1  3309 122 HIGHER GENE EXPRESSION VARIABILITY IN THE MORE AGGRESSIVE SUBTYPE OF CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PRESENTS TWO SUBTYPES WHICH HAVE DRASTICALLY DIFFERENT CLINICAL OUTCOMES, IGVH MUTATED (M-CLL) AND IGVH UNMUTATED (U-CLL). SO FAR, THESE TWO SUBTYPES ARE NOT ASSOCIATED TO CLEAR DIFFERENCES IN GENE EXPRESSION PROFILES. INTERESTINGLY, RECENT RESULTS HAVE HIGHLIGHTED IMPORTANT ROLES FOR HETEROGENEITY, BOTH AT THE GENETIC AND AT THE EPIGENETIC LEVEL IN CLL PROGRESSION. METHODS: WE ANALYZED GENE EXPRESSION DATA OF TWO LARGE COHORTS OF CLL PATIENTS AND QUANTIFIED EXPRESSION VARIABILITY ACROSS INDIVIDUALS TO INVESTIGATE DIFFERENCES BETWEEN THE TWO SUBTYPES USING DIFFERENT MEASURES AND STATISTICAL TESTS. FUNCTIONAL SIGNIFICANCE WAS EXPLORED BY PATHWAY ENRICHMENT AND NETWORK ANALYSES. FURTHERMORE, WE IMPLEMENTED A RANDOM FOREST APPROACH BASED ON EXPRESSION VARIABILITY TO CLASSIFY PATIENTS INTO DISEASE SUBTYPES. RESULTS: WE FOUND THAT U-CLL, THE MORE AGGRESSIVE TYPE OF THE DISEASE, SHOWS SIGNIFICANTLY INCREASED VARIABILITY OF GENE EXPRESSION ACROSS PATIENTS AND THAT, OVERALL, GENES THAT SHOW HIGHER VARIABILITY IN THE AGGRESSIVE SUBTYPE ARE RELATED TO CELL CYCLE, DEVELOPMENT AND INTER-CELLULAR COMMUNICATION. THESE FUNCTIONS INDICATE A POTENTIAL RELATION BETWEEN GENE EXPRESSION VARIABILITY AND THE FASTER PROGRESSION OF THIS CLL SUBTYPE. FINALLY, A CLASSIFIER BASED ON GENE EXPRESSION VARIABILITY WAS ABLE TO CORRECTLY PREDICT THE DISEASE SUBTYPE OF CLL PATIENTS. CONCLUSIONS: THERE ARE STRONG RELATIONS BETWEEN GENE EXPRESSION VARIABILITY AND DISEASE SUBTYPE LINKING SIGNIFICANTLY INCREASED EXPRESSION VARIABILITY TO PHENOTYPES SUCH AS AGGRESSIVENESS AND RESISTANCE TO THERAPY IN CLL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  1957  34 EPIGENETIC AGE PREDICTORS IN COMMUNITY-DWELLING ADULTS WITH HIGH IMPACT KNEE PAIN. GERONTOLOGICAL RESEARCH REVEALS CONSIDERABLE INTERINDIVIDUAL VARIABILITY IN AGING PHENOTYPES, AND EMERGING EVIDENCE SUGGESTS THAT HIGH IMPACT CHRONIC PAIN MAY BE ASSOCIATED WITH VARIOUS ACCELERATED BIOLOGICAL AGING PROCESSES. IN PARTICULAR, EPIGENETIC AGING IS A ROBUST PREDICTOR OF HEALTH-SPAN AND DISABILITY COMPARED TO CHRONOLOGICAL AGE ALONE. THE CURRENT STUDY AIMED TO DETERMINE WHETHER SEVERAL EPIGENETIC AGING BIOMARKERS WERE ASSOCIATED WITH HIGH IMPACT CHRONIC PAIN IN MIDDLE TO OLDER AGE ADULTS (44-78 YEARS OLD). PARTICIPANTS (N = 213) UNDERWENT A BLOOD DRAW, DEMOGRAPHIC, PSYCHOSOCIAL, PAIN AND FUNCTIONAL ASSESSMENTS. WE ESTIMATED FIVE EPIGENETIC CLOCKS AND CALCULATED THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, WHICH HAS BEEN PREVIOUSLY REPORTED TO PREDICT OVERALL MORTALITY RISK, AS WELL AS INCLUDED ADDITIONAL DERIVED VARIABLES OF EPIGENETIC AGE PREVIOUSLY ASSOCIATED WITH PAIN. THERE WERE SIGNIFICANT DIFFERENCES ACROSS PAIN IMPACT GROUPS IN THREE OUT OF THE FIVE EPIGENETIC CLOCKS EXAMINED (DNAMAGE, DNAMPHENOAGE AND DNAMGRIMAGE), INDICATING THAT PAIN-RELATED DISABILITY DURING THE PAST 6 MONTHS WAS ASSOCIATED WITH MARKERS OF EPIGENETIC AGING. ONLY DNAMPHENOAGE AND DNAMGRIMAGE WERE ASSOCIATED WITH HIGHER KNEE PAIN INTENSITY DURING THE PAST 48 H. FINALLY, PAIN CATASTROPHIZING, DEPRESSIVE SYMPTOMATOLOGY AND MORE NEUROPATHIC PAIN SYMPTOMS WERE SIGNIFICANTLY ASSOCIATED WITH AN OLDER EPIGENOME IN ONLY ONE OF THE FIVE EPIGENETIC CLOCKS (I.E. DNAMGRIMAGE) AFTER CORRECTING FOR MULTIPLE COMPARISONS (CORRECTED P'S < 0.05). GIVEN THE SCANT LITERATURE IN RELATION TO EPIGENETIC AGING AND THE COMPLEX EXPERIENCE OF PAIN, ADDITIONAL RESEARCH IS NEEDED TO UNDERSTAND WHETHER EPIGENETIC AGING MAY HELP IDENTIFY PEOPLE WITH CHRONIC PAIN AT GREATER RISK OF FUNCTIONAL DECLINE AND POORER HEALTH OUTCOMES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3  5395  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4  1050  27 CLINICAL FEATURES ASSOCIATED TO REFRACTORY OBSESSIVE-COMPULSIVE DISORDER. SOME PATIENTS WITH OBSESSIVE-COMPULSIVE DISORDER (OCD) EXHIBIT AN UNSATISFACTORY REDUCTION IN SYMPTOM SEVERITY DESPITE BEING TREATED WITH ALL THE AVAILABLE THERAPEUTIC ALTERNATIVES. THE CLINICAL VARIABLES ASSOCIATED WITH TREATMENT-REFRACTORINESS IN OCD ARE INCONSISTENTLY DESCRIBED IN THE LITERATURE. METHODS: TO INVESTIGATE FACTORS ASSOCIATED WITH TREATMENT-REFRACTORINESS OF PATIENTS WITH OCD, WE CONDUCTED A CASE-CONTROL STUDY, COMPARING 23 PATIENTS WITH TREATMENT-REFRACTORY OCD TO 26 PATIENTS WITH TREATMENT-RESPONDING OCD. RESULTS: THE FACTORS ASSOCIATED WITH REFRACTORINESS OF OCD WERE HIGHER SEVERITY OF SYMPTOMS SINCE THE ONSET OF OCD (P<0.001), CHRONIC COURSE (P=0.003), LACK OF A PARTNER (P=0.037), UNEMPLOYMENT (P=0.025), LOW ECONOMIC STATUS (P=0.015), PRESENCE OF OBSESSIVE-COMPULSIVE SYMPTOMS OF SEXUAL/RELIGIOUS CONTENT (P=0.043), AND HIGHER SCORES ON FAMILY ACCOMMODATION (P<0.001). ONLY THE THREE LATTER VARIABLES REMAINED SIGNIFICANTLY ASSOCIATED WITH TREATMENT-REFRACTORINESS AFTER REGRESSION ANALYSES. LIMITATIONS: SMALL SAMPLE SIZE, THE BIASES AND DRAWBACKS INHERENT TO A CASE-CONTROL STUDY, AND THE INCLUSION CRITERIA USED TO DEFINE THE STUDY GROUPS MAY HAVE LIMITED THE GENERALISATION OF THE RESULTS. CONCLUSION: A MAJOR STRENGTH OF THIS STUDY IS THE SYSTEMATIC AND STRUCTURED EVALUATION OF A VAST ARRAY OF VARIABLES RELATED TO THE CLINICAL EXPRESSION OF OCD, INCLUDING EPIGENETIC FACTORS AND RATINGS DERIVED FROM INSTRUMENTS EVALUATING FAMILY ACCOMMODATION. THE PRESENCE OF SEXUAL/RELIGIOUS SYMPTOMS, LOW ECONOMIC STATUS AND HIGH MODIFICATION ON FAMILY FUNCTION DUE TO OCD WERE INDEPENDENTLY ASSOCIATED WITH TREATMENT-REFRACTORINESS. FUTURE LONGITUDINAL STUDIES ARE WARRANTED TO VERIFY IF THESE VARIABLES REPRESENT PREDICTIVE FACTORS OF TREATMENT NON-RESPONSE.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  5957  29 TELOMERE LENGTH AND EPIGENETIC AGE ACCELERATION IN ADOLESCENTS WITH ANXIETY DISORDERS. EVIDENCE ON THE RELATIONSHIP BETWEEN GENETICS AND MENTAL HEALTH ARE FLOURISHING. HOWEVER, FEW STUDIES ARE EVALUATING EARLY BIOMARKERS THAT MIGHT LINK GENES, ENVIRONMENT, AND PSYCHOPATHOLOGY. WE AIMED TO STUDY TELOMERE LENGTH (TL) AND EPIGENETIC AGE ACCELERATION (AA) IN A COHORT OF ADOLESCENTS WITH AND WITHOUT ANXIETY DISORDERS (N = 234). WE EVALUATED A REPRESENTATIVE SUBSAMPLE OF PARTICIPANTS AT BASELINE AND AFTER 5 YEARS (N = 76) AND CATEGORIZED THEM ACCORDING TO THEIR ANXIETY DISORDER DIAGNOSIS AT BOTH TIME POINTS: (1) CONTROL GROUP (NO ANXIETY DISORDER, N = 18), (2) VARIABLE GROUP (ANXIETY DISORDER IN ONE EVALUATION, N = 38), AND (3) PERSISTENT GROUP (ANXIETY DISORDER AT BOTH TIME POINTS, N = 20). WE ASSESSED RELATIVE MEAN TL BY REAL-TIME QUANTITATIVE PCR AND DNA METHYLATION BY INFINIUM HUMANMETHYLATION450 BEADCHIP. WE CALCULATED AA USING THE HORVATH AGE ESTIMATION ALGORITHM AND ANALYZED DIFFERENCES AMONG GROUPS USING GENERALIZED LINEAR MIXED MODELS. THE PERSISTENT GROUP OF ANXIETY DISORDER DID NOT CHANGE TL OVER TIME (P = 0.495). THE VARIABLE GROUP HAD HIGHER BASELINE TL (P = 0.003) BUT NO ACCELERATED TL EROSION IN COMPARISON TO THE NON-ANXIETY CONTROL GROUP (P = 0.053). FURTHERMORE, THERE WERE NO DIFFERENCES IN AA AMONG GROUPS OVER TIME. OUR FINDINGS SUGGEST THAT ADOLESCENTS WITH CHRONIC ANXIETY DID NOT CHANGE TELOMERE LENGTH OVER TIME, WHICH COULD BE RELATED TO A DELAY IN NEURONAL DEVELOPMENT IN THIS PERIOD OF LIFE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  2411  26 EPIGENETIC SCORES FOR THE CIRCULATING PROTEOME AS TOOLS FOR DISEASE PREDICTION. PROTEIN BIOMARKERS HAVE BEEN IDENTIFIED ACROSS MANY AGE-RELATED MORBIDITIES. HOWEVER, CHARACTERISING EPIGENETIC INFLUENCES COULD FURTHER INFORM DISEASE PREDICTIONS. HERE, WE LEVERAGE EPIGENOME-WIDE DATA TO STUDY LINKS BETWEEN THE DNA METHYLATION (DNAM) SIGNATURES OF THE CIRCULATING PROTEOME AND INCIDENT DISEASES. USING DATA FROM FOUR COHORTS, WE TRAINED AND TESTED EPIGENETIC SCORES (EPISCORES) FOR 953 PLASMA PROTEINS, IDENTIFYING 109 SCORES THAT EXPLAINED BETWEEN 1% AND 58% OF THE VARIANCE IN PROTEIN LEVELS AFTER ADJUSTING FOR KNOWN PROTEIN QUANTITATIVE TRAIT LOCI (PQTL) GENETIC EFFECTS. BY PROJECTING THESE EPISCORES INTO AN INDEPENDENT SAMPLE (GENERATION SCOTLAND; N = 9537) AND RELATING THEM TO INCIDENT MORBIDITIES OVER A FOLLOW-UP OF 14 YEARS, WE UNCOVERED 137 EPISCORE-DISEASE ASSOCIATIONS. THESE ASSOCIATIONS WERE LARGELY INDEPENDENT OF IMMUNE CELL PROPORTIONS, COMMON LIFESTYLE AND HEALTH FACTORS, AND BIOLOGICAL AGING. NOTABLY, WE FOUND THAT OUR DIABETES-ASSOCIATED EPISCORES HIGHLIGHTED PREVIOUS TOP BIOMARKER ASSOCIATIONS FROM PROTEOME-WIDE ASSESSMENTS OF DIABETES. THESE EPISCORES FOR PROTEIN LEVELS CAN THEREFORE BE A VALUABLE RESOURCE FOR DISEASE PREDICTION AND RISK STRATIFICATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  5606  34 RPPA-BASED PROTEOMICS RECOGNIZES DISTINCT EPIGENETIC SIGNATURES IN CHRONIC LYMPHOCYTIC LEUKEMIA WITH CLINICAL CONSEQUENCES. THE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ARMAMENTARIUM HAS EVOLVED SIGNIFICANTLY, WITH NOVEL THERAPIES THAT INHIBIT BRUTON TYROSINE KINASE, PI3K DELTA AND/OR THE BCL2 PROTEIN IMPROVING OUTCOMES. STILL, THE CLINICAL COURSE OF CLL PATIENTS IS HIGHLY VARIABLE AND MOST PREVIOUSLY RECOGNIZED PROGNOSTIC FEATURES LACK THE CAPACITY TO PREDICT RESPONSE TO MODERN TREATMENTS INDICATING THE NEED FOR NEW PROGNOSTIC MARKERS. IN THIS STUDY, WE IDENTIFIED FOUR EPIGENETICALLY DISTINCT PROTEOMIC SIGNATURES OF A LARGE COHORT OF CLL AND RELATED DISEASES DERIVED SAMPLES (N = 871) USING REVERSE PHASE PROTEIN ARRAY TECHNOLOGY. THESE SIGNATURES ARE ASSOCIATED WITH CLINICAL FEATURES INCLUDING AGE, CYTOGENETIC ABNORMALITIES [TRISOMY 12, DEL(13Q) AND DEL(17P)], IMMUNOGLOBULIN HEAVY-CHAIN LOCUS (IGHV) MUTATIONAL LOAD, ZAP-70 STATUS, BINET AND RAI STAGING AS WELL AS WITH THE OUTCOME MEASURES OF TIME TO TREATMENT AND OVERALL SURVIVAL. PROTEIN SIGNATURE MEMBERSHIP WAS IDENTIFIED AS PREDICTIVE MARKER FOR OVERALL SURVIVAL REGARDLESS OF OTHER CLINICAL FEATURES. AMONG THE ANALYZED EPIGENETIC PROTEINS, EZH2, HDAC6, AND LOSS OF H3K27ME3 LEVELS WERE THE MOST INDEPENDENTLY ASSOCIATED WITH POOR SURVIVAL. THESE FINDINGS DEMONSTRATE THAT PROTEOMIC BASED EPIGENETIC BIOMARKERS CAN BE USED TO BETTER CLASSIFY CLL PATIENTS AND PROVIDE THERAPEUTIC GUIDANCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8    70  40 A METHOD TO DETECT DIFFERENTIALLY METHYLATED LOCI WITH NEXT-GENERATION SEQUENCING. EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION AT CPG LOCI HAVE IMPORTANT IMPLICATIONS IN CANCER AND OTHER COMPLEX DISEASES. WITH THE DEVELOPMENT OF NEXT-GENERATION SEQUENCING (NGS), IT IS FEASIBLE TO GENERATE DATA TO INTERROGATE THE DIFFERENCE IN METHYLATION STATUS FOR GENOME-WIDE LOCI USING CASE-CONTROL DESIGN. HOWEVER, A PROPER AND EFFICIENT STATISTICAL TEST IS LACKING. THERE ARE SEVERAL CHALLENGES. FIRST, UNLIKE METHYLATION EXPERIMENTS USING MICROARRAYS, WHERE THERE IS ONE MEASURE OF METHYLATION FOR ONE INDIVIDUAL AT A PARTICULAR CPG SITE, HERE WE HAVE THE COUNTS OF METHYLATION ALLELE AND UNMETHYLATION ALLELE FOR EACH INDIVIDUAL. SECOND, DUE TO THE NATURE OF SAMPLE PREPARATION, THE MEASURED METHYLATION REFLECTS THE METHYLATION STATUS OF A MIXTURE OF CELLS INVOLVED IN SAMPLE PREPARATION. THEREFORE, THE UNDERLYING DISTRIBUTION OF THE MEASURED METHYLATION LEVEL IS UNKNOWN, AND A ROBUST TEST IS MORE DESIRABLE THAN PARAMETRIC APPROACH. THIRD, CURRENTLY NGS MEASURES METHYLATION AT OVER 2 MILLION CPG SITES. ANY STATISTICAL TESTS HAVE TO BE COMPUTATIONALLY EFFICIENT IN ORDER TO BE APPLIED TO THE NGS DATA. TAKING THESE CHALLENGES INTO ACCOUNT, WE PROPOSE A TEST FOR DIFFERENTIAL METHYLATION BASED ON CLUSTERED DATA ANALYSIS BY MODELING THE METHYLATION COUNTS. WE PERFORMED SIMULATIONS TO SHOW THAT IT IS ROBUST UNDER SEVERAL DISTRIBUTIONS FOR THE MEASURED METHYLATION LEVELS. IT HAS GOOD POWER AND IS COMPUTATIONALLY EFFICIENT. FINALLY, WE APPLY THE TEST TO OUR NGS DATA ON CHRONIC LYMPHOCYTIC LEUKEMIA. THE RESULTS INDICATE THAT IT IS A PROMISING AND PRACTICAL TEST.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  1599  38 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES.	2014	
                                                                                                                                                                                                                                                                             
10  1516  32 DNA METHYLATION AS A BIOMARKER OF AGING IN EPIDEMIOLOGIC STUDIES. CANCER IS LARGELY AN AGING DISEASE. ACCELERATED BIOLOGICAL AGING MAY BE THE STRONGEST PREDICTOR OF CANCER AND OTHER CHRONIC DISEASE RISKS. IN THE ABSENCE OF RELIABLE AND QUANTIFIABLE BIOMARKERS OF AGING TO DATE, IT HAS LONG BEEN OBSERVED THAT TUMORIGENESIS SHARES DISTINCT EPIGENETIC ALTERATIONS WITH THE AGING PROCESS. RECENTLY, EPIGENETIC AGE ESTIMATES HAVE BEEN DEVELOPED BASED ON THE AVAILABILITY OF GENOME-WIDE DNA METHYLATION PROFILES, BY APPLYING IN THE PREDICTION FORMULA THE METHYLATION LEVEL AT A SUBSET OF HIGHLY PREDICTIVE METHYLATION SITES, CALLED EPIGENETIC CLOCK. THESE DNA METHYLATION AGE ESTIMATES HAVE PRODUCED REMARKABLY STRONG CORRELATIONS WITH CHRONOLOGICAL AGE, WITH A SMALL DEVIATION AND HIGH REPRODUCIBILITY ACROSS DIFFERENT AGE GROUPS AND STUDY POPULATIONS. MOREOVER, AN INCREASING NUMBER OF EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED AN INDEPENDENT ASSOCIATION OF DNA METHYLATION AGE OR THE EXTENT OF ACCELERATION WITH MORTALITY AND VARIOUS AGING-RELATED CONDITIONS, EVEN AFTER ACCOUNTING FOR DIFFERENCES IN CHRONOLOGICAL AGE AND OTHER RISK FACTORS. ALTHOUGH EPIGENETIC PROFILES ARE KNOWN TO BE TISSUE-SPECIFIC, BOTH TARGET TISSUE- AND MULTIPLE TISSUE-DERIVED ESTIMATES APPEAR TO PERFORM WELL TO CAPTURE WHAT IS THOUGHT TO BE THE CUMULATIVE EPIGENETIC DRIFT THAT REPRESENTS A MULTIFACTORIAL DEGENERATIVE PROCESS ACROSS TISSUES AND ORGANISMS. FURTHER REFINEMENT OF THE EPIGENETIC AGE ESTIMATES IS ANTICIPATED OVER TIME TO ACCOMMODATE A BETTER TECHNOLOGICAL COVERAGE OF THE METHYLOME AND A BETTER UNDERSTANDING OF THE BIOLOGY UNDERLYING PREDICTIVE REGIONS. EPIDEMIOLOGIC PRINCIPLES WILL REMAIN CRITICAL FOR THE EVALUATION OF RESEARCH FINDINGS INVOLVING, FOR EXAMPLE, DIFFERENT STUDY POPULATIONS, DESIGN, FOLLOW-UP TIME, AND QUALITY OF COVARIATE DATA. OVERALL, THE EPIGENETIC AGE ESTIMATES ARE AN EXCITING DEVELOPMENT WITH USEFUL IMPLICATIONS FOR BIOMEDICAL RESEARCH OF HEALTHY AGING AND DISEASE PREVENTION AND CONTROL.	2018	
                                                                                                                                                                                                                                                                                                                                                              
11  2734  32 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  6112  33 THE EPIGENETIC CLOCK AS A PREDICTOR OF DISEASE AND MORTALITY RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: AGEING IS ONE OF THE PRINCIPAL RISK FACTORS FOR MANY CHRONIC DISEASES. HOWEVER, THERE IS CONSIDERABLE BETWEEN-PERSON VARIATION IN THE RATE OF AGEING AND INDIVIDUAL DIFFERENCES IN THEIR SUSCEPTIBILITY TO DISEASE AND DEATH. EPIGENETIC MECHANISMS MAY PLAY A ROLE IN HUMAN AGEING, AND DNA METHYLATION AGE BIOMARKERS MAY BE GOOD PREDICTORS OF AGE-RELATED DISEASES AND MORTALITY RISK. THE AIMS OF THIS SYSTEMATIC REVIEW WERE TO IDENTIFY AND SYNTHESISE THE EVIDENCE FOR AN ASSOCIATION BETWEEN PERIPHERALLY MEASURED DNA METHYLATION AGE AND LONGEVITY, AGE-RELATED DISEASE, AND MORTALITY RISK. METHODS: A SYSTEMATIC SEARCH WAS CONDUCTED IN LINE WITH THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. USING RELEVANT SEARCH TERMS, MEDLINE, EMBASE, COCHRANE CENTRAL REGISTER OF CONTROLLED TRIALS, AND PSYCHINFO DATABASES WERE SEARCHED TO IDENTIFY ARTICLES MEETING THE INCLUSION CRITERIA. STUDIES WERE ASSESSED FOR BIAS USING JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLISTS. DATA WAS EXTRACTED FROM STUDIES MEASURING AGE ACCELERATION AS A PREDICTOR OF AGE-RELATED DISEASES, MORTALITY OR LONGEVITY, AND THE FINDINGS FOR SIMILAR OUTCOMES COMPARED. USING REVIEW MANAGER 5.3 SOFTWARE, TWO META-ANALYSES (ONE PER EPIGENETIC CLOCK) WERE CONDUCTED ON STUDIES MEASURING ALL-CAUSE MORTALITY. RESULTS: TWENTY-THREE RELEVANT ARTICLES WERE IDENTIFIED, INCLUDING A TOTAL OF 41,607 PARTICIPANTS. FOUR STUDIES FOCUSED ON AGEING AND LONGEVITY, 11 ON AGE-RELATED DISEASE (CANCER, CARDIOVASCULAR DISEASE, AND DEMENTIA), AND 11 ON MORTALITY. THERE WAS SOME, ALTHOUGH INCONSISTENT, EVIDENCE FOR AN ASSOCIATION BETWEEN INCREASED DNA METHYLATION AGE AND RISK OF DISEASE. META-ANALYSES INDICATED THAT EACH 5-YEAR INCREASE IN DNA METHYLATION AGE WAS ASSOCIATED AN 8 TO 15% INCREASED RISK OF MORTALITY. CONCLUSION: DUE TO THE SMALL NUMBER OF STUDIES AND HETEROGENEITY IN STUDY DESIGN AND OUTCOMES, THE ASSOCIATION BETWEEN DNA METHYLATION AGE AND AGE-RELATED DISEASE AND LONGEVITY IS INCONCLUSIVE. INCREASED EPIGENETIC AGE WAS ASSOCIATED WITH MORTALITY RISK, BUT POSITIVE PUBLICATION BIAS NEEDS TO BE CONSIDERED. FURTHER RESEARCH IS NEEDED TO DETERMINE THE EXTENT TO WHICH DNA METHYLATION AGE CAN BE USED AS A CLINICAL BIOMARKER.	2019	

13  3560  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  5655  29 SEX-BASED MEDICINE MEETS PSORIATIC ARTHRITIS: LESSONS LEARNED AND TO LEARN. HUMORALLY ASSOCIATED AUTOIMMUNE DISEASES GENERALLY SHOW A FEMALE PREDOMINANCE WHEREAS ANKYLOSING SPONDYLITIS, A DISEASE THAT OVERLAPS WITH PSORIATIC ARTHRITIS (PSA), SHOWS A MALE PREDOMINANCE. THE PRESENT REVIEW ASCERTAINS THE CURRENT KNOWLEDGE OF SEX-SPECIFIC DIFFERENCES RELATED TO PSORIATIC ARTHRITIS (PSA), A CHRONIC, INFLAMMATORY CONDITION ASSOCIATED WITH PSORIASIS. SEX DIFFERENCES MAY HAVE IMPORTANT IMPLICATIONS FOR CLINICAL RESEARCH IN PSA AND IN TERMS OF EPIDEMIOLOGY (INCIDENCE, PREVALENCE, LIFETIME RISK, SURVIVAL, AND MORTALITY), CLINICAL, RADIOLOGICAL, AND LABORATORY FEATURES, AND RESPONSE TO TREATMENT. WHILE NATIONWIDE SURVEYS AND LARGE-SCALE DATABASES AND REGISTRIES SHOW NO SEX-SPECIFIC DIFFERENCES, VARYING MALE/FEMALE RATIOS HAVE BEEN REPORTED, RANGING FROM 0.42 TO 2.75 (COMPARABLE WITH THOSE REPORTED FOR PSORIASIS VULGARIS: RANGING FROM 0.28 TO 2.38). THIS MAY REFLECT SUBTLE, COMPLEX, NONLINEAR INTERACTIONS BETWEEN THE BIOLOGICAL MAKE-UP OF THE INDIVIDUAL (GENETIC AND EPIGENETIC DIFFERENCES), HORMONAL COMPONENTS INCLUDING MENOPAUSAL STATUS, ENVIRONMENTAL EXPOSURES INCLUDING SKELETAL PHYSICAL STRESSING, AND PSYCHOLOGICAL VARIABLES. THERE EXISTS METHODOLOGICAL HETEROGENEITY AND PAUCITY OF DATA CONCERNING SEX-SPECIFIC DIFFERENCES, IN TERMS OF THE SPECIFIC POPULATION STUDIED, STUDY DESIGN, AND THE DIAGNOSTIC CRITERIA UTILIZED. HARMONIZING AND RECONCILING THESE DISCREPANCIES WOULD BE OF CRUCIAL IMPORTANCE IN ACHIEVING THE AMBITIOUS GOALS OF PERSONALIZED/INDIVIDUALIZED MEDICINE AND FURTHER STANDARDIZED META-DATA AND BIG DATA COULD HELP DISENTANGLE AND ELUCIDATE THE PRECISE MECHANISMS OF UNDERLYING POTENTIAL PSA SEX-SPECIFIC DIFFERENCES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  5884  22 SYSTEMIC INFLAMMATION AND BIOLOGICAL AGING IN THE HEALTH AND RETIREMENT STUDY. CHRONIC, LOW-LEVEL SYSTEMIC INFLAMMATION ASSOCIATED WITH AGING, OR INFLAMMAGING, IS A RISK FACTOR FOR SEVERAL CHRONIC DISEASES AND MORTALITY. USING DATA FROM THE HEALTH AND RETIREMENT STUDY, WE GENERATED A CONTINUOUS LATENT VARIABLE FOR SYSTEMIC INFLAMMATION FROM SEVEN MEASURED INDICATORS OF INFLAMMATION AND EXAMINED ASSOCIATIONS WITH ANOTHER BIOMARKER OF BIOLOGICAL AGING, DNA METHYLATION AGE ACCELERATION MEASURED BY EPIGENETIC CLOCKS, AND 4-YEAR MORTALITY (N = 3,113). WE FOUND THAT GREATER SYSTEMIC INFLAMMATION WAS POSITIVELY ASSOCIATED WITH DNA METHYLATION AGE ACCELERATION FOR 10 OF THE 13 EPIGENETIC CLOCKS, AFTER ADJUSTMENT FOR SOCIODEMOGRAPHICS AND CHRONIC DISEASE RISK FACTORS. THE LATENT VARIABLE FOR SYSTEMIC INFLAMMATION WAS ASSOCIATED WITH 4-YEAR MORTALITY INDEPENDENT OF DNA METHYLATION AGE ACCELERATION AND WAS A BETTER PREDICTOR OF 4-YEAR MORTALITY THAN ANY OF THE EPIGENETIC CLOCKS EXAMINED, AS WELL AS MORTALITY RISK FACTORS, INCLUDING OBESITY AND MULTIMORBIDITY. INFLAMMAGING AND DNA METHYLATION AGE ACCELERATION MAY REPRESENT DIFFERENT BIOLOGICAL PROCESSES CONTRIBUTING TO MORTALITY RISK. LEVERAGING MULTIPLE MEASURED INFLAMMATION MARKERS TO CAPTURE INFLAMMAGING IS IMPORTANT FOR BIOLOGY OF AGING RESEARCH.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  4922  36 PARENTAL AGE AND RISK OF LYMPHOID NEOPLASMS. HIGH PARENTAL AGE AT CHILDBIRTH HAS REPEATEDLY BEEN LINKED TO CHILDHOOD MALIGNANCIES, WHILE FEW STUDIES HAVE FOCUSED ON THE OFFSPRING'S RISK OF ADULT CANCER. IN THIS POPULATION-BASED CASE-CONTROL STUDY, WE IDENTIFIED 32,000 PATIENTS WITH LYMPHOID NEOPLASMS, DIAGNOSED AT AGES 0-79 YEARS DURING THE PERIOD 1987-2011, AND 160,000 MATCHED CONTROLS IN SWEDEN. USING PROSPECTIVELY REGISTERED DATA ON THEIR FIRST-DEGREE RELATIVES, WE EVALUATED THE IMPACT OF PARENTAL AGE ON THE RISK OF LYMPHOID NEOPLASMS BY SUBTYPE. OVERALL, EACH 5-YEAR INCREMENT IN MATERNAL AGE WAS ASSOCIATED WITH A 3% INCREASE IN INCIDENCE OF OFFSPRING LYMPHOID NEOPLASMS (HAZARD RATIO = 1.03, 95% CONFIDENCE INTERVAL: 1.02, 1.04). THE ASSOCIATION WAS SIMILAR FOR PATERNAL AGE AND PRESENT EVEN AMONG INDIVIDUALS OLDER THAN 70 YEARS OF AGE AT DIAGNOSIS. STRATIFIED ANALYSES FURTHER REVEALED THAT THE ASSOCIATION WAS LIMITED TO CERTAIN SUBTYPES, MOSTLY OF INDOLENT NATURE. RISKS OF CHRONIC LYMPHOCYTIC LEUKEMIA, FOLLICULAR LYMPHOMA, AND MANTLE CELL LYMPHOMA WERE 5%-10% HIGHER PER 5-YEAR INCREMENT IN MATERNAL AGE, BUT NO ASSOCIATIONS WERE OBSERVED FOR ACUTE LYMPHOBLASTIC LEUKEMIA, PLASMA CELL NEOPLASMS, OR DIFFUSE LARGE B-CELL LYMPHOMA. THESE FINDINGS INDICATED THAT PRENATAL GENETIC OR EPIGENETIC CHANGES INFLUENCE RISK OF ADULT LYMPHOID NEOPLASMS AND SUGGEST A DIFFERENCE IN THIS ASSOCIATION BETWEEN AGGRESSIVE AND INDOLENT LYMPHOMA SUBTYPES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   437  31 ANTIGEN RECEPTOR STEREOTYPY IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE DISCOVERY OF ALMOST IDENTICAL OR 'STEREOTYPED' B-CELL RECEPTOR IMMUNOGLOBULINS (BCR IG) AMONG UNRELATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CEMENTED THE IDEA OF ANTIGEN SELECTION IN DISEASE ONTOGENY AND EVOLUTION. THE SYSTEMATIC ANALYSIS OF THE STEREOTYPY PHENOMENON IN CLL REVEALED THAT AROUND ONE-THIRD OF CLL PATIENTS MAY BE GROUPED INTO SUBSETS BASED ON SHARED SEQUENCE MOTIFS WITHIN THE VARIABLE HEAVY COMPLEMENTARITY DETERMINING REGION 3. STEREOTYPED SUBSETS DISPLAY A STRIKINGLY SIMILAR BIOLOGY OF THE LEUKEMIC CLONES, REFERRING TO MANY DIFFERENT LEVELS, FROM THE IMMUNOGENETIC AND GENETIC AND EXTENDING TO THE EPIGENETIC AND FUNCTIONAL LEVELS. EVEN MORE IMPORTANTLY, THE HOMOGENEITY OF STEREOTYPED SUBSETS HAS CLINICAL CONSEQUENCES AS PATIENTS ASSIGNED TO THE SAME STEREOTYPED SUBSET GENERALLY EXHIBIT AN OVERALL SIMILAR DISEASE COURSE AND OUTCOME. IN OTHER WORDS, STEREOTYPY-BASED PATIENT CLASSIFICATION OF CLL HAS ALREADY PROVIDED A MORE COMPARTMENTALIZED VIEW OF THIS OTHERWISE HETEROGENEOUS DISEASE AND CAN ASSIST IN REFINING PROGNOSTICATION MODELS. WHILE THIS IS RELEVANT ONLY FOR THE ONE-THIRD OF CASES EXPRESSING STEREOTYPED BCR IG; IN PRINCIPLE, HOWEVER, THE FINDINGS FROM FURTHER ANALYSIS OF THE STEREOTYPED SUBSETS MAY ALSO CONTRIBUTE TOWARDS IMPROVED UNDERSTANDING OF THE REMAINING NON-STEREOTYPED FRACTION OF CLL PATIENTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  2106  36 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY.	2019	
                                          
19   524  38 ASSOCIATIONS OF BDNF GENOTYPE AND PROMOTER METHYLATION WITH ACUTE AND LONG-TERM STROKE OUTCOMES IN AN EAST ASIAN COHORT. BACKGROUND: BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN POSTSTROKE RECOVERY. BDNF SECRETION IS INFLUENCED BY GENETIC AND EPIGENETIC PROFILES. THIS STUDY AIMED TO INVESTIGATE WHETHER BDNF VAL66MET POLYMORPHISM AND PROMOTER METHYLATION STATUS WERE ASSOCIATED WITH OUTCOMES AT TWO WEEKS AND ONE YEAR AFTER STROKE. METHODS AND FINDINGS: A TOTAL OF 286 PATIENTS WERE EVALUATED AT THE TIME OF ADMISSION AND TWO WEEKS AFTER STROKE, AND 222 (78%) WERE FOLLOWED ONE YEAR LATER IN ORDER TO EVALUATE CONSEQUENCES OF STROKE AT BOTH ACUTE AND CHRONIC STAGES. STROKE OUTCOMES WERE DICHOTOMISED INTO GOOD AND POOR BY THE MODIFIED RANKIN SCALE. STROKE SEVERITY (NATIONAL INSTITUTES OF HEALTH STROKE SCALE), PHYSICAL DISABILITY (BARTHEL INDEX), AND COGNITIVE FUNCTION (MINI-MENTAL STATE EXAMINATION) WERE MEASURED. ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION STATUS ON STROKE OUTCOMES AND ASSESSMENT SCALE SCORES WERE INVESTIGATED USING LOGISTIC REGRESSION, REPEATED MEASURES ANOVA AND PARTIAL CORRELATION TESTS. BDNF VAL66MET POLYMORPHISM WAS INDEPENDENTLY ASSOCIATED WITH POOR OUTCOME AT 2 WEEKS AND AT 1 YEAR, AND WITH WORSENING PHYSICAL DISABILITY AND COGNITIVE FUNCTION OVER THAT PERIOD. HIGHER BDNF PROMOTER METHYLATION STATUS WAS INDEPENDENTLY ASSOCIATED WITH WORSE OUTCOMES AT 1 YEAR, AND WITH THE WORSENING OF PHYSICAL DISABILITY AND COGNITIVE FUNCTION. NO SIGNIFICANT GENOTYPE-METHYLATION INTERACTIONS WERE FOUND. CONCLUSIONS: A ROLE FOR BDNF IN POSTSTROKE RECOVERY WAS SUPPORTED, AND CLINICAL UTILITY OF BDNF GENETIC AND EPIGENETIC PROFILE AS PROGNOSTIC BIOMARKERS AND A TARGET FOR DRUG DEVELOPMENT WAS SUGGESTED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  2677  26 EVALUATING THE CHALLENGES AND REPRODUCIBILITY OF STUDIES INVESTIGATING DNA METHYLATION SIGNATURES OF PSYCHOLOGICAL STRESS. PSYCHOLOGICAL STRESS CAN INCREASE THE RISK OF A WIDE RANGE OF NEGATIVE HEALTH OUTCOMES. STUDIES HAVE BEEN COMPLETED TO DETERMINE IF DNA METHYLATION CHANGES OCCUR IN THE HUMAN BRAIN BECAUSE OF STRESS AND ARE ASSOCIATED WITH LONG-TERM EFFECTS AND DISEASE, BUT RESULTS HAVE BEEN INCONSISTENT. HUMAN CANDIDATE GENE STUDIES (150) AND EPIGENOME-WIDE ASSOCIATION STUDIES (67) WERE SYSTEMATICALLY EVALUATED TO ASSESS HOW DNA METHYLATION IS IMPACTED BY STRESS DURING THE PRENATAL PERIOD, EARLY CHILDHOOD AND ADULTHOOD. THE ASSOCIATION BETWEEN DNA METHYLATION OF NR3C1 EXON 1F AND CHILD MALTREATMENT AND EARLY LIFE ADVERSITY WAS WELL DEMONSTRATED, BUT OTHER GENES DID NOT EXHIBIT A CLEAR ASSOCIATION. THE REPRODUCIBILITY OF INDIVIDUAL CPG SITES IN EPIGENOME-WIDE ASSOCIATION STUDIES WAS ALSO POOR. HOWEVER, BIOLOGICAL PATHWAYS, INCLUDING STRESS RESPONSE, BRAIN DEVELOPMENT AND IMMUNITY, HAVE BEEN CONSISTENTLY IDENTIFIED ACROSS DIFFERENT STRESSORS THROUGHOUT THE LIFE SPAN. FUTURE STUDIES WOULD BENEFIT FROM THE INCREASED SAMPLE SIZE, LONGITUDINAL DESIGN, STANDARDIZED METHODOLOGY, OPTIMAL QUALITY CONTROL, AND IMPROVED STATISTICAL PROCEDURES.	2022