1 1622 117 DNA METHYLTRANSFERASES IN MALAR MELASMA AND THEIR MODIFICATION BY SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. BACKGROUND: MALAR MELASMA HAS A CHRONIC AND RECURRENT CHARACTER THAT MAY BE RELATED TO EPIGENETIC CHANGES. OBJECTIVE: TO RECOGNIZE THE EXPRESSION AND DNA METHYLATION OF DNA METHYLTRANSFERASES (DNMTS) IN MALAR MELASMA AND PERILESIONAL SKIN, AS WELL AS THE CHANGES IN DNMTS AFTER THEIR TREATMENT WITH SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. METHODS: THIRTY FEMALE PATIENTS WERE CLINICALLY EVALUATED FOR THE EXPRESSION OF DNMT1 AND DNMT3B USING REAL-TIME PCR AND IMMUNOFLUORESCENCE. THESE INITIAL RESULTS WERE COMPARED TO RESULTS AFTER EIGHT WEEKS OF TREATMENT WITH SUNSCREEN IN COMBINATION WITH NIACINAMIDE, RETINOIC ACID, OR PLACEBO. RESULTS: THE RELATIVE EXPRESSION OF DNMT1 WAS SIGNIFICANTLY ELEVATED IN MELASMA COMPARED WITH UNAFFECTED SKIN IN ALL SUBJECTS, INDICATING DNA HYPERMETHYLATION. AFTER TREATMENT, IT WAS DECREASED IN ALL GROUPS: NIACINAMIDE (7 VERSUS 1; P<0.01), RETINOIC ACID (7 VERSUS 2; P<0.05), AND PLACEBO (7 VERSUS 3; P<0.05), WHICH CORRELATES WITH CLINICAL IMPROVEMENT. DNMT3B WAS NOT OVEREXPRESSED IN LESIONAL SKIN BUT REDUCED IN ALL GROUPS. CONCLUSIONS: WE FOUND DNA HYPERMETHYLATION IN MELASMA LESIONS. ENVIRONMENTAL FACTORS SUCH AS SOLAR RADIATION MAY INDUCE CELLULAR CHANGES THAT TRIGGER HYPERPIGMENTATION THROUGH THE ACTIVATION OF PATHWAYS REGULATED BY EPIGENETIC MODIFICATIONS. HOWEVER, LIMITING OR DECREASING DNA METHYLATION THROUGH SUNSCREEN, NIACINAMIDE, AND RETINOIC ACID TREATMENTS THAT PROVIDE PHOTOPROTECTION AND GENETIC TRANSCRIPTION CAN COUNTERACT THIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  145  40 ABERRANT DNA METHYLATION STATUS AND MRNA EXPRESSION LEVEL OF SMG1 GENE IN CHRONIC MYELOID LEUKEMIA: A CASE-CONTROL STUDY. OOBJECTIVE: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE MALIGNANCY WITH DIFFERENT STAGES. ABERRANT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HAVE BEEN INTRODUCED AS A SIGNATURE FOR DIVERSE CANCERS WHICH ALSO PLAYS A CRUCIAL ROLE IN CML PATHOGENESIS AND DEVELOPMENT. SUPPRESSOR WITH MORPHOGENETIC EFFECT ON GENITALIA (SMG1) GENE RECENTLY HAS BEEN BROUGHT TO THE SPOTLIGHT AS A POTENT TUMOR SUPPRESSOR GENE THAT CAN BE SUPPRESSED BY TUMORS FOR FURTHER PROGRESS. THE PRESENT STUDY AIMS TO INVESTIGATE SMG1 STATUS IN CML PATIENTS. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, PERIPHERAL BLOOD FROM 30 PATIENTS WITH DIFFERENT PHASES OF CML [NEW CASE (N)=10, COMPLETE MOLECULAR REMISSION (CMR)=10, BLASTIC PHASE (BP)=10] AND 10 HEALTHY SUBJECTS WERE COLLECTED. METHYLATION STATUS AND EXPRESSION LEVEL OF SMG1 GENE PROMOTER WAS ASSESSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND QUANTITATIVE REVERSE-TRANSCRIPTION PCR, RESPECTIVELY. RESULTS: MSP RESULTS OF SMG1 GENE PROMOTOR IN THE NEW CASE GROUP WERE METHYLATED (60% METHYLATED, 30% HEMIMETHYLATED AND 10% UNMETHYLATED). ALL CMR AND CONTROL GROUP PATIENTS WERE UNMETHYLATED IN THE SMG1 GENE PROMOTER. IN THE BP GROUP, METHYLATED SMG1 PROMOTER WAS SEEN (50% OF PATIENTS HAD A METHYLATED STATUS AND 50% HAD HEMIMETHYLATED STATUS). IN COMPARISON WITH THE HEALTHY SUBJECTS, EXPRESSION LEVEL OF SMG1 IN THE NEW CASE GROUP WAS DECREASED (P<0.01); IN THE CMR GROUP AND BP-CML GROUPS, IT WAS INCREASED (P<0.05). NO SIGNIFICANT CORRELATION BETWEEN PATIENTS' HEMATOLOGICAL FEATURES AND SMG1 METHYLATION WAS SEEN. CONCLUSION: OUR RESULTS DEMONSTRATED THAT ABERRANT METHYLATION OF SMG1 OCCURRED IN CML PATIENTS AND IT HAD A SIGNIFICANT ASSOCIATION WITH SMG1 EXPRESSION. SMG1 GENE PROMOTER SHOWED DIVERSE METHYLATED STATUS AND SUBSEQUENT EXPRESSION LEVELS IN DIFFERENT PHASES OF CML. THESE FINDINGS SUGGESTED POSSIBLE PARTICIPATION OF SMG1 SUPPRESSION IN THE CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 1067  38 CLINICAL UTILITY OF PDSS2 EXPRESSION TO STRATIFY PATIENTS AT RISK FOR RECURRENCE OF HEPATOCELLULAR CARCINOMA. IDENTIFICATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS IS REQUIRED FOR OPTIMAL STRATIFICATION OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AT RISK FOR RECURRENCE AND ADVERSE PROGNOSIS. COENZYME Q10 (COQ10), WHICH MEDIATES APOPTOSIS, IS SYNTHESIZED BY PRENYL DIPHOSPHATE SYNTHASE SUBUNIT 2 (PDSS2). IN THE PRESENT STUDY WE EVALUATED THE CLINICAL SIGNIFICANCE AND REGULATORY MECHANISMS OF PDSS2 EXPRESSION IN HCC. PDSS2 EXPRESSION LEVELS AND THOSE OF GENES ENCODING POTENTIALLY INTERACTING PROTEINS AS WELL AS THE METHYLATION STATUS OF THE PDSS2 PROMOTER REGION WERE ANALYZED IN HCC CELL LINES. PDSS2 MRNA LEVELS IN 151 PAIRS OF RESECTED SPECIMENS WERE DETERMINED TO EVALUATE THE ASSOCIATION OF PDSS2 EXPRESSION AND CLINICOPATHOLOGICAL FACTORS. THE EXPRESSION AND DISTRIBUTION OF PDSS2 WERE DETERMINED USING IMMUNOHISTOCHEMISTRY. PDSS2 MRNA EXPRESSION WAS DECREASED IN SIX OF NINE HCC CELL LINES AND SIGNIFICANTLY CORRELATED WITH THOSE OF HEPATOCYTE NUCLEAR FACTOR 4ALPHA. PDSS2 TRANSCRIPTION IN HCC CELLS WITH DECREASED PDSS2 EXPRESSION ACCOMPANYING HYPERMETHYLATION WAS REACTIVATED AFTER TREATING THESE CELLS WITH A METHYLATION INHIBITOR. MEAN EXPRESSION LEVELS OF PDSS2 MRNA RELATIVE TO THAT OF UNINVOLVED LIVER DIMINISHED GRADUALLY IN THE ORDER OF CHRONIC HEPATITIS TO CIRRHOSIS, AND EACH WAS SIGNIFICANTLY HIGHER THAN THOSE OF HCCS. PDSS2 AND PDSS2 MRNA LEVELS WERE CONSISTENT. DECREASED PDSS2 MRNA LEVELS WERE DETECTED IN HCC TISSUES OF 56 PATIENTS, CORRELATED WITH SHORTER DISEASE-SPECIFIC SURVIVAL, AND WAS IDENTIFIED AS AN INDEPENDENT PROGNOSTIC FACTOR. PDSS2 IS A PUTATIVE TUMOR SUPPRESSOR, AND PROMOTER HYPERMETHYLATION IS A KEY REGULATORY MECHANISM IN HCC. DECREASED LEVELS OF PDSS2 MRNA EXPRESSION MAY REPRESENT A NOVEL BIOMARKER OF HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4 3907  28 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5 3484  39 IDENTIFICATION OF CHROMATIN REMODELING GENES ARID4A AND ARID4B AS LEUKEMIA SUPPRESSOR GENES. BACKGROUND: LEUKEMIA EVOLVES THROUGH A MULTISTEP PROCESS FROM PREMALIGNANCY TO MALIGNANCY. EPIGENETIC ALTERATIONS, INCLUDING HISTONE MODIFICATIONS, HAVE BEEN PROPOSED TO PLAY AN IMPORTANT ROLE IN TUMORIGENESIS. THE INVOLVEMENT OF TWO CHROMATIN REMODELING GENES, RETINOBLASTOMA-BINDING PROTEIN 1 (RBBP1/ARID4A) AND RBBP1-LIKE 1 (RBBP1L1/ARID4B), IN LEUKEMOGENESIS WAS NOT CHARACTERIZED. METHODS: THE LEUKEMIC PHENOTYPE OF MICE DEFICIENT FOR ARID4A WITH OR WITHOUT HAPLOINSUFFICIENCY FOR ARID4B WAS INVESTIGATED BY SERIALLY MONITORING COMPLETE BLOOD COUNTS TOGETHER WITH MICROSCOPIC HISTOLOGIC ANALYSIS AND FLOW CYTOMETRIC ANALYSIS OF BONE MARROW AND SPLEEN FROM THE ARID4A(-/-) MICE OR ARID4A(-/-)ARID4B(+/-) MICE. REGULATION IN BONE MARROW CELLS OF DOWNSTREAM GENES IMPORTANT FOR NORMAL HEMATOPOIESIS WAS ANALYZED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION. GENOTYPIC EFFECTS ON HISTONE MODIFICATIONS WERE EXAMINED BY WESTERN BLOTTING AND IMMUNOFLUORESCENCE ANALYSIS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: YOUNG (2-5 MONTHS OLD) ARID4A-DEFICIENT MICE HAD INEFFECTIVE BLOOD CELL PRODUCTION IN ALL HEMATOPOIETIC LINEAGES. BEYOND 5 MONTHS OF AGE, THE ARID4A(-/-) MICE MANIFESTED MONOCYTOSIS, ACCOMPANIED BY SEVERE ANEMIA AND THROMBOCYTOPENIA. THESE SICK ARID4A(-/-) MICE SHOWED BONE MARROW FAILURE WITH MYELOFIBROSIS ASSOCIATED WITH SPLENOMEGALY AND HEPATOMEGALY. FIVE OF 42 ARID4A(-/-) MICE AND 10 OF 12 ARID4A(-/-)ARID4B(+/-) MICE PROGRESSED TO ACUTE MYELOID LEUKEMIA (AML) AND HAD RAPID FURTHER INCREASES OF LEUKOCYTE COUNTS. EXPRESSION OF HOX GENES (HOXB3, HOXB5, HOXB6, AND HOXB8) WAS DECREASED IN ARID4A-DEFICIENT BONE MARROW CELLS WITH OR WITHOUT ARID4B HAPLOINSUFFICIENCY, AND FOXP3 EXPRESSION WAS REDUCED IN ARID4A(-/-)ARID4B(+/-) BONE MARROW. INCREASES OF HISTONE TRIMETHYLATION OF H3K4, H3K9, AND H4K20 (FOLD INCREASES IN TRIMETHYLATION = 32, 95% CONFIDENCE INTERVAL [CI] = 27 TO 32; 45, 95% CI = 41 TO 49; AND 2.2, 95% CI = 1.7 TO 2.7, RESPECTIVELY) WERE OBSERVED IN THE BONE MARROW OF ARID4A-DEFICIENT MICE. CONCLUSIONS: ARID4A-DEFICIENT MICE INITIALLY DISPLAY INEFFECTIVE HEMATOPOIESIS, FOLLOWED BY TRANSITION TO CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)-LIKE MYELODYSPLASTIC/MYELOPROLIFERATIVE DISORDER, AND THEN TRANSFORMATION TO AML. THE DISEASE PROCESSES IN THE ARID4A-DEFICIENT MICE ARE VERY SIMILAR TO THE COURSE OF EVENTS IN HUMANS WITH CMML AND AML. THIS MOUSE MODEL HAS THE POTENTIAL TO FURNISH ADDITIONAL INSIGHTS INTO THE ROLE OF EPIGENETIC ALTERATIONS IN LEUKEMOGENESIS, AND IT MAY BE USEFUL IN DEVELOPING NOVEL PHARMACOLOGICAL APPROACHES TO TREATMENT OF PRELEUKEMIC AND LEUKEMIC STATES.	2008	
                                                                                                                                                                                                                                                                                      
6 2761  37 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  154  28 ABERRANT METHYLATION OF NUCLEOTIDE EXCISION REPAIR GENES IS ASSOCIATED WITH CHRONIC ARSENIC POISONING. OBJECTIVE: TO DEFINE WHETHER ABERRANT METHYLATION OF DNA REPAIR GENES IS ASSOCIATED WITH CHRONIC ARSENIC POISONING. METHODS: HUNDRED AND TWO ENDEMIC ARSENICOSIS PATIENTS AND 36 HEALTHY SUBJECTS WERE RECRUITED. METHYLIGHT AND BISULFITE SEQUENCING (BSP) ASSAYS WERE USED TO EXAMINE THE METHYLATION STATUS OF ERCC1, ERCC2 AND XPC GENES IN PERIPHERAL BLOOD LYMPHOCYTES (PBLS) AND SKIN LESIONS OF ARSENICOSIS PATIENTS AND NAASO(2)-TREATED HACAT CELLS. RESULTS: HYPERMETHYLATION OF ERCC1 AND ERCC2 AND SUPPRESSED GENE EXPRESSION WERE FOUND IN PBLS AND SKIN LESIONS OF ARSENICOSIS PATIENTS AND WAS CORRELATED WITH THE LEVEL OF ARSENIC EXPOSURE. PARTICULARLY, THE EXPRESSION OF ERCC1 AND ERCC2 WAS ASSOCIATED WITH THE SEVERITY OF SKIN LESIONS. IN VITRO STUDIES REVEALED AN INDUCTION OF ERCC2 HYPERMETHYLATION AND DECREASED MRNA EXPRESSION IN RESPONSE TO NAASO(2) TREATMENT. CONCLUSION: HYPERMETHYLATION OF ERCC1 AND ERCC2 AND CONCOMITANT SUPPRESSION OF GENE EXPRESSION MIGHT BE SERVED AS THE EPIGENETIC MARKS ASSOCIATED WITH ARSENIC EXPOSURE AND ADVERSE HEALTH EFFECTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8 2763  32 EXPRESSION OF THE LEUKEMIC PROGNOSTIC MARKER CD7 IS LINKED TO EPIGENETIC MODIFICATIONS IN CHRONIC MYELOID LEUKEMIA. BACKGROUND: EXPRESSION LEVELS OF THE CELL SURFACE GLYCOPROTEIN, CD7, AND THE SERINE PROTEASE, ELASTASE 2 (ELA2), IN THE LEUKEMIC CELLS OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) HAVE BEEN ASSOCIATED WITH CLINICAL OUTCOME. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS THAT UNDERLIE THE VARIABLE EXPRESSION OF THESE GENES IN THE LEUKEMIC CELLS. RESULTS: TO ADDRESS THIS QUESTION, WE COMPARED THE LEVEL OF THEIR EXPRESSION WITH THE DNA METHYLATION AND HISTONE ACETYLATION STATUS OF 5' SEQUENCES OF BOTH GENES IN LEUKEMIC CELL LINES AND PRIMITIVE (LIN-CD34+) LEUKEMIC CELLS FROM CHRONIC PHASE CML PATIENTS. DNA METHYLATION OF THE ELA2 GENE PROMOTER DID NOT CORRELATE WITH ITS EXPRESSION PATTERN IN LIN-CD34+ CELLS FROM CHRONIC PHASE CML PATIENT SAMPLES EVEN THOUGH THERE WAS CLEAR DIFFERENTIAL DNA METHYLATION OF THIS LOCUS IN ELA2-EXPRESSING AND NON-EXPRESSING CELL LINES. IN CONTRAST, WE FOUND A STRONG RELATION BETWEEN CD7 EXPRESSION AND TRANSCRIPTION-PERMISSIVE CHROMATIN MODIFICATIONS, BOTH AT THE LEVEL OF DNA METHYLATION AND HISTONE ACETYLATION WITH EVIDENCE OF HYPOMETHYLATION OF THE CD7 PROMOTER REGION IN THE LIN-CD34+ CELLS FROM CML PATIENTS WITH HIGH CD7 EXPRESSION. CONCLUSION: THESE FINDINGS INDICATE A LINK BETWEEN EPIGENETIC MODIFICATIONS AND CD7 EXPRESSION IN PRIMITIVE CML CELLS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9 1843  30 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10 1298  28 DECREASED NUCLEAR RECEPTOR ACTIVITY AND EPIGENETIC MODULATION ASSOCIATES WITH DOWN-REGULATION OF HEPATIC DRUG-METABOLIZING ENZYMES IN CHRONIC KIDNEY DISEASE. PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) REQUIRE MANY MEDICATIONS. CYP2C AND CYP3A DRUG-METABOLIZING ENZYMES PLAY A CRITICAL ROLE IN DETERMINING THE PHARMACOKINETICS OF THE MAJORITY OF PRESCRIBED MEDICATIONS. THESE ENZYMES ARE TRANSCRIPTIONALLY REGULATED BY THE NUCLEAR RECEPTORS PREGNANE X RECEPTOR (PXR) AND HEPATIC NUCLEAR FACTOR 4ALPHA (HNF-4ALPHA). EXPRESSION OF CYP2C AND CYP3A IS DECREASED IN CKD; HOWEVER, THE MECHANISMS BY WHICH THIS OCCURS IS UNKNOWN. WE INDUCED CKD IN RATS BY 5/6 NEPHRECTOMY AND USED CHROMATIN IMMUNOPRECIPITATION (CHIP) TO DETERMINE NUCLEAR RECEPTOR- AND EPIGENETIC ALTERATION-MEDIATED DIFFERENCES IN THE PROMOTER REGION OF THE CYP2C AND CYP3A GENES. RNA POLYMERASE II AND HNF-4ALPHA BINDING WAS DECREASED 76 AND 57% IN THE CYP2C11 PROMOTOR AND 71 AND 77% IN THE CYP3A2 PROMOTER, RESPECTIVELY (P<0.05). CHIP ALSO REVEALED A 57% DECREASE IN PXR BINDING TO THE CYP3A2 PROMOTER IN CKD RATS (P<0.05). THE DECREASE IN PXR AND HNF-4ALPHA BINDING WAS ACCOMPANIED BY DIMINISHED HISTONE 4 ACETYLATION IN THE CYP3A2 PROMOTER (48%) AND HISTONE 3 ACETYLATION IN THE CYP2C11 (77%) AND CYP3A2 (77%) PROMOTER LOCI FOR NUCLEAR RECEPTOR ACTIVATION (P<0.05). THIS STUDY SUGGESTS THAT DECREASED NUCLEAR RECEPTOR BINDING AND HISTONE ACETYLATION MAY CONTRIBUTE TO THE MECHANISM OF DRUG-METABOLIZING ENZYME DOWN-REGULATION AND ALTERED PHARMACOKINETICS IN CKD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11 6636  39 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	

12 1950  32 EPIGENETIC ACTIVATION OF TENSIN 4 PROMOTES GASTRIC CANCER PROGRESSION. GASTRIC CANCER (GC) IS A COMPLEX DISEASE INFLUENCED BY MULTIPLE GENETIC AND EPIGENETIC FACTORS. CHRONIC INFLAMMATION CAUSED BY HELICOBACTER PYLORI INFECTION AND DIETARY RISK FACTORS CAN RESULT IN THE ACCUMULATION OF ABERRANT DNA METHYLATION IN GASTRIC MUCOSA, WHICH PROMOTES GC DEVELOPMENT. TENSIN 4 (TNS4), A MEMBER OF THE TENSIN FAMILY OF PROTEINS, IS LOCALIZED TO FOCAL ADHESION SITES, WHICH CONNECT THE EXTRACELLULAR MATRIX AND CYTOSKELETAL NETWORK. WE IDENTIFIED UPREGULATION OF TNS4 IN GC USING QUANTITATIVE REVERSE TRANSCRIPTION PCR WITH 174 PAIRED SAMPLES OF GC TUMORS AND ADJACENT NORMAL TISSUES. TRANSCRIPTIONAL ACTIVATION OF TNS4 OCCURRED EVEN DURING THE EARLY STAGE OF TUMOR DEVELOPMENT. TNS4 DEPLETION IN GC CELL LINES THAT EXPRESSED HIGH TO MODERATE LEVELS OF TNS4, I.E., SNU-601, KATO III, AND MKN74, REDUCED CELL PROLIFERATION AND MIGRATION, WHEREAS ECTOPIC EXPRESSION OF TNS4 IN THOSE LINES THAT EXPRESSED LOWER LEVELS OF TNS4, I.E., SNU-638, MKN1, AND MKN45 INCREASED COLONY FORMATION AND CELL MIGRATION. THE PROMOTER REGION OF TNS4 WAS HYPOMETHYLATED IN GC CELL LINES THAT SHOWED UPREGULATION OF TNS4. WE ALSO FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN TNS4 EXPRESSION AND CPG METHYLATION IN 250 GC TUMORS BASED ON THE CANCER GENOME ATLAS (TCGA) DATA. THIS STUDY ELUCIDATES THE EPIGENETIC MECHANISM OF TNS4 ACTIVATION AND FUNCTIONAL ROLES OF TNS4 IN GC DEVELOPMENT AND PROGRESSION AND SUGGESTS A POSSIBLE APPROACH FOR FUTURE GC TREATMENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 2626  39 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14 6835  29 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15 5621  32 SCREENING METHYLATION OF DNA REPAIR GENES IN THE ORAL MUCOSA OF CHRONIC SMOKERS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EPIGENETIC CHANGES IN THE PROCESS OF ORAL CARCINOGENESIS BY SCREENING THE METHYLATION OF REPAIR GENES IN CHRONIC SMOKERS. DESIGN: TWO GROUPS WERE FORMED: GROUP 1: 16 SMOKERS WITH CONSUMPTION OF 20 CIGARETTES/DAY FOR AT LEAST 10 YEARS; AND GROUP 2: 10 NON-SMOKING. EXFOLIATIVE CYTOLOGY OF THE TONGUE WAS PERFORMED, AND THE EXTRACTED DNA WAS TREATED BY ENZYMES. THE PCR ARRAY SYSTEM PERFORMED METHYLATION SCREENING TO EVALUATE 22 DNA REPAIR GENES, AND THE RESULTS WERE VALIDATED BY RT-QPCR FOR EACH GENE WITH METHYLATION LEVELS >/=10%. RESULTS: HIGHEST PERCENTAGES OF METHYLATION WERE OBSERVED FOR MLH3 AND XRCC1 GENES (11-20% METHYLATION) AND IN ONE CASE FOR MRE11A AND PMS2 (>50% METHYLATION). STATISTICAL ANALYSIS SHOWED SIGNIFICANT DIFFERENCES IN THE EXPRESSION OF THE GENES MRE11A (P = 0.0002), PMS2(P = 0.0068), XRCC1 (P = 0.0080) AND MLH3 (0.0057) BETWEEN THE TWO GROUPS. CONCLUSION: THE EFFECTS OF CHRONIC SMOKING ON ORAL MUCOSA LED TO THE METHYLATION OF GENES MRE11A PMS2, XRCC1 AND MLH3, BUT RESULTED IN A REDUCTION OF GENE EXPRESSION OF MRE11A AND PMS2, WHICH SHOWED >/=50% METHYLATION. THESE RESULTS PROVIDE EVIDENCE THAT SMOKING CAUSE METHYLATION AND REDUCED EXPRESSION OF REPAIR GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 6465  27 TISSUE REMODELING IN ADULT VERNAL KERATOCONJUNCTIVITIS. OUR AIM IS TO DESCRIBE LOCAL TISSUE REMODELING IN A COHORT OF ADULT VKC PATIENTS. MALE PATIENTS DIAGNOSED WITH ACTIVE VKC WERE ENROLLED IN AN OPEN PILOT STUDY INTO TWO GROUPS ACCORDING DISEASE ONSET: CHILDHOOD CLASSIC VKC AND ADULT VKC. VISUAL ACUITY AND OCULAR SURFACE CLINICAL EXAMINATION FOCUSING ON CHRONIC INFLAMMATORY SEQUELAE AND IMPRESSION CYTOLOGY WERE PERFORMED IN ALL ENROLLED SUBJECTS. CONJUNCTIVAL IMPRINTS WERE PROCESSED FOR MOLECULAR, BIOCHEMICAL AND IMMUNOFLUORESCENT ANALYSIS FOR TISSUE REMODELING (TGFBETA1,2,3 AND ALPHASMA) AND EPIGENETIC (DNMT3A, KEAP1; NRF2) MARKERS AS WELL AS ANDROGEN RECEPTORS WERE INVESTIGATED AND COMPARED BETWEEN GROUPS. CLINICAL ASSESSMENT SHOWED INCREASED CONJUNCTIVAL SCARRING IN ADULT VKC COMPARED TO CLASSIC VKC. IMMUNOREACTIVITY FOR ALPHASMA AND EXPRESSION OF TGFBETA WERE HIGHER IN ADULT VKC GROUP. SIGNIFICANTLY HIGHER LEVELS OF TGFBETA3 (3.44 +/- 1.66; P < 0.05) WERE DETECTED IN ADULT VKC COMPARED TO CHILDHOOD VKC, ASSOCIATED WITH AN INCREASING TREND OF TGFBETA1 (1.58 +/- 0.25) AND TGFBETA2 (1.65 +/- 0.20) ISOFORMS LEVELS. MOLECULAR ANALYSIS SHOWED A RELATIVE INCREASE IN TISSUE REMODELING/FIBROGENIC TRANSCRIPTS (TGFBETA ISOFORMS AND ALPHASMA) ASSOCIATED TO A SIGNIFICANT INCREASE OF SELECTIVE EPIGENETIC TARGETS (DNMT3, NRF2 AND KEAP1) IN ADULT VKC PHENOTYPE. INCREASED LOCAL CONJUNCTIVAL ANDROGEN RECEPTORS WAS DETECTED IN PATIENTS WITH ADULT VARIANTS COMPARED TO CLASSIC CHILDHOOD VKC AND HEALTHY SUBJECTS. FINALLY, A DIRECT CORRELATION BETWEEN TGFBETA AND ANDROGEN RECEPTOR EXPRESSION WAS ALSO DETECTED. A PRO-FIBROTIC CLINICAL AND BIOMOLECULAR TRAIT WAS UNVEILED IN ADULT VARIANT OF VKC, WHICH CAUSES OCULAR SURFACE DISEASE AND VISUAL IMPAIRMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 1429  35 DIFFERENTIAL EXPRESSION OF MICRORNAS IN THE HIPPOCAMPI OF MALE AND FEMALE RODENTS AFTER CHRONIC ALCOHOL ADMINISTRATION. BACKGROUND: WOMEN ARE MORE VULNERABLE THAN MEN TO THE NEUROTOXICITY AND SEVERE BRAIN DAMAGE CAUSED BY CHRONIC HEAVY ALCOHOL USE. IN ADDITION, BRAIN DAMAGE DUE TO CHRONIC HEAVY ALCOHOL USE MAY BE ASSOCIATED WITH SEX-DEPENDENT EPIGENETIC MODIFICATIONS. THIS STUDY AIMED TO IDENTIFY MICRORNAS (MIRNAS) AND THEIR TARGET GENES THAT ARE DIFFERENTIALLY EXPRESSED IN THE HIPPOCAMPI OF MALE AND FEMALE ANIMAL MODELS IN RESPONSE TO ALCOHOL. METHODS: AFTER CHRONIC ALCOHOL ADMINISTRATION (3~3.5 G/KG/DAY) IN MALE (CONTROL, N = 10; ALCOHOL, N = 12) OR FEMALE (CONTROL, N = 10; ALCOHOL, N = 12) SPRAGUE-DAWLEY RATS FOR 6 WEEKS, WE MEASURED BODY WEIGHTS AND DOUBLECORTIN (DCX; A NEUROGENESIS MARKER) CONCENTRATIONS AND ANALYZED UP- OR DOWNREGULATED MIRNAS USING GENECHIP MIRNA 4.0 ARRAYS. THE DIFFERENTIALLY EXPRESSED MIRNAS AND THEIR PUTATIVE TARGET GENES WERE VALIDATED BY RT-QPCR. RESULTS: ALCOHOL ATTENUATED BODY WEIGHT GAIN ONLY IN THE MALE GROUP. ON THE OTHER HAND, ALCOHOL LED TO INCREASED SERUM AST IN FEMALE RATS AND DECREASED SERUM TOTAL CHOLESTEROL CONCENTRATIONS IN MALE RATS. THE EXPRESSION OF DCX WAS SIGNIFICANTLY REDUCED IN THE HIPPOCAMPI OF MALE ALCOHOL-TREATED RATS. NINE MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN MALE ALCOHOL-TREATED RATS, INCLUDING UPREGULATION OF MIR-125A-3P, LET-7A-5P, AND MIR-3541, AND DOWNREGULATION OF THEIR TARGET GENES (PRDM5, SUV39H1, PTPRZ1, MAPK9, ING4, WT1, NKX3-1, DAB2IP, RNF152, RIPK1, LIN28A, APBB3, NRAS, AND ACVR1C). ON THE OTHER HAND, 7 MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN ALCOHOL-TREATED FEMALE RATS, INCLUDING DOWNREGULATION OF MIR-881-3P AND MIR-504 AND UPREGULATION OF THEIR TARGET GENES (NAA50, CLOCK, CBFB, ARIH1, UBE2G1, AND GNG7). CONCLUSIONS: THESE RESULTS SUGGEST THAT CHRONIC HEAVY ALCOHOL USE PRODUCES SEX-DEPENDENT EFFECTS ON NEUROGENESIS AND MIRNA EXPRESSION IN THE HIPPOCAMPUS AND THAT SEX DIFFERENCES SHOULD BE CONSIDERED WHEN DEVELOPING MIRNA BIOMARKERS TO DIAGNOSE OR TREAT ALCOHOLICS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18 2304  34 EPIGENETIC REGULATION OF CATHEPSIN L EXPRESSION IN CHRONIC MYELOID LEUKAEMIA. THE EXPRESSION AND SIGNIFICANCE OF CATHEPSIN L (CTSL) HAS BEEN EXTENSIVELY STUDIED IN SOLID TUMOURS. HOWEVER NO SUCH INFORMATION IN CHRONIC MYELOID LEUKAEMIA (CML) WAS AVAILABLE. WE INVESTIGATED THE ACTIVITY AND EXPRESSION OF THIS PROTEASE IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF 47 ADULT CML PATIENTS. THIRTY ADULTS SUFFERING FROM SYSTEMIC DISEASES AND 50 HEALTHY VOLUNTEERS SERVED AS CONTROLS. THE MRNA LEVELS OF CTSL, ITS SPECIFIC ENDOGENOUS INHIBITOR CYSTATIN C AND TRANSCRIPTIONAL UP-REGULATOR VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) WERE QUANTITATED BY REAL-TIME QPCR. CTSL PROTEASE ACTIVITY AND ITS MRNA EXPRESSION WERE SIGNIFICANTLY HIGHER IN CML CHRONIC PHASE (CP) PATIENTS COMPARED TO CML ACCELERATED PHASE/BLAST CRISIS (AP/BC) PATIENTS AND CONTROLS (P</= 0.001). VEGF WHOSE EXPRESSION WAS MOST PRONOUNCED IN CP AND DECLINED (P</= 0.001) IN THE ADVANCED PHASES OF THE MALIGNANCY EXHIBITED A STRONG POSITIVE CORRELATION WITH CTSL EXPRESSION (R= 0.97; P</= 0.001). CYSTATIN C EXPRESSION WAS SIGNIFICANTLY LOWER (P</= 0.001) IN CML AND DISPLAYED INVERSE CORRELATION WITH CTSL (R=-0.713; P</= 0.001) ACTIVITY. CTSL PROMOTER WAS SIGNIFICANTLY HYPOMETHYLATED IN CML CP COMPARED TO CML AP/BC PATIENTS AS WELL AS CONTROLS. K562, A BC CML CELL LINE DISPLAYED CTSL ACTIVITY, EXPRESSION AND METHYLATION STATUS OF CTSL PROMOTER THAT WAS COMPARABLE TO CML AP/BC PATIENTS. TREATMENT OF THESE CELLS OR PBMCS ISOLATED FROM CML AP/BC PATIENTS WITH 5'-AZA-CYTIDINE RESULTED IN A DRAMATIC INCREASE IN CSTL ACTIVITY AND/OR EXPRESSION THEREBY DEMONSTRATING THE ROLE OF PROMOTER METHYLATION IN THE STAGE SPECIFIC EXPRESSION OF CTSL IN CML. DIFFERENTIAL EXPRESSION OF CTSL IN CML AT VARIOUS STAGES OF MALIGNANCY MAY PROVE USEFUL IN IDENTIFICATION OF THE HIGH-RISK PATIENTS THEREBY FACILITATING BETTER MANAGEMENT OF DISEASE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19 1187  29 COPD GWAS VARIANT AT 19Q13.2 IN RELATION WITH DNA METHYLATION AND GENE EXPRESSION. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AMONG THE MAJOR HEALTH BURDENS IN ADULTS. WHILE CIGARETTE SMOKING IS THE LEADING RISK FACTOR, A GROWING NUMBER OF GENETIC VARIATIONS HAVE BEEN DISCOVERED TO INFLUENCE DISEASE SUSCEPTIBILITY. EPIGENETIC MODIFICATIONS MAY MEDIATE THE RESPONSE OF THE GENOME TO SMOKING AND REGULATE GENE EXPRESSION. CHROMOSOME 19Q13.2 REGION IS ASSOCIATED WITH BOTH SMOKING AND COPD, YET ITS FUNCTIONAL ROLE IS UNCLEAR. OUR STUDY AIMED TO DETERMINE WHETHER RS7937 (RAB4B, EGLN2), A TOP GENETIC VARIANT IN 19Q13.2 REGION IDENTIFIED IN GENOME-WIDE ASSOCIATION STUDIES OF COPD, IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD (N = 1490) AND GENE EXPRESSION IN BLOOD (N = 721) AND LUNGS (N = 1087). WE COMBINED GENETIC AND EPIGENETIC DATA FROM THE ROTTERDAM STUDY (RS) TO PERFORM THE EPIGENOME-WIDE ASSOCIATION ANALYSIS OF RS7937. FURTHER, WE USED GENETIC AND TRANSCRIPTOMIC DATA FROM BLOOD (RS) AND FROM LUNG TISSUE (LUNG EXPRESSION QUANTITATIVE TRAIT LOCI MAPPING STUDY), TO PERFORM THE TRANSCRIPTOME-WIDE ASSOCIATION STUDY OF RS7937. RS7937 WAS SIGNIFICANTLY (FDR < 0.05) AND CONSISTENTLY ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION IN BLOOD AT 4 CPG SITES IN CIS, INDEPENDENT OF SMOKING. ONE METHYLATION SITE (CG11298343-EGLN2) WAS ALSO ASSOCIATED WITH COPD (P = 0.001). ADDITIONALLY, RS7937 WAS ASSOCIATED WITH GENE EXPRESSION LEVELS IN BLOOD IN CIS (EGLN2), 42% MEDIATED THROUGH CG11298343, AND IN LUNG TISSUE, IN CIS AND TRANS (NUMBL, EGLN2, DNMT3A, LOC101929709 AND PAK2). OUR RESULTS SUGGEST THAT CHANGES OF DNA METHYLATION AND GENE EXPRESSION MAY BE INTERMEDIATE STEPS BETWEEN GENETIC VARIANTS AND COPD, BUT FURTHER CAUSAL STUDIES IN LUNG TISSUE SHOULD CONFIRM THIS HYPOTHESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20 2674  37 ETHOSUXIMIDE REDUCES EPILEPTOGENESIS AND BEHAVIORAL COMORBIDITY IN THE GAERS MODEL OF GENETIC GENERALIZED EPILEPSY. PURPOSE: ETHOSUXIMIDE (ESX) IS A DRUG OF CHOICE FOR THE SYMPTOMATIC TREATMENT OF ABSENCE SEIZURES. CHRONIC TREATMENT WITH ESX HAS BEEN REPORTED TO HAVE DISEASE-MODIFYING ANTIEPILEPTOGENIC ACTIVITY IN THE WAG/RIJ RAT MODEL OF GENETIC GENERALIZED EPILEPSY (GGE) WITH ABSENCE SEIZURES. HERE WE EXAMINED WHETHER CHRONIC TREATMENT WITH ESX (1) POSSESSES ANTIEPILEPTOGENIC EFFECTS IN THE GENETIC ABSENCE EPILEPSY RATS FROM STRASBOURG (GAERS) MODEL OF GGE, (2) IS ASSOCIATED WITH A MITIGATION OF BEHAVIORAL COMORBIDITIES, AND (3) INFLUENCES GENE EXPRESSION IN THE SOMATOSENSORY CORTEX REGION WHERE SEIZURES ARE THOUGHT TO ORIGINATE. METHODS: GAERS AND NONEPILEPTIC CONTROL (NEC) RATS WERE CHRONICALLY TREATED WITH ESX (IN DRINKING WATER) OR CONTROL (TAP WATER) FROM 3 TO 22 WEEKS OF AGE. SUBSEQUENTLY, ALL ANIMALS RECEIVED TAP WATER ONLY FOR ANOTHER 12 WEEKS TO ASSESS ENDURING EFFECTS OF TREATMENT. SEIZURE FREQUENCY AND ANXIETY-LIKE BEHAVIORS WERE SERIALLY ASSESSED THROUGHOUT THE EXPERIMENTAL PARADIGM. TREATMENT EFFECTS ON THE EXPRESSION OF KEY COMPONENTS OF THE EPIGENETIC MOLECULAR MACHINERY, THE DNA METHYLTRANSFERASE ENZYMES, WERE ASSESSED USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR). KEY FINDINGS: ESX TREATMENT SIGNIFICANTLY REDUCED SEIZURES IN GAERS DURING THE TREATMENT PHASE, AND THIS EFFECT WAS MAINTAINED DURING THE 12-WEEK POSTTREATMENT PHASE (P < 0.05). FURTHERMORE, THE ANXIETY-LIKE BEHAVIORS PRESENT IN GAERS WERE REDUCED BY ESX TREATMENT (P < 0.05). MOLECULAR ANALYSIS REVEALED THAT ESX TREATMENT WAS ASSOCIATED WITH INCREASED EXPRESSION OF DNA METHYLTRANSFERASE ENZYME MESSENGER RNA (MRNA) IN CORTEX. SIGNIFICANCE: CHRONIC ESX TREATMENT HAS DISEASE-MODIFYING EFFECTS IN THE GAERS MODEL OF GGE, WITH ANTIEPILEPTOGENIC EFFECTS AGAINST ABSENCE SEIZURES AND MITIGATION OF BEHAVIORAL COMORBIDITIES. THE CELLULAR MECHANISM FOR THESE EFFECTS MAY INVOLVE EPIGENETIC MODIFICATIONS.	2013