1  5245 146 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  5243  40 PROGNOSTIC IMPACT OF EPIGENETIC CLASSIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: THE CASE OF SUBSET #2. BASED ON THE METHYLATION STATUS OF 5 SINGLE CPG SITES, A NOVEL EPIGENETIC CLASSIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WAS RECENTLY PROPOSED, CLASSIFYING CLL PATIENTS INTO 3 CLINICO-BIOLOGICAL SUBGROUPS WITH DIFFERENT OUTCOME, TERMED MEMORY LIKE CLL (M-CLL), NAIVE LIKE CLL (N-CLL), AND A THIRD INTERMEDIATE CLL SUBGROUP (I-CLL). WHILE M-CLL AND N-CLL PATIENTS AT LARGE CORRESPONDED TO PATIENTS CARRYING MUTATED AND UNMUTATED IGHV GENES, RESPECTIVELY, LIMITED INFORMATION EXISTS REGARDING THE LESS DEFINED I-CLL GROUP. USING PYROSEQUENCING, WE INVESTIGATED THE PROGNOSTIC IMPACT OF THE PROPOSED 5 CPG SIGNATURE IN A WELL-CHARACTERIZED CLL COHORT (135 CASES), INCLUDING IGHV-MUTATED AND UNMUTATED PATIENTS AS WELL AS CLINICALLY AGGRESSIVE STEREOTYPED SUBSET #2 PATIENTS. OVERALL, WE CONFIRMED THE SIGNATURE'S ASSOCIATION WITH ESTABLISHED PROGNOSTIC MARKERS. MOREOVER, IN THE PRESENCE OF THE IGHV MUTATIONAL STATUS, THE EPIGENETIC SIGNATURE REMAINED INDEPENDENTLY ASSOCIATED WITH BOTH TIME-TO-FIRST-TREATMENT AND OVERALL SURVIVAL IN MULTIVARIATE ANALYSES. AS A PRIME FINDING, WE OBSERVED THAT SUBSET #2 PATIENTS WERE PREDOMINANTLY CLASSIFIED AS I-CLL, PROBABLY REFLECTING THEIR BORDERLINE IGHV MUTATIONAL STATUS (97-99% GERMLINE IDENTITY), THOUGH HAVING A SIMILARLY POOR PROGNOSIS AS N-CLL PATIENTS. IN SUMMARY, WE VALIDATED THE EPIGENETIC CLASSIFIER AS AN INDEPENDENT FACTOR IN CLL PROGNOSTICATION AND PROVIDE FURTHER EVIDENCE THAT SUBSET #2 IS A MEMBER OF THE I-CLL GROUP, HENCE SUPPORTING THE EXISTENCE OF A THIRD, INTERMEDIATE EPIGENETIC SUBGROUP.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  1737  42 EARLY DETECTION OF ACCELERATED AGING AND CELLULAR DECLINE (AACD): A CONSENSUS STATEMENT. THE CELLULAR HALLMARKS OF ACCELERATED AGING AND THEIR CLINICAL EXPRESSION MAY BE GROUPED USING THE TERMS 'ACCELERATED AGING AND CELLULAR DECLINE' (AACD) AND/OR 'AGE-ASSOCIATED CELLULAR DECLINE'. THIS CONSTRUCT IS DESIGNED TO CAPTURE THE BIOLOGICAL BACKGROUND PREDISPOSING THE DEVELOPMENT OF AGE-RELATED CONDITIONS. BY CLASSIFYING RISK FACTORS, EARLY INDICATORS, AND CLINICAL DIFFERENTIATORS OF AACD THROUGH EXPERT CONSENSUS, THIS STUDY AIMED TO IDENTIFY THE SIGNS, SYMPTOMS, AND MARKERS INDICATIVE OF AACD. IN DOING SO, THIS WORK PAVES THE WAY FOR FUTURE IMPLEMENTATION OF THE AACD CONCEPT IN THE CLINICAL AND RESEARCH SETTINGS. AN INTERDISCIPLINARY PANEL OF EXPERTS WITH CLINICAL AND RESEARCH EXPERTISE WAS SELECTED TO PARTICIPATE IN A VIRTUAL WORKSHOP TO DISCUSS AACD. A MODIFIED NOMINAL GROUP TECHNIQUE WAS USED TO ESTABLISH CONSENSUS AMONG THE GROUP. AN EXTENDED GROUP OF INTERNATIONAL EXPERTS CRITICALLY REVIEWED AN EARLY DRAFT OF THE MANUSCRIPT, AND THEIR FEEDBACK WAS THEN INCORPORATED INTO THE MODEL. EXPERTS IDENTIFIED 13 FACTORS PREDISPOSING TO OR CLINICALLY MANIFESTING AACD. AMONG THESE, CHRONIC DISEASES, OBESITY, AND UNFAVORABLE GENETIC BACKGROUND WERE CONSIDERED AS THE MOST IMPORTANT. THERE WAS A CONSENSUS THAT A GRADUAL AND NONSPECIFIC DEVELOPMENT OFTEN CHARACTERIZES AACD, MAKING ITS CLINICAL DETECTION POTENTIALLY CHALLENGING. IN ADDITION, SIGNS AND SYMPTOMS MIGHT HAVE MULTIFACTORIAL CAUSES AND OVERLAPPING ORIGINS, SUCH AS GENETIC AND EPIGENETIC PREDISPOSITIONS. AS A RESULT, AN INITIAL CHECKLIST WAS OUTLINED, LISTING CLINICAL FACTORS OF SPECIAL RELEVANCE (E.G., FATIGUE, LOW QUALITY OF SLEEP, AND LOW MOOD) TO REPRESENT EARLY MANIFESTATIONS OF THE ORGANISM'S EXHAUSTION, WHICH ARE ALSO FREQUENTLY NEGLECTED IN THE CLINICAL SETTING. DIFFERENTIATING AACD FROM OTHER CONDITIONS IS ESSENTIAL. THE USE OF A COMBINATION OF BIOMARKERS WAS PROPOSED AS A VIABLE METHOD IN A TWO-STEP PROCESS OF DIFFERENTIATION: 1) IDENTIFICATION OF EARLY AACD CLINICAL INDICATORS, FOLLOWED BY 2) SYMPTOM AND BIOMARKER CONFIRMATION WITH A FOCUS ON SYSTEM DOMAINS (TO BE POTENTIALLY TARGETED BY FUTURE SPECIFIC INTERVENTIONS). ALTHOUGH THE AACD CONSTRUCT IS NOT YET READY FOR ROUTINE USE IN CLINICAL PRACTICE, ITS OPERATIONALIZATION MAY SUPPORT THE EARLY IDENTIFICATION OF AGE-RELATED CONDITIONS (WHEN THIS MIGHT STILL BE AMENABLE TO REVERSION) AND ALSO ENCOURAGE PREVENTATIVE INTERVENTIONS. FURTHER INVESTIGATION IS NEEDED TO ESTABLISH SPECIFIC BIOMARKERS THAT CONFIRM INDEPENDENT RISK FACTORS FOR AACD AND PROVIDE A MORE DEFINITIVE STRUCTURE TO THE CONCEPT OF AACD (AND AGE-ASSOCIATED CELLULAR DECLINE).	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  3208  35 HEAD CIRCUMFERENCE AS AN EPIGENETIC RISK FACTOR FOR MATERNAL NUTRITION. NUTRITION INDICATORS FOR MALNUTRITION CAN BE SCREENED BY MANY SIGNS SUCH AS STUNTING, UNDERWEIGHT OR OBESITY, MUSCLE WASTING, AND LOW CALORIC AND NUTRIENTS INTAKE. THOSE DEFICIENCIES ARE ALSO ASSOCIATED WITH LOW SOCIOECONOMIC STATUS. ANTHROPOMETRY CAN ASSESS NUTRITIONAL STATUS BY MATERNAL WEIGHT MEASUREMENTS DURING PREGNANCY. HOWEVER, MOST STUDIES HAVE FOCUSED PRIMARILY ON IDENTIFYING CHANGES IN WEIGHT OR BODY MASS INDEX (BMI), AND THEIR EFFECTS ON NEONATAL MEASURES AT PRESENT TIME. WHEREAS HEAD CIRCUMFERENCE (HC) HAS BEEN ASSOCIATED WITH NUTRITION IN THE PAST. WHEN THE MOTHER WAS EXPOSED TO POOR NUTRITION AND UNFAVORABLE SOCIAL CONDITIONS DURING FETAL LIFE, IT WAS HYPOTHESIZED THAT THE INTERGENERATIONAL CYCLE WAS POTENTIALLY MEDIATED BY EPIGENETIC MECHANISMS. TO INVESTIGATE THIS THEORY, MATERNAL HEAD CIRCUMFERENCE (MHC) WAS ASSOCIATED WITH NEONATAL HEAD CIRCUMFERENCE (NHC) IN PREGNANT WOMEN WITHOUT PREEXISTING CHRONIC CONDITIONS, DIFFERENTIATED BY SOCIODEMOGRAPHIC CHARACTERISTICS. A MULTIPLE LINEAR REGRESSION MODEL SHOWED THAT EACH 1 CM-INCREASE IN MHC CORRELATED WITH A 0.11 CM INCREASE IN NHC (BETA95% CI 0.07 TO 0.15). NOTWITHSTANDING, ASSOCIATIONS BETWEEN MATERNAL AND NEONATAL ANTHROPOMETRICS ACCORDING TO GESTATIONAL AGE AT BIRTH HAVE BEEN EXTENSIVELY EXPLAINED. PATH ANALYSIS SHOWED THE INFLUENCE OF SOCIAL STATUS AND THE LATENT VARIABLE WAS SOCIOECONOMIC STATUS. A MODEL OF MATERNAL HEIGHT AND HEAD CIRCUMFERENCE WAS TESTED WITH EFFECTS ON NEONATAL HC. THE SOCIAL VARIABLE LACKED SIGNIFICANCE TO PREDICT NEONATAL HC IN THE TOTAL SAMPLE (P = 0.212) AND IN THE SOUTH/SOUTHEAST (P = 0.095), IN CONTRAST TO THE NORTHEAST (P = 0.047). THIS STUDY HIGHLIGHTS THE POTENTIAL INTERGENERATIONAL INFLUENCE OF MATERNAL NUTRITION ON HC, SUGGESTING THAT MATERNAL NUTRITION MAY BE MORE RELEVANT IN FAMILIES WITH MAJOR SOCIAL VULNERABILITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  1040  47 CLINICAL AND GENETIC CHARACTERIZATION OF EPSTEIN-BARR VIRUS-ASSOCIATED T/NK-CELL LYMPHOPROLIFERATIVE DISEASES. BACKGROUND: EPSTEIN-BARR VIRUS (EBV)-ASSOCIATED T-/NATURAL KILLER (T/NK)-CELL LYMPHOPROLIFERATIVE DISEASES CLINICALLY TAKE ON VARIOUS FORMS, RANGING FROM AN INDOLENT COURSE TO AN AGGRESSIVE CONDITION. OBJECTIVE: CLINICALLY, FAILURE TO ESTABLISH PRECISE DIAGNOSIS AND PROVIDE PROPER TREATMENT MAKES IT DIFFICULT TO HELP PATIENTS. WE SOUGHT TO BETTER UNDERSTAND THE UNDERLYING PATHOGENESIS AND TO IDENTIFY GENETIC PROGNOSTIC FACTORS TO ACHIEVE BETTER TREATMENT EFFICACY. METHODS: IN THIS STUDY, 119 CASES OF EBV-ASSOCIATED LYMPHOPROLIFERATIVE DISEASES, INCLUDING EBV-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (N = 46) AND CHRONIC ACTIVE EBV DISEASE OF T/NK CELL TYPE (N = 73), WERE RETROSPECTIVELY EXAMINED. RESULTS: ADULTS AGED >20 YEARS AT ONSET ACCOUNTED FOR 71.4% OF OUR COHORT. ABOUT 54.6% PATIENTS WITH UNFAVORABLE OVERALL SURVIVAL DEVELOPED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND HAD HIGHER PLASMA EBV LOAD. ALLOGENIC HEMATOPOIETIC STEM-CELL TRANSPLANTATION WAS THE SOLE INDEPENDENT FAVORABLE FACTOR. WE SYSTEMATICALLY SCREENED GERMLINE AND SOMATIC ABERRATIONS BY WHOLE-EXOME AND TARGETED SEQUENCING. AMONG 372 ANTIVIRAL IMMUNITY GENES, GERMLINE VARIANTS OF 8 GENES WERE SIGNIFICANTLY ENRICHED. FROM A PANEL OF 24 DRIVER GENES, SOMATIC MUTATIONS WERE FREQUENTLY IDENTIFIED IN DOMINANT EBV-INFECTED T/NK CELLS. PATIENTS CARRYING ANY GERMLINE/SOMATIC ABERRATIONS IN EPIGENETIC MODIFIERS AND RIG-I-LIKE RECEPTOR (RLR) PATHWAY HAD WORSE OVERALL SURVIVAL THAN THOSE WITHOUT 2 TYPE ABERRATIONS. IMPORTANTLY, PATIENTS WITH IFIH1 AND/OR DDX3X ABERRATIONS IN THE RLR PATHWAY HAD HIGHER PLASMA AND NK-CELL EBV LOAD. KNOCKDOWN OF DDX3X IN NKYS CELLS DOWNREGULATED RLR SIGNALING ACTIVITIES AND ELEVATED THE EXPRESSION OF EBV-ENCODED ONCOGENES SUCH AS LMP1 AND EBNA1. CONCLUSION: GENETIC DEFECTS WERE PREVALENT IN ADULT EBV-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS PATIENTS AND PATIENTS WITH CHRONIC ACTIVE EBV DISEASE OF T/NK CELL TYPE; THESE DEFECTS WERE ASSOCIATED WITH UNFAVORABLE PROGNOSIS. THESE FINDINGS CAN HELP CLINICIANS WORK OUT MORE PRECISE STAGING OF THE CONDITION AND PROVIDE NEW INSIGHTS INTO THESE EBV-ASSOCIATED DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  4922  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  1960  35 EPIGENETIC AGING IN CHILDREN FROM A SMALL-SCALE FARMING SOCIETY IN THE CONGO BASIN: ASSOCIATIONS WITH CHILD GROWTH AND FAMILY CONFLICT. DEVELOPMENTAL ENVIRONMENTS INFLUENCE INDIVIDUALS' LONG-TERM HEALTH TRAJECTORIES, AND THERE IS INCREASING EMPHASIS ON UNDERSTANDING THE BIOLOGICAL PATHWAYS THROUGH WHICH THIS OCCURS. EPIGENETIC AGING EVALUATES DNA METHYLATION AT A SUITE OF DISTINCT CPG SITES IN THE GENOME, AND EPIGENETIC AGE ACCELERATION (EAA) IS LINKED TO HEIGHTENED CHRONIC MORBIDITY AND MORTALITY RISKS IN ADULTS. CONSEQUENTLY, EAA PROVIDES INSIGHTS ON TRAJECTORIES OF BIOLOGICAL AGING, WHICH EARLY LIFE EXPERIENCES MAY HELP SHAPE. HOWEVER, FEW STUDIES HAVE MEASURED CORRELATES OF CHILDREN'S EPIGENETIC AGING, ESPECIALLY OUTSIDE OF THE U.S. AND EUROPE. IN PARTICULAR, LITTLE IS KNOWN ABOUT HOW CHILDREN'S GROWTH AND DEVELOPMENT RELATE TO EAA IN ECOLOGIES IN WHICH ENERGETIC AND PATHOGENIC STRESSORS ARE COMMONPLACE. WE STUDIED EAA FROM DRIED BLOOD SPOTS AMONG BONDONGO CHILDREN (N = 54) RESIDING IN A SMALL-SCALE, FISHER-FARMER SOCIETY IN A REMOTE REGION OF THE REPUBLIC OF THE CONGO. HERE, INFECTIOUS DISEASE BURDENS AND THEIR RESULTANT ENERGY DEMANDS ARE HIGH. CHILDREN WHO WERE HEAVIER FOR HEIGHT OR TALLER FOR AGE, RESPECTIVELY, EXHIBITED GREATER EAA, INCLUDING INTRINSIC EAA, WHICH IS CONSIDERED TO MEASURE EAA INTERNAL TO CELLS. FURTHERMORE, WE FOUND THAT CHILDREN IN FAMILIES WITH MORE CONFLICT BETWEEN PARENTS HAD GREATER INTRINSIC EAA. THESE RESULTS SUGGEST THAT IN CONTEXTS IN WHICH LIMITED ENERGY MUST BE ALLOCATED TO COMPETING DEMANDS, MORE INVESTMENT IN GROWTH MAY COINCIDE WITH GREATER EAA, WHICH PARALLELS FINDINGS IN EUROPEAN CHILDREN WHO DO NOT FACE SIMILAR ENERGETIC CONSTRAINTS. OUR FINDINGS ALSO INDICATE THAT ASSOCIATIONS BETWEEN ADVERSE FAMILY ENVIRONMENTS AND GREATER INTRINSIC EAA WERE NONETHELESS OBSERVABLE BUT ONLY AFTER ADJUSTMENT FOR COVARIATES RELEVANT TO THE ENERGETICALLY AND IMMUNOLOGICALLY DEMANDING NATURE OF THE LOCAL ECOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  1956  38 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	
                                                                                                                                                 
9  6066  30 THE DEVELOPMENTAL ORIGINS OF HEALTH AND CHRONIC KIDNEY DISEASE: CURRENT STATUS AND PRACTICES IN JAPAN. THE CONCEPT OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) VIEWS UNFAVORABLE PERINATAL CIRCUMSTANCES AS CONTRIBUTING TO THE DEVELOPMENT OF DISEASES IN LATER LIFE. IT IS WELL KNOWN THAT SUCH UNFAVORABLE CIRCUMSTANCES PLAY AN IMPORTANT ROLE AS A RISK FACTOR FOR CHRONIC KIDNEY DISEASE (CKD) IN INFANTS BORN WITH PREMATURITY. LOW BIRTHWEIGHT (LBW) IS BELIEVED TO BE A POTENTIAL CONTRIBUTOR TO CKD IN ADULTHOOD. PRETERM AND/OR LBW INFANTS ARE BORN WITH INCOMPLETE NEPHROGENESIS. AS A RESULT, THE NUMBER OF NEPHRONS IS LOW. THE POOR INTRAUTERINE ENVIRONMENT ALSO CAUSES EPIGENETIC CHANGES THAT ADVERSELY AFFECT POSTNATAL RENAL FUNCTION. AFTER BIRTH, HYPERFILTRATION OF INDIVIDUAL NEPHRONS DUE TO LOW NEPHRON NUMBERS CAUSES PROTEINURIA AND SECONDARY GLOMERULOSCLEROSIS. FURTHERMORE, THE RISK OF CKD INCREASES AS RENAL DAMAGE TAKES A SECOND HIT FROM EXPOSURE TO NEPHROTOXIC SUBSTANCES AND ACQUIRED INSULTS SUCH AS ACUTE KIDNEY INJURY AFTER BIRTH AMONG INFANTS IN NEONATAL INTENSIVE CARE. MEANWHILE, UNFORTUNATELY, RECENT STUDIES HAVE SHOWN THAT THE NUMBER OF NEPHRONS IN HEALTHY JAPANESE INDIVIDUALS IS APPROXIMATELY TWO-THIRDS LOWER THAN THAT IN PREVIOUS REPORTS. THIS MEANS THAT JAPANESE PREMATURE INFANTS ARE CLEARLY AT A HIGH RISK OF DEVELOPING CKD IN LATER LIFE. RECENTLY, SEVERAL DOHAD-RELATED CKD STUDIES FROM JAPANESE RESEARCHERS HAVE BEEN REPORTED. HERE, WE SUMMARIZE THE RELEVANCE OF CKD IN CONJUNCTION WITH DOHAD AND REVIEW RECENT STUDIES THAT HAVE EXAMINED THE IMPACT OF THE UPWARD LBW TREND IN JAPAN ON RENAL HEALTH.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  5085  34 PILOT STUDY OF ABSOLUTE TELOMERE LENGTHS IN PRETERM INFANTS. BACKGROUND: ANNUALLY, APPROXIMATELY 15 MILLION BABIES ARE BORN PRETERM (<37 WEEKS GESTATIONAL AGE) GLOBALLY. IN THE NEONATAL INTENSIVE CARE UNIT (NICU) ENVIRONMENT, INFANTS ARE EXPOSED TO REPEATED STRESSFUL OR PAINFUL PROCEDURES AS PART OF ROUTINE LIFESAVING CARE. THESE PROCEDURES HAVE BEEN ASSOCIATED WITH EPIGENETIC ALTERATIONS THAT MAY LEAD TO AN INCREASED RISK OF NEURODEVELOPMENTAL DISORDERS. TELOMERE LENGTH HAS BEEN NEGATIVELY ASSOCIATED WITH ADVERSE LIFE EXPERIENCES IN STUDIES OF ADULTS. OBJECTIVES: THIS PILOT STUDY AIMED TO DESCRIBE TELOMERE LENGTH IN A SAMPLE OF PRETERM INFANTS AT NICU DISCHARGE AND EXAMINE ANY ASSOCIATIONS WITH PAIN, FEEDING METHOD, AND NEURODEVELOPMENT. METHODS: THIS DESCRIPTIVE PILOT STUDY SAMPLE INCLUDES BASELINE ABSOLUTE TELOMERE LENGTH (ATL) OF 36 PRETERM INFANTS IMMEDIATELY PRIOR TO DISCHARGE. QUANTITATIVE POLYMERASE CHAIN REACTION WAS USED TO DETERMINE ATL. INFANT DEMOGRAPHICS, PAIN/STRESS, TYPE OF FEEDING, ANTIBIOTIC USE, NEURODEVELOPMENT, AND BUCCAL SWAB DATA WERE COLLECTED. DESCRIPTIVE DATA ANALYSIS WAS USED TO DESCRIBE THE TELOMERE LENGTH USING GRAPHS. RESULTS: AMONG OUR PRETERM INFANT SAMPLES, THE MEAN ATL WAS FAR GREATER THAN THE AVERAGE ADULT TELOMERE LENGTH. ALTHOUGH NO SIGNIFICANT ASSOCIATIONS WERE FOUND BETWEEN ATL AND PAIN, FEEDING METHOD, AND NEURODEVELOPMENT, A TREND BETWEEN SEX WAS NOTED WHERE MALE TELOMERE LENGTHS WERE SHORTER THAN FEMALES AS THEY AGED. DISCUSSION: THIS IS ONE OF FEW STUDIES TO EVALUATE PRETERM INFANT TELOMERE LENGTH. ALTHOUGH OTHER RESEARCHERS HAVE USED RELATIVE TELOMERE LENGTH, WE USED THE MORE ACCURATE ATL. WE FOUND NONSIGNIFICANT SHORTER TELOMERE LENGTHS AMONG MALES. ADDITIONAL LARGE-SCALE, LONGITUDINAL STUDIES ARE NEEDED TO BETTER IDENTIFY THE PREDICTORS OF TELOMERE LENGTH AT THE TIME OF DISCHARGE FROM NICU.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  3294  35 HIGH INCIDENCE OF MGMT AND RARBETA PROMOTER METHYLATION IN PRIMARY GLIOBLASTOMAS: ASSOCIATION WITH HISTOPATHOLOGICAL CHARACTERISTICS, INFLAMMATORY MEDIATORS AND CLINICAL OUTCOME. GLIOBLASTOMAS, THE MOST FREQUENT PRIMARY BRAIN TUMORS IN ADULTS, ARE CHARACTERIZED BY A HIGHLY AGGRESSIVE, INFLAMMATORY AND ANGIOGENIC PHENOTYPE. METHYLATION OF CPG ISLANDS IN CANCER-RELATED GENES MAY SERVE AS AN EPIGENETIC BIOMARKER FOR GLIOBLASTOMA DIAGNOSIS AND PROGNOSIS. THE AIM OF THIS STUDY WAS TO ANALYZE THE METHYLATION STATUS OF FOUR CRITICAL TUMOR-ASSOCIATED GENES (MGMT, RARBETA, RASSF1A, CDH13), AND INVESTIGATE POSSIBLE LINKS WITH INFLAMMATORY (INTERLEUKIN [IL]-6, IL-8) AND ANGIOGENIC MEDIATORS (VASCULAR ENDOTHELIAL GROWTH FACTOR [VEGF], CYCLOOXYGENASE [COX]-2) AND CLINICAL OUTCOME IN 23 GLIOMA SAMPLES (6 GRADE II ASTROCYTOMAS, 17 GRADE IV GLIOBLASTOMAS). RARBETA AND MGMT GENES WERE MORE FREQUENTLY METHYLATED IN 70.58% AND 58.8% OF GLIOBLASTOMAS, RESPECTIVELY. RASSF1A AND CDH13 DISPLAYED A SIMILAR METHYLATION FREQUENCY (23.52%) IN GLIOBLASTOMAS. NO GENE METHYLATION WAS OBSERVED IN GRADE II ASTROCYTOMAS. TUMOR GRADE CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION (P = 0.005 AND P = 0.019, RESPECTIVELY) AND THE EXTENT OF NECROSIS (P = 0.001 AND P = 0.003). INTERESTINGLY, THE MARKER OF CHRONIC INFLAMMATION, IL-6, WAS POSITIVELY ASSOCIATED WITH METHYLATION OF MGMT (P = 0.004), RARBETA (P = 0.002), AND RASSF1A (P = 0.0081) AS WELL AS THE TOTAL NUMBER OF METHYLATED GENES (P < 0.0001), INDICATING THE IMPORTANT ROLE OF IL-6 IN MAINTAINING PROMOTER METHYLATION OF THESE GENES. VEGF EXPRESSION CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION ALTHOUGH THESE RELATIONSHIPS WERE OF MARGINAL SIGNIFICANCE (P = 0.0679 AND P = 0.0757). KAPLAN-MEIER UNIVARIATE SURVIVAL ANALYSIS INDICATED AN UNFAVORABLE SURVIVAL PERIOD IN PATIENTS WITH MGMT METHYLATION COMPARED WITH THOSE WITHOUT METHYLATION (P = 0.0474). OUR STUDY HIGHLIGHTS THE IMPLICATION OF MGMT AND RARBETA METHYLATION IN THE AGGRESSIVE PHENOTYPE OF PRIMARY GLIOBLASTOMAS. THE ASSOCIATION OF MGMT METHYLATION WITH CLINICAL OUTCOME INDICATES ITS POTENTIAL PROGNOSTIC VALUE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12   649  31 BIRTHWEIGHT, MATERNAL WEIGHT TRAJECTORIES AND GLOBAL DNA METHYLATION OF LINE-1 REPETITIVE ELEMENTS. LOW BIRTHWEIGHT, PREMATURE BIRTH, INTRAUTERINE GROWTH RETARDATION, AND MATERNAL MALNUTRITION HAVE BEEN RELATED TO AN INCREASED RISK OF CARDIOVASCULAR DISEASE, TYPE 2 DIABETES MELLITUS, OBESITY, AND NEUROPSYCHIATRIC DISORDERS LATER IN LIFE. CONVERSELY, HIGH BIRTHWEIGHT HAS BEEN LINKED TO FUTURE RISK OF CANCER. GLOBAL DNA METHYLATION ESTIMATED BY THE METHYLATION OF REPETITIVE SEQUENCES IN THE GENOME IS AN INDICATOR OF SUSCEPTIBILITY TO CHRONIC DISEASES. WE USED DATA AND BIOSPECIMENS FROM AN EPIGENETIC BIRTH COHORT TO EXPLORE THE ASSOCIATION BETWEEN TRAJECTORIES OF FETAL AND MATERNAL WEIGHT AND LINE-1 METHYLATION IN 319 MOTHER-CHILD DYADS. NEWBORNS WITH LOW OR HIGH BIRTHWEIGHT HAD SIGNIFICANTLY LOWER LINE-1 METHYLATION LEVELS IN THEIR CORD BLOOD COMPARED TO NORMAL WEIGHT INFANTS AFTER ADJUSTING FOR GESTATIONAL AGE, SEX OF THE CHILD, MATERNAL AGE AT DELIVERY, AND MATERNAL SMOKING DURING PREGNANCY (P = 0.007 AND P = 0.036, RESPECTIVELY), BUT THE MAGNITUDE OF THE DIFFERENCE WAS SMALL. INFANTS BORN PREMATURELY ALSO HAD LOWER LINE-1 METHYLATION LEVELS IN CORD BLOOD COMPARED TO TERM INFANTS, AND THIS DIFFERENCE, THOUGH SMALL, WAS STATISTICALLY SIGNIFICANT (P = 0.004). WE DID NOT FIND IMPORTANT ASSOCIATIONS BETWEEN MATERNAL PREPREGNANCY BMI OR GESTATIONAL WEIGHT GAIN AND GLOBAL METHYLATION OF THE CORD BLOOD OR FETAL PLACENTAL TISSUE. IN CONCLUSION, WE FOUND SIGNIFICANT DIFFERENCES IN CORD BLOOD LINE-1 METHYLATION AMONG NEWBORNS WITH LOW AND HIGH BIRTHWEIGHT AS WELL AS AMONG PREMATURELY BORN INFANTS. FUTURE STUDIES MAY ELUCIDATE WHETHER CHROMOSOMAL INSTABILITIES OR OTHER FUNCTIONAL CONSEQUENCES OF THESE CHANGES CONTRIBUTE TO THE INCREASED RISK OF CHRONIC DISEASES AMONG INDIVIDUALS WITH THESE CHARACTERISTICS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13  3560  42 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    25  30 A 3' TRNA-DERIVED FRAGMENT PRODUCED BY TRNA(LEUAAG) AND TRNA(LEUTAG) IS ASSOCIATED WITH POOR PROGNOSIS IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA, INDEPENDENTLY OF CLASSICAL PROGNOSTIC FACTORS. OBJECTIVE: 3' TRNA-DERIVED FRAGMENTS (3' TRFS) ARE IMPORTANT EPIGENETIC REGULATORS IN NORMAL AND PATHOLOGICAL CONDITIONS. IN THIS STUDY, WE AIMED TO EXPLORE THE POTENTIAL VALUE OF A 3' TRF AS A PROGNOSTIC AND/OR SCREENING BIOMARKER FOR B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL). METHODS: PUBLICLY AVAILABLE NEXT-GENERATION SEQUENCING DATA FROM 20 B-CLL CASES WERE ANALYZED, FOLLOWED BY PREDICTION OF TARGETS OF THE MOST ABUNDANTLY AND UBIQUITOUSLY EXPRESSED 3' TRFS, LEADING TO SELECTION OF TRF-LEU(AAG/TAG) . PBMCS WERE ISOLATED FROM BLOOD SAMPLES OF 91 B-CLL PATIENTS AND 43 NON-LEUKEMIC DONORS, FOLLOWED BY TOTAL RNA EXTRACTION, IN-VITRO POLYADENYLATION, AND FIRST-STRAND CDNA SYNTHESIS. NEXT, A REAL-TIME QUANTITATIVE PCR (QPCR) ASSAY WAS DEVELOPED FOR THE ACCURATE QUANTIFICATION OF TRF-LEU(AAG/TAG) AND APPLIED IN ALL SAMPLES, PRIOR TO BIOSTATISTICAL ANALYSIS. RESULTS: HIGH TRF-LEU(AAG/TAG) LEVELS ARE ASSOCIATED WITH INFERIOR OVERALL SURVIVAL (OS) OF B-CLL PATIENTS. THE UNFAVORABLE SIGNIFICANCE OF TRF-LEU(AAG/TAG) WAS INDEPENDENT OF ESTABLISHED PROGNOSTIC FACTORS IN B-CLL. STRATIFIED KAPLAN-MEIER OS ANALYSIS UNCOVERED THE UNFAVORABLE PROGNOSTIC ROLE OF HIGH TRF-LEU(AAG/TAG) LEVELS FOR PATIENTS IN BINET A OR RAI I STAGE, NEGATIVE CD38 EXPRESSION, MUTATED, OR UNMUTATED IGHV GENOMIC LOCUS. CONCLUSION: OUR APPROACH REVEALED THE INDEPENDENT PROGNOSTIC VALUE OF A PARTICULAR 3' TRF, DERIVED FROM TRNA(LEUAAG) AND TRNA(LEUTAG) (TRF-LEU(AAG/TAG) ) IN B-CLL.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  4417  31 MOLECULAR AND CLINICOPATHOLOGICAL ASPECTS OF PROSTATE CANCER IN BULGARIAN PROBANDS. TO CORRELATE THE MOLECULAR DATA TO THE CLINICOPATHOLOGICAL PARAMETERS IN BULGARIAN PROSTATE CANCER PATIENTS. PCA3 OVEREXPRESSION, TMPRSS2-ERG GENE FUSION, GSTP1 PROMOTER HYPERMETHYLATION, SOMATIC MUTATIONS IN THE AR GENE AND THE IVS1-27G > A POLYMORPHISM IN THE KLF6 GENE WERE STUDIED. A TOTAL OF 148 PATIENTS WERE ANALYZED: 16 AGGRESSIVE PCA, 83 NON-AGGRESSIVE PCA, 25 BPH AND 24 CHRONIC INFLAMMATORY DISEASES. REAL-TIME RT-PCR, DNA SEQUENCING, AND BISULFITE CONVERSION OF DNA, WERE APPLIED. ALL CASES WITH AGGRESSIVE PCA BEFORE TREATMENT WERE TESTED POSITIVE FOR PCA3 OVEREXPRESSION, EXPRESSION OF A T2-ERG GENE FUSION PRODUCT AND GSTP1 PROMOTER HYPERMETHYLATION. NO SOMATIC MUTATIONS WERE DETECTED IN THE AR GENE AND ALL PATIENTS SHOWED NORMAL KLF6-IVS1-27G > A GENOTYPE. THE TMPRSS2-ERG POSITIVE STATUS CORRELATES WITH MODERATE TO POORLY DIFFERENTIATED PROSTATE TUMORS AND IT IS CONSIDERED AS UNFAVORABLE DISEASE PREDICTOR. POSITIVE GSTP1 PROMOTER HYPERMETHYLATION SEEMS TO BE HIGHLY SPECIFIC AND THE EARLIEST EPIGENETIC CHANGE IN THE PROSTATE GLAND, WHICH INDICATES THE BEGINNING OF THE PATHOLOGICAL PROCESS. THE APPEARANCE OF POSITIVE MOLECULAR MARKERS IN BLOOD WAS CONSIDERED AS A PREDICTOR OF PCA DISSEMINATION. GSTP1 PROMOTER HYPERMETHYLATION WAS FOUND AS THE EARLIEST AND A LONG-LASTING EPIGENETIC MARKER IN BLOOD SAMPLES OF PCA PATIENTS, WHICH MAKES IT SUITABLE AS A MARKER FOR TREATMENT FOLLOW-UP. THE MOLECULAR PROFILE OF PROSTATE CANCER NEEDS TO BE STRICTLY MONITORED DURING THE COURSE OF DISEASE TREATMENT, WHICH IS OF A GREAT HELP IN DETERMINING THE PATIENT'S INDIVIDUAL THERAPY RESPONSE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  3786  34 INTERGENERATIONAL INFLUENCES ON CHILD GROWTH AND UNDERNUTRITION. INTERGENERATIONAL EFFECTS ON LINEAR GROWTH ARE WELL DOCUMENTED. SEVERAL GENERATIONS ARE NECESSARY IN ANIMAL MODELS TO 'WASH OUT' EFFECTS OF UNDERNUTRITION, CONSISTENT WITH THE UNFOLDING OF THE SECULAR TREND IN HEIGHT IN EUROPE AND NORTH AMERICA. BIRTHWEIGHT IS CORRELATED ACROSS GENERATIONS AND SHORT MATERNAL STATURE, WHICH REFLECTS INTRAUTERINE AND INFANT GROWTH FAILURE, IS ASSOCIATED WITH LOW BIRTHWEIGHT, CHILD STUNTING, DELIVERY COMPLICATIONS AND INCREASED CHILD MORTALITY, EVEN AFTER ADJUSTING FOR SOCIO-ECONOMIC STATUS. A NUTRITION INTERVENTION IN GUATEMALA REDUCED CHILDHOOD STUNTING; IT ALSO IMPROVED GROWTH OF THE NEXT GENERATION, BUT ONLY IN THE OFFSPRING OF GIRLS. POSSIBLE MECHANISMS EXPLAINING INTERGENERATIONAL EFFECTS ON LINEAR GROWTH ARE NOT MUTUALLY EXCLUSIVE AND INCLUDE, AMONG OTHERS, SHARED GENETIC CHARACTERISTICS, EPIGENETIC EFFECTS, PROGRAMMING OF METABOLIC CHANGES, AND THE MECHANICS OF A REDUCED SPACE FOR THE FETUS TO GROW. THERE ARE ALSO SOCIO-CULTURAL FACTORS AT PLAY THAT ARE IMPORTANT SUCH AS THE INTERGENERATIONAL TRANSMISSION OF POVERTY AND THE FEAR OF BIRTHING A LARGE BABY, WHICH LEADS TO 'EATING DOWN' DURING PREGNANCY. IT IS NOT CLEAR WHETHER THERE IS AN UPPER LIMIT FOR IMPACT ON INTRAUTERINE AND INFANT LINEAR GROWTH THAT PROGRAMMES IN DEVELOPING COUNTRIES COULD ACHIEVE THAT IS SET BY EARLY CHILDHOOD MALNUTRITION IN THE MOTHER. SUBSTANTIAL IMPROVEMENTS IN LINEAR GROWTH CAN BE ACHIEVED THROUGH ADOPTION AND MIGRATION, AND IN A FEW SELECTED COUNTRIES, FOLLOWING RAPID ECONOMIC AND SOCIAL DEVELOPMENT. IT WOULD SEEM, DESPITE CLEAR DOCUMENTATION OF INTERGENERATIONAL EFFECTS, THAT NEARLY NORMAL LENGTHS CAN BE ACHIEVED IN CHILDREN BORN TO MOTHERS WHO WERE MALNOURISHED IN CHILDHOOD WHEN PROFOUND IMPROVEMENTS IN HEALTH, NUTRITION AND THE ENVIRONMENT TAKE PLACE BEFORE CONCEPTION. TO ACHIEVE SIMILAR LEVELS OF IMPACT THROUGH PUBLIC HEALTH PROGRAMMES ALONE IN POOR COUNTRIES IS HIGHLY UNLIKELY. THE REALITY IN POOR COUNTRIES LIMITS THE SCOPE, QUALITY AND COVERAGE OF PROGRAMMES THAT CAN BE IMPLEMENTED AND MODEST IMPACT SHOULD BE EXPECTED INSTEAD. THE LANCET SERIES ON MATERNAL AND CHILD UNDERNUTRITION ESTIMATED THAT IMPLEMENTATION TO SCALE OF PROVEN INTERVENTIONS IN HIGH BURDEN COUNTRIES WOULD REDUCE STUNTING BY ONE-THIRD; THIS IS PERHAPS A REALISTIC UPPER BOUND FOR IMPACT FOR HIGH QUALITY PROGRAMMES, UNLESS ACCOMPANIED BY SWEEPING IMPROVEMENTS IN SOCIAL SERVICES AND MARKED REDUCTIONS IN POVERTY. FINALLY, BECAUSE SO MUCH CAN BE ACHIEVED IN A SINGLE GENERATION, INTERGENERATIONAL INFLUENCES ARE UNLIKELY TO BE AN IMPORTANT EXPLANATION FOR LACK OF PROGRAMME IMPACT AIMED AT THE WINDOW OF THE FIRST 1000 DAYS. FAILURE TO PREVENT LINEAR GROWTH FAILURE IN DEVELOPING COUNTRIES HAS SERIOUS CONSEQUENCES FOR SHORT- AND LONG-TERM HEALTH AS WELL AS FOR THE FORMATION OF HUMAN CAPITAL. THE NUTRITION TRANSITION HAS CREATED A DOUBLE BURDEN BY ADDING OBESITY AND RELATED CHRONIC DISEASES TO THE PUBLIC HEALTH AGENDA OF COUNTRIES STILL STRUGGLING WITH THE 'OLD' PROBLEMS OF MATERNAL AND CHILD UNDERNUTRITION. THE CHALLENGE AHEAD IS TO INCREASE EFFORTS TO PREVENT LINEAR GROWTH FAILURE WHILE KEEPING CHILD OVERWEIGHT AT BAY.	2012	

18  5606  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19   249  31 ADVANCED AGING PHENOTYPE IS REVEALED BY EPIGENETIC MODIFICATIONS IN RAT LIVER AFTER IN UTERO MALNUTRITION. ADVERSE ENVIRONMENTAL EXPOSURES OF MOTHERS DURING FETAL PERIOD PREDISPOSE OFFSPRING TO A RANGE OF AGE-RELATED DISEASES EARLIER IN LIFE. HERE, WE SET TO DETERMINE WHETHER A DEREGULATED EPIGENETIC PATTERN IS SIMILAR IN YOUNG ANIMALS WHOSE MOTHERS' NUTRITION WAS MODULATED DURING FETAL GROWTH TO THAT ACQUIRED DURING NORMAL AGING IN ANIMALS. USING A RODENT MODEL OF MATERNAL UNDERNUTRITION (UN) OR OVERNUTRITION (ON), WE EXAMINED CYTOSINE METHYLATION PROFILES OF LIVER FROM YOUNG FEMALE OFFSPRING AND COMPARED THEM TO AGE-MATCHED YOUNG CONTROLS AND AGED (20-MONTH-OLD) ANIMALS. HELP-TAGGING, A GENOMEWIDE RESTRICTION ENZYME AND SEQUENCING ASSAY DEMONSTRATES THAT FETAL EXPOSURE TO TWO DIFFERENT MATERNAL DIETS IS ASSOCIATED WITH NONRANDOM DYSREGULATION OF METHYLATION LEVELS WITH PROFILES SIMILAR TO THOSE SEEN IN NORMAL AGING ANIMALS AND OCCUR IN REGIONS MAPPED TO GENES RELEVANT TO METABOLIC DISEASES AND AGING. FUNCTIONAL CONSEQUENCES WERE ASSESSED BY GENE EXPRESSION AT 9 WEEKS OLD WITH MORE SIGNIFICANT CHANGES AT 6 MONTHS OF AGE. EARLY DEVELOPMENTAL EXPOSURES TO UNFAVORABLE MATERNAL DIETS RESULT IN ALTERED METHYLATION PROFILES AND TRANSCRIPTIONAL DYSREGULATION IN PRKCB, PC, NCOR2, AND SMAD3 THAT IS ALSO SEEN WITH NORMAL AGING. THESE NOTCH PATHWAY AND LIPOGENESIS GENES MAY BE USEFUL FOR PREDICTION OF LATER SUSCEPTIBILITY TO CHRONIC DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20   437  38 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