1  5333 140 PYRUVATE KINASE DEFICIENCY: THE GENOTYPE-PHENOTYPE ASSOCIATION. RED CELL PYRUVATE KINASE (PK) DEFICIENCY IS THE MOST FREQUENT ENZYME ABNORMALITY OF GLYCOLYSIS CAUSING CHRONIC NON-SPHEROCYTIC HAEMOLYTIC ANAEMIA. THE DISEASE IS TRANSMITTED AS AN AUTOSOMAL RECESSIVE TRAIT, CLINICAL SYMPTOMS USUALLY OCCURRING IN COMPOUND HETEROZYGOTES FOR TWO MUTANT ALLELES AND IN HOMOZYGOTES. THE SEVERITY OF HAEMOLYSIS IS HIGHLY VARIABLE, RANGING FROM VERY MILD OR FULLY COMPENSATED FORMS TO LIFE-THREATENING NEONATAL ANAEMIA NECESSITATING EXCHANGE TRANSFUSIONS. ERYTHROCYTE PK IS SYNTHESISED UNDER THE CONTROL OF THE PK-LR GENE LOCATED ON CHROMOSOME 1. ONE HUNDRED EIGHTY DIFFERENT MUTATIONS IN PK-LR GENE, MOSTLY MISSENSE, HAVE BEEN SO FAR REPORTED ASSOCIATED TO PK DEFICIENCY. FIRST ATTEMPTS TO DELINEATE THE GENOTYPE-PHENOTYPE ASSOCIATION WERE MAINLY BASED ON THE ANALYSIS OF THE ENZYME'S THREE-DIMENSIONAL STRUCTURE AND THE OBSERVATION OF THE FEW HOMOZYGOUS PATIENTS. MORE RECENTLY, THE COMPARISON OF THE RECOMBINANT MUTANTS OF HUMAN RED CELL PK WITH THE WILD-TYPE ENZYME HAS ENABLED THE EFFECTS OF AMINO ACID REPLACEMENTS ON THE ENZYME MOLECULAR PROPERTIES TO BE DETERMINED. HOWEVER, THE CLINICAL MANIFESTATIONS OF RED CELL ENZYME DEFECTS ARE NOT MERELY DEPENDENT ON THE MOLECULAR PROPERTIES OF THE MUTANT PROTEIN BUT RATHER REFLECT THE COMPLEX INTERACTIONS OF ADDITIONAL FACTORS, INCLUDING GENETIC BACKGROUND, CONCOMITANT FUNCTIONAL POLYMORPHISMS OF OTHER ENZYMES, POSTTRANSLATIONAL OR EPIGENETIC MODIFICATIONS, INEFFECTIVE ERYTHROPOIESIS AND DIFFERENCES IN SPLENIC FUNCTION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  1837  34 EFFECTS OF PALMITATE ON GENOME-WIDE MRNA EXPRESSION AND DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. BACKGROUND: CIRCULATING FREE FATTY ACIDS ARE OFTEN ELEVATED IN PATIENTS WITH TYPE 2 DIABETES (T2D) AND OBESE INDIVIDUALS. CHRONIC EXPOSURE TO HIGH LEVELS OF SATURATED FATTY ACIDS HAS DETRIMENTAL EFFECTS ON ISLET FUNCTION AND INSULIN SECRETION. ALTERED GENE EXPRESSION AND EPIGENETICS MAY CONTRIBUTE TO T2D AND OBESITY. HOWEVER, THERE IS LIMITED INFORMATION ON WHETHER FATTY ACIDS ALTER THE GENOME-WIDE TRANSCRIPTOME PROFILE IN CONJUNCTION WITH DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. TO DISSECT THE MOLECULAR MECHANISMS LINKING LIPOTOXICITY TO IMPAIRED INSULIN SECRETION, WE INVESTIGATED THE EFFECTS OF A 48 H PALMITATE TREATMENT IN VITRO ON GENOME-WIDE MRNA EXPRESSION AND DNA METHYLATION PATTERNS IN HUMAN PANCREATIC ISLETS. METHODS: GENOME-WIDE MRNA EXPRESSION WAS ANALYZED USING AFFYMETRIX GENECHIP((R)) HUMAN GENE 1.0 ST WHOLE TRANSCRIPT-BASED ARRAY (N = 13) AND GENOME-WIDE DNA METHYLATION WAS ANALYZED USING INFINIUM HUMANMETHYLATION450K BEADCHIP (N = 13) IN HUMAN PANCREATIC ISLETS EXPOSED TO PALMITATE OR CONTROL MEDIA FOR 48 H. A NON-PARAMETRIC PAIRED WILCOXON STATISTICAL TEST WAS USED TO ANALYZE MRNA EXPRESSION. APOPTOSIS WAS MEASURED USING APO-ONE((R)) HOMOGENEOUS CASPASE-3/7 ASSAY (N = 4). RESULTS: WHILE GLUCOSE-STIMULATED INSULIN SECRETION WAS DECREASED, THERE WAS NO SIGNIFICANT EFFECT ON APOPTOSIS IN HUMAN ISLETS EXPOSED TO PALMITATE. WE IDENTIFIED 1,860 DIFFERENTIALLY EXPRESSED GENES IN PALMITATE-TREATED HUMAN ISLETS. THESE INCLUDE CANDIDATE GENES FOR T2D, SUCH AS TCF7L2, GLIS3, HNF1B AND SLC30A8. ADDITIONALLY, GENES IN GLYCOLYSIS/GLUCONEOGENESIS, PYRUVATE METABOLISM, FATTY ACID METABOLISM, GLUTATHIONE METABOLISM AND ONE CARBON POOL BY FOLATE WERE DIFFERENTIALLY EXPRESSED IN PALMITATE-TREATED HUMAN ISLETS. PALMITATE TREATMENT ALTERED THE GLOBAL DNA METHYLATION LEVEL AND DNA METHYLATION LEVELS OF CPG ISLAND SHELVES AND SHORES, 5'UTR, 3'UTR AND GENE BODY REGIONS IN HUMAN ISLETS. MOREOVER, 290 GENES WITH DIFFERENTIAL EXPRESSION HAD A CORRESPONDING CHANGE IN DNA METHYLATION, FOR EXAMPLE, TCF7L2 AND GLIS3. IMPORTANTLY, OUT OF THE GENES DIFFERENTIALLY EXPRESSED DUE TO PALMITATE TREATMENT IN HUMAN ISLETS, 67 WERE ALSO ASSOCIATED WITH BMI AND 37 WERE DIFFERENTIALLY EXPRESSED IN ISLETS FROM T2D PATIENTS. CONCLUSION: OUR STUDY DEMONSTRATES THAT PALMITATE TREATMENT OF HUMAN PANCREATIC ISLETS GIVES RISE TO EPIGENETIC MODIFICATIONS THAT TOGETHER WITH ALTERED GENE EXPRESSION MAY CONTRIBUTE TO IMPAIRED INSULIN SECRETION AND T2D.	2014	
                                    
3  4707  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4    12  32 2017 CLINICAL TRIALS UPDATE IN NEW TREATMENTS OF BETA-THALASSEMIA. THE UNDERLYING BASIS OF BETA-THALASSEMIA PATHOLOGY IS THE DIMINISHED BETA-GLOBIN SYNTHESIS LEADING TO ALPHA-GLOBIN ACCUMULATION AND PREMATURE APOPTOTIC DESTRUCTION OF ERYTHROBLASTS, CAUSING OXIDATIVE STRESS-INDUCED INEFFECTIVE ERYTHROPOIESIS, BONE MARROW HYPERPLASIA, SPLENOMEGALY, AND INCREASED INTESTINAL IRON ABSORPTION WITH PROGRESSIVE IRON OVERLOAD. BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE LED TO THE RECOGNITION OF NEW TARGETS WITH POTENTIAL THERAPEUTIC UTILITY. AGENTS SUCH AS JAK2 INHIBITORS AND TGF-BETA LIGAND TRAPS THAT REDUCE THE INEFFECTIVE ERYTHROPOIESIS PROCESS ARE ALREADY BEING TESTED IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS THAT AIM TO REDUCE OXIDATIVE STRESS (ACTIVATORS OF FOXO3, HRI-EIF2AP, PRX2, HSP70, AND PK ANTI-OXIDANT SYSTEMS AND INHIBITORS OF HO-1) AND TO DECREASE IRON OVERLOAD (HEPCIDIN AGONISTS, ERYTHROFERRONE INHIBITORS AND EXOGENOUS TRANSFERRIN) ARE ALSO UNDER EXPERIMENTAL INVESTIGATION. SIGNIFICANT PROGRESS HAS ALSO BEEN MADE IN THE AREA OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH SEVERAL ONGOING CLINICAL TRIALS EXAMINING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONOR SELECTION AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS REACHED A CRITICAL POINT AND PHASE 1 CLINICAL TRIALS HAVE RECENTLY BEEN LAUNCHED TO EXAMINE THE EFFECTIVENESS AND ESPECIALLY LONG TERM SAFETY. EPIGENETIC MANIPULATION AND GENOMIC EDITING OF THE GAMMA- OR BETA-GLOBIN GENE ARE NOVEL AND PROMISING EXPERIMENTAL GENE THERAPY APPROACHES FOR BETA-THALASSEMIA GIVING HOPE FOR CURE FOR THIS CHRONIC DISEASE. THIS REVIEW OUTLINES THE KEY POINTS OF THE MOLECULAR MECHANISMS UNDERLYING BETA-THALASSEMIA IN RELATION TO THE DEVELOPMENT OF NEW THERAPIES AND AN UPDATE IS GIVEN BOTH AT THE PRE-CLINICAL AND CLINICAL LEVEL. AM. J. HEMATOL. 91:1135-1145, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  3056  31 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                       
6  4753  33 NOVEL THERAPEUTIC ADVANCES IN BETA-THALASSEMIA. THE MAIN CHARACTERISTIC OF THE PATHOPHYSIOLOGY OF BETA-THALASSEMIA IS REDUCED BETA-GLOBIN CHAIN PRODUCTION. THE INEVITABLE IMBALANCE IN THE ALPHA/BETA-GLOBIN RATIO AND ALPHA-GLOBIN ACCUMULATION LEAD TO OXIDATIVE STRESS IN THE ERYTHROID LINEAGE, APOPTOSIS, AND INEFFECTIVE ERYTHROPOIESIS. THE RESULT IS COMPENSATORY HEMATOPOIETIC EXPANSION AND IMPAIRED HEPCIDIN PRODUCTION THAT CAUSES INCREASED INTESTINAL IRON ABSORPTION AND PROGRESSIVE IRON OVERLOAD. CHRONIC HEMOLYSIS AND RED BLOOD CELL TRANSFUSIONS ALSO CONTRIBUTE TO IRON TISSUE DEPOSITION. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS LED TO THE DETECTION OF NEW CURATIVE OR "DISEASE-MODIFYING" THERAPEUTIC OPTIONS. SUBSTANTIAL EVOLVEMENT HAS BEEN MADE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH CURRENT CLINICAL TRIALS INVESTIGATING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONORS AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS ALSO MOVED FORWARD, AND PHASE 2 CLINICAL TRIALS WITH THE USE OF BETA-GLOBIN INSERTION TECHNIQUES HAVE RECENTLY BEEN SUCCESSFULLY COMPLETED LEADING TO APPROVAL FOR USE IN TRANSFUSION-DEPENDENT PATIENTS. GENETIC AND EPIGENETIC MANIPULATION OF THE GAMMA- OR BETA-GLOBIN GENE HAVE ENTERED THE CLINICAL TRIAL SETTING. AGENTS SUCH AS TGF-BETA LIGAND TRAPS AND PYRUVATE KINASE ACTIVATORS, WHICH REDUCE THE INEFFECTIVE ERYTHROPOIESIS, HAVE BEEN TESTED IN CLINICAL TRIALS WITH FAVORABLE RESULTS. ONE TGF-BETA LIGAND TRAP, LUSPATERCEPT, HAS BEEN APPROVED FOR USE IN ADULTS WITH TRANSFUSION-DEPENDENT BETA-THALASSEMIA. THE INDUCTION OF HBF WITH THE PHOSPHODIESTERASE 9 INHIBITOR IMR-687, WHICH INCREASE CYCLIC GUANOSINE MONOPHOSPHATE, IS CURRENTLY BEING TESTED. ANOTHER THERAPEUTIC APPROACH IS TO TARGET THE DYSREGULATION OF IRON HOMEOSTASIS, USING, FOR EXAMPLE, HEPCIDIN AGONISTS (INHIBITORS OF TMPRSS6 AND MINIHEPCIDINS) OR FERROPORTIN INHIBITORS (VIT-2763). THIS REVIEW PROVIDES AN UPDATE ON THE NOVEL THERAPEUTIC OPTIONS THAT ARE PRESENTLY IN DEVELOPMENT AT THE CLINICAL LEVEL IN BETA-THALASSEMIA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  3410  28 HOXA5 UNDERGOES DYNAMIC DNA METHYLATION AND TRANSCRIPTIONAL REPRESSION IN THE ADIPOSE TISSUE OF MICE EXPOSED TO HIGH-FAT DIET. BACKGROUND/OBJECTIVES: THE GENOMIC BASES OF THE ADIPOSE TISSUE ABNORMALITIES INDUCED BY CHRONIC POSITIVE CALORIE EXCESS HAVE BEEN ONLY PARTIALLY ELUCIDATED. WE ADOPTED A GENOME-WIDE APPROACH TO DIRECTLY TEST WHETHER LONG-TERM HIGH-FAT DIET (HFD) EXPOSURE AFFECTS THE DNA METHYLATION PROFILE OF THE MOUSE ADIPOSE TISSUE AND TO IDENTIFY THE FUNCTIONAL CONSEQUENCES OF THESE CHANGES. SUBJECTS/METHODS: WE HAVE USED EPIDIDYMAL FAT OF MICE FED EITHER HIGH-FAT (HFD) OR REGULAR CHOW (STD) DIET FOR 5 MONTHS AND PERFORMED GENOME-WIDE DNA METHYLATION ANALYSES BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). MOUSE HOMEOBOX (HOX) GENE DNA METHYLATION PCR, RT-QPCR AND BISULPHITE SEQUENCING ANALYSES WERE THEN PERFORMED. RESULTS: MICE FED THE HFD PROGRESSIVELY EXPANDED THEIR ADIPOSE MASS ACCOMPANIED BY A SIGNIFICANT DECREASE IN GLUCOSE TOLERANCE (P<0.001) AND INSULIN SENSITIVITY (P<0.05). MEDIP-SEQ DATA ANALYSIS REVEALED A UNIFORM DISTRIBUTION OF DIFFERENTIALLY METHYLATED REGIONS (DMR) THROUGH THE ENTIRE ADIPOCYTE GENOME, WITH A HIGHER NUMBER OF HYPERMETHYLATED REGIONS IN HFD MICE (P<0.005). THIS DIFFERENT METHYLATION PROFILE WAS ACCOMPANIED BY INCREASED EXPRESSION OF THE DNMT3A DNA METHYLTRANSFERASE (DNMT; P<0.05) AND THE METHYL-CPG-BINDING DOMAIN PROTEIN MBD3 (P<0.05) GENES IN HFD MICE. GENE ONTOLOGY ANALYSIS REVEALED THAT, IN THE HFD-TREATED MICE, THE HOX FAMILY OF DEVELOPMENT GENES WAS HIGHLY ENRICHED IN DIFFERENTIALLY METHYLATED GENES (P=0.008). TO VALIDATE THIS FINDING, HOXA5, WHICH IS IMPLICATED IN FAT TISSUE DIFFERENTIATION AND REMODELING, HAS BEEN SELECTED AND ANALYZED BY BISULPHITE SEQUENCING, CONFIRMING HYPERMETHYLATION IN THE ADIPOSE TISSUE FROM THE HFD MICE. HOXA5 HYPERMETHYLATION WAS ASSOCIATED WITH DOWNREGULATION OF HOXA5 MRNA AND PROTEIN EXPRESSION. FEEDING ANIMALS PREVIOUSLY EXPOSED TO THE HFD WITH A STANDARD CHOW DIET FOR TWO FURTHER MONTHS IMPROVED THE METABOLIC PHENOTYPE OF THE ANIMALS, ACCOMPANIED BY RETURN OF HOXA5 METHYLATION AND EXPRESSION LEVELS (P<0.05) TO VALUES SIMILAR TO THOSE OF THE CONTROL MICE MAINTAINED UNDER STANDARD CHOW. CONCLUSIONS: HFD INDUCES ADIPOSE TISSUE ABNORMALITIES ACCOMPANIED BY EPIGENETIC CHANGES AT THE HOXA5 ADIPOSE TISSUE REMODELING GENE.	2016	
                                                                                                                                                                                                                                                                             
8  3850  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9   561  33 BARIATRIC SURGERY-INDUCED WEIGHT LOSS AND ASSOCIATED GENOME-WIDE DNA-METHYLATION ALTERATIONS IN OBESE INDIVIDUALS. BACKGROUND: OBESITY IS A MULTIFACTORIAL AND CHRONIC CONDITION OF GROWING UNIVERSAL CONCERN. IT HAS RECENTLY BEEN REPORTED THAT BARIATRIC SURGERY IS A MORE SUCCESSFUL TREATMENT FOR SEVERE OBESITY THAN OTHER NONINVASIVE INTERVENTIONS, RESULTING IN RAPID SIGNIFICANT WEIGHT LOSS AND ASSOCIATED CHRONIC DISEASE REMISSION. THE IDENTIFICATION OF DISTINCT EPIGENETIC PATTERNS IN PATIENTS WHO ARE OBESE OR HAVE METABOLIC IMBALANCES HAS SUGGESTED A POTENTIAL ROLE FOR EPIGENETIC ALTERATIONS IN CAUSAL OR MEDIATING PATHWAYS IN THE DEVELOPMENT OF OBESITY-RELATED PATHOLOGIES. SPECIFIC CHANGES IN THE EPIGENOME (DNA METHYLOME), ASSOCIATED WITH METABOLIC DISORDERS, CAN BE DETECTED IN THE BLOOD. WE INVESTIGATED WHETHER SUCH EPIGENETIC CHANGES ARE REVERSIBLE AFTER WEIGHT LOSS USING GENOME-WIDE DNA METHYLOME ANALYSIS OF BLOOD SAMPLES FROM INDIVIDUALS WITH SEVERE OBESITY (MEAN BMI ~ 45) UNDERGOING BARIATRIC SURGERY. RESULTS: OUR ANALYSIS REVEALED 41 SIGNIFICANT (BONFERRONI P < 0.05) AND 1169 (FALSE DISCOVERY RATE P < 0.05) SUGGESTIVE DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH WEIGHT LOSS DUE TO BARIATRIC SURGERY. AMONG THE 41 SIGNIFICANT DMPS, 5 CPGS WERE REPLICATED IN AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS (THE HEAVIER TWIN UNDERWENT DIET-INDUCED WEIGHT LOSS). THE EFFECT SIZES OF THESE 5 CPGS WERE CONSISTENT ACROSS DISCOVERY AND REPLICATION SETS (P < 0.05). WE ALSO IDENTIFIED 192 DIFFERENTIALLY METHYLATED REGIONS (DMRS) AMONG WHICH SMAD6 AND PFKFB3 GENES WERE THE TOP HYPERMETHYLATED AND HYPOMETHYLATED REGIONS, RESPECTIVELY. PATHWAY ENRICHMENT ANALYSIS OF THE DMR-ASSOCIATED GENES SHOWED THAT FUNCTIONAL PATHWAYS RELATED TO IMMUNE FUNCTION AND TYPE 1 DIABETES WERE SIGNIFICANT. WEIGHT LOSS DUE TO BARIATRIC SURGERY ALSO SIGNIFICANTLY DECELERATED EPIGENETIC AGE 12 MONTHS AFTER THE INTERVENTION (MEAN = - 4.29; P = 0.02). CONCLUSIONS: WE IDENTIFIED WEIGHT LOSS-ASSOCIATED DNA-METHYLATION ALTERATIONS TARGETING IMMUNE AND INFLAMMATORY GENE PATHWAYS IN BLOOD SAMPLES FROM BARIATRIC-SURGERY PATIENTS. THE TOP HITS WERE REPLICATED IN SAMPLES FROM AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS FOLLOWING A HYPOCALORIC DIET. ENERGY RESTRICTION AND BARIATRIC SURGERY THUS SHARE CPGS THAT MAY REPRESENT EARLY INDICATORS OF RESPONSE TO THE METABOLIC EFFECTS OF WEIGHT LOSS. THE ANALYSIS OF BARIATRIC SURGERY-ASSOCIATED DMRS SUGGESTS THAT EPIGENETIC REGULATION OF GENES INVOLVED IN ENDOTHELIAL AND ADIPOSE TISSUE FUNCTION IS KEY IN THE PATHOPHYSIOLOGY OF OBESITY.	2022	

10  4491  37 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS.	1992	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  5448  24 REPRESSION OF HDAC5 BY ACETATE RESTORES HYPOTHALAMIC-PITUITARY-OVARIAN FUNCTION IN TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) ACCOUNTS FOR 90-95 % OF WORLDWIDE DIABETES CASES AND IS PRIMARILY CHARACTERIZED BY INSULIN RESISTANCE. ITS PROGRESSION AS A CHRONIC METABOLIC DISEASE HAS BEEN LARGELY ASSOCIATED WITH FEMALE REPRODUCTIVE ABNORMALITIES, INCLUDING OVARIAN DYSFUNCTION WITH CONSEQUENT INFERTILITY. EPIGENETIC MODIFICATIONS HAVE BEEN SUGGESTED AS A POSSIBLE LINK TO METABOLIC COMORBIDITIES. WE THEREFORE HYPOTHESIZED THAT SHORT CHAIN FATTY ACIDS, ACETATE (ACA), A POTENTIAL HISTONE DEACETYLASE INHIBITOR (HDAC) AMELIORATES HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) DYSFUNCTION IN T2DM. FEMALE WISTAR RATS WEIGHING 160-190 G WERE ALLOTTED INTO THREE GROUPS (N = 6/GROUP): CONTROL (VEHICLE; PO), T2D AND T2D + ACA (200 MG/KG; PO). T2DM WAS INDUCED BY FRUCTOSE ADMINISTRATION (10 %; W/V) FOR 6 WEEKS AND SINGLE DOSE OF STREPTOZOTOCIN (35 MG/KG; IP). THE PRESENT DATA SHOWED THAT IN ADDITION TO INSULIN RESISTANCE, INCREASED FASTING BLOOD GLUCOSE AND INSULIN, T2DM INDUCED ELEVATED PLASMA, HYPOTHALAMIC AND OVARIAN TRIGLYCERIDE, LIPID PEROXIDATION, TNF-ALPHA AND GLUTATHIONE DEPLETION. ASIDE, T2DM ALSO LED TO INCREASED PLASMA LACTATE PRODUCTION AND GAMMA-GLUTAMYL TRANSFERASE AS WELL AS DECREASED GONADOTROPINS/17BETA-ESTRADIOL. HISTOLOGICALLY, HYPOTHALAMUS, PITUITARY AND OVARIES REVEALED DISRUPTED NEURONAL CELLS/MODERATE HEMORRHAGE, ALTERED MORPHOLOGY/VASCULAR CONGESTIONS, AND DEGENERATED ANTRAL FOLLICLE/GRAAFIAN FOLLICLE WITH MILD FIBROSIS AND INFILTRATED INFLAMMATORY CELLS RESPECTIVELY IN T2D ANIMALS. INTERESTINGLY, THESE ALTERATIONS WERE ACCOMPANIED BY ELEVATED PLASMA/HYPOTHALAMIC HDAC5 AND ATTENUATED WHEN TREATED WITH ACETATE. THE PRESENT RESULTS DEMONSTRATE THAT T2DM INDUCES HPO DYSFUNCTION, WHICH IS ACCOMPANIED BY ELEVATED CIRCULATING/HYPOTHALAMIC HDAC5. THE RESULTS IN ADDITION SUGGEST THAT ACETATE RESTORES HPO FUNCTION IN T2DM BY SUPPRESSION OF HDAC5 AND ENHANCEMENT OF INSULIN SENSITIVITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12  3383  29 HNF1B NEPHROPATHY HAS A SLOW-PROGRESSIVE PHENOTYPE IN CHILDHOOD-WITH THE EXCEPTION OF VERY EARLY ONSET CASES: RESULTS OF THE GERMAN MULTICENTER HNF1B CHILDHOOD REGISTRY. BACKGROUND: HNF1B GENE MUTATIONS ARE AN IMPORTANT CAUSE OF BILATERAL (CYSTIC) DYSPLASIA IN CHILDREN, COMPLICATED BY CHRONIC RENAL INSUFFICIENCY. THE CLINICAL VARIABILITY, THE ABSENCE OF GENOTYPE-PHENOTYPE CORRELATIONS, AND LIMITED LONG-TERM DATA RENDER COUNSELING OF AFFECTED FAMILIES DIFFICULT. METHODS: LONGITUDINAL DATA OF 62 CHILDREN PROBANDS WITH GENETICALLY PROVEN HNF1B NEPHROPATHY WAS OBTAINED IN A MULTICENTER APPROACH. GENETIC FAMILY CASCADE SCREENING WAS PERFORMED IN 30/62 CASES. RESULTS: EIGHTY-SEVEN PERCENT OF PATIENTS HAD BILATERAL DYSPLASIA, 74% VISIBLE BILATERAL, AND 16% UNILATERAL RENAL CYSTS AT THE END OF OBSERVATION. CYST DEVELOPMENT WAS NON-PROGRESSIVE IN 72% WITH A MEAN GLOMERULAR FILTRATION RATE (GFR) LOSS OF - 0.33 ML/MIN/1.73M(2) PER YEAR (+/- 8.9). IN PATIENTS WITH AN INCREASE IN CYST NUMBER, THE ANNUAL GFR REDUCTION WAS - 2.8 ML/MIN/1.73M(2) (+/- 13.2), IN THE TOTAL COHORT - 1.0 ML/MIN/1.73M(2) (+/-10.3). A SUBSET OF HNF1B PATIENTS DIFFERS FROM THIS GROUP AND DEVELOPS END STAGE RENAL DISEASE (ESRD) AT VERY EARLY AGES < 2 YEARS. HYPERURICEMIA (37%) WAS A FREQUENT FINDING AT YOUNG AGE (MEDIAN 1 YEAR), WHEREAS HYPOMAGNESEMIA (24%), ELEVATED LIVER ENZYMES (21%), AND HYPERGLYCEMIA (8%) SHOWED AN INCREASED INCIDENCE IN THE TEENAGED CHILD. GENETIC ANALYSIS REVEALED NO GENOTYPE-PHENOTYPE CORRELATIONS BUT A SIGNIFICANT PARENT-OF-ORIGIN EFFECT WITH A PREPONDERANCE OF 81% OF MATERNAL INHERITANCE IN DOMINANT CASES. CONCLUSIONS: IN MOST CHILDREN, HNF1B NEPHROPATHY HAS A NON-PROGRESSIVE COURSE OF CYST DEVELOPMENT AND A SLOW-PROGRESSIVE COURSE OF KIDNEY FUNCTION. A SUBGROUP OF PATIENTS DEVELOPED ESRD AT VERY YOUNG AGE < 2 YEARS REQUIRING SPECIAL MEDICAL ATTENTION. THE PARENT-OF-ORIGIN EFFECT SUGGESTS AN INFLUENCE OF EPIGENETIC MODIFIERS IN HNF1B DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  1495  23 DNA HYPERMETHYLATION OF CELL CYCLE (P15 AND P16) AND APOPTOTIC (P14, P53, DAPK AND TMS1) GENES IN PERIPHERAL BLOOD OF LEUKEMIA PATIENTS. ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES HAS BEEN REPORTED IN ALL MAJOR TYPES OF LEUKEMIA WITH POTENTIAL INVOLVEMENT IN THE INACTIVATION OF REGULATORY CELL CYCLE AND APOPTOSIS GENES. HOWEVER, MOST OF THE PREVIOUS REPORTS DID NOT SHOW THE EXTENT OF CONCURRENT METHYLATION OF MULTIPLE GENES IN THE FOUR LEUKEMIA TYPES. HERE, WE ANALYZED SIX KEY GENES (P14, P15, P16, P53, DAPK AND TMS1) FOR DNA METHYLATION USING METHYLATION SPECIFIC PCR TO ANALYZE PERIPHERAL BLOOD OF 78 LEUKEMIA PATIENTS (24 CML, 25 CLL, 12 AML, AND 17 ALL) AND 24 HEALTHY VOLUNTEERS. IN CML, METHYLATION WAS DETECTED FOR P15 (11%), P16 (9%), P53 (23%) AND DAPK (23%), IN CLL, P14 (25%), P15 (19%), P16 (12%), P53 (17%) AND DAPK (36%), IN AML, P14 (8%), P15 (45%), P53 (9%) AND DAPK (17%) AND IN ALL, P15 (14%), P16 (8%), AND P53 (8%). THIS STUDY HIGHLIGHTED AN ESSENTIAL ROLE OF DAPK METHYLATION IN CHRONIC LEUKEMIA IN CONTRAST TO P15 METHYLATION IN THE ACUTE CASES, WHEREAS TMS1 HYPERMETHYLATION WAS ABSENT IN ALL CASES. FURTHERMORE, HYPERMETHYLATION OF MULTIPLE GENES PER PATIENT WAS OBSERVED, WITH OBVIOUS SELECTIVENESS IN THE 9P21 CHROMOSOMAL REGION GENES (P14, P15 AND P16). INTERESTINGLY, METHYLATION OF P15 INCREASED THE RISK OF METHYLATION IN P53, AND VICE VERSA, BY FIVE FOLDS (P=0.03) INDICATING POSSIBLE SYNERGISTIC EPIGENETIC DISRUPTION OF DIFFERENT PHASES OF THE CELL CYCLE OR BETWEEN THE CELL CYCLE AND APOPTOSIS. THE INVESTIGATION OF MULTIPLE RELATIONSHIPS BETWEEN METHYLATED GENES MIGHT SHED LIGHT ON TUMOR SPECIFIC INACTIVATION OF THE CELL CYCLE AND APOPTOTIC PATHWAYS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14  5478  22 RESULTS OF A RANDOMIZED STUDY OF 3 SCHEDULES OF LOW-DOSE DECITABINE IN HIGHER-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA. EPIGENETIC THERAPY WITH HYPOMETHYLATING DRUGS IS NOW THE STANDARD OF CARE IN MYELODYSPLASTIC SYNDROME (MDS). RESPONSE RATES REMAIN LOW, AND MECHANISM-BASED DOSE OPTIMIZATION HAS NOT BEEN REPORTED. WE INVESTIGATED THE CLINICAL AND PHARMACODYNAMIC RESULTS OF DIFFERENT DOSE SCHEDULES OF DECITABINE. ADULTS WITH ADVANCED MDS OR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) WERE RANDOMIZED TO 1 OF 3 DECITABINE SCHEDULES: (1) 20 MG/M2 INTRAVENOUSLY DAILY FOR 5 DAYS; (2) 20 MG/M2 SUBCUTANEOUSLY DAILY FOR 5 DAYS; AND (3) 10 MG/M2 INTRAVENOUSLY DAILY FOR 10 DAYS. RANDOMIZATION FOLLOWED A BAYESIAN ADAPTIVE DESIGN. NINETY-FIVE PATIENTS WERE TREATED (77 WITH MDS, AND 18 WITH CMML). OVERALL, 32 PATIENTS (34%) ACHIEVED A COMPLETE RESPONSE (CR), AND 69 (73%) HAD AN OBJECTIVE RESPONSE BY THE NEW MODIFIED INTERNATIONAL WORKING GROUP CRITERIA. THE 5-DAY INTRAVENOUS SCHEDULE, WHICH HAD THE HIGHEST DOSE-INTENSITY, WAS SELECTED AS OPTIMAL; THE CR RATE IN THAT ARM WAS 39%, COMPARED WITH 21% IN THE 5-DAY SUBCUTANEOUS ARM AND 24% IN THE 10-DAY INTRAVENOUS ARM (P < .05). THE HIGH DOSE-INTENSITY ARM WAS ALSO SUPERIOR AT INDUCING HYPOMETHYLATION AT DAY 5 AND AT ACTIVATING P15 EXPRESSION AT DAYS 12 OR 28 AFTER THERAPY. WE CONCLUDE THAT A LOW-DOSE, DOSE-INTENSITY SCHEDULE OF DECITABINE OPTIMIZES EPIGENETIC MODULATION AND CLINICAL RESPONSES IN MDS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  4686  39 NEW THERAPEUTIC TARGETS IN TRANSFUSION-DEPENDENT AND -INDEPENDENT THALASSEMIA. BETA-THALASSEMIAS ARE CHARACTERIZED BY REDUCED PRODUCTION OF BETA-GLOBIN CHAIN, RESULTING IN ALPHA/BETA-CHAIN UNBALANCE AND PRECIPITATION OF ALPHA-GLOBIN-HEME COMPLEXES AND DETERMINING INEFFECTIVE ERYTHROPOIESIS. INEFFECTIVE ERYTHROPOIESIS, CHRONIC HEMOLYTIC ANEMIA, AND COMPENSATORY HEMATOPOIETIC EXPANSION ARE THE DISEASE HALLMARKS, AND THEY ARE RELATED TO THE SEVERITY OF THE CHAIN UNBALANCE. SEVERAL CLINICAL FORMS OF BETA-THALASSEMIA, INCLUDING THE COINHERITANCE OF BETA-THALASSEMIA WITH HEMOGLOBIN E RESULTING IN HEMOGLOBIN E/BETA-THALASSEMIA, HAVE BEEN DESCRIBED. CLINICALLY, BETA-THALASSEMIAS CAN BE CLASSIFIED AS TRANSFUSION-DEPENDENT THALASSEMIA (TDT) AND NON-TRANSFUSION-DEPENDENT THALASSEMIA (NTDT) ACCORDING TO THE SEVERITY OF THE PHENOTYPE, WHICH IS CAUSED BY A WIDE SPECTRUM OF MUTATIONS IN A HOMOZYGOUS OR COMPOUND HETEROZYGOUS STATE. CURRENT TREATMENT OF TDT CONSISTS OF REGULAR TRANSFUSIONS THAT LEAD TO IRON OVERLOAD, REQUIRING IRON CHELATION TO PREVENT IRON-RELATED ORGAN TOXICITY. NTDT PATIENTS DO NOT REQUIRE TRANSFUSIONS OR ONLY OCCASIONALLY REQUIRE THEM; HOWEVER, THEY DEVELOP IRON OVERLOAD AS WELL BECAUSE OF INCREASED INTESTINAL IRON ABSORPTION CAUSED BY CHRONIC ANEMIA. HEMATOPOIETIC STEM CELL ALLOGENIC TRANSPLANT IS THE ONLY APPROVED CURE FOR BETA-THALASSEMIA; HOWEVER, IT IS STILL LIMITED BY CLINICAL CONDITIONS AND THE AVAILABILITY OF MATCHED DONORS AS WELL AS BY POTENTIAL GRAFT-VERSUS-HOST DISEASE (GVHD). GENE THERAPY COULD AVOID THE GVHD RISK, ALTHOUGH HEMATOPOIETIC STEM CELLS MUST BE GENETICALLY MODIFIED EX VIVO. EPIGENETIC MANIPULATION AND GENOMIC EDITING ARE NOVEL EXPERIMENTAL APPROACHES. AN INCREASED UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT CONTROLS THE DISEASE PROCESS PROMPTED US TO EXPLORE ALTERNATIVE THERAPEUTIC APPROACHES THAT ADDRESS THE UNDERLYING CHAIN UNBALANCE, INEFFECTIVE ERYTHROPOIESIS, AND IRON DYSREGULATION. MOLECULES, SUCH AS JAK2 INHIBITORS AND THE ACTIVIN-RECEPTOR LIGAND TRAP THAT TARGET INEFFECTIVE ERYTHROPOIESIS, ARE ALREADY IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS AIMED TO GENERATE IRON-RESTRICTED ERYTHROPOIESIS ARE ALSO UNDER EXPERIMENTAL EVALUATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                              
16  6386  21 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   414  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  4989  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  1140  21 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  5613  23 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