1 6145 355 THE EXPANDING PHENOTYPES OF COHESINOPATHIES: ONE RING TO RULE THEM ALL! PRESERVATION AND DEVELOPMENT OF LIFE DEPEND ON THE ADEQUATE SEGREGATION OF SISTER CHROMATIDS DURING MITOSIS AND MEIOSIS. THIS PROCESS IS ENSURED BY THE COHESIN MULTI-SUBUNIT COMPLEX. MUTATIONS IN THIS COMPLEX HAVE BEEN ASSOCIATED WITH AN INCREASING NUMBER OF DISEASES, TERMED COHESINOPATHIES. THE BEST CHARACTERIZED COHESINOPATHY IS CORNELIA DE LANGE SYNDROME (CDLS), IN WHICH INTELLECTUAL AND GROWTH RETARDATIONS ARE THE MAIN PHENOTYPIC MANIFESTATIONS. DESPITE SOME OVERLAP, THE CLINICAL MANIFESTATIONS OF COHESINOPATHIES VARY CONSIDERABLY. NOVEL ROLES OF THE COHESIN COMPLEX HAVE EMERGED DURING THE PAST DECADES, SUGGESTING THAT IMPORTANT CELL CYCLE REGULATORS EXERT IMPORTANT BIOLOGICAL EFFECTS THROUGH NON-COHESION-RELATED FUNCTIONS AND BROADENING THE POTENTIAL PATHOMECHANISMS INVOLVED IN COHESINOPATHIES. THIS REVIEW FOCUSES ON NON-COHESION-RELATED FUNCTIONS OF THE COHESIN COMPLEX, GENE DOSAGE EFFECT, EPIGENETIC REGULATION AND TGF-BETA IN COHESINOPATHY CONTEXT, ESPECIALLY IN COMPARISON TO CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) SYNDROME, A VERY DISTINCT COHESINOPATHY CAUSED BY A HOMOZYGOUS SHUGOSHIN-1 (SGO1) MUTATION (K23E) AND CHARACTERIZED BY PACEMAKER FAILURE IN BOTH HEART (SICK SINUS SYNDROME FOLLOWED BY ATRIAL FLUTTER) AND GUT (CHRONIC INTESTINAL PSEUDO-OBSTRUCTION) WITH NO INTELLECTUAL OR GROWTH DELAY. WE DISCUSS THE POSSIBLE IMPACT OF SGO1 ALTERATIONS IN HUMAN PATHOLOGIES AND THE POTENTIAL IMPACT OF THE SGO1 K23E MUTATION IN THE SINUS NODE AND GUT DEVELOPMENT AND FUNCTIONS. WE SUGGEST THAT THE HUMAN PHENOTYPES OBSERVED IN CDLS, CAID SYNDROME AND OTHER COHESINOPATHIES CAN INFORM FUTURE STUDIES INTO THE LESS WELL-KNOWN NON-COHESION-RELATED FUNCTIONS OF COHESIN COMPLEX GENES. ABBREVIATIONS: AD: ALZHEIMER DISEASE; AFF4: AF4/FMR2 FAMILY MEMBER 4; ANKRD11: ANKYRIN REPEAT DOMAIN 11; APC: ANAPHASE PROMOTER COMPLEX; ASD: ATRIAL SEPTAL DEFECT; ATRX: ATRX CHROMATIN REMODELER; ATRX: ALPHA THALASSEMIA X-LINKED INTELLECTUAL DISABILITY SYNDROME; BIRC5: BACULOVIRAL IAP REPEAT CONTAINING 5; BMP: BONE MORPHOGENETIC PROTEIN; BRD4: BROMODOMAIN CONTAINING 4; BUB1: BUB1 MITOTIC CHECKPOINT SERINE/THREONINE KINASE; CAID: CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA; CDK1: CYCLIN DEPENDENT KINASE 1; CDLS: CORNELIA DE LANGE SYNDROME; CHD: CONGENITAL HEART DISEASE; CHOPS: COGNITIVE IMPAIRMENT, COARSE FACIES, HEART DEFECTS, OBESITY, PULMONARY INVOLVEMENT, SHORT STATURE, AND SKELETAL DYSPLASIA; CIPO: CHRONIC INTESTINAL PSEUDO-OBSTRUCTION; C-KIT: KIT PROTO-ONCOGENE RECEPTOR TYROSINE KINASE; COATS: COHESIN ACETYLTRANSFERASES; CTCF: CCCTC-BINDING FACTOR; DDX11: DEAD/H-BOX HELICASE 11; ERG: TRANSCRIPTIONAL REGULATOR ERG; ESCO2: ESTABLISHMENT OF SISTER CHROMATID COHESION N-ACETYLTRANSFERASE 2; GJC1: GAP JUNCTION PROTEIN GAMMA 1; H2A: HISTONE H2A; H3K4: HISTONE H3 LYSINE 4; H3K9: HISTONE H3 LYSINE 9; HCN4: HYPERPOLARIZATION ACTIVATED CYCLIC NUCLEOTIDE GATED POTASSIUM AND SODIUM CHANNEL 4;P HDAC8: HISTONE DEACETYLASES 8; HP1: HETEROCHROMATIN PROTEIN 1; ICC: INTERSTITIAL CELLS OF CAJAL; ICC-MP: MYENTERIC PLEXUS INTERSTITIAL CELLS OF CAJAL; ICC-DMP: DEEP MUSCULAR PLEXUS INTERSTITIAL CELLS OF CAJAL; I(F): PACEMAKER FUNNY CURRENT; IP3: INOSITOL TRISPHOSPHATE; JNK: C-JUN N-TERMINAL KINASE; LDS: LOEYS-DIETZ SYNDROME; LOAD: LATE-ONSET ALZHEIMER DISEASE; MAPK: MITOGEN-ACTIVATED PROTEIN KINASE; MAU: MAU SISTER CHROMATID COHESION FACTOR; MFS: MARFAN SYNDROME; NIPBL: NIPBL, COHESIN LOADING FACTOR; OCT4: OCTAMER-BINDING PROTEIN 4; P38: P38 MAP KINASE; PDA: PATENT DUCTUS ARTERIOSUS; PDS5: PDS5 COHESIN ASSOCIATED FACTOR; P-H3: PHOSPHO HISTONE H3; PLK1: POLO LIKE KINASE 1; POPDC1: POPEYE DOMAIN CONTAINING 1; POPDC2: POPEYE DOMAIN CONTAINING 2; PP2A: PROTEIN PHOSPHATASE 2; RAD21: RAD21 COHESIN COMPLEX COMPONENT; RBS: ROBERTS SYNDROME; REC8: REC8 MEIOTIC RECOMBINATION PROTEIN; RNAP2: RNA POLYMERASE II; SAN: SINOATRIAL NODE; SCN5A: SODIUM VOLTAGE-GATED CHANNEL ALPHA SUBUNIT 5; SEC: SUPER ELONGATION COMPLEX; SGO1: SHOGOSHIN-1; SMAD: SMAD FAMILY MEMBER; SMC1A: STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC3: STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SNV: SINGLE NUCLEOTIDE VARIANT; SOX2: SRY-BOX 2; SOX17: SRY-BOX 17; SSS: SICK SINUS SYNDROME; STAG2: COHESIN SUBUNIT SA-2; TADS: TOPOLOGY ASSOCIATED DOMAINS; TBX: T-BOX TRANSCRIPTION FACTORS; TGF-BETA: TRANSFORMING GROWTH FACTOR BETA; TGFBR: TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TOF: TETRALOGY OF FALLOT; TREK1: TREK-1 K(+) CHANNEL SUBUNIT; VSD: VENTRICULAR SEPTAL DEFECT; WABS: WARSAW BREAKAGE SYNDROME; WAPL: WAPL COHESIN RELEASE FACTOR. 2019 2 4484 53 MOLECULAR SIGNATURE OF CAID SYNDROME: NONCANONICAL ROLES OF SGO1 IN REGULATION OF TGF-BETA SIGNALING AND EPIGENOMICS. BACKGROUND & AIMS: A GENERALIZED HUMAN PACEMAKING SYNDROME, CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) (OMIM 616201), IS CAUSED BY A HOMOZYGOUS SGO1 MUTATION (K23E), LEADING TO CHRONIC INTESTINAL PSEUDO-OBSTRUCTION AND ARRHYTHMIAS. BECAUSE CAID PATIENTS DO NOT SHOW PHENOTYPES CONSISTENT WITH PERTURBATION OF KNOWN ROLES OF SGO1, WE HYPOTHESIZED THAT NONCANONICAL ROLES OF SGO1 DRIVE THE CLINICAL MANIFESTATIONS OBSERVED. METHODS: TO IDENTIFY A MOLECULAR SIGNATURE FOR CAID SYNDROME, WE ACHIEVED UNBIASED SCREENS IN CELL LINES AND GUT TISSUES FROM CAID PATIENTS VS WILD-TYPE CONTROLS. WE PERFORMED RNA SEQUENCING ALONG WITH STABLE ISOTOPE LABELING WITH AMINO ACIDS IN CELL CULTURE. IN ADDITION, WE DETERMINED THE GENOME-WIDE DNA METHYLATION AND CHROMATIN ACCESSIBILITY SIGNATURES USING REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING. FUNCTIONAL STUDIES INCLUDED PATCH-CLAMP, QUANTITATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, AND IMMUNOHISTOCHEMISTRY IN CAID PATIENT GUT BIOPSY SPECIMENS. RESULTS: PROTEOME AND TRANSCRIPTOME STUDIES CONVERGE ON CELL-CYCLE REGULATION, CARDIAC CONDUCTION, AND SMOOTH MUSCLE REGULATION AS DRIVERS OF CAID SYNDROME. SPECIFICALLY, THE INWARD RECTIFIER CURRENT, AN IMPORTANT REGULATOR OF CELLULAR FUNCTION, WAS DISRUPTED. IMMUNOHISTOCHEMISTRY CONFIRMED OVEREXPRESSION OF BUDDING UNINHIBITED BY BENZIMIDAZOLES 1 (BUB1) IN PATIENTS, IMPLICATING THE TGF-BETA PATHWAY IN CAID PATHOGENESIS. CANONICAL TGF-BETA SIGNALING WAS UP-REGULATED AND UNCOUPLED FROM NONCANONICAL SIGNALING IN CAID PATIENTS. REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING EXPERIMENTS SHOWED SIGNIFICANT CHANGES OF CHROMATIN STATES IN CAID, POINTING TO EPIGENETIC REGULATION AS A POSSIBLE PATHOLOGIC MECHANISM. CONCLUSIONS: OUR FINDINGS POINT TO IMPAIRED INWARD RECTIFIER POTASSIUM CURRENT, DYSREGULATION OF CANONICAL TGF-BETA SIGNALING, AND EPIGENETIC REGULATION AS POTENTIAL DRIVERS OF INTESTINAL AND CARDIAC MANIFESTATIONS OF CAID SYNDROME. TRANSCRIPT PROFILING AND GENOMICS DATA ARE AS FOLLOWS: REPOSITORY URL: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO; SUPERSERIES GSE110612 WAS COMPOSED OF THE FOLLOWING SUBSERIES: GSE110309, GSE110576, AND GSE110601. 2019 3 500 23 ASSOCIATION BETWEEN NEUROPATHIC PAIN CHARACTERISTICS AND DNA METHYLATION OF TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 IN HUMAN PERIPHERAL BLOOD. ELUCIDATION OF EPIGENETIC MECHANISMS CORRELATING WITH NEUROPATHIC PAIN IN HUMANS IS CRUCIAL FOR THE PREVENTION AND TREATMENT OF THIS TREATMENT-RESISTANT PAIN STATE. IN THE PRESENT STUDY, ASSOCIATIONS BETWEEN NEUROPATHIC PAIN CHARACTERISTICS AND DNA METHYLATION OF THE TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1) GENE WERE EVALUATED IN CHRONIC PAIN PATIENTS AND PREOPERATIVE PATIENTS. PAIN AND PSYCHOLOGICAL STATES WERE PROSPECTIVELY ASSESSED IN PATIENTS WHO SUFFERED CHRONIC PAIN OR WERE SCHEDULED FOR THORACIC SURGERY. NEUROPATHIC CHARACTERISTICS WERE ASSESSED USING THE DOULEUR NEUROPATHIQUE 4 (DN4) QUESTIONNAIRE. DNA METHYLATION LEVELS OF THE CPG ISLANDS IN THE TRPA1 GENE WERE EXAMINED USING WHOLE BLOOD. FORTY-EIGHT ADULT PATIENTS WERE ENROLLED IN THIS STUDY. INCREASES IN DNA METHYLATION RATES AT CPG -51 SHOWED POSITIVE CORRELATIONS WITH INCREASES IN THE DN4 SCORE BOTH IN PREOPERATIVE AND CHRONIC PAIN PATIENTS. COMBINED METHYLATION RATES AT CPG -51 IN THESE PATIENTS ALSO SIGNIFICANTLY INCREASED TOGETHER WITH INCREASE IN DN4 SCORES. NEUROPATHIC PAIN CHARACTERISTICS ARE LIKELY ASSOCIATED WITH METHYLATION RATES AT THE PROMOTER REGION OF THE TRPA1 GENE IN HUMAN PERIPHERAL BLOOD. 2020 4 849 33 CHILDHOOD TRAUMATIZATION IS ASSOCIATED WITH DIFFERENCES IN TRPA1 PROMOTER METHYLATION IN FEMALE PATIENTS WITH MULTISOMATOFORM DISORDER WITH PAIN AS THE LEADING BODILY SYMPTOM. BACKGROUND: THE CONSTRUCT OF MULTISOMATOFORM DISORDER (MSD) IS A COMMON POINT OF REFERENCE FOR PATIENTS IN DIFFERENT SOMATIC AND PSYCHOSOMATIC SPECIALTIES AND THEREFORE USEFUL IN STUDYING LARGE WELL-CHARACTERIZED COHORTS OF A PROTOTYPE OF A SOMATOFORM DISORDER AND IN PARALLEL AS A FUNCTIONAL SOMATIC SYNDROME (FSS). THIS DISORDER IS CHARACTERIZED BY DISTRESSING AND FUNCTIONALLY DISABLING SOMATIC SYMPTOMS WITH CHRONIC PAIN AS THE MOST FREQUENT AND CLINICALLY RELEVANT COMPLAINT. PAIN IS PERCEIVED BY NOCICEPTIVE NERVE FIBERS AND TRANSFERRED THROUGH THE GENERATION OF ACTION POTENTIALS BY DIFFERENT RECEPTOR MOLECULES KNOWN TO DETERMINE PAIN SENSITIVITY IN PATHOPHYSIOLOGICAL PROCESSES. PREVIOUS STUDIES HAVE SHOWN THAT FOR THE TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), RECEPTOR METHYLATION OF A PARTICULAR CPG DINUCLEOTIDE IN THE PROMOTER REGION IS INVERSELY ASSOCIATED WITH BOTH HEAT PAIN AND PRESSURE PAIN THRESHOLDS. IN THIS STUDY, WE HYPOTHESIZED THAT TRPA1 PROMOTER METHYLATION REGULATES PAIN SENSITIVITY OF PATIENTS WITH MULTISOMATOFORM DISORDER (MSD). A COHORT OF 151 PATIENTS WITH MSD AND 149 MATCHED HEALTHY VOLUNTEERS WERE EVALUATED USING QUANTITATIVE SENSORY TESTING, CLINICAL AND PSYCHOMETRIC ASSESSMENT, AND METHYLATION ANALYSIS USING DNA ISOLATED FROM WHOLE BLOOD. RESULTS: WE FOUND CPG -628 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD AND CPG -411 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD IN FEMALE VOLUNTEERS, I.E., HIGHER METHYLATION LEVELS LEAD TO HIGHER PAIN THRESHOLDS. A NOVEL FINDING IS THAT METHYLATION LEVELS WERE SIGNIFICANTLY DIFFERENT BETWEEN PATIENTS WITH NO AND SEVERE LEVELS OF CHILDHOOD TRAUMA. CPG METHYLATION ALSO CORRELATED WITH PSYCHOMETRIC ASSESSMENT OF PAIN AND PAIN LEVELS RATED ON A VISUAL ANALOG SCALE. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT EPIGENETIC REGULATION OF TRPA1 PLAYS A ROLE IN MECHANICAL PAIN SENSITIVITIES IN HEALTHY VOLUNTEERS. THEY FURTHER PROVIDE EVIDENCE FOR THE POSSIBLE INFLUENCE OF CHILDHOOD TRAUMATIC EXPERIENCES ON THE EPIGENETIC REGULATION OF TRPA1 IN PATIENTS WITH MSD. 2019 5 1216 30 CRANIAL TREPHINATION AND INFECTIOUS DISEASE IN THE EASTERN MEDITERRANEAN: THE EVIDENCE FROM TWO ELITE BROTHERS FROM LATE BRONZE MEGIDDO, ISRAEL. HERE WE PRESENT THE PALEOPATHOLOGICAL PROFILES OF TWO YOUNG ADULT MALES, IDENTIFIED AS BROTHERS THROUGH ANCIENT DNA ANALYSIS, WHO WERE BURIED TOGETHER BENEATH THE FLOOR OF AN ELITE EARLY LATE BRONZE AGE I (CA. 1550-1450 BC) DOMESTIC STRUCTURE AT THE URBAN CENTER OF MEGIDDO (MODERN ISRAEL). BOTH INDIVIDUALS DISPLAYED UNCOMMON MORPHOLOGICAL VARIANTS RELATED TO DEVELOPMENTAL CONDITIONS, AND EACH EXHIBITED EXTENSIVE BONE REMODELING CONSISTENT WITH CHRONIC INFECTIOUS DISEASE. ADDITIONALLY, ONE BROTHER HAD A HEALED FRACTURE OF THE NOSE, AS WELL AS A LARGE SQUARE PIECE OF BONE CUT FROM THE FRONTAL BONE (CRANIAL TREPHINATION). WE CONSIDER THE POTENTIAL ETIOLOGIES FOR THE APPEARANCE OF THE SKELETAL ANOMALIES AND LESIONS. BASED ON THE BIOARCHAEOLOGICAL CONTEXT, WE PROPOSE THAT A SHARED EPIGENETIC LANDSCAPE PREDISPOSED THE BROTHERS TO ACQUIRING AN INFECTIOUS DISEASE AND THEIR ELITE STATUS PRIVILEGED THEM ENOUGH TO ENDURE IT. WE THEN CONTEXTUALIZE THESE POTENTIAL ILLNESSES AND DISORDERS WITH THE TREPHINATION PROCEDURE. THE INFREQUENCY OF TREPHINATION IN THE REGION INDICATES THAT ONLY SELECTED INDIVIDUALS COULD ACCESS SUCH A PROCEDURE, AND THE SEVERITY OF THE PATHOLOGICAL LESIONS SUGGESTS THE PROCEDURE WAS POSSIBLY INTENDED AS CURATIVE TO DETERIORATING HEALTH. ULTIMATELY, BOTH BROTHERS WERE BURIED WITH THE SAME RITES AS OTHERS IN THEIR COMMUNITY, THUS DEMONSTRATING THEIR CONTINUED INTEGRATION IN SOCIETY EVEN AFTER DEATH. 2023 6 2078 30 EPIGENETIC DIVERGENCE IN THE TRPA1 PROMOTER CORRELATES WITH PRESSURE PAIN THRESHOLDS IN HEALTHY INDIVIDUALS. THE EXPRESSION PATTERN OF IMPORTANT TRANSDUCTION MOLECULES IN NOCICEPTIVE SENSORY NEURONS IS LIKELY TO DICTATE PAIN SENSITIVITY. WHILE THIS NOTION IS WELL ESTABLISHED FOR INCREASED PAIN SENSITIVITIES UNDER CONDITIONS LIKE INFLAMMATION AND NEUROPATHY, LESS IS KNOWN AS TO WHICH MOLECULES ARE DEFINING INTERINDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY IN HEALTHY SUBJECTS. A GENOME-WIDE METHYLATION ANALYSIS ON MONOZYGOTIC TWINS FOUND THAT METHYLATION OF A CPG DINUCLEOTIDE IN THE PROMOTER OF TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1) IS INVERSELY ASSOCIATED WITH THE THRESHOLD FOR HEAT-INDUCED PAIN. SEVERAL IN VITRO STUDIES ALSO SUGGEST THAT TRPA1 MEDIATES MECHANICAL SENSITIVITY OF SENSORY AFFERENTS, THUS POTENTIALLY MEDIATING PRESSURE-EVOKED PAIN. IN THE PRESENT STUDY, WE THEREFORE INVESTIGATED THE EPIGENETIC PREDISPOSITION FOR PRESSURE PAIN BY ANALYZING THE METHYLATION STATUS OF 47 CPG SITES IN THE PROMOTER REGION OF TRPA1. USING DNA FROM WHOLE-BLOOD SAMPLES OF 75 HEALTHY VOLUNTEERS, WE FOUND THAT THE SAME CPG SITE PREVIOUSLY FOUND TO AFFECT THE THRESHOLD FOR HEAT-EVOKED PAIN IS HYPERMETHYLATED IN SUBJECTS WITH A LOW THRESHOLD FOR PRESSURE PAIN. WE ALSO FOUND GENDER DIFFERENCES, WITH FEMALES DISPLAYING HIGHER METHYLATION RATES COMBINED WITH HIGHER PRESSURE PAIN SENSITIVITIES AS COMPARED WITH MALES. IN CONCLUSION, OUR FINDINGS SUPPORT THE NOTION THAT EPIGENETIC REGULATION OF TRPA1 SEEMS TO REGULATE THERMAL AND MECHANICAL PAIN SENSITIVITIES. 2017 7 1092 45 COHESIN MUTATIONS IN MYELOID MALIGNANCIES. COHESIN IS A MULTISUBUNIT PROTEIN COMPLEX THAT FORMS A RING-LIKE STRUCTURE AROUND DNA. IT IS ESSENTIAL FOR SISTER CHROMATID COHESION, CHROMATIN ORGANIZATION, TRANSCRIPTIONAL REGULATION, AND DNA DAMAGE REPAIR AND PLAYS A MAJOR ROLE IN DYNAMICALLY SHAPING THE GENOME ARCHITECTURE AND MAINTAINING DNA INTEGRITY. THE CORE COMPLEX SUBUNITS STAG2, RAD21, SMC1, AND SMC3, AS WELL AS ITS MODULATORS PDS5A/B, WAPL, AND NIPBL, HAVE BEEN FOUND TO BE RECURRENTLY MUTATED IN HEMATOLOGIC AND SOLID MALIGNANCIES. THESE MUTATIONS ARE FOUND ACROSS THE FULL SPECTRUM OF MYELOID NEOPLASIA, INCLUDING PEDIATRIC DOWN SYNDROME-ASSOCIATED ACUTE MEGAKARYOBLASTIC LEUKEMIA, MYELODYSPLASTIC SYNDROMES, CHRONIC MYELOMONOCYTIC LEUKEMIA, AND DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIAS. THE MECHANISMS BY WHICH COHESIN MUTATIONS ACT AS DRIVERS OF CLONAL EXPANSION AND DISEASE PROGRESSION ARE STILL POORLY UNDERSTOOD. RECENT STUDIES HAVE DESCRIBED THE IMPACT OF COHESIN ALTERATIONS ON SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH ARE ASSOCIATED WITH CHANGES IN CHROMATIN AND EPIGENETIC STATE DIRECTING LINEAGE COMMITMENT, AS WELL AS GENOMIC INTEGRITY. HEREIN, WE REVIEW THE ROLE OF THE COHESIN COMPLEX IN HEALTHY AND MALIGNANT HEMATOPOIESIS. WE DISCUSS CLINICAL IMPLICATIONS OF COHESIN MUTATIONS IN MYELOID MALIGNANCIES AND DISCUSS OPPORTUNITIES FOR THERAPEUTIC TARGETING. 2021 8 5822 24 STRESS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES. DESPITE SUBSTANTIAL GROUNDS FOR SUCH RESEARCH, THE ROLE OF CHRONIC EXPOSURE TO STRESSORS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES (LDS) IS LARGELY UNEXPLORED. IN THIS REVIEW, WE FIRST CONSIDER THE HORMONAL, (EPI)GENETIC, AND NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THE IMPACT OF ADVERSE CHILDHOOD EXPERIENCES, A FORM OF CHRONIC STRESSORS, ON THE ONSET OF LDS. WE THEN FOUND THAT STRESS FACTORS COMBINED WITH FEELINGS OF INFERIORITY, LOW SELF-ESTEEM, AND PEER VICTIMIZATION COULD POTENTIALLY FURTHER AGGRAVATE ACADEMIC FAILURES IN CHILDREN WITH LDS. SINCE EFFECTIVE EVIDENCE-BASED INTERVENTIONS FOR REDUCING CHRONIC STRESS IN CHILDREN WITH LDS COULD IMPROVE THEIR ACADEMIC PERFORMANCE, CONSIDERATION OF THE ROLE OF EXPOSURE TO STRESSORS IN CHILDREN WITH LDS HAS BOTH THEORETICAL AND PRACTICAL IMPORTANCE, ESPECIALLY WHEN DELIVERED IN COMBINATION WITH ACADEMIC INTERVENTIONS. 2021 9 6569 40 TRANSPLANTATION OF EPIGENETICALLY MODIFIED ADULT CARDIAC C-KIT+ CELLS RETARDS REMODELING AND IMPROVES CARDIAC FUNCTION IN ISCHEMIC HEART FAILURE MODEL. CARDIAC C-KIT+ CELLS HAVE A MODEST CARDIOGENIC POTENTIAL THAT COULD LIMIT THEIR EFFICACY IN HEART DISEASE TREATMENT. THE PRESENT STUDY WAS DESIGNED TO AUGMENT THE CARDIOGENIC POTENTIAL OF CARDIAC C-KIT+ CELLS THROUGH CLASS I HISTONE DEACETYLASE (HDAC) INHIBITION AND EVALUATE THEIR THERAPEUTIC POTENCY IN THE CHRONIC HEART FAILURE (CHF) ANIMAL MODEL. MYOCARDIAL INFARCTION (MI) WAS CREATED BY CORONARY ARTERY OCCLUSION IN RATS. C-KIT+ CELLS WERE TREATED WITH MOCETINOSTAT (MOCE), A SPECIFIC CLASS I HDAC INHIBITOR. AT 3 WEEKS AFTER MI, CHF ANIMALS WERE RETROGRADELY INFUSED WITH UNTREATED (CONTROL) OR MOCE-TREATED C-KIT+ CELLS (MOCE/C-KIT+ CELLS) AND EVALUATED AT 3 WEEKS AFTER CELL INFUSION. WE FOUND THAT CLASS I HDAC INHIBITION IN C-KIT+ CELLS ELEVATED THE LEVEL OF ACETYLATED HISTONE H3 (ACH3) AND INCREASED ACH3 LEVELS IN THE PROMOTER REGIONS OF PLURIPOTENT AND CARDIAC-SPECIFIC GENES. EPIGENETIC CHANGES WERE ACCOMPANIED BY INCREASED EXPRESSION OF CARDIAC-SPECIFIC MARKERS. TRANSPLANTATION OF CHF RATS WITH EITHER CONTROL OR MOCE/C-KIT+ CELLS RESULTED IN AN IMPROVEMENT IN CARDIAC FUNCTION, RETARDATION OF CHF REMODELING MADE EVIDENT BY INCREASED VASCULARIZATION AND SCAR SIZE, AND CARDIOMYOCYTE HYPERTROPHY REDUCTION. COMPARED WITH CHF INFUSED WITH CONTROL CELLS, INFUSION OF MOCE/C-KIT+ CELLS RESULTED IN A FURTHER REDUCTION IN LEFT VENTRICLE END-DIASTOLIC PRESSURE AND TOTAL COLLAGEN AND AN INCREASE IN INTERLEUKIN-6 EXPRESSION. THE LOW ENGRAFTMENT OF INFUSED CELLS SUGGESTS THAT PARACRINE EFFECTS MIGHT ACCOUNT FOR THE BENEFICIAL EFFECTS OF C-KIT+ CELLS IN CHF. IN CONCLUSION, SELECTIVE INHIBITION OF CLASS I HDACS INDUCED EXPRESSION OF CARDIAC MARKERS IN C-KIT+ CELLS AND PARTIALLY AUGMENTED THE EFFICACY OF THESE CELLS FOR CHF REPAIR. SIGNIFICANCE: THE STUDY HAS SHOWN THAT SELECTIVE CLASS 1 HISTONE DEACETYLASE INHIBITION IS SUFFICIENT TO REDIRECT C-KIT+ CELLS TOWARD A CARDIAC FATE. EPIGENETICALLY MODIFIED C-KIT+ CELLS IMPROVED CONTRACTILE FUNCTION AND RETARDED REMODELING OF THE CONGESTIVE HEART FAILURE HEART. THIS STUDY PROVIDES NEW INSIGHTS INTO THE EFFICACY OF CARDIAC C-KIT+ CELLS IN THE ISCHEMIC HEART FAILURE MODEL. 2015 10 404 33 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS. 2020 11 521 34 ASSOCIATIONS BETWEEN MATERNAL PSYCHOSOCIAL STRESS, DNA METHYLATION, AND NEWBORN BIRTH WEIGHT IDENTIFIED BY INVESTIGATING METHYLATION AT INDIVIDUAL, REGIONAL, AND GENOME LEVELS. STRESS IS KNOWN TO AFFECT HEALTH THROUGHOUT LIFE AND INTO FUTURE GENERATIONS, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNKNOWN. WE TESTED THE HYPOTHESIS THAT MATERNAL PSYCHOSOCIAL STRESS INFLUENCES DNA METHYLATION (DNAM), WHICH IN TURN IMPACTS NEWBORN HEALTH OUTCOMES. SPECIFICALLY, WE ANALYZED DNAM AT INDIVIDUAL, REGIONAL, AND GENOME-WIDE LEVELS TO TEST FOR ASSOCIATIONS WITH MATERNAL STRESS AND NEWBORN BIRTH WEIGHT. MATERNAL VENOUS BLOOD AND NEWBORN CORD BLOOD (N = 24 AND 22, RESPECTIVELY) WERE ASSAYED FOR METHYLATION AT APPROXIMATELY 450,000 CPG SITES. METHYLATION WAS ANALYZED BY EXAMINING CPG SITES INDIVIDUALLY IN AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS), AS REGIONAL GROUPS USING VARIABLY METHYLATED REGION (VMR) ANALYSIS IN MATERNAL BLOOD ONLY, AND THROUGH THE EPIGENOME-WIDE MEASURES USING GENOME-WIDE MEAN METHYLATION (GMM), HORVATH'S EPIGENETIC CLOCK, AND MITOTIC AGE. THESE METHYLATION MEASURES WERE TESTED FOR ASSOCIATION WITH THREE MEASURES OF MATERNAL STRESS (MATERNAL WAR TRAUMA, CHRONIC STRESS, AND EXPERIENCE OF SEXUAL VIOLENCE) AND ONE HEALTH OUTCOME (NEWBORN BIRTH WEIGHT). WE OBSERVED THAT MATERNAL EXPERIENCES OF WAR TRAUMA, CHRONIC STRESS, AND SEXUAL ASSAULT WERE EACH ASSOCIATED WITH DECREASED NEWBORN BIRTH WEIGHT (P < 1.95 X 10(-7) IN ALL CASES). TESTING INDIVIDUAL CPG SITES USING EWAS, WE OBSERVED NO ASSOCIATIONS BETWEEN DNAM AND ANY MEASURE OF MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER MATERNAL OR CORD BLOOD, AFTER BONFERRONI MULTIPLE TESTING CORRECTION. HOWEVER, THE TOP-RANKED CPG SITE IN MATERNAL BLOOD THAT ASSOCIATED WITH MATERNAL CHRONIC STRESS AND SEXUAL VIOLENCE BEFORE MULTIPLE TESTING CORRECTION IS LOCATED NEAR THE SPON1 GENE. TESTING AT A REGIONAL LEVEL, WE FOUND INCREASED METHYLATION OF A VMR IN MATERNAL BLOOD NEAR SPON1 THAT WAS ASSOCIATED WITH CHRONIC STRESS AND SEXUAL VIOLENCE AFTER BONFERRONI MULTIPLE TESTING CORRECTION (P = 1.95 X 10(-7) AND 8.3 X 10(-6), RESPECTIVELY). AT THE EPIGENOMIC LEVEL, CORD BLOOD GMM WAS ASSOCIATED WITH SIGNIFICANTLY HIGHER LEVELS OF WAR TRAUMA (P = 0.025) AND WAS SUGGESTIVELY ASSOCIATED WITH SEXUAL VIOLENCE (P = 0.053). THE OTHER TWO EPIGENOME-WIDE MEASURES WERE NOT ASSOCIATED WITH MATERNAL STRESS OR NEWBORN BIRTH WEIGHT IN EITHER TISSUE TYPE. DESPITE OUR SMALL SAMPLE SIZE, WE IDENTIFIED ASSOCIATIONS EVEN AFTER CONSERVATIVE MULTIPLE TESTING CORRECTION. SPECIFICALLY, WE FOUND ASSOCIATIONS BETWEEN DNAM AND THE THREE MEASURES OF MATERNAL STRESS ACROSS BOTH TISSUES; SPECIFICALLY, A VMR IN MATERNAL BLOOD AND GMM IN CORD BLOOD WERE BOTH ASSOCIATED WITH DIFFERENT MEASURES OF MATERNAL STRESS. THE ASSOCIATION OF CORD BLOOD GMM, BUT NOT MATERNAL BLOOD GMM, WITH MATERNAL STRESS MAY SUGGEST DIFFERENT RESPONSES TO STRESS IN MOTHER AND NEWBORN. IT IS NOTEWORTHY THAT WE FOUND ASSOCIATIONS ONLY WHEN CPG SITES WERE ANALYZED IN AGGREGATE, EITHER AS VMRS OR AS A BROAD SUMMARY MEASURE OF GMM. 2019 12 6748 25 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS. 2013 13 1093 21 COHESIN RAD21 GENE PROMOTER METHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY THE PRESENCE OF SPECIFIC CYTOGENETIC ABNORMALITIES. CLL RESEARCH HAS BEEN FOCUSED ON EPIGENETIC PROCESSES LIKE GENE PROMOTER METHYLATION OF CPG ISLANDS. IN THE PRESENT STUDY, THE METHYLATION STATUS OF THE RAD21 GENE IS STUDIED AND ASSOCIATED WITH CYTOGENETIC FINDINGS IN CLL PATIENTS IN ORDER TO INVESTIGATE ITS POSSIBLE IMPLICATION IN CLL PATHOGENESIS AND THE FORMATION OF CLL CHROMOSOMAL ABNORMALITIES. 2018 14 223 32 ACUTE PSYCHOSOCIAL STRESS-MEDIATED CHANGES IN THE EXPRESSION AND METHYLATION OF PERFORIN IN CHRONIC FATIGUE SYNDROME. PERFORIN (PRF1) IS ESSENTIAL FOR IMMUNE SURVEILLANCE AND STUDIES REPORT DECREASED PERFORIN IN CHRONIC FATIGUE SYNDROME (CFS), AN ILLNESS POTENTIALLY ASSOCIATED WITH STRESS AND/OR INFECTION. WE HYPOTHESIZE THAT STRESS CAN INFLUENCE REGULATION OF PRF1 EXPRESSION, AND THAT THIS REGULATION WILL DIFFER BETWEEN CFS AND NON-FATIGUED (NF) CONTROLS. WE USED THE TRIER SOCIAL STRESS TEST (TSST) AS A STANDARDIZED ACUTE PSYCHOSOCIAL STRESS, AND EVALUATED ITS EFFECT ON PRF1 EXPRESSION AND METHYLATION IN CFS (N = 34) COMPARED WITH NF (N = 47) PARTICIPANTS. DURING THE TSST, NATURAL KILLER (NK) CELLS INCREASED SIGNIFICANTLY IN BOTH CFS (P = <0.0001) AND NF SUBJECTS (P = <0.0001). UNLIKE PREVIOUS REPORTS, THERE WAS NO SIGNIFICANT DIFFERENCE IN PRF1 EXPRESSION AT BASELINE OR DURING TSST BETWEEN CFS AND NF. HOWEVER, WHOLE BLOOD PRF1 EXPRESSION INCREASED 1.6 FOLD DURING THE TSST IN BOTH CFS (P = 0.0003) AND NF (P = <0.0001). FURTHER, THE PEAK RESPONSE IMMEDIATELY FOLLOWING THE TSST WAS LOWER IN CFS COMPARED WITH NF (P = 0.04). IN ADDITION, AT 1.5 HOURS POST TSST, PRF1 EXPRESSION WAS ELEVATED IN CFS COMPARED WITH NF (WHOLE BLOOD, P = 0.06; PBMC, P = 0.02). METHYLATION OF SEVEN CPG SITES IN THE METHYLATION SENSITIVE REGION OF THE PRF1 PROMOTER RANGED FROM 38%-79% WITH NO SIGNIFICANT DIFFERENCES BETWEEN CFS AND NF. ALTHOUGH, THE AVERAGE BASELINE METHYLATION OF ALL SEVEN CPG SITES DID NOT DIFFER BETWEEN CFS AND NF GROUPS, IT SHOWED A SIGNIFICANT NEGATIVE CORRELATION WITH PRF1 EXPRESSION AT ALL TSST TIME POINTS IN BOTH CFS (R = -0.56, P = <0.0001) AND NF (R = -0.38, P = <0.0001). AMONG PARTICIPANTS WITH HIGH AVERAGE METHYLATION (>/=65%), PRF1 EXPRESSION WAS SIGNIFICANTLY LOWER IN CFS THAN NF SUBJECTS IMMEDIATELY FOLLOWING TSST. THESE FINDINGS SUGGEST METHYLATION COULD BE AN IMPORTANT EPIGENETIC DETERMINANT OF INTER-INDIVIDUAL DIFFERENCES IN PRF1 EXPRESSION AND THAT THE DIFFERENCES IN PRF1 EXPRESSION AND METHYLATION BETWEEN CFS AND NF IN THE ACUTE STRESS RESPONSE REQUIRE FURTHER INVESTIGATION. 2013 15 4708 36 NO ASSOCIATION OF POLYMORPHISMS IN NAV1.7 OR NERVE GROWTH FACTOR RECEPTOR GENES WITH TRIGEMINAL NEURALGIA. OBJECTIVE: TRIGEMINAL NEURALGIA IS DEFINED AS A SUDDEN SEVERE SHOCK-LIKE PAIN WITHIN THE DISTRIBUTION OF THE TRIGEMINAL NERVE. PAIN IS A SUBJECTIVE EXPERIENCE THAT IS INFLUENCED BY GENDER, CULTURE, ENVIRONMENT, PSYCHOLOGICAL TRAITS, AND GENES. SODIUM CHANNELS AND NERVE GROWTH FACTOR PLAY IMPORTANT ROLES IN THE TRANSMISSION OF NOCICEPTIVE SIGNALS AND PAIN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE OCCURRENCE OF NAV1.7 SODIUM CHANNEL AND NERVE GROWTH FACTOR RECEPTOR TRKA GENE POLYMORPHISMS (SCN9A/RS6746030 AND NTRK1/RS633, RESPECTIVELY) IN TRIGEMINAL NEURALGIA PATIENTS. METHODS: NINETY-SIX SUBJECTS FROM PAIN SPECIALTY CENTERS IN THE SOUTHEASTERN REGION OF BRAZIL WERE DIVIDED INTO 2 GROUPS: 48 WITH CLASSICAL TRIGEMINAL NEURALGIA DIAGNOSIS AND 48 CONTROLS. PAIN WAS EVALUATED USING THE VISUAL ANALOG SCALE AND MULTIDIMENSIONAL MCGILL PAIN QUESTIONNAIRE. GENOMIC DNA WAS OBTAINED FROM ORAL SWABS IN ALL INDIVIDUALS AND WAS ANALYZED BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NO ASSOCIATION WAS OBSERVED BETWEEN EVALUATED POLYMORPHISMS AND TRIGEMINAL NEURALGIA. FOR ALLELE ANALYSES, PATIENTS AND CONTROLS HAD SIMILAR FREQUENCIES FOR BOTH GENES. GENOTYPE DISTRIBUTION OR ALLELE FREQUENCIES OF POLYMORPHISMS ANALYZED HERE DID NOT CORRELATE TO PAIN SCORES. CONCLUSIONS: ALTHOUGH NO ASSOCIATION OF EVALUATED POLYMORPHISMS AND TRIGEMINAL NEURALGIA DIAGNOSIS OR PAIN SEVERITY WAS OBSERVED, OUR DATA DO NOT EXCLUDE THE POSSIBILITY THAT OTHER GENOTYPES AFFECTING THE EXPRESSION OF NAV1.7 OR TRKA ARE ASSOCIATED WITH THE DISEASE. FURTHER STUDIES SHOULD INVESTIGATE DISTINCT GENETIC POLYMORPHISMS AND EPIGENETIC FACTORS THAT MAY BE IMPORTANT IN EXPRESSION OF THESE MOLECULES. 2019 16 3850 31 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 17 2734 27 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 18 308 29 ALCOHOL AND DNA METHYLATION: AN EPIGENOME-WIDE ASSOCIATION STUDY IN BLOOD AND NORMAL BREAST TISSUE. THE BIOLOGICAL MECHANISMS DRIVING ASSOCIATIONS BETWEEN ALCOHOL CONSUMPTION AND CHRONIC DISEASES MIGHT INCLUDE EPIGENETIC MODIFICATION OF DNA METHYLATION. WE EXPLORED THE HYPOTHESIS THAT ALCOHOL CONSUMPTION IS ASSOCIATED WITH METHYLATION IN AN EPIGENOME-WIDE ASSOCIATION STUDY OF BLOOD AND NORMAL BREAST TISSUE DNA. INFINIUM HUMANMETHYLATION450 BEADCHIP (ILLUMINA INC., SAN DIEGO, CALIFORNIA) ARRAY DATA ON BLOOD DNA METHYLATION WAS EXAMINED IN A DISCOVERY SET OF 2,878 NON-HISPANIC WHITE WOMEN FROM THE SISTER STUDY (UNITED STATES, 2004-2015) WHO PROVIDED DETAILED QUESTIONNAIRE INFORMATION ON LIFETIME ALCOHOL USE. ROBUST LINEAR REGRESSION MODELING WAS USED TO IDENTIFY SIGNIFICANT ASSOCIATIONS (FALSE DISCOVERY RATE OF Q < 0.05) BETWEEN THE NUMBER OF ALCOHOLIC DRINKS PER WEEK AND DNA METHYLATION AT 5,458 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES. ASSOCIATIONS WERE REPLICATED (P < 0.05) FOR 677 CPGS IN AN INDEPENDENT SET OF 187 BLOOD DNA SAMPLES FROM THE SISTER STUDY AND FOR 628 CPGS IN AN INDEPENDENT SET OF 171 NORMAL BREAST DNA SAMPLES; 1,207 CPGS WERE REPLICATED IN EITHER BLOOD OR NORMAL BREAST, WITH 98 CPGS REPLICATED IN BOTH TISSUES. INDIVIDUAL GENE EFFECTS WERE NOTABLE FOR PHOSPHOGLYCERATE DEHYDROGENASE (PGHDH), PEPTIDYL-PROLYL CIS-TRANS ISOMERASE (PPIF), SOLUTE CARRIER 15 (SLC15), SOLUTE CARRIER FAMILY 43 MEMBER 1 (SLC43A1), AND SOLUTE CARRIER FAMILY 7 MEMBER 11 (SLC7A11). WE ALSO FOUND THAT HIGH ALCOHOL CONSUMPTION WAS ASSOCIATED WITH SIGNIFICANTLY LOWER GLOBAL METHYLATION AS MEASURED BY THE AVERAGE OF CPGS ON THE ENTIRE ARRAY. 2019 19 5395 28 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD. 2023 20 173 23 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD. 2023