1  6242 148 THE MATRICELLULAR PROTEIN SPARC DECREASES IN THE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. PURPOSE: SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC) IS A MATRICELLULAR GLYCOPROTEIN ABUNDANTLY EXPRESSED IN BASEMENT MEMBRANES AND CAPSULES SURROUNDING A VARIETY OF ORGANS AND TISSUES. IT MEDIATES EXTRACELLULAR MATRIX ORGANIZATION AND HAS BEEN IMPLICATED IN CELL CONTRACTION. HERE, WE EVALUATED THE EXPRESSION OF SPARC IN THE MURINE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. METHODS: LACRIMAL GLANDS OF YOUNG MICE (4-6 WEEKS OLD) AND ADULT MICE (32-40 WEEKS OLD) WERE USED FOR EXTRACTION OF DNA, RNA, AND PROTEIN. THE PRESENCE OF SPARC WAS ASSESSED BY QUANTITATIVE PCR, ELISA, AND IMMUNOFLUORESCENCE MICROSCOPY. 5-METHYLCYTOSINE AND DNA METHYLATION WERE EVALUATED USING ELISA AND BISULFITE GENOMIC SEQUENCING, RESPECTIVELY. THE EFFECTS OF CYTOKINES AND INFLAMMATION IN SPARC EXPRESSION WERE EVALUATED IN VITRO AND IN THE NON-OBESE DIABETIC (NOD) MOUSE MODEL OF SJOGREN'S SYNDROME. RESULTS: THE MRNA AND PROTEIN LEVELS OF SPARC WERE DOWNREGULATED IN LACRIMAL GLANDS OF MATURE ADULT MICE PRESENTING AGE-RELATED HISTOLOGICAL ALTERATIONS SUCH AS INCREASED DEPOSITION OF LIPOFUSCIN AND LIPIDS. EPIGENETIC ANALYSES INDICATED THAT GLANDS IN ADULT MICE CONTAIN HIGHER LEVELS OF GLOBAL DNA METHYLATION AND SHOW INCREASED HYPERMETHYLATION OF SPECIFIC CPG SITES WITHIN THE SPARC GENE PROMOTER. ANALYSIS OF SMOOTH MUSCLE ACTIN (SMA)-GREEN FLUORESCENT PROTEIN (GFP) TRANSGENIC MICE REVEALED THAT SPARC LOCALIZES PRIMARILY TO MYOEPITHELIAL CELLS WITHIN THE GLAND. TREATMENT OF MYOEPITHELIAL CELLS WITH IL-1BETA OR TNF-ALPHA AND THE DEVELOPMENT OF INFLAMMATION IN THE NOD MICE LED TO DECREASED TRANSCRIPTION OF SPARC. CONCLUSIONS: SPARC IS A NOVEL MATRICELLULAR GLYCOPROTEIN EXPRESSED BY MYOEPITHELIAL CELLS IN THE LACRIMAL GLAND. LOSS OF SPARC DURING ADULTHOOD AND CHRONIC INFLAMMATION MIGHT HAVE DETRIMENTAL CONSEQUENCES ON MYOEPITHELIAL CELL CONTRACTION AND THE SECRETION OF TEAR FLUID.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  5723  27 SJOGREN'S SYNDROME X-CHROMOSOME DOSE EFFECT: AN EPIGENETIC PERSPECTIVE. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING EXOCRINE GLANDS LEADING TO MOUTH AND EYES DRYNESS. THE EXTENT TO WHICH EPIGENETIC DNA METHYLATION CHANGES ARE RESPONSIBLE FOR AN X-CHROMOSOME DOSE EFFECT HAS YET TO BE DETERMINED. OUR OBJECTIVES WERE TO (I) DESCRIBE HOW EPIGENETIC DNA METHYLATION CHANGES COULD EXPLAIN AN X-CHROMOSOME DOSE EFFECT IN SS FOR WOMEN WITH NORMAL 46,XX GENOTYPE AND (II) DETERMINE THE RELEVANT RELATIONSHIPS TO THIS DOSE EFFECT, BETWEEN X-LINKED GENES, GENES CONTROLLING X-CHROMOSOME INACTIVATION (XCI) AND GENES ENCODING ASSOCIATED TRANSCRIPTION FACTORS, ALL OF WHICH ARE DIFFERENTIALLY EXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN THE SALIVARY GLANDS OF PATIENTS WITH SS. WE IDENTIFIED 58 UPREGULATED X-CHROMOSOME GENES, INCLUDING 22 GENES PREVIOUSLY SHOWN TO ESCAPE XCI, BASED ON THE ANALYSIS OF SS PATIENT SALIVARY GLAND GEO2R GENE EXPRESSION DATASETS. MOREOVER, WE FOUND XIST AND ITS CIS REGULATORS RLIM, FTX, AND CHIC1, AND POLYCOMB REPRESSOR GENES OF THE PRC1/2 COMPLEXES TO BE UPREGULATED. MANY OF THE X-CHROMOSOME GENES IMPLICATED IN SS PATHOGENESIS CAN BE REGULATED BY TRANSCRIPTION FACTORS WHICH WE FOUND TO BE OVEREXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN PATIENTS WITH SS. DETERMINATION OF THE MECHANISMS UNDERLYING METHYLATION-DEPENDENT GENE EXPRESSION AND IMPAIRED XCI IS NEEDED TO FURTHER ELUCIDATE THE ETIOPATHOGENESIS OF SS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  6050  23 THE CONTRIBUTION OF EPIGENETICS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS THAT COMBINES EXOCRINE GLAND DYSFUNCTIONS AND LYMPHOCYTIC INFILTRATIONS. WHILE THE PATHOGENESIS OF SS REMAINS UNCLEAR, ITS ETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC PREDISPOSITIONS, ENVIRONMENTAL FACTORS, AND EPIGENETIC FACTORS. RECENTLY, INTEREST HAS GROWN IN THE INVOLVEMENT OF EPIGENETICS IN AUTOIMMUNE DISEASES. EPIGENETICS IS DEFINED AS CHANGES IN GENE EXPRESSION, THAT ARE INHERITABLE AND THAT DO NOT ENTAIL CHANGES IN THE DNA SEQUENCE. IN SS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION THAT PREDOMINATES IN EPITHELIAL CELLS, AN ABNORMAL EXPRESSION OF MICRORNAS, AND ABNORMAL CHROMATIN POSITIONING-ASSOCIATED WITH AUTOANTIBODY PRODUCTION. LAST BUT NOT LEAST, EPIGENETIC MODIFICATIONS ARE REVERSIBLE AS OBSERVED IN MINOR SALIVARY GLANDS FROM SS PATIENTS AFTER B CELL DEPLETION USING RITUXIMAB. THUS EPIGENETIC FINDINGS IN SS OPEN NEW PERSPECTIVES FOR THERAPEUTIC APPROACHES AS WELL AS THE POSSIBLE IDENTIFICATION OF NEW BIOMARKERS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4  1603  32 DNA METHYLATION STUDIES IN SALIVA OF PATIENTS WITH SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A RELATIVELY COMMON SYSTEMIC AUTOIMMUNE DISEASE OF UNKNOWN AETIOLOGY, ALTHOUGH GENETIC, HORMONAL, IMMUNOLOGIC, AND ENVIRONMENTAL FACTORS ARE THOUGHT TO BE INVOLVED IN DISEASE PATHOGENESIS. IT IS ALSO TERMED "AUTOIMMUNE EPITHELITIS", AND AFFLICTS MAINLY THE EPITHELIAL STRUCTURES OF SALIVARY AND LACHRYMAL GLANDS, THROUGH PERIEPITHELIAL LYMPHOCYTIC INFILTRATION RESPONSIBLE FOR THE OCCURRENCE OF DRYNESS SYMPTOMS. SJOGREN'S SYNDROME (SS) IS ALSO CHARACTERISED BY B CELL HYPERACTIVITY AS REFLECTED BY THE PRESENCE OF HYPERGAMMAGLOBULINEMIA AND THE PRODUCTION OF AUTOANTIBODIES, WHICH SEEMS TO BE ASSOCIATED WITH THE PRESENCE OF ECTOPIC GERMINAL CENTRES WITHIN THE INFLAMED MINOR SALIVARY GLANDS. CHRONIC ANTIGENIC STIMULATION MAY LEAD TO EXPANSION OF B CELL AUTOREACTIVE CLONES WITH RHEUMATOID FACTOR ACTIVITY, AND ADDITIONAL MOLECULAR EVENTS MEDIATE MALIGNANT TRANSFORMATION INTO NON-HODGKIN'S LYMPHOMAS OF B CELL ORIGIN. THEREFORE, THE INTERACTION BETWEEN THE IMMUNE CELLS OF THE INFLAMMATORY INFILTRATE AND THE SALIVARY EPITHELIUM SEEMS TO HAVE AN IMPORTANT CONTRIBUTION IN DISEASE PROCESS. RECENT HISTOPATHOLOGIC AND MOLECULAR STUDIES HAVE SHOWN THAT DNA METHYLATION LEVELS OF SS PATIENTS COMPARED TO HEALTHY INDIVIDUALS DIFFER IN EPITHELIAL CELLS OF SALIVARY GLANDS AND PERIPHERAL BLOOD MONONUCLEAR CELLS. IN THE PRESENT STUDY, WE INTEND TO ANALYSE THE EPIGENETIC MODIFICATIONS OF DNA IN THE SALIVA OF SS PATIENTS COMPARED TO HEALTHY CONTROLS. MORE SPECIFICALLY, SALIVARY DNA METHYLATION LEVELS OF SELECTED GENETIC LOCI PREVIOUSLY FOUND TO DIFFER IN OTHER TISSUES, WILL BE COMPARED BETWEEN SS PATIENTS AND HEALTHY CONTROLS. THE STUDY INCLUDES SALIVA COLLECTION FROM SS PATIENTS AND HEALTHY INDIVIDUALS, EXTRACTION OF GENOMIC DNA AND METHYLATION ASSESSMENT. THE EPIGENETIC PROFILE OF EACH GENETIC LOCUS WILL BE CORRELATED WITH SS PATIENTS' CLINICAL CHARACTERISTICS AND THE POSSIBILITY OF GENETIC LOCI WITH DIFFERENTIAL DIFFERENCES IN METHYLATION TO BE USED AS POTENTIAL DIAGNOSTIC BIOMARKERS WILL BE EXPLORED. THE CURRENT STUDY IS ANTICIPATED TO REVEAL POTENTIAL BIOMARKERS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES, OFFERING THE ADVANTAGE TO UTILISE THE EASILY COLLECTED AND HANDLED SALIVA AS THE MAIN BIOLOGIC MATERIAL.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5   207  30 ACTIVATION OF THE TYPE I INTERFERON PATHWAY IN PRIMARY SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS), A CHRONIC AUTOIMMUNE SYSTEMIC DISEASE AFFECTING MIDDLE AGED WOMEN, IS CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE SALIVARY AND LACHRYMAL GLANDS RESULTING IN DRY EYES AND DRY MOUTH. RECENT ADVANCES HAVE REVEALED A MAJOR ROLE FOR ACTIVATION OF THE TYPE I INTERFERON (IFN) PATHWAY IN THE PATHOGENESIS OF THE SYNDROME, AS EVIDENCED BY THE INCREASED CIRCULATING TYPE I IFN ACTIVITY AND AN IFN "SIGNATURE" IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND MINOR SALIVARY GLAND (MSG) BIOPSIES FROM THESE PATIENTS. POLYMORPHISMS IN GENES INVOLVED IN THE IFNALPHA PATHWAY, SUCH AS IRF5 AND STAT4, HAVE BEEN FOUND TO BE ASSOCIATED WITH DISEASE SUSCEPTIBILITY. WHILE THE INITIAL TRIGGERS OF THE INNATE IMMUNE RESPONSE IN SS REMAIN ELUSIVE, PRELIMINARY EVIDENCE SUPPORTS THE ROLE OF INAPPROPRIATELY EXPRESSED ENDOGENOUS LINE-1 (L1) RETROELEMENTS AS POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION IN SS, POSSIBLY THROUGH TOLL-LIKE RECEPTOR (TLR) DEPENDENT OR INDEPENDENT PATHWAYS. PROTEINS OF THE METHYLATION MACHINERY AND THE APOBEC FAMILY OF CYTIDINE DEAMINASES ARE COORDINATELY OVEREXPRESSED, SUGGESTING THAT THOSE PROTEINS MIGHT CONTRIBUTE TO REGULATION OF THE INAPPROPRIATELY EXPRESSED L1 ENDOGENOUS RETROELEMENTS IN SS. GIVEN THE APPARENT CENTRAL ROLE OF IFNALPHA IN THE PATHOGENESIS OF SS, BLOCKADE OF THIS CYTOKINE MAY BE A RATIONAL THERAPEUTIC APPROACH. IN THE CURRENT REVIEW WE SUMMARIZE THE CURRENT EVIDENCE REGARDING THE POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION AS WELL AS THE DATA SUPPORTING GENETIC AND EPIGENETIC REGULATION OF THE TYPE I IFN SYSTEM IN SS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6  2222  34 EPIGENETIC MODIFICATIONS IN SALIVARY GLANDS FROM PATIENTS WITH SJOGREN'S SYNDROME AFFECT CYTOKERATIN 19 EXPRESSION. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS, AND SEVERAL LINES OF EXPERIMENTS INDICATE THAT MULTIFACTORIAL FACTORS CONTRIBUTE TO SALIVARY GLAND EPITHELIAL CELLS (SGEC) DYSFUNCTIONS INCLUDING A COMBINATION OF ENVIRONMENTAL FACTORS, LYMPHOCYTIC INFILTRATIONS, GENETIC PREDISPOSITIONS AS WELL AS EPIGENETIC DEFECTS. SUCH STATEMENT IS REINFORCED BY THE OBSERVATION THAT GLOBAL DNA METHYLATION (5MECYT) IS ALTERED IN MINOR SALIVARY GLANDS FROM PSS PATIENTS AND THAT SUCH DEFECT IS ASSOCIATED CYTOKERATIN 19 (KRT19) OVEREXPRESSION. AN EPIGENETIC DEREGULATION OF THE KRT19 GENE WAS FURTHER TESTED BY TREATING THE HUMAN SALIVARY GLAND (HSG) CELL LINE WITH THE DNA DEMETHYLATING AGENT 5-AZACYTIDIN, AND WITH THE HISTONE ACETYLASE INHIBITOR TRICHOSTATIN A. BLOCKING DNA METHYLATION, BUT NOT HISTONE ACETYLATION, WITH 5-AZACYTIDIN WAS ASSOCIATED WITH KRT19 OVEREXPRESSION AT BOTH TRANSCRIPTIONAL AND PROTEIN LEVEL. NEXT, ANALYSIS OF THE CPG GENOME-WIDE METHYLOME ARRAY IN THE KTR19 LOCUS FROM LONG TERM CULTURED SGEC OBTAINED FROM 8 PSS PATIENTS REVEALED A MORE REDUCED DNA METHYLATION LEVEL IN THOSE PATIENTS WITH DEFECTIVE GLOBAL DNA METHYLATION. ALTOGETHER, OUR DATA, THEREFORE, SUGGEST THAT ALTERATION OF DNA METHYLATION IN SGEC MAY CONTRIBUTE TO PSS PATHOPHYSIOLOGY IN PART BY CONTROLLING THE EXPRESSION OF KRT19.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  1165  32 CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SJOGREN'S SYNDROME: A REVIEW. SJOGREN'S SYNDROME (SS) IS A CHRONIC SYSTEMIC DISEASE CHARACTERISED BY SALIVARY AND LACRIMAL GLAND DYSFUNCTION WITH SEVERE IMPLICATIONS FOR THE WELL-BEING OF BEARING INDIVIDUALS. ALTHOUGH ITS ORIGIN HAS NOT YET BEEN FULLY ELUCIDATED, IT IS KNOWN THAT GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS ARE IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF THIS SYNDROME. DNA METHYLATION IS A RELEVANT, WIDELY STUDIED EPIGENETIC FACTOR THAT IS POSSIBLY RELATED TO THE ESTABLISHMENT OF SS. THE AIM OF THE PRESENT STUDY WAS TO PERFORM A SYSTEMATIC REVIEW OF THE LITERATURE TO COMPILE STUDIES ON THE CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SS. A LITERATURE SEARCH WAS PERFORMED IN 4 DATABASES (PUBMED, WEB OF SCIENCE, LILACS, AND SCOPUS) USING PREVIOUSLY SELECTED MEDICAL SUBJECT HEADINGS (MESH) DESCRIPTORS, AND ARTICLE SELECTION CONSIDERED OBSERVATIONAL STUDIES ONLY. AFTER A FULL-TEXT READING OF THE SELECTED ARTICLES, 15 STUDIES WERE IN ACCORDANCE WITH THE ELIGIBILITY CRITERIA FOR DATA EXTRACTION. METHYLATION DETECTION APPROACHES INCLUDED GLOBAL METHYLATION, GENOME-WIDE ASSESSMENT OF DIFFERENTIALLY METHYLATED REGIONS, AND SITE-SPECIFIC METHYLATION. FOURTEEN ARTICLES REPORTED ASSOCIATIONS OF DNA METHYLATION PROFILES IN SS PATIENTS, BOTH GLOBALLY AND IN SEVERAL GENES IN SALIVARY GLANDS AND BLOOD CELLS. THUS, DNA METHYLATION MAY CONTRIBUTE TO THE PATHOGENESIS OF SS. THE FINDINGS REINFORCE THE IMPORTANCE OF EPIGENETIC MARKERS IN THE DYNAMICS OF SS AND MAY DIRECT EFFORTS TOWARD THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8  2552  28 EPIGENETICS IN PRIMARY SJOGREN'S SYNDROME. PRIMARY SJOGREN'S SYNDROME (SJS) IS A CHRONIC AND SYSTEMIC AUTOIMMUNE EPITHELITIS WITH PREDOMINANT FEMALE INCIDENCE, WHICH IS CHARACTERIZED BY EXOCRINE GLAND DYSFUNCTION. INCOMPLETELY UNDERSTOOD, THE ETIOLOGY OF SJS IS MULTI-FACTORIAL AND EVIDENCE IS GROWING TO CONSIDER THAT EPIGENETIC FACTORS ARE PLAYING A CRUCIAL ROLE IN ITS DEVELOPMENT. INDEPENDENT FROM DNA SEQUENCE MUTATIONS, EPIGENETICS IS DESCRIBED AS INHERITABLE AND REVERSIBLE PROCESSES THAT MODIFY GENE EXPRESSION. EPIGENETIC MODIFICATIONS REPORTED IN MINOR SALIVARY GLAND AND LYMPHOCYTES FROM SJS PATIENTS ARE RELATED TO (I) AN ABNORMAL DNA METHYLATION PROCESS INDUCING IN TURN DEFECTIVE CONTROL OF NORMALLY REPRESSED GENES INVOLVING SUCH MATTERS AS AUTOANTIGENS, RETROTRANSPOSONS, AND THE X CHROMOSOME IN WOMEN; (II) ALTERED NUCLEOSOME POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION; AND (III) ALTERED CONTROL OF MICRORNA. RESULTS FROM EPIGENOME-WIDE ASSOCIATION STUDIES HAVE FURTHER REVEALED THE IMPORTANCE OF THE INTERFERON PATHWAY IN DISEASE PROGRESSION, THE CALCIUM SIGNALING PATHWAY FOR CONTROLLING FLUID SECRETIONS, AND A CELL-SPECIFIC CROSS TALK WITH RISK FACTORS ASSOCIATED WITH SJS. IMPORTANTLY, EPIGENETIC MODIFICATIONS ARE REVERSIBLE THUS OPENING OPPORTUNITIES FOR THERAPEUTIC PROCEDURES IN THIS CURRENTLY INCURABLE DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9  1985  31 EPIGENETIC ALTERATIONS IN PRIMARY SJOGREN'S SYNDROME - AN OVERVIEW. PRIMARY SJOGREN'S SYNDROME (PSS) IS A CHRONIC AUTOIMMUNE RHEUMATIC DISEASE CHARACTERIZED BY INFLAMMATION OF EXOCRINE GLANDS, MAINLY SALIVARY AND LACRIMAL GLANDS. IN ADDITION, PSS MAY AFFECT MULTIPLE OTHER ORGANS RESULTING IN SYSTEMIC MANIFESTATIONS. ALTHOUGH THE PRECISE ETIOLOGY OF PSS REMAINS ELUSIVE, PSS IS CONSIDERED TO BE A MULTI-FACTORIAL DISEASE, WHERE UNDERLYING GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS CONTRIBUTE TO DISEASE DEVELOPMENT. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS, MAY CONSTITUTE A DYNAMIC LINK BETWEEN GENOME, ENVIRONMENT AND PHENOTYPIC MANIFESTATION BY THEIR MODULATING EFFECTS ON GENE EXPRESSION. A GROWING BODY OF STUDIES REPORTING ALTERED EPIGENETIC LANDSCAPES IN PSS SUGGESTS THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE PATHOGENESIS OF PSS, AND THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS SUGGESTS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC DYSREGULATION IN PSS. THIS ARTICLE REVIEWS OUR CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSS AND DISCUSSES IMPLICATIONS FOR NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10   823  37 CHARACTERIZATION OF COMPREHENSIVE DYNAMIC EPIGENETIC CHANGES DURING HUMAN PRIMARY SJOGREN'S SYNDROME PROGRESSION. BACKGROUND: PRIMARY SJOGREN'S SYNDROME (PSS) IS A SYSTEMIC AUTOIMMUNE DISEASE CHARACTERIZED BY REDUCED EXOCRINE GLAND (PRINCIPALLY THE SALIVARY AND LACRIMAL GLANDS) ACTIVITY CAUSED BY CHRONIC LYMPHOCYTIC INFILTRATION. ALTHOUGH PSS HAS BEEN CLOSELY ASSOCIATED WITH AN INCREASED RISK OF MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA, THE DYNAMIC EPIGENETIC CHANGES IN THE GLAND CELLS THAT ACCOMPANY THE PATHOGENESIS ARE NOT ENTIRELY UNDERSTOOD. METHODS: IN THIS STUDY, WE HARVESTED TISSUE SAMPLES FROM THE LABIAL GLAND WITH (LG_PSS) OR WITHOUT PSS (LG_NC) BEFORE MALT DEVELOPMENT, AS WELL AS THE PAROTID GLAND WITH TUMOR TISSUES (PG_MALT) AND PARACANCEROUS TISSUES (PG_NC) OF TWO PSS PATIENTS WITH MALT LYMPHOMA, AND CONDUCTED RNA-SEQ AND CHIP-SEQ FOR TRI-METHYLATED HISTONE 3 LYSINE 4, 9, 27, 36, AND 79 (H3K4/9/27/36/79ME3). RESULTS: TRANSCRIPTOME LANDSCAPES INDICATED TWO OUTCOMES OF PSS PROGRESSION WITH OR WITHOUT MALT LYMPHOMA REPRESENTED BY DISTINCT POPULATIONS OF DIFFERENTIALLY EXPRESSED GENES AND THEIR FUNCTIONS. FURTHERMORE, THE EPIGENETIC ATLAS OF GENOME-WIDE H3K4/9/27/36/79ME3 WAS IN DIFFERENT STAGES FOR VARIOUS SAMPLES, INDICATING THAT THE VARIANCE OF H3K4ME3 WAS THE EARLIEST EVENT, FOLLOWED BY SELECTIVE ALTERATIONS OF H3K9/27/36/79ME3. THESE FOUR EPIGENETIC MODIFICATIONS DETERMINE THE FINAL OUTCOME OF PSS PROGRESSION. CONCLUSIONS: OUR RESULTS NOT ONLY ADVANCE THE UNDERSTANDING OF THE DYNAMICS OF PSS PROGRESSION AND HIGHLIGHT THE IMPORTANCE OF EPIGENETIC ALTERATIONS IN REGULATING TRANSCRIPTION DURING THIS PATHOLOGICAL PROCESS, BUT ALSO IDENTIFY POTENTIAL THERAPEUTIC TARGETS FOR PSS TREATMENT AND LYMPHOMA INTERVENTION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11  4268  32 MICROBIAL AGENTS AS PUTATIVE INDUCERS OF B CELL LYMPHOMA IN SJOGREN'S SYNDROME THROUGH AN IMPAIRED EPIGENETIC CONTROL: THE STATE-OF-THE-ART. INTRODUCTION: UNDERSTANDING THE MECHANISMS UNDERLYING THE PATHOGENESIS OF SJOGREN'S SYNDROME (SS) IS CRUCIALLY IMPORTANT IN ORDER TO BE ABLE TO DISCRIMINATE THE STEPS THAT LEAD TO B CELL TRANSFORMATION AND PROMPTLY IDENTIFY THE PATIENTS AT RISK OF LYMPHOMAGENESIS. THE AIM OF THIS NARRATIVE REVIEW IS TO DESCRIBE THE EVIDENCE CONCERNING THE ROLE THAT INFECTIONS OR DYSBIOSIS PLAYS IN THE EPIGENETIC CONTROL OF GENE EXPRESSION IN SS PATIENTS AND THEIR POSSIBLE INVOLVEMENT IN B CELL LYMPHOMAGENESIS. MATERIALS AND METHODS: WE SEARCHED THE PUBMED AND GOOGLE SCHOLAR DATABASES AND SELECTED A TOTAL OF 92 ARTICLES PUBLISHED DURING THE LAST 25 YEARS THAT DESCRIBE EXPERIMENTAL AND CLINICAL STUDIES OF THE POTENTIAL ASSOCIATIONS OF MICROBIOTA AND EPIGENETIC ABERRATIONS WITH THE RISK OF B CELL LYMPHOMA IN SS PATIENTS. RESULTS AND DISCUSSION: THE GENETIC BACKGROUND OF SS PATIENTS IS CHARACTERIZED BY THE HYPEREXPRESSION OF GENES THAT ARE MAINLY INVOLVED IN REGULATING THE INNATE AND ADAPTIVE IMMUNE RESPONSES AND ONCOGENESIS. IN ADDITION, SALIVARY GLAND EPITHELIAL CELLS AND LYMPHOCYTES BOTH HAVE AN ALTERED EPIGENETIC BACKGROUND THAT ENHANCES THE ACTIVATION OF PROINFLAMMATORY AND SURVIVAL PATHWAYS. DYSBIOSIS OR CHRONIC LATENT INFECTIONS MAY TUNE THE IMMUNE RESPONSE AND MODIFY THE CELL EPIGENETIC MACHINERY IN SUCH A WAY AS TO GIVE B LYMPHOCYTES AN ACTIVATED OR TRANSFORMED PHENOTYPE. IT IS ALSO WORTH NOTING THAT TRANSPOSABLE INTEGRATED RETROELEMENTS MAY PARTICIPATE IN THE PATHOGENESIS OF SS AND B CELL LYMPHOMAGENESIS BY INDUCING DNA BREAKS, MODULATING CELL GENE EXPRESSION, OR GENERATING ABERRANT TRANSCRIPTS THAT CHRONICALLY STIMULATE THE IMMUNE SYSTEM. CONCLUSIONS: MICROORGANISMS MAY EPIGENETICALLY MODIFY TARGET CELLS AND INDUCE THEIR TRANSCRIPTOME TO GENERATE AN ACTIVATED OR TRANSFORMED PHENOTYPE. THE OCCURRENCE OF LYMPHOMA IN MORE THAN 15% OF SS PATIENTS MAY BE THE END RESULT OF A COMBINATION OF GENETICS, EPIGENETICS, AND DYSBIOSIS OR LATENT INFECTIONS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  1227  31 CRITICAL ROLE OF MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA: OVEREXPRESSION OF THE ONCOGENE PLAG1 BY DEREGULATED MIRNAS. MICRORNAS (MIRNAS) ARE SMALL, GENE ENCODED RNAS WHICH ARE ABLE TO INFLUENCE GENE EXPRESSION IN BINDING TO THE 3'UTR OF MRNAS. COMPARED TO HEALTHY TISSUES, THE GLOBAL EXPRESSION OF MIRNAS IN CANCEROUS TISSUE IS FREQUENTLY DOWN-REGULATED. LIKEWISE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DOWN-REGULATION OF SEVERAL MIRNAS HAS BEEN REPORTED. ANALYSIS OF MIRNA PROMOTERS FOR EPIGENETIC MODIFICATIONS REVEALED A STRONGER METHYLATION OF DOWN-REGULATED MIRNAS IN CLL. TO DATE, SEVERAL TARGET GENES AFFECTED BY DEREGULATED MIRNAS HAVE BEEN IDENTIFIED THAT HAVE IMPACT ON CLL PATHOGENESIS. THE BEST-DESCRIBED CONSEQUENCE OF MIRNA DEREGULATION IS FOR MIRNA-15/16 CLUSTER DELETION, WHICH IS FREQUENTLY DOWN-REGULATED IN A SUBGROUP OF PATIENTS WITH CLL CARRYING 13Q14 DELETION. SO FAR, MODELS FOR MIRNA DEREGULATION HAVE ADDRESSED JUST SINGLE MIRNAS. FOR ASSESSMENT OF COMPLETE MIRNA DEREGULATION, FURTHER EVALUATION OF THE RESULTS FROM MICROARRAY STUDIES IS NEEDED. PREVIOUSLY WE IDENTIFIED THE ONCOGENE PLAG1, WHOSE EXPRESSION IS AFFECTED BY VARIOUS MIRNAS DEREGULATED IN CLL. THE INVOLVEMENT OF MIRNAS IN PLAG1 EXPRESSION WAS SHOWN TO BE RELEVANT IN PLEOMORPHIC ADENOMAS OF THE SALIVARY GLAND, TOO. AS PLAG1 IS HIGHLY OVEREXPRESSED, AND ITS TARGET GENES APPEAR TO BE DEREGULATED IN CLL, E.G. BCL-2, PLAG1 IS A PUTATIVE NEW RELEVANT ONCOGENE INVOLVED IN THE PATHOGENESIS OF CLL.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13  2405  39 EPIGENETIC RESPONSE IN MICE MASTITIS: ROLE OF HISTONE H3 ACETYLATION AND MICRORNA(S) IN THE REGULATION OF HOST INFLAMMATORY GENE EXPRESSION DURING STAPHYLOCOCCUS AUREUS INFECTION. BACKGROUND: THERE IS RENEWED INTEREST TOWARDS UNDERSTANDING THE HOST-PATHOGEN INTERACTION IN THE LIGHT OF EPIGENETIC MODIFICATIONS. ALTHOUGH EPITHELIAL TISSUE IS THE MAJOR SITE FOR HOST-PATHOGEN INTERACTIONS, THERE IS HANDFUL OF STUDIES TO SHOW HOW EPITHELIAL CELLS RESPOND TO PATHOGENS. BACTERIAL INFECTION IN THE MAMMARY GLAND PARENCHYMA INDUCES LOCAL AND SUBSEQUENTLY SYSTEMIC INFLAMMATION THAT RESULTS IN A COMPLEX DISEASE CALLED MASTITIS. GLOBALLY STAPHYLOCOCCUS AUREUS IS THE SINGLE LARGEST MASTITIS PATHOGEN AND THE INFECTION CAN ULTIMATELY RESULT IN EITHER SUBCLINICAL OR CHRONIC AND SOMETIMES LIFELONG INFECTION. RESULTS: IN THE PRESENT REPORT WE HAVE ADDRESSED THE DIFFERENTIAL INFLAMMATORY RESPONSE IN MICE MAMMARY TISSUE DURING INTRAMAMMARY INFECTION AND THE ALTERED EPIGENETIC CONTEXT INDUCED BY TWO CLOSELY RELATED STRAINS OF S. AUREUS, ISOLATED FROM FIELD SAMPLES. IMMUNOHISTOCHEMICAL AND IMMUNOBLOTTING ANALYSIS SHOWED STRAIN SPECIFIC HYPERACETYLATION AT HISTONE H3K9 AND H3K14 RESIDUES. GLOBAL GENE EXPRESSION ANALYSIS IN S. AUREUS INFECTED MICE MAMMARY TISSUE REVEALED A SELECTIVE SET OF UPREGULATED GENES THAT SIGNIFICANTLY CORRELATED WITH THE PROMOTER SPECIFIC, HISTONE H3K14 ACETYLATION. FURTHERMORE, WE HAVE IDENTIFIED SEVERAL DIFFERENTIALLY EXPRESSED KNOWN MIRNAS AND 3 NOVEL MIRNAS IN S. AUREUS INFECTED MICE MAMMARY TISSUE BY SMALL RNA SEQUENCING. BY EMPLOYING THESE GENE EXPRESSION DATA, AN ATTEMPT HAS BEEN MADE TO DELINEATE THE GENE REGULATORY NETWORKS IN THE STRAIN SPECIFIC INFLAMMATORY RESPONSE. APPARENTLY, ONE OF THE ISOLATES OF S. AUREUS ACTIVATED THE NF-KAPPAB SIGNALING LEADING TO DRASTIC INFLAMMATORY RESPONSE AND INDUCTION OF IMMUNE SURVEILLANCE, WHICH COULD POSSIBLY LEAD TO RAPID CLEARANCE OF THE PATHOGEN. THE OTHER STRAIN REPRESSED MOST OF THE INFLAMMATORY RESPONSE, WHICH MIGHT HELP IN ITS SUSTENANCE IN THE HOST TISSUE. CONCLUSION: TAKEN TOGETHER, OUR STUDIES SHED SUBSTANTIAL LIGHTS TO UNDERSTAND THE MECHANISMS OF STRAIN SPECIFIC DIFFERENTIAL INFLAMMATORY RESPONSE TO S. AUREUS INFECTION DURING MASTITIS. IN A BROADER PERSPECTIVE THIS STUDY ALSO PAVES THE WAY TO UNDERSTAND HOW CERTAIN BACTERIA CAN EVADE THE IMMUNE SURVEILLANCE AND CAUSE SUSTAINED INFECTION WHILE OTHERS ARE RAPIDLY CLEARED FROM THE HOST BODY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  2515  28 EPIGENETICS AND SJOGREN'S SYNDROME. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS IN THE DNA ITSELF, MAY PLAY AN ESSENTIAL ROLE IN AUTOIMMUNE DISEASES (AID). IN SJOGREN'S SYNDROME (SS), A CHRONIC AID CHARACTERIZED BY AN EPITHELIS OF THE EXOCRINE GLANDS, EPIGENETIC STUDIES HAVE FOCUSED ON THREE MECHANISMS: DNA METHYLATION AND ITS CONSEQUENCES INCLUDING HUMAN ENDOGENOUS RETROVIRUS (HERV) EXPRESSION; MICRORNA EXPRESSION; AND PROTEIN POST-TRANSLATIONAL MODIFICATIONS ASSOCIATED WITH AUTOANTIBODY PRODUCTION. ALTHOUGH IN ITS INFANCY, COMPREHENSION OF THE EPIGENETIC (DYS)REGULATION IN SS MAY HELP US TO UNDERSTAND: WHY SS AFFECTS PREDOMINANTLY MIDDLE-AGED WOMEN; WHY GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP SS BUT NOT OTHERS; WHY FLARE-UPS OCCUR; WHY TREATMENT RESPONSES DIFFER BETWEEN PATIENTS; AND WHY SOME PATIENTS DEVELOP LYMPHOMA. FROM THESE STUDIES WILL ARISE A BETTER COMPREHENSION OF THE PATHOPHYSIOLOGY OF SS AS WELL AS DEVELOPMENT OF NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, AND NOVEL THERAPEUTICS FOR PREVENTION AND PERHAPS EARLY INTERVENTION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  1064  45 CLINICAL SIGNIFICANCE OF PROMOTER METHYLATION STATUS OF TUMOR SUPPRESSOR GENES IN CIRCULATING DNA OF PANCREATIC CANCER PATIENTS. INTRODUCTION: PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS A VERY AGGRESSIVE CANCER. THERE ARE VARIOUS SUB-CELLULAR EVENTS (BOTH GENETIC AND EPIGENETIC) THAT GET DYSREGULATED LEADING TO TUMORIGENESIS. METHYLATION IN PROMOTERS OF TUMOR SUPPRESSOR GENES IS ONE OF THESE EPIGENETIC PHENOMENA CONTRIBUTING TO THE PATHOGENESIS OF CANCER. GENES ANALYZED FOR PROMOTER METHYLATION STATUS IN THIS STUDY NAMELY SPARC (SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE, UCHL1 (UBIQUITIN CARBOXY-TERMINAL HYDROLASE L1), NPTX2 (NEURONAL PENTRAXIN 2), PENK (PROENKEPHALIN) HAD BEEN STUDIED IN PANCREATIC CANCER, BUT THERE IS A NEED TO CHECK METHYLATION IN THESE GENES AS CIRCULATORY NON-INVASIVE MARKERS. THIS STUDY ANALYZED THE ABSOLUTE QUANTIFICATION OF METHYLATION LEVELS OF SPARC, UCHL1, PENK, AND NPTX2 GENES PROMOTERS IN PDAC PATIENTS AS WELL AS IN CHRONIC PANCREATITIS (CP) PATIENTS AND HEALTHY SUBJECTS (HC) AND EVALUATED ITS CLINICAL SIGNIFICANCE IN PDAC. MATERIALS AND METHODS: THE STUDY INCLUDED 65 PDAC PATIENTS, 25 CP PATIENTS, AND 25 HEALTHY CONTROLS. DNA WAS EXTRACTED FROM THEIR PLASMA SAMPLES AND SUBSEQUENTLY GIVEN BISULFITE TREATMENT. ABSOLUTE QUANTIZATION OF METHYLATED AND UNMETHYLATED COPIES OF GENE PROMOTERS OF ALL THE FOUR GENES WAS PERFORMED USING REAL-TIME PCR (SYBR GREEN) BY THE STANDARD CURVE METHOD. METHYLATION LEVELS WERE EXPRESSED AS METHYLATION INDEX (MI) FOR EACH GENE IN EACH PATIENT. MI WAS CALCULATED FROM ABSOLUTE COPY NUMBERS AS FOLLOWS: MI-METHYLATED COPY NUMBER/METHYLATED COPY NUMBER + UNMETHYLATED COPY NUMBER). THESE INDICES WERE USED TO COMPARE GENE METHYLATION LEVELS WITHIN DIFFERENT GROUPS AND TO CORRELATE WITH CLINICOPATHOLOGICAL FEATURES AND SURVIVAL OF PANCREATIC CANCER PATIENTS. AN APPROPRIATE STATISTICAL ANALYSIS WAS APPLIED. RESULTS: METHYLATION INDICES FOR ALL THE FOUR GENES IN PDAC CASES WERE FOUND TO BE SIGNIFICANTLY HIGHER AS COMPARED TO THAT IN HEALTHY INDIVIDUALS. SPARC MI VALUES WERE FOUND TO DIFFERENTIATE EARLY-STAGE PDAC PATIENTS FROM CP PATIENTS. PDAC PATIENTS WITH THE METASTASIZED DISEASE AND STAGE IV DISEASE WERE FOUND TO HAVE HIGH MI FOR THE SPARC GENE AS WELL AS FOR THE NPTX2 GENE, WHILE A HIGHER UCHL1 METHYLATION INDEX WAS FOUND TO CORRELATE WITH AN ADVANCED STAGE OF THE DISEASE. HIGHER MI VALUES FOR SPARC AND NPTX2 GENES WERE FOUND TO ASSOCIATE WITH POOR SURVIVAL IN PATIENTS WITH PDAC. CONCLUSION: METHYLATION LOAD IN THE FORM OF MI FOR EACH OF THE FOUR GENES ASSESSED IN PLASMA MAY EMERGE AS A NON-INVASIVE BIOMARKER TO DIFFERENTIATE PANCREATIC CANCER FROM HEALTHY INDIVIDUALS. BUT ONLY SPARC AND NPTX2 HYPERMETHYLATION WERE ABLE TO DISTINGUISH PANCREATIC CANCER FROM CHRONIC PANCREATITIS. ASSOCIATION OF ABERRANT METHYLATION IN SPARC AND NPTX2 GENE WITH METASTASIS AND POOR SURVIVAL OF PATIENTS SUGGEST THE ROLE OF METHYLATION IN THESE GENES AS PROGNOSTIC MARKERS.	2020	

16  2633  37 EPIGENOME-WIDE DNA METHYLATION PATTERNS ASSOCIATED WITH FATIGUE IN PRIMARY SJOGREN'S SYNDROME. OBJECTIVE: CHRONIC FATIGUE IS A COMMON, DISABLING AND POORLY UNDERSTOOD PHENOMENON. RECENT STUDIES INDICATE THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN THE EXPRESSION OF FATIGUE, A PROMINENT FEATURE OF PRIMARY SS (PSS). THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER DNA METHYLATION PROFILES OF WHOLE BLOOD ARE ASSOCIATED WITH FATIGUE IN PATIENTS WITH PSS. METHODS: FORTY-EIGHT PSS PATIENTS WITH HIGH (N = 24) OR LOW (N = 24) FATIGUE AS MEASURED BY A VISUAL ANALOGUE SCALE WERE INCLUDED. GENOME-WIDE DNA METHYLATION WAS INVESTIGATED USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY. AFTER QUALITY CONTROL, A TOTAL OF 383 358 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES REMAINED FOR FURTHER ANALYSIS. AGE, SEX AND DIFFERENTIAL CELL COUNT ESTIMATES WERE INCLUDED AS COVARIATES IN THE ASSOCIATION MODEL. A FALSE DISCOVERY RATE-CORRECTED P < 0.05 WAS CONSIDERED SIGNIFICANT, AND A CUT-OFF OF 3% AVERAGE DIFFERENCE IN METHYLATION LEVELS BETWEEN HIGH- AND LOW-FATIGUE PATIENTS WAS APPLIED. RESULTS: A TOTAL OF 251 DIFFERENTIALLY METHYLATED CPG SITES WERE ASSOCIATED WITH FATIGUE. THE CPG SITE WITH THE MOST PRONOUNCED HYPOMETHYLATION IN PSS HIGH FATIGUE ANNOTATED TO THE SBF2-ANTISENSE RNA1 GENE. THE MOST DISTINCT HYPERMETHYLATION WAS OBSERVED AT A CPG SITE ANNOTATED TO THE LYMPHOTOXIN ALPHA GENE. FUNCTIONAL PATHWAY ANALYSIS OF GENES WITH DIFFERENTLY METHYLATED CPG SITES IN SUBJECTS WITH HIGH VS LOW FATIGUE REVEALED ENRICHMENT IN SEVERAL PATHWAYS ASSOCIATED WITH INNATE AND ADAPTIVE IMMUNITY. CONCLUSION: SOME GENES INVOLVED IN REGULATION OF THE IMMUNE SYSTEM AND IN INFLAMMATION ARE DIFFERENTLY METHYLATED IN PSS PATIENTS WITH HIGH VS LOW FATIGUE. THESE FINDINGS POINT TO FUNCTIONAL NETWORKS THAT MAY UNDERLIE FATIGUE. EPIGENETIC CHANGES COULD CONSTITUTE A FATIGUE-REGULATING MECHANISM IN PSS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  5753  39 SOCIAL ISOLATION REDUCES MAMMARY DEVELOPMENT, TUMOR INCIDENCE, AND EXPRESSION OF EPIGENETIC REGULATORS IN WILD-TYPE AND P53-HETEROZYGOTIC MICE. CHRONIC STRESS IS ASSOCIATED WITH MORE RAPID TUMOR PROGRESSION, AND RECENT EVIDENCE SUGGESTS THAT STRESS MAY CONTRIBUTE TO SOCIAL AND ETHNIC DISPARITIES IN THE INCIDENCE AND MORTALITY OF BREAST CANCER. WE EVALUATED THE P53(+/-) FVB/N MOUSE AS A MODEL TO INVESTIGATE EFFECTS OF CHRONIC SOCIAL STRESS ON MAMMARY GLAND DEVELOPMENT, GENE EXPRESSION, AND TUMORIGENESIS. WE INDIVIDUALLY HOUSED (IH) WILD-TYPE AND P53(+/-) FEMALE FVB/N MICE, STARTING AT WEANING. AT 14 WEEKS OF AGE, BOTH WILD-TYPE AND P53(+/-) IH MICE SHOWED STRIKINGLY REDUCED MAMMARY DEVELOPMENT COMPARED WITH GROUP-HOUSED (GH) CONTROLS, WITH IH MICE HAVING SIGNIFICANTLY FEWER PRETERMINAL END BUDS. THIS MORPHOLOGIC DIFFERENCE WAS NOT REFLECTED IN LEVELS OF MAMMARY TRANSCRIPTS FOR ESTROGEN RECEPTOR-ALPHA OR PROGESTIN RECEPTOR. HOWEVER, IH INCREASED LEVELS OF MRNA FOR THE KISSPEPTIN RECEPTOR IN THE MEDIAL PREOPTIC AREA OF THE HYPOTHALAMUS, ASSOCIATED WITH REDUCED DURATION OF ESTROUS CYCLES. FURTHERMORE, IH ALTERED MAMMARY TRANSCRIPTS OF GENES ASSOCIATED WITH DNA METHYLATION; TRANSCRIPTS FOR METHYL-BINDING PROTEIN 2 AND DNA METHYLTRANSFERASE 3B (DNMT3B), BUT NOT DNMT1 AND DNMT3A, WERE REDUCED IN IH COMPARED WITH GH FEMALES. INTERESTINGLY, THE GLANDS OF P53(+/-) FEMALES SHOWED REDUCED EXPRESSION OF ALL THESE MEDIATORS COMPARED WITH WILD-TYPE FEMALES. HOWEVER, CONTRARY TO OUR INITIAL HYPOTHESIS, IH DID NOT INCREASE MAMMARY TUMORIGENESIS. RATHER, P53(+/-) GH FEMALES DEVELOPED SIGNIFICANTLY MORE MAMMARY TUMORS THAN IH MICE. TOGETHER, THESE DATA SUGGEST THAT SOCIAL ISOLATION INITIATED AT PUBERTY MIGHT CONFOUND STUDIES OF TUMORIGENESIS BY ALTERING MAMMARY DEVELOPMENT IN MOUSE MODELS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  2019  36 EPIGENETIC CHANGE IN E-CADHERIN AND COX-2 TO PREDICT CHRONIC PERIODONTITIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES FREQUENTLY OCCURS IN NEOPLASTIC CELLS. ALTHOUGH THE CAUSE REMAINS UNKNOWN, MANY GENES HAVE BEEN IDENTIFIED WITH SUCH ATYPICAL METHYLATION IN NEOPLASTIC CELLS. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION SUCH AS CHRONIC PERIODONTITIS MAY DEMONSTRATE MILD LESION/MUTATION EPIGENETIC LEVEL. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES WHICH ARE OFTEN FOUND IN BREAST CANCER PATIENTS WITH THAT IN CHRONIC PERIODONTITIS. METHODS: TOTAL DNA WAS EXTRACTED FROM THE BLOOD SAMPLES OF 108 SYSTEMICALLY HEALTHY NON-PERIODONTITIS SUBJECTS, AND THE GINGIVAL TISSUES AND BLOOD SAMPLES OF 110 CHRONIC PERIODONTITIS PATIENT AS WELL AS NEOPLASTIC TISSUES OF 106 BREAST CANCER PATIENTS. METHYLATION-SPECIFIC PCR FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PCR PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 38% AND 35% OF THE BREAST CANCER SAMPLES, RESPECTIVELY. IN CHRONIC PERIODONTITIS PATIENTS THE DETECTION RATE WAS 25% AND 19% RESPECTIVELY, AND NONE WAS FOUND IN THE SYSTEMICALLY HEALTHY NON-PERIODONTITIS CONTROL SUBJECTS. THE HYPERMETHYLATION STATUS WAS SHOWN TO BE CORRELATED AMONG THE THREE GROUPS WITH STATISTICAL SIGNIFICANCE (P < 0.0001). THE METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 GENES IN PERIODONTITIS PATIENTS OCCURS MORE FREQUENTLY IN PERIODONTITIS PATIENTS THAN IN THE CONTROL SUBJECTS, BUT OCCURS LESS FREQUENTLY THAN IN THE BREAST CANCER PATIENTS. CONCLUSIONS: THIS SET OF DATA SHOWS THAT THE EPIGENETIC CHANGE IN E-CADHERIN AND CYCLOOXYGENASE-2 IS ASSOCIATED WITH CHRONIC PERIODONTITIS. THE EPIGENETIC CHANGES PRESENTED IN CHRONIC INFLAMMATION PATIENTS MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC PERIODONTITIS TO SOME EXTENT MIGHT BE ASSOCIATED WITH DNA HYPERMETHYLATION WHICH IS RELATED TO CANCER RISK FACTORS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  4364  29 MIRNA DEREGULATION BY EPIGENETIC SILENCING DISRUPTS SUPPRESSION OF THE ONCOGENE PLAG1 IN CHRONIC LYMPHOCYTIC LEUKEMIA. MICRORNAS (MIRNA) PLAY A KEY ROLE IN CELLULAR REGULATION AND, IF DEREGULATED, IN THE DEVELOPMENT OF NEOPLASTIC DISORDERS INCLUDING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). RNAS FROM PRIMARY CELLS OF 50 TREATMENT-NAIVE CLL PATIENTS AND PERIPHERAL B CELLS OF 14 HEALTHY DONORS WERE APPLIED TO MIRNA EXPRESSION PROFILING USING BEAD CHIP TECHNOLOGY. IN CLL CELLS, A SET OF 7 UP- AND 19 DOWN-REGULATED MIRNAS WAS IDENTIFIED. AMONG THE MIRNAS DOWN-REGULATED IN CLL CELLS, 6 OF 10 MIRNA PROMOTERS EXAMINED SHOWED GAIN OF METHYLATION COMPARED WITH NORMAL B-CELL CONTROLS. SUBSEQUENT TARGET PREDICTION OF DEREGULATED MIRNAS REVEALED A HIGHLY SIGNIFICANT BINDING PREDICTION AT THE 3' UNTRANSLATED REGION OF THE PLEOMORPHIC ADENOMA GENE 1 (PLAG1) ONCOGENE. LUCIFERASE REPORTER ASSAYS INCLUDING SITE-DIRECTED MUTAGENESIS OF BINDING SITES REVEALED A SIGNIFICANT REGULATION OF PLAG1 BY MIR-181A, MIR-181B, MIR-107, AND MIR-424. ALTHOUGH EXPRESSION OF PLAG1 MRNA WAS NOT AFFECTED, PLAG1 PROTEIN EXPRESSION WAS SHOWN TO BE SIGNIFICANTLY ELEVATED IN CLL CELLS COMPARED WITH THE LEVELS IN HEALTHY DONOR B CELLS. IN SUMMARY, WE COULD DEMONSTRATE DISRUPTION OF MIRNA-MEDIATED TRANSLATIONAL CONTROL, PARTLY DUE TO EPIGENETIC TRANSCRIPTIONAL SILENCING OF MIRNAS, WITH SUBSEQUENT OVEREXPRESSION OF THE ONCOGENIC TRANSCRIPTION FACTOR PLAG1 AS A PUTATIVE NOVEL MECHANISM OF CLL PATHOGENESIS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  2436  35 EPIGENETIC SILENCING OF SOCS3 IDENTIFIES A SUBSET OF PROSTATE CANCER WITH AN AGGRESSIVE BEHAVIOR. BACKGROUND: CHRONIC INFLAMMATION AND SUBSEQUENT TISSUTAL ALTERATIONS MAY PLAY A KEY ROLE IN PROSTATE CARCINOGENESIS. IN THIS WAY, MOLECULAR ALTERATIONS OF THE SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3), ONE OF THE MOST IMPORTANT INHIBITORY MOLECULE OF INFLAMMATORY SIGNAL TRANSDUCTION CIRCUITRIES, COULD CONTRIBUTE TO EXPLAIN THE PLEIOTROPIC ROLE OF INTERLEUKIN-6 (IL-6) IN THIS TYPE OF CANCER. METHODS: WE ANALYZED THE METHYLATION STATUS AND MRNA EXPRESSION OF SOCS3 IN 20 BENIGN PROSTATE HYPERPLASIAS (BPH) AND IN 51 PROSTATE CANCER SPECIMENS. WE ANALYZED THE SOCS3 METHYLATION STATUS USING METHYLATION-SPECIFIC PCR. HYPERMETHYLATION WAS CONFIRMED BY SEQUENCING AFTER SUBCLONING. EPIGENETIC SILENCING OF THIS GENE WAS ALSO DEMONSTRATED BY REAL-TIME PCR AND BY IMMUNOHISTOCHEMISTRY. RESULTS AND CORRELATION WITH CLINICAL DATA WERE STATISTICALLY ANALYZED. RESULTS: WE FOUND THAT THE PROMOTER OF SOCS3 WAS METHYLATED IN 39.2% OF PROSTATE CANCER. ON THE CONTRARY, ALL BPH AND NORMAL CONTROLS HAD AN UNMETHYLATED PATTERN. REAL-TIME ANALYSIS SHOWED THAT IN METHYLATED CASES SOCS3 MRNA EXPRESSION WAS REDUCED BY THREE AND FOUR FOLDS AS COMPARED TO BPH AND UNMETHYLATED CASES, RESPECTIVELY. INTERESTINGLY, SOCS3 MRNA LEVEL WAS HIGHER IN UNMETHYLATED PROSTATE CANCER THAN IN BPH. THE IMMUNOHISTOCHEMICAL STAINING ANALYSIS FOR SOCS 3 CONFIRMED MRNA RESULTS. MOREOVER, METHYLATION OF SOCS3 PROMOTER SIGNIFICANTLY ASSOCIATED WITH INTERMEDIATE-HIGH GRADE GLEASON SCORE (P = 0.0007) AND WITH AN UNFAVORABLE CLINICAL OUTCOME (P = 0.0019). CONCLUSIONS: OUR DATA SUGGEST THAT SOCS3 HYPERMETHYLATION MAY BE INVOLVED IN THE PATHOGENESIS OF PROSTATE CANCER AND COULD IDENTIFY A TUMOR SUBSET WITH AN AGGRESSIVE BEHAVIOR.	2011