1  5854 112 SUBSTANCE P AND NEPRILYSIN IN CHRONIC PANCREATITIS. BACKGROUND/AIMS: WE AIMED TO ANALYZE SUBSTANCE P (SP) AND NEPRILYSIN (NEP), THE MEMBRANE METALLOPEPTIDASE THAT DEGRADES SP, IN CHRONIC PANCREATITIS (CP). METHODS: SP AND NEP MRNA LEVELS WERE ANALYZED BY QRT-PCR IN TISSUE SAMPLES FROM 30 PATIENTS WITH CP AND 8 ORGAN DONORS. IN ADDITION, SP SERUM LEVELS WERE DETERMINED BEFORE AND AFTER SURGERY IN THE SAME PATIENTS, BY MEANS OF A COMPETITIVE ELISA ASSAY. GENETIC AND EPIGENETIC ANALYSES OF THE NEP GENE WERE ALSO PERFORMED. RESULTS: SP MRNA EXPRESSION LEVELS WERE HIGHER IN CP TISSUES COMPARED TO CONTROLS (P = 0.0152), WHILE NEP MRNA SHOWED NO SIGNIFICANT DIFFERENCES BETWEEN CP AND HEALTHY SUBJECTS (P = 0.2102). IN CP PATIENTS, SP SERUM LEVELS CORRELATED WITH THOSE IN TISSUE, AND AFTER SURGICAL RESECTION SP SERUM LEVELS WERE REDUCED COMPARED TO THE PREOPERATIVE VALUES. FAILURE OF NEP TO OVEREXPRESS IN CP TISSUES WAS ASSOCIATED WITH SIGNIFICANT MIR-128A OVEREXPRESSION (P = 0.02), RATHER THAN WITH MUTATIONS IN THE NEP CODING REGION OR THE PRESENCE OF HYPERMETHYLATION SITES IN THE NEP PROMOTER REGION. CONCLUSION: TISSUE AND SERUM LEVELS OF SP WERE INCREASED IN CP, WHILE NEP LEVELS REMAINED UNALTERED. IN AN SP/NEP-MEDIATED PATHWAY, IT WOULD APPEAR THAT NEP FAILS TO PROVIDE ADEQUATE SURVEILLANCE OF SP LEVELS. FAILURE OF NEP TO OVEREXPRESS COULD BE ASSOCIATED WITH MIRNA REGULATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  4588  28 NANOPARTICLE EXPOSURES FROM NANO-ENABLED TONER-BASED PRINTING EQUIPMENT AND HUMAN HEALTH: STATE OF SCIENCE AND FUTURE RESEARCH NEEDS. TONER FORMULATIONS USED BY LASER PRINTERS (LP) AND PHOTOCOPIERS (PC), COLLECTIVELY CALLED "TONER-BASED PRINTING EQUIPMENT" (TPE), ARE NANO-ENABLED PRODUCTS (NEP) BECAUSE THEY CONTAIN SEVERAL ENGINEERED NANOMATERIALS (ENM) THAT IMPROVE TONER PERFORMANCE. IT HAS BEEN SHOWN THAT DURING CONSUMER USE (PRINTING), THESE ENM ARE RELEASED IN THE AIR, TOGETHER WITH OTHER SEMI-VOLATILE ORGANIC NANOPARTICLES, AND NEWLY FORMED GASEOUS CO-POLLUTANTS SUCH AS VOLATILE ORGANIC COMPOUNDS (VOC). THE AIM OF THIS REVIEW IS TO DETAIL AND ANALYZE PHYSICO-CHEMICAL AND MORPHOLOGICAL (PCM), AS WELL AS THE TOXICOLOGICAL PROPERTIES OF PARTICULATE MATTER (PM) EMISSIONS FROM TPE. THE REVIEW COVERS EVOLUTION OF SCIENCE SINCE THE EARLY 2000, WHEN THIS PRINTING TECHNOLOGY FIRST BECAME A SUBJECT OF PUBLIC INTEREST, AS WELL AS THE LAGGING REGULATORY FRAMEWORK AROUND IT. IMPORTANT STUDIES THAT HAVE SIGNIFICANTLY CHANGED OUR UNDERSTANDING OF THESE EXPOSURES ARE ALSO HIGHLIGHTED. THE REVIEW CONTINUES WITH A CRITICAL APPRAISAL OF THE MOST UP-TO-DATE CELLULAR, ANIMAL AND HUMAN TOXICOLOGICAL EVIDENCE ON THE POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF PM EMITTED FROM TPE. WE HIGHLIGHT SEVERAL LIMITATIONS OF EXISTING STUDIES, INCLUDING (I) USE OF HIGH AND OFTEN UNREALISTIC DOSES IN VITRO OR IN VIVO; (II) UNREALISTICALLY HIGH-DOSE RATES IN INTRATRACHEAL INSTILLATION STUDIES; (III) IMPROPER USE OF TONERS AS SURROGATE FOR EMITTED NANOPARTICLES; (IV) LACK OF OR INADEQUATE PCM CHARACTERIZATION OF EXPOSURES; AND (V) LACK OF DOSIMETRY CONSIDERATIONS IN IN VITRO STUDIES. PRESENTLY, THERE IS COMPELLING EVIDENCE THAT THE PM(0.1) FROM TPE ARE BIOLOGICALLY ACTIVE AND CAPABLE OF INDUCING OXIDATIVE STRESS IN VITRO AND IN VIVO, RESPIRATORY TRACT INFLAMMATION IN VIVO (IN RATS) AND IN HUMANS, SEVERAL ENDPOINTS OF CELLULAR INJURY IN MONOCULTURES AND CO-CULTURES, INCLUDING MODERATE EPIGENETIC MODIFICATIONS IN VITRO. IN HUMANS, LIMITED EPIDEMIOLOGICAL STUDIES REPORT TYPICALLY 2-3 TIMES HIGHER PREVALENCE OF CHRONIC COUGH, WHEEZING, NASAL BLOCKAGE, EXCESSIVE SPUTUM PRODUCTION, BREATHING DIFFICULTIES, AND SHORTNESS OF BREATH, IN COPIER OPERATORS RELATIVE TO CONTROLS. SUCH SYMPTOMS CAN BE EXACERBATED DURING CHRONIC EXPOSURES, AND IN INDIVIDUALS SUSCEPTIBLE TO INHALED POLLUTANTS. THUS RESPIRATORY, IMMUNOLOGICAL, CARDIOVASCULAR, AND OTHER DISORDERS MAY BE DEVELOPED FOLLOWING SUCH EXPOSURES; HOWEVER, FURTHER TOXICOLOGICAL AND LARGER SCALE MOLECULAR EPIDEMIOLOGICAL STUDIES MUST BE DONE TO FULLY UNDERSTAND THE MECHANISM OF ACTION OF THESE TPE EMITTED NANOPARTICLES. MAJOR RESEARCH GAPS HAVE ALSO BEEN IDENTIFIED. AMONG THEM, A METHODICAL RISK ASSESSMENT BASED ON "REAL WORLD" EXPOSURES RATHER THAN ON THE TONER PARTICLES ALONE NEEDS TO BE PERFORMED TO PROVIDE THE MUCH-NEEDED DATA TO ESTABLISH REGULATORY GUIDELINES PROTECTIVE OF INDIVIDUALS EXPOSED TO TPE EMISSIONS AT BOTH THE OCCUPATIONAL AND CONSUMER LEVEL. INDUSTRY-WIDE MOLECULAR EPIDEMIOLOGY AS WELL AS MECHANISTIC ANIMAL AND HUMAN STUDIES ARE ALSO URGENTLY NEEDED.	2017	
                                                                                                                                                                                  
3   965  19 CHRONIC NEURODEGENERATIVE CONSEQUENCES OF TRAUMATIC BRAIN INJURY. TRAUMATIC BRAIN INJURY (TBI) IS A SERIOUS PUBLIC HEALTH CONCERN AND A MAJOR CAUSE OF DEATH AND DISABILITY WORLDWIDE. EACH YEAR, AN ESTIMATED 1.7 MILLION AMERICANS SUSTAIN TBI OF WHICH ~52,000 PEOPLE DIE, ~275,000 PEOPLE ARE HOSPITALIZED AND 1,365,000 PEOPLE ARE TREATED AS EMERGENCY OUTPATIENTS. CURRENTLY THERE ARE ~5.3 MILLION AMERICANS LIVING WITH TBI. TBI IS MORE OF A DISEASE PROCESS THAN OF AN EVENT THAT IS ASSOCIATED WITH IMMEDIATE AND LONG-TERM SENSOMOTOR, PSYCHOLOGICAL AND COGNITIVE IMPAIRMENTS. TBI IS THE BEST KNOWN ESTABLISHED EPIGENETIC RISK FACTOR FOR LATER DEVELOPMENT OF NEURODEGENERATIVE DISEASES AND DEMENTIA. PEOPLE SUSTAINING TBI ARE ~4 TIMES MORE LIKELY TO DEVELOP DEMENTIA AT A LATER STAGE THAN PEOPLE WITHOUT TBI. SINGLE BRAIN INJURY IS LINKED TO LATER DEVELOPMENT OF SYMPTOMS RESEMBLING ALZHEIMER'S DISEASE WHILE REPETITIVE BRAIN INJURIES ARE LINKED TO LATER DEVELOPMENT OF CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE) AND/OR DEMENTIA PUGILISTICA (DP). FURTHERMORE, GENETIC BACKGROUND OF SS-AMYLOID PRECURSOR PROTEIN (APP), APOLIPOPROTEIN E (APOE), PRESENILIN (PS) AND NEPRILYSIN (NEP) GENES IS ASSOCIATED WITH EXACERBATION OF NEURODEGENERATIVE PROCESS AFTER TBI. THIS REVIEW ENCOMPASSES ACUTE EFFECTS AND CHRONIC NEURODEGENERATIVE CONSEQUENCES AFTER TBI.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  3712  17 INHALED POLLUTANTS: THE MOLECULAR SCENE BEHIND RESPIRATORY AND SYSTEMIC DISEASES ASSOCIATED WITH ULTRAFINE PARTICULATE MATTER. AIR POLLUTION OF ANTHROPOGENIC ORIGIN IS LARGELY FROM THE COMBUSTION OF BIOMASS (E.G., WOOD), FOSSIL FUELS (E.G., CARS AND TRUCKS), INCINERATORS, LANDFILLS, AGRICULTURAL ACTIVITIES AND TOBACCO SMOKE. AIR POLLUTION IS A COMPLEX MIXTURE THAT VARIES IN SPACE AND TIME, AND CONTAINS HUNDREDS OF COMPOUNDS INCLUDING VOLATILE ORGANIC COMPOUNDS (E.G., BENZENE), METALS, SULPHUR AND NITROGEN OXIDES, OZONE AND PARTICULATE MATTER (PM). PM(0.1) (ULTRAFINE PARTICLES (UFP)), THOSE PARTICLES WITH A DIAMETER LESS THAN 100 NM (INCLUDES NANOPARTICLES (NP)) ARE CONSIDERED ESPECIALLY DANGEROUS TO HUMAN HEALTH AND MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF NUMEROUS RESPIRATORY AND CARDIOVASCULAR DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND ATHEROSCLEROSIS. SOME OF THE PATHOGENIC MECHANISMS THROUGH WHICH PM(0.1) MAY CONTRIBUTE TO CHRONIC DISEASE IS THEIR ABILITY TO INDUCE INFLAMMATION, OXIDATIVE STRESS AND CELL DEATH BY MOLECULAR MECHANISMS THAT INCLUDE TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR KAPPAB (NF-KAPPAB) AND NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NRF2). EPIGENETIC MECHANISMS INCLUDING NON-CODING RNA (NCRNA) MAY ALSO CONTRIBUTE TOWARDS THE DEVELOPMENT OF CHRONIC DISEASE ASSOCIATED WITH EXPOSURE TO PM(0.1). THIS PAPER HIGHLIGHTS EMERGING MOLECULAR CONCEPTS ASSOCIATED WITH INHALATIONAL EXPOSURE TO PM(0.1) AND THEIR ABILITY TO CONTRIBUTE TO CHRONIC RESPIRATORY AND SYSTEMIC DISEASE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5   403  32 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022	

6  1344  21 DETECTION OF BRAIN AMYLOID BETA DEPOSITION IN PATIENTS WITH NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TRAUMATIC BRAIN INJURY: PET EVALUATION USING PITTSBURGH COMPOUND-B. OBJECTIVE: TRAUMATIC BRAIN INJURY (TBI) IS AN EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD) AND AMYLOID BETA (ABETA) DEPOSITION IS OBSERVED HISTOPATHOLOGICALLY IN THE TRAUMATIZED BRAIN. THIS STUDY WAS CONDUCTED TO DETECT CEREBRAL ABETA DEPOSITION USING AMYLOID POSITRON EMISSION TOMOGRAPHY (PET) IN PATIENTS WITH NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TBI. METHODS: TWELVE PATIENTS WITH POST-TRAUMATIC NEUROPSYCHOLOGICAL IMPAIRMENT (11 MEN AND ONE WOMAN, AGE RANGE = 21-78 YEARS) WERE EXAMINED USING PITTSBURGH COMPOUND B ((11)C-PIB) PET AT THE CHRONIC STAGE AFTER TBI (RANGE = 5-129 MONTHS). RESULTS: (11)C-PIB WAS POSITIVE IN THREE PATIENTS AND NEGATIVE IN THE OTHER NINE PATIENTS. THERE WAS NO CORRELATION BETWEEN (11)C-PIB DEPOSITION AND THE SEVERITY OF INJURY; INITIAL CT FINDINGS; ELAPSED TIME FROM THE INJURY; AND NEUROPSYCHOLOGICAL TEST SCORES. CONCLUSIONS: THE ABSENCE OF ABETA DEPOSITION IN MANY PATIENTS WITH CHRONIC NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TBI DOES NOT SUPPORT THE PREMISE THAT ABETA PATHOLOGY PROGRESSES OVER TIME IN THE TRAUMATIZED BRAIN. EARLY AND SEQUENTIAL (11)C-PIB PET EXAMINATION MAY CLARIFY THE TIME COURSE OF ABETA DEPOSITION IN THE TRAUMATIZED BRAIN AND THE RELATIONSHIP BETWEEN TRAUMATIC BRAIN INSULT AND SUBSEQUENT NEUROPSYCHOLOGICAL IMPAIRMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  1735  33 EARLY AND SUSTAINED EXPANSION OF ADAPTIVE NATURAL KILLER CELLS FOLLOWING HAPLOIDENTICAL TRANSPLANTATION AND CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS DISSOCIATE GRAFT-VERSUS-LEUKEMIA AND GRAFT-VERSUS-HOST EFFECTS. BACKGROUND: ADAPTIVE OR MEMORY NATURAL KILLER (NK) CELLS WITH EPIGENETIC IMPRINTS SIMILAR TO MEMORY T CELLS HAVE BEEN SHOWN TO DEVELOP IN RESPONSE TO CYTOMEGALOVIRUS (CMV) INFECTION WITH UPREGULATION OF ACTIVATING RECEPTOR NKG2C. THESE CELLS HAVE BEEN SHOWN TO POSSESS STRONG ANTI-TUMOUR EFFICACY BOTH IN-VITRO AS WELL AS IN-VIVO. OBJECTIVES: TO DETERMINE IF RECONSTITUTION OF ADAPTIVE NK CELLS (CD56(DIM)NKG2C(+)NKG2A(-)) IN PATIENTS WITH ADVANCED LEUKEMIA UNDERGOING HAPLOIDENTICAL HCT HAD ANY IMPACT ON DISEASE PROGRESSION (DP). STUDY DESIGN: THE STUDY COHORT COMPRISED OF 60 PATIENTS WITH ADVANCED ACUTE LEUKEMIA, AGED 2-65 YEARS, RECEIVING MYELOABLATIVE PTCY BASED HAPLOIDENTICAL TRANSPLANTATION FROM CMV SEROPOSITIVE DONORS, FOLLOWED BY CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS (DLI). THEY WERE EVALUATED FOR THE KINETICS OF RECONSTITUTION OF ADAPTIVE NK CELLS, BOTH PHENOTYPIC AND FUNCTIONAL, AT DAYS +30,+60, +90 AND AT REGULAR INTERVALS, TO 3 YEARS OF FOLLOW-UP, IN RELATION TO DP. RECONSTITUTION OF ADAPTIVE NK CELLS WAS COMPARED WITH A RETROSPECTIVE COHORT OF PATIENTS IN THE SAME PROTOCOL RECEIVING DLI WITHOUT CTLA4IG. RESULTS: NON-RELAPSE MORTALITY, ACUTE AND CHRONIC GVHD WERE 5.1%, 10.3% AND 14.5%. DP WAS 17.5% AT A MEDIAN FOLLOW-UP OF 28 MONTHS. ADAPTIVE NK CELLS WERE SIGNIFICANTLY HIGHER IN PATIENTS WITHOUT DP AT DAYS+30, +60 AND +90 (P = 0.0001), IRRESPECTIVE OF CMV REACTIVATION AND REMAINED ELEVATED UNTIL 36 MONTHS POST-HCT. THESE CELLS MAINTAINED THEIR FUNCTIONAL COMPETENCE AS MEASURED BY ROBUST INTERFERON-GAMMA PRODUCTION WITH HIGHER EXPRESSIONS OF KIR, NKG2D AND CD57, WITHOUT ANY INCREASE IN PD1 EXPRESSION. GRAFTS FROM DONORS WITH HIGHER ADAPTIVE NK CELLS WERE ASSOCIATED WITH A LOWER RISK OF DP (P = 0.0001). IN MULTIVARIATE ANALYSIS, ADAPTIVE NK CELL RECOVERY AT DAY +90 HAD THE MOST FAVORABLE IMPACT ON DP (HR-0.7). TREGS RECONSTITUTED BRISKLY ALONG WITH THE ADAPTIVE NK CELLS AND WERE SUSTAINED AS WELL, WITHOUT COMPROMISING THE GVL EFFECT. COMPARISON WITH A RETROSPECTIVE COHORT RECEIVING THE SAME PROTOCOL WITH DLI WITHOUT CTLA4IG, SHOWED A SUPERIOR RECONSTITUTION OF ADAPTIVE NK CELLS IN THOSE RECEIVING CTLA4IG-DLI (P < 0.0001). CONCLUSION: OUR STUDY SUGGESTS THAT MYELOABLATIVE TRANSPLANTATION FROM CMV SEROPOSITIVE HAPLOIDENTICAL DONORS AUGMENTED WITH CTLA4IG-PRIMED DLI MIGHT FAVOR EARLY AND SUSTAINED EXPANSION OF FUNCTIONALLY COMPETENT ADAPTIVE NK CELLS IRRESPECTIVE OF CMV REACTIVATION, WITH A FAVORABLE OUTCOME.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  5957  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  4989  35 PCSK9 IS INCREASED IN CEREBROSPINAL FLUID OF INDIVIDUALS WITH ALCOHOL USE DISORDER. BACKGROUND: RECENT STUDIES HAVE SHOWN THAT ALCOHOL USE AFFECTS THE REGULATION AND EXPRESSION OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9). WHILE A MAJOR ROLE OF PCSK9 IN HEPATIC FUNCTION AND LIPID REGULATION HAS BEEN CLEARLY ESTABLISHED, OTHER PLEIOTROPIC EFFECTS REMAIN POORLY UNDERSTOOD. EXISTING RESEARCH SUGGESTS A POSITIVE ASSOCIATION BETWEEN PCSK9 EXPRESSION IN THE BRAIN AND PSYCHOPATHOLOGY, WITH INCREASED LEVELS OF PCSK9 IN THE CEREBROSPINAL FLUID (CSF) OF INDIVIDUALS WITH DEMENTIA AND EPIGENETIC MODIFICATIONS OF PCSK9 ASSOCIATED WITH ALCOHOL USE DISORDER (AUD). IN THIS STUDY, WE HYPOTHESIZED THAT CHRONIC ALCOHOL USE WOULD INCREASE PCSK9 EXPRESSION IN CSF. METHODS: PCSK9 LEVELS IN CSF WERE MEASURED IN INDIVIDUALS WITH AUD (N = 42) ADMITTED TO AN INPATIENT REHABILITATION PROGRAM AND CONTROLS (N = 25). CSF SAMPLES IN AUD WERE ASSESSED AT 2 TIME POINTS, AT DAY 5 AND DAY 21 AFTER ADMISSION. FURTHERMORE, PLASMA SAMPLES WERE COLLECTED AND MEASURED FROM THE INDIVIDUALS WITH AUD. RESULTS: PCSK9 IN CSF WAS SIGNIFICANTLY INCREASED IN THE AUD GROUP AT DAY 5 AND DAY 21 COMPARED TO THE CONTROLS (P < 0.0001). PLASMA PCSK9 LEVELS WERE CORRELATED POSITIVELY WITH CSF PCSK9 LEVELS IN AUD (P = 0.0493). CONCLUSIONS: OUR DATA SUGGEST THAT PCSK9 IS ELEVATED IN THE CSF OF INDIVIDUALS WITH AUD, WHICH MAY INDICATE A POTENTIAL ROLE OF PCSK9 IN AUD. ADDITIONAL STUDIES ARE NECESSARY TO FURTHER ELUCIDATE THE FUNCTIONS OF PCSK9 IN THE BRAIN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  5683  29 SHORTER TELOMERE LENGTH IN PERIPHERAL BLOOD LYMPHOCYTES OF WORKERS EXPOSED TO POLYCYCLIC AROMATIC HYDROCARBONS. SHORTER TELOMERE LENGTH (TL) IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) IS PREDICTIVE OF LUNG CANCER RISK. POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) ARE ESTABLISHED LUNG CARCINOGENS THAT CAUSE CHROMOSOME INSTABILITY. WHETHER PAH EXPOSURE AND ITS MOLECULAR EFFECTS ARE LINKED WITH SHORTER TL HAS NEVER BEEN EVALUATED. IN THE PRESENT STUDY, WE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO PAHS ON TL MEASURED IN PBLS OF POLISH MALE NON-CURRENT SMOKING COKEOVEN WORKERS AND MATCHED CONTROLS. PAH EXPOSURE AND MOLECULAR EFFECTS WERE CHARACTERIZED USING MEASURES OF INTERNAL DOSE (URINARY 1-PYRENOL), EFFECTIVE DOSE [ANTI-BENZO[A]PYRENE DIOLEPOXIDE (ANTI-BPDE)-DNA ADDUCT], GENETIC INSTABILITY (MICRONUCLEI, MN) AND DNA METHYLATION [P53 PROMOTER AND ALU AND LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) REPETITIVE ELEMENTS, AS SURROGATE MEASURES OF GLOBAL METHYLATION] IN PBLS. TL WAS MEASURED BY REAL-TIME POLYMERASE CHAIN REACTION. COKEOVEN WORKERS WERE HEAVILY EXPOSED TO PAHS (79% EXCEEDED THE URINARY 1-PYRENOL BIOLOGICAL EXPOSURE INDEX) AND EXHIBITED LOWER TL (P = 0.038) THAN CONTROLS, AS WELL AS HIGHER LEVELS OF GENETIC AND CHROMOSOMAL ALTERATIONS [I.E. ANTI-BPDE-DNA ADDUCT AND MN (P < 0.0001)] AND EPIGENETIC CHANGES [I.E. P53 GENE-SPECIFIC PROMOTER AND GLOBAL METHYLATION (P <OR= 0.001)]. TL DECREASED WITH LONGER DURATION OF WORK AS COKEOVEN WORKER (P = 0.039) AND IN ALL SUBJECTS WITH HIGHER LEVELS OF ANTI-BPDE-DNA ADDUCT (P = 0.042), P53 HYPOMETHYLATION (P = 0.005) AND MN (P = 0.009). IN MULTIVARIATE ANALYSIS, YEARS OF WORK IN COKERY (P = 0.008) AND P53 HYPOMETHYLATION (P = 0.001) WERE THE PRINCIPAL DETERMINANTS OF SHORTER TL. OUR RESULTS INDICATE THAT SHORTER TL IS ASSOCIATED WITH CHRONIC PAH EXPOSURE. THE INTERRELATIONS WITH OTHER GENETIC AND EPIGENETIC MECHANISMS IN OUR DATA SUGGEST THAT SHORTER TL COULD BE A CENTRAL EVENT IN PAH CARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  6018  26 THE ASSOCIATION OF EPIGENETIC AGE ACCELERATION AND MULTIMORBIDITY AT AGE 90 IN THE WOMEN'S HEALTH INITIATIVE. BACKGROUND: EPIGENETIC AGE ACCELERATION (EAA), A MEASURE OF ACCELERATED BIOLOGICAL AGING, HAS BEEN ASSOCIATED WITH INCREASED RISK OF SEVERAL AGE-RELATED CHRONIC CONDITIONS. THIS IS THE FIRST STUDY TO PROSPECTIVELY EXAMINE THE RELATIONSHIP BETWEEN EAA AND BOTH MULTIMORBIDITY COUNT AND A WEIGHTED MULTIMORBIDITY SCORE AMONG LONG-LIVED POSTMENOPAUSAL WOMEN. METHODS: WE INCLUDED 1,951 WOMEN FROM THE WOMEN'S HEALTH INITIATIVE WHO COULD HAVE SURVIVED TO AGE 90. EAA WAS ESTIMATED USING THE HORVATH PAN-TISSUE, HANNUM, PHENOAGE AND GRIMAGE "CLOCKS." TWELVE CHRONIC CONDITIONS WERE INCLUDED IN THE MULTIMORBIDITY COUNT. THE MULTIMORBIDITY SCORE WAS WEIGHTED FOR EACH MORBIDITY'S RELATIONSHIP WITH MORTALITY IN THE STUDY POPULATION. USING MIXED-EFFECTS POISSON AND LINEAR REGRESSION MODELS THAT INCLUDED BASELINE COVARIATES ASSOCIATED WITH BOTH EAA AND MULTIMORBIDITY, WE ESTIMATED RELATIVE RISKS (RRS) AND 95% CONFIDENCE INTERVALS (CIS) FOR THE RELATIONSHIPS BETWEEN EACH EAA MEASURE AT STUDY BASELINE WITH BOTH MULTIMORBIDITY COUNT AND WEIGHTED MULTIMORBIDITY SCORE AT AGE 90, RESPECTIVELY. RESULTS: FOR EVERY ONE-STANDARD DEVIATION INCREASE IN AGEACCELPHENO, THE RATE OF MULTIMORBIDITY ACCUMULATION INCREASED 6% (RR=1.06; 95% CI=1.01-1.12; P=0.025) AND THE MULTIMORBIDITY SCORE BY 7% (RR=1.07; 95% CI=1.01-1.13; P=0.014) FOR WOMEN WHO SURVIVED TO AGE 90. THE RESULTS FOR A ONE-STANDARD DEVIATION INCREASE IN AGEACCELHORVATH, AGEACCELHANNUM AND AGEACCELGRIM WITH MULTIMORBIDITY ACCUMULATION AND SCORE WERE WEAKER COMPARED TO AGEACCELPHENO, AND THE LATTER TWO DID NOT REACH STATISTICAL SIGNIFICANCE. CONCLUSION: AGEACCELPHENO AND AGEACCELHANNUM MAY PREDICT MULTIMORBIDITY COUNT AND SCORE AT AGE 90 IN OLDER WOMEN AND, THUS, MAY BE USEFUL AS A BIOMARKER PREDICTOR OF MULTIMORBIDITY BURDEN IN THE LAST DECADES OF LIFE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  3850  31 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  2044  32 EPIGENETIC CLOCK ANALYSIS OF BLOOD SAMPLES IN DRUG-NAIVE FIRST-EPISODE SCHIZOPHRENIA PATIENTS. BACKGROUND: SCHIZOPHRENIA (SCZ) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH PREMATURE AGE-RELATED PHYSIOLOGICAL CHANGES. HOWEVER, NUMEROUS PREVIOUS STUDIES EXAMINED THE EPIGENETIC AGE ACCELERATION IN SCZ PATIENTS AND YIELDED INCONCLUSIVE RESULTS. IN THIS STUDY, WE PROPOSE TO EXPLORE THE EPIGENETIC AGE ACCELERATION IN DRUG-NAIVE FIRST-EPISODE SCZ (FSCZ) PATIENTS AND INVESTIGATE WHETHER EPIGENETIC AGE ACCELERATION IS ASSOCIATED WITH ANTIPSYCHOTIC TREATMENT, PSYCHOTIC SYMPTOMS, COGNITION, AND SUBCORTICAL VOLUMES. METHODS: WE ASSESSED THE EPIGENETIC AGE IN 38 DRUG-NAIVE FSCZ PATIENTS AND 38 HEALTHY CONTROLS BY USING THREE INDEPENDENT CLOCKS, INCLUDING HORVATH, HANNUM AND LEVINE ALGORITHMS. THE EPIGENETIC AGE MEASUREMENTS IN SCZ PATIENTS WERE REPEATED AFTER RECEIVING 8 WEEKS RISPERIDONE MONOTHERAPY. RESULTS: OUR FINDINGS SHOWED SIGNIFICANTLY POSITIVE CORRELATIONS BETWEEN EPIGENETIC AGES ASSESSED BY THREE CLOCKS AND CHRONOLOGICAL AGE IN BOTH FSCZ PATIENTS AND HEALTHY CONTROLS. COMPARED WITH HEALTHY CONTROLS, DRUG-NAIVE FSCZ PATIENTS HAVE A SIGNIFICANT EPIGENETIC AGE DECELERATION IN HORVATH CLOCK (P = 0.01), BUT NOT IN HANNUM CLOCK (P = 0.07) AND LEVINE CLOCK (P = 0.43). THE EPIGENETIC AGES OF HANNUM CLOCK (P = 0.002) AND LEVINE CLOCK (P = 0.01) WERE SIGNIFICANTLY ACCELERATED IN SCZ PATIENTS AFTER 8-WEEK RISPERIDONE TREATMENT. HOWEVER, NO SIGNIFICANT ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION AND PSYCHOTIC SYMPTOMS, COGNITIVE FUNCTION, AS WELL AS SUBCORTICAL VOLUMES WERE OBSERVED IN FSCZ PATIENTS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  1512  30 DNA METHYLATION AND PROTEIN MARKERS OF CHRONIC INFLAMMATION AND THEIR ASSOCIATIONS WITH BRAIN AND COGNITIVE AGING. BACKGROUND AND OBJECTIVES: TO INVESTIGATE CHRONIC INFLAMMATION IN RELATION TO COGNITIVE AGING BY COMPARISON OF AN EPIGENETIC AND SERUM BIOMARKER OF C-REACTIVE PROTEIN AND THEIR ASSOCIATIONS WITH NEUROIMAGING AND COGNITIVE OUTCOMES. METHODS: AT BASELINE, PARTICIPANTS (N = 521) WERE COGNITIVELY NORMAL, AROUND 73 YEARS OF AGE (MEAN 72.4, SD 0.716), AND HAD INFLAMMATION, VASCULAR RISK (CARDIOVASCULAR DISEASE HISTORY, HYPERTENSION, DIABETES, SMOKING, ALCOHOL CONSUMPTION, BODY MASS INDEX), AND NEUROIMAGING (STRUCTURAL AND DIFFUSION MRI) DATA AVAILABLE. BASELINE INFLAMMATORY STATUS WAS QUANTIFIED BY A TRADITIONAL MEASURE OF PERIPHERAL INFLAMMATION-SERUM C-REACTIVE PROTEIN (CRP)-AND AN EPIGENETIC MEASURE (DNA METHYLATION [DNAM] SIGNATURE OF CRP). LINEAR MODELS WERE USED TO EXAMINE THE INFLAMMATION-BRAIN HEALTH ASSOCIATIONS; MEDIATION ANALYSES WERE PERFORMED TO INTERROGATE THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION, BRAIN STRUCTURE, AND COGNITIVE FUNCTIONING. RESULTS: WE DEMONSTRATE THAT DNAM CRP SHOWS SIGNIFICANTLY (ON AVERAGE 6.4-FOLD) STRONGER ASSOCIATIONS WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP. DNAM CRP IS ASSOCIATED WITH TOTAL BRAIN VOLUME (BETA = -0.197, 95% CONFIDENCE INTERVAL [CI] -0.28 TO -0.12, P (FDR) = 8.42 X 10(-6)), GRAY MATTER VOLUME (BETA = -0.200, 95% CI -0.28 TO -0.12, P (FDR) = 1.66 X 10(-5)), AND WHITE MATTER VOLUME (BETA = -0.150, 95% CI -0.23 TO -0.07, P (FDR) = 0.001) AND REGIONAL BRAIN ATROPHY. WE ALSO FIND THAT DNAM CRP HAS AN INVERSE ASSOCIATION WITH GLOBAL AND DOMAIN-SPECIFIC (SPEED, VISUOSPATIAL, AND MEMORY) COGNITIVE FUNCTIONING AND THAT BRAIN STRUCTURE PARTIALLY MEDIATES THIS CRP-COGNITIVE ASSOCIATION (UP TO 29.7%), DEPENDENT ON LIFESTYLE AND HEALTH FACTORS. DISCUSSION: THESE RESULTS SUPPORT THE HYPOTHESIS THAT CHRONIC INFLAMMATION MAY CONTRIBUTE TO NEURODEGENERATIVE BRAIN CHANGES THAT UNDERLIE DIFFERENCES IN COGNITIVE ABILITY IN LATER LIFE AND HIGHLIGHT THE POTENTIAL OF DNAM PROXIES FOR INDEXING CHRONIC INFLAMMATORY STATUS. CLASSIFICATION OF EVIDENCE: THIS STUDY PROVIDES CLASS II EVIDENCE THAT A DNAM SIGNATURE OF CRP LEVELS IS MORE STRONGLY ASSOCIATED WITH BRAIN HEALTH OUTCOMES THAN SERUM CRP LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  2777  33 EXTREMELY LOW BIRTH WEIGHT AND ACCELERATED BIOLOGICAL AGING. BACKGROUND AND OBJECTIVES: EXTREMELY LOW BIRTH WEIGHT (ELBW) (<1000 G) SURVIVORS ARE EXPOSED TO ELEVATED LEVELS OF PHYSIOLOGIC STRESS DURING THEIR LIVES AND MAY BE SUSCEPTIBLE TO ACCELERATED AGING. USING THE OLDEST KNOWN LONGITUDINALLY FOLLOWED COHORT OF ELBW SURVIVORS, WE COMPARED BIOLOGICAL AGING IN THIS GROUP USING AN EPIGENETIC CLOCK TO A SAMPLE OF MATCHED NORMAL BIRTH WEIGHT (NBW) (>2500 G) CONTROL PARTICIPANTS. METHODS: BUCCAL CELLS WERE COLLECTED FROM 45 ELBW SURVIVORS AND 49 NBW CONTROL PARTICIPANTS AT 30 TO 35 YEARS OF AGE. EPIGENETIC AGE WAS CALCULATED FROM THE WEIGHTED AVERAGE OF DNA METHYLATION AT 353 CYTOSINE-PHOSPHATE-GUANINE SEQUENCE WITHIN DNA SITES, BY USING THE ILLUMINA INFINIUM HUMAN METHYLATION EPIC 850K BEADCHIP ARRAY. RESULTS: BEFORE AND AFTER STATISTICALLY ADJUSTING FOR NEUROSENSORY IMPAIRMENT AND THE PRESENCE OF CHRONIC HEALTH CONDITIONS, A SIGNIFICANT SEX BY BIRTH WEIGHT GROUP INTERACTION WAS OBSERVED IN THE 353-SITE EPIGENETIC-CLOCK ASSAY (P = .03), WHEREBY ELBW MEN HAD A SIGNIFICANTLY OLDER EPIGENETIC AGE THAN NBW MEN (4.6 YEARS; P = .01). WOMEN BORN AT ELBW WERE NOT FOUND TO BE EPIGENETICALLY OLDER THAN THEIR NBW PEERS. CONCLUSIONS: THE RESULTS OF THIS STUDY SUGGEST THAT PRENATAL EXPOSURES MAY PLAY AN IMPORTANT ROLE IN AGING, AND THAT MEN BORN PRETERM MAY EXPERIENCE ACCELERATED AGING RELATIVE TO THEIR PEERS. WE FURTHER HIGHLIGHT THE NEED TO MONITOR AND PROMOTE THE HEALTH OF PRETERM SURVIVORS, WITH A PARTICULAR FOCUS ON HEALTHY AGING ACROSS THE LIFE SPAN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  1785  25 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17  2734  25 EXPLORING THE RELATIONSHIP BETWEEN DNA METHYLATION AGE MEASURES AND PSYCHONEUROLOGICAL SYMPTOMS IN WOMEN WITH EARLY-STAGE BREAST CANCER. PURPOSE: THE EPIGENETIC CLOCK HAS BEEN ACKNOWLEDGED AS AN INDICATOR FOR MOLECULAR AGING, BUT FEW STUDIES HAVE EXAMINED POSSIBLE ASSOCIATIONS OF DNA METHYLATION (DNAM) AGE OR AGE ACCELERATION (AA) WITH SYMPTOM BURDEN IN INDIVIDUALS WHO ARE TREATED FOR CANCER. THIS STUDY EXPLORED THE ASSOCIATION OF DNAM AGE OR AA WITH PSYCHONEUROLOGICAL (PN) SYMPTOMS, INCLUDING COGNITIVE IMPAIRMENT, FATIGUE, SLEEP DISTURBANCES, PAIN, AND DEPRESSIVE SYMPTOMS, IN BREAST CANCER SURVIVORS OVER A 2-YEAR PERIOD. METHODS: WE MEASURED PN SYMPTOMS USING RELIABLE INSTRUMENTS AND DNAM LEVELS BY INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 72). DNAM AGE WAS CALCULATED BY THE HORVATH, GRIM, AND HANNUM-BASED INTRINSIC AND EXTRINSIC AGE ESTIMATIONS. AA WAS DEFINED BY THE RESIDUAL REGRESSING ESTIMATED EPIGENETIC AGE ON CHRONOLOGICAL AGE. MIXED REGRESSION MODELS WERE FITTED FOR AA AND CHANGES IN AA TO STUDY THE ASSOCIATION OVER TIME. SEPARATE LINEAR REGRESSION MODELS AND A MIXED-EFFECTS MODEL WERE FITTED FOR AA AT EACH TIME POINT. RESULTS: HORVATH-AA, GRIM-AA, AND EXTRINSIC EPIGENETIC AA WERE SIGNIFICANTLY CHANGED OVER TIME, WHILE INTRINSIC EPIGENETIC AA DID NOT EXHIBIT ANY TEMPORAL CHANGES. INCREASED AA WAS ASSOCIATED WITH GREATER ANXIETY AND FATIGUE, AS WELL AS WORSE COGNITIVE MEMORY, ADJUSTING FOR RACE, BMI, INCOME, CHEMOTHERAPY, RADIATION THERAPY, AND CHRONOLOGICAL AGE. INCREASED DNAM AGE WAS ASSOCIATED WITH GREATER ANXIETY OVER 2 YEARS. CONCLUSION: OUR FINDINGS SUGGEST DNAM AGE AND AA MAY BE ASSOCIATED WITH PN SYMPTOMS OVER THE COURSE OF CANCER TREATMENT AND SURVIVORSHIP. SOME PN SYMPTOMS MAY BE AMENABLE TO PREVENTIVE INTERVENTIONS TARGETED TO EPIGENETIC CLOCKS THAT INFLUENCE AGING-ASSOCIATED PROCESSES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  1956  22 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	
                                                                                                                                                                                                                                     
19  3179  37 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20   974  34 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018