1  5108 174 POLYMORPHISMS OF TNF-ALPHA (- 308), IL-1BETA (+ 3954) AND IL1-RA (VNTR) ARE ASSOCIATED TO SEVERE STAGE OF ENDOMETRIOSIS IN MEXICAN WOMEN: A CASE CONTROL STUDY. BACKGROUND: ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT AND CHRONIC INFLAMMATORY DISEASE AFFECTING UP TO 10% OF WOMEN. IT IS THE RESULT OF A COMBINED INTERACTION OF GENETIC, EPIGENETIC, ENVIRONMENTAL, LIFESTYLE, REPRODUCTIVE AND LOCAL INFLAMMATORY FACTORS. IN THIS STUDY, WE INVESTIGATED WHETHER SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) MAPPING TO TNF-ALPHA (TNF, RS1800629) AND IL-1BETA (IL1B, RS1143634) AND VARIABLE NUMBER TANDEM REPEAT POLYMORPHISM MAPPING TO IL1-RA (IL1RN INTRON 2, RS2234663) GENETIC LOCI ARE ASSOCIATED WITH RISK FOR ENDOMETRIOSIS IN A MEXICAN MESTIZO POPULATION. METHODS: THIS STUDY INCLUDED 183 WOMEN WITH CONFIRMED ENDOMETRIOSIS (ENDO) DIAGNOSED AFTER SURGICAL LAPAROSCOPY AND 186 WOMEN WITH SATISFIED PARITY AND WITHOUT ENDOMETRIOSIS AS CONTROLS (CTR). PCR/RFLP TECHNIQUE WAS USED FOR GENOTYPING SNPS (RS1800629 AND RS1143634); PCR FOR GENOTYPING RS2234663. RESULTS: WE FOUND NO STATISTICAL DIFFERENCES IN AGE BETWEEN GROUPS NOR AMONG STAGES OF ENDOMETRIOSIS AND THE CTR GROUP. WE OBSERVED NO DIFFERENCE IN GENOTYPE AND ALLELE FREQUENCIES, NOR CARRIAGE RATE BETWEEN GROUPS IN NONE OF THE THREE STUDIED POLYMORPHISMS. THE PREVALENCE OF TNF*2-ALLELE HETEROZYGOTES (P = 0.025; OR 3.8), TNF*2-ALLELE (P = 0.029; OR 3.4), IL1B*2-ALLELE HETEROZYGOTES (P = 0.044; OR 2.69) AND ITS CARRIAGE RATE (P = 0.041; OR 2.64) IN ENDOMETRIOSIS STAGE IV WAS HIGHER THAN THE CTR GROUP. SURPRISINGLY, THE CARRIAGE RATE OF IL1RN*2-ALLELE (ENDO: P = 0.0004; OR 0.4; STAGE I: P = 0.002, OR 0.38; STAGE II: P = 0.002, OR 0.35; STAGE III: P = 0.003, OR 0.33), AS WELL AS THE IL1RN*2-ALLELE FREQUENCIES (ENDO: P = 0.0008, OR 0.55; I: P = 0.037, OR 0.60; II: P = 0.002, OR 0.41; III: P = 0.003, OR 0.38) WERE LOWER THAN THE CTR GROUP. WOMEN WITH ENDOMETRIOSIS STAGE IV (SEVERE) HAD FREQUENCIES MORE ALIKE TO THE CTR GROUP IN THE IL1RN*2 ALLELE FREQUENCY (31.2% VS. 27.2%) AND CARRIAGE RATE (37.5% VS. 41.9%). CONCLUSION: ALTHOUGH THESE POLYMORPHISMS ARE NOT ASSOCIATED WITH THE RISK OF ENDOMETRIOSIS, MEXICAN MESTIZO WOMEN WITH SEVERE STAGE OF ENDOMETRIOSIS HAVE HIGHER FREQUENCIES OF TNF*2-, IL1B*2- AND IL1RN*2-ALLELES, WHICH MAY EXPLAIN A POSSIBLE CORRELATION WITH DISEASE SEVERITY RATHER THAN PREDISPOSITION OR RISK.	2022	
                                                                                                                                                                                                                                                                                                                  
2  5904  47 T677T METHYLENETETRAHYDROFOLATE REDUCTASE SINGLE NUCLEOTIDE POLYMORPHISMS INCREASED PREVALENCE IN A SUBGROUP OF INFERTILE PATIENTS WITH ENDOMETRIOSIS. BACKGROUND: APPROXIMATELY 10% (190 MILLION) OF WOMEN WORLDWIDE ARE AFFECTED BY ENDOMETRIOSIS, ECTOPIC DEPOSITS OF ENDOMETRIAL TISSUE THAT CREATE A MAJOR SOURCE OF PAIN THAT AFFECTS LIFESTYLE AND REPRODUCTIVE FUNCTION. THE PATHOGENESIS OF ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT INFLAMMATORY PROCESS, INFLUENCED/CATALYZED BY OXIDATIVE STRESS AND CONSEQUENTLY DEFECTIVE METHYLATION, WITH BIOCHEMICAL FEATURES CENTERED AROUND THE FOLATE AND ONE-CARBON CYCLES. WE AIMED TO DETERMINE WHETHER A LINK COULD BE FOUND BETWEEN THE TWO MAJOR METHYLENETETRAHYDROFOLATE REDUCTASE SINGLE NUCLEOTIDE POLYMORPHISMS (MTHFR SNPS), C.677C>T AND C.1298A>C, INVOLVED IN METHYLATION PROCESS/EPIGENETIC MARKING FAILURES, AND ENDOMETRIOSIS. MATERIAL AND METHODS: WE STUDIED A POPULATION OF 158 PATIENTS IN A GROUP OF >1500 REFERRED FOR TREATMENT OF INFERTILITY. ALL THE PATIENTS HAD EXPERIENCED >2 FAILED ASSISTED REPRODUCTIVE TECHNOLOGY CYCLES AND/OR >2 MISCARRIAGES, A CLASSICAL COHORT FOR INVESTIGATION IN OUR GROUP. PATIENTS WITH ENDOMETRIOSIS HAD AT LEAST STAGE 2+ DISEASE CONFIRMED BY LAPAROSCOPY. RESULTS: THE PREVALENCE OF THE HOMOZYGOUS C.677C>T ISOFORM IS DOUBLED IN THE ENDOMETRIOSIS GROUP, 21.5% VERSUS 10.2% IN THE NON-ENDOMETRIOSIS GROUP (P > 0.01). SYMMETRICALLY, THE PERCENTAGE OF PATIENTS IN THE ENDOMETRIOSIS GROUP WITH THE WILD TYPE MTHFR SIGNIFICANTLY DECREASED BY ONE-HALF (8.2%-17.2%) IN THE NON-ENDOMETRIOSIS GROUP (P < 0.001). CONCLUSION: DETERMINATION OF MTHFR C.677C>T SHOULD NOT BE OVERLOOKED IN PATIENTS WITH HARMFUL ENDOMETRIOSIS AFFECTING THEIR FERTILITY. AS FOLATES METABOLISM IS IMPAIRED IN THESE MTHFR SNPS CARRIER PATIENTS, CO-TREATMENT WITH 5-METHYL FOLATE MAY CONSTITUTE A SUCCESSFUL (CO)-TREATMENT MODALITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  1292  33 DECREASED BLOOD PRESSURE IS RELATED TO CHANGES IN NF-KB PROMOTER METHYLATION LEVELS AFTER BARIATRIC SURGERY. BACKGROUND: OBESITY IS CHARACTERIZED BY A CHRONIC, LOW-GRADE INFLAMMATION, AND BARIATRIC SURGERY IS PROPOSED AS AN EFFECTIVE TREATMENT FOR REDUCING THE OBESITY-RELATED CO-MORBIDITIES. EPIGENETIC MODIFICATIONS COULD BE INVOLVED IN THE METABOLIC IMPROVEMENT AFTER SURGERY. OBJECTIVE: THE MAIN AIM OF THIS STUDY WAS TO EVALUATE WHETHER DNA METHYLATION PATTERN FROM GENES RELATED TO INFLAMMATION AND INSULIN RESPONSE IS ASSOCIATED WITH THE METABOLIC IMPROVEMENT AFTER BARIATRIC SURGERY IN MORBIDLY OBESE PATIENTS AND IF THESE CHANGES DEPEND ON THE SURGICAL PROCEDURE. SETTING: UNIVERSITY HOSPITAL, SPAIN. METHODS: WE STUDIED 60 SEVERELY OBESE PATIENTS; 31 UNDERWENT ROUX-EN-Y GASTRIC BYPASS AND 29 UNDERWENT LAPAROSCOPIC SLEEVE GASTRECTOMY. ALL PATIENTS WERE EXAMINED BEFORE AND AT 6 MONTHS AFTER BARIATRIC SURGERY. DNA METHYLATION PROFILE OF GENES RELATED TO THE INFLAMMATORY RESPONSE AND INSULIN SENSITIVITY WAS MEASURED BY PYROSEQUENCING. RESULTS: THE PROMOTER METHYLATION LEVELS OF THE NFKB1 GENE WERE INCREASED SIGNIFICANTLY AFTER SURGERY (2.16 +/- .9 VERSUS 2.8 +/- 1.03). THE DECREASE IN BLOOD PRESSURE, BOTH SYSTOLIC AND DIASTOLIC, AFTER SURGERY WAS SIGNIFICANTLY ASSOCIATED WITH THE CHANGES IN THE PROMOTER METHYLATION LEVELS OF THE NFKB1 GENE (BETA = -.513, P = .003 AND BETA = -.543, P = .004, RESPECTIVELY). A DECREASE IN INFLAMMATION STATUS, MEASURED BY HIGH SENSITIVITY C-REACTIVE PROTEIN VALUES, WAS ASSOCIATED WITH CHANGES IN SLC19A1 METHYLATION LEVELS. CONCLUSION: OUR STUDY SHOWS FOR THE FIRST TIME AN ASSOCIATION BETWEEN NFKB1 METHYLATION LEVELS AND BLOOD PRESSURE AFTER BARIATRIC SURGERY, HIGHLIGHTING THE POSSIBLE FUNCTION OF THIS GENE IN THE REGULATION OF ARTERIAL PRESSURE. REGARDING SLC19A1, THIS GENE COULD POSITION AS A POTENTIAL TARGET LINKING INFLAMMATION AND INSULIN RESISTANCE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  3085  34 GENOME-WIDE SCREEN OF OVARY-SPECIFIC DNA METHYLATION IN POLYCYSTIC OVARY SYNDROME. OBJECTIVE: TO COMPARE GENOME-WIDE DNA METHYLATION PROFILES IN OVARY TISSUE FROM WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS) AND HEALTHY CONTROLS. DESIGN: CASE-CONTROL STUDY MATCHED FOR AGE AND BODY MASS INDEX. SETTING: UNIVERSITY-AFFILIATED HOSPITAL. PATIENT(S): TEN WOMEN WITH PCOS WHO UNDERWENT OVARIAN DRILLING TO INDUCE OVULATION AND 10 HEALTHY WOMEN WHO WERE UNDERGOING LAPAROSCOPIC STERILIZATION, HYSTERECTOMY FOR BENIGN CONDITIONS, DIAGNOSTIC LAPAROSCOPY FOR PELVIC PAIN, OR OOPHORECTOMY FOR NONOVARIAN INDICATIONS. INTERVENTION(S): NONE. MAIN OUTCOME MEASURE(S): GENOME-WIDE DNA METHYLATION PATTERNS DETERMINED BY IMMUNOPRECIPITATION AND MICROARRAY (MEDIP-CHIP) ANALYSIS. RESULT(S): THE METHYLATION LEVELS WERE STATISTICALLY SIGNIFICANTLY HIGHER IN CPG ISLAND SHORES (CGI SHORES), WHICH LIE OUTSIDE OF CORE PROMOTER REGIONS, AND LOWER WITHIN GENE BODIES IN WOMEN WITH PCOS RELATIVE TO THE CONTROLS. IN ADDITION, HIGH CPG CONTENT PROMOTERS WERE THE MOST FREQUENTLY HYPERMETHYLATED PROMOTERS IN PCOS OVARIES BUT WERE MORE OFTEN HYPOMETHYLATED IN CONTROLS. SECOND, 872 CGIS, SPECIFICALLY METHYLATED IN PCOS, REPRESENTED 342 GENES THAT COULD BE ASSOCIATED WITH VARIOUS MOLECULAR FUNCTIONS, INCLUDING PROTEIN BINDING, HORMONE ACTIVITY, AND TRANSCRIPTION REGULATOR ACTIVITY. FINALLY, METHYLATION DIFFERENCES WERE VALIDATED IN SEVEN GENES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THESE GENES CORRELATED TO SEVERAL FUNCTIONAL FAMILIES RELATED TO THE PATHOGENESIS OF PCOS AND MAY BE POTENTIAL BIOMARKERS FOR THIS DISEASE. CONCLUSION(S): OUR RESULTS DEMONSTRATED THAT EPIGENETIC MODIFICATION DIFFERS BETWEEN PCOS AND NORMAL OVARIES, WHICH MAY HELP TO FURTHER UNDERSTAND THE PATHOPHYSIOLOGY OF THIS DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  1189  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  1893  37 ENDOMETRIOSIS: NEW PERSPECTIVE FOR THE DIAGNOSIS OF CERTAIN CYTOKINES IN WOMEN AND ADOLESCENT GIRLS, AS WELL AS THE PROGRESSION OF DISEASE OUTGROWTH: A SYSTEMATIC REVIEW. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGICAL DISORDER THAT UNDOUBTEDLY IMPACTS ON QUALITY OF LIFE, AND IS ONE OF THE MORE COMPLEX AND MYSTERIOUS ILLNESSES OF OUR CENTURY, WHICH IS ASSOCIATED WITH THE IMPROPER GROWTH OF ENDOMETRIAL TISSUE OUTSIDE OF THE UTERINE CAVITY. THIS PATHOLOGICALLY IMPLANTED TISSUE CAN BE FOUND MOST FREQUENTLY IN THE MINOR PELVIS, BUT ALSO IN THE PERITONEAL CAVITY, AND CAN AFFECT MANY ORGANS, LEADING TO CHRONIC PELVIC PAIN SYNDROME, INFERTILITY, AND DYSMENORRHEA. ENDOMETRIAL TISSUE IS A PARTICULARLY DYNAMIC TISSUE THAT HAS A DIRECT IMPACT ON THE PROGRESSION OF THE DISEASE, WITH ALTERED IMMUNITY, AS WELL AS CYTOKINE STORMS WITHIN THE METAPLASTIC ENDOMETRIOTIC SITE, AS POSSIBLE KEY FACTORS. CURRENTLY, DIAGNOSIS OF THIS MYSTERIOUS CHRONIC ILLNESS RELIES ON PERFORMING A LAPAROSCOPIC PROCEDURE WITH TISSUE SAMPLING. ONE OF THE MOST TROUBLESOME OUTCOMES OF THIS UNINTENDED PROGRESSION IS THAT WE LACK ANY SPECIFIC, SENSITIVE, NON-INVASIVE DIAGNOSTIC TOOLS. CURRENTLY, THE VAST MAJORITY OF REGIME STEWARDSHIP OPTIONS RELY ON ANTI-CONTRACEPTIVE DRUGS, OR OTHER REMEDIES THAT SUPPRESS THE RELEASE OF ESTROGEN THROUGH THE GONADS-ALTHOUGH IN MOST CLINICAL TRIALS, ENDOMETRIOSIS IS A CHRONIC PROGRESSIVE DISORDER THAT DEPENDS MOSTLY ON THE HIGH CONCENTRATION OF ESTROGEN. MOREOVER, MANY SPECIFIC TRIALS HAVE DEMONSTRATED THAT THE EUTOPIC ENDOMETRIAL CELLS IN INDIVIDUALS WITH ENDOMETRIOSIS REMAIN MUCH MORE RESISTANT TO THE IMMUNOLOGICAL ANNIHILATION PROCESS CAUSED BY CERTAIN ELEMENTS OF THE IMMUNE SYSTEM. NEVERTHELESS, EUTOPIC ENDOMETRIAL CELLS HAVE THE POTENTIAL TO SIMILARLY ESCALATE THE EXPRESSION OF AROMATASE RECEPTORS ON THE SURFACE OF THE PATHOLOGICAL CELLS, WHICH IN THE FINAL CASCADE CAUSE AN INCREASE IN THE CONCENTRATION OF ESTROGEN, AS WELL AS OTHER INFLAMMATORY PROTEINS THAT CONTRIBUTE TO PATHOLOGICAL OUTGROWTH. DATA REVEAL OCCURRENCE AMONG FIRST-DEGREE RELATIVES, SUGGESTING THAT THE SPECIFIC CASCADE COULD BE RELATED TO INHERITED AS WELL AS EPIGENETIC (ACQUIRED) MECHANISMS. IN WOMEN WITH THE DISEASE, CONFIRMED BY LAPAROSCOPIC PROCEDURES, DIAGNOSIS OF ENDOMETRIOSIS CAN BE ESTABLISHED ALSO VIA DETECTION BY GENE POLYMORPHISM IN THE GENES WHICH ARE RESPONSIBLE FOR RESPONSIBLE FOR THE DETOXIFICATION PHASE OF ESTROGEN RECEPTORS AND OTHER IMMUNOMODULATOR COMPONENTS. A RECENT PUBLICATION AIMS TO REVEAL A NEW PROSPECT FOR THE NON-INVASIVE DIAGNOSIS, DETECTION, AND ESTIMATION OF CERTAIN BIOMARKERS FOR MUCH MORE SPECIFIC INVESTIGATION OF THE DISEASE'S PROGRESSION.	2021	

7  5118  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  3456  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9  3850  36 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  4688  33 NEW UNDERSTANDING OF DIAGNOSIS, TREATMENT AND PREVENTION OF ENDOMETRIOSIS. FOR 100 YEARS, PELVIC ENDOMETRIOSIS HAS BEEN CONSIDERED TO ORIGINATE FROM THE IMPLANTATION OF ENDOMETRIAL CELLS FOLLOWING RETROGRADE MENSTRUATION OR METAPLASIA. SINCE SOME OBSERVATIONS, SUCH AS THE CLONAL ASPECT, THE BIOCHEMICAL VARIABILITY OF LESIONS AND ENDOMETRIOSIS IN WOMEN WITHOUT ENDOMETRIUM, THE GENETIC-EPIGENETIC (G-E) THEORY DESCRIBES THAT ENDOMETRIOSIS ONLY BEGINS AFTER A SERIES OF CUMULATIVE G-E CELLULAR CHANGES. THIS EXPLAINS THAT THE ENDOMETRIOTIC MAY ORIGINATE FROM ANY PLURIPOTENT CELL APART FROM THE ENDOMETRIUM, THAT 'ENDOMETRIUM-LIKE CELLS' CAN HARBOUR IMPORTANT G-E DIFFERENCES, AND THAT THE RISK IS HIGHER IN PREDISPOSED WOMEN WITH MORE INHERITED INCIDENTS. A CONSEQUENCE IS A HIGH RISK AFTER PUBERTY WHICH DECREASES PROGRESSIVELY THEREAFTER. CONSIDERING A 10-YEAR DELAY BETWEEN INITIATION AND PERFORMING A LAPAROSCOPY, THIS WAS OBSERVED IN THE UNITED ARAB EMIRATES, BELGIUM, FRANCE AND USA. THE SUBSEQUENT GROWTH VARIES WITH THE G-E CHANGES AND THE ENVIRONMENT BUT IS SELF-LIMITING PROBABLY BECAUSE OF THE IMMUNOLOGIC REACTION AND FIBROSIS. THAT EACH LESION HAS A DIFFERENT SET OF G-E INCIDENTS EXPLAINS THE VARIABILITY OF PAIN AND THE RESPONSE TO HORMONAL TREATMENT. NEW LESIONS MAY DEVELOP, BUT RECURRENCES AFTER SURGICAL EXCISION ARE RARE. THE FIBROSIS AROUND ENDOMETRIOSIS BELONGS TO THE BODY AND DOES NOT NEED TO BE REMOVED. THIS SUGGESTS CONSERVATIVE EXCISION OR MINIMAL BOWEL WITHOUT SAFETY MARGINS AND SUPERFICIAL TREATMENT OF OVARIAN ENDOMETRIOSIS. THIS G-E CONCEPT ALSO SUGGESTS PREVENTION BY DECREASING OXIDATIVE STRESS FROM RETROGRADE MENSTRUATION OR THE PERITONEAL MICROBIOME. THIS SUGGESTS THE PREVENTION OF VAGINAL INFECTIONS AND CHANGES IN THE GASTROINTESTINAL MICROBIOTA THROUGH FOOD INTAKE AND EXERCISE. IN CONCLUSION, A HIGHER RISK OF INITIATING ENDOMETRIOSIS DURING ADOLESCENCE WAS OBSERVED IN UAE, FRANCE, BELGIUM AND USA. THIS NEW UNDERSTANDING AND THE LIMITED GROWTH OPENS PERSPECTIVES FOR EARLIER DIAGNOSIS AND BETTER TREATMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11   401  37 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2149  33 EPIGENETIC MARKERS TO PREDICT CONVERSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES. CONTEXT: LIFESTYLE FACTORS MEDIATE EPIGENETIC CHANGES THAT CAN CAUSE CHRONIC DISEASES. ALTHOUGH ANIMAL AND LABORATORY STUDIES LINK EPIGENETIC CHANGES TO DIABETES, EPIGENETIC INFORMATION IN WOMEN WITH GESTATIONAL DIABETES (GDM) AND TYPE 2 DIABETES IS LACKING. OBJECTIVE: THIS STUDY SOUGHT TO MEASURE EPIGENETIC MARKERS ACROSS PREGNANCY AND EARLY POSTPARTUM AND IDENTIFY MARKERS THAT COULD BE USED AS PREDICTORS FOR CONVERSION FROM GDM TO TYPE 2 DIABETES. DESIGN: GLOBAL HISTONE H3 DIMETHYLATION WAS MEASURED IN WHITE BLOOD CELLS AT THREE TIME POINTS: 30 WK GESTATION, 8-10 WK POSTPARTUM, AND 20 WK POSTPARTUM, FROM FOUR GROUPS OF WOMEN WITH AND WITHOUT DIABETES. SETTING AND PARTICIPANTS: A TOTAL OF 39 PARTICIPANTS (SIX TO NINE IN EACH GROUP) WERE RECRUITED INCLUDING: NONDIABETIC WOMEN; WOMEN WITH GDM WHO DEVELOPED POSTPARTUM TYPE 2 DIABETES; WOMEN WITH GDM WITHOUT POSTPARTUM TYPE 2 DIABETES; AND WOMEN WITH TYPE 2 DIABETES. MAIN OUTCOME MEASURE: PERCENTAGES OF DIMETHYLATION OF H3 HISTONES RELATIVE TO TOTAL H3 HISTONE METHYLATION WERE COMPARED BETWEEN DIABETIC/NONDIABETIC GROUPS USING APPROPRIATE COMPARATIVE STATISTICS. RESULTS: H3K27 DIMETHYLATION WAS 50-60% LOWER AT 8-10 AND 20 WK POSTPARTUM IN WOMEN WITH GDM WHO DEVELOPED TYPE 2 DIABETES, COMPARED WITH NONDIABETIC WOMEN. H3K4 DIMETHYLATION WAS 75% LOWER AT 8-10 WK POSTPARTUM IN WOMEN WITH GDM WHO SUBSEQUENTLY DEVELOPED TYPE 2 DIABETES COMPARED WITH WOMEN WHO HAD GDM WHO DID NOT. CONCLUSIONS: THE PERCENTAGE OF DIMETHYLATION OF HISTONES H3K27 AND H3K4 VARIED WITH DIABETIC STATE AND HAS THE POTENTIAL AS A PREDICTIVE TOOL TO IDENTIFY WOMEN WHO WILL CONVERT FROM GDM TO TYPE 2 DIABETES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  3179  42 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  2205  37 EPIGENETIC MODIFICATION OF THE X CHROMOSOME INFLUENCES SUSCEPTIBILITY TO POLYCYSTIC OVARY SYNDROME. CONTEXT: THE CAUSE OF POLYCYSTIC OVARY SYNDROME (PCOS) IS UNKNOWN, ALTHOUGH GENETIC AND ENVIRONMENTAL INFLUENCES ARE CLEARLY IMPLICATED. SOME GENETIC STUDIES HAVE SUGGESTED THE INVOLVEMENT OF X-LINKED GENES IN PCOS, BUT THE INFLUENCE OF X CHROMOSOME INACTIVATION (XCI) ON MANIFESTATION OF THIS DISORDER HAS NOT PREVIOUSLY BEEN EXAMINED. OBJECTIVE: THE OBJECTIVE OF THE STUDY WAS TO TEST THE NULL HYPOTHESIS THAT XCI HAS NO INFLUENCE ON CLINICAL PRESENTATION OF PCOS. DESIGN: WE EXAMINED PATTERNS OF XCI BETWEEN SISTER PAIRS WITH THE SAME GENOTYPE AT A POLYMORPHIC LOCUS ON THE X CHROMOSOME IN FAMILIES WITH PCOS. SETTING: THE STUDY WAS CONDUCTED AT A PRIVATE PRACTICE. PARTICIPANTS: PCOS WAS DEFINED AS HYPERANDROGENEMIA WITH CHRONIC ANOVULATION. FORTY FAMILIES WERE STUDIED IN WHICH DNA WAS OBTAINED FROM AT LEAST ONE PARENT, THE PROBAND, AND ONE SISTER THAT COULD BE ACCURATELY DIAGNOSED AS BEING AFFECTED OR UNAFFECTED. MAIN OUTCOME MEASURE(S): RELATIVE EXPRESSION OF TWO X-LINKED ALLELES WAS DETERMINED, AND THE RATIO OF ONE TO THE OTHER REPRESENTED THE PATTERN OF XCI. RESULTS: THE STATISTICAL ODDS ON A DIFFERENT CLINICAL PRESENTATION BETWEEN SISTERS WAS APPROXIMATELY 29 TIMES HIGHER IN SISTER PAIRS WITH DIFFERENT PATTERNS OF XCI, COMPARED WITH SISTER PAIRS WITH THE SAME PATTERN OF XCI (ODDS RATIO 28.9; 95% CONFIDENCE INTERVAL 4.0-206; P = 0.0008). CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE TO REFUTE THE NULL HYPOTHESIS AND PROPOSE A CLOSER INSPECTION OF X-LINKED GENES IN PCOS, ONE IN WHICH BOTH GENOTYPE AND EPIGENOTYPE ARE CONSIDERED. ENVIRONMENTAL DETERMINANTS OF PCOS MAY ALTER CLINICAL PRESENTATION VIA EPIGENETIC MODIFICATIONS, WHICH CURRENTLY REMAIN UNDETECTED IN TRADITIONAL GENETIC ANALYSES.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  3047  24 GENOME-WIDE ANALYSIS OF DNA METHYLATION IN ENDOMETRIOSIS USING ILLUMINA HUMAN METHYLATION 450 K BEADCHIPS. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGIC DISORDER CHARACTERIZED BY THE PRESENCE AND GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE OF THE UTERINE CAVITY. ALTHOUGH THE EXACT ETIOLOGY REMAINS UNCLEAR, EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, ARE THOUGHT TO CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. HERE, WE USED THE ILLUMINA HUMAN METHYLATION 450 K BEADCHIP ARRAY TO ANALYZE THE GENOME-WIDE DNA METHYLATION PROFILES OF SIX ENDOMETRIOTIC LESIONS AND SIX EUTOPIC ENDOMETRIA FROM PATIENTS WITH OVARIAN ENDOMETRIOSIS AND SIX ENDOMETRIA OF WOMEN WITHOUT ENDOMETRIOSIS. COMPARED WITH THE EUTOPIC ENDOMETRIA OF WOMEN WITH ENDOMETRIOSIS, 12,159 DIFFERENTIALLY METHYLATED CPG SITES AND 375 DIFFERENTIALLY METHYLATED PROMOTER REGIONS WERE IDENTIFIED IN ENDOMETRIOTIC LESIONS. GO ANALYSES SHOWED THAT THESE PUTATIVE DIFFERENTIALLY METHYLATED GENES WERE PRIMARILY ASSOCIATED WITH IMMUNE RESPONSE, INFLAMMATORY RESPONSE, RESPONSE TO STEROID HORMONE STIMULUS, CELL ADHESION, NEGATIVE REGULATION OF APOPTOSIS, AND ACTIVATION OF THE MAPK ACTIVITY. IN ADDITION, THE EXPRESSION LEVELS OF DNMT1, DNMT3A, DNMT3B, AND MBD2 IN ENDOMETRIOTIC LESIONS AND EUTOPIC ENDOMETRIA WERE SIGNIFICANTLY DECREASED COMPARED WITH CONTROL ENDOMETRIA. OUR FINDINGS SUGGEST THAT ABERRANT DNA METHYLATION STATUS IN ENDOMETRIOTIC LESIONS MAY PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS AND PROGRESSION OF ENDOMETRIOSIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16   561  37 BARIATRIC SURGERY-INDUCED WEIGHT LOSS AND ASSOCIATED GENOME-WIDE DNA-METHYLATION ALTERATIONS IN OBESE INDIVIDUALS. BACKGROUND: OBESITY IS A MULTIFACTORIAL AND CHRONIC CONDITION OF GROWING UNIVERSAL CONCERN. IT HAS RECENTLY BEEN REPORTED THAT BARIATRIC SURGERY IS A MORE SUCCESSFUL TREATMENT FOR SEVERE OBESITY THAN OTHER NONINVASIVE INTERVENTIONS, RESULTING IN RAPID SIGNIFICANT WEIGHT LOSS AND ASSOCIATED CHRONIC DISEASE REMISSION. THE IDENTIFICATION OF DISTINCT EPIGENETIC PATTERNS IN PATIENTS WHO ARE OBESE OR HAVE METABOLIC IMBALANCES HAS SUGGESTED A POTENTIAL ROLE FOR EPIGENETIC ALTERATIONS IN CAUSAL OR MEDIATING PATHWAYS IN THE DEVELOPMENT OF OBESITY-RELATED PATHOLOGIES. SPECIFIC CHANGES IN THE EPIGENOME (DNA METHYLOME), ASSOCIATED WITH METABOLIC DISORDERS, CAN BE DETECTED IN THE BLOOD. WE INVESTIGATED WHETHER SUCH EPIGENETIC CHANGES ARE REVERSIBLE AFTER WEIGHT LOSS USING GENOME-WIDE DNA METHYLOME ANALYSIS OF BLOOD SAMPLES FROM INDIVIDUALS WITH SEVERE OBESITY (MEAN BMI ~ 45) UNDERGOING BARIATRIC SURGERY. RESULTS: OUR ANALYSIS REVEALED 41 SIGNIFICANT (BONFERRONI P < 0.05) AND 1169 (FALSE DISCOVERY RATE P < 0.05) SUGGESTIVE DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH WEIGHT LOSS DUE TO BARIATRIC SURGERY. AMONG THE 41 SIGNIFICANT DMPS, 5 CPGS WERE REPLICATED IN AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS (THE HEAVIER TWIN UNDERWENT DIET-INDUCED WEIGHT LOSS). THE EFFECT SIZES OF THESE 5 CPGS WERE CONSISTENT ACROSS DISCOVERY AND REPLICATION SETS (P < 0.05). WE ALSO IDENTIFIED 192 DIFFERENTIALLY METHYLATED REGIONS (DMRS) AMONG WHICH SMAD6 AND PFKFB3 GENES WERE THE TOP HYPERMETHYLATED AND HYPOMETHYLATED REGIONS, RESPECTIVELY. PATHWAY ENRICHMENT ANALYSIS OF THE DMR-ASSOCIATED GENES SHOWED THAT FUNCTIONAL PATHWAYS RELATED TO IMMUNE FUNCTION AND TYPE 1 DIABETES WERE SIGNIFICANT. WEIGHT LOSS DUE TO BARIATRIC SURGERY ALSO SIGNIFICANTLY DECELERATED EPIGENETIC AGE 12 MONTHS AFTER THE INTERVENTION (MEAN = - 4.29; P = 0.02). CONCLUSIONS: WE IDENTIFIED WEIGHT LOSS-ASSOCIATED DNA-METHYLATION ALTERATIONS TARGETING IMMUNE AND INFLAMMATORY GENE PATHWAYS IN BLOOD SAMPLES FROM BARIATRIC-SURGERY PATIENTS. THE TOP HITS WERE REPLICATED IN SAMPLES FROM AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS FOLLOWING A HYPOCALORIC DIET. ENERGY RESTRICTION AND BARIATRIC SURGERY THUS SHARE CPGS THAT MAY REPRESENT EARLY INDICATORS OF RESPONSE TO THE METABOLIC EFFECTS OF WEIGHT LOSS. THE ANALYSIS OF BARIATRIC SURGERY-ASSOCIATED DMRS SUGGESTS THAT EPIGENETIC REGULATION OF GENES INVOLVED IN ENDOTHELIAL AND ADIPOSE TISSUE FUNCTION IS KEY IN THE PATHOPHYSIOLOGY OF OBESITY.	2022	
                                                               
17  4957  36 PATHOGENESIS OF ENDOMETRIOSIS: THE GENETIC/EPIGENETIC THEORY. OBJECTIVE: TO STUDY THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. DESIGN: OVERVIEW OF OBSERVATIONS ON ENDOMETRIOSIS. SETTING: NOT APPLICABLE. PATIENT(S): NONE. INTERVENTIONS(S): NONE. MAIN OUTCOME MEASURE(S): THE HYPOTHESIS IS COMPATIBLE WITH ALL OBSERVATIONS. RESULT(S): ENDOMETRIOSIS, ENDOMETRIUM-LIKE TISSUE OUTSIDE THE UTERUS, HAS A VARIABLE MACROSCOPIC APPEARANCE AND A POORLY UNDERSTOOD NATURAL HISTORY. IT IS A HEREDITARY AND HETEROGENEOUS DISEASE WITH MANY BIOCHEMICAL CHANGES IN THE LESIONS, WHICH ARE CLONAL IN ORIGIN. IT IS ASSOCIATED WITH PAIN, INFERTILITY, ADENOMYOSIS, AND CHANGES IN THE JUNCTIONAL ZONE, PLACENTATION, IMMUNOLOGY, PLASMA, PERITONEAL FLUID, AND CHRONIC INFLAMMATION OF THE PERITONEAL CAVITY. THE SAMPSON HYPOTHESIS OF IMPLANTED ENDOMETRIAL CELLS FOLLOWING RETROGRADE MENSTRUATION, ANGIOGENIC SPREAD, LYMPHOGENIC SPREAD, OR THE METAPLASIA THEORY CANNOT EXPLAIN ALL OBSERVATIONS IF METAPLASIA IS DEFINED AS CELLS WITH REVERSIBLE CHANGES AND AN ABNORMAL BEHAVIOR/MORPHOLOGY DUE TO THE ABNORMAL ENVIRONMENT. WE PROPOSE A POLYGENETIC/POLYEPIGENETIC MECHANISM. THE SET OF GENETIC AND EPIGENETIC INCIDENTS TRANSMITTED AT BIRTH COULD EXPLAIN THE HEREDITARY ASPECTS, THE PREDISPOSITION, AND THE ENDOMETRIOSIS-ASSOCIATED CHANGES IN THE ENDOMETRIUM, IMMUNOLOGY, AND PLACENTATION. TO DEVELOP TYPICAL, CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS, A VARIABLE SERIES OF ADDITIONAL TRANSMISSIBLE GENETIC AND EPIGENETIC INCIDENTS ARE REQUIRED TO OCCUR IN A CELL WHICH MAY VARY FROM ENDOMETRIAL TO STEM CELLS. SUBTLE LESIONS ARE VIEWED AS ENDOMETRIUM IN A DIFFERENT ENVIRONMENT UNTIL ADDITIONAL INCIDENTS OCCUR. TYPICAL CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS ARE HETEROGENEOUS AND REPRESENT THREE DIFFERENT DISEASES. CONCLUSION(S): THE GENETIC EPIGENETIC THEORY IS COMPATIBLE WITH ALL OBSERVATIONS ON ENDOMETRIOSIS. IMPLICATIONS FOR TREATMENT AND PREVENTION ARE DISCUSSED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  3665  37 INFECTION AS A POTENTIAL COFACTOR IN THE GENETIC-EPIGENETIC PATHOPHYSIOLOGY OF ENDOMETRIOSIS: A SYSTEMATIC REVIEW. BACKGROUND: THE GENETIC-EPIGENETIC THEORY POSTULATES THAT ENDOMETRIOSIS IS TRIGGERED BY A CUMULATIVE SET OF GENETIC-EPIGENETIC (GE) INCIDENTS. PELVIC AND UPPER GENITAL TRACT INFECTION MIGHT INDUCE GE INCIDENTS AND THUS PLAY A ROLE IN THE PATHOGENESIS OF ENDOMETRIOSIS. THUS, THIS ARTICLE AIMS TO REVIEW THE ASSOCIATION OF ENDOMETRIOSIS WITH UPPER GENITAL TRACT AND PELVIC INFECTIONS. METHODS: PUBMED, SCOPUS AND GOOGLE SCHOLAR WERE SEARCHED FOR 'ENDOMETRIOSIS AND (INFECTION OR PID OR BACTERIA OR VIRUSES OR MICROBIOME OR MICROBIOTA)', FOR 'REPRODUCTIVE MICROBIOME' AND FOR 'REPRODUCTIVE MICROBIOME AND ENDOMETRIOSIS', RESPECTIVELY. ALL 384 ARTICLES, THE FIRST 120 'BEST MATCH' ARTICLES IN PUBMED FOR 'REPRODUCTIVE MICROBIOME' AND THE FIRST 160 HITS IN GOOGLE SCHOLAR FOR 'REPRODUCTIVE MICROBIOME AND ENDOMYTRIOSIS' WERE HAND SEARCHED FOR DATA DESCRIBING AN ASSOCIATION BETWEEN ENDOMETRIOSIS AND BACTERIAL, VIRAL OR OTHER INFECTIONS. ALL 31 ARTICLES FOUND WERE INCLUDED IN THIS MANUSCRIPT. RESULTS: WOMEN WITH ENDOMETRIOSIS HAVE A SIGNIFICANTLY INCREASED RISK OF LOWER GENITAL TRACT INFECTION, CHRONIC ENDOMETRITIS, SEVERE PID AND SURGICAL SITE INFECTIONS AFTER HYSTERECTOMY. THEY HAVE MORE COLONY FORMING UNITS OF GARDNERELLA, STREPTOCOCCUS, ENTEROCOCCI AND ESCHERICHIA COLI IN THE ENDOMETRIUM. IN THE CERVIX ATOPOBIUM IS ABSENT, BUT GARDNERELLA, STREPTOCOCCUS, ESCHERICHIA, SHIGELLA, AND UREOPLASMA ARE INCREASED. THEY HAVE HIGHER CONCENTRATIONS OF ESCHERICHIA COLI AND HIGHER CONCENTRATIONS OF BACTERIAL ENDOTOXINS IN MENSTRUAL BLOOD. A SHIGELLA/ESCHERICHIA DOMINANT STOOL MICROBIOME IS MORE FREQUENT. THE PERITONEAL FLUID OF WOMEN WITH ENDOMETRIOSIS CONTAINS HIGHER CONCENTRATIONS OF BACTERIAL ENDOTOXINS AND AN INCREASED INCIDENCE OF MOLLICUTES AND OF HPV VIRUSES. ENDOMETRIOSIS LESIONS HAVE A SPECIFIC BACTERIAL COLONISATION WITH MORE FREQUENTLY MOLLICUTES (54%) AND BOTH HIGH AND MEDIUM-RISK HPV INFECTIONS (11%). THEY CONTAIN DNA WITH 96% HOMOLOGY WITH SHIGELLA. IN MICE TRANSPLANTED ENDOMETRIUM CHANGES THE GUT MICROBIOME WHILE THE GUT MICROBIOME INFLUENCES THE GROWTH OF THESE ENDOMETRIOSIS LESIONS. CONCLUSIONS: ENDOMETRIOSIS IS ASSOCIATED WITH MORE UPPER GENITAL TRACT AND PERITONEAL INFECTIONS. THESE INFECTIONS MIGHT BE CO-FACTORS CAUSING GE INCIDENTS AND INFLUENCING ENDOMETRIOSIS GROWTH.	2019	
                                                                                                                                                                                                                                                                    
19  6250  44 THE METHYLENETETRAHYDROFOLATE REDUCTASE 677C>T GENE POLYMORPHISM IS NOT ASSOCIATED WITH CHRONIC PLAQUE PSORIASIS. BACKGROUND: METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) IS INVOLVED IN THE FORMATION OF METHYL DONORS, WHICH CONTRIBUTE TO DNA METHYLATION. DNA METHYLATION IS AN ESSENTIAL EPIGENETIC FEATURE PLAYING A CRITICAL ROLE IN GENE REGULATION AND CELLULAR DIFFERENTIATION. IN ADDITION, MTHFR ACTIVITY AFFECTS PLASMA HOMOCYSTEINE LEVELS. A FUNCTIONAL POLYMORPHISM IN THE MTHFR GENE (677C>T, RS1801133) LEADING TO REDUCED ENZYME ACTIVITY HAS BEEN ASSOCIATED WITH CHRONIC PLAQUE PSORIASIS IN A CHINESE POPULATION. THIS FINDING, HOWEVER, HAS NOT YET BEEN EITHER CONFIRMED OR REFUTED IN OTHER POPULATIONS. THE PURPOSE OF THE PRESENT STUDY WAS TO INVESTIGATE A HYPOTHESIZED ASSOCIATION BETWEEN THE MTHFR 677C>T POLYMORPHISM AND THE PRESENCE OF CHRONIC PLAQUE PSORIASIS IN A CAUCASIAN POPULATION. METHODS: GENOTYPES FOR THE MTHFR 677C>T POLYMORPHISM WERE DETERMINED IN 310 PATIENTS AND 247 CONTROL SUBJECTS. IN A SUBGROUP OF 33 PATIENTS AND 33 SEX- AND AGE-MATCHED CONTROL SUBJECTS, FASTING PLASMA HOMOCYSTEINE CONCENTRATIONS WERE DETERMINED BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND IMMUNOLOGICAL ASSAYS WERE USED FOR THE MEASUREMENT OF FOLATE AND VITAMIN B(12). RESULTS: PREVALENCE OF THE HOMOZYGOUS MTHFR 677TT GENOTYPE DID NOT SIGNIFICANTLY DIFFER BETWEEN PATIENTS AND CONTROLS (15.2% VS 11.7%, P = 0.24). MEAN PLASMA HOMOCYSTEINE CONCENTRATIONS WERE SIGNIFICANTLY HIGHER IN PSORIASIS PATIENTS THAN AMONG CONTROL SUBJECTS (13.5 +/- 5.3 MICROMOL/L VS 11.0 +/- 2.2 MICROMOL/L, P = 0.026). NO SIGNIFICANT DIFFERENCES BETWEEN EITHER MEAN PLASMA FOLATE OR VITAMIN B(12) CONCENTRATIONS WERE OBSERVED BETWEEN BOTH GROUPS. CONCLUSION: OUR DATA SUGGEST THAT THE MTHFR 677C>T GENE POLYMORPHISM IS NOT ASSOCIATED WITH CHRONIC PLAQUE PSORIASIS AMONG CAUCASIANS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  5957  35 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE.	2021