1  5949 101 TARGETING THE PRC2-DEPENDENT EPIGENETIC PROGRAM ALLEVIATES URINARY TRACT INFECTIONS. URINARY TRACT INFECTION (UTI) IS A PERVASIVE HEALTH PROBLEM WORLDWIDE. PATIENTS WITH A HISTORY OF UTIS SUFFER INCREASED RISK OF RECURRENT INFECTIONS, A MAJOR RISK OF ANTIBIOTIC RESISTANCE. HERE, WE SHOW THAT BLADDER INFECTIONS INDUCE EXPRESSION OF EZH2 IN BLADDER UROTHELIAL CELLS. EZH2 IS THE METHYLTRANSFERASE OF POLYCOMB REPRESSOR COMPLEX 2 (PRC2)-A POTENT EPIGENETIC REGULATOR. UROTHELIUM-SPECIFIC INACTIVATION OF PRC2 RESULTS IN REDUCED URINE BACTERIAL BURDEN, MUTED INFLAMMATORY RESPONSE, AND DECREASED ACTIVITY OF THE NF-KAPPAB SIGNALING PATHWAY. PRC2 INACTIVATION ALSO FACILITATES PROPER REGENERATION AFTER UROTHELIAL DAMAGE FROM UTIS, BY ATTENUATING BASAL CELL HYPERPLASIA AND INCREASING UROTHELIAL DIFFERENTIATION. IN ADDITION, TREATMENT WITH EZH2-SPECIFIC SMALL-MOLECULE INHIBITORS IMPROVES OUTCOMES OF THE CHRONIC AND SEVERE BLADDER INFECTIONS IN MICE. THESE FINDINGS COLLECTIVELY SUGGEST THAT THE PRC2-DEPENDENT EPIGENETIC REPROGRAMING CONTROLS THE AMPLITUDE OF INFLAMMATION AND SEVERITY OF UTIS AND THAT EZH2 INHIBITORS MAY BE A VIABLE NON-ANTIBIOTIC STRATEGY TO MANAGE CHRONIC AND SEVERE UTIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  3131  24 GLOBAL AND SPECIFIC HISTONE ACETYLATION PATTERN IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY, A WORLDWIDE DISEASE. ABSTRACT BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) IS A CHRONIC TUBULOINTERSTITIAL NEPHROPATHY PRESENT IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES. THERE APPEARS TO BE A POLYGENIC SUSCEPTIBILITY TO THE DISEASE IN INTERACTION WITH MULTIPLE ENVIRONMENTAL FACTORS (ARISTOLOCHIC ACID, OCHRATOXIN A). IN A PREVIOUS STUDY SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS OF BEN PATIENTS FROM SERBIA AND BULGARIA. EMERGING CONNECTIONS BETWEEN DNA METHYLATION AND HISTONE ACETYLATION PROMPTED THE PRESENT STUDY ON HISTONE ACETYLATION IN PATIENTS WITH BEN. METHODS: THE STUDY INVOLVED 39 PATIENTS WITH BEN, AND 39 CONTROLS COLLECTED FROM NON-ENDEMIC REGIONS IN SERBIA. THE EPISEEKER HISTONE H3 AND H4 TOTAL ACETYLATION DETECTION COLORIMETRIC KITS AND SPECIFIC ACETYLATED AT LYSINE 18 H3K18 AND H3K36 ACETYLATED AT LYSINE 36 DETECTION KITS WERE USED. RESULTS: IT WAS DOCUMENTED THAT TOTAL H4 HISTONE ACETYLATION LEVEL WAS INCREASED SIGNIFICANTLY, WHILE TOTAL H3 HISTONE ACETYLATION DID NOT DIFFER SIGNIFICANTLY. SPECIFIC HISTONE STRUCTURE AND FUNCTIONAL PROPERTIES MAY BE AFFECTED BY THE OBSERVED DERANGEMENT OF H3 HISTONE ACETYLATION PATTERN, SINCE H3K36 SITE WAS SIGNIFICANTLY MORE ACETYLATED, WHILE H3K18 TENDED TO BE LESS ACETYLATED THAN IN CONTROL SUBJECTS. MULTIPLE REGRESSION ANALYSIS REVEALED A STATISTICALLY SIGNIFICANT RELATIONSHIP BETWEEN H4, H3T AND H3K36 IN BEN PATIENTS. CONCLUSION: THIS PRELIMINARY STUDY SUGGESTS THAT THE ACETYLATION OF HISTONE LYSINE RESIDUES WAS DETECTABLE AND FOUND INCREASED AT SPECIFIC SITES OF H3 AND TOTAL H4 HISTONES ISOLATED FROM UROTHELIAL CELLS OF PATIENTS WITH BEN. HAVING IN MIND A POSSIBLE MECHANISM AND BIOLOGICAL ROLE OF EPIGENETIC CHROMATIN MODIFICATION IN UROTHELIAL TUMOR DEVELOPMENT THEY OBTAINED RESULTS MAY OPEN OPPORTUNITY FOR SELECTIVE THERAPEUTIC INTERVENTIONS IN PATIENTS WITH BEN.	2014	
                                                                                                                                                                                                                                                                                 
3  3983  24 LONG-TERM EXPOSURE TO CIGARETTE SMOKE EXTRACT INDUCES HYPOMETHYLATION AT THE RUNX3 AND IGF2-H19 LOCI IN IMMORTALIZED HUMAN UROTHELIAL CELLS. CIGARETTE SMOKING IS THE SINGLE MOST IMPORTANT EPIDEMIOLOGICAL RISK FACTOR FOR BLADDER CANCER BUT IT IS NOT KNOWN WHETHER EXPOSURE OF UROTHELIAL CELLS TO THE SYSTEMIC SOLUBLE CONTENTS OF CIGARETTE SMOKE IS DIRECTLY CAUSATIVE TO BLADDER CANCER AND THE ASSOCIATED EPIGENETIC CHANGES SUCH AS TUMOR SUPPRESSOR GENE HYPERMETHYLATION. WE UNDERTOOK THIS STUDY TO INVESTIGATE IF LONG-TERM TREATMENT OF HUMAN UROTHELIAL CELLS WITH CIGARETTE SMOKE EXTRACT (CSE) RESULTS IN TUMOR SUPPRESSOR GENE HYPERMETHYLATION, A PHENOTYPE THAT WAS PREVIOUSLY ASSOCIATED WITH LONG-TERM CONSTANT CSE TREATMENT OF AIRWAY EPITHELIAL CELLS. WE CHRONICALLY TREATED AN IMMORTALIZED HUMAN UROTHELIAL CELL LINE UROTSA WITH CSE USING A CYCLIC DAILY REGIMEN BUT THE CELLS WERE CULTURED IN CSE-FREE MEDIUM BETWEEN DAILY TREATMENTS. BISULFITE SEQUENCING AND REAL-TIME PCR ARRAY-BASED METHYLATION PROFILING WERE EMPLOYED TO EVALUATE METHYLATION CHANGES AT TUMOR SUPPRESSOR GENE LOCI IN THE CHRONICALLY CSE-TREATED CELLS VERSUS THE PASSAGE-MATCHED UNTREATED CONTROL CELLS. THE RUNX3 TUMOR SUPPRESSOR GENE PROMOTER WAS HYPOMETHYLATED WITH A SIGNIFICANT INCREASE IN PROPORTION OF THE COMPLETELY UNMETHYLATED HAPLOTYPE AFTER THE LONG-TERM CSE TREATMENT; WHEREAS RUNX3 PROMOTER HYPERMETHYLATION WAS PREVIOUSLY REPORTED FOR BLADDER CANCERS OF SMOKERS. HYPOMETHYLATION INDUCED BY THE LONG-TERM CSE TREATMENT WAS ALSO OBSERVED FOR THE IGF2-H19 LOCUS. THE METHYLATION STATUS AT THE PRSS8/PROSTASIN AND 16 ADDITIONAL LOCI HOWEVER, WAS UNAFFECTED BY THE CHRONIC CSE TREATMENT. TRANSIENT CSE TREATMENT OVER 1 DAILY REGIMEN RESULTED IN TRANSCRIPTIONAL DOWN-REGULATION OF RUNX3 AND H19, BUT ONLY THE H19 TRANSCRIPTION WAS DOWN-REGULATED IN THE CHRONICALLY CSE-TREATED UROTHELIAL CELLS. TRANSCRIPTION OF A KEY ENZYME IN ONE-CARBON METABOLISM, DIHYDROFOLATE REDUCTASE (DHFR) WAS GREATLY REDUCED BY THE LONG-TERM CSE TREATMENT, POTENTIALLY SERVING AS A MECHANISM FOR THE HYPOMETHYLATION PHENOTYPE VIA A REDUCED SUPPLY OF METHYL DONOR. IN CONCLUSION, CHRONIC CYCLIC CSE TREATMENT OF UROTHELIAL CELLS INDUCED HYPOMETHYLATION RATHER THAN HYPERMETHYLATION AT SPECIFIC LOCI.	2013	
                        
4   334  18 ALTERATIONS IN DEOXYRIBONUCLEIC ACID (DNA) METHYLATION PATTERNS OF CALCA, TIMP3, MMP2, AND IGF2R ARE ASSOCIATED WITH CHRONIC CYSTITIS IN A CYCLOPHOSPHAMIDE-INDUCED MOUSE MODEL. OBJECTIVE: TO DETERMINE WHETHER EPIGENETIC CHANGES OCCUR DURING CYCLOPHOSPHAMIDE-INDUCED CHRONIC BLADDER INFLAMMATION IN MICE. MATERIALS AND METHODS: EPIGENETIC CHANGES PLAY A ROLE IN THE REGULATION OF INFLAMMATORY GENES IN NONCANCER DISEASES SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, EPIGENETIC (DEOXYRIBONUCLEIC ACID [DNA] METHYLATION) CHANGES DURING CHRONIC BLADDER INFLAMMATION HAVE NOT BEEN PREVIOUSLY DESCRIBED. CHRONIC CYSTITIS WAS INDUCED IN 3 GROUPS OF ADULT CD-1 MALE MICE USING MULTIPLE WEIGHT-BASED INTRAPERITONEAL CYCLOPHOSPHAMIDE INJECTIONS DURING A 3-MONTH PERIOD. HISTOPATHOLOGIC AND METHYLIGHT ASSAYS WERE PERFORMED ON SPECIMENS WITH CHRONIC BLADDER INFLAMMATION AT MULTIPLE POINTS TO MONITOR CYSTITIS PROGRESSION AND DNA METHYLATION CHANGES COMPARED WITH THE CONTROL SPECIMENS. RESULTS: HISTOPATHOLOGIC ANALYSIS SHOWED THE MOST EXTENSIVE EDEMA AND UROTHELIAL SLOUGHING AT THE 1-MONTH POINT. METHYLIGHT ANALYSES REVEALED STATISTICALLY SIGNIFICANT CHANGES IN DNA METHYLATION ASSOCIATED WITH THE CALCA, TIMP3, MMP2, AND IGF2R GENES IN THE CHRONIC BLADDER INJURY MODEL. THE CHANGES IN DNA METHYLATION ASSOCIATED WITH CHRONIC CYSTITIS WERE DNA HYPOMETHYLATION OF THE CALCA GENE IN THE CONTROL TISSUE AND DNA HYPERMETHYLATION FOR THE CALCA, TIMP3, MMP2, AND IGF2R GENES COMPARED WITH THAT IN THE CONTROL TISSUE. CONCLUSION: DNA METHYLATION CHANGES WERE NOTED IN THE CALCA, TIMP3, MMP2, AND IGF2R GENES DURING CHRONIC CYSTITIS IN A MURINE MODEL. EPIGENETIC CHANGES APPEAR TO PLAY A ROLE IN THE REGULATION OF INFLAMMATORY BLADDER GENES DURING CHRONIC CYSTITIS; HOWEVER, ADDITIONAL STUDIES ARE NEEDED TO ELUCIDATE THE PATHWAYS ASSOCIATED WITH THESE GENES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                             
5  6748  25 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                
6  2403  32 EPIGENETIC REPROGRAMMING: A POSSIBLE ETIOLOGICAL FACTOR IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS? PURPOSE: THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS IS POORLY UNDERSTOOD. THE POSSIBILITY THAT EPIGENETIC REPROGRAMMING MAY HAVE A ROLE IS DISCUSSED. MATERIALS AND METHODS: A LITERATURE SEARCH WAS PERFORMED WITH THE ENTREZ-PUBMED(R) DATABASE USING THE KEY WORDS URINARY BLADDER, EPIGENETICS, EPIGENETIC MECHANISMS, INTERSTITIAL CYSTITIS, DIAGNOSIS, ETIOLOGY, UROTHELIAL CELLS, MAST CELLS, NERVE FIBERS, NERVES, NERVE GROWTH FACTOR, RECURRENT INJURY, STEM CELLS, INFLAMMATORY MEDIATORS AND DEMETHYLASES. RESULTS: THE UROEPITHELIUM IS INTIMATELY ASSOCIATED WITH THE NERVOUS SYSTEM. SENSORY INPUT AT THE APICAL SURFACE OF UMBRELLA CELLS REGULATES BLADDER FUNCTION VIA A TRANSMURAL SIGNALING PATHWAY. WHEN UMBRELLA CELLS ARE SHED IN RESPONSE TO NOXIOUS STIMULI, STEM CELLS IN THE BASAL LAYER BECOME EXPOSED. THE POLYCOMB GROUP GENES ARE KEY IN THE MAINTENANCE OF ADULT STEM CELLS. THE POLYCOMB GROUP GENES MEDIATE GENE SILENCING AND REPRESS TRANSDIFFERENTIATION BY METHYLATING LYSINE 27 OF HISTONE H3 (H3K27ME3). JMJD3, AN ENZYME DEMETHYLATING H3K27ME3, ANTAGONIZES POLYCOMB GROUP GENES MEDIATED SILENCING. INFLAMMATORY STIMULI ARE STRONG INDUCERS OF JMJD3 AND MAY REVERSE GENE SILENCING IN STEM CELLS, MODIFYING THE DIFFERENTIATION PATTERN. EPIGENETIC PROCESSES INVOLVING H3K27 METHYLATION ARE MULTISTABLE PROCESSES. TRANSIENT SIGNALING, EG BY LIPOPOLYSACCHARIDE, TRIGGERS EPIGENETIC REPROGRAMMING AND ESTABLISHES ONE OF THE ALTERNATIVE REGULATORY STATES. ONCE ESTABLISHED SUCH STATES CAN BE MAINTAINED AND PROPAGATED EVEN IN THE ABSENCE OF THE INITIAL SIGNAL. CONCLUSIONS: WE POSTULATE THAT SIMILAR EPIGENETIC REPROGRAMMING MECHANISMS IN THE BLADDER MAY PROVIDE AN EXPLANATION FOR UROEPITHELIAL, MAST CELLS AND NERVE CELL ABNORMALITIES IN BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS, AS WELL AS PROPAGATION OF THIS ALTERED STATE IN THE ABSENCE OF THE SIGNAL THAT MAY HAVE TRIGGERED IT. IT ALSO PROVIDES A NEW EXPERIMENTAL PARADIGM FOR EXPLORING THE ETIOLOGY OF BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS. DATA SUPPORTING THIS HYPOTHESIS WOULD PROVIDE A RATIONALE FOR NEW DIAGNOSTIC AS WELL AS TREATMENT OPTIONS FOR BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS.	2009	

7   471  24 ARISTOLOCHIC ACID CONTAINING HERBS INDUCE GENDER-RELATED ONCOLOGICAL DIFFERENCES IN UPPER TRACT UROTHELIAL CARCINOMA PATIENTS. BACKGROUND: IN CHINA, UPPER TRACT UROTHELIAL CARCINOMA (UTUC) IS LESS PREVALENT BUT MORE MALIGNANT IN MALES. THIS STUDY INVESTIGATES THE PROGNOSTIC FACTORS AND CAUSES OF GENDER-BASED DIFFERENCES IN CHINESE POPULATIONS. METHODS: BETWEEN 1999 AND 2011, 687 UTUC PATIENTS WHO UNDERWENT SURGERY WERE UTILIZED FOR THIS STUDY. WE EVALUATED THE DIFFERENCES IN ONCOLOGICAL CHARACTERISTICS, EPIGENETIC BIOMARKERS, CANCER-SPECIFIC SURVIVAL (CSS), BLADDER RECURRENCE (BR) RATE, AND CONTRALATERAL UPPER TRACT RECURRENCE (CUTR) RATE. SMOKING HISTORY, BENZENE EXPOSURE HISTORY, AND THE HISTORY OF USING ARISTOLOCHIC ACID (AA) CONTAINING HERBS WERE ANALYZED IN DETAIL. RESULTS: COMPARED WITH MALE PATIENTS, FEMALE PATIENTS SHOWED POORER RENAL FUNCTION, LOWER PROPORTIONS OF TUMOR STAGE III/IV, AND SMALLER TUMOR DIAMETERS. THE CSS IN MALE PATIENTS WAS LOWER THAN THAT IN FEMALE PATIENTS. SIGNIFICANT GENDER-RELATED DIFFERENCES WERE OBSERVED CONCERNING VARIOUS PROGNOSTIC FACTORS. IN FEMALE PATIENTS, POORER SURVIVAL RATES WERE ATTRIBUTED TO THE PRIMARY TUMOR LOCATION IN THE URETER, LARGE DIAMETER PRIMARY TUMORS, SEVERE CHRONIC KIDNEY DISEASE, PAPILLARY TUMOR ARCHITECTURE, HIGH TUMOR STAGES, POSITIVE N STATUS, AND METHYLATED ABCC6 PROMOTERS. IN MALE PATIENTS, OLDER AGE, IPSILATERAL HYDRONEPHROSIS, LARGE TUMOR DIAMETERS, SESSILE TUMOR ARCHITECTURE, HIGH TUMOR STAGES, AND METHYLATED TMEFF2 PROMOTERS WERE ASSOCIATED WITH HIGHER CANCER-SPECIFIC MORTALITY. AA MIGHT BE THE MAIN CAUSE OF THESE GENDER-BASED DIFFERENCES. THE AA-INDUCED UTUC PATIENTS PRESENTED SMALLER TUMOR DIAMETERS, LOWER TUMOR STAGES, FEWER POSITIVE N STATUSES, MORE MULTIFOCAL TUMORS, LOWER METHYLATION INDICES, AND POORER RENAL FUNCTION. ALTHOUGH AA-INDUCED UTUC PATIENTS EXHIBITED BETTER SURVIVAL RATES, BR AND CUTR RATES WERE SIGNIFICANTLY WORSE. CONCLUSION: IN CHINA, THERE EXIST SIGNIFICANT AA-INDUCED DIFFERENCES BETWEEN MALE AND FEMALE UTUC PATIENTS. THE BLADDERS AND CONTRALATERAL UPPER URINARY TRACTS OF AA-INDUCED UTUC PATIENTS SHOULD BE CAREFULLY MONITORED AFTER SURGERY.	2018	
                                                                                                                  
8  1470  26 DISTINCT GENE EXPRESSION PROFILES IN IMMORTALIZED HUMAN UROTHELIAL CELLS EXPOSED TO INORGANIC ARSENITE AND ITS METHYLATED TRIVALENT METABOLITES. INORGANIC ARSENIC IS AN ENVIRONMENTAL CARCINOGEN. THE GENERATION OF TOXIC TRIVALENT METHYLATED METABOLITES COMPLICATES THE STUDY OF ARSENIC-MEDIATED CARCINOGENESIS. THIS STUDY SYSTEMATICALLY EVALUATED THE EFFECT OF CHRONIC TREATMENT WITH SODIUM ARSENITE (IAS(III)), MONOMETHYLARSONOUS ACID (MMA(III)), AND DIMETHYLARSINOUS ACID (DMA(III)) ON IMMORTALIZED HUMAN UROEPITHELIAL CELLS (SV-HUC-1 CELLS) USING CDNA MICROARRAY. AFTER EXPOSURE FOR 25 PASSAGES TO IAS(III) (0.5 MICROM), MMA(III) (0.05, 0.1, OR 0.2 MICROM), OR DMA(III) (0.2 OR 0.5 MICROM), SIGNIFICANT COMPOUND-SPECIFIC MORPHOLOGIC CHANGES WERE OBSERVED. A SET OF 114 GENES (5.7% OF THE EXAMINED GENES) WAS DIFFERENTIALLY EXPRESSED IN ONE OR MORE SETS OF ARSENICAL-TREATED CELLS COMPARED WITH UNTREATED CONTROLS. EXPRESSION ANALYSIS SHOWED THAT EXPOSURE OF CELLS TO DMA(III) RESULTED IN A GENE PROFILE DIFFERENT FROM THAT IN CELLS EXPOSED TO IAS(III) OR MMA(III), AND THAT THE IAS(III)-INDUCED GENE PROFILE WAS CLOSEST TO THAT IN THE TUMORIGENIC HUC-1-DERIVED 3-METHYLCHOLANTHRENE-INDUCED TUMORIGENIC CELL LINE MC-SV-HUC T2, WHICH WAS DERIVED FROM SV-HUC-1 CELLS BY METHYLCHOLANTHRENE TREATMENT. OF THE GENES AFFECTED BY ALL THREE ARSENICALS, ONLY ONE, THAT CODING FOR INTERLEUKIN-1 RECEPTOR, TYPE II, SHOWED ENHANCED EXPRESSION, A FINDING CONFIRMED BY THE REDUCED INCREASE IN NF-KAPPAB (NUCLEAR FACTOR KAPPA B) ACTIVITY SEEN IN RESPONSE TO INTERLEUKIN-1BETA IN IAS(III)-EXPOSED CELLS. THE EXPRESSION OF 11 GENES WAS SUPPRESSED BY ALL THREE ARSENICALS. 5-AZA-DEOXYCYTIDINE PARTIALLY RESTORED THE TRANSCRIPTION OF SEVERAL SUPPRESSED GENES, SHOWING THAT EPIGENETIC DNA METHYLATION WAS PROBABLY INVOLVED IN ARSENICAL-INDUCED GENE REPRESSION. OUR DATA DEMONSTRATE THAT CHRONIC EXPOSURE TO IAS(III), MMA(III), OR DMA(III) HAS DIFFERENT EPIGENETIC EFFECTS ON UROTHELIAL CELLS AND REPRESSES NF-KAPPAB ACTIVITY.	2006	
                                                                                                                                                                                                                                                                                 
9  4822  16 OCHRATOXIN A: 50 YEARS OF RESEARCH. SINCE OCHRATOXIN A (OTA) WAS DISCOVERED, IT HAS BEEN UBIQUITOUS AS A NATURAL CONTAMINANT OF MOLDY FOOD AND FEED. THE MULTIPLE TOXIC EFFECTS OF OTA ARE A REAL THREAT FOR HUMAN BEINGS AND ANIMAL HEALTH. FOR EXAMPLE, OTA CAN CAUSE PORCINE NEPHROPATHY BUT CAN ALSO DAMAGE POULTRIES. HUMANS EXPOSED TO OTA CAN DEVELOP (NOTABLY BY INHALATION IN THE DEVELOPMENT OF ACUTE RENAL FAILURE WITHIN 24 H) A RANGE OF CHRONIC DISORDERS SUCH AS UPPER UROTHELIAL CARCINOMA. OTA PLAYS THE MAIN ROLE IN THE PATHOGENESIS OF SOME RENAL DISEASES INCLUDING BALKAN ENDEMIC NEPHROPATHY, KIDNEY TUMORS OCCURRING IN CERTAIN ENDEMIC REGIONS OF THE BALKAN PENINSULA, AND CHRONIC INTERSTITIAL NEPHROPATHY OCCURRING IN NORTHERN AFRICAN COUNTRIES AND LIKELY IN OTHER PARTS OF THE WORLD. OTA LEADS TO DNA ADDUCT FORMATION, WHICH IS KNOWN FOR ITS GENOTOXICITY AND CARCINOGENICITY. THE PRESENT ARTICLE DISCUSSES HOW RENAL CARCINOGENICITY AND NEPHROTOXICITY CAUSE BOTH OXIDATIVE STRESS AND DIRECT GENOTOXICITY. CAREFUL ANALYSES OF THE DATA SHOW THAT OTA CARCINOGENIC EFFECTS ARE DUE TO COMBINED DIRECT AND INDIRECT MECHANISMS (E.G., GENOTOXICITY, OXIDATIVE STRESS, EPIGENETIC FACTORS). ALTOGETHER THIS PROVIDES STRONG EVIDENCE THAT OTA CARCINOGENICITY CAN ALSO OCCUR IN HUMANS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  6671  33 UROPATHOGENIC ESCHERICHIA COLI INFECTION-INDUCED EPITHELIAL TRAINED IMMUNITY IMPACTS URINARY TRACT DISEASE OUTCOME. PREVIOUS URINARY TRACT INFECTIONS (UTIS) CAN PREDISPOSE ONE TO FUTURE INFECTIONS; HOWEVER, THE UNDERLYING MECHANISMS AFFECTING RECURRENCE ARE POORLY UNDERSTOOD. WE PREVIOUSLY FOUND THAT UTIS IN MICE CAUSE DIFFERENTIAL BLADDER EPITHELIAL (UROTHELIAL) REMODELLING, DEPENDING ON DISEASE OUTCOME, THAT IMPACTS SUSCEPTIBILITY TO RECURRENT UTI. HERE WE COMPARED UROTHELIAL STEM CELL (USC) LINES ISOLATED FROM MICE WITH A HISTORY OF EITHER RESOLVED OR CHRONIC UROPATHOGENIC ESCHERICHIA COLI (UPEC) INFECTION, ELUCIDATING EVIDENCE OF MOLECULAR IMPRINTING THAT INVOLVED EPIGENETIC CHANGES, INCLUDING DIFFERENCES IN CHROMATIN ACCESSIBILITY, DNA METHYLATION AND HISTONE MODIFICATION. EPIGENETIC MARKS IN USCS FROM CHRONICALLY INFECTED MICE ENHANCED CASPASE-1-MEDIATED CELL DEATH UPON UPEC INFECTION, PROMOTING BACTERIAL CLEARANCE. INCREASED PTGS2OS2 EXPRESSION ALSO OCCURRED, POTENTIALLY CONTRIBUTING TO SUSTAINED CYCLOOXYGENASE-2 EXPRESSION, BLADDER INFLAMMATION AND MUCOSAL WOUNDING-RESPONSES ASSOCIATED WITH SEVERE RECURRENT CYSTITIS. THUS, UPEC INFECTION ACTS AS AN EPI-MUTAGEN REPROGRAMMING THE UROTHELIAL EPIGENOME, LEADING TO UROTHELIAL-INTRINSIC REMODELLING AND TRAINING OF THE INNATE RESPONSE TO SUBSEQUENT INFECTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11  4820  21 OCHRATOXIN A AS A POTENTIAL ETIOLOGIC FACTOR IN ENDEMIC NEPHROPATHY: LESSONS FROM TOXICITY STUDIES IN RATS. VARIOUS REPORTS SUGGEST THAT CHRONIC DIETARY EXPOSURE TO OCHRATOXIN A (OTA), A MYCOTOXIN FREQUENTLY DETECTED IN VARIOUS FOOD ITEMS MAY BE LINKED TO THE PATHOGENESIS OF ENDEMIC NEPHROPATHY, A CHRONIC TUBULOINTERSTITIAL KIDNEY DISEASE WHICH OCCURS IN GEOGRAPHICALLY LIMITED AREAS OF THE BALKAN REGION. OTA IS A POTENT NEPHROTOXIN AND RENAL CARCINOGEN. HOWEVER, THE PATHOLOGICAL LESIONS OBSERVED IN KIDNEYS OF RATS TREATED WITH OTA APPEAR BE RATHER DIFFERENT FROM THE CLINICAL AND PATHOLOGICAL CHARACTERISTICS OF ENDEMIC NEPHROPATHY. MOREOVER, INCREASING EVIDENCE SUGGESTS THAT OTA DOES NOT BIND TO DNA BUT INDUCES TUMORS BY AN EPIGENETIC, THRESHOLDED MECHANISM. THIS IMPLIES THAT THERE IS A DOSE BELOW WHICH NO ADVERSE HEALTH EFFECTS ARE EXPECTED TO OCCUR. BASED ON FOOD CONSUMPTION DATA AND OTA SERUM CONCENTRATIONS, IT APPEARS THAT HUMAN EXPOSURE - EVEN IN AREAS WITH RELATIVELY HIGH DIETARY EXPOSURE TO OTA SUCH AS ENDEMIC VILLAGES - IS SEVERAL ORDERS OF MAGNITUDE BELOW DOSES KNOWN TO CAUSE NEPHROTOXICITY AND TUMOR FORMATION IN LABORATORY ANIMALS. WHILE IT IS UNDOUBTEDLY IMPORTANT TO ENCOURAGE PREVENTION OF FOOD CONTAMINATION BY OTA AND OTHER MYCOTOXINS, THESE OBSERVATIONS SUGGEST THAT OTA IS NOT LIKELY TO BE AN ETIOLOGICAL FACTOR INVOLVED IN BEN AND INDICATE A NEED TO SEARCH FOR NEW CLUES FOR THE ETIOLOGY OF THIS ENDEMIC KIDNEY DISEASE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  1582  24 DNA METHYLATION PROFILES IN PRECANCEROUS TISSUE AND CANCERS: CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION BASED ON DNA METHYLATION STATUS. ALTERATIONS IN DNA METHYLATION, WHICH ARE ASSOCIATED WITH DNA METHYLTRANSFERASE ABNORMALITIES AND RESULT IN SILENCING OF TUMOR-RELATED GENES AND CHROMOSOMAL INSTABILITY, ARE INVOLVED EVEN IN PRECANCEROUS CHANGES IN VARIOUS ORGANS. DNA METHYLATION ALTERATIONS ALSO ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. THEREFORE, WE HAVE ANALYZED DNA METHYLATION ON A GENOME-WIDE SCALE IN CLINICAL TISSUE SAMPLES. OUR APPROACH USING THE BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION METHOD HAS REVEALED THAT DNA METHYLATION ALTERATIONS CORRELATED WITH THE FUTURE DEVELOPMENT OF MORE MALIGNANT CANCERS ARE ALREADY ACCUMULATED AT THE PRECANCEROUS STAGE IN THE KIDNEY, LIVER AND URINARY TRACT. DNA METHYLATION PROFILES AT PRECANCEROUS STAGES ARE BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. SUCH DNA METHYLATION ALTERATIONS MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. ON THE BASIS OF BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION DATA, INDICATORS FOR CARCINOGENETIC RISK ESTIMATION HAVE BEEN ESTABLISHED USING LIVER TISSUE SPECIMENS FROM PATIENTS WITH HEPATITIS VIRUS INFECTION, CHRONIC HEPATITIS AND LIVER CIRRHOSIS OR HISTOLOGICALLY NORMAL UROTHELIA, AND FOR PROGNOSTICATION USING BIOPSY OR SURGICALLY RESECTED SPECIMENS FROM PATIENTS WITH RENAL CELL CARCINOMA, HEPATOCELLULAR CARCINOMA AND UROTHELIAL CARCINOMA. SUCH GENOME-WIDE DNA METHYLATION PROFILING HAS NOW FIRMLY ESTABLISHED THE CLINICAL RELEVANCE OF TRANSLATIONAL EPIGENETICS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  4824  19 OCHRATOXIN A: THE CONTINUING ENIGMA. THE MYCOTOXIN OCHRATOXIN A (OTA) HAS BEEN LINKED TO THE GENESIS OF SEVERAL DISEASE STATES IN BOTH ANIMALS AND HUMANS. IT HAS BEEN DESCRIBED AS NEPHROTOXIC, CARCINOGENIC, TERATOGENIC, IMMUNOTOXIC, AND HEPATOTOXIC IN LABORATORY AND DOMESTIC ANIMALS, AS WELL AS BEING THOUGHT TO BE THE PROBABLE CAUSAL AGENT IN THE DEVELOPMENT OF NEPHROPATHIES (BALKAN ENDEMIC NEPHROPATHY, BEN AND CHRONIC INTERSTITIAL NEPHROPATHY, CIN) AND UROTHELIAL TUMORS IN HUMANS. AS A RESULT, SEVERAL INTERNATIONAL AGENCIES ARE CURRENTLY ATTEMPTING TO DEFINE SAFE LEGAL LIMITS FOR OTA CONCENTRATION IN FOODSTUFFS (E.G., GRAIN, MEAT, WINE, AND COFFEE), IN PROCESSED FOODS, AND IN ANIMAL FODDER. IN ORDER TO ACHIEVE THIS GOAL, AN ACCURATE RISK ASSESSMENT OF OTA TOXICITY INCLUDING MECHANISTIC AND EPIDEMIOLOGICAL STUDIES MUST BE CARRIED OUT. OCHRATOXIN HAS BEEN SUGGESTED BY VARIOUS RESEARCHERS TO MEDIATE ITS TOXIC EFFECTS VIA INDUCTION OF APOPTOSIS, DISRUPTION OF MITOCHONDRIAL RESPIRATION AND/OR THE CYTOSKELETON, OR, INDEED, VIA THE GENERATION OF DNA ADDUCTS. THUS, IT IS STILL UNCLEAR IF THE PREDOMINANT MECHANISM IS OF A GENOTOXIC OR AN EPIGENETIC NATURE. ONE ASPECT THAT IS CLEAR, HOWEVER, IS THAT THE TOXICITY OF OTA IS SUBJECT TO AND CHARACTERIZED BY LARGE SPECIES- AND SEX-SPECIFIC DIFFERENCES, AS WELL AS AN APPARENTLY STRICT STRUCTURE-ACTIVITY RELATIONSHIP. THESE CONSIDERATIONS COULD BE CRUCIAL IN THE INVESTIGATION OF OTA-MEDIATED TOXICITY. FURTHERMORE, THE USE OF APPROPRIATE IN VIVO AND IN VITRO MODEL SYSTEMS APPEARS TO BE VITAL IN THE GENERATION OF RELEVANT EXPERIMENTAL DATA. THE INTENTION OF THIS REVIEW IS TO COLLATE AND DISCUSS THE CURRENTLY AVAILABLE DATA ON OTA-MEDIATED TOXICITY WITH PARTICULAR FOCUS ON THEIR RELEVANCE FOR THE IN VIVO SITUATION, AND ALSO TO SUGGEST POSSIBLE FUTURE STRATEGIES FOR UNLOCKING THE SECRETS OF OCHRATOXIN A.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                            
14  6837  21 [INTERSTITIAL CYSTITIS: THE LATEST FINDINGS ON ITS AETIOPATHOGENESIS]. NEW FINDINGS PROVIDE PROGRESS IN THE UNDERSTANDING OF THE COMPLICATED AETIOPATHOGENESIS OF INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME (IC/BPS), WHOSE CAUSALITIES HAVE ONLY BEEN DECIPHERED IN FRAGMENTS SO FAR. AN INCREASINGLY COMPLEX NETWORK OF PATHOMECHANISMS IS EMERGING, IN WHICH THE FREQUENTLY MENTIONED MAST CELLS AND UROTHELIAL CHANGES SEEM TO BE ONLY A FRAGMENT OF THE PATHOLOGICAL CHANGES. THE LATEST FINDINGS REGARDING A POSSIBLE GENETIC AND EPIGENETIC PREDISPOSITION ARE BASED ON PEDIGREE ANALYSES, DETECTION OF SINGLE NUCLEOTIDE POLYMORPHISMS AND SIGNIFICANT CHANGES IN DIFFERENTIALLY EXPRESSED GENES. MULTIPLE ALTERATIONS CAN BE DETECTED AT THE MOLECULAR LEVEL. PLATELET-ACTIVATING FACTOR, VEGF, CORTICOTROPIN-RELEASING HORMONE AND THE INFLAMMASOME ARE IMPORTANT PLAYERS IN UNDERSTANDING THE DISEASE, BUT THE PATHOMECHANISM UNDERLYING THE "ACTIVATION" OF IC REMAINS UNCLEAR. NEW STARTING POINTS COULD BE THE DETECTION OF VIRUSES (EPSTEIN-BARR VIRUS, BK POLYOMAVIRUSES) OR BACTERIAL INFLAMMATION BY PATHOGENS THAT CANNOT BE DETECTED IN STANDARD CULTURES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  1819  18 EFFECTS OF CHRONIC OCHRATOXIN A EXPOSURE ON P53 HETEROZYGOUS AND P53 HOMOZYGOUS MICE. EXPOSURE TO THE MYCOTOXIN OCHRATOXIN A (OTA) CAUSES NEPHROPATHY IN DOMESTIC ANIMALS AND RODENTS AND RENAL TUMORS IN RODENTS AND POULTRY. HUMANS ARE EXPOSED TO OTA BY CONSUMING FOODS MADE WITH CONTAMINATED CEREAL GRAINS AND OTHER COMMODITIES. MANAGEMENT OF HUMAN HEALTH RISKS DUE TO OTA EXPOSURE DEPENDS, IN PART, ON ESTABLISHING A MODE OF ACTION (MOA) FOR OTA CARCINOGENESIS. TO FURTHER INVESTIGATE OTA'S MOA, P53 HETEROZYGOUS (P53+/-) AND P53 HOMOZYGOUS (P53+/+) MICE WERE EXPOSED TO OTA IN DIET FOR 26 WEEKS. THE FORMER ARE SUSCEPTIBLE TO TUMORIGENESIS UPON CHRONIC EXPOSURE TO GENOTOXIC CARCINOGENS. OTA-INDUCED RENAL DAMAGE BUT NO TUMORS WERE OBSERVED IN EITHER STRAIN, INDICATING THAT P53 HETEROZYGOSITY CONFERRED LITTLE ADDITIONAL SENSITIVITY TO OTA. RENAL CHANGES INCLUDED DOSE-DEPENDENT INCREASES IN CELLULAR PROLIFERATION, APOPTOSIS, KARYOMEGALY, AND TUBULAR DEGENERATION IN PROXIMAL TUBULES, WHICH WERE CONSISTENT WITH OCHRATOXICOSIS. THE LOWEST OBSERVED EFFECT LEVEL FOR RENAL CHANGES IN P53+/- AND P53+/+ MICE WAS 200 MUG OTA/KG BW/DAY. BASED ON THE LACK OF TUMORS AND THE SEVERITY OF RENAL AND BODY WEIGHT CHANGES AT A MAXIMUM TOLERATED DOSE, THE RESULTS WERE INTERPRETED AS SUGGESTIVE OF A PRIMARILY NONGENOTOXIC (EPIGENETIC) MOA FOR OTA CARCINOGENESIS IN THIS MOUSE MODEL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  1437  23 DIFFERENTIAL METHYLATION PATTERN OF XENOBIOTIC METABOLIZING GENES AND SUSCEPTIBILITY TO BALKAN ENDEMIC NEPHROPATHY, IN A COHORT OF ROMANIAN PATIENTS. A SEVERE, CHRONIC AND IRREVERSIBLE KIDNEY DISEASE AFFECTING DISCRETE RURAL POPULATIONS IN THE BALKAN PENINSULA COUNTRIES, BALKAN ENDEMIC NEPHROPATHY (BEN) HAS BEEN A SCIENTIFIC PUZZLE FOR MORE THAN HALF A CENTURY. MANY ENVIRONMENTAL AND OTHER FACTORS HAVE BEEN SUGGESTED AS THE PRIMARY CAUSE AND RECENT SIGNIFICANT FINDINGS HAVE LINKED BEN TO ARISTOLOCHIC ACIDS, PHYTOTOXINS DERIVED FROM THE PLANT ARISTOLOCHIA CLEMATITIS, FOUND IN HIGH DENSITY IN THE ENDEMIC AREAS. HOWEVER, GIVEN THAT THE INCIDENCE OF BEN IS LESS THAN 10% IN AFFECTED VILLAGES, AND IT TENDS TO HAVE A FAMILY AGGREGATION, AS YET UNIDENTIFIED GENETIC FACTORS MAY ALSO PLAY A ROLE. TO FURTHER EXPLORE THIS POSSIBILITY, A PILOT STUDY WAS INITIATED TO INVESTIGATE THE DNA METHYLATION OF CYP1A1, CYP1A2, NAT1, NQO1 AND GSTT1 IN BLOOD SAMPLES FROM A GROUP OF ROMANIAN BEN PATIENTS, COMPARED TO HEALTHY CONTROLS AND NON-BEN CHRONIC KIDNEY DISEASE (CKD) SUBJECTS. OUR STUDY REVEALED A MORE PRONOUNCED HYPOMETHYLATION PATTERN IN BEN AND NON-BEN CKD GROUPS, COMPARED TO THE HEALTHY CONTROL GROUP AT SPECIFIC CPGS ACROSS ALL FIVE GENES INTERROGATED. AVERAGE METHYLATION ACROSS THE FIVE REGIONS INVESTIGATED INDICATED SIGNIFICANT DIFFERENCES ONLY AT GSTT1, IN BOTH BEN PATIENTS (P = 0.028) AND NON-BEN DISEASE SUBJECTS (P = 0.015), RELATIVE TO HEALTHY INDIVIDUALS. SINCE GSTT1 ACTIVE GENOTYPE APPEARS TO BE A COMMON FEATURE OF SERBIAN AND ROMANIAN BEN PATIENTS, GSTT1 EPIGENETIC VARIATION AND INCREASED GENE ACTIVITY COULD ACT AS A PREDISPOSING (CO)FACTOR IN BEN POPULATIONS FROM THE AFFECTED COUNTRIES. BEN AND NON-BEN CKD GROUPS SHOW SIMILAR METHYLATION PATTERNS WITH EXCEPTION OF GSTT1 CPG8 (P = 0.046).	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17   473  25 ARSENIC AND URINARY BLADDER CELL PROLIFERATION. EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED THAT A CLOSE ASSOCIATION EXISTS BETWEEN THE ELEVATED LEVELS OF ARSENIC IN DRINKING WATER AND THE INCIDENCE OF CERTAIN CANCERS, INCLUDING TRANSITIONAL CELL CARCINOMAS OF THE URINARY BLADDER. WE HAVE EMPLOYED IN VITRO AND IN VIVO MODELS TO EXAMINE THE EFFECTS OF SODIUM ARSENITE ON THE URINARY BLADDER EPITHELIUM. MICE EXPOSED TO 0.01% SODIUM ARSENITE IN DRINKING WATER DEMONSTRATED HYPERPROLIFERATION OF THE BLADDER UROEPITHELIUM WITHIN 4 WEEKS AFTER INITIATING TREATMENT. THIS OCCURRED IN THE ABSENCE OF AMORPHOUS PRECIPITATES AND WAS ACCOMPANIED BY THE ACCUMULATION OF TRIVALENT ARSENITE (IAS(3+)), AND TO A LESSER EXTENT DIMETHYLARSENIC (DMA), ARSENATE (IAS(5+)), AND MONOMETHYLARSENIC (MMA) IN BLADDER TISSUE. IN CONTRAST TO THE BLADDER, URINARY SECRETION WAS PRIMARILY IN THE FORM OF DMA AND MMA. ARSENIC-INDUCED CELL PROLIFERATION IN THE BLADDER EPITHELIUM WAS CORRELATED WITH ACTIVATION OF THE MAP KINASE PATHWAY, LEADING TO EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) KINASE ACTIVITY, AP-1 ACTIVATION, AND EXPRESSION OF AP-1-ASSOCIATED GENES INVOLVED IN CELL PROLIFERATION. ACTIVATION OF THE MAP KINASE PATHWAY INVOLVED BOTH EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR-DEPENDENT AND -INDEPENDENT EVENTS, THE LATTER INVOLVING SRC ACTIVATION. STUDIES SUMMARIZED IN THIS REVIEW SUGGEST THAT ARSENIC ACCUMULATES IN URINARY BLADDER EPITHELIUM CAUSING ACTIVATION OF SPECIFIC SIGNALING PATHWAYS THAT LEAD TO CHRONIC INCREASED CELL PROLIFERATION. THIS MAY PLAY A NON-EPIGENETIC ROLE IN CARCINOGENESIS BY INCREASING THE PROLIFERATION OF INITIATED CELLS OR INCREASING THE MUTATIONAL RATE.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18   143  14 ABERRANT DNA METHYLATION OF TWO TUMOR SUPPRESSOR GENES, P14(ARF) AND P15(INK4B), AFTER CHRONIC OCCUPATIONAL EXPOSURE TO LOW LEVEL OF BENZENE. BACKGROUND: EXPOSURE TO BENZENE WOULD BE ASSOCIATED WITH MANY DISEASES INCLUDING LEUKEMIA. EPIGENETIC ALTERATIONS SEEM TO BE AMONG THE MAIN MECHANISMS INVOLVED. OBJECTIVE: TO DETERMINE IF CHRONIC OCCUPATIONAL EXPOSURE TO LOW LEVEL OF BENZENE WOULD BE ASSOCIATED WITH DNA METHYLATION. METHODS: GLOBAL DNA METHYLATION AND PROMOTER-SPECIFIC METHYLATION OF THE TWO TUMOR SUPPRESSOR GENES, P14(ARF) AND P15(INK4B), WERE ASSESSED EMPLOYING METHYLATION-SPECIFIC PCR USING THE DNA EXTRACTED FROM 40 PETROCHEMICAL WORKERS EXPOSED TO AMBIENT BENZENE LEVELS OF <1 PPM, AND 31 OFFICE WORKERS NOT EXPOSED TO BENZENE OR ITS DERIVATIVES. RESULTS: WHILE AN INCREASE IN GLOBAL DNA METHYLATION OF 5% IN P14(ARF) (P=0.501) AND 28% IN P15(INK4B) (P=0.02) GENES WAS OBSERVED IN THE EXPOSED GROUP, NO HYPERMETHYLATION IN EITHER OF THE STUDIED GENES WAS OBSERVED IN THE UNEXPOSED GROUP. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN THE FREQUENCY OF ABERRANT METHYLATION AND EITHER OF AGE, WORK EXPERIENCE, AND SMOKING HABIT IN THE EXPOSED GROUP. CONCLUSION: CHRONIC OCCUPATIONAL EXPOSURE TO LOWER THAN THE PERMISSIBLE EXPOSURE LIMIT OF BENZENE MAY STILL RESULT IN DNA METHYLATION OF TUMOR SUPPRESSOR GENES THAT MAY ULTIMATELY LEAD TO DEVELOPMENT OF CANCER.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19   329  27 ALPHA-OXOGLUTARATE INHIBITS THE PROLIFERATION OF IMMORTALIZED NORMAL BLADDER EPITHELIAL CELLS VIA AN EPIGENETIC SWITCH INVOLVING ARID1A. INTERSTITIAL CYSTITIS (IC) IS A CHRONIC URINARY TRACT DISEASE THAT IS CHARACTERIZED BY UNPLEASANT SENSATIONS, SUCH AS PERSISTENT PELVIC PAIN, IN THE ABSENCE OF INFECTION OR OTHER IDENTIFIABLE CAUSES. WE PREVIOUSLY PERFORMED COMPREHENSIVE METABOLOMICS PROFILING OF URINE SAMPLES FROM IC PATIENTS USING NUCLEAR MAGNETIC RESONANCE AND GAS-CHROMATOGRAPHY/MASS SPECTROMETRY AND FOUND THAT URINARY ALPHA-OXOGLUTARATE (ALPHA-OG), WAS SIGNIFICANTLY ELEVATED. ALPHA-OG, A TRICARBOXYLIC ACID (TCA) CYCLE INTERMEDIATE, REPORTEDLY FUNCTIONS TO SUPPRESS THE PROLIFERATION OF IMMORTALIZED NORMAL HUMAN BLADDER EPITHELIAL CELLS. HERE, WE IDENTIFIED AT-RICH INTERACTIVE DOMAIN 1 A (ARID1A), A KEY CHROMATIN REMODELER, AS BEING HYPOMETHYLATED AND UPREGULATED BY ALPHA-OG TREATMENT. THIS WAS DONE THROUGH EPIC DNA METHYLATION PROFILING AND SUBSEQUENT BIOCHEMICAL APPROACHES, INCLUDING QUANTITATIVE RT-PCR AND WESTERN BLOT ANALYSES. FURTHERMORE, WE FOUND THAT ALPHA-OG ALMOST COMPLETELY SUPPRESSES TEN-ELEVEN TRANSLOCATION (TET) ACTIVITY, BUT DOES NOT AFFECT DNA METHYLTRANSFERASE (DNMT) ACTIVITY. ALTOGETHER, OUR STUDIES REVEAL THE POTENTIAL ROLE OF ALPHA-OG IN EPIGENETIC REMODELING THROUGH ITS EFFECTS ON ARID1A AND TET EXPRESSION IN THE BLADDER. THIS MAY PROVIDE A NEW POSSIBLE THERAPEUTIC STRATEGY IN TREATING IC.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20   414  18 ANALYSIS OF PROMOTER METHYLATION IN STOOL: A NOVEL METHOD FOR THE DETECTION OF COLORECTAL CANCER. BACKGROUND & AIMS: DETECTION OF TUMOR-DERIVED DNA ALTERATIONS IN STOOL IS AN INTRIGUING NEW APPROACH WITH HIGH POTENTIAL FOR THE NONINVASIVE DETECTION OF COLORECTAL CANCER (CRC). BECAUSE OF HETEROGENEITY OF TUMORS, USUALLY MULTIPLE MARKERS DISTRIBUTED THROUGHOUT THE HUMAN GENOME NEED TO BE ANALYZED. THIS IS LABOR INTENSIVE AND DOES NOT ALLOW FOR HIGH THROUGH-PUT SCREENING. THEREFORE, MARKERS WITH HIGH SENSITIVITY AND GOOD SPECIFICITY ARE NEEDED. WE EXPLORED THE POTENTIAL OF A SINGLE EPIGENETIC MARKER IN COMPARISON WITH FECAL OCCULT BLOOD TESTING (FOBT) FOR THE DISCRIMINATION OF PATIENTS WITH CRCS AND ADENOMAS FROM THOSE WITHOUT. METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) WAS PERFORMED TO ANALYZE HYPERMETHYLATED IN CANCER 1 (HIC1) PROMOTER METHYLATION STATUS IN A BLINDED FASHION IN STOOL SAMPLES FROM 26 PATIENTS WITH CRC, 13 WITH ADENOMA > OR =1 CM, 9 WITH HYPERPLASTIC POLYPS, 9 WITH CHRONIC INFLAMMATORY BOWEL DISEASE, AND 32 WITH ENDOSCOPICALLY NORMAL COLON. RESULTS: NINETY-SEVEN PERCENT OF THE STOOL SAMPLES CONTAINED AMPLIFIABLE DNA. FORTY-TWO PERCENT OF THE SAMPLES FROM PATIENTS WITH CRC AND 31% OF THE SAMPLES FROM PATIENTS WITH COLORECTAL ADENOMA > OR =1 CM WERE POSITIVE FOR HIC1 PROMOTER METHYLATION. NO METHYLATED HIC1 PROMOTER DNA WAS DETECTED IN THE FECAL DNA FROM PATIENTS WITH ENDOSCOPICALLY NORMAL COLON OR HYPERPLASTIC POLYPS. CONCLUSIONS: THE EPIGENETIC MARKER HIC1 PROMOTER METHYLATION CARRIES HIGH POTENTIAL FOR THE REMOTE DETECTION OF CRCS. WE POSTULATE THAT A PANEL OF MERELY A FEW GENETIC AND EPIGENETIC MARKERS WILL BE REQUIRED FOR THE HIGHLY SENSITIVE AND SPECIFIC DETECTION OF CRCS AND ADENOMAS IN FECAL SAMPLES FROM AFFECTED PATIENTS.	2005