1 1358 142 DEVELOPMENT OF RATIOMETRIC ELECTROCHEMICAL MOLECULAR SWITCHES TO ASSAY ENDOGENOUS FORMALDEHYDE IN LIVE CELLS, WHOLE BLOOD AND CREATININE IN SALIVA. FORMALDEHYDE IS A REACTIVE CARBONYL SPECIES (RCS) THAT IS PRODUCED NATURALLY IN THE HUMAN BODY VIA METABOLIC AND EPIGENETIC BIOCHEMICAL PROCESSES, YET IN HIGH CONCENTRATIONS IS HIGHLY TOXIC TO THE ENVIRONMENT AS WELL AS TO LIVING ORGANISMS. THEREFORE, WE DESIGNED TWO RATIOMETRIC ELECTROCHEMICAL MOLECULAR REDOX PROBES, FORMALDEHYDE OXIDATIVE LATENT PROBE (FOLP) AND DIHYDROXY-FORMALDEHYDE OXIDATIVE LATENT PROBE (HFOLP), FOR THE SELECTIVE PROFILING OF ENDOGENOUS FORMALDEHYDE. FOLP AND HFOLP EACH UNDERWENT THE AZA-COPE REACTION WITH FORMALDEHYDE FOLLOWED BY HYDROLYSIS TO ELIMINATE UNMASK REDOX REPORTER N-ALKYLATED AMINOFERROCENE (AAF) TO MONITOR THEIR RESPONSE CURRENT. THE FOLP AND HFOLP SENSORS SHOWED BROAD DYNAMIC RANGES OF 0.12-1000 MUM AND 0.09-3 MM FOR FORMALDEHYDE WITH DETECTION LIMITS OF 48.2 NM AND 31.6 MUM, RESPECTIVELY. ALSO, SINCE FORMALDEHYDE IS THE BYPRODUCT OF BIOCHEMICAL REACTIONS FOR DETECTING CREATININE AND CREATININE IS AN IMPORTANT BIOMARKER FOR CHRONIC KIDNEY DISEASE (CKD), WE TESTED THE FOLP PROBE FOR ITS ABILITY TO MONITOR CREATININE. IT SUCCESSFULLY DID SO, AND THIS ABILITY WAS USED TO DEVELOP AN ELECTROCHEMICAL PLATFORM FOR THE QUANTIFICATION OF CREATININE; IT SHOWED A DYNAMIC RANGE OF 3.25-200 MUM AND A LIMIT OF DETECTION (1.3 MUM). IN ADDITION, THE FOLP-BASED ASSAY PLATFORM DELIVERED A RELIABLE ANALYTICAL PERFORMANCE FOR THE QUANTIFICATION OF FORMALDEHYDE IN HUMAN WHOLE BLOOD AND OF CREATININE IN SALIVA, AND ALSO FOR THE REAL-TIME MONITORING OF ENDOGENOUS FORMALDEHYDE SECRETION IN HELA CELLS. MOREOVER, THE CONCENTRATIONS DETERMINED USING OUR METHOD WERE FOUND TO BE CONSISTENT WITH THOSE DETERMINED USING FORMALDEHYDE AND CREATININE FLUOROMETRIC ASSAY KITS. 2021 2 6835 26 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION. 2022 3 6484 23 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC). 1998 4 3074 27 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022 5 2761 24 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY. 2012 6 491 29 ASSESSING THE IMPACT OF POLYETHYLENE NANO/MICROPLASTIC EXPOSURE ON HUMAN VAGINAL KERATINOCYTES. THE GLOBAL RISE OF SINGLE-USE THROW-AWAY PLASTIC PRODUCTS HAS ELICITED A MASSIVE INCREASE IN THE NANO/MICROPLASTICS (N/MPLS) EXPOSURE BURDEN IN HUMANS. RECENTLY, IT HAS BEEN DEMONSTRATED THAT DISPOSABLE PERIOD PRODUCTS MAY RELEASE N/MPLS WITH USAGE, WHICH REPRESENTS A POTENTIAL THREAT TO WOMEN'S HEALTH WHICH HAS NOT BEEN SCIENTIFICALLY ADDRESSED YET. BY USING POLYETHYL ENE (PE) PARTICLES (200 NM TO 9 MUM), WE SHOWED THAT ACUTE EXPOSURE TO A HIGH CONCENTRATION OF N/MPLS INDUCED CELL TOXICITY IN VAGINAL KERATINOCYTES AFTER EFFECTIVE CELLULAR UPTAKE, AS VIABILITY AND APOPTOSIS DATA SUGGEST, ALONG WITH TRANSMISSION ELECTRON MICROSCOPY (TEM) OBSERVATIONS. THE INTERNALISED N/MPLS ALTERED THE EXPRESSION OF JUNCTIONAL AND ADHERENCE PROTEINS AND THE ORGANISATION OF THE ACTIN CORTEX, INFLUENCING THE LEVEL OF GENES INVOLVED IN OXIDATIVE STRESS SIGNALLING PATHWAYS AND THAT OF MIRNAS RELATED TO EPITHELIAL BARRIER FUNCTION. WHEN THE EXPOSURE TO PE N/MPLS WAS DISCONTINUED OR BECAME CHRONIC, CELLS WERE ABLE TO RECOVER FROM THE NEGATIVE EFFECTS ON VIABILITY AND DIFFERENTIATION/PROLIFERATION GENE EXPRESSION IN A FEW DAYS. HOWEVER, IN ALL CASES, PE N/MPL EXPOSURE PROMPTED A SUSTAINED ALTERATION OF DNA METHYLTRANSFERASE AND DNA DEMETHYLASE EXPRESSION, WHICH MIGHT IMPACT EPIGENETIC REGULATION PROCESSES, LEADING TO ACCELERATED CELL AGEING AND INFLAMMATION, OR THE OCCURRENCE OF MALIGNANT TRANSFORMATION. 2023 7 1109 25 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES. 2016 8 3883 26 KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. BACKGROUND: A RECENT REVIEW BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) UPDATED THE ASSESSMENTS OF THE > 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912. 2016 9 3552 22 IMMUNOSUPPRESSION BY CHRONIC EXPOSURE TO N-NITROSODIMETHYLAMINE (NDMA) IN MICE. IMMUNOSUPPRESSION OF HUMORAL AND CELLULAR RESPONSES FOLLOWING CHRONIC ORAL EXPOSURE TO 1, 5, 10, AND 20 PPM N-NITROSODIMETHYLAMINE (NDMA) WAS EXAMINED IN CD-1 MICE. MONITORING OF CUMULATIVE MORTALITY AND THE INCIDENCE OF PERITONEAL ASCITES IN ANIMALS SHOWED AN NDMA DOSE-RELATED MORTALITY AND HEPATOTOXICITY. NO VISIBLE CHANGES IN IMMUNOLOGICAL PARAMETERS WERE NOTED AT THE 1 PPM NDMA DOSE. IMMUNOSUPPRESSION OF IMMUNOGLOBULIN M (IGM) ANTIBODY RESPONSE BY NDMA TO SHEEP RED BLOOD CELLS (SRBC) WAS TIME-RELATED, DOSE-RELATED, AND COULD BE REVERSED WITHIN 30 D BY REMOVAL OF THE CHEMICAL FROM THE DRINKING WATER. CELLULAR IMMUNE RESPONSE, MONITORED BY ALLOGENEIC STIMULATION OF CELLS IN MIXED LYMPHOCYTE REACTION (MLR), WAS MARKEDLY SUPPRESSED BY 10 AND 20 PPM NDMA. THUS, CHRONIC EXPOSURE TO NDMA, EXCEPT FOR THE LOW-HEPATOTOXIC DOSES OF NITROSAMINE, RESULTED IN A MARKED AND PERSISTENT IMMUNOSUPPRESSION OF CELLULAR AND HUMORAL RESPONSES IN CD-1 MICE. IN CONCLUSION, CHRONIC EXPOSURE TO THE HEPATOTOXIC (ASCITE-INDUCING) DOSES OF NDMA SUPPRESSED HUMORAL AND CELLULAR IMMUNITY. THE PERSISTENT IMMUNOSUPPRESSION COULD BE REVERSED AFTER THE REMOVAL OF NDMA FROM THE DRINKING WATER. ALTHOUGH NO DIRECT NDMA-RELATED CANCER WAS REPORTED IN HUMANS, OUR DATA POINT TO A POTENTIAL EPIGENETIC CARCINOGENICITY OF NITROSAMINES DUE TO CHRONIC IMMUNOSUPPRESSION. 1992 10 3198 27 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES. 2018 11 11 27 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING. 2015 12 452 24 APPLICATION OF THE KEY CHARACTERISTICS OF CARCINOGENS TO PER AND POLYFLUOROALKYL SUBSTANCES. PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) CONSTITUTE A LARGE CLASS OF ENVIRONMENTALLY PERSISTENT CHEMICALS USED IN INDUSTRIAL AND CONSUMER PRODUCTS. HUMAN EXPOSURE TO PFAS IS EXTENSIVE, AND PFAS CONTAMINATION HAS BEEN REPORTED IN DRINKING WATER AND FOOD SUPPLIES AS WELL AS IN THE SERUM OF NEARLY ALL PEOPLE. THE MOST WELL-STUDIED MEMBER OF THE PFAS CLASS, PERFLUOROOCTANOIC ACID (PFOA), INDUCES TUMORS IN ANIMAL BIOASSAYS AND HAS BEEN ASSOCIATED WITH ELEVATED RISK OF CANCER IN HUMAN POPULATIONS. GENX, ONE OF THE PFOA REPLACEMENT CHEMICALS, INDUCES TUMORS IN ANIMAL BIOASSAYS AS WELL. USING THE KEY CHARACTERISTICS OF CARCINOGENS FRAMEWORK FOR CANCER HAZARD IDENTIFICATION, WE CONSIDERED THE EXISTING EPIDEMIOLOGICAL, TOXICOLOGICAL AND MECHANISTIC DATA FOR 26 DIFFERENT PFAS. WE FOUND STRONG EVIDENCE THAT MULTIPLE PFAS INDUCE OXIDATIVE STRESS, ARE IMMUNOSUPPRESSIVE, AND MODULATE RECEPTOR-MEDIATED EFFECTS. WE ALSO FOUND SUGGESTIVE EVIDENCE INDICATING THAT SOME PFAS CAN INDUCE EPIGENETIC ALTERATIONS AND INFLUENCE CELL PROLIFERATION. EXPERIMENTAL DATA INDICATE THAT PFAS ARE NOT GENOTOXIC AND GENERALLY DO NOT UNDERGO METABOLIC ACTIVATION. DATA ARE CURRENTLY INSUFFICIENT TO ASSESS WHETHER ANY PFAS PROMOTE CHRONIC INFLAMMATION, CELLULAR IMMORTALIZATION OR ALTER DNA REPAIR. WHILE MORE RESEARCH IS NEEDED TO ADDRESS DATA GAPS, EVIDENCE EXISTS THAT SEVERAL PFAS EXHIBIT ONE OR MORE OF THE KEY CHARACTERISTICS OF CARCINOGENS. 2020 13 6351 24 THE ROLE OF EPIGENOMICS IN MAPPING POTENTIAL PRECURSORS FOR FOOT AND ANKLE TENDINOPATHY: A SYSTEMATIC REVIEW. TENDINOPATHY OF THE FOOT AND ANKLE IS A COMMON CLINICAL PROBLEM FOR WHICH THE EXACT ETIOLOGY IS POORLY UNDERSTOOD. THE FIELD OF EPIGENETICS HAS BEEN A RECENT FOCUS OF THIS INVESTIGATION. THE PURPOSE OF THIS ARTICLE WAS TO REVIEW THE GENOMIC ADVANCES IN FOOT AND ANKLE TENDINOPATHY THAT COULD POTENTIALLY BE USED TO STRATIFY DISEASE RISK AND CREATE PREVENTATIVE OR THERAPEUTIC AGENTS. A MULTI-DATABASE SEARCH OF PUBMED, COCHRANE, GOOGLE SCHOLAR, AND CLINICALTRIALS.GOV FROM JANUARY 1, 2000 TO JULY 1, 2022 WAS PERFORMED. A TOTAL OF 18 ARTICLES MET INCLUSION AND EXCLUSION CRITERIA FOR THIS REVIEW. THE MAJORITY OF SUCH RESEARCH UTILIZED CASE-CONTROL CANDIDATE GENE ASSOCIATION TO IDENTIFY DIFFERENT GENETIC RISK FACTORS ASSOCIATED WITH CHRONIC TENDINOPATHY. POLYMORPHISMS IN COLLAGEN GENES COL5A1, COL27A1, AND COL1A1 WERE NOTED AT A SIGNIFICANTLY HIGHER FREQUENCY IN ACHILLES TENDINOPATHY VERSUS CONTROL GROUPS. OTHER ALLELIC VARIATIONS THAT WERE OBSERVED AT AN INCREASED INCIDENCE IN ACHILLES TENDINOPATHY WERE TNC AND CASP8. THE EXTRACELLULAR MATRIX (ECM) DEMONSTRATED MACROSCOPIC CHANGES IN ACHILLES TENDINOPATHY, INCLUDING AN INCREASE IN AGGRECAN AND BIGLYCAN MRNA EXPRESSION, AND INCREASED EXPRESSION OF MULTIPLE MATRIX METALLOPROTEINASES. CYTOKINE EXPRESSION WAS ALSO INFLUENCED IN PATHOLOGY AND ABERRANTLY DEMONSTRATED DYNAMIC RESPONSE TO MECHANICAL LOAD. THE PATHOLOGIC ACCUMULATION OF ECM PROTEINS AND CYTOKINE EXPRESSION ALTERS THE ADAPTIVE RESPONSE NORMAL TENDON HAS TO PHYSIOLOGIC STRESS, FURTHER PROPAGATING THE RISK FOR TENDINOPATHY. BY IDENTIFYING AND UNDERSTANDING THE EPIGENETIC MEDIATORS THAT LEAD TO TENDINOPATHY, THERAPEUTIC AGENTS CAN BE DEVELOPED TO TARGET THE EXACT UNDERLYING ETIOLOGY AND MINIMIZE SIDE EFFECTS.LEVEL OF EVIDENCE: LEVEL IV: SYSTEMATIC REVIEW OF LEVEL II-IV STUDIES. 2023 14 6731 24 WATERPIPE SMOKING INDUCES EPIGENETIC CHANGES IN THE SMALL AIRWAY EPITHELIUM. WATERPIPE (ALSO CALLED HOOKAH, SHISHA, OR NARGHILE) SMOKING IS A COMMON FORM OF TOBACCO USE IN THE MIDDLE EAST. ITS USE IS BECOMING MORE PREVALENT IN WESTERN SOCIETIES, ESPECIALLY AMONG YOUNG ADULTS AS AN ALTERNATIVE FORM OF TOBACCO USE TO TRADITIONAL CIGARETTES. WHILE THE RISK TO CIGARETTE SMOKING IS WELL DOCUMENTED, THE RISK TO WATERPIPE SMOKING IS NOT WELL DEFINED WITH LIMITED INFORMATION ON ITS HEALTH IMPACT AT THE EPIDEMIOLOGIC, CLINICAL AND BIOLOGIC LEVELS WITH RESPECT TO LUNG DISEASE. BASED ON THE KNOWLEDGE THAT AIRWAY EPITHELIAL CELL DNA METHYLATION IS MODIFIED IN RESPONSE TO CIGARETTE SMOKE AND IN CIGARETTE SMOKING-RELATED LUNG DISEASES, WE ASSESSED THE IMPACT OF LIGHT-USE WATERPIPE SMOKING ON DNA METHYLATION OF THE SMALL AIRWAY EPITHELIUM (SAE) AND WHETHER CHANGES IN METHYLATION WERE LINKED TO THE TRANSCRIPTIONAL OUTPUT OF THE CELLS. SMALL AIRWAY EPITHELIUM WAS OBTAINED FROM 7 NONSMOKERS AND 7 LIGHT-USE (2.6 +/- 1.7 SESSIONS/WK) WATERPIPE-ONLY SMOKERS. GENOME-WIDE COMPARISON OF SAE DNA METHYLATION OF WATERPIPE SMOKERS TO NONSMOKERS IDENTIFIED 727 PROBESETS DIFFERENTIALLY METHYLATED (FOLD-CHANGE >1.5, P<0.05) REPRESENTING 673 UNIQUE GENES. DOMINANT PATHWAYS ASSOCIATED WITH THESE EPIGENETIC CHANGES INCLUDE THOSE LINKED TO G-PROTEIN COUPLED RECEPTOR SIGNALING, ARYL HYDROCARBON RECEPTOR SIGNALING AND XENOBIOTIC METABOLISM SIGNALING, ALL OF WHICH HAVE BEEN ASSOCIATED WITH CIGARETTE SMOKING AND LUNG DISEASE. OF THE GENES DIFFERENTIALLY METHYLATED, 11.3% EXHIBITED A CORRESPONDING SIGNIFICANT (P<0.05) CHANGE IN GENE EXPRESSION WITH ENRICHMENT IN PATHWAYS RELATED TO REGULATION OF MRNA TRANSLATION AND PROTEIN SYNTHESIS (EIF2 SIGNALING AND REGULATION OF EIF4 AND P70S6K SIGNALING). OVERALL, THESE DATA DEMONSTRATE THAT LIGHT-USE WATERPIPE SMOKING IS ASSOCIATED WITH EPIGENETIC CHANGES AND RELATED TRANSCRIPTIONAL MODIFICATIONS IN THE SAE, THE CELL POPULATION DEMONSTRATING THE EARLIEST PATHOLOGIC ABNORMALITIES ASSOCIATED WITH CHRONIC CIGARETTE SMOKING. 2017 15 1121 18 COMPARISON OF EPIGENETIC PROFILES OF HUMAN ORAL EPITHELIAL CELLS FROM HIV-POSITIVE (ON HAART) AND HIV-NEGATIVE SUBJECTS. HIV-INFECTED SUBJECTS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) ARE SUSCEPTIBLE TO COMORBID MICROBIAL INFECTIONS IN THE ORAL CAVITY. WE OBSERVED THAT PRIMARY ORAL EPITHELIAL CELLS (POECS) ISOLATED FROM HIV+ SUBJECTS ON HAART GROW MORE SLOWLY AND ARE LESS INNATE IMMUNE RESPONSIVE TO MICROBIAL CHALLENGE WHEN COMPARED WITH POECS FROM NORMAL SUBJECTS. THESE ABERRANT CELLS ALSO DEMONSTRATE EPIGENETIC DIFFERENCES THAT INCLUDE REDUCTION IN HISTONE DEACETYLASE 1 (HDAC-1) LEVELS AND REDUCED TOTAL DNA METHYLTRANSFERASE (DNMT) ACTIVITY SPECIFIC TO ENZYMES DNMT1 AND DNMT3A. THE DNMT ACTIVITY CORRELATES WELL WITH GLOBAL DNA METHYLATION, INDICATING THAT ABERRANT DNMT ACTIVITY IN HIV+ (ON HAART) POECS LEADS TO AN ABERRANTLY METHYLATED EPITHELIAL CELL PHENOTYPE. OVERALL, OUR RESULTS LEAD US TO HYPOTHESIZE THAT, IN PATIENTS WITH CHRONIC HIV INFECTION ON HAART, EPIGENETIC CHANGES IN KEY GENES RESULT IN INCREASED VULNERABILITY TO MICROBIAL INFECTION IN THE ORAL CAVITY. 2013 16 2896 22 GASTRIC ENTEROCHROMAFFIN-LIKE CELL HYPERPLASIA AND NEOPLASIA IN THE RAT: AN INDIRECT EFFECT OF THE HISTAMINE H2-RECEPTOR ANTAGONIST, BL-6341. ORAL ADMINISTRATION OF BL-6341 HYDROCHLORIDE, A LONG-ACTING HISTAMINE H2-RECEPTOR ANTAGONIST, TO RATS FOR 2 YEARS AT DOSES OF 10, 55 OR 300 MG/KG/DAY RESULTED IN SEVERAL CHANGES IN THE FUNDIC (OXYNTIC) MUCOSA OF THE GLANDULAR STOMACH. THE MOST SIGNIFICANT ALTERATION WAS A PROLIFERATION OF ARGYROPHIL ENDOCRINE CELLS THAT WAS DEMONSTRATED TO BE ENTEROCHROMAFFIN-LIKE (ECL) CELLS. THE ECL CELL PROLIFERATION CONSISTED OF A CONTINUUM OF CHANGES INVOLVING DIFFUSE HYPERPLASIA, FOCAL ADENOMATOUS HYPERPLASIA, AND CARCINOID TUMOR FORMATION AT THE HIGHEST DOSE LEVEL OF 300 MG/KG. AT 55 MG/KG ONLY ECL CELL HYPERPLASIA OCCURRED, AND AT THE LOW DOSE OF 10 MG/KG THERE WERE NO REMARKABLE PROLIFERATIVE CHANGES. THE REFERENCE COMPOUND, CIMETIDINE (950 MG/KG), PRODUCED A DEGREE OF ECL CELL PROLIFERATION THAT WAS SLIGHTLY LESS, BUT NOT SIGNIFICANTLY DIFFERENT THAN, THAT OBSERVED WITH 55 MG/KG OF BL-6341. DOSE-RELATED ELEVATIONS OF SERUM GASTRIN WERE OBSERVED WITH BL-6341, WHILE CIMETIDINE PRODUCED HYPERGASTRINEMIA THAT WAS GENERALLY INTERMEDIATE BETWEEN THAT PRODUCED BY THE MIDDLE AND LOW DOSES OF BL-6341. THE HYPERGASTRINEMIA RESULTED FROM THE PHARMACOLOGIC INHIBITION OF ACID SECRETION, WHICH IS THE NEGATIVE FEEDBACK MECHANISM CONTROLLING THE PRODUCTION OF GASTRIN. ONLY THE 300 MG/KG DOSE OF BL-6341 PRODUCED A SIGNIFICANT, SUSTAINED (24 HOURS) HYPERGASTRINEMIA AND CARCINOID TUMORS. THE CHRONIC, SUSTAINED HYPERGASTRINEMIA WAS CONSIDERED TO BE THE PRIMARY CAUSE OF THE ECL CELL CARCINOID NEOPLASIA. ALL GENETIC TOXICOLOGY TESTS PERFORMED WITH BL-6341 WERE NEGATIVE. IT WAS CONCLUDED THAT THE DEMONSTRATED HYPERGASTRINEMIA REPRESENTS AN INDIRECT, HORMONAL, EPIGENETIC MECHANISM OF TUMORIGENESIS. 1988 17 6464 21 TISSUE MISREPAIR HYPOTHESIS FOR RADIATION CARCINOGENESIS. DOSE-RESPONSE CURVES FOR CHRONIC LEUKEMIA IN A-BOMB SURVIVORS AND LIVER TUMORS IN PATIENTS GIVEN THOROTRAST (COLLOIDAL THORIUM DIOXIDE) SHOW LARGE THRESHOLD EFFECTS. THE EXISTENCE OF THESE THRESHOLD EFFECTS CAN BE EXPLAINED BY THE FOLLOWING HYPOTHESIS. A HIGH DOSE OF RADIATION CAUSES A PERSISTENT WOUND IN A CELL-RENEWABLE TISSUE. DISORDER OF THE INJURED CELL SOCIETY PARTLY FREES THE COMPONENT CELLS FROM TERRITORIAL RESTRAINTS ON THEIR PROLIFERATION, ENABLING THEM TO CONTINUE DEVELOPMENT OF THEIR CELLULAR FUNCTIONS TOWARD ADVANCED AUTONOMY. THIS PROGRESSION MIGHT BE ACHIEVED BY CONTINUED EPIGENETIC AND GENETIC CHANGES AS A RESULT OF OCCASIONAL ERRORS IN THE OTHERWISE CONCERTED HEALING ACTION OF VARIOUS ENDOGENOUS FACTORS RECRUITED FOR TISSUE REPAIR. CARCINOGENESIS IS NOT SIMPLY A SINGLE-CELL PROBLEM BUT A CELL-SOCIETY PROBLEM. THEREFORE, IT IS NOT WARRANTED TO ESTIMATE RISK AT LOW DOSES BY LINEAR EXTRAPOLATION FROM CANCER DATA AT HIGH DOSES WITHOUT KNOWLEDGE OF THE MECHANISM OF RADIATION CARCINOGENESIS. 1991 18 1265 29 CYSTINURIA POORLY RESPONDING TO TREATMENT - THE RISK OF CHRONIC KIDNEY DISEASE. CYSTINURIA IS THE GENETIC CONDITION FOR THE INCREASED EXCRETION OF CYSTINE IN THE URINE. PATIENTS MAINLY SUFFER FROM AFFLICTIONS RELATED TO THE PRESENCE AND PASSAGE OF KIDNEY STONES. THE CURRENTLY AVAILABLE TREATMENT METHODS INCLUDE CONSERVATIVE TREATMENT BASED ON INCREASED FLUID INTAKE, APPROPRIATE DIET, MEDICATIONS AND UROLOGICAL PROCEDURES. THE CAUSAL TREATMENT HAS NOT YET BEEN INVENTED. A CASE REPORT: A PATIENT CASE WAS DESCRIBED WHOSE FIRST SYMPTOMATIC KIDNEY STONES APPEARED AFTER THE SECOND YEAR OF LIFE. URINARY CYSTINE EXCRETION WAS SIGNIFICANTLY INCREASED - 25,431 MUMOL/1G CREATININE (NORM: 167-333 MUMOL/1G CREATININE), WHICH WAS ALSO SHOWN, BUT LOWER, IN BOTH PARENTS OF THE PATIENT. DESPITE THE EARLY INITIATION OF THERAPY INCLUDING LOW SODIUM DIET, ABUNDANT HYDRATION, ALKALIZATION, CAPTOPRIL AND COMPLIANCE WITH STRINGENT RESTRICTIONS, THE LEVEL OF URINARY CYSTINE EXCRETION WAS STILL NOT WITHIN THE NORMAL RANGE. THERE HAVE BEEN MANY MODIFICATIONS TO THE THERAPY AND DOSE INCREASES OF DRUGS, BUT WITHOUT VISIBLE RESULTS. THE PATIENT UNDERWENT SEVERAL UROLOGICAL PROCEDURES, INCLUDING: ESWL (EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY), URSL (URETEROSCOPIC LITHOTRIPSY), PCNL (PERCUTANEOUS NEPHROLITHOTOMY) AND OPEN SURGERY TO REMOVE CYSTINE DEPOSITS THAT WERE STILL PRODUCED IN THE KIDNEYS. IN ADDITION, FOR MANY YEARS THE DISEASE WAS COMPLICATED BY RECURRENT URINARY TRACT INFECTIONS, UNDERWEIGHT AND LESIONS LIKE EPITHELIAL METAPLASIA IN THE BLADDER. RENAL PARAMETERS WERE REPEATEDLY EXAMINED. ELEVATED RESULTS SUCH AS: SERUM CREATININE 0.9 MG/DL, CYSTATIN C CONCENTRATION 1.10 MG/L, ALBUMIN-CREATININE INDEX 0.197, CREATININE CLEARANCE 50.7 ML/MIN /1.73 M2 AND EGFR 73 ML/MIN/1.73 M2 ALLOWED FOR THE DIAGNOSIS OF CHRONIC KIDNEY DISEASE BEFORE THE AGE OF 18. AFTER MANY YEARS OF CONSERVATIVE TREATMENT, ONLY THE INTRODUCTION OF THIOPRONINE, STILL LITTLE KNOWN IN POLAND, REDUCED THE LEVEL OF CYSTINE EXCRETED IN THE URINE. THE INCLUSION OF THE DRUG REDUCED THE TENDENCY TO PRODUCE KIDNEY STONES, WHICH ALLOWED TO INHIBIT THE PROGRESSION OF RENAL FAILURE. CONCLUSIONS: DESPITE MANY YEARS OF RESEARCH AND MODERN DRUGS, CYSTINURIA IS STILL A DISEASE WITH WHICH PATIENTS ARE ASSOCIATED FOR THE REST OF THEIR LIVES. THE ONGOING RESEARCH, ALONG WITH ATTEMPTS TO UNDERSTAND THE GENETIC AND EPIGENETIC MECHANISMS RESPONSIBLE FOR THE EMERGENCE OF MUTATIONS IN THE MAIN GENES CAUSING THE DISEASE AND THE COURSE OF THE DISEASE, GIVES HOPE FOR FINDING A METHOD OF CAUSAL TREATMENT FOR CYSTINURIA. 2021 19 3390 24 HOPX PLAYS A CRITICAL ROLE IN ANTIRETROVIRAL DRUGS INDUCED EPIGENETIC MODIFICATION AND CARDIAC HYPERTROPHY. PEOPLE LIVING WITH HIV (PLWH) HAVE TO TAKE AN ANTIRETROVIRAL THERAPY (ART) FOR LIFE AND SHOW NONCOMMUNICABLE ILLNESSES SUCH AS CHRONIC INFLAMMATION, IMMUNE ACTIVATION, AND MULTIORGAN DYSREGULATION. RECENT STUDIES SUGGEST THAT LONG-TERM USE OF ART INDUCES COMORBID CONDITIONS AND IS ONE OF THE LEADING CAUSES OF HEART FAILURE IN PLWH. HOWEVER, THE MOLECULAR MECHANISM OF ANTIRETROVIRAL DRUGS (ARVS) INDUCED HEART FAILURE IS UNCLEAR. TO DETERMINE THE MECHANISM OF ARVS INDUCED CARDIAC DYSFUNCTION, WE PERFORMED GLOBAL TRANSCRIPTOMIC PROFILING OF ARVS TREATED NEONATAL RAT VENTRICULAR CARDIOMYOCYTES IN CULTURE. DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED BY RNA-SEQUENCING. OUR DATA SHOW THAT ARVS TREATMENT CAUSES UPREGULATION OF SEVERAL BIOLOGICAL FUNCTIONS ASSOCIATED WITH CARDIOTOXICITY, HYPERTROPHY, AND HEART FAILURE. GLOBAL GENE EXPRESSION DATA WERE VALIDATED IN CARDIAC TISSUE ISOLATED FROM HIV PATIENTS HAVING A HISTORY OF ART. INTERESTINGLY, WE FOUND THAT HOMEODOMAIN-ONLY PROTEIN HOMEOBOX (HOPX) EXPRESSION WAS SIGNIFICANTLY INCREASED IN CARDIOMYOCYTES TREATED WITH ARVS AND IN THE HEART TISSUE OF HIV PATIENTS. FURTHERMORE, WE FOUND THAT HOPX PLAYS A CRUCIAL ROLE IN ARVS MEDIATED CELLULAR HYPERTROPHY. MECHANISTICALLY, WE FOUND THAT HOPX PLAYS A CRITICAL ROLE IN EPIGENETIC REGULATION, THROUGH DEACETYLATION OF HISTONE, WHILE THE HDAC INHIBITOR, TRICHOSTATIN A, CAN RESTORE THE ACETYLATION LEVEL OF HISTONE 3 IN THE PRESENCE OF ARVS. 2021 20 5353 28 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED. 2019