1  5144 109 POTENTIAL ROLE OF LNCRNA-TSIX, MIR-548-A-3P, AND SOGA1 MRNA IN THE DIAGNOSIS OF HEPATOCELLULAR CARCINOMA. RECENT TRENDS ARE MOVING TOWARDS THE USE OF THE CIRCULATING TRANSCRIPTOME AS A POTENTIAL DIAGNOSTIC AND THERAPEUTIC TOOL FOR HEPATOCELLULAR CARCINOMA (HCC). THE AIM OF THIS STUDY IS TO IDENTIFY CIRCULATORY RNA BASED BIOMARKER PANEL, IN ADDITION TO THEIR RELATIONSHIP TO THE OUTCOME IN HCC. FIRST, UTILIZING BIOINFORMATICS TOOLS, WE SELECTED AN HCC-SPECIFIC RNA-BASED BIOMARKER PANEL THAT DEPENDED ON THE INTEGRATION OF SUPPRESSOR OF GLUCOSE AUTOPHAGY-ASSOCIATED (SOGA1) GENE EXPRESSION WITH THE CHOSEN PANEL OF EPIGENETIC REGULATORS OF THIS GENE [LONG NON-CODING RNA ANTISENSE FOR X-INACTIVE-SPECIFIC TRANSCRIPT (LNCRNA-TSIX) AND MICRORNA-548-A-3P (MIR-548-A-3P)]. SECOND, WE ATTEMPTED TO VALIDATE THESE BIOMARKERS USING THE SERA OF 65 PATIENTS WITH HCC, 34 PATIENTS WITH CHRONIC HEPATITIS C VIRUS (CHC) INFECTION AND 32 HEALTHY VOLUNTEERS. FINALLY, THE EXPRESSION LEVELS OF THE CHOSEN RNA-BASED BIOMARKER PANEL WERE ASSESSED IN THE SERUM SAMPLES USING QRT-PCR ASSAYS. THE PANEL OF 3 RNA-BASED BIOMARKERS (LNCRNA-TSIX, MIR-548-A-3P, AND SOGA1) EXHIBITED HIGH SENSITIVITY AND SPECIFICITY IN DIFFERENTIATING HCC PATIENTS FROM CHC PATIENTS AND HEALTHY CONTROLS. AMONG THESE 3 RNAS, SERUM LNCRNA-TSIX AND SOGA1 WERE INDEPENDENT PROGNOSTIC FACTOR. THE CHOSEN CIRCULATORY RNA-BASED BIOMARKER PANEL MAY SERVE AS A DIAGNOSTIC AND PROGNOSTIC BIOMARKER FOR HCC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  2902  26 GENDER DIFFERENCES IN THE LIVERS OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND CHRONIC HEPATITIS C INFECTION. OBJECTIVES: A UNIQUE CAUSATIVE ASPECT OF HEPATOCELLULAR CARCINOMA (HCC) IS A GENDER DIFFERENCE IN ITS INCIDENCE. TO DETERMINE THE SPECIFIC FACTORS THAT CONTRIBUTE TO A MALE PREDOMINANCE, WE ANALYZED THE CLINICOPATHOLOGICAL FACTORS, AND GENETIC AND EPIGENETIC ALTERATIONS OF HCCS IN MALE AND FEMALE PATIENTS. METHODS: WE RETROSPECTIVELY ANALYZED THREE COHORTS OF PATIENTS: THE FIRST COHORT CONSISTED OF 547 PATIENTS IDENTIFIED WITH THE FIRST EVENT OF HCC, THE SECOND COHORT INCLUDED 176 HCC PATIENTS, AND THE THIRD 127 PATIENTS WITH CHRONIC HEPATITIS C (CHC). RESULTS: MALE PATIENTS WERE FOUND TO HAVE HCC MORE FREQUENTLY THAN FEMALE PATIENTS IN CASES OF NON-CIRRHOTIC LIVER (P = 0.0030 BY THE CHI(2) TEST), ESPECIALLY IN HEPATITIS C-POSITIVE CASES. HOWEVER, THERE WERE NO GENDER-SPECIFIC DIFFERENCES IN THE GENETIC AND EPIGENETIC ALTERATIONS OF CANCER-RELATED GENES. DEPOSITION OF IRON WAS MORE SEVERE IN MALE CHC PATIENTS THAN IN FEMALE PATIENTS. CONCLUSIONS: MALE PATIENTS WITH CHC DEVELOP HCC MORE FREQUENTLY WHEN THEY HAVE A NON-CIRRHOTIC LIVER THAN DO FEMALE PATIENTS. THIS GENDER DIFFERENCE COULD BE, AT LEAST PARTIALLY, ATTRIBUTED TO A DIFFERENT DEGREE OF IRON DEPOSITION, WHICH CONTRIBUTES TO THE DEVELOPMENT OF HCC IN THE ABSENCE OF LIVER CIRRHOSIS IN MEN WITH CHC.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3   817  41 CHARACTERISTIC PATTERNS OF ALTERED DNA METHYLATION PREDICT EMERGENCE OF HUMAN HEPATOCELLULAR CARCINOMA. WE AIMED TO IDENTIFY THE SPECIFIC SUBSET OF TUMOR SUPPRESSOR GENES (TSGS) THAT ARE METHYLATION-SILENCED DURING THE EARLIEST STEPS OF HEPATOCARCINOGENESIS, AND TO FURTHER EVALUATE WHETHER THESE GENES CAN SERVE AS PREDICTIVE BIOMARKERS OF HEPATOCELLULAR CARCINOMA (HCC) EMERGENCE. A TOTAL OF 482 LIVER TISSUES INCLUDING 177 PAIRS OF HCCS AND MATCHED NONTUMOR LIVERS AND 128 LIVER BIOPSIES FROM CHRONIC HEPATITIS C (CHC) PATIENTS WERE ANALYZED FOR QUANTITATIVE METHYLATION ANALYSIS IN 24 TSG PROMOTERS AND THREE MINT LOCI. THE TUMORS WERE CLASSIFIED AS EARLY, LESS-PROGRESSED, AND HIGHLY PROGRESSED HCCS USING HISTOLOGY AND RADIOLOGICAL APPROACHES. A SUBSET OF TSGS THAT HARBORED DISTINCTLY HIGH LEVELS OF METHYLATION IN EARLY HCCS WERE SELECTED. BASED ON THE METHYLATION PROFILES OF THESE GENES, KAPLAN-MEIER ANALYSES WERE PERFORMED TO DETERMINE TIME-TO-HCC OCCURRENCE IN CHC PATIENTS. SUBSEQUENTLY, MULTIVARIATE ANALYSIS WAS PERFORMED USING AGE, GENDER, FIBROSIS STAGE, AND NUMBER OF METHYLATED TSGS AS COVARIATES. AMONG TSGS ANALYZED, A SUBSET OF EIGHT TSGS (HIC1, GSTP1, SOCS1, RASSF1, CDKN2A, APC, RUNX3, AND PRDM2) DEMONSTRATED A DISTINCT CLUSTER BY HIERARCHICAL CLUSTERING AND RECEIVER OPERATING CHARACTERISTIC ANALYSES. THIS SUBSET OF TSGS SHOWED SIGNIFICANTLY HIGHER METHYLATION LEVELS IN THE EARLY HCCS (P < 0.0001). IN THE CHC PATIENTS, METHYLATION FREQUENCIES IN THESE TSGS WERE ASSOCIATED WITH SHORTER TIME-TO-HCC OCCURRENCE (P < 0.0001), AND NUMBER OF METHYLATED GENES WAS AN INDEPENDENT RISK FACTOR FOR HCC (HAZARD RATIO = 5.21, 95% CONFIDENCE INTERVAL = 2.25-11.76, P = 0.0002). CONCLUSION: EPIGENETIC INACTIVATION OF A SUBSET OF TSGS PLAYS A CRITICAL ROLE IN THE EARLIEST STEPS OF HEPATOCARCINOGENESIS. FURTHERMORE, EPIGENETIC INACTIVATION OF THESE GENES IN CHC PROVIDES A PROGNOSTIC VALUE FOR DETERMINING THE RISK FOR DEVELOPING HCC LATER IN LIFE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  4903  21 P16 PROMOTER HYPERMETHYLATION IN HUMAN HEPATOCELLULAR CARCINOMA WITH OR WITHOUT HEPATITIS VIRUS INFECTION. BACKGROUND: EPIGENETIC ALTERATION THROUGH METHYLATION IS ONE OF THE MOST IMPORTANT STEPS IN CARCINOGENESIS. HOWEVER, THE RELATION BETWEEN HEPATITIS VIRUS INFECTION AND EPIGENETIC ALTERATIONS IS POORLY UNDERSTOOD. METHODS: SIXTEEN PATIENTS WITHOUT HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) AND 35 PATIENTS WITH HBV OR HCV WHO UNDERWENT LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA (HCC) WERE STUDIED. MUTATION OF P53 WAS DETECTED BY DIRECT SEQUENCING. METHYLATION STATUS OF P16 WAS EVALUATED IN TUMOR AND NONCANCEROUS LIVER TISSUES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: IN HCC WITHOUT HBV AND HCV, P53 MUTATIONS WERE DETECTED IN 5 (31%) OF 16 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (25%) OF 8 MODERATELY DIFFERENTIATED HCCS, 6 (75%) OF 8 POORLY DIFFERENTIATED HCCS, AND NONE OF 16 NONCANCEROUS TISSUE SPECIMENS. IN HCC WITH HBV OR HCV, P53 MUTATIONS WERE DETECTED IN 8 (23%) OF 35 HCCS. METHYLATION OF P16 PROMOTER WAS DETECTED IN 2 (100%) OF 2 WELL-DIFFERENTIATED HCCS, 13 (76%) OF 17 MODERATELY DIFFERENTIATED HCCS, 12 (75%) OF 16 POORLY DIFFERENTIATED HCCS, AND 9 (26%) OF 35 NONCANCEROUS LIVER TISSUE SPECIMENS. CONCLUSIONS: OUR RESULTS SUGGEST THAT HEPATITIS VIRUSES MIGHT INDUCE METHYLATION OF P16 PROMOTER IN LIVER WITH CHRONIC INFLAMMATION, BEFORE APPEARANCE OF HCC.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  2679  64 EVALUATION OF CIRCULATORY RNA-BASED BIOMARKER PANEL IN HEPATOCELLULAR CARCINOMA. BACKGROUND: THE CIRCULATING TRANSCRIPTOME (CODING AND NON-CODING) PLAYS A CRITICAL ROLE IN CANCER. NOVEL ACCURATE STRATEGIES FOR EARLY DETECTION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STRONGLY NEEDED. PATIENTS AND METHODS: WE CHOSE AN HCC-SPECIFIC RNA-BASED BIOMARKER PANEL BASED ON THE INTEGRATION OF DIFFERENTIAL LYSOSOMAL-ASSOCIATED MEMBRANE PROTEIN 2 (LAMP2) GENE EXPRESSION WITH ITS SELECTED EPIGENETIC REGULATORS USING BIOINFORMATIC METHODS. THIS WAS FOLLOWED BY RT-QPCR VALIDATION IN SERUM OF 78 PATIENTS WITH HCC, 36 PATIENTS WITH CHRONIC HEPATITIS C (CHC) INFECTION AND 44 HEALTHY VOLUNTEERS. WE USED RISK-SCORE ANALYSIS TO EVALUATE THE DIAGNOSTIC EFFICACY OF THE SERUM PROFILING SYSTEM. MOREOVER, IN TWENTY OF THE 78 HCC CASES INVOLVED IN THE STUDY WE EXAMINED THE EXPRESSION OF RNA-BASED BIOMARKER PANEL IN BOTH HCC AND ADJACENT NON-TUMOR TISSUES AND ASSESSED THEIR CORRELATION WITH THE SERUM LEVEL OF THIS PANEL. RESULTS: THE FOUR RIBONUCLEIC ACID (RNA)-BASED BIOMARKER PANEL [LONG NON-CODING RNA-C TERMINAL BINDING PROTEIN, ANDROGEN RESPONSIVE (LNCRNA-CTBP), MICRORNA-16-2 (MIR-16-2), MICRORNA-21-5-P (MIR-21-5P) AND LAMP2], HAD HIGH SENSITIVITY AND SPECIFICITY FOR DISCRIMINATING HCC FROM HEALTHY CONTROLS AND ALSO FROM CHC PATIENTS. AMONG THESE FOUR RNAS, SERUM MIR-16-2 AND MIR-21-5P WERE INDEPENDENT PROGNOSTIC FACTORS. CONCLUSION: THE CIRCULATORY RNA-BASED BIOMARKER PANEL CAN SERVE AS A POTENTIAL BIOMARKER FOR HCC DIAGNOSIS AND PROGNOSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6  1393  37 DIAGNOSTIC VALUE OF THE HYPOMETHYLATION OF THE WISP1 PROMOTER IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ASSOCIATED WITH HEPATITIS B VIRUS. WNT1-INDUCIBLE SIGNALING PATHWAY PROTEIN 1 (WISP1) REGULATES CELL PROLIFERATION, DIFFERENTIATION, ADHESION, MIGRATION AND SURVIVAL. ABNORMAL WISP1 EXPRESSION IS ASSOCIATED WITH THE CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA (HCC). ABERRANT DNA METHYLATION IS ONE OF THE MAJOR EPIGENETIC ALTERATIONS IN HCC. HOWEVER, THE METHYLATION STATUS OF THE WISP1 PROMOTER IS STILL UNCLEAR. WE THEREFORE AIMED TO DETERMINE THE METHYLATION STATUS OF THE WISP1 PROMOTER AND EVALUATE ITS CLINICAL VALUE IN HCC. THE STUDY ENROLLED 251 PARTICIPANTS, INCLUDING 123 PARTICIPANTS WITH HCC, 90 PARTICIPANTS WITH CHRONIC HEPATITIS B (CHB) AND 38 HEALTHY CONTROLS (HCS). WISP1 METHYLATION STATUS, MRNA LEVELS AND PLASMA SOLUBLE WISP1 WERE DETECTED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), QUANTITATIVE REAL-TIME PCR (RT-QPCR) AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. WE FOUND THAT THE METHYLATION FREQUENCY OF WISP1 IN PATIENTS WITH HCC WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH CHB AND HCS, WHILE THE RELATIVE EXPRESSION LEVELS OF WISP1 MRNA WERE MARKEDLY HIGHER IN PATIENTS WITH HCC THAN IN PATIENTS WITH CHB AND HCS. FURTHERMORE, THE PLASMA SOLUBLE WISP1 IN PATIENTS WITH HCC WAS OBVIOUSLY LOWER THAN IN THAT IN PATIENTS WITH CHB AND HCS. ALPHA-FETOPROTEIN (AFP) IS A WIDELY RECOGNIZED BIOMARKER TO DIAGNOSE HCC WHICH LACKS ENOUGH SENSITIVITY AND SPECIFICITY. WISP1 PROMOTER METHYLATION STATUS COMBINED WITH AFP SIGNIFICANTLY IMPROVED THE DIAGNOSTIC ABILITY IN DISCRIMINATING HCC FROM CHB COMPARED WITH AFP OR WISP1 METHYLATION STATUS ALONE. IN CONCLUSION, HYPOMETHYLATION OF THE WISP1 GENE PROMOTER MAY SERVE AS A NONINVASIVE BIOMARKER FOR DETECTING HBV-ASSOCIATED HCC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  3025  25 GENETICS AND PATHOPHYSIOLOGY OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND ITS MAIN AUTOANTIGEN PROTEINASE 3. GRANULOMATOSIS WITH POLYANGIITIS (GPA) IS A SEVERE AUTOIMMUNE DISEASE AND ONE OF THE SMALL VESSEL ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIDES. ALTHOUGH ITS ETIOLOGY AND PATHOPHYSIOLOGY ARE STILL WIDELY UNKNOWN, IT IS ACCEPTED THAT INFECTIONS, ENVIRONMENTAL FACTORS, EPIGENETIC MODIFICATIONS, AND A GENETIC PREDISPOSITION PROVIDE THE BASIS FOR THIS SYSTEMIC DISORDER. GPA TYPICALLY EVOLVES INTO TWO PHASES: AN INITIAL PHASE CHARACTERIZED BY EAR, NOSE AND THROAT (ENT) MANIFESTATIONS, SUCH AS CHRONIC SINUSITIS AND OTITIS, ULCERATION OF THE ORAL CAVITY AND PHARYNX, AS WELL AS PULMONARY NODULES AND A SEVERE GENERALIZED PHASE, DEFINED BY THE OCCURRENCE OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS, PULMONARY HEMORRHAGE, AND ARTHRITIS. ANCAS, DIRECTED AGAINST THE NEUTROPHILIC ENZYMES PROTEINASE 3 AND MYELOPEROXIDASE, ARE PRESENT IN UP TO 90% OF THE AFFECTED PATIENTS IN THE SYSTEMIC PHASE. AS THE HUMORAL IMMUNITY IS PREDOMINANTLY DIRECTED AGAINST NEUTROPHILIC ANTIGENS, IT IS APPARENT THAT NEUTROPHILS PLAY A CRITICAL ROLE IN GPA BOTH AS TARGET AND EFFECTOR CELLS. ALTHOUGH GPA PATHOGENESIS IS NOT WELL KNOWN, SOME SUSCEPTIBILITY GENES AND LOCI HAVE BEEN IDENTIFIED BY CANDIDATE GENE APPROACHES, GENOME-WIDE ASSOCIATION STUDIES, AND META-ANALYSES, AS WELL AS FAMILIAL ASSOCIATION STUDIES. SUCH GENES ARE CTLA4, PTPN22, COL11A2, SERPINA1, AND THE MHC CLASS II GENE CLUSTER. THIS REVIEW HIGHLIGHTS THE CLINICAL, PATHOPHYSIOLOGICAL, AND GENETIC BACKGROUND OF GPA AND AIMS TO GIVE AN OVERVIEW OF RECENT EFFORTS TO IDENTIFY GPA SUSCEPTIBILITY GENES. WE POINT OUT THE GENETIC BASIS OF THE MAIN AUTOANTIGEN PR3 AND WHY IT IS SO DIFFICULT TO ESTABLISH A MURINE GPA MODEL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  5357  33 REACTIVE OXYGEN SPECIES INDUCE EPIGENETIC INSTABILITY THROUGH THE FORMATION OF 8-HYDROXYDEOXYGUANOSINE IN HUMAN HEPATOCARCINOGENESIS. CHRONIC HEPATITIS C (CHC) TRIGGERS OXIDATIVE STRESS AND CONTRIBUTES TO THE EMERGENCE OF HEPATOCELLULAR CARCINOMA (HCC). WE PREVIOUSLY REPORTED THAT TUMOR SUPPRESSOR GENE (TSG) METHYLATION IS A CRITICAL FACTOR DURING THE EARLY STAGES OF HEPATOCARCINOGENESIS. IN THIS STUDY, WE CLARIFY THE ASSOCIATION BETWEEN OXIDATIVE STRESS AND EPIGENETIC ALTERATIONS DURING HEPATOCARCINOGENESIS. WE EXAMINED DNA OXIDATION AND METHYLATION PROFILES IN 128 LIVER BIOPSY SAMPLES FROM CHC PATIENTS. THE DNA OXIDATION AND METHYLATED TSG NUMBERS WERE QUANTIFIED USING IMMUNOHISTOCHEMICAL ANALYSIS OF 8-HYDROXYDEOXYGUANOSINE (8-OHDG) AND QUANTITATIVE PCR FOR 11 TSGS, RESPECTIVELY. THE QUANTITATIVE CHROMATIN IMMUNOPRECIPITATION-PCR (CHIP-QPCR) ASSAY IN HEPG2 AND FETAL LIVER HC CELLS TREATED WITH H2O2 WAS USED TO QUANTIFY TRIMETHYL-H3K4, ACETYLATED-H4K16 (AN ACTIVE CHROMATIN MARKER), TRIMETHYL-H3K27 (A REPRESSIVE CHROMATIN MARKER) AND 8-OHDG. WE ANALYZED 30 PROMOTERS OF 25 DIFFERENT TSGS BY QPCR. THE HIGH LEVELS OF 8-OHDG WAS THE ONLY VARIABLE THAT WAS SIGNIFICANTLY ASSOCIATED WITH THE INCREASED NUMBER OF METHYLATED TSGS IN CHC (P < 0.0001). THE CHIP-QPCR REVEALED THAT AFTER H2O2 TREATMENT OF THE CELL LINES, THE 8-OHDG-BOUND PROMOTERS SHOWED A MODIFICATION FROM AN ACTIVE CHROMATIN (TRIMETHYL-H3K4 AND ACETYLATED-H4K16 DOMINANT) TO A REPRESSIVE CHROMATIN (TRIMETHYL-H3K27 DOMINANT) STATUS. WE CONCLUDE THAT OXIDATIVE STRESS ALTERS THE CHROMATIN STATUS, WHICH LEADS TO ABNORMAL METHYLATION OF TSGS, AND CONTRIBUTES TO HEPATOCARCINOGENESIS IN CHC PATIENTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  5760  33 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10   353  35 ALTERED LEVELS OF IMMUNE-REGULATORY MICRORNAS IN PLASMA SAMPLES OF PATIENTS WITH LUPUS NEPHRITIS. INTRODUCTION: LUPUS NEPHRITIS (LN) IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THE PATIENTS WITH LUPUS, A CHRONIC AUTOIMMUNE DISEASE. THE ROLE OF GENETIC AND EPIGENETIC FACTORS IS EMPHASIZED IN THE PATHOGENESIS OF LN. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE LEVELS OF IMMUNE-REGULATORY MICRORNAS (E.G., MIR-31, MIR-125A, MIR-142-3P, MIR-146A, AND MIR-155) IN PLASMA SAMPLES OF PATIENTS WITH LN. METHODS: IN THIS STUDY, 26 PATIENTS WITH LN AND 26 HEALTHY INDIVIDUALS WERE INCLUDED. THE PLASMA LEVELS OF THE MICRORNAS WERE EVALUATED BY A QUANTITATIVE REAL-TIME PCR. MOREOVER, THE CORRELATION OF CIRCULATING PLASMA MICRORNAS WITH DISEASE ACTIVITY AND PATHOLOGICAL FINDINGS ALONG WITH THEIR ABILITY TO DISTINGUISH PATIENTS WITH LN WERE ASSESSED. RESULTS: PLASMA LEVELS OF MIR-125A (P = 0.048), MIR-146A (P = 0.005), AND MIR-155 (P< 0.001) WERE SIGNIFICANTLY HIGHER IN COMPARISON BETWEEN THE CASES AND CONTROLS. THE PLASMA LEVEL OF MIR-146A SIGNIFICANTLY CORRELATED WITH THE LEVEL OF ANTI-DOUBLE STRAND-DNA ANTIBODY AND PROTEINURIA. MOREOVER, THERE WAS A SIGNIFICANT CORRELATION BETWEEN MIR-142-3P LEVELS AND DISEASE CHRONICITY AND ACTIVITY INDEX (P <0.05). THE MULTIVARIATE ROC CURVE ANALYSIS INDICATED THE PLASMA CIRCULATING MIR-125A, MIR-142-3P, MIR-146, AND MIR-155 TOGETHER COULD DISCRIMINATE MOST OF THE PATIENTS WITH LN FROM CONTROLS WITH AREA AN UNDER CURVE (AUC) OF 0.89 [95% CI, 0.80-0.98, P<0.001], 88% SENSITIVITY, AND 78% SPECIFICITY. CONCLUSION: BASED ON THE FINDINGS OF THE PRESENT STUDY, THE STUDIED MICRORNAS MAY BE INVOLVED IN THE PATHOGENESIS AND DEVELOPMENT OF LN AND HAVE THE POTENTIAL TO BE USED AS DIAGNOSTIC AND THERAPEUTIC MARKERS IN LN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  2759  36 EXPRESSION OF IL-17 AND ITS GENE PROMOTER METHYLATION STATUS ARE ASSOCIATED WITH THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS INFECTION. TO EXPLORE INTERLEUKIN-17 (IL-17) AND ITS EPIGENETIC REGULATION DURING THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION.A TOTAL OF 162 PATIENTS WITH CHRONIC HBV INFECTION, INCLUDING 75 WITH CHRONIC HEPATITIS B (CHB), 54 WITH HEPATITIS B-ASSOCIATED LIVER CIRRHOSIS AND 33 WITH HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA (HBV-HCC), WERE ENROLLED IN THIS STUDY. THIRTY HEALTHY ADULTS OF THE SAME ETHNICITY WERE ENROLLED IN THE CONTROL GROUP. WHOLE VENOUS BLOOD WAS OBTAINED FROM THE PATIENTS AND NORMAL CONTROLS (N = 30). CLINICAL AND LABORATORY PARAMETERS WERE ASSESSED, AND WE PERFORMED ENZYME-LINKED IMMUNOSORBENT ASSAY AND QUANTITATIVE REAL-TIME PCR TO MEASURE THE SERUM LEVELS AND RELATIVE MRNA EXPRESSION OF IL-17, RESPECTIVELY. IL-17 PROMOTER METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS WAS ASSESSED BY METHYLATION-SPECIFIC PCR. WE ANALYZED THE SERUM AND MRNA LEVELS OF IL-17 AND IL-17 PROMOTER METHYLATION IN THE 4 GROUPS AS WELL AS THE EFFECT OF METHYLATION ON SERUM IL-17 LEVELS. CORRELATIONS BETWEEN THE IL-17 PROMOTER METHYLATION STATUS AND CLINICAL PARAMETERS WERE ANALYZED BY SPEARMAN CORRELATION ANALYSIS.COMPARED TO THE NORMAL CONTROL GROUP, THE PATIENT GROUPS EXHIBITED SIGNIFICANTLY HIGHER SERUM AND RELATIVE MRNA LEVELS OF IL-17. THE METHYLATION DISTRIBUTION AMONG THE PATIENTS WAS SIGNIFICANTLY LOWER THAN THAT AMONG THE NORMAL CONTROLS (P < .05), WITH THE HBV-HCC GROUP SHOWING THE LOWEST IL-17 GENE METHYLATION FREQUENCY. THE AVERAGE IL-17 PROMOTER CG METHYLATION LEVEL WAS NEGATIVELY CORRELATED WITH IL-17 MRNA EXPRESSION (R = -0.39, P = .03), AND NEGATIVE CORRELATIONS BETWEEN IL-17 PROMOTER METHYLATION AND PROTHROMBIN TIME ACTIVITY (R = -0.585, P = .035), ALANINE AMINOTRANSFERASE (R = -0.522, P < .01), ASPARTATE AMINOTRANSFERASE (R = -0.315, P < .05), AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE (R = -0.461, P < .05) WERE OBSERVED. IL-17 SERUM LEVELS IN THE METHYLATED-PROMOTER GROUPS WERE SIGNIFICANTLY LOWER THAN THOSE IN THE UNMETHYLATED-PROMOTER GROUPS.IL-17 EXPRESSION AND PROMOTER METHYLATION WERE ASSOCIATED WITH CHRONIC HBV INFECTION PROGRESSION, ESPECIALLY IN THE HBV-HCC GROUP. THE IL-17 PROMOTER STATUS MAY HELP CLINICIANS INITIATE THE CORRECT TREATMENT STRATEGY AT THE CHB STAGE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12   740  32 CANCER/TESTIS ANTIGENS: EXPRESSION, REGULATION, TUMOR INVASION, AND USE IN IMMUNOTHERAPY OF CANCERS. CANCER/TESTIS ANTIGENS (CTAS) ARE NAMED BASED ON THEIR EXPRESSION PATTERN THAT IS RESTRICTED IN A NUMBER OF NORMAL AND ABNORMAL TISSUES. TUMOR CELLS FREQUENTLY EXPRESS ANTIGENS WHOSE EXPRESSION IS TYPICALLY RESTRICTED TO GERM CELLS. THEIR UNIQUE EXPRESSION PATTERN IS GUARANTEED BY PRECISE EPIGENETIC REGULATORY MECHANISMS. BECAUSE OF THEIR TUMOR-LIMITED, HIGH IMMUNOGENICITY, AND BIASED EXPRESSION, DISCOVERY OF THESE MOLECULES PROVIDES UNPRECEDENTED OPPORTUNITIES FOR FURTHER RESEARCH AND CLINICAL DEVELOPMENT IN THE FIELD OF CANCER DIAGNOSIS AND IMMUNOTHERAPY. EVOLVING EVIDENCE REVEALS THAT A NUMBER OF CTAS STIMULATE EPITHELIAL MESENCHYMAL TRANSITION (EMT) AND GENERATION OF CANCER STEM-LIKE CELLS, INTENSIFYING METASTASIS, INVASION, AND TUMORIGENESIS. BASED ON THESE FEATURES, CTAS ATTRACT ATTENTION TO BE CONSIDERED AS IDEAL TARGETS FOR DEVELOPING SEVERAL CLINICAL TRIALS, MANY OF THEM CONCENTRATING ON CTA VACCINE THERAPY. ACCORDING TO RECENT PRACTICAL CLINICAL INTEREST, MORE CHARACTERIZATIONS OF CTA REGULATION ARE IDENTIFIED. CTA EXPRESSION HAS BEEN DEMONSTRATED IN A VARIETY OF HUMAN CANCER TISSUES, AND SOME OF THEM HAVE BEEN FOUND TO ELICIT HUMORAL AND/OR CELLULAR IMMUNE RESPONSES IN CANCER PATIENTS. CTAS ARE BRILLIANT TARGETS FOR ANTICANCER DRUG DISCOVERY, TARGETED TUMOR THERAPY, AND DIAGNOSTIC BIOMARKERS, FURTHERMORE, VALUED GENES IN THE STUDY OF IMMUNOTHERAPY, PROMOTING TUMORIGENESIS, AND MALIGNANT PROGRESSION. THIS REVIEW OUTLINES AND CATEGORIZES OUR CURRENT UNDERSTANDING OF THE COMPLEX AND BIASED PROCESS OF CTAS MRNA AND PROTEIN EXPRESSION IN CANCER, AND SUPPLIES THE MOST RECENT INFORMATION ON THEIR REGULATION AND FUNCTION. BESIDES, A CONCISE SYNOPSIS OF THE MAJOR CLINICAL TRIALS INVOLVING CTAS, AS THERAPEUTIC AVENUES, IS DISCUSSED. ABBREVIATIONS: AIRE: AUTOIMMUNE REGULATOR; CAMP: CYCLIC ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE; CEA: CARCINOEMBRYONIC ANTIGEN; CML: CHRONIC MYELOID LEUKEMIA; CREB: CYCLICAMP RESPONSE ELEMENT BINDING; CSCS: CANCER STEM CELLS; CTAS: CANCER/TESTIS ANTIGENS; CTL: CYTOTOXIC T LYMPHOCYTE; DCS: DENDRITIC CELLS; EMT: EPITHELIAL-MESENCHYMAL TRANSITION; ERK: EXTRACELLULAR SIGNAL-REGULATED KINASE; ESCC: ESOPHAGEAL SQUAMOUS CELL CARCINOMA; ETS: E26 TRANSFORMATION-SPECIFIC; HIS: HISTIDINE; HLA: HUMAN LEUKOCYTE ANTIGEN; HNSCC: HEAD AND NECK SQUAMOUS CELL CARCINOMA; IFN-GAMMA: INTERFERON-GAMMA; IHC: IMMUNOHISTOCHEMISTRY; IL-7: INTERLEUKIN7; MHC: MAJOR HISTOCOMPATIBILITY COMPLEX; MMP2: MATRIX METALLOPROTEINASE 2; MTECS: MEDULLARY THYMUS EPITHELIAL CELLS; MUC1: MUCIN 1; NSCLC: NON-SMALL CELL LUNG CANCER; PRAME: PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA; RDA: REPRESENTATIONAL DIFFERENCE ANALYSIS; SEREX: SEROLOGICAL ANALYSIS OF CDNA EXPRESSION; SSX: SYNOVIAL SARCOMA X CHROMOSOME; TAAS: TUMOR-ASSOCIATED ANTIGENS; TCR: T-CELL RECEPTOR; TCGA: THE CANCER GENOME ATLAS; TGF-BETA: TRANSFORMING GROWTH FACTOR-BETA.	2016	

13  2684  26 EVALUATION OF X CHROMOSOME INACTIVATION WITH RESPECT TO HLA GENETIC SUSCEPTIBILITY IN RHEUMATOID ARTHRITIS AND SYSTEMIC SCLEROSIS. BACKGROUND: AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS (RA) AND SYSTEMIC SCLEROSIS (SSC) ARE CHARACTERIZED BY A STRONG GENETIC SUSCEPTIBILITY FROM THE HUMAN LEUCOCYTE ANTIGEN (HLA) LOCUS. ADDITIONALLY, DISORDERS OF EPIGENETIC PROCESSES, IN PARTICULAR NON-RANDOM X CHROMOSOME INACTIVATION (XCI), HAVE BEEN REPORTED IN MANY FEMALE-PREDOMINANT AUTOIMMUNE DISEASES. HERE WE TEST THE HYPOTHESIS THAT WOMEN WITH RA OR SSC WHO ARE STRONGLY GENETICALLY PREDISPOSED ARE LESS SUSCEPTIBLE TO XCI BIAS. METHODS: USING METHYLATION SENSITIVE GENOTYPING OF THE ANDROGEN RECEPTOR (AR) GENE, XCI PROFILES WERE PERFORMED IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 161 WOMEN WITH RA, 96 WOMEN WITH SSC AND 100 HEALTHY WOMEN. HLA-DRB1 AND DQB1 WERE GENOTYPED. PRESENCE OF SPECIFIC AUTOANTIBODIES WAS DOCUMENTED FOR PATIENTS. XCI SKEWING WAS DEFINED AS HAVING A RATIO >/= 80:20 OF CELLS INACTIVATING THE SAME X CHROMOSOME. RESULTS: 110 WOMEN WITH RA, 68 WOMEN WITH SSC, AND 69 CONTROLS WERE INFORMATIVE FOR THE AR POLYMORPHISM. AMONG THEM 40.9% OF RA PATIENTS AND 36.8% OF SSC PATIENTS HAD SKEWED XCI COMPARED TO 17.4% OF HEALTHY WOMEN (P = 0.002 AND 0.018, RESPECTIVELY). PRESENCE OF RA-SUSCEPTIBILITY ALLELES CODING FOR THE "SHARED EPITOPE" CORRELATED WITH HIGHER SKEWING AMONG RA PATIENTS (P = 0.002) AND SUCH CORRELATION WAS NOT OBSERVED IN OTHER WOMEN, HEALTHY OR WITH SSC. PRESENCE OF SSC-SUSCEPTIBILITY ALLELES DID NOT CORRELATE WITH XCI PATTERNS AMONG SSC PATIENTS. CONCLUSION: DATA DEMONSTRATE XCI SKEWING IN BOTH RA AND SSC COMPARED TO HEALTHY WOMEN. UNEXPECTEDLY, SKEWED XCI OCCURS MORE OFTEN IN WOMEN WITH RA CARRYING THE SHARED EPITOPE, WHICH USUALLY REFLECTS SEVERE DISEASE. THIS REINFORCES THE VIEW THAT LOSS OF MOSAICISM IN PERIPHERAL BLOOD MAY BE A CONSEQUENCE OF CHRONIC AUTOIMMUNITY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  6368  32 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15  3056  27 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  6415  29 THE STUDY OF P16 AND P15 GENE METHYLATION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA AND THEIR QUANTITATIVE EVALUATION IN PLASMA BY REAL-TIME PCR. EPIGENETIC SILENCING OF THE P16 AND P15 GENES BY PROMOTER METHYLATION ARE COMMONLY OBSERVED IN HUMAN EPITHELIAL MALIGNANCIES, INCLUDING HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC). IN THIS STUDY, A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) WAS USED TO EVALUATE THE METHYLATION STATUS OF THE P16 AND P15 GENES IN 73 HNSCC SURGICAL SPECIMENS. P16 AND P15 GENE METHYLATION WAS ALSO EXAMINED IN 29 PAIRED METASTATIC LYMPH NODES AND 29 PAIRED HISTOLOGICALLY, NORMAL RESECTION MARGIN MUCOSAE. THE QUANTITY OF CELL-FREE METHYLATED P16 AND P15 DNA IN THE PLASMA SAMPLES OF 20 HNSCC PATIENTS AND 24 HEALTHY CONTROLS WAS ALSO EXAMINED USING A FLUORESCENCE-BASED REAL-TIME PCR ASSAY. THE FREQUENCIES OF P16 AND P15 METHYLATION IN THE PRIMARY TUMOUR WERE 49% AND 60%, RESPECTIVELY. CONCORDANT METHYLATION OF P16 AND P15 IN TUMOUR SAMPLES AND METASTATIC LYMPH NODES WAS FOUND IN 59 AND 38% OF CASES, RESPECTIVELY. A SIGNIFICANTLY HIGHER PREVALENCE OF P15 METHYLATION WAS FOUND IN HISTOLOGICALLY-NORMAL SURGICAL MARGIN EPITHELIA OF HNSCC PATIENTS WITH CHRONIC SMOKING AND DRINKING HABITS COMPARED WITH NON-SMOKERS AND NON-DRINKERS. IN ADDITION, METHYLATED P16 AND P15 DNA LEVELS WERE SIGNIFICANTLY HIGHER IN THE PLASMA OF HNSCC PATIENTS (MEAN 56 COPIES/ML PLASMA AND 65 COPIES/ML PLASMA, RESPECTIVELY) COMPARED WITH NORMAL CONTROLS (MEAN 6 COPIES/ML PLASMA AND 16 COPIES/ML PLASMA, RESPECTIVELY). IN CONCLUSION, PROMOTER METHYLATION OF THE P16 AND P15 GENES IS INVOLVED IN THE PATHOGENESIS OF HNSCC AND MAY BE RELATED TO CHRONIC SMOKING AND DRINKING. THE DIFFERENTIAL LEVELS OF METHYLATED P16 AND P15 DNA IN PLASMA MIGHT BE POTENTIAL USEFUL MARKERS IN SCREENING HIGH-RISK POPULATIONS FOR EARLY HNSCC AND MONITORING THEIR TREATMENT RESPONSE.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  3190  36 HCV-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH LIVER CANCER RISK PERSIST AFTER SUSTAINED VIROLOGIC RESPONSE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE EFFECTIVE ANTIVIRAL THERAPIES, THE RISK FOR HCC IS DECREASED BUT NOT ELIMINATED AFTER A SUSTAINED VIROLOGIC RESPONSE (SVR) TO DIRECT-ACTING ANTIVIRAL (DAA) AGENTS, AND THE RISK IS HIGHER IN PATIENTS WITH ADVANCED FIBROSIS. WE INVESTIGATED HCV-INDUCED EPIGENETIC ALTERATIONS THAT MIGHT AFFECT RISK FOR HCC AFTER DAA TREATMENT IN PATIENTS AND MICE WITH HUMANIZED LIVERS. METHODS: WE PERFORMED GENOME-WIDE CHIPMENTATION-BASED CHIP-SEQ AND RNA-SEQ ANALYSES OF LIVER TISSUES FROM 6 PATIENTS WITHOUT HCV INFECTION (CONTROLS), 18 PATIENTS WITH CHRONIC HCV INFECTION, 8 PATIENTS WITH CHRONIC HCV INFECTION CURED BY DAA TREATMENT, 13 PATIENTS WITH CHRONIC HCV INFECTION CURED BY INTERFERON THERAPY, 4 PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION, AND 7 PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS IN EUROPE AND JAPAN. HCV-INDUCED EPIGENETIC MODIFICATIONS WERE MAPPED BY COMPARATIVE ANALYSES WITH MODIFICATIONS ASSOCIATED WITH OTHER LIVER DISEASE ETIOLOGIES. UPA/SCID MICE WERE ENGRAFTED WITH HUMAN HEPATOCYTES TO CREATE MICE WITH HUMANIZED LIVERS AND GIVEN INJECTIONS OF HCV-INFECTED SERUM SAMPLES FROM PATIENTS; MICE WERE GIVEN DAAS TO ERADICATE THE VIRUS. PATHWAYS ASSOCIATED WITH HCC RISK WERE IDENTIFIED BY INTEGRATIVE PATHWAY ANALYSES AND VALIDATED IN ANALYSES OF PAIRED HCC TISSUES FROM 8 PATIENTS WITH AN SVR TO DAA TREATMENT OF HCV INFECTION. RESULTS: WE FOUND CHRONIC HCV INFECTION TO INDUCE SPECIFIC GENOME-WIDE CHANGES IN H3K27AC, WHICH CORRELATED WITH CHANGES IN EXPRESSION OF MRNAS AND PROTEINS. THESE CHANGES PERSISTED AFTER AN SVR TO DAAS OR INTERFERON-BASED THERAPIES. INTEGRATIVE PATHWAY ANALYSES OF LIVER TISSUES FROM PATIENTS AND MICE WITH HUMANIZED LIVERS DEMONSTRATED THAT HCV-INDUCED EPIGENETIC ALTERATIONS WERE ASSOCIATED WITH LIVER CANCER RISK. COMPUTATIONAL ANALYSES ASSOCIATED INCREASED EXPRESSION OF SPHK1 WITH HCC RISK. WE VALIDATED THESE FINDINGS IN AN INDEPENDENT COHORT OF PATIENTS WITH HCV-RELATED CIRRHOSIS (N = 216), A SUBSET OF WHICH (N = 21) ACHIEVED VIRAL CLEARANCE. CONCLUSIONS: IN AN ANALYSIS OF LIVER TISSUES FROM PATIENTS WITH AND WITHOUT AN SVR TO DAA THERAPY, WE IDENTIFIED EPIGENETIC AND GENE EXPRESSION ALTERATIONS ASSOCIATED WITH RISK FOR HCC. THESE ALTERATIONS MIGHT BE TARGETED TO PREVENT LIVER CANCER IN PATIENTS TREATED FOR HCV INFECTION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  1571  36 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT.	2021	
                                                                                                                               
19  3456  28 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20  3057  28 GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIES HLA-B*27 DEPENDENT AND INDEPENDENT DNA METHYLATION CHANGES IN WHOLE BLOOD. BACKGROUND AND OBJECTIVE: ANKYLOSING SPONDYLITIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY INFLAMMATION OF THE SACROILIAC JOINTS AND THE SPINE THAT CAN LEAD TO SIGNIFICANT PAIN, IMMOBILITY, AND DISABILITY. THE ETIOLOGY AND PATHOGENESIS OF ANKYLOSING SPONDYLITIS ARE INCOMPLETELY UNDERSTOOD, THOUGH MOST PATIENTS CARRY THE HLA-B*27 ALLELE. THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE DNA METHYLATION CHANGES IN ANKYLOSING SPONDYLITIS WITH THE GOAL OF REVEALING NOVEL MECHANISTIC INSIGHTS INTO THIS DISEASE. METHODS: GENOME-WIDE DNA METHYLATION ANALYSIS WAS PERFORMED IN WHOLE BLOOD DNA SAMPLES USING THE INFINIUM METHYLATIONEPIC ARRAY IN PATIENTS WITH ANKYLOSING SPONDYLITIS COMPARED TO AGE, SEX, AND RACE MATCHED PATIENTS WITH OSTEOARTHRITIS AS A NON-INFLAMMATORY DISEASE CONTROL. WE STUDIED 24 PATIENTS WITH ANKYLOSING SPONDYLITIS, INCLUDING 12 PATIENTS WHO CARRY HLA-B*27 AND 12 PATIENTS WHO ARE HLA-B*27 NEGATIVE. DNA METHYLATION ANALYSIS WAS PERFORMED WITH ADJUSTMENT FOR BLOOD CELL COMPOSITION IN EACH SAMPLE. RESULTS: WE IDENTIFIED A TOTAL OF 67 DIFFERENTIALLY METHYLATED SITES BETWEEN ANKYLOSING SPONDYLITIS PATIENTS AND OSTEOARTHRITIS CONTROLS. HYPERMETHYLATED GENES FOUND INCLUDED GTPASE-RELATED GENES, WHILE HYPOMETHYLATED GENES INCLUDED HCP5, WHICH ENCODES A LNCRNA WITHIN THE MHC REGION, PREVIOUSLY ASSOCIATED WITH GENETIC RISK FOR PSORIASIS AND TOXIC EPIDERMAL NECROLYSIS. CARRYING HLA-B*27 WAS ASSOCIATED WITH ROBUST HYPOMETHYLATION OF HCP5, TUBULIN FOLDING COFACTOR A (TBCA) AND PHOSPHOLIPASE D FAMILY MEMBER 6 (PLD6) IN ANKYLOSING SPONDYLITIS PATIENTS. HYPOMETHYLATION WITHIN HCP5 INVOLVES A CPG SITE THAT CONTAINS A SINGLE NUCLEOTIDE POLYMORPHISM IN LINKAGE DISEQUILIBRIUM WITH HLA-B*27 AND THAT CONTROLS DNA METHYLATION AT THIS LOCUS IN AN ALLELE-SPECIFIC MANNER. CONCLUSIONS: A GENOME-WIDE DNA METHYLATION ANALYSIS IN ANKYLOSING SPONDYLITIS IDENTIFIED DNA METHYLATION PATTERNS THAT COULD PROVIDE POTENTIAL NOVEL INSIGHTS INTO THIS DISEASE. OUR FINDINGS SUGGEST THAT HLA-B*27 MIGHT PLAY A ROLE IN ANKYLOSING SPONDYLITIS IN PART THROUGH INDUCING EPIGENETIC DYSREGULATION.	2019