1  1572 127 DNA METHYLATION PATTERNS IN JUVENILE SYSTEMIC SCLEROSIS AND LOCALIZED SCLERODERMA. SCLERODERMA REFERS TO A GROUP OF CHRONIC FIBROTIC IMMUNE-MEDIATED DISEASES OF UNKNOWN ETIOLOGY. CHARACTERIZING EPIGENETIC CHANGES IN CHILDHOOD-ONSET SCLERODERMA, SYSTEMIC SCLEROSIS OR LOCALIZED SCLERODERMA, HAS NOT BEEN PREVIOUSLY PERFORMED. THE AIM OF THIS STUDY WAS TO ASSESS DNA METHYLATION DIFFERENCES AND SIMILARITIES BETWEEN JUVENILE SYSTEMIC SCLEROSIS (JSSC) AND JUVENILE LOCALIZED SCLERODERMA (JLS) COMPARED TO MATCHED HEALTHY CONTROLS. GENOME-WIDE DNA METHYLATION CHANGES IN PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES WERE ASSESSED USING THE METHYLATIONEPIC ARRAY FOLLOWED BY BIOINFORMATIC ANALYSIS AND LIMITED FUNCTIONAL ASSESSMENT. WE IDENTIFIED A TOTAL OF 105 AND 144 DIFFERENTIALLY METHYLATED SITES COMPARED TO HEALTHY CONTROLS IN JSSC AND JLS, RESPECTIVELY. THE MAJORITY OF DIFFERENTIALLY METHYLATED SITES AND GENES REPRESENTED WERE UNIQUE TO EITHER JSSC OR JLS SUGGESTING A DIFFERENT UNDERLYING EPIGENETIC PATTERN IN BOTH DISEASES. AMONG SHARED DIFFERENTIALLY METHYLATED GENES, METHYLATION LEVELS IN A CPG SITE IN FGFR2 CAN DISTINGUISH BETWEEN LS AND HEALTHY PBMCS WITH A HIGH ACCURACY. CANONICAL PATHWAY ANALYSIS REVEALED THAT INFLAMMATORY PATHWAYS WERE ENRICHED IN GENES DIFFERENTIALLY METHYLATED IN JSSC, INCLUDING STAT3, NF-KAPPAB, AND IL-15 PATHWAYS. IN CONTRAST, THE HIPPO SIGNALING PATHWAY WAS ENRICHED IN JLS. OUR DATA ALSO SUGGEST A POTENTIAL ROLE FOR NOTCH3 IN BOTH JSSC AND JLS, AND REVEALED A NUMBER OF TRANSCRIPTION FACTORS UNIQUE TO EACH OF THE TWO DISEASES. IN SUMMARY, OUR DATA REVEALED IMPORTANT INSIGHTS INTO JSSC AND JLS AND SUGGEST A POTENTIALLY NOVEL EPIGENETIC DIAGNOSTIC BIOMARKER FOR LS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  5639  37 SERUM MICRORNAS IN SYSTEMIC SCLEROSIS, ASSOCIATIONS WITH DIGITAL VASCULOPATHY AND LUNG INVOLVEMENT. BACKGROUND AND AIMS: SYSTEMIC SCLEROSIS (SSC) IS AN AUTOIMMUNE, RARE MULTISYSTEM CHRONIC DISEASE THAT IS STILL NOT WELL-UNDERSTOOD AETIOLOGICALLY AND IS CHALLENGING DIAGNOSTICALLY. IN THE LITERATURE, THERE ARE EVER-INCREASING ASSUMPTIONS REGARDING THE EPIGENETIC MECHANISMS INVOLVED IN SSC DEVELOPMENT; ONE OF THEM IS CIRCULATING MICRORNAS. MANY OF THEM REGULATE TLR PATHWAYS AND ARE SIGNIFICANT IN AUTOIMMUNE BALANCE. THE AIM OF THIS STUDY WAS TO DETERMINE PROFILE EXPRESSION OF SELECTED MICRORNAS IN SSC PATIENTS, INCLUDING MIR-126, -132, -143, -145, -155, -181A, -29A AND -3148, IN COMPARISON TO HEALTHY CONTROLS. METHODS: SERUM MICRORNAS WERE ISOLATED FROM 45 PATIENTS WITH SSC AND 57 HEALTHY DONORS (HC). ADDITIONALLY, SSC PATIENTS WERE CONSIDERED IN THE ASPECT OF DISEASE SUBTYPE, INCLUDING DIFFUSE SYSTEMIC SCLEROSIS (DCSSC) AND LIMITED SYSTEMIC SCLEROSIS (LCSSC). RESULTS: MIR-3148 WAS DETECTED NEITHER IN THE SERUM OF HC NOR IN SSC PATIENTS. ALL OF THE REST OF THE ANALYZED MICRORNAS, EXCLUDING MIR-126, MIR-29A AND MIR-181A, WERE SIGNIFICANTLY UPREGULATED IN SSC PATIENTS IN COMPARISON TO HC. HOWEVER, MIR-181A HAS BEEN REVEALED ONLY IN THE SERUM OF PATIENTS WITH LCSSC BUT NOT DCSSC. MODERATE POSITIVE CORRELATIONS BETWEEN THE TRANSFER FACTOR OF THE LUNG FOR CARBON MONOXIDE (TLCO) AND MIR-126 AND MIR-145 WERE OBSERVED. A SIGNIFICANT CORRELATION HAS BEEN FOUND BETWEEN SERUM MIR-143 LEVEL AND FORCED VITAL CAPACITY (FVC). SSC PATIENTS WITH FVC </= 70% WERE CHARACTERIZED BY SIGNIFICANTLY LOWER LEVELS OF MIR-143 COMPARED TO PATIENTS WITH NORMAL FVC. ADDITIONALLY, THE EXPRESSION OF MIR-132 WAS SIGNIFICANTLY HIGHER IN DCSSC SUBGROUP WITH DETECTED ACTIVE LUNG LESIONS COMPARED TO DCSSC PATIENTS WITH FIBROTIC LESIONS. PATIENTS WITH AN EARLY SCLERODERMA PATTERN OF MICROANGIOPATHY SEEN ON NAILFOLD VIDEO-CAPILLAROSCOPY (NVC) REVEALED HIGHER EXPRESSION OF MIR-155 IN SERUM THAN THOSE WITH A LATE PATTERN. CONCLUSIONS: THE EXPRESSION PROFILE OF CIRCULATING CELL-FREE MIRNAS IS SIGNIFICANTLY CHANGED IN THE SERUM OF SSC PATIENTS COMPARED TO HEALTHY INDIVIDUALS. DOWNREGULATION OF MIRNA-181A AND OVEREXPRESSION OF MIR-132, MIR-143, MIR-145 AND MIR-155 IN SERUM MAY BE SIGNIFICANT IN SSC IN THE CONTEXT OF BIOMARKERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  2554  25 EPIGENETICS IN REACTIVE AND REPARATIVE CARDIAC FIBROGENESIS: THE PROMISE OF EPIGENETIC THERAPY. EPIGENETIC CHANGES PLAY A PIVOTAL ROLE IN THE DEVELOPMENT OF A WIDE SPECTRUM OF HUMAN DISEASES INCLUDING CARDIOVASCULAR DISEASES, CANCER, DIABETES, AND INTELLECTUAL DISABILITIES. CARDIAC FIBROGENESIS IS A COMMON PATHOPHYSIOLOGICAL PROCESS SEEN DURING CHRONIC AND STRESS-INDUCED ACCELERATED CARDIAC AGING. WHILE ADEQUATE PRODUCTION OF EXTRACELLULAR MATRIX (ECM) PROTEINS IS NECESSARY FOR POST-INJURY WOUND HEALING, EXCESSIVE SYNTHESIS AND ACCUMULATION OF EXTRACELLULAR MATRIX PROTEIN IN THE STRESSED OR INJURED HEARTS CAUSES DECREASED OR LOSS OF LUSITROPY THAT LEADS TO CARDIAC FAILURE. THIS SELF-PERPETUATING DEPOSITION OF COLLAGEN AND OTHER MATRIX PROTEINS EVENTUALLY ALTER CELLULAR HOMEOSTASIS; IMPAIR TISSUE ELASTICITY AND LEADS TO MULTI-ORGAN FAILURE, AS SEEN DURING PATHOGENESIS OF CARDIOVASCULAR DISEASES, CHRONIC KIDNEY DISEASES, CIRRHOSIS, IDIOPATHIC PULMONARY FIBROSIS, AND SCLERODERMA. IN THE LAST 25 YEARS, MULTIPLE STUDIES HAVE INVESTIGATED THE MOLECULAR BASIS OF ORGAN FIBROSIS AND HIGHLIGHTED ITS MULTI-FACTORIAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL REGULATION. IN THIS MINIREVIEW, WE FOCUS ON FIVE MAJOR EPIGENETIC REGULATORS AND DISCUSS THEIR CENTRAL ROLE IN CARDIAC FIBROGENESIS. ADDITIONALLY, WE COMPARE AND CONTRAST THE EPIGENETIC REGULATION OF HYPERTENSION-INDUCED REACTIVE FIBROGENESIS AND MYOCARDIAL INFARCTION-INDUCED REPARATIVE OR REPLACEMENT CARDIAC FIBROGENESIS. AS MICRORNAS-ONE OF THE MAJOR EPIGENETIC REGULATORS-CIRCULATE IN PLASMA, WE ALSO ADVOCATE THEIR POTENTIAL DIAGNOSTIC ROLE IN CARDIAC FIBROSIS. LASTLY, WE DISCUSS THE EVOLUTION OF NOVEL EPIGENETIC-REGULATING DRUGS AND PREDICT THEIR CLINICAL ROLE IN THE SUPPRESSION OF PATHOLOGICAL CARDIAC REMODELING, CARDIAC AGING, AND HEART FAILURE. J. CELL. PHYSIOL. 232: 1941-1956, 2017. (C) 2016 WILEY PERIODICALS, INC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  4575  35 MYOFIBROBLASTS. PURPOSE OF REVIEW: INTEREST IN THE MYOFIBROBLAST AS A KEY PLAYER IN PROPAGATION OF CHRONIC PROGRESSIVE FIBROSIS CONTINUES TO ELICIT MANY PUBLICATIONS, WITH FOCUS ON ITS CELLULAR ORIGINS AND THE MECHANISMS UNDERPINNING THEIR DIFFERENTIATION AND/OR TRANSITION. THE OBJECTIVE OF THE REVIEW IS TO HIGHLIGHT THIS RECENT PROGRESS. RECENT FINDINGS: THE EPITHELIAL ORIGIN OF THE MYOFIBROBLAST IN FIBROSIS HAS BEEN CHALLENGED BY RECENT STUDIES, WITH THE PERICYTE SUGGESTED AS A POSSIBLE PRECURSOR INSTEAD. ADDITIONAL SIGNALING PATHWAYS, INCLUDING NOTCH, WNT, AND HEDGEHOG, ARE IMPLICATED IN MYOFIBROBLAST DIFFERENTIATION. THE IMPORTANCE OF NADPH OXIDASE 4 WAS HIGHLIGHTED RECENTLY TO SUGGEST A POTENTIAL LINK BETWEEN CELLULAR/OXIDATIVE STRESS AND THE GENESIS OF THE MYOFIBROBLAST. RECENT OBSERVATIONS ON THE IMPORTANCE OF LYSOPHOSPHATIDIC ACID IN FIBROSIS SUGGEST THAT THIS MAY BE DUE, IN PART, TO ITS ABILITY TO REGULATE MYOFIBROBLAST DIFFERENTIATION. FINALLY, THERE IS INCREASING EVIDENCE FOR THE ROLE OF EPIGENETIC MECHANISMS IN REGULATING MYOFIBROBLAST DIFFERENTIATION, INCLUDING DNA METHYLATION AND MIRNA REGULATION OF GENE EXPRESSION. SUMMARY: THESE RECENT DISCOVERIES OPEN UP A WHOLE NEW ARRAY OF POTENTIAL TARGETS FOR NOVEL ANTIFIBROTIC THERAPIES. THIS IS OF SPECIAL IMPORTANCE GIVEN THE CURRENT BLEAK OUTLOOK FOR CHRONIC PROGRESSIVE FIBROTIC DISEASES, SUCH AS SCLERODERMA, DUE TO LACK OF EFFECTIVE THERAPIES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  5139  30 POTENTIAL NOVEL BIOMARKERS IN CHRONIC GRAFT-VERSUS-HOST DISEASE. PROGNOSTIC, DIAGNOSTIC OR PREDICTIVE BIOMARKERS ARE URGENTLY NEEDED FOR ASSESSMENT OF CHRONIC GRAFT-VERSUS-HOST DISEASE (CGVHD), A MAJOR RISK FOR PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION. THE MAIN GOAL OF THIS REVIEW GENERATED WITHIN THE COST ACTION EUROGRAFT "INTEGRATED EUROPEAN NETWORK ON CHRONIC GRAFT VERSUS HOST DISEASE" WAS TO IDENTIFY POTENTIAL NOVEL BIOMARKERS FOR CGVHD BESIDES THE WIDELY ACCEPTED MOLECULAR AND CELLULAR BIOMARKERS. THUS, THE FOCUS WAS ON CELLULAR BIOMARKERS, ALLOANTIBODIES, GLYCOMICS, ENDOTHELIAL DERIVED PARTICLES, EXTRACELLULAR VESICLES, MICROBIOME, EPIGENETIC AND NEUROLOGIC CHANGES IN CGVHD PATIENTS. BOTH HOST-REACTIVE ANTIBODIES IN GENERAL, AND PARTICULARLY ALLOANTIBODIES HAVE BEEN ASSOCIATED WITH CGVHD AND REQUIRE FURTHER CONSIDERATION. GLYCANS ATTACHED TO IGG MODULATE ITS ACTIVITY AND REPRESENT A PROMISING PREDICTIVE AND/OR STRATIFICATION BIOMARKER FOR CGVHD. FURTHERMORE, EPIGENETIC CHANGES SUCH AS MICRORNAS AND DNA METHYLATION REPRESENT POTENTIAL BIOMARKERS FOR MONITORING CGVHD PATIENTS AND NOVEL TARGETS FOR DEVELOPING NEW TREATMENT APPROACHES. FINALLY, THE MICROBIOME LIKELY AFFECTS THE PATHOPHYSIOLOGY OF CGVHD; BACTERIAL STRAINS AS WELL AS MICROBIAL METABOLITES COULD DISPLAY POTENTIAL BIOMARKERS FOR DYSBIOSIS AND RISK FOR THE DEVELOPMENT OF CGVHD. IN SUMMARY, ALTHOUGH THERE ARE NO VALIDATED BIOMARKERS CURRENTLY AVAILABLE FOR CLINICAL USE TO BETTER INFORM ON THE DIAGNOSIS, PROGNOSIS OR PREDICTION OF OUTCOME FOR CGVHD, MANY NOVEL SOURCES OF POTENTIAL MARKERS HAVE SHOWN PROMISE AND WARRANT FURTHER INVESTIGATION USING WELL CHARACTERIZED, MULTI-CENTER PATIENT COHORTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6  4573  27 MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT, A LONG NONCODING RNA, IS OVEREXPRESSED DURING DILATED CARDIOMYOPATHY DUE TO CHRONIC CHAGAS DISEASE. LONG NONCODING RNAS (LNCRNAS) MODULATE GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVELS. DYSREGULATION OF THE LNCRNA KNOWN AS MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT (MIAT) HAS BEEN ASSOCIATED WITH MYOCARDIAL INFARCTION. CHAGAS DISEASE CAUSES A SEVERE INFLAMMATORY DILATED CHRONIC CARDIOMYOPATHY (CCC). WE INVESTIGATED THE ROLE OF MIAT IN CCC. A WHOLE-TRANSCRIPTOME ANALYSIS OF HEART BIOPSY SPECIMENS AND FORMALIN-FIXED, PARAFFIN-EMBEDDED SAMPLES REVEALED THAT MIAT WAS OVEREXPRESSED IN PATIENTS WITH CCC, COMPARED WITH SUBJECTS WITH NONINFLAMMATORY DILATED CARDIOMYOPATHY AND CONTROLS. THESE RESULTS WERE CONFIRMED IN A MOUSE MODEL. RESULTS SUGGEST THAT MIAT IS A SPECIFIC BIOMARKER OF CCC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  1906  30 ENHANCER OF ZESTE HOMOLOG 2-CATALYSED H3K27 TRIMETHYLATION PLAYS A KEY ROLE IN ACUTE-ON-CHRONIC LIVER FAILURE VIA TNF-MEDIATED PATHWAY. ACUTE-ON-CHRONIC LIVER FAILURE IS MAINLY DUE TO HOST IMMUNITY SELF-DESTRUCTION. THE HISTONE H3 LYSINE 27 (H3K27) TRIMETHYLATING ENZYME, ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MEDIATES EPIGENETIC SILENCING OF GENE EXPRESSION AND REGULATES IMMUNITY, ALSO INVOLVES PATHOGENESIS OF SEVERAL LIVER DISEASES. THE CURRENT STUDY WAS TO DETERMINE THE ROLE OF METHYLTRANSFERASE EZH2 AND ITS CATALYSED H3K27 TRIMETHYLATION (H3K27ME3) IN LIVER FAILURE, AND TO FURTHER INVESTIGATE THE POTENTIAL TARGET FOR LIVER FAILURE TREATMENT. EZH2 AND ITS CATALYSED H3K27ME3 WERE DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM LIVER FAILURE PATIENTS AND KUPFFER CELLS FROM EXPERIMENTAL MICE. FURTHERMORE, GSK126 (AN INHIBITOR FOR EZH2 TRIMETHYLATION FUNCTION) WAS APPLIED IN LIVER FAILURE MICE IN VIVO, AND LIPOPOLYSACCHARIDE-STIMULATED MONONUCLEAR CELLS IN VITRO. EZH2 AND H3K27ME3 WERE SIGNIFICANTLY UPREGULATED IN HUMAN PBMC FROM LIVER FAILURE PATIENTS OR MURINE KUPFFER CELLS FROM THE LIVER FAILURE ANIMALS, RESPECTIVELY. GSK126 AMELIORATED DISEASE SEVERITY IN LIVER FAILURE MICE, WHICH MAYBE ATTRIBUTE TO DOWN-REGULATE CIRCULATING AND HEPATIC PROINFLAMMATORY CYTOKINES, ESPECIALLY TNF VIA REDUCING H3K27ME3. IN-DEPTH CHROMATIN IMMUNOPRECIPITATION ANALYSIS UNRAVELLED THAT DECREASED ENRICHMENT OF H3K27ME3 ON TNF PROMOTOR, RESULTING IN TNF ELEVATION IN KUPFFER CELLS FROM LIVER FAILURE MICE. NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND PROTEIN KINASE B (AKT) SIGNALLING PATHWAYS WERE ACTIVATED UPON LIPOPOLYSACCHARIDE STIMULATION, BUT ATTENUATED BY USING GSK126, ACCOMPANIED WITH DECREASED TNF IN VITRO. IN CONCLUSION, EZH2 AND H3K27ME3 CONTRIBUTED TO THE PATHOGENESIS OF LIVER FAILURE VIA TRIGGERING TNF AND OTHER INDISPENSABLE PROINFLAMMATORY CYTOKINES. EZH2 WAS TO MODIFY H3K27ME3 ENRICHMENT, AS WELL AS, ACTIVATION OF THE DOWNSTREAM NF-KAPPAB AND AKT SIGNALLING PATHWAYS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  5144  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9   353  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  5575  34 ROLE OF MICRORNAS IN SIGNALING PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS: A FOCUS ON EPITHELIAL-MESENCHYMAL TRANSITION. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC AND PROGRESSIVE DISEASE WITH HIGH MORTALITY AND UNCLEAR ETIOLOGY. PREVIOUS EVIDENCE SUPPORTS THAT THE ORIGIN OF THIS DISEASE IS ASSOCIATED WITH EPIGENETIC ALTERATIONS, AGE, AND ENVIRONMENTAL FACTORS. IPF INITIATES WITH CHRONIC EPITHELIAL LUNG INJURIES, FOLLOWED BY BASAL MEMBRANE DESTRUCTION, WHICH PROMOTES THE ACTIVATION OF MYOFIBROBLASTS AND EXCESSIVE SYNTHESIS OF EXTRACELLULAR MATRIX (ECM) PROTEINS, AS WELL AS EPITHELIAL-MESENCHYMAL TRANSITION (EMT). DUE TO MIRNAS' ROLE AS REGULATORS OF APOPTOSIS, PROLIFERATION, DIFFERENTIATION, AND CELL-CELL INTERACTION PROCESSES, SOME STUDIES HAVE INVOLVED MIRNAS IN THE BIOGENESIS AND PROGRESSION OF IPF. IN THIS CONTEXT, THE ANALYSIS AND DISCUSSION OF THE PROBABLE ASSOCIATION OF MIRNAS WITH THE SIGNALING PATHWAYS INVOLVED IN THE DEVELOPMENT OF IPF WOULD IMPROVE OUR KNOWLEDGE OF THE ASSOCIATED MOLECULAR MECHANISMS, THEREBY FACILITATING ITS EVALUATION AS A THERAPEUTIC TARGET FOR THIS SEVERE LUNG DISEASE. IN THIS WORK, THE MOST RECENT PUBLICATIONS EVALUATING THE ROLE OF MIRNAS AS REGULATORS OR ACTIVATORS OF SIGNAL PATHWAYS ASSOCIATED WITH THE PATHOGENESIS OF IPF WERE ANALYZED. THE SEARCH IN PUBMED WAS MADE USING THE FOLLOWING TERMS: "MIRNAS AND IDIOPATHIC PULMONARY FIBROSIS (IPF)"; "MIRNAS AND IPF AND SIGNALING PATHWAYS (SP)"; AND "MIRNAS AND IPF AND SP AND IPF PATHOGENESIS". ADDITIONALLY, WE FOCUS MAINLY ON THOSE WORKS WHERE THE SIGNALING PATHWAYS INVOLVED WITH EMT, FIBROBLAST DIFFERENTIATION, AND SYNTHESIS OF ECM COMPONENTS WERE ASSESSED. FINALLY, THE IMPORTANCE AND SIGNIFICANCE OF MIRNAS AS POTENTIAL THERAPEUTIC OR DIAGNOSTIC TOOLS FOR THE TREATMENT OF IPF ARE DISCUSSED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11   597  34 BET-BROMODOMAIN AND EZH2 INHIBITOR-TREATED CHRONIC GVHD MICE HAVE BLUNTED GERMINAL CENTERS WITH DISTINCT TRANSCRIPTOMES. DESPITE ADVANCES IN THE FIELD, CHRONIC GRAFT-VERSUS-HOST-DISEASE (CGVHD) REMAINS A LEADING CAUSE OF MORBIDITY AND MORTALITY FOLLOWING ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANT. BECAUSE TREATMENT OPTIONS REMAIN LIMITED, WE TESTED EFFICACY OF ANTICANCER, CHROMATIN-MODIFYING ENZYME INHIBITORS IN A CLINICALLY RELEVANT MURINE MODEL OF CGVHD WITH BRONCHIOLITIS OBLITERANS (BO). WE OBSERVED THAT THE NOVEL ENHANCER OF ZESTE HOMOLOG 2 (EZH2) INHIBITOR JQ5 AND THE BET-BROMODOMAIN INHIBITOR JQ1 EACH IMPROVED PULMONARY FUNCTION; IMPAIRED THE GERMINAL CENTER (GC) REACTION, A PREREQUISITE IN CGVHD/BO PATHOGENESIS; AND JQ5 REDUCED EZH2-MEDIATED H3K27ME3 IN DONOR T CELLS. USING CONDITIONAL EZH2 KNOCKOUT DONOR CELLS, WE DEMONSTRATED THAT EZH2 IS OBLIGATORY FOR THE INITIATION OF CGVHD/BO. IN A SCLERODERMATOUS CGVHD MODEL, JQ5 REDUCED THE SEVERITY OF CUTANEOUS LESIONS. TO DETERMINE HOW THE 2 DRUGS COULD LEAD TO THE SAME PHYSIOLOGICAL IMPROVEMENTS WHILE TARGETING UNIQUE EPIGENETIC PROCESSES, WE ANALYZED THE TRANSCRIPTOMES OF SPLENIC GCB CELLS (GCBS) FROM TRANSPLANTED MICE TREATED WITH EITHER DRUG. MULTIPLE INFLAMMATORY AND SIGNALING PATHWAYS ENRICHED IN CGVHD/BO GCBS WERE REDUCED BY EACH DRUG. GCBS FROM JQ5- BUT NOT JQ1-TREATED MICE WERE ENRICHED FOR PROPROLIFERATIVE PATHWAYS ALSO SEEN IN GCBS FROM BONE MARROW-ONLY TRANSPLANTED MICE, LIKELY REFLECTING THEIR UNDERLYING BIOLOGY IN THE UNPERTURBED STATE. IN CONJUNCTION WITH IN VIVO DATA, THESE INSIGHTS LED US TO CONCLUDE THAT EPIGENETIC TARGETING OF THE GC IS A VIABLE CLINICAL APPROACH FOR THE TREATMENT OF CGVHD, AND THAT THE EZH2 INHIBITOR JQ5 AND THE BET-BROMODOMAIN INHIBITOR JQ1 DEMONSTRATED CLINICAL POTENTIAL FOR EZH2I AND BETI IN PATIENTS WITH CGVHD/BO.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  1026  36 CIRCULATING MIRNAS EXPRESSION IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX MULTIFACTORIAL DISEASE THAT CAUSES INCREASING MORBIDITY WORLDWIDE, AND MANY INDIVIDUALS WITH ME/CFS SYMPTOMS REMAIN UNDIAGNOSED DUE TO THE LACK OF DIAGNOSTIC BIOMARKERS. ITS ETIOLOGY IS STILL UNKNOWN, BUT INCREASING EVIDENCE SUPPORTS A ROLE OF HERPESVIRUSES (INCLUDING HHV-6A AND HHV-6B) AS POTENTIAL TRIGGERS. INTERESTINGLY, THE INFECTION BY THESE VIRUSES HAS BEEN REPORTED TO IMPACT THE EXPRESSION OF MICRORNAS (MIRNAS), SHORT NON-CODING RNA SEQUENCES WHICH HAVE BEEN SUGGESTED TO BE EPIGENETIC FACTORS MODULATING ME/CFS PATHOGENIC MECHANISMS. NOTABLY, THE PRESENCE OF CIRCULATING MIRNAS IN PLASMA HAS RAISED THE POSSIBILITY TO USE THEM AS VALUABLE BIOMARKERS FOR DISTINGUISHING ME/CFS PATIENTS FROM HEALTHY CONTROLS. THUS, THIS STUDY AIMED AT DETERMINING THE ROLE OF EIGHT MIRNAS, WHICH WERE SELECTED FOR THEIR PREVIOUS ASSOCIATION WITH ME/CFS, AS POTENTIAL CIRCULATING BIOMARKERS OF THE DISEASE. THEIR PRESENCE WAS QUANTITATIVELY EVALUATED IN PLASMA FROM 40 ME/CFS PATIENTS AND 20 HEALTHY CONTROLS BY SPECIFIC TAQMAN ASSAYS, AND THE RESULTS SHOWED THAT SIX OUT OF THE EIGHT OF THE SELECTED MIRNAS WERE DIFFERENTLY EXPRESSED IN PATIENTS COMPARED TO CONTROLS; MORE SPECIFICALLY, FIVE MIRNAS WERE SIGNIFICANTLY UPREGULATED (MIR-127-3P, MIR-142-5P, MIR-143-3P, MIR-150-5P, AND MIR-448), AND ONE WAS DOWNMODULATED (MIR-140-5P). MIRNA LEVELS DIRECTLY CORRELATED WITH DISEASE SEVERITY, WHEREAS NO SIGNIFICANT CORRELATIONS WERE OBSERVED WITH THE PLASMA LEVELS OF SEVEN PRO-INFLAMMATORY CYTOKINES OR WITH THE PRESENCE/LOAD OF HHV-6A/6B GENOME, AS JUDGED BY SPECIFIC PCR AMPLIFICATION. THE RESULTS MAY OPEN THE WAY FOR FURTHER VALIDATION OF MIRNAS AS NEW POTENTIAL BIOMARKERS IN ME/CFS AND INCREASE THE KNOWLEDGE OF THE COMPLEX PATHWAYS INVOLVED IN THE ME/CFS DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  5227  22 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  4563  27 MYELOID DNA METHYLTRANSFERASE3B DEFICIENCY AGGRAVATES PULMONARY FIBROSIS BY ENHANCING PROFIBROTIC MACROPHAGE ACTIVATION. BACKGROUND: IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE AND SEVERE DISEASE CHARACTERIZED BY EXCESSIVE MATRIX DEPOSITION IN THE LUNGS. MACROPHAGES PLAY CRUCIAL ROLES IN MAINTAINING LUNG HOMEOSTASIS BUT ARE ALSO CENTRAL IN THE PATHOGENESIS OF LUNG DISEASES LIKE PULMONARY FIBROSIS. ESPECIALLY, MACROPHAGE POLARIZATION/ACTIVATION SEEMS TO PLAY A CRUCIAL ROLE IN PATHOLOGY AND EPIGENETIC REPROGRAMING IS WELL-KNOWN TO REGULATE MACROPHAGE POLARIZATION. DNA METHYLATION ALTERATIONS IN IPF LUNGS HAVE BEEN WELL DOCUMENTED, BUT THE ROLE OF DNA METHYLATION IN SPECIFIC CELL TYPES, ESPECIALLY MACROPHAGES, IS POORLY DEFINED. METHODS: IN ORDER TO DETERMINE THE ROLE OF DNA METHYLATION IN MACROPHAGES DURING PULMONARY FIBROSIS, WE SUBJECTED MACROPHAGE SPECIFIC DNA METHYLTRANSFERASE (DNMT)3B, WHICH MEDIATES THE DE NOVO DNA METHYLATION, DEFICIENT MICE TO THE BLEOMYCIN-INDUCED PULMONARY FIBROSIS MODEL. MACROPHAGE POLARIZATION AND FIBROTIC PARAMETERS WERE EVALUATED AT 21 DAYS AFTER BLEOMYCIN ADMINISTRATION. DNMT3B KNOCKOUT AND WILD TYPE BONE MARROW-DERIVED MACROPHAGES WERE STIMULATED WITH EITHER INTERLEUKIN (IL)4 OR TRANSFORMING GROWTH FACTOR BETA 1 (TGFB1) IN VITRO, AFTER WHICH PROFIBROTIC GENE EXPRESSION AND DNA METHYLATION AT THE ARG1 PROMOTOR WERE DETERMINED. RESULTS: WE SHOW THAT DNMT3B DEFICIENCY PROMOTES ALTERNATIVE MACROPHAGE POLARIZATION INDUCED BY IL4 AND TGFB1 IN VITRO AND ALSO ENHANCES PROFIBROTIC MACROPHAGE POLARIZATION IN THE ALVEOLAR SPACE DURING PULMONARY FIBROSIS IN VIVO. MOREOVER, MYELOID SPECIFIC DELETION OF DNMT3B PROMOTED THE DEVELOPMENT OF EXPERIMENTAL PULMONARY FIBROSIS. CONCLUSIONS: IN SUMMARY, THESE DATA SUGGEST THAT MYELOID DNMT3B REPRESSES FIBROTIC MACROPHAGE POLARIZATION AND PROTECTS AGAINST BLEOMYCIN INDUCED PULMONARY FIBROSIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  6386  38 THE ROLE OF QUANTITATIVE NPTX2 HYPERMETHYLATION AS A NOVEL SERUM DIAGNOSTIC MARKER IN PANCREATIC CANCER. OBJECTIVES: THE MAJORITY OF PANCREATIC CANCERS ARE FOUND TO BE UNRESECTABLE, AND THE ONLY CHANCE FOR CURE LIES ON EARLY DETECTION AND COMPLETE RESECTION. SEVERAL GENES HAVE BEEN DISCOVERED TO BE ABERRANTLY METHYLATED IN PRIMARY PANCREATIC CANCER TISSUE, AND THIS CANCER DNA CAN BE DETECTED IN THE PLASMA. THE AIMS OF THIS STUDY WERE TO DEVELOP A NOVEL DIAGNOSTIC MARKER BASED ON EPIGENETIC CHARACTERISTICS OF PANCREATIC CANCER. METHODS: WE ENROLLED 104 PATIENTS WITH PANCREATIC CANCER, 60 WITH CHRONIC PANCREATITIS, AND 5 WITH BENIGN BILIARY STONE DISEASES. THE BLOOD SAMPLES WERE COLLECTED BEFORE SURGERY OR ANY KINDS OF TREATMENT MODALITIES. DNA WAS EXTRACTED FROM THE PLASMA OF EACH PATIENT, AND NPTX2 (NEURONAL PENTRAXIN II) CPG ISLAND HYPERMETHYLATION WAS EXAMINED QUANTITATIVELY BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NPTX2 HYPERMETHYLATION LEVELS WERE SIGNIFICANTLY HIGHER COMPARED WITH CHRONIC PANCREATITIS (P = 0.016). THE SENSITIVITY AND SPECIFICITY WERE 80% AND 76%, RESPECTIVELY (CUTOFF = 0.015). NPTX2 GENE HYPERMETHYLATION LEVEL WAS SIGNIFICANTLY ELEVATED IN CORRELATION WITH HIGHER AMERICAN JOINT COMMITTEE ON CANCER STAGES. CONCLUSIONS: THE ABERRANTLY METHYLATED NPTX2 GENE MAY HELP TO DISTINGUISH BETWEEN CHRONIC PANCREATITIS AND PANCREATIC CANCER WITH CONVENTIONAL DIAGNOSTIC TOOLS AND COULD BECOME A VALUABLE DIAGNOSTIC MARKER.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  2326  32 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  4724  29 NONINVASIVE MULTIMODAL METHODS TO DIFFERENTIATE INFLAMED VS FIBROTIC STRICTURES IN PATIENTS WITH CROHN'S DISEASE. FIBROTIC STRICTURES OCCUR IN 30% OF PATIENTS WITH CROHN'S DISEASE (CD). HOWEVER, THERE ARE NO THERAPEUTIC AGENTS THAT PREVENT OR REVERSE FIBROTIC STRICTURES. STRICTURES ARE TREATED BY ENDOSCOPIC DILATATION PROCEDURES AND SURGICAL PROCEDURES, BUT THERE ARE HIGH RATES OF RECURRENCE. TWO ANTIFIBROTIC AGENTS (NINTEDANIB AND PIRFENIDONE) RECENTLY WERE APPROVED FOR THE TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS AND INHIBITORS OF RHO-ASSOCIATED PROTEIN KINASES 1 AND 2 REVERSED FIBROSIS IN MICE WITH CHRONIC INTESTINAL INFLAMMATION. CROSS-SECTIONAL IMAGING TECHNIQUES, SUCH AS MAGNETIC RESONANCE (MR) ENTEROGRAPHY, COMPUTED TOMOGRAPHY ENTEROGRAPHY, AND BOWEL ULTRASOUND, ARE USED TO ASSESS SMALL-BOWEL AND CD-RELATED COMPLICATIONS, INCLUDING STRICTURES. IT IS IMPORTANT TO BE ABLE TO DETERMINE THE DEGREE OF INFLAMMATION AND FIBROSIS IN STRICTURES TO SELECT THE BEST THERAPY; THIS CAN BE A CHALLENGE BECAUSE INFLAMMATION AND FIBROSIS CO-EXIST TO VARYING DEGREES IN A DAMAGED BOWEL SEGMENT. DELAYED GADOLINIUM ENHANCEMENT, MAGNETIZATION TRANSFER MR IMAGING, AND ULTRASOUND ELASTOGRAPHY SEEM TO BE PROMISING TOOLS FOR ASSESSING FIBROSIS IN PATIENTS WITH CD. WE REVIEW NONINVASIVE TECHNIQUES FOR FIBROSIS ASSESSMENT, INCLUDING ANALYSES OF GENETIC, EPIGENETIC, AND PROTEIN MARKERS. WE DISCUSS THE POTENTIAL OF IMAGING TECHNIQUES SUCH AS DIFFUSION-WEIGHTED AND MAGNETIZATION TRANSFER MR IMAGING, STRAIN ELASTOGRAPHY, SHEAR-WAVE IMAGING, AND POSITRON EMISSION TOMOGRAPHY TO GUIDE THERAPEUTIC DECISIONS FOR PATIENTS WITH STRICTURING CD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  5054  33 PHARMACOPROTEOMICS REVEAL NOVEL PROTECTIVE ACTIVITY OF BROMODOMAIN CONTAINING 4 INHIBITORS ON VASCULAR HOMEOSTASIS IN TLR3-MEDIATED AIRWAY REMODELING. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. WE REPORT A SYSTEMS-LEVEL PHARMACOPROTEOMICS IN A STANDARDIZED MURINE MODEL OF TOLL-LIKE RECEPTOR TLR3-NFKAPPAB/RELA INNATE INFLAMMATION IN THE ABSENCE OR PRESENCE OF A HIGHLY SELECTIVE BRD4 INHIBITOR (ZL0454) OR NONSELECTIVE BROMODOMAIN AND EXTRATERMINAL DOMAIN INHIBITOR (JQ1). PROTEOMICS OF BRONCHOALVEOLAR LAVAGE FLUID (BALF) SECRETOME AND EXOSOMAL PROTEINS FROM THIS MURINE MODEL REVEALED INCREASED, SELECTIVE, CAPILLARY LEAK ASSOCIATED WITH PERICYTE-MYOFIBROBLAST TRANSITION, A PHENOMENON BLOCKED BY BRD4 INHIBITORS. BALF PROTEOMICS ALSO SUGGESTED THAT ZL0454 BETTER REDUCED THE VASCULAR LEAKAGE AND EXTRACELLULAR MATRIX DEPOSITION THAN JQ1. A SIGNIFICANT SUBSET OF INFLAMMATION-MEDIATED REMODELING FACTORS WAS ALSO IDENTIFIED IN A MOUSE MODEL OF IDIOPATHIC PULMONARY FIBROSIS PRODUCED BY BLEOMYCIN. BALF EXOSOME ANALYSIS INDICATED THAT BRD4 INHIBITORS REDUCED THE INDUCTION OF EXOSOMES ENRICHED IN COAGULATION FACTORS WHOSE PRESENCE CORRELATED WITH INTERSTITIAL FIBRIN DEPOSITION. FINALLY, BALF SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR UPREGULATIONS OF ORM2, APCS, SPARCL1, FGA, AND FN1, SUGGESTING THEIR POTENTIAL AS BIOMARKERS FOR EARLY DETECTION OF AIRWAY REMODELING AND/OR MONITORING OF THERAPY RESPONSE. SIGNIFICANCE: REPETITIVE AND CHRONIC VIRAL UPPER RESPIRATORY TRACT INFECTIONS TRIGGER TOLL-LIKE RECEPTOR (TLR)3-NFKAPPAB/RELA MEDIATED AIRWAY REMODELING WHICH IS LINKED TO A PROGRESSIVE DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SMALL MOLECULE INHIBITORS OF THE EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) ARE POTENTIAL THERAPEUTICS FOR VIRAL AND ALLERGEN-INDUCED AIRWAY REMODELING. A LIMITATION OF THEIR PRECLINICAL ADVANCEMENT IS THE LACK OF DETAILED UNDERSTANDING OF MECHANISMS OF ACTION AND BIOMARKERS OF EFFECT. OUR STUDY REVEALED THAT THE ACTIVATION OF (TLR)3-NFKAPPAB/RELA PATHWAY IN THE LUNG INDUCED AN ELEVATION IN COAGULATION, COMPLEMENT, AND PLATELET FACTORS, INDICATING THE INCREASED VASCULAR LEAK DURING AIRWAY REMODELING. THE MECHANISM OF VASCULAR LEAKAGE WAS CHRONIC INFLAMMATION-INDUCED PERICYTE-MYOFIBROBLAST TRANSITION, WHICH WAS BLOCKED BY BRD4 INHIBITORS. FINALLY, PROTEOMICS ANALYSIS OF THE BRONCHOALVEOLAR LAVAGE FLUID SAMPLES FROM HUMANS WITH SEVERE ASTHMA DEMONSTRATED SIMILAR FINDINGS THAT WE OBSERVED IN THE ANIMAL MODEL.	2019	

19  6208  35 THE INTERACTION BETWEEN MICRORNA-152 AND DNA METHYLTRANSFERASE-1 AS AN EPIGENETIC PROGNOSTIC BIOMARKER IN HCV-INDUCED LIVER CIRRHOSIS AND HCC PATIENTS. THE NECESSITY FOR EARLY DETECTION AND HENCE IMPROVING THE OUTCOME OF TREATMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS CRITICAL ESPECIALLY IN HEPATITIS C VIRUS (HCV)-GENOTYPE 4 INDUCED CASES. IN OUR CURRENT WORK, WE EXAMINED THE MIRNA-152 AND DNMT-1 EXPRESSION IN CHRONIC LIVER DISEASE (CLD) DUE TO HCV GENOTYPE 4 INFECTION WITH/WITHOUT CIRRHOSIS AND HCC PATIENTS AS AN ATTEMPT TO EVALUATE THE POTENTIAL BENEFITS OF THESE NEW CIRCULATING, NONINVASIVE, PROGNOSTIC, EPIGENETIC MARKERS FOR LIVER CIRRHOSIS AND CARCINOGENESIS OF EGYPTIAN PATIENTS. EIGHTY SUBJECTS WERE INCLUDED IN THIS STUDY, DIVIDED INTO TWO GROUPS; GROUP I (40 PATIENTS) WERE CLASSIFIED INTO SUBGROUP IA (CLD WITHOUT CIRRHOSIS, N = 18) AND SUBGROUP IB (CLD WITH CIRRHOSIS, N = 22), GROUP II (CLD PATIENTS WITH HCC, N = 20), AND CONTROL (HEALTHY VOLUNTEER, N = 20). THE EXPRESSION OF MIRNA-152 AND DNMT-1 GENES WERE ANALYZED USING REAL-TIME PCR. MIRNA-152 SHOWED A PERSISTENT AND SIGNIFICANT DOWNREGULATION IN ALL DISEASED GROUPS, WHICH WAS IN CONSISTENCE WITH THE PROGRESSION OF THE DISEASE TOWARD THE HCC STAGE. DNMT-1 SHOWED UPREGULATION IN ALL DISEASED GROUPS WHEN COMPARED TO CONTROL AND SUBGROUP IA. THE MIRNA-152 WAS SHOWN TO CORRELATE INVERSELY WITH DNMT-1 IN SUBGROUP IA, IB AND GROUP II (R = -0.557, P < 0.01), (R = -0.850, P < 0.001) AND (R = -0.544, P < 0.02) RESPECTIVELY. IN ADDITION, MIRNA-152 AND DNMT-1 SHOWED A DIAGNOSTIC ABILITY TO DISCRIMINATE BETWEEN CASES OF CIRRHOSIS AND HCC AGAINST CLD WITHOUT CIRRHOSIS (P < 0.01), WHILE DNMT-1 DID NOT, EXCEPT BETWEEN HCC AND CIRRHOTIC CASES. FURTHERMORE, BOTH GENES CAN BE CONSIDERED AS PREDICTOR AND PROGNOSTIC PARAMETERS FOR CIRRHOSIS (OR = 1.041, P = 0.043) AND (OR = 1.039, P = 0.04) RESPECTIVELY, WHILE MIRNA-152 ALONE IS PROVED AS A PROGNOSTIC MARKER FOR HCC (OR = 1.003, P = 0.044). FINALLY, THE PERSISTENT REVERSE CORRELATION BETWEEN MIRNA-152 WITH DNMT-1 PROMPTS THEIR USE AS NONINVASIVE PROGNOSTIC BIOMARKERS FOR HCV INDUCED LIVER CIRRHOSIS AND HCC IN HCV GENOTYPE 4 PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  4677  33 NEW LNCRNAS IN CHRONIC HEPATITIS C PROGRESSION: FROM FIBROSIS TO HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH IN THE WORLD, AND ABOUT 80% OF THE CASES ARE ASSOCIATED WITH HEPATITIS B OR C. GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED OVER DECADES OF CHRONIC INJURY AND MAY AFFECT THE FUNCTIONING OF TUMOR SUPPRESSOR GENES AND PROTOONCOGENES. STUDIES HAVE EVIDENCED THE ROLE OF LONG NON-CODING RNAS (LNCRNA) WITH ONCOGENIC OR TUMOR SUPPRESSOR ACTIVITIES, SUGGESTING A GREAT POTENTIAL IN THE TREATMENT, DIAGNOSIS OR INDICATOR OF PROGNOSIS IN CANCER. IN THIS CONTEXT, THE AIM OF THIS STUDY WAS TO EVALUATE THE GLOBAL EXPRESSION PROFILE LNCRNA IN HEPATIC TISSUE SAMPLES WITH DIFFERENT STAGES OF FIBROSIS ASSOCIATED WITH CHRONIC HEPATITIS C, HCC AND NORMAL LIVER, IN ORDER TO IDENTIFY NEW LNCRNAS THAT COULD CONTRIBUTE TO STUDY THE PROGRESSION OF HEPATIC FIBROSIS TO HCC ASSOCIATED WITH CHRONIC HEPATITIS C. RNA-SEQ WAS PERFORMED ON ILLUMINA NEXTSEQ PLATFORM TO IDENTIFY LNCRNAS EXPRESSED DIFFERENTLY IN 15 PATIENTS WITH CHRONIC HEPATITIS C, THREE PATIENTS WITH HCC AND THREE NORMAL LIVER SPECIMENS. WHEN THE PATHOLOGICAL TISSUES (FIBROSIS AND CARCINOMA) WERE COMPARED TO NORMAL HEPATIC TISSUE, WERE IDENTIFIED 2, 6 E 34 DIFFERENTIALLY EXPRESSED LNCRNAS IN MODERATE FIBROSIS, ADVANCED FIBROSIS AND HCC, RESPECTIVELY. THE CARCINOMA GROUP HAD THE HIGHEST PROPORTION OF DIFFERENTIALLY EXPRESSED LNCRNA (34) AND OF THESE, 29 WERE EXCLUSIVE IN THIS TYPE OF TISSUE. A HEAT MAP OF THE DEREGULATED LNCRNA REVEALED DIFFERENT EXPRESSION PATTERNS ALONG THE PROGRESSION OF FIBROSIS TO HCC. THE RESULTS SHOWED THE DEREGULATION OF SOME LNCRNA ALREADY CLASSIFIED AS TUMOR SUPPRESSORS IN HCC AND OTHER CANCERS, AS WELL AS SOME UNPUBLISHED LNCRNA WHOSE FUNCTION IS UNKNOWN. SOME OF THESE LNCRNAS ARE DYSREGULATED SINCE THE EARLY STAGES OF LIVER INJURY IN PATIENTS WITH HEPATITIS C, OTHERS OVEREXPRESSED ONLY IN TUMOR TISSUE, INDICATING THEMSELVES AS CANDIDATES OF MARKERS OF FIBROSIS PROGRESSION OR TUMOR, WITH POTENTIAL CLINICAL APPLICATIONS IN PROGNOSIS AS WELL AS A THERAPEUTIC TARGET. ALTHOUGH THERE ARE ALREADY STUDIES ON LNCRNA IN HEPATOCELLULAR CARCINOMA, THIS IS THE FIRST STUDY CONDUCTED IN SAMPLES EXCLUSIVELY OF HCV-RELATED LIVER AND HCV HCC.	2020