFECTION. WE HYPOTHESIZE THAT STRESS CAN INFLUENCE REGULATION OF PRF1 EXPRESSION, AND THAT THIS REGULATION WILL DIFFER BETWEEN CFS AND NON-FATIGUED (NF) CONTROLS. WE USED THE TRIER SOCIAL STRESS TEST (TSST) AS A STANDARDIZED ACUTE PSYCHOSOCIAL STRESS, AND EVALUATED ITS EFFECT ON PRF1 EXPRESSION AND METHYLATION IN CFS (N = 34) COMPARED WITH NF (N = 47) PARTICIPANTS. DURING THE TSST, NATURAL KILLER (NK) CELLS INCREASED SIGNIFICANTLY IN BOTH CFS (P = <0.0001) AND NF SUBJECTS (P = <0.0001). UNLIKE PREVIOUS REPORTS, THERE WAS NO SIGNIFICANT DIFFERENCE IN PRF1 EXPRESSION AT BASELINE OR DURING TSST BETWEEN CFS AND NF. HOWEVER, WHOLE BLOOD PRF1 EXPRESSION INCREASED 1.6 FOLD DURING THE TSST IN BOTH CFS (P = 0.0003) AND NF (P = <0.0001). FURTHER, THE PEAK RESPONSE IMMEDIATELY FOLLOWING THE TSST WAS LOWER IN CFS COMPARED WITH NF (P = 0.04). IN ADDITION, AT 1.5 HOURS POST TSST, PRF1 EXPRESSION WAS ELEVATED IN CFS COMPARED WITH NF (WHOLE BLOOD, P = 0.06; PBMC, P = 0.02). METHYLATION OF SEVEN CPG SITES IN THE METHYLATION SENSITIVE REGION OF THE PRF1 PROMOTER RANGED FROM 38%-79% WITH NO SIGNIFICANT DIFFERENCES BETWEEN CFS AND NF. ALTHOUGH, THE AVERAGE BASELINE METHYLATION OF ALL SEVEN CPG SITES DID NOT DIFFER BETWEEN CFS AND NF GROUPS, IT SHOWED A SIGNIFICANT NEGATIVE CORRELATION WITH PRF1 EXPRESSION AT ALL TSST TIME POINTS IN BOTH CFS (R = -0.56, P = <0.0001) AND NF (R = -0.38, P = <0.0001). AMONG PARTICIPANTS WITH HIGH AVERAGE METHYLATION (>/=65%), PRF1 EXPRESSION WAS SIGNIFICANTLY LOWER IN CFS THAN NF SUBJECTS IMMEDIATELY FOLLOWING TSST. THESE FINDINGS SUGGEST METHYLATION COULD BE AN IMPORTANT EPIGENETIC DETERMINANT OF INTER-INDIVIDUAL DIFFERENCES IN PRF1 EXPRESSION AND THAT THE DIFFERENCES IN PRF1 EXPRESSION AND METHYLATION BETWEEN CFS AND NF IN THE ACUTE STRESS RESPONSE REQUIRE FURTHER INVESTIGATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  4349  39 MIR-155 AND MIR-122 EXPRESSION OF SPERMATOZOA IN OBESE SUBJECTS. OBESITY IS CHARACTERIZED BY MILD CHRONIC INFLAMMATION THAT IS LINKED WITH IMPAIRED IRON HOMEOSTASIS. STUDIES IN HUMAN AND MURINE SHOW THAT THERE IS A TRANSGENERATIONAL EPIGENETIC INHERITANCE VIA THE GAMETES IN OBESITY; HOWEVER, THERE IS LITTLE INFORMATION ON CHANGES IN THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION AND IRON HOMEOSTASIS IN SPERMATOZOA FROM OBESE SUBJECTS. THE PRESENT STUDY INVESTIGATED THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION (MIR-21 Y MIR-155) AND IRON NUTRITION (MIR-122 AND MIR-200B) IN PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND SPERMATOZOA FROM NORMOZOOSPERMIC CONTROLS (CN; N = 17; BMI: 24.6 +/- 2.0) AND OBESE (OB; N = 17; BMI: 32.6 +/- 4.4) MEN. TO DETERMINE THE INFLAMMATION LEVELS, WE MEASURED IL-6, TNF-ALPHA, AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP1) BY MAGNETIC LUMINEX((R)) ASSAY. MRNA EXPRESSION OF IL6, TNF-ALPHA, AND HEPCIDIN (HAMP) IN PBMC WERE EVALUATED BY RT-QPCR. THE ANALYSIS OF MICRORNAS WAS PERFORMED USING THE TAQMAN((R)) ASSAYS. THE IRON CONTENT IN PBMC, SEMINAL PLASMA, AND SPERMATOZOA WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS). HIGH SERUM IL6, TNF-ALPHA, AND MCP1 LEVELS WERE OBSERVED IN OB GROUP (P < 0.05). GENE EXPRESSION ANALYSIS SHOWED AN INCREASED ABUNDANCE RELATIVE OF TNF-ALPHA (P = 0.018), HAMP (P = 0.03), AND IL6 (P = 0.02) IN PBMC FROM OBESE SUBJECTS. ALSO, WE OBSERVED HIGH LEVELS OF SERUM FERRITIN (P = 0.03), IRON CONTENT IN SEMINAL PLASMA (P = 0.04), AND SPERMATOZOA (P = 0.002), BUT LOWER SERUM FE (P = 0.007) IN OBESE SUBJECTS. IN THE OB GROUP, A HIGH EXPRESSION OF MIR-155 (P = 0.02) AND MIR-21 (P = 0.03) WAS OBSERVED IN PBMC AND MIR-122 (P = 0.03) IN PLASMA. IN SPERM, BOTH MIR-155 (P = 0.004) AND MIR-122 (P = 0.028) WERE HIGH IN THE OB GROUP. OUR RESULTS SHOWED THAT OBESE SUBJECTS HAVE INCREASED EXPRESSIONS OF MIR-155 AND MIR-122, TWO MICRORNAS THAT WERE PREVIOUSLY RELATED WITH INFLAMMATION AND IRON METABOLISM, RESPECTIVELY, AT BOTH THE SYSTEMIC AND SPERM LEVELS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3    93  38 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  2326  28 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  1061  43 CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS IS CHARACTERIZED BY AN UPREGULATION OF PERIPHERAL T-REGULATORY CELL POLARIZED TOWARDS T-BET AND TIGIT. BACKGROUND: NON-INFECTIOUS UVEITIS CAN CAUSE CHRONIC RELAPSING AND REMITTING OCULAR INFLAMMATION, WHICH MAY REQUIRE HIGH DOSE SYSTEMIC IMMUNOSUPPRESSION TO PREVENT SEVERE SIGHT LOSS. IT HAS BEEN CLASSICALLY DESCRIBED AS AN AUTOIMMUNE DISEASE, MEDIATED BY PRO-INFLAMMATORY TH1 AND TH17 T-CELL SUBSETS. STUDIES SUGGEST THAT NATURAL IMMUNOSUPPRESSIVE CD4(+)CD25(+)FOXP3(+) T-REGULATORY CELLS (TREGS) ARE INVOLVED IN RESOLUTION OF INFLAMMATION AND MAY BE INVOLVED IN THE MAINTENANCE OF CLINICAL REMISSION. OBJECTIVE: TO INVESTIGATE WHETHER THERE IS A PERIPHERAL BLOOD IMMUNOREGULATORY PHENOTYPE ASSOCIATED WITH CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS BY COMPARING PERIPHERAL BLOOD LEVELS OF TREG, TH1, AND TH17, AND ASSOCIATED DNA METHYLATION AND CYTOKINE LEVELS IN PATIENTS WITH ACTIVE UVEITIC DISEASE, CONTROL SUBJECTS AND PATIENTS (WITH PREVIOUSLY ACTIVE DISEASE) IN CLINICAL REMISSION INDUCED BY IMMUNOSUPPRESSIVE DRUGS. METHODS: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM PERIPHERAL BLOOD SAMPLES FROM PROSPECTIVELY RECRUITED SUBJECTS WERE ANALYZED BY FLOW CYTOMETRY FOR CD3, CD4, FOXP3, TIGIT, T-BET, AND RELATED ORPHAN RECEPTOR GAMMAT. EPIGENETIC DNA METHYLATION LEVELS OF FOXP3 TREG-SPECIFIC DEMETHYLATED REGION (TSDR), FOXP3 PROMOTER, TBX21, RORC2, AND TIGIT LOCI WERE DETERMINED IN CRYOPRESERVED PBMC USING A NEXT-GENERATION SEQUENCING APPROACH. RELATED CYTOKINES WERE MEASURED IN BLOOD SERA. FUNCTIONAL SUPPRESSIVE CAPACITY OF TREG WAS ASSESSED USING T-CELL PROLIFERATION ASSAYS. RESULTS: FIFTY PATIENTS WITH UVEITIS (INTERMEDIATE, POSTERIOR, AND PANUVEITIS) AND 10 CONTROL SUBJECTS WERE RECRUITED. THE FREQUENCY OF CD4(+)CD25(+)FOXP3(+) TREG, TIGIT(+) TREG, AND T-BET(+) TREG AND THE RATIO OF TREG TO TH1 WERE SIGNIFICANTLY HIGHER IN REMISSION PATIENTS COMPARED WITH PATIENTS WITH ACTIVE UVEITIC DISEASE; AND TIGIT(+) TREGS WERE A SIGNIFICANT PREDICTOR OF CLINICAL REMISSION. TREG FROM PATIENTS IN CLINICAL REMISSION DEMONSTRATED A HIGH LEVEL OF IN VITRO SUPPRESSIVE FUNCTION COMPARED WITH TREG FROM CONTROL SUBJECTS AND FROM PATIENTS WITH UNTREATED ACTIVE DISEASE. PBMC FROM PATIENTS IN CLINICAL REMISSION HAD SIGNIFICANTLY LOWER METHYLATION LEVELS AT THE FOXP3 TSDR, FOXP3 PROMOTER, AND TIGIT LOCI AND HIGHER LEVELS AT RORC LOCI THAN THOSE WITH ACTIVE DISEASE. CLINICAL REMISSION WAS ALSO ASSOCIATED WITH SIGNIFICANTLY HIGHER SERUM LEVELS OF TRANSFORMING GROWTH FACTOR BETA AND IL-10, WHICH POSITIVELY CORRELATED WITH TREG LEVELS, AND LOWER SERUM LEVELS OF IFNGAMMA, IL-17A, AND IL-22 COMPARED WITH PATIENTS WITH ACTIVE DISEASE. CONCLUSION: CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS HAS AN IMMUNOREGULATORY PHENOTYPE CHARACTERIZED BY UPREGULATION OF PERIPHERAL TREG, POLARIZED TOWARD T-BET AND TIGIT. THESE FINDINGS MAY ASSIST WITH INDIVIDUALIZED THERAPY OF UVEITIS, BY INFORMING WHETHER DRUG THERAPY HAS INDUCED PHENOTYPICALLY STABLE TREG ASSOCIATED WITH LONG-TERM CLINICAL REMISSION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  5760  40 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  3456  39 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  1627  45 DNMT1 MODULATION IN CHRONIC HEPATITIS B PATIENTS AND HYPOTHETIC INFLUENCE ON MITOCHONDRIAL DNA METHYLATION STATUS DURING LONG-TERM NUCLEO(T)SIDE ANALOGS THERAPY. INHIBITION OF VIRAL REPLICATION IS THE MOST IMPORTANT GOAL IN PATIENTS WITH HEPATITIS B VIRUS CHRONIC INFECTION (CHB). CURRENTLY, FIVE ORAL NUCLEO(T)SIDE ANALOGS (NAS), INCLUDING LAMIVUDINE, ADEFOVIR, TELBIVUDINE, ENTECAVIR, AND TENOFOVIR, HAVE BEEN APPROVED FOR TREATMENT. THE WIDESPREAD USE OF NAS HAS ALSO BEEN LINKED WITH A PROGRESSIVE GROWTH OF UNLIKELY ANOMALY ATTRIBUTABLE TO MITOCHONDRIAL DYSFUNCTIONS, NOT PREVIOUSLY RECOGNIZED. HERE, WE EXPLORE THE HYPOTHESIS THAT NAS MAY CAUSE PERSISTENT EPIGENETIC CHANGES DURING PROLONGED NAS THERAPY IN CHB PATIENTS. WE OBTAINED PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM WHOLE BLOOD SAMPLES OF CONSECUTIVE PATIENTS WITH CHRONIC HBV INFECTION, 18 RECEIVING NAS AND 20 UNTREATED PATIENTS. ALL PATIENTS WERE CAUCASIAN AND ITALIANS. EPIGENETIC ANALYSIS WAS PERFORMED BY BISULPHITE SEQUENCING PCR TO SEARCH THE EXISTENCE OF METHYLATED CYTOSINE RESIDUES IN THE LIGHT (L)-STRANDS OF MITOCHONDRIAL DNA CONTROL REGION (D-LOOP). GENE EXPRESSION ANALYSIS OF DNA METHYLTRANSFERASES 1 WAS PERFORMED BY A QUANTITATIVE RELATIVE REAL-TIME POLYMERASE CHAIN REACTION (PCR). DNMT1 EXPRESSION WAS SIGNIFICANTLY (P < 000001) HIGHER IN NA TREATED PATIENTS (4.09, IQR 3.52-5.15) WHEN COMPARED WITH HBV NAIVES (0.61, IQR 0.34-0.82). BESIDES, DNMT1 EXPRESSION WAS SIGNIFICANTLY CORRELATED WITH NA THERAPY DURATION (SPEARMAN RHO = 0.67; P < 0.05). FURTHERMORE, NA THERAPY DURATION WAS THE ONLY SIGNIFICANT PREDICTOR OF DNMT1 EXPRESSION AT MULTIVARIATE ANALYSIS (BETA = 0.95, P < 0.0000001). BISULPHITE PCR SEQUENCING SHOWED THAT METHYLATION OF CYTOSINE RESIDUES OCCURRED IN A HIGHER PERCENTAGE IN PATIENTS TREATED WITH NAS IN COMPARISON WITH UNTREATED PATIENTS AND HEALTHY CONTROLS. OUR DATA SHOWED A DNMT1 OVEREXPRESSION SIGNIFICANTLY CORRELATED TO NA THERAPY DURATION AND AN HIGHER REGIONAL MTDNA HYPERMETHYLATION. THIS MIGHT SUGGEST AN EPIGENETIC ALTERATION THAT COULD BE INVOLVED IN ONE OF THE POSSIBLE MECHANISMS OF MITOCHONDRIAL GENE REGULATION DURING NAS THERAPY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  2969  34 GENETIC AND EPIGENETIC REGULATION OF THE INNATE IMMUNE RESPONSE TO GOUT. GOUT IS A DISEASE CAUSED BY URIC ACID (UA) ACCUMULATION IN THE JOINTS, CAUSING INFLAMMATION. TWO UA FORMS - MONOSODIUM URATE (MSU) AND SOLUBLE URIC ACID (SUA) HAVE BEEN SHOWN TO INTERACT PHYSICALLY WITH INFLAMMASOMES, ESPECIALLY WITH THE NOD-LIKE RECEPTOR (NLR) FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3), ALBEIT THE ROLE OF THE IMMUNE RESPONSE TO UA IS POORLY UNDERSTOOD, GIVEN THAT ASYMPTOMATIC HYPERURICEMIA DOES ALSO EXIST. MACROPHAGE PHAGOCYTOSIS OF UA ACTIVATE NLRP3, LEAD TO CYTOKINES RELEASE, AND ULTIMATELY, LEAD TO CHEMOATTRACT NEUTROPHILS AND LYMPHOCYTES TO THE GOUT FLARE JOINT SPOT. GENETIC VARIANTS OF INFLAMMASOME GENES AND OF GENES ENCODING THEIR MOLECULAR PARTNERS MAY INFLUENCE HYPERURICEMIA AND GOUT SUSCEPTIBILITY, WHILE ALSO INFLUENCING OTHER COMORBIDITIES SUCH AS METABOLIC SYNDROME AND CARDIOVASCULAR DISEASES. IN THIS REVIEW, WE SUMMARIZE THE INFLAMMATORY RESPONSES IN ACUTE AND CHRONIC GOUT, SPECIFICALLY FOCUSING ON INNATE IMMUNE CELL MECHANISMS AND GENETIC AND EPIGENETIC CHARACTERISTICS OF PARTICIPATING MOLECULES. UNPRECEDENTLY, A NOVEL UA BINDING PROTEIN - THE NEURONAL APOPTOSIS INHIBITOR PROTEIN (NAIP) - IS SUGGESTED AS RESPONSIBLE FOR THE ASYMPTOMATIC HYPERURICEMIA PARADOX.ABBREVIATION: BETA2-INTEGRINS: LEUKOCYTE-SPECIFIC ADHESION MOLECULES; ABCG2: ATP-BINDING CASSETE FAMILY/BREAST CANCER-RESISTANT PROTEIN; ACR: AMERICAN COLLEGE OF RHEUMATOLOGY; AIM2: ABSENT IN MELANOMA 2, TYPE OF PATTERN RECOGNITION RECEPTOR; ALPK1: ALPHA-PROTEIN KINASE 1; ANGPTL2: ANGIOPOIETIN-LIKE PROTEIN 2; ASC: APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN; BIR: BACULOVIRUS INHIBITOR OF APOPTOSIS PROTEIN REPEAT; BIRC1: BACULOVIRUS IAP REPEAT-CONTAINING PROTEIN 1; BIRC2: BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 2; C5A: COMPLEMENT ANAPHYLATOXIN; CAMP: CYCLIC ADENOSINE MONOPHOSPHATE; CARD: CASPASE ACTIVATION AND RECRUITMENT DOMAINS; CARD8: CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 8; CASP1: CASPASE 1; CCL3: CHEMOKINE (C-C MOTIF) LIGAND 3; CD14: CLUSTER OF DIFFERENTIATION 14; CD44: CLUSTER OF DIFFERENTIATION 44; CG05102552: DNA-METHYLATION SITE, USUALLY CYTOSINE FOLLOWED BY GUANINE NUCLEOTIDES; CONTAINS ARBITRARY IDENTIFICATION CODE; CIDEC: CELL DEATH-INDUCING DNA FRAGMENTATION FACTOR-LIKE EFFECTOR FAMILY; CKD: CHRONIC KIDNEY DISEASE; CNV: COPY NUMBER VARIATION; CPT1A: CARNITINE PALMITOYL TRANSFERASE - TYPE 1A; CXCL1: CHEMOKINE (CXC MOTIF) LIGAND 1; DAMPS: DAMAGE ASSOCIATED MOLECULAR PATTERNS; DC: DENDRITIC CELLS; DNMT(1): MAINTENANCE DNA METHYLTRANSFERASE; EQTL: EXPRESSION QUANTITATIVE TRAIT LOCI; ERK1: EXTRACELLULAR SIGNAL-REGULATED KINASE 1; ERK2: EXTRACELLULAR SIGNAL-REGULATED KINASE 2; EULAR: EUROPEAN LEAGUE AGAINST RHEUMATISM; GMCSF: GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; GWAS: GLOBAL WIDE ASSOCIATION STUDIES; H3K27ME3: TRI-METHYLATION AT THE 27TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME1: MONO-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; H3K4ME3: TRI-METHYLATION AT THE 4TH LYSINE RESIDUE OF THE HISTONE H3 PROTEIN; HOTAIR: HUMAN GENE LOCATED BETWEEN HOXC11 AND HOXC12 ON CHROMOSOME 12; IKAPPABALPHA: CYTOPLASMATIC PROTEIN/NF-KAPPAB TRANSCRIPTION INHIBITOR; IAP: INHIBITORY APOPTOSIS PROTEIN; IFNGAMMA: INTERFERON GAMMA; IL-1BETA: INTERLEUKIN 1 BETA; IL-12: INTERLEUKIN 12; IL-17: INTERLEUKIN 17; IL18: INTERLEUKIN 18; IL1R1: INTERLEUKIN-1 RECEPTOR; IL-1RA: INTERLEUKIN-1 RECEPTOR ANTAGONIST; IL-22: INTERLEUKIN 22; IL-23: INTERLEUKIN 23; IL23R: INTERLEUKIN 23 RECEPTOR; IL-33: INTERLEUKIN 33; IL-6: INTERLEUKIN 6; IMP: INOSINE MONOPHOSPHATE; INSIG1: INSULIN-INDUCED GENE 1; JNK1: C-JUN N-TERMINAL KINASE 1; LNCRNA: LONG NON-CODING RIBONUCLEIC ACID; LRR: LEUCINE-RICH REPEATS; MIR: MATURE NON-CODING MICRORNAS MEASURING FROM 20 TO 24 NUCLEOTIDES, ANIMAL ORIGIN; MIR-1: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-145: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-146A: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "A" STANDS FOR MIR FAMILY; "A" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "B" FAMILY, BUT DIFFERENT PRECURSORS; MIR-20B: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "B" STANDS FOR MIR FAMILY; "B" FAMILY PRESENTS SIMILAR MIR SEQUENCE TO "A" FAMILY, BUT DIFFERENT PRECURSORS; MIR-221: MIR - FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-221-5P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "5P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 5' ARM OF THE PRE-MIRNA HAIRPIN; MIR-223: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; MIR-223-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE; "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MIR-22-3P: MIR FOLLOWED BY ARBITRARY IDENTIFICATION CODE, "3P" INDICATES DIFFERENT MATURE MIRNAS GENERATED FROM THE 3' ARM OF THE PRE-MIRNA HAIRPIN; MLKL: MIXED LINEAGE KINASE DOMAIN-LIKE PSEUDO KINASE; MM2P: INDUCTOR OF M2-MACROPHAGE POLARIZATION; MSU: MONOSODIUM URATE; MTOR: MAMMALIAN TARGET OF RAPAMYCIN; MYD88: MYELOID DIFFERENTIATION PRIMARY RESPONSE 88; N-3-PUFAS: N-3-POLYUNSATURATED FATTY-ACIDS; NACHT: ACRONYM FOR NAIP (NEURONAL APOPTOSIS INHIBITOR PROTEIN), C2TA (MHC CLASS 2 TRANSCRIPTION ACTIVATOR), HET-E (INCOMPATIBILITY LOCUS PROTEIN FROM PODOSPORA ANSERINA) AND TP1 (TELOMERASE-ASSOCIATED PROTEIN); NAIP: NEURONAL APOPTOSIS INHIBITORY PROTEIN (HUMAN); NAIP1: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 1 (MURINE); NAIP5: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 5 (MURINE); NAIP6: NEURONAL APOPTOSIS INHIBITORY PROTEIN TYPE 6 (MURINE); NBD: NUCLEOTIDE-BINDING DOMAIN; NEK7: SMALLEST NIMA-RELATED KINASE; NET: NEUTROPHIL EXTRACELLULAR TRAPS; NF-KAPPAB: NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS; NFIL3: NUCLEAR-FACTOR, INTERLEUKIN 3 REGULATED PROTEIN; NIIMA: NETWORK OF IMMUNITY IN INFECTION, MALIGNANCY, AND AUTOIMMUNITY; NLR: NOD-LIKE RECEPTOR; NLRA: NOD-LIKE RECEPTOR NLRA CONTAINING ACIDIC DOMAIN; NLRB: NOD-LIKE RECEPTOR NLRA CONTAINING BIR DOMAIN; NLRC: NOD-LIKE RECEPTOR NLRA CONTAINING CARD DOMAIN; NLRC4: NOD-LIKE RECEPTOR FAMILY CARD DOMAIN CONTAINING 4; NLRP: NOD-LIKE RECEPTOR NLRA CONTAINING PYD DOMAIN; NLRP1: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 1; NLRP12: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN, LEUCINE-RICH REPEAT, AND PYRIN DOMAIN CONTAINING 12; NLRP3: NOD-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3; NOD2: NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN; NRBP1: NUCLEAR RECEPTOR-BINDING PROTEIN; NRF2: NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2; OR: ODDS RATIO; P2X: GROUP OF MEMBRANE ION CHANNELS ACTIVATED BY THE BINDING OF EXTRACELLULAR; P2X7: P2X PURINOCEPTOR 7 GENE; P38: MEMBER OF THE MITOGEN-ACTIVATED PROTEIN KINASE FAMILY; PAMPS: PATHOGEN ASSOCIATED MOLECULAR PATTERS; PBMC: PERIPHERAL BLOOD MONONUCLEAR CELLS; PGGT1B: GERANYLGERANYL TRANSFERASE TYPE-1 SUBUNIT BETA; PHGDH: PHOSPHOGLYCERATE DEHYDROGENASE; PI3-K: PHOSPHO-INOSITOL; PPARGAMMA: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA; PPARGC1B: PEROXISOME PROLIFERATIVE ACTIVATED RECEPTOR, GAMMA, COACTIVATOR 1 BETA; PR3: PROTEINASE 3 ANTIGEN; PRO-CASP1: INACTIVE PRECURSOR OF CASPASE 1; PRO-IL1BETA: INACTIVE PRECURSOR OF INTERLEUKIN 1 BETA; PRR: PATTERN RECOGNITION RECEPTORS; PYD: PYRIN DOMAIN; RAPTOR: REGULATORY ASSOCIATED PROTEIN OF MTOR COMPLEX 1; RAS: RENIN-ANGIOTENSIN SYSTEM; REDD1: REGULATED IN DNA DAMAGE AND DEVELOPMENT 1; ROS: REACTIVE OXYGEN SPECIES; RS000*G: SINGLE NUCLEAR POLYMORPHISM, "*G" IS RELATED TO SNP WHERE REPLACED NUCLEOTIDE IS GUANINE, USUALLY PRECEDED BY AN ID NUMBER; SLC2A9: SOLUTE CARRIER FAMILY 2, MEMBER 9; SLC7A11: SOLUTE CARRIER FAMILY 7, MEMBER 11; SMA: SMOOTH MUSCULAR ATROPHY; SMAC: SECOND MITOCHONDRIAL-DERIVED ACTIVATOR OF CASPASES; SNP: SINGLE NUCLEAR POLYMORPHISM; SP3: SPECIFICITY PROTEIN 3; ST2: SERUM STIMULATION-2; STK11: SERINE/THREONINE KINASE 11; SUA: SOLUBLE URIC ACID; SYK: SPLEEN TYROSINE KINASE; TAK1: TRANSFORMING GROWTH FACTOR BETA ACTIVATED KINASE; TH1: TYPE 1 HELPER T CELLS; TH17: TYPE 17 HELPER T CELLS; TH2: TYPE 2 HELPER T CELLS; TH22: TYPE 22 HELPER T CELLS; TLR: TOOL-LIKE RECEPTOR; TLR2: TOLL-LIKE RECEPTOR 2; TLR4: TOLL-LIKE RECEPTOR 4; TNFALPHA: TUMOR NECROSIS FACTOR ALPHA; TNFR1: TUMOR NECROSIS FACTOR RECEPTOR 1; TNFR2: TUMOR NECROSIS FACTOR RECEPTOR 2; UA: URIC ACID; UBAP1: UBIQUITIN ASSOCIATED PROTEIN; ULT: URATE-LOWERING THERAPY; URAT1: URATE TRANSPORTER 1; VDAC1: VOLTAGE-DEPENDENT ANION-SELECTIVE CHANNEL 1.	2023	

10   812  40 CHANGES IN DNA METHYLATION PROFILES OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME PATIENTS REFLECT SYSTEMIC DYSFUNCTIONS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A LIFELONG DEBILITATING DISEASE WITH A COMPLEX PATHOLOGY NOT YET CLEARLY DEFINED. SUSCEPTIBILITY TO ME/CFS INVOLVES GENETIC PREDISPOSITION AND EXPOSURE TO ENVIRONMENTAL FACTORS, SUGGESTING AN EPIGENETIC ASSOCIATION. EPIGENETIC STUDIES WITH OTHER ME/CFS COHORTS HAVE USED ARRAY-BASED TECHNOLOGY TO IDENTIFY DIFFERENTIALLY METHYLATED INDIVIDUAL SITES. CHANGES IN RNA QUANTITIES AND PROTEIN ABUNDANCE HAVE BEEN DOCUMENTED IN OUR PREVIOUS INVESTIGATIONS WITH THE SAME ME/CFS COHORT USED FOR THIS STUDY. RESULTS: DNA FROM A WELL-CHARACTERISED NEW ZEALAND COHORT OF 10 ME/CFS PATIENTS AND 10 AGE-/SEX-MATCHED HEALTHY CONTROLS WAS ISOLATED FROM PERIPHERAL BLOOD MONONUCLEAR (PBMC) CELLS, AND USED TO GENERATE REDUCED GENOME-SCALE DNA METHYLATION MAPS USING REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS). THE SEQUENCING DATA WERE ANALYSED UTILISING THE DMAP ANALYSIS PIPELINE TO IDENTIFY DIFFERENTIALLY METHYLATED FRAGMENTS, AND THE METHYLKIT PIPELINE WAS USED TO QUANTIFY METHYLATION DIFFERENCES AT INDIVIDUAL CPG SITES. DMAP IDENTIFIED 76 DIFFERENTIALLY METHYLATED FRAGMENTS AND METHYLKIT IDENTIFIED 394 DIFFERENTIALLY METHYLATED CYTOSINES THAT INCLUDED BOTH HYPER- AND HYPO-METHYLATION. FOUR CLUSTERS WERE IDENTIFIED WHERE DIFFERENTIALLY METHYLATED DNA FRAGMENTS OVERLAPPED WITH OR WERE WITHIN CLOSE PROXIMITY TO MULTIPLE DIFFERENTIALLY METHYLATED INDIVIDUAL CYTOSINES. THESE CLUSTERS IDENTIFIED REGULATORY REGIONS FOR 17 PROTEIN ENCODING GENES RELATED TO METABOLIC AND IMMUNE ACTIVITY. ANALYSIS OF DIFFERENTIALLY METHYLATED GENE BODIES (EXONS/INTRONS) IDENTIFIED 122 UNIQUE GENES. COMPARISON WITH OTHER STUDIES ON PBMCS FROM ME/CFS PATIENTS AND CONTROLS WITH ARRAY TECHNOLOGY SHOWED 59% OF THE GENES IDENTIFIED IN THIS STUDY WERE ALSO FOUND IN ONE OR MORE OF THESE STUDIES. FUNCTIONAL PATHWAY ENRICHMENT ANALYSIS IDENTIFIED 30 ASSOCIATED PATHWAYS. THESE INCLUDED IMMUNE, METABOLIC AND NEUROLOGICAL-RELATED FUNCTIONS DIFFERENTIALLY REGULATED IN ME/CFS PATIENTS COMPARED TO THE MATCHED HEALTHY CONTROLS. CONCLUSIONS: MAJOR DIFFERENCES WERE IDENTIFIED IN THE DNA METHYLATION PATTERNS OF ME/CFS PATIENTS THAT CLEARLY DISTINGUISHED THEM FROM THE HEALTHY CONTROLS. OVER HALF FOUND IN GENE BODIES WITH RRBS IN THIS STUDY HAD BEEN IDENTIFIED IN OTHER ME/CFS STUDIES USING THE SAME CELLS BUT WITH ARRAY TECHNOLOGY. WITHIN THE ENRICHED FUNCTIONAL IMMUNE, METABOLIC AND NEUROLOGICAL PATHWAYS, A NUMBER OF ENRICHED NEUROTRANSMITTER AND NEUROPEPTIDE REACTOME PATHWAYS HIGHLIGHTED A DISTURBED NEUROLOGICAL PATHOPHYSIOLOGY WITHIN THE PATIENT GROUP.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11  4601  34 NDRG2 MRNA LEVELS AND MIR-28-5P AND MIR-650 ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: NDRG2 IS IDENTIFIED AS A TUMOR SUPPRESSOR GENE IN MANY TUMORS, AND FUNCTIONS IN CELL PROLIFERATION, DIFFERENTIATION AND APOPTOSIS. RECENT DATA INDICATE THAT NDRG2 EXPRESSION IS UP-REGULATED BY TP53. MOREOVER, PROPOSED MECHANISMS OF NDRG2 INACTIVATION INCLUDE EPIGENETIC SILENCING OF THE NDRG2 PROMOTER AND DOWN-REGULATION BY MICRORNAS (MIRNAS). HOWEVER, FEW STUDIES HAVE EVER BEEN DONE ON THE ROLE OF NDRG2 AND THE NDRG2-REGULATING MIRNAS INTERFERENCE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). METHODS: NDRG2 AND MICRORNAS MRNA LEVELS IN CLL SUBJECTS WERE ASSESSED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR). THE DUAL-LUCIFERASE REPORTER ASSAY WAS PERFORMED TO DETERMINE NDRG2-RELATED MIRNAS. LOW EXPRESSION OF MATURE EXOGENOUS MIRNAS IN CLL CELLS WAS ESTABLISHED BY TRANSIENT TRANSFECTION. NDRG2 PROTEIN LEVELS IN CLL CELLS WERE DETECTED BY WESTERN BLOT. IN ADDITION, FLOW CYTOMETRY WAS CONDUCTED TO EXAMINE THE APOPTOSIS OF CLL CELLS. RESULTS: LOWER EXPRESSION OF NDRG2 WAS FOUND IN THE B-CELLS FROM 102 CLL PATIENTS COMPARED THE 40 NORMAL SUBJECTS (P < 0.001). PATIENTS WITH ADVANCED BINET STAGE (P = 0.001), HIGH LACTATE DEHYDROGENASE (LDH) LEVEL (P = 0.036), UN-MUTATED IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION GENE (IGHV) (P = 0.004) AND THOSE WITH P53 ABERRATIONS (P < 0.001) HAD A MARKEDLY LOWER LEVELS OF NDRG2 MRNA. THIS DECREASE WAS ASSOCIATED WITH BRIEFER TIME-TO-TREATMENT (P = 0.001) AND POORER SURVIVAL (P < 0.001). HIGH EXPRESSION OF MIR-28-5P AND MIR-650 WAS ASSOCIATED WITH BINET B/C STAGE (P = 0.044) AND IGHV UN-MUTATED (P = 0.011), AS WELL AS BINET B/C STAGE (P = 0.013) AND P53 ABERRATIONS (P = 0.037), RESPECTIVELY. INHIBITION OF MIR-28-5P OR MIR-650 COULD INDUCE MORE APOPTOSIS IN CLL CELLS WITH GERMLINE TP53. CONCLUSIONS: NDRG2 MRNA LEVELS MIGHT BE A USEFUL PROGNOSTIC VARIABLE FOR PATIENTS OF CLL AND UP-REGULATING NDRG2 TRANSCRIPTION MAY BE A THERAPY APPROACH IN CLL WITHOUT P53 ABERRATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  3448  35 HYPERMETHYLATION OF THE N-MYC DOWNSTREAM-REGULATED GENE 2 PROMOTER IN PERIPHERAL BLOOD MONONUCLEAR CELLS IS ASSOCIATED WITH LIVER FIBROSIS IN CHRONIC HEPATITIS B. DNA METHYLATION IS A FUNDAMENTAL EPIGENETIC MODIFICATION TO REGULATE GENE EXPRESSION. N-MYC DOWNSTREAM-REGULATED GENE (NDRG) 2 IS A CYTOPLASMIC PROTEIN AND PARTICIPATES IN THE PATHOGENESIS OF LIVER FIBROSIS. IN THIS STUDY, THE MRNA EXPRESSION AND METHYLATION STATUS OF NDRG2 WAS EVALUATED IN PATIENTS WITH CHRONIC HEPATITIS B (CHB). THE STUDY INCLUDED 143 CHB PATIENTS AND 65 NORMAL CONTROLS (NC). THE MRNA EXPRESSION OF NDRG2 IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WAS DETECTED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION. THE METHYLATION STATUS OF THE NDRG2 PROMOTER IN PBMCS WAS DETECTED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THE NDRG2 MRNA LEVEL WAS LOWER IN THE CHB GROUP THAN IN THE NC GROUP (P < 0.001). METHYLATION FREQUENCY OF THE NDRG2 PROMOTER WAS SIGNIFICANTLY HIGHER IN CHB PATIENTS THAN IN THE NC GROUP (52.44% VS. 26.15%, P < 0.001). IMPORTANTLY, THE RELATIVE EXPRESSION LEVELS OF NDRG2 MRNA WERE SIGNIFICANTLY LOWER IN THE METHYLATED GROUP THAN IN THE UNMETHYLATED GROUP IN BOTH CHB PATIENTS AND NC (P < 0.001). FURTHERMORE, A LOWER MRNA LEVEL AND HYPERMETHYLATION OF NDRG2 WERE ASSOCIATED WITH LIVER FIBROSIS AND INFLAMMATION GRADE IN CHB. THE ASPARTATE AMINOTRANSFERASE-TO-PLATELET RATIO INDEX (APRI) SCORE IS WIDELY USED TO PREDICT LIVER FIBROSIS. THE MRNA EXPRESSION LEVELS AND METHYLATION STATUS OF NDRG2 SHOWED A BETTER SCORE COMPARED TO APRI FOR DISCRIMINATING THE SEVERITY OF LIVER FIBROSIS. IN CONCLUSION, HYPERMETHYLATION OF NDRG2 IN PBMCS WAS CORRELATED WITH DECREASED MRNA EXPRESSION AND WITH LIVER FIBROSIS. THE METHYLATION STATUS OF THE NDRG2 PROMOTER IN PBMCS IS A POTENTIAL NONINVASIVE BIOMARKER TO PREDICT THE SEVERITY OF LIVER FIBROSIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  3460  37 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  1495  30 DNA HYPERMETHYLATION OF CELL CYCLE (P15 AND P16) AND APOPTOTIC (P14, P53, DAPK AND TMS1) GENES IN PERIPHERAL BLOOD OF LEUKEMIA PATIENTS. ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES HAS BEEN REPORTED IN ALL MAJOR TYPES OF LEUKEMIA WITH POTENTIAL INVOLVEMENT IN THE INACTIVATION OF REGULATORY CELL CYCLE AND APOPTOSIS GENES. HOWEVER, MOST OF THE PREVIOUS REPORTS DID NOT SHOW THE EXTENT OF CONCURRENT METHYLATION OF MULTIPLE GENES IN THE FOUR LEUKEMIA TYPES. HERE, WE ANALYZED SIX KEY GENES (P14, P15, P16, P53, DAPK AND TMS1) FOR DNA METHYLATION USING METHYLATION SPECIFIC PCR TO ANALYZE PERIPHERAL BLOOD OF 78 LEUKEMIA PATIENTS (24 CML, 25 CLL, 12 AML, AND 17 ALL) AND 24 HEALTHY VOLUNTEERS. IN CML, METHYLATION WAS DETECTED FOR P15 (11%), P16 (9%), P53 (23%) AND DAPK (23%), IN CLL, P14 (25%), P15 (19%), P16 (12%), P53 (17%) AND DAPK (36%), IN AML, P14 (8%), P15 (45%), P53 (9%) AND DAPK (17%) AND IN ALL, P15 (14%), P16 (8%), AND P53 (8%). THIS STUDY HIGHLIGHTED AN ESSENTIAL ROLE OF DAPK METHYLATION IN CHRONIC LEUKEMIA IN CONTRAST TO P15 METHYLATION IN THE ACUTE CASES, WHEREAS TMS1 HYPERMETHYLATION WAS ABSENT IN ALL CASES. FURTHERMORE, HYPERMETHYLATION OF MULTIPLE GENES PER PATIENT WAS OBSERVED, WITH OBVIOUS SELECTIVENESS IN THE 9P21 CHROMOSOMAL REGION GENES (P14, P15 AND P16). INTERESTINGLY, METHYLATION OF P15 INCREASED THE RISK OF METHYLATION IN P53, AND VICE VERSA, BY FIVE FOLDS (P=0.03) INDICATING POSSIBLE SYNERGISTIC EPIGENETIC DISRUPTION OF DIFFERENT PHASES OF THE CELL CYCLE OR BETWEEN THE CELL CYCLE AND APOPTOSIS. THE INVESTIGATION OF MULTIPLE RELATIONSHIPS BETWEEN METHYLATED GENES MIGHT SHED LIGHT ON TUMOR SPECIFIC INACTIVATION OF THE CELL CYCLE AND APOPTOTIC PATHWAYS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  2759  42 EXPRESSION OF IL-17 AND ITS GENE PROMOTER METHYLATION STATUS ARE ASSOCIATED WITH THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS INFECTION. TO EXPLORE INTERLEUKIN-17 (IL-17) AND ITS EPIGENETIC REGULATION DURING THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION.A TOTAL OF 162 PATIENTS WITH CHRONIC HBV INFECTION, INCLUDING 75 WITH CHRONIC HEPATITIS B (CHB), 54 WITH HEPATITIS B-ASSOCIATED LIVER CIRRHOSIS AND 33 WITH HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA (HBV-HCC), WERE ENROLLED IN THIS STUDY. THIRTY HEALTHY ADULTS OF THE SAME ETHNICITY WERE ENROLLED IN THE CONTROL GROUP. WHOLE VENOUS BLOOD WAS OBTAINED FROM THE PATIENTS AND NORMAL CONTROLS (N = 30). CLINICAL AND LABORATORY PARAMETERS WERE ASSESSED, AND WE PERFORMED ENZYME-LINKED IMMUNOSORBENT ASSAY AND QUANTITATIVE REAL-TIME PCR TO MEASURE THE SERUM LEVELS AND RELATIVE MRNA EXPRESSION OF IL-17, RESPECTIVELY. IL-17 PROMOTER METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS WAS ASSESSED BY METHYLATION-SPECIFIC PCR. WE ANALYZED THE SERUM AND MRNA LEVELS OF IL-17 AND IL-17 PROMOTER METHYLATION IN THE 4 GROUPS AS WELL AS THE EFFECT OF METHYLATION ON SERUM IL-17 LEVELS. CORRELATIONS BETWEEN THE IL-17 PROMOTER METHYLATION STATUS AND CLINICAL PARAMETERS WERE ANALYZED BY SPEARMAN CORRELATION ANALYSIS.COMPARED TO THE NORMAL CONTROL GROUP, THE PATIENT GROUPS EXHIBITED SIGNIFICANTLY HIGHER SERUM AND RELATIVE MRNA LEVELS OF IL-17. THE METHYLATION DISTRIBUTION AMONG THE PATIENTS WAS SIGNIFICANTLY LOWER THAN THAT AMONG THE NORMAL CONTROLS (P < .05), WITH THE HBV-HCC GROUP SHOWING THE LOWEST IL-17 GENE METHYLATION FREQUENCY. THE AVERAGE IL-17 PROMOTER CG METHYLATION LEVEL WAS NEGATIVELY CORRELATED WITH IL-17 MRNA EXPRESSION (R = -0.39, P = .03), AND NEGATIVE CORRELATIONS BETWEEN IL-17 PROMOTER METHYLATION AND PROTHROMBIN TIME ACTIVITY (R = -0.585, P = .035), ALANINE AMINOTRANSFERASE (R = -0.522, P < .01), ASPARTATE AMINOTRANSFERASE (R = -0.315, P < .05), AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE (R = -0.461, P < .05) WERE OBSERVED. IL-17 SERUM LEVELS IN THE METHYLATED-PROMOTER GROUPS WERE SIGNIFICANTLY LOWER THAN THOSE IN THE UNMETHYLATED-PROMOTER GROUPS.IL-17 EXPRESSION AND PROMOTER METHYLATION WERE ASSOCIATED WITH CHRONIC HBV INFECTION PROGRESSION, ESPECIALLY IN THE HBV-HCC GROUP. THE IL-17 PROMOTER STATUS MAY HELP CLINICIANS INITIATE THE CORRECT TREATMENT STRATEGY AT THE CHB STAGE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  6589  36 TUMOR NECROSIS FACTOR-ALPHA GENE PROMOTER METHYLATION IN JAPANESE ADULTS WITH CHRONIC PERIODONTITIS AND RHEUMATOID ARTHRITIS. BACKGROUND AND OBJECTIVE: OVER-EXPRESSION OF TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PLAYS A PATHOLOGICAL ROLE IN CHRONIC PERIODONTITIS (CP) AND RHEUMATOID ARTHRITIS (RA), WHICH MIGHT BE REGULATED BY THE EPIGENETIC MECHANISM. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE WHETHER THERE IS A UNIQUE METHYLATION PROFILE OF THE TNF-ALPHA GENE PROMOTER IN BLOOD CELLS OF INDIVIDUALS WITH CP AND RA. MATERIAL AND METHODS: THE STUDY PARTICIPANTS CONSISTED OF 30 JAPANESE ADULTS WITH RA (RA GROUP), 30 RACE-MATCHED ADULTS WITH CP ONLY (CP GROUP) AND 30 RACE-MATCHED HEALTHY CONTROLS (H GROUP). GENOMIC DNA ISOLATED FROM PERIPHERAL BLOOD WAS MODIFIED BY SODIUM BISULFITE AND ANALYZED, BY DIRECT SEQUENCING, TO INVESTIGATE DNA METHYLATION OF THE TNF-ALPHA GENE PROMOTER REGION. THE LEVEL OF TNF-ALPHA PRODUCED IN MONONUCLEAR CELLS STIMULATED WITH PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE WAS DETERMINED USING ELISA. RESULTS: TWELVE CYTOSINE-GUANINE DINUCLEOTIDE (CPG) MOTIFS WERE IDENTIFIED IN THE TNF-ALPHA PROMOTER FRAGMENT FROM -343 TO +57 BP. THE CP GROUP SHOWED A SIGNIFICANTLY HIGHER METHYLATION RATE AND FREQUENCY AT -72 BP THAN THE H GROUP (P < 0.01). THE RA GROUP EXHIBITED SIGNIFICANTLY HIGHER METHYLATION RATES AT SEVEN CPG MOTIFS (-302, -163, -119, -72, -49, -38 AND +10 BP), AND SIGNIFICANTLY HIGHER METHYLATION FREQUENCIES AT SIX CPG MOTIFS (-163, -119, -72, -49, -38 AND +10 BP), THAN THE H GROUP (P < 0.01 FOR ALL COMPARISONS). THE LEVELS OF TNF-ALPHA PRODUCED WERE SIGNIFICANTLY DIFFERENT BETWEEN INDIVIDUALS WITH AND WITHOUT METHYLATION AT -163 BP (P = 0.03). CONCLUSION: THESE RESULTS SUGGEST THAT THE HYPERMETHYLATED STATUS OF CPG MOTIFS IN THE TNF-ALPHA GENE PROMOTER IN BLOOD CELLS MAY BE UNIQUE TO JAPANESE ADULTS WITH CP AND RA.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17  3496  39 IDENTIFICATION OF MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME-ASSOCIATED DNA METHYLATION PATTERNS. BACKGROUND: MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX CONDITION INVOLVING MULTIPLE ORGAN SYSTEMS AND CHARACTERIZED BY PERSISTENT/RELAPSING DEBILITATING FATIGUE, IMMUNE DYSFUNCTION, NEUROLOGICAL PROBLEMS, AND OTHER SYMPTOMS NOT CURABLE FOR AT LEAST 6 MONTHS. DISRUPTION OF DNA METHYLATION PATTERNS HAS BEEN TIED TO VARIOUS IMMUNE AND NEUROLOGICAL DISEASES; HOWEVER, ITS STATUS IN ME/CFS REMAINS UNCERTAIN. OUR STUDY AIMED AT IDENTIFYING CHANGES IN THE DNA METHYLATION PATTERNS THAT ASSOCIATE WITH ME/CFS. METHODS: WE EXTRACTED GENOMIC DNA FROM PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 13 ME/CFS STUDY SUBJECTS AND 12 HEALTHY CONTROLS AND MEASURED GLOBAL DNA METHYLATION BY ELISA-LIKE METHOD AND SITE-SPECIFIC METHYLATION STATUS USING ILLUMINA METHYLATIONEPIC MICROARRAYS. PYROSEQUENCING VALIDATION INCLUDED 33 ME/CFS CASES AND 31 CONTROLS FROM TWO GEOGRAPHICALLY DISTANT COHORTS. RESULTS: GLOBAL DNA METHYLATION LEVELS OF ME/CFS CASES WERE SIMILAR TO THOSE OF CONTROLS. HOWEVER, MICROARRAY-BASED APPROACH ALLOWED DETECTION OF 17,296 DIFFERENTIALLY METHYLATED CPG SITES IN 6,368 GENES ACROSS REGULATORY ELEMENTS AND WITHIN CODING REGIONS OF GENES. ANALYSIS OF DNA METHYLATION IN PROMOTER REGIONS REVEALED 307 DIFFERENTIALLY METHYLATED PROMOTERS. INGENUITY PATHWAY ANALYSIS INDICATED THAT GENES ASSOCIATED WITH DIFFERENTIALLY METHYLATED PROMOTERS PARTICIPATED IN AT LEAST 15 DIFFERENT PATHWAYS MOSTLY RELATED TO CELL SIGNALING WITH A STRONG IMMUNE COMPONENT. CONCLUSIONS: THIS IS THE FIRST STUDY THAT HAS EXPLORED GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH ME/CFS USING THE ADVANCED ILLUMINA METHYLATIONEPIC MICROARRAYS COVERING ABOUT 850,000 CPG SITES IN TWO GEOGRAPHICALLY DISTANT COHORTS OF ME/CFS CASES AND MATCHED CONTROLS. OUR RESULTS ARE ALIGNED WITH PREVIOUS STUDIES THAT INDICATE A DYSREGULATION OF THE IMMUNE SYSTEM IN ME/CFS. THEY ALSO SUGGEST A POTENTIAL ROLE OF EPIGENETIC DE-REGULATION IN THE PATHOBIOLOGY OF ME/CFS. WE PROPOSE SCREENING OF LARGER COHORTS OF ME/CFS CASES TO DETERMINE THE EXTERNAL VALIDITY OF THESE EPIGENETIC CHANGES IN ORDER TO IMPLEMENT THEM AS POSSIBLE DIAGNOSTIC MARKERS IN CLINICAL SETTING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  5346  48 RAPID CHANGES IN HISTONE DEACETYLASES AND INFLAMMATORY GENE EXPRESSION IN EXPERT MEDITATORS. BACKGROUND: A GROWING BODY OF RESEARCH SHOWS THAT MINDFULNESS MEDITATION CAN ALTER NEURAL, BEHAVIORAL AND BIOCHEMICAL PROCESSES. HOWEVER, THE MECHANISMS RESPONSIBLE FOR SUCH CLINICALLY RELEVANT EFFECTS REMAIN ELUSIVE. METHODS: HERE WE EXPLORED THE IMPACT OF A DAY OF INTENSIVE PRACTICE OF MINDFULNESS MEDITATION IN EXPERIENCED SUBJECTS (N=19) ON THE EXPRESSION OF CIRCADIAN, CHROMATIN MODULATORY AND INFLAMMATORY GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC). IN PARALLEL, WE ANALYZED A CONTROL GROUP OF SUBJECTS WITH NO MEDITATION EXPERIENCE WHO ENGAGED IN LEISURE ACTIVITIES IN THE SAME ENVIRONMENT (N=21). PBMC FROM ALL PARTICIPANTS WERE OBTAINED BEFORE (T1) AND AFTER (T2) THE INTERVENTION (T2-T1=8H) AND GENE EXPRESSION WAS ANALYZED USING CUSTOM PATHWAY FOCUSED QUANTITATIVE-REAL TIME PCR ASSAYS. BOTH GROUPS WERE ALSO PRESENTED WITH THE TRIER SOCIAL STRESS TEST (TSST). RESULTS: CORE CLOCK GENE EXPRESSION AT BASELINE (T1) WAS SIMILAR BETWEEN GROUPS AND THEIR RHYTHMICITY WAS NOT INFLUENCED IN MEDITATORS BY THE INTENSIVE DAY OF PRACTICE. SIMILARLY, WE FOUND THAT ALL THE EPIGENETIC REGULATORY ENZYMES AND INFLAMMATORY GENES ANALYZED EXHIBITED SIMILAR BASAL EXPRESSION LEVELS IN THE TWO GROUPS. IN CONTRAST, AFTER THE BRIEF INTERVENTION WE DETECTED REDUCED EXPRESSION OF HISTONE DEACETYLASE GENES (HDAC 2, 3 AND 9), ALTERATIONS IN GLOBAL MODIFICATION OF HISTONES (H4AC; H3K4ME3) AND DECREASED EXPRESSION OF PRO-INFLAMMATORY GENES (RIPK2 AND COX2) IN MEDITATORS COMPARED WITH CONTROLS. WE FOUND THAT THE EXPRESSION OF RIPK2 AND HDAC2 GENES WAS ASSOCIATED WITH A FASTER CORTISOL RECOVERY TO THE TSST IN BOTH GROUPS. CONCLUSIONS: THE REGULATION OF HDACS AND INFLAMMATORY PATHWAYS MAY REPRESENT SOME OF THE MECHANISMS UNDERLYING THE THERAPEUTIC POTENTIAL OF MINDFULNESS-BASED INTERVENTIONS. OUR FINDINGS SET THE FOUNDATION FOR FUTURE STUDIES TO FURTHER ASSESS MEDITATION STRATEGIES FOR THE TREATMENT OF CHRONIC INFLAMMATORY CONDITIONS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19  1189  34 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  3841  36 IRON SUPPLEMENTATION REVERSES THE REDUCTION OF HYDROXYMETHYLCYTOSINE IN HEPATIC DNA ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION IN RATS. BACKGROUND: ALCOHOL IS KNOWN TO AFFECT TWO EPIGENETIC PHENOMENA, DNA METHYLATION AND DNA HYDROXYMETHYLATION, AND IRON IS A COFACTOR OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES THAT CATALYZE THE CONVERSION FROM METHYLCYTOSINE TO HYDROXYMETHYLCYTOSINE. IN THE PRESENT STUDY WE AIMED TO DETERMINE THE EFFECTS OF ALCOHOL ON DNA HYDROXYMETHYLATION AND FURTHER EFFECTS OF IRON ON ALCOHOL ASSOCIATED EPIGENETIC CHANGES. METHODS: TWENTY-FOUR MALE SPRAGUE-DAWLEY RATS WERE FED EITHER LIEBER-DECARLI ALCOHOL DIET (36% CALORIES FROM ETHANOL) OR LIEBER-DECARLI CONTROL DIET ALONG WITH OR WITHOUT IRON SUPPLEMENTATION (0.6% CARBONYL IRON) FOR 8 WEEKS. HEPATIC NON-HEME IRON CONCENTRATIONS WERE MEASURED BY COLORIMETRIC ASSAYS. PROTEIN LEVELS OF HEPATIC FERRITIN AND TRANSFERRIN RECEPTOR WERE DETERMINED BY WESTERN BLOTTING. METHYLCYTOSINE, HYDROXYMETHYLCYTOSINE AND UNMODIFIED CYTOSINE IN DNA WERE SIMULTANEOUSLY MEASURED BY LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY METHOD. RESULTS: IRON SUPPLEMENTATION SIGNIFICANTLY INCREASED HEPATIC NON-HEME IRON CONTENTS (P < 0.05) BUT ALCOHOL ALONE DID NOT. HOWEVER, BOTH ALCOHOL AND IRON SIGNIFICANTLY INCREASED HEPATIC FERRITIN LEVELS AND DECREASED HEPATIC TRANSFERRIN RECEPTOR LEVELS (P < 0.05). ALCOHOL REDUCED HEPATIC DNA HYDROXYMETHYLATION (0.21% +/- 0.04% VS. 0.33% +/- 0.04%, P = 0.01) COMPARED TO CONTROL, WHILE IRON SUPPLEMENTATION TO ALCOHOL DIET DID NOT CHANGE DNA HYDROXYMETHYLATION. THERE WAS NO SIGNIFICANT DIFFERENCE IN METHYLCYTOSINE LEVELS, WHILE UNMODIFIED CYTOSINE LEVELS WERE SIGNIFICANTLY INCREASED IN ALCOHOL-FED GROUPS COMPARED TO CONTROL (95.61% +/- 0.08% VS. 95.26% +/- 0.12%, P = 0.03), SUGGESTING THAT ALCOHOL FURTHER INCREASES THE CONVERSION FROM HYDROXYMETHYLCYTOSINE TO UNMODIFIED CYTOSINE. CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION ALTERS GLOBAL DNA HYDROXYMETHYLATION IN THE LIVER BUT IRON SUPPLEMENTATION REVERSES THE EPIGENETIC EFFECT OF ALCOHOL.	2016