1  2822 195 FIRST-IN-HUMAN STUDY OF INHALED AZACITIDINE IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER. BACKGROUND: AEROSOLIZED AZACITIDINE HAS BEEN SHOWN TO INHIBIT ORTHOTOPIC LUNG CANCER GROWTH AND INDUCE RE-EXPRESSION OF METHYLATED TUMOR SUPPRESSOR GENES IN MURINE MODELS. WE HYPOTHESIZED THAT INHALED AZACITIDINE IS SAFE AND EFFECTIVE IN REVERSING EPIGENETIC CHANGES IN THE BRONCHIAL EPITHELIUM SECONDARY TO CHRONIC SMOKING. PATIENTS AND METHODS: WE REPORT THE FIRST IN HUMAN STUDY OF INHALED AZACITIDINE. AZACITIDINE IN AQUEOUS SOLUTION WAS USED TO GENERATE AN AEROSOL SUSPENSION OF 0.25-5 MUM PARTICLE SIZE. MAIN INCLUSION CRITERIA: STAGE IV OR RECURRENT NSCLC WITH PREDOMINANTLY LUNG INVOLVEMENT, >/=1 PRIOR SYSTEMIC THERAPY, ECOG PS 0-1, AND ADEQUATE PULMONARY FUNCTION. PATIENTS RECEIVED INHALED AZACITIDINE DAILY ON DAYS 1-5 AND 15-19 OF 28-DAY CYCLES, AT 3 ESCALATING DOSES (15, 30 AND 45 MG/M(2) DAILY). THE PRIMARY OBJECTIVE WAS TO DETERMINE THE FEASIBILITY AND TOLERABILITY OF THIS NEW THERAPEUTIC MODALITY. THE KEY SECONDARY OBJECTIVES INCLUDED PHARMACOKINETICS, METHYLATION PROFILES AND EFFICACY. RESULTS: FROM 3/2015 TO 2/2018, EIGHT PATIENTS RECEIVED A MEDIAN NUMBER OF 2 (IQR = 1) CYCLES OF INHALED AZACITIDINE. NO CLINICALLY SIGNIFICANT ADVERSE EVENTS WERE OBSERVED, EXCEPT ONE PATIENT TREATED AT THE HIGHEST DOSE DEVELOPED AN ASYMPTOMATIC GRADE 2 DECREASED DLCO WHICH RESOLVED SPONTANEOUSLY. ONE PATIENT RECEIVING 12 CYCLES OF THERAPY HAD AN OBJECTIVE AND DURABLE PARTIAL RESPONSE, AND TWO PATIENTS HAD STABLE DISEASE. PLASMA AZACITIDINE WAS ONLY BRIEFLY DETECTABLE IN PATIENTS TREATED AT THE HIGHER DOSES. MOREOVER, IN 2 OF 3 PARTICIPANTS WHO AGREED AND UNDERWENT PRE- AND POST-TREATMENT BRONCHOSCOPY, THE GLOBAL DNA METHYLATION IN THE BRONCHIAL EPITHELIUM DECREASED BY 24 % AND 79 % POST-THERAPY, RESPECTIVELY. THE INTERVAL BETWEEN LAST INHALED TREATMENT AND BRONCHOSCOPY WAS 3 DAYS. CONCLUSIONS: INHALED AZACITIDINE RESULTED IN NEGLIGIBLE PLASMA LEVELS COMPARED TO THE PREVIOUSLY REPORTED SUBCUTANEOUS ADMINISTRATION AND WAS WELL-TOLERATED. THE RESULTS JUSTIFY THE CONTINUED DEVELOPMENT OF INHALED AZACITIDINE AT NON-CYTOTOXIC DOSES FOR PATIENTS WITH LUNG-CONFINED MALIGNANT AND/OR PREMALIGNANT LESIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  3178  37 HAEMATOLOGIC MALIGNANCIES WITH UNFAVOURABLE GENE MUTATIONS BENEFIT FROM DONOR LYMPHOCYTE INFUSION WITH/WITHOUT DECITABINE FOR PROPHYLAXIS OF RELAPSE AFTER ALLOGENEIC HSCT: A PILOT STUDY. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE FOR LEUKAEMIA PATIENTS WITH UNFAVOURABLE GENE MUTATIONS WHO RECEIVE ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT). THERE IS NO CONSENSUS ON THE INDICATION OF DONOR LYMPHOCYTE INFUSION (DLI) FOR PROPHYLAXIS OF RELAPSE AFTER ALLO-HSCT. TO EVALUATE THE TOLERANCE AND EFFICACY OF PROPHYLACTIC DLI IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS SUCH AS FLT3-ITD, TP53, ASXL1, DNMT3A OR TET2, WE PERFORMED A PROSPECTIVE, SINGLE-ARM STUDY. PROPHYLACTIC USE OF DECITABINE FOLLOWED BY DLI WAS PLANNED IN PATIENTS WITH TP53 OR EPIGENETIC MODIFIER GENE MUTATIONS. THE PROPHYLAXIS WAS PLANNED IN 46 RECIPIENTS: IT WAS ADMINISTERED IN 28 PATIENTS AND IT WAS NOT ADMINISTERED IN 18 PATIENTS DUE TO CONTRAINDICATIONS. NO DLI-ASSOCIATED PANCYTOPENIA WAS OBSERVED. THE CUMULATIVE INCIDENCES OF GRADE II-IV AND III-IV ACUTE GRAFT-VERSUS-HOST DISEASE (GVHD) AT 100 DAYS POST-DLI WERE 25.8% AND 11.0%, RESPECTIVELY. THE RATES OF CHRONIC GVHD, NON-RELAPSE MORTALITY AND RELAPSE AT 3 YEARS POST-DLI WERE 21.6%, 25.0% AND 26.1%, RESPECTIVELY. THE 3-YEAR RELAPSE-FREE SURVIVAL AND OVERALL SURVIVAL (OS) RATES WERE 48.9% AND 48.2%, RESPECTIVELY. ACUTE GVHD (HR: 2.30, P = 0.016) AND RELAPSE (HR: 2.46, P = 0.003) AFTER DLI WERE INDEPENDENTLY ASSOCIATED WITH INFERIOR OS. DATA IN THE CURRENT STUDY SHOWED THE FEASIBILITY OF PROPHYLACTIC DLI WITH/WITHOUT DECITABINE IN THE EARLY STAGE AFTER ALLO-HSCT IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3  5612  74 SAFETY AND ACTIVITY OF RRX-001 IN PATIENTS WITH ADVANCED CANCER: A FIRST-IN-HUMAN, OPEN-LABEL, DOSE-ESCALATION PHASE 1 STUDY. BACKGROUND: EPIGENETIC ALTERATIONS HAVE BEEN STRONGLY ASSOCIATED WITH TUMOUR FORMATION AND RESISTANCE TO CHEMOTHERAPEUTIC DRUGS, AND EPIGENETIC MODIFICATIONS ARE AN ATTRACTIVE TARGET IN CANCER RESEARCH. RRX-001 IS ACTIVATED BY HYPOXIA AND INDUCES THE GENERATION OF REACTIVE OXYGEN AND NITROGEN SPECIES THAT CAN EPIGENETICALLY MODULATE DNA METHYLATION, HISTONE DEACETYLATION, AND LYSINE DEMETHYLATION. THE AIM OF THIS PHASE 1 STUDY WAS TO ASSESS THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF RRX-001. METHODS: IN THIS OPEN-LABEL, DOSE-ESCALATION, PHASE 1 STUDY, WE RECRUITED ADULT PATIENTS (AGED >18 YEARS) WITH HISTOLOGICALLY OR CYTOLOGICALLY CONFIRMED DIAGNOSIS OF ADVANCED, MALIGNANT, INCURABLE SOLID TUMOURS FROM UNIVERSITY OF CALIFORNIA AT SAN DIEGO, CA, USA, AND SARAH CANNON RESEARCH INSTITUTE, NASHVILLE, TN, USA. KEY ELIGIBILITY CRITERIA INCLUDED EVALUABLE DISEASE, EASTERN COOPERATIVE GROUP PERFORMANCE STATUS OF 2 OR LESS, AN ESTIMATED LIFE EXPECTANCY OF AT LEAST 12 WEEKS, ADEQUATE LABORATORY PARAMETERS, DISCONTINUATION OF ALL PREVIOUS ANTINEOPLASTIC THERAPIES AT LEAST 6 WEEKS BEFORE INTERVENTION, AND NO RESIDUAL SIDE-EFFECTS FROM PREVIOUS THERAPIES. PATIENTS WERE ASSIGNED TO RECEIVE INTRAVENOUS INFUSIONS OF RRX-001 AT INCREASING DOSES (10 MG/M(2), 16.7 MG/M(2), 24.6 MG/M(2), 33 MG/M(2), 55 MG/M(2), AND 83 MG/M(2)) EITHER ONCE OR TWICE-WEEKLY FOR AT LEAST 4 WEEKS, WITH AT LEAST THREE PATIENTS PER DOSE COHORT AND ALLOWING A 2-WEEK OBSERVATION PERIOD BEFORE DOSE ESCALATION. SAMPLES FOR SAFETY AND PHARMACOKINETICS ANALYSIS, INCLUDING STANDARD CHEMISTRY AND HAEMATOLOGICAL PANELS, WERE TAKEN ON EACH TREATMENT DAY. THE PRIMARY OBJECTIVE WAS TO ASSESS SAFETY, TOLERABILITY, AND DOSE-LIMITING TOXIC EFFECTS OF RRX-001, TO DETERMINE SINGLE-DOSE PHARMACOKINETICS, AND TO IDENTIFY A RECOMMENDED DOSE FOR PHASE 2 TRIALS. ALL ANALYSES WERE DONE PER PROTOCOL. ACCRUAL IS COMPLETE AND FOLLOW-UP IS STILL ON-GOING. THIS TRIAL IS REGISTERED WITH CLINICALTRIALS.GOV, NUMBER NCT01359982. FINDINGS: BETWEEN OCT 10, 2011, AND MARCH 18, 2013, WE ENROLLED 25 PATIENTS AND TREATED SIX PATIENTS IN THE 10 MG/M(2) COHORT, THREE PATIENTS IN THE 16.7 MG/M(2) COHORT, THREE PATIENTS IN THE 24.6 MG/M(2) COHORT, FOUR PATIENTS IN THE 33 MG/M(2) COHORT, THREE PATIENTS IN THE 55 MG/M(2), AND SIX PATIENTS IN THE 83 MG/M(2) COHORT. PAIN AT THE INJECTION SITE, MOSTLY GRADE 1 AND GRADE 2, WAS THE MOST COMMON ADVERSE EVENT RELATED TO TREATMENT, EXPERIENCED BY 21 (84%) PATIENTS. OTHER COMMON DRUG-RELATED ADVERSE EVENTS INCLUDED ARM SWELLING OR OEDEMA (EIGHT [32%] PATIENTS), AND VEIN HARDENING (SEVEN [28%] PATIENTS). NO DOSE-LIMITING TOXICITIES WERE OBSERVED. TIME CONSTRAINTS RELATED TO MANAGEMENT OF INFUSION PAIN FROM RRX-001 RESULTED IN A MAXIMALLY FEASIBLE DOSE OF 83 MG/M(2). OF THE 21 EVALUABLE PATIENTS, ONE (5%) PATIENT HAD A PARTIAL RESPONSE, 14 (67%) PATIENTS HAD STABLE DISEASE, AND SIX (29%) PATIENTS HAD PROGRESSIVE DISEASE; ALL RESPONSES WERE ACROSS A VARIETY OF TUMOUR TYPES. FOUR PATIENTS WHO HAD RECEIVED RRX-001 WERE SUBSEQUENTLY RECHALLENGED WITH A TREATMENT THAT THEY HAD BECOME REFRACTORY TO; ALL FOUR RESPONDED TO THE RECHALLENGE. INTERPRETATION: RRX-001 IS A WELL-TOLERATED NOVEL COMPOUND WITHOUT CLINICALLY SIGNIFICANT TOXIC EFFECTS AT THE TESTED DOSES. PRELIMINARY EVIDENCE OF ACTIVITY IS PROMISING AND, ON THE BASIS OF ALL FINDINGS, A DOSE OF 16.7 MG/M(2) WAS RECOMMENDED AS THE TARGETED DOSE FOR PHASE 2 TRIALS. FUNDING: EPICENTRX (FORMERLY RADIORX).	2015	
         
4  2215  27 EPIGENETIC MODIFICATIONS FOLLOWING NOXIOUS STIMULI IN INFANTS. PURPOSE: TO RECRUIT HEALTHY FULL- AND PRETERM INFANTS INTO GENETIC RESEARCH AND DETERMINE THE EFFECTIVENESS OF A NONINVASIVE DNA SAMPLING TECHNIQUE FOR COMPARING EPIGENETIC MODIFICATIONS. BACKGROUND: NOXIOUS STIMULI DURING A VULNERABLE PERIOD OF INFANT NEURONAL PLASTICITY MAY TRIGGER LONG-TERM EPIGENETIC CHANGES AFFECTING NEURODEVELOPMENT, PAIN MODULATION, AND REACTIVITY. RECOGNIZING EPIGENETIC PAIN FINDINGS IS PROBLEMATIC BECAUSE PARENTS ARE RELUCTANT TO ENROLL NEWBORNS INTO GENETIC RESEARCH. METHODS: DESIGN: WITHIN-SUBJECT CHANGE OVER TIME CANDIDATE-GENE DNA METHYLATION ASSOCIATION STUDY. SETTING/ SAMPLE: URBAN TEACHING HOSPITAL'S NEONATAL INTENSIVE CARE UNIT AND NEWBORN NURSERY. CONVENIENCE SAMPLE OF HEALTHY FULL- (>37 WEEKS, N = 6) AND PRETERM (<37 WEEKS, N = 6) INFANTS. PROCEDURE: PARENTS PARTICIPATED IN A GENETIC PRESENTATION PRIOR TO INFORMED CONSENT. INFANT BUCCAL SALIVA WAS COLLECTED AFTER ADMISSION TO THE UNIT AND PRIOR TO DISCHARGE. ANALYSIS: THE METHYLATION PATTERN AT THE 5' END OF MICRO-OPIOID RECEPTOR GENE ( OPRM1) WAS EXAMINED. DNA WAS TREATED WITH BISULFITE TO CONVERT ALL CYTOSINES TO URACIL RESIDUES, LEAVING METHYLATED CYTOSINES UNCHANGED. SEQUENCING OF UNTREATED AND BISULFITE-CONVERTED DNA WAS CARRIED OUT. THE SEQUENCES OF UNCONVERTED AND BISULFITE-CONVERTED DNA WERE ALIGNED WITH CLUSTALW, FIDELITY OF THE POLYMERASE CHAIN REACTION AND THE SEQUENCING REACTION EVALUATED, AND THE METHYLATION PATTERN IDENTIFIED. RESULTS: RECRUITMENT AND ASSESSMENT OF A NONINVASIVE DNA SAMPLING TECHNIQUE FOR COMPARING EPIGENETIC MODIFICATIONS WERE SUCCESSFUL; HOWEVER, INFANT STRESS DID NOT PRODUCE A CHANGE IN OPRM1 METHYLATION EXPRESSION. RELEVANCE: THIS STUDY ESTABLISHED THE FEASIBILITY OF RECRUITING HEALTHY FULL-TERM INFANTS INTO GENETIC RESEARCH AND THE EFFECTIVENESS OF NONINVASIVE DNA SAMPLING FOR COMPARING EPIGENETIC MODIFICATION IN INFANTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5   246  40 ADULT STEM CELL THERAPY FOR CARDIAC REPAIR IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION LEADING TO ISCHEMIC HEART FAILURE: AN OVERVIEW OF EVIDENCE FROM THE RECENT CLINICAL TRIALS. BACKGROUND: CARDIOVASCULAR DISEASES (CVD) STILL REPRESENT THE LEADING CAUSE OF MORTALITY WORLDWIDE, DESPITE THE REMARKABLE ADVANCES IN INTERVENTIONAL CARDIOLOGY, CARDIAC SURGERY, AND MODERN PHARMACOTHERAPY, PARTICULARLY IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION (AMI), CHRONIC ISCHEMIC HEART FAILURE (HF), CARDIOMYOPATHY (CM), AND THE ASSOCIATED LEFT VENTRICULAR (LV) DYSFUNCTION. A SIGNIFICANT LOSS OF CARDIOMYOCYTES THAT UNDERLIES ALL OF THESE CONDITIONS WAS PREVIOUSLY CONSIDERED IRREVERSIBLE. HOWEVER, CURRENT EVIDENCE INDICATES THAT THE HUMAN HEART HAS SOME POTENTIAL FOR REPAIR, AND OVER THE PAST DECADE, MANY RESEARCH STUDIES HAVE BEEN EXPLORING THE USE OF STEM CELLS (SCS) TO FACILITATE RESTORATION OF MYOCARDIUM. CONSEQUENTLY, THE SAFETY, FEASIBILITY, AND EFFECTIVENESS OF SC THERAPY HAVE BEEN REPORTED IN MANY RANDOMIZED CLINICAL TRIALS (RCTS), USING DIFFERENT LINEAGES OF ADULT SCS. NEVERTHELESS, THE CLINICAL BENEFITS OF SC THERAPY ARE NOT YET WELL ESTABLISHED. IN THE NEAR FUTURE, UNDERSTANDING OF THE COMPLEX INTERRELATIONS BETWEEN SCS, PARACRINE FACTORS, GENETIC OR EPIGENETIC PREDISPOSITIONS, AND MYOCARDIAL MICROENVIRONMENT, IN THE CONTEXT OF AN INDIVIDUAL PATIENT, WILL BE CRUCIAL FOR TRANSLATION OF THIS KNOWLEDGE INTO PRACTICAL DEVELOPMENT OF SUCCESSFUL, LONG-TERM REGENERATIVE SC THERAPEUTIC APPLICATIONS, IN A GROWING POPULATION OF PATIENTS SUFFERING FROM PREVIOUS MYOCARDIAL INFARCTION (MI) LEADING TO CHRONIC ISCHEMIC CARDIOMYOPATHY. CONCLUSION: THIS OVERVIEW HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF ADULT SCS IN TERMS OF THEIR POSSIBLE REGENERATIVE CAPACITY, SAFETY, AND CLINICAL OUTCOMES, IN PATIENTS WITH AMI, AND/OR SUBSEQUENT HF (DUE TO CHRONIC ISCHEMIC CARDIOMYOPATHY). THIS REVIEW WAS BASED UPON PUBMED DATABASE SEARCH FOR TRIALS ON SC THERAPY, IN PATIENTS WITH AMI AND HF, AND THE MAIN TIMEFRAME WAS SET FROM 2006 TO 2016.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6  5283  50 PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZACITIDINE AND DONOR LYMPHOCYTE INFUSION TO PREVENT DISEASE RELAPSE FOLLOWING ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME. BECAUSE OF THE PERSISTENTLY HIGH RATES OF RELAPSE OF PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT), POST-TRANSPLANTATION MAINTENANCE THERAPY HAS BEEN PROPOSED. WE PREVIOUSLY INITIATED A PHASE II TRIAL IN WHICH EPIGENETIC THERAPY WAS COMBINED WITH IMMUNOTHERAPY IN AN ATTEMPT TO REDUCE DISEASE RELAPSE. IN THAT STUDY, LOW-DOSE AZACITIDINE (AZA) AND ESCALATING DOSES OF DONOR LYMPHOCYTE INFUSION (DLI) WERE GIVEN AS POST-ALLO-HSCT MAINTENANCE TREATMENT. IN THE PRESENT STUDY, WE RETROSPECTIVELY ANALYZE A LARGER COHORT OF PATIENTS RECEIVING POST-TRANSPLANTATION MAINTENANCE THERAPY AND PROVIDE UPDATES ON SOME PATIENTS OF THE EARLIER STUDY. THE OBJECTIVES OF THE PRESENT STUDY WERE TO ANALYZE THE CUMULATIVE INCIDENCE OF RELAPSE (CIR), OVERALL SURVIVAL (OS), AND PROGRESSION-FREE SURVIVAL (PFS) AND THE INCIDENCE OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) OF PATIENTS WITH HIGH-RISK AML OR MDS RECEIVING POST-TRANSPLANTATION MAINTENANCE TREATMENT WITH AZA WITH OR WITHOUT DLI. WE RETROSPECTIVELY ANALYZED 77 PATIENTS (54 WITH AML, 23 WITH MDS) CONSIDERED AT HIGH RISK BASED ON EITHER THEIR GENOMIC OR CLINICAL STATUS AT TRANSPLANTATION. FOLLOWING ALLOGENEIC TRANSPLANTATION, THEY RECEIVED AT LEAST 1 CYCLE OF PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZA WITH OR WITHOUT ESCALATING DOSES OF DLI TO PREVENT DISEASE RELAPSE. ALMOST ONE-HALF OF THE PATIENTS (47%) WERE ABLE TO RECEIVE THE FULL 12 CYCLES OF SCHEDULED AZA, AND A MAJORITY (79%) RECEIVED AT LEAST 1 DLI. WITH A MEDIAN FOLLOW-UP OF 24 MONTHS, 19 PATIENTS (25%; 16 WITH AML, 3 WITH MDS) RELAPSED, AT A MEDIAN OF 9.8 MONTHS (RANGE, 4 TO 58.6 MONTHS), GIVING A 22% CIR AT 24 MONTHS. OS AND PFS AT 24 MONTHS WERE 70.8% AND 68.3%, RESPECTIVELY. THE CUMULATIVE INCIDENCES OF GRADE II-IV ACUTE GVHD AND CHRONIC GVHD WERE 27.4% AND 45%, RESPECTIVELY. ONLY A MINORITY OF PATIENTS (11%) REQUIRED DELAYED ADMINISTRATION OF AZA. THESE FINDINGS CONFIRM THAT AZA-DLI MAINTENANCE IS BOTH TOLERABLE AND EFFECTIVE IN REDUCING THE RISK OF POST-TRANSPLANTATION RELAPSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  4707  35 NMR PLASMA METABOLOMICS STUDY OF PATIENTS OVERCOMING ACUTE MYOCARDIAL INFARCTION: IN THE FIRST 12 H AFTER ONSET OF CHEST PAIN WITH STATISTICAL DISCRIMINATION TOWARDS METABOLOMIC BIOMARKERS. ACUTE MYOCARDIAL INFARCTION (AMI) IS ONE OF THE LEADING CAUSES OF DEATH AMONG ADULTS IN OLDER AGE. UNDERSTANDING MECHANISMS HOW ORGANISM RESPONDS TO ISCHEMIA IS ESSENTIAL FOR THE ISCHEMIC PATIENT'S PREVENTION AND TREATMENT. DESPITE THE GREAT PREVALENCE AND INCIDENCE ONLY A SMALL NUMBER OF STUDIES UTILIZE A METABOLOMIC APPROACH TO DESCRIBE AMI CONDITION. RECENT STUDIES HAVE SHOWN THE IMPACT OF METABOLITES ON EPIGENETIC CHANGES, IN THESE STUDIES PLASMA METABOLITES WERE RELATED TO NEUROLOGICAL OUTCOME OF THE PATIENTS MAKING METABOLOMIC STUDIES INCREASINGLY INTERESTING. THE AIM OF THIS STUDY WAS TO DESCRIBE METABOLOMIC RESPONSE OF AN ORGANISM TO ISCHEMIC STRESS THROUGH THE CHANGES IN ENERGETIC METABOLITES AND AMINOACIDS IN BLOOD PLASMA IN PATIENTS OVERCOMING ACUTE MYOCARDIAL INFARCTION. BLOOD PLASMA FROM PATIENTS IN THE FIRST 12 H AFTER ONSET OF CHEST PAIN WAS COLLECTED AND COMPARED WITH VOLUNTEERS WITHOUT ANY HISTORY OF ISCHEMIC DISEASES VIA NMR SPECTROSCOPY. LOWERED PLASMA LEVELS OF PYRUVATE, ALANINE, GLUTAMINE AND NEUROTRANSMITTER PRECURSORS TYROSINE AND TRYPTOPHAN WERE FOUND. FURTHER, WE OBSERVED INCREASED PLASMA LEVELS OF 3-HYDROXYBUTYRATE AND ACETOACETATE IN BALANCE WITH DECREASED LEVEL OF LIPOPROTEINS FRACTION, SUGGESTING THE ONGOING KETONIC STATE OF AN ORGANISM. DISCRIMINATORY ANALYSIS SHOWED VERY PROMISING PERFORMANCE WHERE COMPOUNDS: LIPOPROTEINS, ALANINE, PYRUVATE, GLUTAMINE, TRYPTOPHAN AND 3-HYDROXYBUTYRATE WERE OF THE HIGHEST DISCRIMINATORY POWER WITH FEASIBILITY OF SUCCESSFUL STATISTICAL DISCRIMINATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  2418  37 EPIGENETIC SIGNATURE OF CHRONIC LOW BACK PAIN IN HUMAN T CELLS. OBJECTIVE: DETERMINE IF CHRONIC LOW BACK PAIN (LBP) IS ASSOCIATED WITH DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT WILL REVEAL NOVEL MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS AND EXPLORE THE FEASIBILITY OF EPIGENETIC DIAGNOSTIC MARKERS FOR PAIN-RELATED PATHOPHYSIOLOGY. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS OF 850,000 CPG SITES IN WOMEN AND MEN WITH CHRONIC LBP AND PAIN-FREE CONTROLS WAS PERFORMED. T CELLS WERE ISOLATED (DISCOVERY COHORT, N = 32) AND USED TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES, AND GENE ONTOLOGIES AND MOLECULAR PATHWAYS WERE IDENTIFIED. A POLYGENIC DNA METHYLATION SCORE FOR LBP WAS GENERATED IN BOTH WOMEN AND MEN. VALIDATION WAS PERFORMED IN AN INDEPENDENT COHORT (VALIDATION COHORT, N = 63) OF CHRONIC LBP AND HEALTHY CONTROLS. RESULTS: ANALYSIS WITH THE DISCOVERY COHORT REVEALED A TOTAL OF 2,496 AND 419 DIFFERENTIALLY METHYLATED CPGS IN WOMEN AND MEN, RESPECTIVELY. IN WOMEN, MOST OF THESE SITES WERE HYPOMETHYLATED AND ENRICHED IN GENES WITH FUNCTIONS IN THE EXTRACELLULAR MATRIX, IN THE IMMUNE SYSTEM (IE, CYTOKINES), OR IN EPIGENETIC PROCESSES. IN MEN, A UNIQUE CHRONIC LBP DNA METHYLATION SIGNATURE WAS IDENTIFIED CHARACTERIZED BY SIGNIFICANT ENRICHMENT FOR GENES FROM THE MAJOR HISTOCOMPATIBILITY COMPLEX. SEX-SPECIFIC POLYGENIC DNA METHYLATION SCORES WERE GENERATED TO ESTIMATE THE PAIN STATUS OF EACH INDIVIDUAL AND CONFIRMED IN THE VALIDATION COHORT USING PYROSEQUENCING. CONCLUSION: THIS STUDY REVEALS SEX-SPECIFIC DNA METHYLATION SIGNATURES IN HUMAN T CELLS THAT DISCRIMINATES CHRONIC LBP PARTICIPANTS FROM HEALTHY CONTROLS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  5613  47 SAFETY AND EFFICACY OF ABEXINOSTAT, A PAN-HISTONE DEACETYLASE INHIBITOR, IN NON-HODGKIN LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PHASE II STUDY. HISTONE DEACETYLASE INHIBITORS ARE MEMBERS OF A CLASS OF EPIGENETIC DRUGS THAT HAVE PROVEN ACTIVITY IN T-CELL MALIGNANCIES, BUT LITTLE IS KNOWN ABOUT THEIR EFFICACY IN B-CELL LYMPHOMAS. ABEXINOSTAT IS AN ORALLY AVAILABLE HYDROXAMATE-CONTAINING HISTONE DEACETYLASE INHIBITOR THAT DIFFERS FROM APPROVED INHIBITORS; ITS UNIQUE PHARMACOKINETIC PROFILE AND ORAL DOSING SCHEDULE, TWICE DAILY FOUR HOURS APART, ALLOWS FOR CONTINUOUS EXPOSURE AT CONCENTRATIONS REQUIRED TO EFFICIENTLY KILL TUMOR CELLS. IN THIS PHASE II STUDY, PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA RECEIVED ORAL ABEXINOSTAT AT 80 MG BID FOR 14 DAYS OF A 21-DAY CYCLE AND CONTINUED UNTIL PROGRESSIVE DISEASE OR UNACCEPTABLE TOXICITY. A TOTAL OF 100 PATIENTS WITH B-CELL MALIGNANCIES AND T-CELL LYMPHOMAS WERE ENROLLED BETWEEN OCTOBER 2011 AND JULY 2014. ALL PATIENTS RECEIVED AT LEAST ONE DOSE OF STUDY DRUG. PRIMARY REASONS FOR DISCONTINUATION INCLUDED PROGRESSIVE DISEASE (56%) AND ADVERSE EVENTS (25%). GRADE 3 OR OVER ADVERSE EVENTS AND ANY SERIOUS ADVERSE EVENTS WERE REPORTED IN 88% AND 73% OF PATIENTS, RESPECTIVELY. THE MOST FREQUENTLY REPORTED GRADE 3 OR OVER TREATMENT-EMERGENT RELATED ADVERSE EVENTS WERE THROMBOCYTOPENIA (80%), NEUTROPENIA (27%), AND ANEMIA (12%). AMONG THE 87 PATIENTS EVALUABLE FOR EFFICACY, OVERALL RESPONSE RATE WAS 28% (COMPLETE RESPONSE 5%), WITH HIGHEST RESPONSES OBSERVED IN PATIENTS WITH FOLLICULAR LYMPHOMA (OVERALL RESPONSE RATE 56%), T-CELL LYMPHOMA (OVERALL RESPONSE RATE 40%), AND DIFFUSE LARGE B-CELL LYMPHOMA (OVERALL RESPONSE RATE 31%). FURTHER INVESTIGATION OF THE SAFETY AND EFFICACY OF ABEXINOSTAT IN FOLLICULAR LYMPHOMA, T-CELL LYMPHOMA, AND DIFFUSE LARGE B-CELL LYMPHOMA IMPLEMENTING A LESS DOSE-INTENSE WEEK-ON-WEEK-OFF SCHEDULE IS WARRANTED. (TRIAL REGISTERED AT: EUDRACT-2009-013691-47).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  1785  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  3502  52 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12   667  47 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023	

13  1560  37 DNA METHYLATION OF ALZHEIMER DISEASE AND TAUOPATHY-RELATED GENES IN POSTMORTEM BRAIN. DNA METHYLATION OCCURS PREDOMINANTLY AT CYTOSINES THAT PRECEDE GUANINES IN DINUCLEOTIDE CPG SITES; IT IS ONE OF THE MOST IMPORTANT MECHANISMS FOR EPIGENETIC DNA REGULATION DURING NORMAL DEVELOPMENT AND FOR ABERRANT DNA IN CANCER. TO DETERMINE THE FEASIBILITY OF DNA METHYLATION STUDIES IN THE POSTMORTEM HUMAN BRAIN, WE EVALUATED BRAIN SAMPLES WITH VARIABLE POSTMORTEM ARTIFICIALLY INCREASED DELAYS UP TO 48 HOURS. DNA METHYLATION WAS ANALYZED IN SELECTED REGIONS OF MAPT, APP, AND PSEN1 IN THE FRONTAL CORTEX AND HIPPOCAMPUS OF CONTROLS (N=26) AND THOSE WITH ALZHEIMER DISEASE AT STAGES I TO II (N=17); ALZHEIMER DISEASE AT STAGES III TO IV (N=15); ALZHEIMER DISEASE AT STAGES V TO VI (N=12); ARGYROPHILIC GRAIN DISEASE (N=10); FRONTOTEMPORAL LOBAR DEGENERATION LINKED TO TAU MUTATIONS (N=6); FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-IMMUNOREACTIVE INCLUSIONS (N=4); FRONTOTEMPORAL LOBAR DEGENERATION WITH MOTOR NEURON DISEASE (N=3); PICK DISEASE (N=3); PARKINSON DISEASE (N=8); DEMENTIA WITH LEWY BODIES, PURE FORM (N=5); AND DEMENTIA WITH LEWY BODIES, COMMON FORM (N=15). UCHL1 (UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 1 GENE) WAS ANALYZED IN THE FRONTAL CORTEX OF CONTROLS AND THOSE WITH PARKINSON DISEASE AND RELATED SYNUCLEINOPATHIES. DNA METHYLATION SITES WERE VERY REPRODUCIBLE IN EVERY CASE. NO DIFFERENCES IN THE PERCENTAGE OF CPG METHYLATION WERE FOUND BETWEEN CONTROL AND DISEASE SAMPLES OR AMONG THE DIFFERENT PATHOLOGICAL ENTITIES IN ANY REGION ANALYZED. BECAUSE SMALL CHANGES IN METHYLATION OF DNA PROMOTERS IN VULNERABLE CELLS MIGHT HAVE NOT BEEN DETECTED IN TOTAL HOMOGENATES, HOWEVER, THESE RESULTS SHOULD BE INTERPRETED WITH CAUTION, PARTICULARLY AS THEY RELATE TO CHRONIC DEGENERATIVE DISEASES IN WHICH SMALL MODIFICATIONS MAY BE SUFFICIENT TO MODULATE DISEASE PROGRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14   765  44 CC-486 MAINTENANCE AFTER STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROMES. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROMES (MDS). INJECTABLE AZACITIDINE CAN IMPROVE POST-TRANSPLANT OUTCOMES BUT PRESENTS CHALLENGES WITH EXPOSURE AND COMPLIANCE. ORAL CC-486 ALLOWS EXTENDED DOSING TO PROLONG AZACITIDINE ACTIVITY. WE INVESTIGATED USE OF CC-486 MAINTENANCE THERAPY AFTER ALLOSCT. ADULTS WITH MDS OR AML IN MORPHOLOGIC COMPLETE REMISSION AT CC-486 INITIATION (42 TO 84 DAYS AFTER ALLOSCT) WERE INCLUDED. PATIENTS RECEIVED 1 OF 4 CC-486 DOSING SCHEDULES PER 28-DAY CYCLE FOR UP TO 12 CYCLES. ENDPOINTS INCLUDED SAFETY, PHARMACOKINETICS, GRAFT-VERSUS-HOST DISEASE (GVHD) INCIDENCE, RELAPSE/PROGRESSION RATE, AND SURVIVAL. OF 30 PATIENTS, 7 RECEIVED CC-486 ONCE DAILY FOR 7 DAYS PER CYCLE (200 MG, N = 3; 300 MG, N = 4) AND 23 FOR 14 DAYS PER CYCLE (150 MG, N = 4; 200 MG, N = 19 [EXPANSION COHORT]). GRADES 3 TO 4 ADVERSE EVENTS WERE INFREQUENT AND OCCURRED WITH SIMILAR FREQUENCY ACROSS REGIMENS. STANDARD CONCOMITANT MEDICATIONS DID NOT ALTER CC-486 PHARMACOKINETIC PARAMETERS. THREE PATIENTS (10%) EXPERIENCED GRADE III ACUTE GVHD AND 9 EXPERIENCED CHRONIC GVHD. OF 28 EVALUABLE PATIENTS, 6 (21%) RELAPSED OR HAD PROGRESSIVE DISEASE: 3 OF 7 PATIENTS (43%) WHO HAD RECEIVED 7-DAY DOSING AND 3 OF 23 (13%) WHO HAD RECEIVED 14-DAY DOSING. TRANSPLANT-RELATED MORTALITY WAS 3%. AT 19 MONTHS OF FOLLOW-UP, MEDIAN OVERALL SURVIVAL WAS NOT REACHED. ESTIMATED 1-YEAR SURVIVAL RATES WERE 86% AND 81% IN THE 7-DAY AND 14-DAY DOSING COHORTS, RESPECTIVELY. CC-486 MAINTENANCE WAS GENERALLY WELL TOLERATED, WITH LOW RATES OF RELAPSE, DISEASE PROGRESSION, AND GVHD. CC-486 MAINTENANCE MAY PERMIT EPIGENETIC MANIPULATION OF THE ALLOREACTIVE RESPONSE POSTALLOGRAFT. FINDINGS REQUIRE CONFIRMATION IN RANDOMIZED TRIALS. (CLINICALTRIALS.GOV NCT01835587.).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  5486  53 REVERSE INFLAMMAGING: LONG-TERM EFFECTS OF HCV CURE ON BIOLOGICAL AGE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION CAN BE CURED WITH DIRECT-ACTING ANTIVIRALS (DAAS). HOWEVER, NOT ALL SEQUELAE OF CHRONIC HEPATITIS C APPEAR TO BE COMPLETELY REVERSIBLE AFTER SUSTAINED VIROLOGIC RESPONSE (SVR). RECENTLY, CHRONIC VIRAL INFECTIONS HAVE BEEN SHOWN TO BE ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION DEFINED BY THE EPIGENETIC CLOCK. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER CHRONIC HCV INFECTION IS ASSOCIATED WITH EPIGENETIC CHANGES AND BIOLOGICAL AGE ACCELERATION AND WHETHER THIS IS REVERSIBLE AFTER SVR. METHODS: WE INCLUDED 54 WELL-CHARACTERIZED INDIVIDUALS WITH CHRONIC HEPATITIS C WHO ACHIEVED SVR AFTER DAA THERAPY AT THREE TIME POINTS: DAA TREATMENT INITIATION, END OF TREATMENT, AND LONG-TERM FOLLOW-UP (MEDIAN 96 WEEKS AFTER END OF TREATMENT). GENOME-WIDE DNA METHYLATION STATUS WAS DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND USED TO CALCULATE EPIGENETIC AGE ACCELERATION (EAA) USING HORVATH'S CLOCK. RESULTS: INDIVIDUALS WITH HCV HAD AN OVERALL SIGNIFICANT EAA OF 3.12 YEARS AT BASELINE COMPARED WITH -2.61 YEARS IN THE AGE- AND SEX-MATCHED REFERENCE GROUP (P <0.00003). HCV ELIMINATION RESULTED IN A SIGNIFICANT LONG-TERM INCREASE IN DNA METHYLATION DOMINATED BY HYPERMETHYLATED CPGS IN ALL PATIENT GROUPS. ACCORDINGLY, EAA DECREASED TO 1.37 YEARS AT LONG-TERM FOLLOW-UP. THE DECREASE IN EAA WAS SIGNIFICANT ONLY BETWEEN THE END OF TREATMENT AND FOLLOW-UP (P = 0.01). INTERESTINGLY, EIGHT INDIVIDUALS WHO DEVELOPED HEPATOCELLULAR CARCINOMA AFTER SVR HAD THE HIGHEST EAA AND SHOWED NO EVIDENCE OF REVERSAL AFTER SVR. CONCLUSIONS: OUR DATA CONTRIBUTE TO THE UNDERSTANDING OF THE BIOLOGICAL IMPACT OF HCV ELIMINATION AFTER DAA THERAPY AND DEMONSTRATE THAT HCV ELIMINATION CAN LEAD TO "REVERSE INFLAMMAGING". IN ADDITION, OUR DATA SUPPORT THE POTENTIAL USE OF BIOLOGICAL AGE AS A BIOMARKER FOR HCV SEQUELAE AFTER SVR. IMPACT AND IMPLICATIONS: CHRONIC HEPATITIS C VIRUS INFECTION IS NOW CURABLE WITH DIRECT-ACTING ANTIVIRALS, BUT IT REMAINS UNCLEAR WHETHER HEPATITIS C SEQUELAE ARE FULLY REVERSIBLE AFTER VIRAL ELIMINATION. OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OR ACCELERATION OF BIOLOGICAL AGE ARE REVERSIBLE IN PRINCIPLE, BUT THIS REQUIRES TIME, WHILE A LACK OF REVERSIBILITY APPEARS TO BE ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. WHILE MOST CLINICAL RISK SCORES NOW TAKE CHRONOLOGICAL AGE INTO ACCOUNT, IT MAY BE WORTHWHILE TO EXPLORE HOW BIOLOGICAL AGE MIGHT IMPROVE THESE SCORES IN THE FUTURE. BIOLOGICAL AGE MAY BE A CORNERSTONE FOR THE INDIVIDUALIZED CLINICAL ASSESSMENT OF PATIENTS IN THE FUTURE, AS IT BETTER REFLECTS PATIENTS' LIFESTYLE AND ENVIRONMENTAL EXPOSURES OVER DECADES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  6386  41 THE ROLE OF QUANTITATIVE NPTX2 HYPERMETHYLATION AS A NOVEL SERUM DIAGNOSTIC MARKER IN PANCREATIC CANCER. OBJECTIVES: THE MAJORITY OF PANCREATIC CANCERS ARE FOUND TO BE UNRESECTABLE, AND THE ONLY CHANCE FOR CURE LIES ON EARLY DETECTION AND COMPLETE RESECTION. SEVERAL GENES HAVE BEEN DISCOVERED TO BE ABERRANTLY METHYLATED IN PRIMARY PANCREATIC CANCER TISSUE, AND THIS CANCER DNA CAN BE DETECTED IN THE PLASMA. THE AIMS OF THIS STUDY WERE TO DEVELOP A NOVEL DIAGNOSTIC MARKER BASED ON EPIGENETIC CHARACTERISTICS OF PANCREATIC CANCER. METHODS: WE ENROLLED 104 PATIENTS WITH PANCREATIC CANCER, 60 WITH CHRONIC PANCREATITIS, AND 5 WITH BENIGN BILIARY STONE DISEASES. THE BLOOD SAMPLES WERE COLLECTED BEFORE SURGERY OR ANY KINDS OF TREATMENT MODALITIES. DNA WAS EXTRACTED FROM THE PLASMA OF EACH PATIENT, AND NPTX2 (NEURONAL PENTRAXIN II) CPG ISLAND HYPERMETHYLATION WAS EXAMINED QUANTITATIVELY BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NPTX2 HYPERMETHYLATION LEVELS WERE SIGNIFICANTLY HIGHER COMPARED WITH CHRONIC PANCREATITIS (P = 0.016). THE SENSITIVITY AND SPECIFICITY WERE 80% AND 76%, RESPECTIVELY (CUTOFF = 0.015). NPTX2 GENE HYPERMETHYLATION LEVEL WAS SIGNIFICANTLY ELEVATED IN CORRELATION WITH HIGHER AMERICAN JOINT COMMITTEE ON CANCER STAGES. CONCLUSIONS: THE ABERRANTLY METHYLATED NPTX2 GENE MAY HELP TO DISTINGUISH BETWEEN CHRONIC PANCREATITIS AND PANCREATIC CANCER WITH CONVENTIONAL DIAGNOSTIC TOOLS AND COULD BECOME A VALUABLE DIAGNOSTIC MARKER.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17  6112  42 THE EPIGENETIC CLOCK AS A PREDICTOR OF DISEASE AND MORTALITY RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: AGEING IS ONE OF THE PRINCIPAL RISK FACTORS FOR MANY CHRONIC DISEASES. HOWEVER, THERE IS CONSIDERABLE BETWEEN-PERSON VARIATION IN THE RATE OF AGEING AND INDIVIDUAL DIFFERENCES IN THEIR SUSCEPTIBILITY TO DISEASE AND DEATH. EPIGENETIC MECHANISMS MAY PLAY A ROLE IN HUMAN AGEING, AND DNA METHYLATION AGE BIOMARKERS MAY BE GOOD PREDICTORS OF AGE-RELATED DISEASES AND MORTALITY RISK. THE AIMS OF THIS SYSTEMATIC REVIEW WERE TO IDENTIFY AND SYNTHESISE THE EVIDENCE FOR AN ASSOCIATION BETWEEN PERIPHERALLY MEASURED DNA METHYLATION AGE AND LONGEVITY, AGE-RELATED DISEASE, AND MORTALITY RISK. METHODS: A SYSTEMATIC SEARCH WAS CONDUCTED IN LINE WITH THE PREFERRED REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. USING RELEVANT SEARCH TERMS, MEDLINE, EMBASE, COCHRANE CENTRAL REGISTER OF CONTROLLED TRIALS, AND PSYCHINFO DATABASES WERE SEARCHED TO IDENTIFY ARTICLES MEETING THE INCLUSION CRITERIA. STUDIES WERE ASSESSED FOR BIAS USING JOANNA BRIGGS INSTITUTE CRITICAL APPRAISAL CHECKLISTS. DATA WAS EXTRACTED FROM STUDIES MEASURING AGE ACCELERATION AS A PREDICTOR OF AGE-RELATED DISEASES, MORTALITY OR LONGEVITY, AND THE FINDINGS FOR SIMILAR OUTCOMES COMPARED. USING REVIEW MANAGER 5.3 SOFTWARE, TWO META-ANALYSES (ONE PER EPIGENETIC CLOCK) WERE CONDUCTED ON STUDIES MEASURING ALL-CAUSE MORTALITY. RESULTS: TWENTY-THREE RELEVANT ARTICLES WERE IDENTIFIED, INCLUDING A TOTAL OF 41,607 PARTICIPANTS. FOUR STUDIES FOCUSED ON AGEING AND LONGEVITY, 11 ON AGE-RELATED DISEASE (CANCER, CARDIOVASCULAR DISEASE, AND DEMENTIA), AND 11 ON MORTALITY. THERE WAS SOME, ALTHOUGH INCONSISTENT, EVIDENCE FOR AN ASSOCIATION BETWEEN INCREASED DNA METHYLATION AGE AND RISK OF DISEASE. META-ANALYSES INDICATED THAT EACH 5-YEAR INCREASE IN DNA METHYLATION AGE WAS ASSOCIATED AN 8 TO 15% INCREASED RISK OF MORTALITY. CONCLUSION: DUE TO THE SMALL NUMBER OF STUDIES AND HETEROGENEITY IN STUDY DESIGN AND OUTCOMES, THE ASSOCIATION BETWEEN DNA METHYLATION AGE AND AGE-RELATED DISEASE AND LONGEVITY IS INCONCLUSIVE. INCREASED EPIGENETIC AGE WAS ASSOCIATED WITH MORTALITY RISK, BUT POSITIVE PUBLICATION BIAS NEEDS TO BE CONSIDERED. FURTHER RESEARCH IS NEEDED TO DETERMINE THE EXTENT TO WHICH DNA METHYLATION AGE CAN BE USED AS A CLINICAL BIOMARKER.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  3560  33 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  1444  35 DIFFERENTIALLY HYPOMETHYLATED CELL-FREE DNA AND CORONARY COLLATERAL CIRCULATION. BACKGROUND: THE FACTORS AFFECTING CARDIOPROTECTIVE COLLATERAL CIRCULATION ARE STILL INCOMPLETELY UNDERSTOOD. RECENTLY, CHARACTERISTICS, SUCH AS CPG METHYLATION OF CELL-FREE DNA (CFDNA), HAVE BEEN REPORTED AS MARKERS WITH CLINICAL UTILITY. THE AIM OF THIS STUDY WAS TO EVALUATE WHETHER CFDNA METHYLATION PATTERNS ARE ASSOCIATED WITH THE GRADE OF CORONARY COLLATERAL CIRCULATION (CCC). RESULT: IN THIS CASE-CONTROL STUDY, CLINICAL AND ANGIOGRAPHIC DATA WERE OBTAINED FROM 143 PATIENTS (MEAN AGE, 58 YEARS, MALE 71%) WITH CHRONIC TOTAL CORONARY OCCLUSION. ENZYMATIC METHYL-SEQUENCING (EM-SEQ) LIBRARIES WERE PREPARED USING THE CFDNA EXTRACTED FROM THE PLASMA. DATA WERE PROCESSED TO OBTAIN THE AVERAGE METHYLATION FRACTION (AMF) TABLES OF GENOMIC REGIONS FROM WHICH BLACKLISTED REGIONS WERE REMOVED. UNSUPERVISED ANALYSIS OF THE OBTAINED AMF VALUES SHOWED THAT SOME OF THE CHANGES IN METHYLATION WERE DUE TO CCC. THROUGH RANDOM FOREST PREPARATION PROCESS, 256 DIFFERENTIALLY METHYLATED REGION (DMR) CANDIDATES SHOWING STRONG ASSOCIATION WITH CCC WERE SELECTED. A RANDOM FOREST CLASSIFIER WAS THEN CONSTRUCTED, AND THE AREA UNDER THE CURVE OF THE RECEIVER OPERATING CHARACTERISTIC CURVE INDICATED AN APPROPRIATE PREDICTIVE FUNCTION FOR CCC. FINALLY, 20 DMRS WERE IDENTIFIED TO HAVE SIGNIFICANTLY DIFFERENT AMF VALUES BETWEEN THE GOOD AND POOR CCC GROUPS. PARTICULARLY, THE GOOD CCC GROUP EXHIBITED HYPOMETHYLATED DMRS. PATHWAY ANALYSIS REVEALED FIVE PATHWAYS, INCLUDING TGF-BETA SIGNALING, TO BE ASSOCIATED WITH GOOD CCC. CONCLUSION: THESE DATA HAVE DEMONSTRATED THAT DIFFERENTIAL HYPOMETHYLATION WAS IDENTIFIED IN DOZENS OF CFDNA REGIONS IN PATIENTS WITH GOOD CCC. OUR RESULTS SUPPORT THE CLINICAL UTILITY OF NONINVASIVELY OBTAINED EPIGENETIC SIGNATURES FOR PREDICTING COLLATERAL CIRCULATION IN PATIENTS WITH VASCULAR DISEASES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20   414  32 ANALYSIS OF PROMOTER METHYLATION IN STOOL: A NOVEL METHOD FOR THE DETECTION OF COLORECTAL CANCER. BACKGROUND & AIMS: DETECTION OF TUMOR-DERIVED DNA ALTERATIONS IN STOOL IS AN INTRIGUING NEW APPROACH WITH HIGH POTENTIAL FOR THE NONINVASIVE DETECTION OF COLORECTAL CANCER (CRC). BECAUSE OF HETEROGENEITY OF TUMORS, USUALLY MULTIPLE MARKERS DISTRIBUTED THROUGHOUT THE HUMAN GENOME NEED TO BE ANALYZED. THIS IS LABOR INTENSIVE AND DOES NOT ALLOW FOR HIGH THROUGH-PUT SCREENING. THEREFORE, MARKERS WITH HIGH SENSITIVITY AND GOOD SPECIFICITY ARE NEEDED. WE EXPLORED THE POTENTIAL OF A SINGLE EPIGENETIC MARKER IN COMPARISON WITH FECAL OCCULT BLOOD TESTING (FOBT) FOR THE DISCRIMINATION OF PATIENTS WITH CRCS AND ADENOMAS FROM THOSE WITHOUT. METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) WAS PERFORMED TO ANALYZE HYPERMETHYLATED IN CANCER 1 (HIC1) PROMOTER METHYLATION STATUS IN A BLINDED FASHION IN STOOL SAMPLES FROM 26 PATIENTS WITH CRC, 13 WITH ADENOMA > OR =1 CM, 9 WITH HYPERPLASTIC POLYPS, 9 WITH CHRONIC INFLAMMATORY BOWEL DISEASE, AND 32 WITH ENDOSCOPICALLY NORMAL COLON. RESULTS: NINETY-SEVEN PERCENT OF THE STOOL SAMPLES CONTAINED AMPLIFIABLE DNA. FORTY-TWO PERCENT OF THE SAMPLES FROM PATIENTS WITH CRC AND 31% OF THE SAMPLES FROM PATIENTS WITH COLORECTAL ADENOMA > OR =1 CM WERE POSITIVE FOR HIC1 PROMOTER METHYLATION. NO METHYLATED HIC1 PROMOTER DNA WAS DETECTED IN THE FECAL DNA FROM PATIENTS WITH ENDOSCOPICALLY NORMAL COLON OR HYPERPLASTIC POLYPS. CONCLUSIONS: THE EPIGENETIC MARKER HIC1 PROMOTER METHYLATION CARRIES HIGH POTENTIAL FOR THE REMOTE DETECTION OF CRCS. WE POSTULATE THAT A PANEL OF MERELY A FEW GENETIC AND EPIGENETIC MARKERS WILL BE REQUIRED FOR THE HIGHLY SENSITIVE AND SPECIFIC DETECTION OF CRCS AND ADENOMAS IN FECAL SAMPLES FROM AFFECTED PATIENTS.	2005