1  4166 187 MEDICAL, ETHICAL, AND LEGAL ASPECTS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR CROHN'S DISEASE IN BRAZIL. CROHN'S DISEASE (CD) IS A CHRONIC INFLAMMATORY BOWEL DISEASE THAT CAN AFFECT ANY PART OF THE GASTROINTESTINAL TRACT. THE ETIOLOGY OF CD IS UNKNOWN; HOWEVER, GENETIC, EPIGENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS COULD PLAY AN ESSENTIAL ROLE IN THE ONSET AND ESTABLISHMENT OF THE DISEASE. CD RESULTS FROM IMMUNE DYSREGULATION DUE TO LOSS OF THE HEALTHY SYMBIOTIC RELATIONSHIP BETWEEN HOST AND INTESTINAL FLORA AND OR ITS ANTIGENS. IT AFFECTS BOTH SEXES EQUALLY WITH A MALE TO FEMALE RATIO OF 1.0, AND ITS ONSET CAN OCCUR AT ANY AGE, BUT THE DIAGNOSIS IS MOST COMMONLY OBSERVED IN THE RANGE OF 20 TO 40 YEARS OF AGE. CD DIMINISHES QUALITY OF LIFE, INTERFERES WITH SOCIAL ACTIVITIES, TRAUMATIZES DUE TO THE STIGMA OF INCONTINENCE, FISTULAE, STRICTURES, AND COLOSTOMIES, AND IN SEVERE CASES, AFFECTS SURVIVAL WHEN COMPARED TO THE GENERAL POPULATION. SYMPTOMS FLUCTUATE BETWEEN PERIODS OF REMISSION AND ACTIVITY IN WHICH COMPLICATIONS SUCH AS FISTULAS, STRICTURES, AND THE NEED FOR BOWEL RESECTION, SURGERY, AND COLOSTOMY IMPLANTATION MAKE UP THE MOST SEVERE ASPECTS OF THE DISEASE. CD CAN BE PROGRESSIVE AND THE COMPLICATIONS RECURRENT DESPITE TREATMENT WITH ANTI-INFLAMMATORY DRUGS, CORTICOSTEROIDS, IMMUNOSUPPRESSANTS, AND BIOLOGICAL AGENTS. HOWEVER, OVER TIME MANY PATIENTS BECOME REFRACTORY WITHOUT TREATMENT ALTERNATIVES, AND IN THIS SCENARIO, HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) HAS EMERGED AS A POTENTIAL TREATMENT OPTION. THE RATIONALE FOR THE USE OF HSCT FOR CD IS ANCHORED IN ANIMAL STUDIES AND HUMAN CLINICAL TRIALS WHERE HSCT COULD RESET A PATIENT'S IMMUNE SYSTEM BY ELIMINATING DISEASE-CAUSING EFFECTOR CELLS AND UPON IMMUNE RECOVERY INCREASE REGULATORY AND SUPPRESSIVE IMMUNE CELLS. AUTOLOGOUS HSCT USING A NON-MYELOABLATIVE REGIMEN OF CYCLOPHOSPHAMIDE AND ANTI-THYMOCYTE GLOBULIN WITHOUT CD34+ SELECTION HAS BEEN TO DATE THE MOST COMMON TRANSPLANT CONDITIONING REGIMEN ADOPTED. IN THIS REVIEW WE WILL ADDRESS THE CURRENT SITUATION REGARDING CD TREATMENT WITH HSCT AND EMPHASIZE THE MEDICAL, ETHICAL, AND LEGAL ASPECTS THAT PERMEATE THE PROCEDURE IN BRAZIL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  4963  44 PATHOGENESIS OF THYROID NODULES: HISTOLOGICAL CLASSIFICATION? THYROID NODULE GENESIS MAY BE CONSIDERED AS AN AMPLIFICATION OF THYROID HETEROGENEITY DUE TO GENETIC AND/OR EPIGENETIC MECHANISMS. WE CLASSIFIED THE THYROID NODULES IN FIVE TYPES WITH DISTINCT HISTOLOGICAL FEATURES: HYPERPLASTIC, NEOPLASTIC, COLLOID, CYSTIC AND THYROIDITIC NODULES. HYPERPLASTIC: THYROCYTE PROLIFERATION IS UNDER THE CONTROL OF TSH BUT SEVERAL OTHER PARACRINE AND AUTOCRINE FACTORS ARE SECRETED BY FOLLICULAR CELLS, THE STROMAL APPARATUS AND THE LYMPHOCYTES, WHICH ARE IMPLICATED IN INITIATION AND PERPETUATION OF THYROID HYPERPLASIA. GROWTH OCCURS MAINLY THROUGH TSHR, CAMP AND PKA. CONSTITUTIVE CAMP OVERPRODUCTION HAS BEEN SHOWN TO BE DUE TO POINT MUTATION OF THE TSHR OR GS PROTEIN, PRODUCING OVERGROWTH AND HYPERFUNCTION. NEOPLASTIC: SEVERAL ACTIVATED ONCOGENES HAVE BEEN IDENTIFIED IN THYROID MALIGNANCIES. ONCOGENES RELEVANT TO THE THYROID CARCINOGENESIS ARE: MUTATED TSHR AND GSP (CONSTITUTIVE ACTIVATION OF CAMP); TRK (RECEPTOR FOR NGF); RET/PTC (PHOSPHORYLATION OF TYROSINE KINASE RECEPTOR)--AN ISOFORM OF THIS ONCOGENE IS INDUCED BY RADIATION: RAS (IT ENCODES GS PROTEINS TRANSDUCING MITOGENIC SIGNALS); AND C-MET (RECEPTOR FOR HEPATOCYTE GROWTH FACTOR). THE EVOLUTION OF A DIFFERENTIATED THYROID CANCER TOWARDS AN UNDIFFERENTIATED CANCER IS DUE TO A MUTATION OF A FAMILY OF PROTEINS (I.E., P53), WHICH ACTS AS A BRAKE, PREVENTING THE GENOMIC INSTABILITY OF CANCER. IT IS SUGGESTED THAT A TUMOR INITIATES BY RET OR RAS AND POSSIBLY PROGRESSES--AS A RESULT OF ADDITIONAL MUTATIONS AND BY P53 MUTATION--TO ANAPLASTIC CARCINOMA. COLLOID: FLATTENING OF THE EPITHELIUM AND DILATATION OF FOLLICLES CONTAINING VISCOUS MATERIAL--MADE UP BY A CONCENTRATED SOLUTION OF THYROGLOBULIN (HTG)--IS THE CHARACTERISTIC OF THE COLLOID NODULE. A DEFECT OF INTRALUMINAL REABSORPTION OF HTG HAS BEEN SUGGESTED BUT NOT PROVEN. EXPERIMENTALLY, A LOAD OF IODINE IS ABLE TO CHANGE THYROID HYPERPLASIA TO A COLLOID FEATURE; HOWEVER, A LOAD OF IODINE IS RARELY FOUND IN THE CLINICAL HISTORY OF PATIENTS. A NEW CLUE TO THE PATHOGENESIS COMES FROM THE FINDING THAT A RELEVANT PART OF THE COLLOID (10-20%) IS MADE UP OF INSOLUBLE GLOBULES, WHERE HTG IS COMPACTED IN A POLYMERIC FORM. IT IS SUGGESTED THAT STOCKING HTG INTO GLOBULES IS DEFECTIVE IN COLLOID NODULES, LEADING TO ENORMOUS ENLARGEMENT OF THE FOLLICLE. CYSTIC: IT IS ESTIMATED THAT BETWEEN 15 AND 40% OF THYROID NODULES ARE PARTLY OR ENTIRELY CYSTIC. THE 'TRUE CYST' IS RARE; MOST OF THE SO-CALLED CYSTIC NODULES ARE 'PSEUDOCYSTS', WHICH FOLLOW NECROSIS AND COLLIQUATION. NECROSIS ISSUES AS AN IMBALANCE BETWEEN GROWTH AND THE PRECISELY REGULATED PROCESS OF ANGIOGENESIS. MORE RECENTLY, THE VEGF/VPF HAS BEEN FOUND TO BE AT THE ORIGIN OF RECENT AND RECURRENT CYSTS. IMMUNOTOXIC AND APOPTOTIC MECHANISMS HAVE ALSO BEEN SUGGESTED. CHEMICAL ANALYSIS OF CYSTIC FLUID SHOWED A 'DENATURED' AND 'SERUM-LIKE' PATTERN SUGGESTING DIFFERENT MECHANISMS IN THE PATHOGENESIS OF THE PSEUDOCYSTIC THYROID NODULES. THYROIDITIC: NODULAR LYMPHOCYTIC THYROIDITIS (NLT) INCLUDES TWO DIFFERENT ENTITIES: 1) LYMPHOCYTE THYROIDITIS GROWING AS A NODULE IN A HYPERPLASTIC OR NORMAL GLAND, AND 2) LYMPHOCYTE THYROIDITIS ASSOCIATED IN THE SAME NODULE WITH OTHER NODULAR DISEASES OF THE THYROID: PAPILLARY THYROID CARCINOMA AND LYMPHOMA HAVE BEEN FOUND TO BE ASSOCIATED TO CHRONIC LYMPHOCYTIC THYROIDITIS.	2001	

3  3056  35 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  3850  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  2678  29 EVALUATION OF A PROGNOSTIC EPIGENETIC CLASSIFICATION SYSTEM IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. BACKGROUND: METHYLATION AT 5 CPG SITES WAS PREVIOUSLY SHOWN TO CLASSIFY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO 3 PROGNOSTIC SUBGROUPS. HERE, WE AIMED TO VALIDATE THE MARKER SET IN AN ADDITIONAL COHORT AND TO EVALUATE ITS CLINICAL UTILITY FOR CLL PATIENT STRATIFICATION. METHODS: WE EVALUATED THIS EPIGENETIC MARKER SET IN 79 GERMAN PATIENTS USING BISULFITE TREATMENT FOLLOWED BY PYROSEQUENCING AND CLASSIFICATION USING A SUPPORT VECTOR MACHINE-LEARNING TOOL. RESULTS: THE N-CLL, I-CLL, AND M-CLL CLASSIFICATION WAS DETECTED IN 28 (35%), 10 (13%), AND 41 (51%) PATIENTS, RESPECTIVELY. EPIGENETIC GROUPING WAS ASSOCIATED WITH IGHV MUTATIONAL STATUS (P = 2 X 10(-12)), ISOLATED DEL13Q (P = 9 X 10(-6)), DEL17P (P = .015), COMPLEX KARYOTYPE (P = .005), VH-USAGE, AND CLINICAL OUTCOME AS TIME TO FIRST TREATMENT (P = 1.4 X 10(-12)) AND OVERALL SURVIVAL (P = .003). MULTIVARIATE COX REGRESSION ANALYSIS IDENTIFIED N-CLL AS A FACTOR FOR EARLIER TREATMENT HAZARD RATIO (HR), 6.3 (95% CONFIDENCE INTERVAL [CI] 2.4-16.4; P = .0002) COMPARED TO IGHV MUTATIONAL STATUS (HR 4.6, 95% CI 1.9-11.3, P = .0008). IN ADDITION, WHEN COMPARING THE PROGNOSTIC VALUE OF THE EPIGENETIC CLASSIFICATION SYSTEM WITH THE IGHV CLASSIFICATION, EPIGENETIC GROUPING PERFORMED BETTER COMPARED TO IGHV MUTATIONAL STATUS USING KAPLAN-MEIER ESTIMATION AND ALLOWED THE IDENTIFICATION OF A THIRD, INTERMEDIATE (I-CLL) GROUP. THUS, OUR STUDY CONFIRMED THE PROGNOSTIC VALUE OF THE EPIGENETIC MARKER SET FOR PATIENT STRATIFICATION IN ROUTINE CLINICAL DIAGNOSTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6   537  34 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  3151  35 GLUCOCORTICOIDS, EPIGENETIC CONTROL AND STRESS RESILIENCE. GLUCOCORTICOID HORMONES PLAY A PIVOTAL ROLE IN THE RESPONSE TO STRESSFUL CHALLENGES. THE SURGE IN GLUCOCORTICOID HORMONE SECRETION AFTER STRESS NEEDS TO BE TIGHTLY CONTROLLED WITH CHARACTERISTICS LIKE PEAK HEIGHT, CURVATURE AND DURATION DEPENDING ON THE NATURE AND SEVERITY OF THE CHALLENGE. THIS IS IMPORTANT AS CHRONIC HYPER- OR HYPO-RESPONSES ARE DETRIMENTAL TO HEALTH DUE TO INCREASING THE RISK FOR DEVELOPING A STRESS-RELATED MENTAL DISORDER. PROPER GLUCOCORTICOID RESPONSES TO STRESS ARE CRITICAL FOR ADAPTATION. THEREFORE, THE TIGHT CONTROL OF BASELINE AND STRESS-EVOKED GLUCOCORTICOID SECRETION ARE IMPORTANT CONSTITUENTS OF AN ORGANISM'S RESILIENCE. HERE, WE ADDRESS A NUMBER OF MECHANISMS THAT ILLUSTRATE THE MULTITUDE AND COMPLEXITY OF MEASURES SAFEGUARDING THE CONTROL OF GLUCOCORTICOID FUNCTION. THESE MECHANISMS INCLUDE THE CONTROL OF MINERALOCORTICOID (MR) AND GLUCOCORTICOID RECEPTOR (GR) OCCUPANCY AND CONCENTRATION, THE DYNAMIC CONTROL OF FREE GLUCOCORTICOID HORMONE AVAILABILITY BY CORTICOSTEROID-BINDING GLOBULIN (CBG), AND THE CONTROL EXERTED BY GLUCOCORTICOIDS AT THE SIGNALING, EPIGENETIC AND GENOMIC LEVEL ON GENE TRANSCRIPTIONAL RESPONSES TO STRESS. WE REVIEW THE BENEFICIAL EFFECTS OF REGULAR EXERCISE ON HPA AXIS AND SLEEP PHYSIOLOGY, AND COGNITIVE AND ANXIETY-RELATED BEHAVIOR. FURTHERMORE, WE DESCRIBE THAT, POSSIBLY THROUGH CHANGES IN THE GABAERGIC SYSTEM, EXERCISE REDUCES THE IMPACT OF STRESS ON A SIGNALING PATHWAY SPECIFICALLY IN THE DENTATE GYRUS THAT IS STRONGLY IMPLICATED IN THE BEHAVIORAL RESPONSE TO THAT STRESSOR. THESE OBSERVATIONS UNDERLINE THE IMPACT OF LIFE STYLE ON STRESS RESILIENCE. FINALLY, WE ADDRESS HOW SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AFFECTING GLUCOCORTICOID ACTION CAN COMPROMISE STRESS RESILIENCE, WHICH BECOMES MOST APPARENT UNDER CONDITIONS OF CHILDHOOD ABUSE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  3560  33 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  1956  31 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                                                                                                                 
10  1189  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  2734  33 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12   518  34 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13   960  32 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  3179  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  2900  34 GENDER BIAS IN THERAPEUTIC EFFORT: FROM RESEARCH TO HEALTH CARE. THERE ARE RELEVANT DIMENSIONS FROM A GENDER PERSPECTIVE RELATED TO THERAPEUTIC EFFORT. TO ILLUSTRATE AND DISCUSS POSSIBLE GENDER BIAS RELATED TO MEDICINES, THROUGH THE CONSUMPTION ANALYSIS IN WOMEN, THE PRESCRIPTION OF BIOLOGICAL DRUGS ACCORDING TO SEX, THE POTENTIAL GENDER INEQUALITY IN ADVERSE DRUG REACTIONS, AND RESEARCH WITH CLINICAL TRIALS, AS WELL AS THE DECISIONS OF INTERNATIONAL INSTITUTIONS IN THE MARKETING OF MEDICINAL PRODUCTS. THERE IS GREATER TENDENCY TO PRESCRIBE PAIN RELIEVERS, REGARDLESS OF PAIN, AND DRUGS FOR LOW INTENSITY DEPRESSIVE SYMPTOMS IN WOMEN THAN IN MEN. THE OPPOSITE OCCURS IN THE PRESCRIPTION OF STATINS AND ADEQUATE DOSES, AND WITH THE GREATER PROBABILITY OF PRESCRIBING ANTI-TUMOR NECROSIS FACTOR IN MEN THAN IN WOMEN WITH ANKYLOSING SPONDYLITIS, DESPITE A SIMILAR DISEASE BURDEN. ADVERSE DRUG REACTIONS ARE OBSERVED MORE FREQUENTLY IN WOMEN THAN IN MEN, WHERE DETERMINANTS SUCH AS BODY WEIGHT ARE HAVING LITTLE INFLUENCE ON THE DOSAGE. IT IS CURRENTLY SCARCELY CONSIDERED IN THE PRESCRIPTION THAT WOMEN HAVE DIFFERENCES IN THE ACTIVITY OF CYTOCHROME CYPP450 ENZYMES, WHICH CAN AFFECT THE LIVER'S METABOLISM RATE. THERE ARE EVEN IMMUNOLOGICAL, GENETIC AND EPIGENETIC EFFECTS (DUE TO HEREDITY AND UNEVEN GENE DOSING LOCATED IN THE X AND Y CHROMOSOMES) THAT CAN INFLUENCE THESE DIFFERENCES BY SEX. FINALLY, THROUGH CASES OF HORMONAL THERAPY CLINICAL TRIALS, A DRUG FOR WOMEN'S INHIBITED SEXUAL DESIRE AND A CONTRACEPTIVE FOR MEN, GENDER BIAS AND STEREOTYPES ARE SHOWN TO INFLUENCE A POTENTIAL GENERATION OF INEQUALITIES, ESPECIALLY IN ADVERSE DRUG REACTIONS TO THE DETRIMENT OF WOMEN. IN CONCLUSION, HEALTH PROFESSIONALS FREQUENTLY ATTRIBUTE PHYSICAL SYMPTOMS TO WOMEN'S EMOTIONALITY, INFLUENCING THEIR GREATER PRESCRIPTION OF SYMPTOMATIC DRUGS. WHETHER THE SAME REASON INFLUENCES THE LOWER PRESCRIPTION OF THERAPEUTIC DRUGS IN WOMEN THAN IN MEN SHOULD BE ANALYZED. THERE ARE BIOLOGICAL DETERMINANTS TO CONSIDER DUE TO THEIR INFLUENCE ON A GREATER PHARMACOLOGICAL TOXICITY IN WOMEN. CLINICAL TRIALS SHOULD IMPROVE ACCORDING TO THE GENDER RECOMMENDATIONS BY THE FOOD AND DRUGS ADMINISTRATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  5725  36 SKIN MANIFESTATIONS OF INSULIN RESISTANCE: FROM A BIOCHEMICAL STANCE TO A CLINICAL DIAGNOSIS AND MANAGEMENT. WORLDWIDE, MORE THAN 1.9 BILLION ADULTS ARE OVERWEIGHT, AND AROUND 600 MILLION PEOPLE SUFFER FROM OBESITY. SIMILARLY, ~382 MILLION INDIVIDUALS LIVE WITH DIABETES, AND 40-50% OF THE GLOBAL POPULATION IS LABELED AT "HIGH RISK" (I.E., PREDIABETES). THE IMPACT OF THESE TWO CHRONIC CONDITIONS RELIES NOT ONLY ON THE BURDEN OF ILLNESSES PER SE (I.E., ASSOCIATED INCREASED MORBIDITY AND MORTALITY), BUT ALSO ON THEIR INCREASED COST, BURDEN OF TREATMENT, AND DECREASED HEALTH-RELATED QUALITY OF LIFE. FOR THIS REVIEW A COMPREHENSIVE SEARCH IN SEVERAL DATABASES INCLUDING PUBMED (MEDLINE), OVID EMBASE, WEB OF SCIENCE, AND SCOPUS WAS CONDUCTED. IN BOTH DIABETES AND OBESITY, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS OVERLAP AND ARE INCLUSIVE RATHER THAN EXCLUSIVE. DE FACTO, 70-80% OF THE PATIENTS WITH OBESITY AND VIRTUALLY EVERY PATIENT WITH TYPE 2 DIABETES HAVE INSULIN RESISTANCE. INSULIN RESISTANCE IS A WELL-KNOWN PATHOPHYSIOLOGIC FACTOR IN THE DEVELOPMENT OF TYPE 2 DIABETES, CHARACTERISTICALLY APPEARING YEARS BEFORE ITS DIAGNOSIS. THE GOLD STANDARD FOR INSULIN RESISTANCE DIAGNOSIS (THE EUGLYCEMIC INSULIN CLAMP) IS A COMPLEX, INVASIVE, COSTLY, AND HENCE UNFEASIBLE TEST TO IMPLEMENT IN CLINICAL PRACTICE. LIKEWISE, LABORATORY MEASURES AND DERIVED INDEXES [E.G., HOMEOSTASIS MODEL ASSESSMENT OF INSULIN RESISTANCE (HOMA-IR-)] ARE INDIRECT, IMPRECISE, AND NOT HIGHLY ACCURATE AND REPRODUCIBLE TESTS. HOWEVER, SKIN MANIFESTATIONS OF INSULIN RESISTANCE (E.G., ACROCHORDONS, ACANTHOSIS NIGRICANS, ANDROGENETIC ALOPECIA, ACNE, HIRSUTISM) OFFER A RELIABLE, STRAIGHTFORWARD, AND REAL-TIME WAY TO DETECT INSULIN RESISTANCE. THE OBJECTIVE OF THIS REVIEW IS TO AID CLINICIANS IN RECOGNIZING SKIN MANIFESTATIONS OF INSULIN RESISTANCE. DIAGNOSING THESE SKIN MANIFESTATIONS ACCURATELY MAY CASCADE POSITIVELY IN THE PATIENT'S HEALTH BY TRIGGERING AN ADEQUATE METABOLIC EVALUATION, A TIMELY TREATMENT OR REFERRAL WITH THE ULTIMATE OBJECTIVE OF DECREASING DIABETES AND OBESITY BURDEN, AND IMPROVING THE HEALTH AND THE QUALITY OF CARE FOR THESE PATIENTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17   983  32 CHRONIC PROSTATITIS AFFECTS MALE REPRODUCTIVE HEALTH AND IS ASSOCIATED WITH SYSTEMIC AND LOCAL EPIGENETIC INACTIVATION OF C-X-C MOTIF CHEMOKINE 12 RECEPTOR C-X-C CHEMOKINE RECEPTOR TYPE 4. BACKGROUND/AIMS/OBJECTIVES: CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS) HAS DETRIMENTAL EFFECTS ON THE QUALITY OF LIFE INCLUDING THE ASPECT OF SEXUAL DYSFUNCTION. THE AIM OF THE STUDY WAS TO IDENTIFY IF THERE WAS AN ADVERSE EFFECT ON THE MALE GENITAL COMPARTMENT AND IF THERE ARE SYSTEMIC OR COMPARTMENT-SPECIFIC LOCAL SIGNALS FOR EPIGENETIC DYSREGULATION OF INFLAMMATORY FACTORS IN CP/CPPS PATIENTS. METHODS: ONE HUNDRED FIVE NIH IIIB CP/CPPS PATIENTS AND 41 HEALTHY MEN WERE RECRUITED AND UNDERWENT INVESTIGATIONS OF URINES, SEMEN AND BLOOD. PROMOTER METHYLATION AND EXPRESSION OF THE CHEMOKINE C-X-C MOTIF CHEMOKINE 12 AND ITS RECEPTOR C-X-C CHEMOKINE RECEPTOR TYPE 4 (CXCR4) (INVOLVED IN THE RECRUITMENT OF MAST CELLS) WERE ANALYZED IN PROSTATE EPITHELIAL CELL LINES AND IN HEALTHY VOLUNTEERS' AND PATIENTS' BLOOD, EJACULATE CELL PELLETS, AND SEPARATED EJACULATE FRACTIONS (SPERM AND SEMINAL SOMATIC CELLS). RESULTS: INDEPENDENTLY FROM AGE, CP/CPPS NIH IIIB WAS ASSOCIATED WITH SIGNIFICANT IMPAIRMENT OF SPERM MOTILITY, MORPHOLOGY AND SEMEN PH (P < 0.001). PATIENTS OLDER THAN 33 YEARS SHOWED SIGNIFICANTLY INCREASED SEMINAL INTERLEUKIN-8 AND SERUM PROSTATE SPECIFIC ANTIGEN VALUES. IN PATIENTS, THE CXCR4 MRNA-EXPRESSION WAS SIGNIFICANTLY DECREASED IN WHOLE BLOOD AND EJACULATE CELL PELLETS DUE TO PROMOTER HYPERMETHYLATION. ANALYSES ON SEPARATED FRACTIONS OF SPERM AND SEMINAL SOMATIC CELLS REVEALED THAT SPERM DNA WAS UNAFFECTED, WHEREAS SOMATIC CELL DNA WAS DIFFERENTIALLY METHYLATED. CONCLUSIONS: NIH IIIB CP/CPPS HAS NEGATIVE EFFECTS ON SURROGATE PARAMETERS OF MALE FERTILITY AND IS ASSOCIATED SIGNIFICANTLY WITH SYSTEMIC AND LOCAL EPIGENETIC INACTIVATION OF CXCR4.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18   502  33 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  2205  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  6908  18 [THYROID AND HEPATITIS C]. AUTOIMMUNE THYROID DISEASES ARE COMPLEX DISEASES THAT DEVELOP AS A RESULT OF INTERACTIONS BETWEEN GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. IFNA THERAPY OF CHRONIC HCV INFECTION IS ASSOCIATED WITH SUBCLINICAL OR CLINICAL THYROIDITIS, WHILE THE RELATIONSHIP BETWEEN THYROIDITIS AND VIRUS C INFECTION IS STILL DEBATED.	2012