1  5740 136 SMOKING AND TETRAMER TRYPTASE ACCELERATE INTERVERTEBRAL DISC DEGENERATION BY INDUCING METTL14-MEDIATED DIXDC1 M(6) MODIFICATION. ALTHOUGH CIGARETTE SMOKING (CS) AND LOW BACK PAIN (LBP) ARE COMMON WORLDWIDE, THEIR CORRELATIONS AND THE MECHANISMS OF ACTION REMAIN UNCLEAR. WE HAVE SHOWN THAT EXCESSIVE ACTIVATION OF MAST CELLS (MCS) AND THEIR PROTEASES PLAY KEY ROLES IN CS-ASSOCIATED DISEASES, LIKE ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BLOOD COAGULATION, AND LUNG CANCER. PREVIOUS STUDIES HAVE ALSO SHOWN THAT MCS AND THEIR PROTEASES INDUCE DEGENERATIVE MUSCULOSKELETAL DISEASE. BY USING A CUSTOM-DESIGNED SMOKE-EXPOSURE MOUSE SYSTEM, WE DEMONSTRATED THAT CS RESULTS IN INTERVERTEBRAL DISC (IVD) DEGENERATION AND RELEASE OF MC-RESTRICTED TETRAMER TRYPTASES (TTS) IN THE IVDS. TTS WERE FOUND TO REGULATE THE EXPRESSION OF METHYLTRANSFERASE 14 (METTL14) AT THE EPIGENETIC LEVEL BY INDUCING N6-METHYLADENOSINE (M(6)A) DEPOSITION IN THE 3' UNTRANSLATED REGION (UTR) OF THE TRANSCRIPT THAT ENCODES DISHEVELLED-AXIN (DIX) DOMAIN-CONTAINING 1 (DIXDC1). THAT REACTION INCREASES THE MRNA STABILITY AND EXPRESSION OF DIXDC1. DIXDC1 FUNCTIONALLY INTERACTS WITH DISRUPTED IN SCHIZOPHRENIA 1 (DISC1) TO ACCELERATE THE DEGENERATION AND SENESCENCE OF NUCLEUS PULPOSUS (NP) CELLS BY ACTIVATING A CANONICAL WNT PATHWAY. OUR STUDY DEMONSTRATES THE ASSOCIATION BETWEEN CS, MC-DERIVED TTS, AND LBP. THESE FINDINGS RAISE THE POSSIBILITY THAT METTL14-MEDICATED DIXDC1 M(6)A MODIFICATION COULD SERVE AS A POTENTIAL THERAPEUTIC TARGET TO BLOCK THE DEVELOPMENT OF DEGENERATION OF THE NP IN LBP PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
2   725  24 CAN THE BLOOD TRYPTASE BE AN INDICATOR OF THE SEVERITY OF ATOPIC DERMATITIS? ATOPIC DERMATITIS (AD - ATOPIC ECZEMA) IS A CHRONIC INFLAMMATORY DERMATOSIS RESULTING FROM COMPLEX GENETIC, EPIGENETIC AND ENVIRONMENTAL INTERACTIONS WITH AN OVERLAPPING DEFECT IN THE EPIDERMAL BARRIER.AD IS ONE OF THE MOST COMMON INFLAMMATORY DERMATOSES IN CHILDREN AND ADULTS. AIM: THE AIM OF THE STUDY WAS TO ASSESS THE RELATIONSHIP BETWEEN SERUM BASAL TRYPTASE (SBT) AND TOTAL IGE (TIGE) LEVEL IN BLOOD SERUM AND THE SEVERITY OF LESIONS (SCORAD; SCORING ATOPIC DERMATITIS). MATERIALS AND METHODS: THE STUDY WAS PERFORMED IN THE GROUP OF ADULT PATIENTS (57 PEOPLE, F/M: 30/27; AVERAGE AGE: 37.5 YEARS) AND IN THE CONTROL GROUP (10 PEOPLE, K/M: 6/4; AVERAGE AGE: 44 YEARS). DIAGNOSIS OF ATOPIC DERMATITIS WAS ESTABLISHED BY A DERMATOLOGIST-ALLERGIST SPECIALIST BASED ON THE CRITERIA OF HANIFIN AND RAJKA. THE SEVERITY OF LESIONS WAS DETERMINED ON THE SCORAD SCALE (SCORING ATOPIC DERMATITIS). RESULTS: THE DISTRIBUTION OF TRYPTASE CONCENTRATION DID NOT DIFFER STATISTICALLY SIGNIFICANTLY BETWEEN PATIENTS WITH VARIOUS DISEASE SEVERITY AND THE CONTROL GROUP ALSO THE SEVERITY OF SKIN LESIONS WAS SIGNIFICANTLY HIGHER (P<0.001) IN PATIENTS WHOSE TIGE LEVEL EXCEEDED 3500 IU / ML. CONCLUSION. SBT DID NOT PROVE TO BE A USEFUL BIOMARKER IN ASSESSING. CONCLUSIONS: SBT DID NOT PROVE TO BE A USEFUL BIOMARKER IN ASSESSING SEVERITY OF AD. THE PRESENT STUDY DEMONSTRATED THAT IN THE PATIENTS WITH ATOPIC DERMATITIS THE CONCENTRATION OF TOTAL IGE WAS CORRELATED WITH SEVERITY OF THE DISEASE SYMPTOMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3  2284  16 EPIGENETIC REGULATION IN INTERVERTEBRAL DISC DEGENERATION. INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH HAS A STRIKING IMPACT ON NUMEROUS PATIENTS. THEREFORE, COMPREHENSIVELY ILLUMINATING THE REGULATORY MECHANISMS OF IVD DEGENERATION IS OF GREAT SIGNIFICANCE. HERE, WE DISCUSS THE LATEST ADVANCES IN UNDERSTANDING THE MAIN EPIGENETIC MECHANISMS REGULATING IVD DEGENERATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4  4033  42 M6A HYPOMETHYLATION OF DNMT3B REGULATED BY ALKBH5 PROMOTES INTERVERTEBRAL DISC DEGENERATION VIA E4F1 DEFICIENCY. BACKGROUND: THE INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH ACCOUNTS FOR A MAIN CAUSE OF DISABILITY. N6-METHYLADENOSINE (M6A) IS THE MOST ABUNDANT INTERNAL MODIFICATION IN EUKARYOTIC MESSENGER RNAS AND IS INVOLVED IN VARIOUS DISEASES AND CELLULAR PROCESSES BY MODULATING MRNA FATE. HOWEVER, THE CRITICAL ROLE OF M6A REGULATION IN IVD DEGENERATION REMAINS UNCLEAR. NUCLEUS PULPOSUS CELL (NPC) SENESCENCE IS CRITICAL FOR THE PROGRESSION OF IVD DEGENERATION. HERE, WE UNCOVERED THE ROLE AND EXPLORED THE REGULATORY MECHANISM OF M6A IN NPC SENESCENCE DURING IVD DEGENERATION. METHODS: IDENTIFICATION OF NPC SENESCENCE DURING IVD DEGENERATION WAS BASED ON THE ANALYSIS OF TISSUE SAMPLES AND THE CELLULAR MODEL. ALKBH5 UPREGULATION INDUCING CELLULAR SENESCENCE WAS CONFIRMED BY FUNCTIONAL EXPERIMENTS IN VIVO AND IN VITRO. CHIP-QPCR AND DNA-PULLDOWN WERE USED TO REVEAL INCREASED ALKBH5 WAS REGULATED BY KDM4A-MEDIATED H3K9ME3. FURTHERMORE, ME-RIP-SEQ WAS PERFORMED TO IDENTIFY M6A HYPOMETHYLATION OF DNMT3B TRANSCRIPTS IN SENESCENT NPCS. STABILITY ANALYSIS SHOWED THAT DNMT3B EXPRESSION WAS ENHANCED FOR LESS YTHDF2 RECOGNITION AND INCREASED DNMT3B PROMOTED NPC SENESCENCE AND IVD DEGENERATION VIA E4F1 METHYLATION BY IN VIVO AND IN VITRO ANALYSES. RESULTS: EXPRESSION OF ALKBH5 IS ENHANCED DURING IVD DEGENERATION AND NPC SENESCENCE, DUE TO DECREASED KDM4A-MEDIATED H3K9ME3 MODIFICATION. FUNCTIONALLY, ALKBH5 CAUSES NPC SENESCENCE BY DEMETHYLATING DNMT3B TRANSCRIPTS AND IN TURN PROMOTING ITS EXPRESSION VIA LESS YTHDF2 RECOGNITION AND FOLLOWING DEGRADATION DUE TO TRANSCRIPT HYPOMETHYLATION IN VITRO AND IN VIVO. INCREASED DNMT3B PROMOTES THE DEVELOPMENT OF IVD DEGENERATION AND NPC SENESCENCE, MECHANISTICALLY BY METHYLATING CPG ISLANDS OF E4F1 AT THE PROMOTER REGION AND THUS RESTRAINING ITS TRANSCRIPTION AND EXPRESSION. CONCLUSIONS: COLLECTIVELY, OUR FINDINGS REVEAL AN EPIGENETIC INTERPLAY MECHANISM IN NPC SENESCENCE AND IVD DEGENERATION, PRESENTING A CRITICAL PRO-SENESCENCE ROLE OF ALKBH5 AND M6A HYPOMETHYLATION, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF TARGETING THE M6A/DNMT3B/E4F1 AXIS FOR TREATING IVD DEGENERATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  2706  43 EXERCISE ATTENUATES LOW BACK PAIN AND ALTERS EPIGENETIC REGULATION IN INTERVERTEBRAL DISCS IN A MOUSE MODEL. BACKGROUND CONTEXT: CHRONIC LOW BACK PAIN (LBP) IS A MULTIFACTORIAL DISORDER WITH COMPLEX UNDERLYING MECHANISMS, INCLUDING ASSOCIATIONS WITH INTERVERTEBRAL DISC (IVD) DEGENERATION IN SOME INDIVIDUALS. IT HAS BEEN DEMONSTRATED THAT EPIGENETIC PROCESSES ARE INVOLVED IN THE PATHOLOGY OF IVD DEGENERATION. EPIGENETICS REFERS TO SEVERAL MECHANISMS, INCLUDING DNA METHYLATION, THAT HAVE THE ABILITY TO CHANGE GENE EXPRESSION WITHOUT INDUCING ANY CHANGE IN THE UNDERLYING DNA SEQUENCE. DNA METHYLATION CAN ALTER THE ENTIRE STATE OF A TISSUE FOR AN EXTENDED PERIOD OF TIME AND THUS COULD POTENTIALLY BE HARNESSED FOR LONG-TERM PAIN RELIEF. LIFESTYLE FACTORS, SUCH AS PHYSICAL ACTIVITY, HAVE A STRONG INFLUENCE ON EPIGENETIC REGULATION. EXERCISE IS A COMMONLY PRESCRIBED TREATMENT FOR CHRONIC LBP, AND SEX-SPECIFIC EPIGENETIC ADAPTATIONS IN RESPONSE TO ENDURANCE EXERCISE HAVE BEEN REPORTED. HOWEVER, WHETHER EXERCISE INTERVENTIONS THAT ATTENUATE LBP ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS IN DEGENERATING IVDS HAS NOT BEEN EVALUATED. PURPOSE: WE HYPOTHESIZE THAT THE THERAPEUTIC EFFICACY OF PHYSICAL ACTIVITY IS MEDIATED, AT LEAST IN PART, AT THE EPIGENETIC LEVEL. THE PURPOSE OF THIS STUDY WAS TO USE THE SPARC-NULL MOUSE MODEL OF LBP ASSOCIATED WITH IVD DEGENERATION TO CLARIFY (1) IF IVD DEGENERATION IS ASSOCIATED WITH ALTERED EXPRESSION OF EPIGENETIC REGULATORY GENES IN THE IVDS, (2) IF EPIGENETIC REGULATORY MACHINERY IS SENSITIVE TO THERAPEUTIC ENVIRONMENTAL INTERVENTION, AND (3) IF THERE ARE SEX-SPECIFIC DIFFERENCES IN (1) AND/OR (2). STUDY DESIGN: EIGHT-MONTH-OLD MALE AND FEMALE SPARC-NULL AND AGE-MATCHED CONTROL (WT) MICE (N=108) WERE ASSIGNED TO EXERCISE (N=56) OR SEDENTARY (N=52) GROUPS. DELETION OF SPARC IS ASSOCIATED WITH PROGRESSIVE IVD DEGENERATION AND BEHAVIORAL SIGNS OF LBP. THE EXERCISE GROUP RECEIVED A CIRCULAR PLASTIC HOME CAGE RUNNING WHEEL ON WHICH THEY COULD RUN FREELY. THE SEDENTARY GROUP RECEIVED AN IDENTICAL WHEEL SECURED IN PLACE TO PREVENT ROTATION. AFTER 6 MONTHS, THE RESULTS OBTAINED IN EACH GROUP WERE COMPARED. METHODS: AFTER 6 MONTHS OF EXERCISE, LBP-RELATED BEHAVIORAL INDICES WERE DETERMINED, AND GLOBAL DNA METHYLATION (5-METHYLCYTOSINE) AND EPIGENETIC REGULATORY GENE MRNA EXPRESSION IN IVDS WERE ASSESSED. THIS PROJECT WAS SUPPORTED BY THE CANADIAN INSTITUTES FOR HEALTH RESEARCH. THE AUTHORS HAVE NO CONFLICTS OF INTEREST. RESULTS: LUMBAR IVDS FROM WT SEDENTARY AND SPARC-NULL SEDENTARY MICE HAD SIMILAR LEVELS OF GLOBAL DNA METHYLATION (%5-MC) AND COMPARABLE MRNA EXPRESSION OF EPIGENETIC REGULATORY GENES (DNMT1,3A,B, MECP2, MBD2A,B, TET1-3) IN BOTH SEXES. EXERCISE ATTENUATED LBP-RELATED BEHAVIORS, DECREASED GLOBAL DNA METHYLATION IN BOTH WT (P<.05) AND SPARC-NULL MICE (P<.01) AND REDUCED MRNA EXPRESSION OF MECP2 IN SPARC-NULL MICE (P<.05). SEX-SPECIFIC EFFECTS OF EXERCISE ON EXPRESSION OF MRNA WERE ALSO OBSERVED. CONCLUSIONS: EXERCISE ALLEVIATES LBP IN A MOUSE MODEL. THIS MAY BE MEDIATED, IN PART, BY CHANGES IN THE EPIGENETIC REGULATORY MACHINERY IN DEGENERATING IVDS. EPIGENETIC ALTERATIONS DUE TO A LIFESTYLE CHANGE COULD HAVE A LONG-LASTING THERAPEUTIC IMPACT BY CHANGING TISSUE HOMEOSTASIS IN IVDS. CLINICAL SIGNIFICANCE: THIS STUDY CONFIRMED THE THERAPEUTIC BENEFITS OF EXERCISE ON LBP AND SUGGESTS THAT EXERCISE RESULTS IN SEX-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION IN IVDS. ELUCIDATING THE EFFECTS OF EXERCISE ON EPIGENETIC REGULATION MAY ENABLE THE DISCOVERY OF NOVEL GENE TARGETS OR NEW STRATEGIES TO IMPROVE THE TREATMENT OF CHRONIC LBP.	2021	

6  5529  34 RNA N(6) -METHYLADENOSINE MODIFICATIONS AND POTENTIAL TARGETED THERAPEUTIC STRATEGIES IN KIDNEY DISEASE. EPIGENETIC MODIFICATIONS HAVE RECEIVED INCREASING ATTENTION AND HAVE BEEN SHOWN TO BE EXTENSIVELY INVOLVED IN KIDNEY DEVELOPMENT AND DISEASE PROGRESSION. AMONG THEM, THE MOST COMMON RNA MODIFICATION, N(6) -METHYLADENOSINE (M(6) A), HAS BEEN SHOWN TO DYNAMICALLY AND REVERSIBLY EXERT ITS FUNCTIONS IN MULTIPLE WAYS, INCLUDING SPLICING, EXPORT, DECAY AND TRANSLATION INITIATION EFFICIENCY TO REGULATE MRNA FATE. MOREOVER, M(6) A HAS ALSO BEEN REPORTED TO EXERT BIOLOGICAL EFFECTS BY DESTABILIZING BASE PAIRING TO MODULATE VARIOUS FUNCTIONS OF RNAS. MOST IMPORTANTLY, AN INCREASING NUMBER OF KIDNEY DISEASES, SUCH AS RENAL CELL CARCINOMA, ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE, HAVE BEEN FOUND TO BE ASSOCIATED WITH ABERRANT M(6) A PATTERNS. IN THIS REVIEW, WE COMPREHENSIVELY REVIEW THE CRITICAL ROLES OF M(6) A IN KIDNEY DISEASES AND DISCUSS THE POSSIBILITIES AND RELEVANCE OF M(6) A-TARGETED EPIGENETIC THERAPY, WITH AN INTEGRATED COMPREHENSIVE DESCRIPTION OF THE DETAILED ALTERATIONS IN SPECIFIC LOCI THAT CONTRIBUTE TO CELLULAR PROCESSES THAT ARE ASSOCIATED WITH KIDNEY DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  1189  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  5118  23 POSSIBLE ASSOCIATION BETWEEN GERMLINE METHYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND PSORIASIS RISK IN A TURKISH POPULATION. BACKGROUND: PSORIASIS IS A COMMON CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY GENETIC AND EPIGENETIC FACTORS. THERE ARE CONFLICTING RESULTS IN THE LITERATURE ABOUT THE ASSOCIATION BETWEEN PSORIASIS AND THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE (MTHFR), RANGING FROM STRONG LINKAGE TO NO ASSOCIATION. AIM: TO INVESTIGATE THE ASSOCIATION BETWEEN THE GERMLINE MTHFR POLYMORPHISMS C677T AND A1298C WITH PSORIASIS RISK IN A TURKISH POPULATION. METHODS: THE STUDY ENROLLED 84 PATIENTS WITH PSORIASIS AND 212 HEALTHY CONTROLS (HCS) WITHOUT ANY HISTORY OF PSORIASIS. DNA WAS EXTRACTED FROM PERIPHERAL BLOOD SAMPLES OF PATIENTS AND HCS, AND REAL-TIME PCR WAS USED FOR GENOTYPING. RESULTS WERE COMPARED BY PEARSON CHI(2) TEST AND MULTIPLE LOGISTIC REGRESSION MODELS. RESULTS: THE FREQUENCY OF BOTH THE MTHFR 677TT AND A1298C (HOMOZYGOUS) GENOTYPES WAS STATISTICALLY SIGNIFICANTLY DIFFERENT FROM HCS. POINT MUTATIONS WERE DETECTED IN ALL PATIENTS WITH EARLY-ONSET PSORIASIS (BEFORE THE AGE OF 20 YEARS). THE T ALLELE OF MTHFR 677 AND THE C ALLELE OF MTHFR 1298 INCREASED PSORIASIS RISK BY 12.4- AND 17.0-FOLD, RESPECTIVELY, IN PATIENTS COMPARED WITH HCS. CONCLUSION: A POSSIBLE ASSOCIATION WAS DETECTED BETWEENGERMLINE MTHFR 677 C>T AND 1298 A>C GENOTYPES AND PSORIASIS RISK IN A TURKISH POPULATION. THESE RESULTS NEED TO BE CONFIRMED IN FURTHER STUDIES WITH LARGER SAMPLE SIZES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  1564  38 DNA METHYLATION OF PROXIMAL PLAT PROMOTER IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND NASAL POLYPS (NP) ARE CHARACTERIZED BY PSEUDOCYSTS DERIVED FROM STROMAL TISSUE EDEMA AND CAUSE PERSISTENT INFECTIONS IN PATIENTS WITH CHRONIC RHINOSINUSITIS (CRS). A LOW LEVEL OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (GENE NAME PLAT) IS CONSIDERED A CAUSE OF STROMAL TISSUE EDEMA BECAUSE OF INSUFFICIENT PLASMIN ACTIVATION IN NP; HOWEVER, THE MECHANISM REGULATING PLAT GENE EXPRESSION LEVELS IS STILL UNCLEAR. THE EPIGENETIC MECHANISM REGULATING THE PLAT GENE EXPRESSION HAS BEEN STUDIED IN OTHER TISSUES. OBJECTIVE WE AIMED TO INVESTIGATE THE METHYLATION LEVELS IN THE PROXIMAL PLAT PROMOTER AND THEIR EFFECTS ON GENE EXPRESSION IN NP TISSUE. METHODS WE INVESTIGATED THE METHYLATION LEVELS AT 3 CPG SITES IN THE PROXIMAL PLAT PROMOTER REGIONS (-618, -121, AND -105 WITH RESPECT TO THE TRANSCRIPTION INITIATION SITE) BY BISULFITE PYROSEQUENCING AND THEIR EFFECTS ON THE GENE EXPRESSION BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR) IN 20 PAIRED SAMPLES OF NP AND INFERIOR TURBINATE TISSUE (IT) FROM PATIENTS WITH CRS. RESULTS THE DNA METHYLATION LEVELS AT ALL CPG SITES WERE HIGHER ( P < .01), AND THE PLAT EXPRESSION WAS LOWER ( P < .001) IN NP COMPARED WITH IT. THE METHYLATION CHANGES AT THE -618 SITE SHOWED A NEGATIVE CORRELATION WITH THE GENE EXPRESSION CHANGES BETWEEN NP AND IT ( R = -.65, P < .01). CONCLUSIONS HYPERMETHYLATION OF PLAT PROMOTER MAY DOWNREGULATE THE GENE EXPRESSION IN NP, LEADING TO EXCESSIVE FIBRIN DEPOSITION BY ABERRANT COAGULATION CASCADE. DNA METHYLATION OF PROXIMAL PLAT PROMOTER MAY CONTRIBUTE TO NP GROWTH AND HAVE A POTENTIAL AS A NEW THERAPEUTIC TARGET.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10   659  26 BLOOD GLOBAL DNA METHYLATION IS DECREASED IN NON-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS. BACKGROUND: ALTERATIONS IN GLOBAL DNA METHYLATION HAVE BEEN ASSOCIATED WITH OXIDATIVE STRESS (OS). SINCE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY INCREASED OXIDATIVE STRESS WE AIMED TO EVALUATE THE LEVELS OF GLOBAL DNA METHYLATION IN THIS PATIENT GROUP. METHODS: WE ASSESSED METHYLCYTOSINE (MCYT) LEVELS IN DNA FROM BLOOD COLLECTED IN 43 COPD PATIENTS (29 WITH MILD AND 14 WITH MODERATE DISEASE) AND 43 AGE- AND SEX-MATCHED HEALTHY CONTROLS. RESULTS: DNA METHYLATION WAS SIGNIFICANTLY LOWER IN COPD PATIENTS VS. CONTROLS (4.20 +/- 0.18% MCYT VS. 4.29 +/- 0.18% MCYT, P = 0.02). FURTHERMORE, DNA METHYLATION IN COPD PATIENTS WITH MODERATE DISEASE WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH MILD DISEASE (4.14 +/- 0.15% MCYT VS. 4.23 +/- 0.19% MCYT, P < 0.05). UNIVARIATE LOGISTIC REGRESSION ANALYSIS SHOWED THAT LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH PRESENCE OF COPD (CRUDE OR = 0.06, 95% CI 0.00 TO 0.67, P = 0.023). THIS RELATIONSHIP REMAINED SIGNIFICANT AFTER ADJUSTING FOR SEVERAL CONFOUNDERS (OR 0.03, 95% CI 0.00 TO 0.67; P = 0.028). RECEIVER OPERATING CHARACTERISTICS (ROC) CURVE ANALYSIS DEMONSTRATED THE AREA UNDER THE CURVE OF MCYT WAS 0.646, WITH 46.6% SENSITIVITY AND 79.1% SPECIFICITY FOR PRESENCE OF COPD. CONCLUSIONS: THERE WERE NO SIGNIFICANT CORRELATIONS BETWEEN METHYLATION AND OS INDICES. THE PRESENCE AND SEVERITY OF COPD IS ASSOCIATED WITH PROGRESSIVELY LOWER DNA METHYLATION IN BLOOD. HOWEVER, THIS EPIGENETIC ALTERATION SEEMS INDEPENDENT OF OXIDATIVE STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  6247  31 THE METHYLATION PATTERNS OF A DISINTEGRIN AND METALLOPROTEINASE 33 GENE (ADAM33) IN ADULT ASTHMA. BACKGROUND: ASTHMA IS A COMMON CHRONIC INFLAMMATORY RESPIRATORY DISEASE. PREVIOUS STUDIES HAVE SUGGESTED THAT THE PATHOGENESIS OF ASTHMA MAY BE AFFECTED BY EPIGENETIC REGULATION. THE PURPOSE OF THIS STUDY IS TO CHARACTERIZE THE EFFECT OF THE METHYLATION OF EACH CPG SITE IN THE ADAM33 (A DISINTEGRIN AND METALLOPROTEINASE 33) GENE IN ADULT ASTHMA. METHODS: A HUMAN CPG ISLAND MICROARRAY WAS USED TO EXAMINE 4 ASTHMATIC CASES AND 4 HEALTHY CONTROLS, AND THE RESULTS SUGGESTED THAT THERE MIGHT BE DIFFERENCES IN METHYLATION WITHIN EXON 9 OF THE ADAM33 GENE. THEREFORE, WE DESIGNED A CASE-CONTROL STUDY WITH 50 ASTHMATIC PATIENTS AND 50 AGE- AND SEX-MATCHED HEALTHY CONTROLS TO EXAMINE THE RELATIONSHIP BETWEEN THE CPG METHYLATION OF THE ADAM33 GENE AND ASTHMA USING BISULFITE DEOXYRIBONUCLEIC ACID MODIFICATION AND SEQUENCING. RESULTS: BISULFITE SEQUENCING EXPERIMENTS SHOWED THAT THE 14 CPG SITES IN EXON 9 OF THE ADAM33 GENE WERE HIGHLY METHYLATED (100%) IN ALL INDIVIDUALS. THE PROPORTIONS OF METHYLATION OF THE 14 CPG SITES IN ADAM33 IN THE CASE GROUP WERE NOT DIFFERENT FROM THOSE OF THE CONTROL GROUP. THE METHYLATION OF EXON 9 OF THIS LOCUS WAS NOT ASSOCIATED WITH AGE, SEX, IGE LEVELS, OR LUNG FUNCTION. THIS STUDY FOUND NO ASSOCIATION BETWEEN THE METHYLATION OF CPG SITES IN EXON 9 OF THE ADAM33 GENE AND ADULT ASTHMA. CONCLUSIONS: THE 14 CPG SITES WERE HIGHLY METHYLATED IN THE CASE AND CONTROL GROUPS. FURTHER INVESTIGATION OF EXON 9 IN ADAM33 IN A LARGER POPULATION IS NEEDED TO EVALUATE ITS ROLE IN ASTHMA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  5854  26 SUBSTANCE P AND NEPRILYSIN IN CHRONIC PANCREATITIS. BACKGROUND/AIMS: WE AIMED TO ANALYZE SUBSTANCE P (SP) AND NEPRILYSIN (NEP), THE MEMBRANE METALLOPEPTIDASE THAT DEGRADES SP, IN CHRONIC PANCREATITIS (CP). METHODS: SP AND NEP MRNA LEVELS WERE ANALYZED BY QRT-PCR IN TISSUE SAMPLES FROM 30 PATIENTS WITH CP AND 8 ORGAN DONORS. IN ADDITION, SP SERUM LEVELS WERE DETERMINED BEFORE AND AFTER SURGERY IN THE SAME PATIENTS, BY MEANS OF A COMPETITIVE ELISA ASSAY. GENETIC AND EPIGENETIC ANALYSES OF THE NEP GENE WERE ALSO PERFORMED. RESULTS: SP MRNA EXPRESSION LEVELS WERE HIGHER IN CP TISSUES COMPARED TO CONTROLS (P = 0.0152), WHILE NEP MRNA SHOWED NO SIGNIFICANT DIFFERENCES BETWEEN CP AND HEALTHY SUBJECTS (P = 0.2102). IN CP PATIENTS, SP SERUM LEVELS CORRELATED WITH THOSE IN TISSUE, AND AFTER SURGICAL RESECTION SP SERUM LEVELS WERE REDUCED COMPARED TO THE PREOPERATIVE VALUES. FAILURE OF NEP TO OVEREXPRESS IN CP TISSUES WAS ASSOCIATED WITH SIGNIFICANT MIR-128A OVEREXPRESSION (P = 0.02), RATHER THAN WITH MUTATIONS IN THE NEP CODING REGION OR THE PRESENCE OF HYPERMETHYLATION SITES IN THE NEP PROMOTER REGION. CONCLUSION: TISSUE AND SERUM LEVELS OF SP WERE INCREASED IN CP, WHILE NEP LEVELS REMAINED UNALTERED. IN AN SP/NEP-MEDIATED PATHWAY, IT WOULD APPEAR THAT NEP FAILS TO PROVIDE ADEQUATE SURVEILLANCE OF SP LEVELS. FAILURE OF NEP TO OVEREXPRESS COULD BE ASSOCIATED WITH MIRNA REGULATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  5086  28 PILOT STUDY OF DNA METHYLATION IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF ALLERGY AND ATOPY. THIS STUDY AIMED TO IDENTIFY WHETHER DNA METHYLATION ALSO PLAYS AN IMPORTANT ROLE IN THE PATHOGENESIS OF NASAL POLYPS (NP). METHODOLOGY: NP TISSUES WERE OBTAINED FROM 32 PATIENTS WITH CHRONIC RHINOSINUSITIS WITH BILATERAL NP. BIOPSIES OF INFERIOR TURBINATE MUCOSA (ITM) WERE TAKEN FROM 18 PATIENTS WHO UNDERWENT RHINOSEPTOPLASTY (CONTROL GROUP). THE METHYLATED GENES, WHICH WERE DETECTED BY DNA METHYLATION MICROARRAY, WERE VALIDATED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION, BISULPHITE SEQUENCING, REAL-TIME POLYMERASE CHAIN REACTION AND IMMUNOHISTOCHEMISTRY. RESULTS: DNA METHYLATION MICROARRAY IDENTIFIED 8,008 CPG ISLANDS IN 2,848 GENES. ONE HUNDRED AND NINETY-EIGHT GENES WERE FOUND TO HAVE A METHYLATED SIGNAL IN THE PROMOTER REGION IN NP SAMPLES COMPARED WITH ITM SAMPLES. THE FOUR TOP GENES THAT CHANGED, COL18A1, EP300, GNAS AND SMURF1, WERE SELECTED FOR FURTHER STUDY. THE METHYLATION FREQUENCY OF COL18A1 WAS SIGNIFICANTLY HIGHER IN NP SAMPLES THAN IN ITM SAMPLES. CONCLUSIONS: DNA METHYLATION MIGHT PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF NP. PROMOTER METHYLATION OF COL18A1 WAS FOUND TO BE SIGNIFICANTLY INCREASED IN NP TISSUES, FURTHER STUDIES ARE NECESSARY TO CONFIRM THE SIGNIFICANCE OF THESE EPIGENETIC FACTORS IN THE MECHANISMS UNDERLYING THE DEVELOPMENT OR PERSISTENCE OF NP.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14  3518  24 IGE SENSITIZATION PROFILES DIFFER BETWEEN ADULT PATIENTS WITH SEVERE AND MODERATE ATOPIC DERMATITIS. BACKGROUND: ATOPIC DERMATITIS (AD) IS A COMPLEX CHRONIC INFLAMMATORY DISEASE WHERE ALLERGENS CAN ACT AS SPECIFIC TRIGGERING FACTORS. AIM: TO CHARACTERIZE THE SPECIFICITIES OF IGE-REACTIVITY IN PATIENTS WITH AD TO A BROAD PANEL OF EXOGENOUS ALLERGENS INCLUDING MICROBIAL AND HUMAN ANTIGENS. METHODOLOGY: ADULT PATIENTS WITH AD WERE GROUPED ACCORDING TO THE SCORAD INDEX, INTO SEVERE (N = 53) AND MODERATE AD (N = 126). AS CONTROLS 43 PATIENTS WERE INCLUDED WITH SEBORRHOEIC ECZEMA AND 97 INDIVIDUALS WITHOUT HISTORY OF ALLERGY OR SKIN DISEASES. SPECIFIC IGE REACTIVITY WAS ASSESSED IN PLASMA USING PHADIATOP(R), IMMUNOCAP, MICRO-ARRAYED ALLERGENS, DOT-BLOTTED RECOMBINANT MALASSEZIA SYMPODIALIS ALLERGENS, AND IMMUNE-BLOTTED MICROBIAL AND HUMAN PROTEINS. RESULTS: IGE REACTIVITY WAS DETECTED IN 92% OF PATIENTS WITH SEVERE AND 83% OF PATIENTS WITH MODERATE AD. SENSITIZATION TO CAT ALLERGENS OCCURRED MOST FREQUENTLY, FOLLOWED BY SENSITIZATION TO BIRCH POLLEN, GRASS POLLEN, AND TO THE SKIN COMMENSAL YEAST M. SYMPODIALIS. PATIENTS WITH SEVERE AD SHOWED A SIGNIFICANTLY HIGHER FREQUENCY OF IGE REACTIVITY TO ALLERGENS LIKE CAT (RFEL D 1) AND HOUSE DUST MITE (RDER P 4 AND 10), TO STAPHYLOCOCCUS AUREUS, M. SYMPODIALIS, AND TO HUMAN ANTIGENS. IN CONTRAST, THERE WERE NO SIGNIFICANT DIFFERENCES IN THE FREQUENCIES OF IGE REACTIVITY TO THE GRASS POLLEN ALLERGENS RPHL P 1, 2, 5B, AND 6 BETWEEN THE TWO AD GROUPS. FURTHERMORE THE IGE REACTIVITY PROFILE OF PATIENTS WITH SEVERE AD WAS MORE SPREAD TOWARDS SEVERAL DIFFERENT ALLERGEN MOLECULES AS COMPARED TO PATIENTS WITH MODERATE AD. CONCLUSION: WE HAVE REVEALED A HITHERTO UNKNOWN DIFFERENCE REGARDING THE MOLECULAR SENSITIZATION PROFILE IN PATIENTS WITH SEVERE AND MODERATE AD. MOLECULAR PROFILING TOWARDS ALLERGEN COMPONENTS MAY PROVIDE A BASIS FOR FUTURE INVESTIGATIONS AIMING TO EXPLORE THE ENVIRONMENTAL, GENETIC AND EPIGENETIC FACTORS WHICH COULD BE RESPONSIBLE FOR THE DIFFERENT APPEARANCE AND SEVERITY OF DISEASE PHENOTYPES IN AD.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  6589  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  5553  33 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. CHRONIC RHINOSINUSITIS (CRS) IS A HIGHLY PREVALENT DISEASE CHARACTERIZED BY MUCOSAL INFLAMMATION OF THE NOSE AND PARANASAL SINUSES. CRS CAN BE DIVIDED INTO TWO MAIN CATEGORIES, CRS WITH NASAL POLYPS (NPS; CRSWNP) AND CRS WITHOUT NPS (CRSSNP). ALTHOUGH THE PATHOPHYSIOLOGY OF CRS REMAINS UNCLEAR, DNA METHYLATION HAS BEEN IMPLICATED IN THE ETIOLOGY OF CRSWNP. THE AIM OF THE PRESENT STUDY WAS TO ELUCIDATE WHETHER DNA METHYLATION OF SPECIFIC GENES IS INVOLVED IN THE DEVELOPMENT OF NPS. IN TOTAL, 18 INDIVIDUALS WERE INCLUDED IN THE PRESENT STUDY, AND WERE DIVIDED INTO THREE GROUPS: CRSWNP (N=7), CRSSNP (N=7) AND HEALTHY CONTROLS (N=4). NP TISSUES WERE OBTAINED FROM THE SEVEN PATIENTS WITH CRSWNP AND BIOPSIES OF THE INFERIOR TURBINATE MUCOSA FROM ALL THREE GROUPS WERE USED AS CONTROLS. METHYLATED GENES DETECTED BY METHYL?CPG?BINDING DOMAIN SEQUENCING WERE VALIDATED BY METHYLATION?SPECIFIC POLYMERASE CHAIN REACTION (PCR), BISULFITE SEQUENCING, AND REVERSE TRANSCRIPTION?QUANTITATIVE PCR (RT?QPCR). METHYL?CPG?BINDING DOMAIN SEQUENCING IDENTIFIED 43,674 CPG ISLANDS IN 518 GENES. THE PROMOTOR REGIONS OF 10 AND 30 GENES WERE HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, IN NP SAMPLES COMPARED WITH CONTROLS. THE TOP FOUR GENES WITH ALTERED HYPOMETHYLATION IN NP TISSUES WERE, KERATIN 19 (KRT19), NUCLEAR RECEPTOR SUBFAMILY 2 GROUP F MEMBER 2 (NR2F2), A DISINTEGRIN?LIKE AND METALLOPEPTIDASE (REPROLYSIN TYPE) WITH THROMBOSPONDIN TYPE 1 MOTIF 1 (ADAMTS1) AND ZINC FINGER PROTEIN 222 (ZNF222). RT?QPCR DEMONSTRATED THAT THE EXPRESSION LEVELS OF KRT19, NR2F2 AND ADAMTS1 WERE SIGNIFICANTLY INCREASED IN NP TISSUES; HOWEVER, THERE WAS NO DIFFERENCE IN THE LEVELS OF ZNF222 BETWEEN NP AND CONTROL TISSUES. FURTHER STUDIES ARE REQUIRED TO CONFIRM THE RELEVANCE OF THESE EPIGENETIC MODIFICATIONS IN THE MECHANISMS UNDERLYING NP FORMATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  3448  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  3637  25 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  4825  22 OCULAR FUNDUS ABNORMALITIES IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY AND OTHER CHRONIC KIDNEY DISEASES. AIM: THE AIM OF THIS STUDY WAS TO EXAMINE THE OCULAR FUNDUS PATHOLOGY IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY (BN) AND CHRONIC KIDNEY DISEASES (CKD). METHODS: THE STUDY INCLUDED 51 PATIENTS WITH BN FROM THE SOUTH MORAVA RIVER REGION IN SERBIA, AND 102 SUBJECTS WITH DIFFERENT STAGES OF CHRONIC RENAL DISEASES, MATCHED ACCORDING TO AGE AND GENDER, OBTAINED FROM A DATABASE USED IN A RECENTLY PUBLISHED STUDY. ALL PATIENTS HAD VISITED OUTPATIENT DEPARTMENT OF THE CLINIC OF NEPHROLOGY, CLINICAL CENTER NIS. ALL PATIENTS UNDERWENT ROUTINE OPHTHALMIC EXAMINATIONS. RESULTS: THERE WERE SIGNIFICANTLY MORE (P < 0.001) PATIENTS WITH AGE-RELATED MACULAR DEGENERATION (AMD) IN THE GROUP WITH BN (31.37 %) THAN IN THOSE WITH CKD (5.88 %). MULTIVARIATE LOGISTIC REGRESSION ANALYSIS CONFIRMED THAT THE SIGNIFICANT FACTORS RELATED TO AMD IN THE GROUP WITH BN WERE ALBUMINURIA (P < 0.05) AND PROTEINURIA (P < 0.05); IN CKD PATIENTS, THE LEVEL OF HDL (P < 0.05), WHILE NEGATIVE CORRELATION WITH THE LEVEL OF TRIGLYCERIDE WAS REGISTERED (P < 0.05). THERE WAS NO ASSOCIATION BETWEEN ESTIMATED GLOMERULAR FILTRATION RATE AND AMD. THE SIGNIFICANT FACTORS RELATED TO RETINOPATHY IN THE GROUP WITH BN ARE AGE (P < 0.05) AND SERUM CREATININE VALUES (P < 0.05), IN PATIENTS WITH CKD INCREASING AGE (P < 0.001) AND DM (P < 0.05). CONCLUSION: OCULAR FUNDUS PATHOLOGY IN PATIENTS WITH BN IS SIMILAR TO THE PATHOLOGY OF OTHER CKD, BUT WITH SIGNIFICANTLY MORE AMD (ABOUT FOUR TIMES), PROBABLY RELATED TO THE GENETIC/EPIGENETIC FACTORS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  2418  27 EPIGENETIC SIGNATURE OF CHRONIC LOW BACK PAIN IN HUMAN T CELLS. OBJECTIVE: DETERMINE IF CHRONIC LOW BACK PAIN (LBP) IS ASSOCIATED WITH DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT WILL REVEAL NOVEL MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS AND EXPLORE THE FEASIBILITY OF EPIGENETIC DIAGNOSTIC MARKERS FOR PAIN-RELATED PATHOPHYSIOLOGY. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS OF 850,000 CPG SITES IN WOMEN AND MEN WITH CHRONIC LBP AND PAIN-FREE CONTROLS WAS PERFORMED. T CELLS WERE ISOLATED (DISCOVERY COHORT, N = 32) AND USED TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES, AND GENE ONTOLOGIES AND MOLECULAR PATHWAYS WERE IDENTIFIED. A POLYGENIC DNA METHYLATION SCORE FOR LBP WAS GENERATED IN BOTH WOMEN AND MEN. VALIDATION WAS PERFORMED IN AN INDEPENDENT COHORT (VALIDATION COHORT, N = 63) OF CHRONIC LBP AND HEALTHY CONTROLS. RESULTS: ANALYSIS WITH THE DISCOVERY COHORT REVEALED A TOTAL OF 2,496 AND 419 DIFFERENTIALLY METHYLATED CPGS IN WOMEN AND MEN, RESPECTIVELY. IN WOMEN, MOST OF THESE SITES WERE HYPOMETHYLATED AND ENRICHED IN GENES WITH FUNCTIONS IN THE EXTRACELLULAR MATRIX, IN THE IMMUNE SYSTEM (IE, CYTOKINES), OR IN EPIGENETIC PROCESSES. IN MEN, A UNIQUE CHRONIC LBP DNA METHYLATION SIGNATURE WAS IDENTIFIED CHARACTERIZED BY SIGNIFICANT ENRICHMENT FOR GENES FROM THE MAJOR HISTOCOMPATIBILITY COMPLEX. SEX-SPECIFIC POLYGENIC DNA METHYLATION SCORES WERE GENERATED TO ESTIMATE THE PAIN STATUS OF EACH INDIVIDUAL AND CONFIRMED IN THE VALIDATION COHORT USING PYROSEQUENCING. CONCLUSION: THIS STUDY REVEALS SEX-SPECIFIC DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT DISCRIMINATES CHRONIC LBP PARTICIPANTS FROM HEALTHY CONTROLS.	2021