1 5435 148 RELATIVE ROLE OF METHYLATOR AND TUMOR SUPPRESSOR PATHWAYS IN ULCERATIVE COLITIS-ASSOCIATED COLON CANCER. BACKGROUND: CHRONIC ULCERATIVE COLITIS (UC) IS ASSOCIATED WITH AN INCREASED COLORECTAL CANCER RISK WHICH MAY BE SECONDARY TO REPETITIVE MUCOSAL INJURY. BOTH EPIGENETIC METHYLATION AND THE CLASSIC ADENOMA-TO-CARCINOMA SEQUENCE HAVE BEEN IMPLICATED IN THIS MALIGNANT TRANSFORMATION, BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN POORLY DEFINED. THIS STUDY COMPARES THE MOLECULAR CHARACTERISTICS OF COLITIS-ASSOCIATED AND COMMON COLORECTAL CANCERS. METHODS: NINETEEN PATIENTS WITH COLORECTAL ADENOCARCINOMAS ARISING WITHIN UC WERE MATCHED FOR AGE AND CANCER SITE WITH 54 PATIENTS WITH SPORADIC ADENOCARCINOMAS. TUMOR TISSUE WAS EXAMINED FOR BRAF MUTATIONS, CPG ISLAND METHYLATOR PHENOTYPE (CIMP), AND MLH1 PROMOTER METHYLATION. MUTATIONS OF KRAS AND P53 WERE ASSESSED BY SEQUENCING. RESULTS: PATIENT DEMOGRAPHICS WERE SIMILAR FOR THE TWO GROUPS. CIMP WAS OBSERVED IN 22% OF SPORADIC COLORECTAL CANCERS AND IN 5% OF UC CANCERS (P = 0.162). RATES OF BRAF MUTATION (4% VS 5%, P = 1.0), MLH1 METHYLATION (9% VERSUS 5%, P = 0.682), AND KRAS MUTATIONS (24% VERSUS 32%, P = 0.552) WERE SIMILAR BETWEEN THE GROUPS. HOWEVER, COLITIS-ASSOCIATED COLORECTAL CANCERS WERE MORE LIKELY TO HAVE A P53 MUTATION COMPARED TO SPORADIC ADENOCARCINOMAS (95% VERSUS 53%, P = 0.001). THE DOMINANT MUTATION FOR COLITIS-ASSOCIATED CANCERS WAS A MUTATION IN CODON 4, REPRESENTING HALF OF THE MUTATIONS. FURTHERMORE, COLITIS-ASSOCIATED CANCERS HAD A HIGHER RATE OF MUTATION IN CODON 8 (48% VERSUS 6%, P < 0.001) THAN SPORADIC COUNTERPARTS. CONCLUSIONS: UNLIKE OTHER INFLAMMATORY GASTROINTESTINAL CANCERS, COLITIS-ASSOCIATED COLORECTAL CANCERS DO NOT PREFERENTIALLY ARISE VIA A METHYLATOR PATHWAY WHEN COMPARED TO SPORADIC COLORECTAL CANCERS. CHROMOSOMAL INSTABILITY REMAINS AN IMPORTANT ETIOLOGY, BUT WITH A UNIQUE P53 FREQUENCY AND MUTATION PATTERN. 2011 2 6817 36 [FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY: REPORT OF SEVEN PATIENTS]. BACKGROUND: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY IS THE THIRD MOST COMMON MUSCULAR DYSTROPHY WITH AN ESTIMATED PREVALENCE OF 1 PER 20.000 AND A NORMAL LIFE EXPECTANCY IN THE MAJORITY OF PATIENTS. HOWEVER, APPROXIMATELY 15% OF PATIENTS BECOME WHEELCHAIR BOUND IN THE COURSE OF THEIR LIFE. IT IS A HEREDITARY AUTOSOMAL DOMINANT DISEASE WITH HIGH (95%) PENETRANCE BY THE AGE OF 20, BUT WITH VARIABLE DEGREE OF PHENOTYPIC EXPRESSION EVEN IN THE SAME FAMILY GROUP. SYMPTOMS FREQUENTLY START IN THE SECOND DECADE OF LIFE, WITH FACIAL AND SCAPULAR WEAKNESS. AIM: TO REPORT THE CLINICAL FEATURES OF SEVEN PATIENTS WITH THE DISEASE, SEEN AT A PUBLIC HOSPITAL. MATERIAL AND METHODS: ANALYSIS OF SEVEN PATIENTS WITH GENETIC STUDY SEEN IN A PUBLIC HOSPITAL IN SANTIAGO. RESULTS: THE AGE OF PATIENTS FLUCTUATED FROM 18 TO 61 YEARS AND FOUR WERE FEMALES. THE MEAN AGE AT ONSET OF SYMPTOMS WAS 29 YEARS AND FOUR HAD A FAMILY HISTORY OF THE DISEASE. THE USUAL PRESENTING COMPLAINT WAS ARM OR SHOULDER ASYMMETRIC WEAKNESS. FOUR PATIENTS HAD BONE PAIN. FACIAL INVOLVEMENT WAS PRESENT IN FOUR. A GENETIC STUDY WAS DONE IN FIVE PATIENTS, THE OTHER TWO PATIENTS WERE RELATIVES, CONFIRMING THE CONTRACTION OR LOWER NUMBER OF REPETITIONS IN D4Z4 REGION. AFTER 12 YEARS OF FOLLOW UP ONLY 2 PATIENTS OLDER THAN 60 YEARS CANNOT WORK AND ONE FEMALE PATIENTS IS IN A SEMI DEPENDENT STATE AT THE AGE OF 30. CONCLUSIONS: THE CLINICAL WORKUP IN THE DIAGNOSIS AND THE TIMELY INDICATION OF GENETIC STUDIES ARE HIGHLIGHTED, TO AVOID UNNECESSARY AND INVASIVE PROCEDURES. THE VARIABILITY IN THE PHENOTYPIC EXPRESSION IN A SIMILAR GENETIC DEFECT IS DISCUSSED AND THE GENETIC OR EPIGENETIC MECHANISMS OF THIS MUSCULAR DYSTROPHY ARE DESCRIBED. 2015 3 4099 29 MBD2 ENABLES TUMOURIGENESIS WITHIN THE INTESTINE WHILE PREVENTING TUMOUR-PROMOTING INFLAMMATION. EPIGENETIC REGULATION PLAYS A KEY ROLE IN THE LINK BETWEEN INFLAMMATION AND CANCER. HERE WE EXAMINE MBD2, WHICH MEDIATES EPIGENETIC TRANSCRIPTIONAL SILENCING BY BINDING TO METHYLATED DNA. IN SEPARATE STUDIES THE MBD2(-/-) MOUSE HAS BEEN SHOWN (1) TO BE RESISTANT TO INTESTINAL TUMOURIGENESIS AND (2) TO HAVE AN ENHANCED INFLAMMATORY/IMMUNE RESPONSE, OBSERVATIONS THAT ARE INCONSISTENT WITH THE LINKS BETWEEN INFLAMMATION AND CANCER. TO CLARIFY ITS ROLE IN TUMOURIGENESIS AND INFLAMMATION, WE USED CONSTITUTIVE AND CONDITIONAL MODELS OF MBD2 DELETION TO EXPLORE ITS EPITHELIAL AND NON-EPITHELIAL ROLES IN THE INTESTINE. USING A CONDITIONAL MODEL, WE FOUND THAT SUPPRESSION OF INTESTINAL TUMOURIGENESIS IS DUE PRIMARILY TO THE ABSENCE OF MBD2 WITHIN THE EPITHELIA. NEXT, WE DEMONSTRATED, USING THE DSS COLITIS MODEL, THAT NON-EPITHELIAL ROLES OF MBD2 ARE KEY IN PREVENTING THE TRANSITION FROM ACUTE TO TUMOUR-PROMOTING CHRONIC INFLAMMATION. COMBINING MODELS REVEALED THAT PRIOR TO INFLAMMATION THE ALTERED MBD2(-/-) IMMUNE RESPONSE PLAYS A ROLE IN INTESTINAL TUMOUR SUPPRESSION. HOWEVER, FOLLOWING INFLAMMATION THE INTESTINE CONVERTS FROM TUMOUR SUPPRESSIVE TO TUMOUR PROMOTING. TO SUMMARISE, IN THE INTESTINE THE NORMAL FUNCTION OF MBD2 IS EXPLOITED BY CANCER CELLS TO ENABLE TUMOURIGENESIS, WHILE IN THE IMMUNE SYSTEM IT PLAYS A KEY ROLE IN PREVENTING TUMOUR-ENABLING INFLAMMATION. WHICH ROLE IS DOMINANT DEPENDS ON THE INFLAMMATION STATUS OF THE INTESTINE. AS ENVIRONMENTAL INTERACTIONS WITHIN THE INTESTINE CAN ALTER DNA METHYLATION PATTERNS, WE PROPOSE THAT MBD2 PLAYS A KEY ROLE IN DETERMINING WHETHER THESE INTERACTIONS ARE ANTI- OR PRO-TUMOURIGENIC AND THIS MAKES IT A USEFUL NEW EPIGENETIC MODEL FOR INFLAMMATION-ASSOCIATED CARCINOGENESIS. (C) 2018 THE AUTHORS. THE JOURNAL OF PATHOLOGY PUBLISHED BY JOHN WILEY & SONS LTD ON BEHALF OF PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. 2018 4 852 39 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA. 2020 5 6418 34 THE TEMPORAL EXPRESSION OF CIRCULATING MICRORNAS AFTER ACUTE EXPERIMENTAL PAIN IN HUMANS. BACKGROUND: MICRORNAS (MIRNAS) CAN MODULATE SEVERAL BIOLOGICAL SYSTEMS, INCLUDING THE PAIN SYSTEM. THIS STUDY AIMED TO EVALUATE THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY VOLUNTEERS AS A MARKER FOR EPIGENETIC CHANGES BEFORE AND AFTER AN ACUTE, EXPERIMENTAL, PAIN PROVOCATION BY INTRAMUSCULAR HYPERTONIC SALINE INJECTION. METHODS: TWENTY VOLUNTEERS WERE RANDOMLY ALLOCATED INTO TWO GROUPS AND RECEIVED EITHER HYPERTONIC (PAIN) OR ISOTONIC (CONTROL) SALINE INJECTION IN THE FIRST DORSAL INTEROSSEOUS MUSCLE OF THEIR DOMINANT HAND. PAIN INTENSITY WAS CONTINUOUSLY RECORDED FOR 20 MINUTES AFTER INJECTION ON A VAS SCALE FROM 0 TO 100 (0 INDICATES NO PAIN AND 100 THE WORST IMAGINABLE PAIN). BLOOD SAMPLES WERE TAKEN AT BASELINE, 30 MINUTES, 3 HOURS, AND 24 HOURS POST-INJECTION, AND PLASMA WAS SEPARATED. MIRNA EXTRACTS WERE USED FOR RNA SEQUENCING WITH THE ILLUMINA NEXTSEQ PLATFORM. MIRNA TRANSCRIPTS WERE COMPARED BETWEEN THE PAIN AND THE NO-PAIN, CONTROL GROUP AT EVERY TIME POINT. SIGNIFICANT DIFFERENCES WERE CONSIDERED WHEN FOLDS WERE >2 AND THE FALSE DISCOVERY RATE WAS P < 0.05. RESULTS: AFTER 30 MINUTES, 4 MIRNAS WERE SIGNIFICANTLY ALTERED IN THE PAIN GROUP COMPARED TO CONTROLS, WHICH INCREASED TO 24 AFTER 3 HOURS AND TO 42 AFTER 24 HOURS FROM BASELINE (P < 0.0001). TWO MIRNAS WERE CONSISTENTLY UPREGULATED THROUGHOUT THE EXPERIMENT. ENRICHMENT ANALYSIS SHOWED SIGNIFICANT MIRNAS INVOLVED IN BRAIN PERCEPTION OF PAIN, BRAIN SIGNALLING AND RESPONSE TO STIMULI. CONCLUSIONS: THIS EXPLORATORY STUDY IS THE FIRST TO REPORT ON THE TEMPORAL EXPRESSION OF CIRCULATING MIRNAS AFTER AN ACUTE, HUMAN EXPERIMENTAL MUSCLE PAIN MODEL. SIGNIFICANCE: THIS EXPLORATORY STUDY EVALUATED THE TEMPORAL PROFILE OF CIRCULATING MIRNAS IN THE PLASMA OF HEALTHY SUBJECTS AFTER ACUTE EXPERIMENTAL PAIN. SEVERAL MIRNAS WERE ALTERED IN SUBJECTS AT THE TIMES OF FOLLOW-UP AFTER THE ACUTE PAIN MODEL WHEN COMPARED TO CONTROLS. MIRNAS PREVIOUSLY ASSOCIATED WITH PAIN PROCESSES WERE ALTERED IN THE PAIN GROUP. OUR RESULTS, BY SHOWING THE FAST AND PROLONGED MODIFICATIONS OF MIRNA ELICITED BY THE ACUTE EXPERIMENTAL PAIN MODEL, ADD NEW PERSPECTIVES TO THE TOPIC OF EPIGENETICS AND PAIN. 2023 6 3478 24 IDENTIFICATION OF ADPKD-RELATED GENES AND PATHWAYS IN CELLS OVEREXPRESSING PKD2. CONSISTENT WITH THE GENE DOSAGE EFFECT HYPOTHESIS, RENAL CYSTS CAN ARISE IN TRANSGENIC MURINE MODELS OVEREXPRESSING EITHER PKD1 OR PKD2, WHICH ARE CAUSAL GENES FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD). TO DETERMINE WHETHER PKD GENE OVEREXPRESSION IS A UNIVERSAL MECHANISM DRIVING CYSTOGENESIS OR IS MERELY RESTRICTED TO RODENTS, OTHER ANIMAL MODELS ARE REQUIRED. PREVIOUSLY, WE FAILED TO OBSERVE ANY RENAL CYSTS IN A TRANSGENIC PORCINE MODEL OF PKD2 OVEREXPRESSION PARTIALLY DUE TO EPIGENETIC SILENCING OF THE TRANSGENE. THUS, TO EXPLORE THE FEASIBILITY OF PORCINE MODELS AND IDENTIFY POTENTIAL GENES/PATHWAYS AFFECTED IN ADPKD, LLC-PK1 CELLS WITH HIGH PKD2 EXPRESSION WERE GENERATED. MRNA SEQUENCING (RNA-SEQ) WAS PERFORMED, AND MYC, IER3, AND ADM WERE FOUND TO BE UPREGULATED GENES COMMON TO THE DIFFERENT PKD2 OVEREXPRESSION CELL MODELS. MYC IS A WELL-CHARACTERIZED FACTOR CONTRIBUTING TO CYSTOGENESIS, AND ADM IS A BIOMARKER FOR CHRONIC KIDNEY DISEASE. THUS, THESE GENES MIGHT BE INDICATORS OF DISEASE PROGRESSION. ADDITIONALLY, SOME ADPKD-ASSOCIATED PATHWAYS, E.G., THE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) PATHWAY, WERE ENRICHED IN THE CELLS. MOREOVER, GENE ONTOLOGY (GO) ANALYSIS DEMONSTRATED THAT PROLIFERATION, APOPTOSIS, AND CELL CYCLE REGULATION, WHICH ARE HALLMARKS OF ADPKD, WERE ALTERED. THEREFORE, OUR EXPERIMENT IDENTIFIED SOME BIOMARKERS OR INDICATORS OF ADPKD, INDICATING THAT HIGH PKD2 EXPRESSION WOULD LIKELY DRIVE CYSTOGENESIS IN FUTURE PORCINE MODELS. 2020 7 5742 26 SMOKING MOLECULAR DAMAGE IN BRONCHIAL EPITHELIUM. OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LUNG CANCER IS ADVANCING RAPIDLY WITH SEVERAL SPECIFIC GENES AND CHROMOSOMAL REGIONS BEING IDENTIFIED. LUNG CANCER APPEARS TO REQUIRE MANY MUTATIONS IN BOTH DOMINANT AND RECESSIVE ONCOGENES TO POSSESS MALIGNANT PHENOTYPES. SEVERAL GENETIC AND EPIGENETIC CHANGES ARE COMMON TO ALL LUNG CANCER HISTOLOGIC TYPES, WHILE OTHERS APPEAR TO BE CELL TYPE SPECIFIC. HOWEVER, SPECIFIC ROLES OF THE GENES UNDERGOING MUTATIONS AND THE ORDER OF CUMULATIVE MOLECULAR CHANGES THAT LEAD TO THE DEVELOPMENT OF EACH LUNG TUMOR HISTOLOGIC TYPE REMAIN TO BE FULLY ELUCIDATED. RECENT FINDINGS OF MOLECULAR ABNORMALITIES IN NORMAL APPEARING AND PRENEOPLASTIC BRONCHIAL EPITHELIUM FROM PATIENTS WITH LUNG CANCER AND CHRONIC SMOKERS SUGGEST THAT GENETIC CHANGES MAY SERVE AS BIOMARKERS FOR EARLY DIAGNOSIS, RISK ASSESSMENT AND MONITORING RESPONSE TO CHEMOPREVENTION. 2002 8 4856 28 OPTIMIZING RETROVIRAL GENE EXPRESSION FOR EFFECTIVE THERAPIES. WITH THEIR ABILITY TO INTEGRATE THEIR GENETIC MATERIAL INTO THE TARGET CELL GENOME, RETROVIRAL VECTORS (RV) OF BOTH THE GAMMA-RETROVIRAL (GAMMA-RV) AND LENTIVIRAL VECTOR (LV) CLASSES CURRENTLY REMAIN THE MOST EFFICIENT AND THUS THE SYSTEM OF CHOICE FOR ACHIEVING TRANSGENE RETENTION AND THEREFORE POTENTIALLY LONG-TERM EXPRESSION AND THERAPEUTIC BENEFIT. HOWEVER, GAMMA-RV AND LV INTEGRATION COMES AT A COST IN THAT TRANSCRIPTION UNITS WILL BE PRESENT WITHIN A NATIVE CHROMATIN ENVIRONMENT AND THUS BE SUBJECT TO EPIGENETIC EFFECTS (DNA METHYLATION, HISTONE MODIFICATIONS) THAT CAN NEGATIVELY IMPACT ON THEIR FUNCTION. INDEED, HIGHLY VARIABLE EXPRESSION AND SILENCING OF GAMMA-RV AND LV TRANSGENES ESPECIALLY RESULTING FROM PROMOTER DNA METHYLATION IS WELL DOCUMENTED AND WAS THE CAUSE OF THE FAILURE OF GENE THERAPY IN A CLINICAL TRIAL FOR X-LINKED CHRONIC GRANULOMATOUS DISEASE. THIS REVIEW WILL CRITICALLY EXPLORE THE USE OF DIFFERENT CLASSES OF GENETIC CONTROL ELEMENTS THAT CAN IN PRINCIPLE REDUCE VECTOR INSERTION SITE POSITION EFFECTS AND EPIGENETIC-MEDIATED SILENCING. THESE TRANSCRIPTIONAL REGULATORY ELEMENTS BROADLY DIVIDE THEMSELVES INTO EITHER THOSE WITH A CHROMATIN BOUNDARY OR BORDER FUNCTION (SCAFFOLD/MATRIX ATTACHMENT REGIONS, INSULATORS) OR THOSE WITH A DOMINANT CHROMATIN REMODELING AND TRANSCRIPTIONAL ACTIVATING CAPABILITY (LOCUS CONTROL REGIONS,, UBIQUITOUS CHROMATIN OPENING ELEMENTS). ALL THESE TYPES OF ELEMENTS HAVE THEIR STRENGTHS AND WEAKNESSES WITHIN THE CONSTRAINTS OF A GAMMA-RV AND LV BACKBONE, SHOWING VARYING DEGREES OF EFFICACY IN IMPROVING REPRODUCIBILITY AND STABILITY OF TRANSGENE FUNCTION. COMBINATIONS OF BOUNDARY AND CHROMATIN REMODELING; TRANSCRIPTIONAL ACTIVATING ELEMENTS, WHICH DO NOT IMPEDE VECTOR PRODUCTION; TRANSDUCTION EFFICIENCY; AND STABILITY ARE MOST LIKELY TO MEET THE REQUIREMENTS WITHIN A GENE THERAPY CONTEXT ESPECIALLY WHEN TARGETING A STEM CELL POPULATION. 2013 9 5221 25 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS. 2020 10 5329 26 PURINERGIC SIGNALING IN THE LUMEN OF A NORMAL NEPHRON AND IN REMODELED PKD ENCAPSULATED CYSTS. THE NEPHRON IS THE FUNCTIONAL UNIT OF THE KIDNEY. BLOOD AND PLASMA ARE CONTINUALLY FILTERED WITHIN THE GLOMERULI THAT BEGIN EACH NEPHRON. ADENOSINE 5' TRIPHOSPHATE (ATP) AND ITS METABOLITES ARE FREELY FILTERED BY EACH GLOMERULUS AND ENTER THE LUMEN OF EACH NEPHRON BEGINNING AT THE PROXIMAL CONVOLUTED TUBULE (PCT). FLOW RATE, OSMOLALITY, AND OTHER MECHANICAL OR CHEMICAL STIMULI FOR ATP SECRETION ARE PRESENT IN EACH NEPHRON SEGMENT. THESE ATP-RELEASE STIMULI ARE ALSO DIFFERENT IN EACH NEPHRON SEGMENT DUE TO WATER OR SALT PERMEABILITY OR IMPERMEABILITY ALONG DIFFERENT LUMINAL MEMBRANES OF THE CELLS THAT LINE EACH NEPHRON SEGMENT. EACH OF THE ABOVE STIMULI CAN TRIGGER ADDITIONAL ATP RELEASE INTO THE LUMEN OF A NEPHRON SEGMENT. EACH NEPHRON-LINING EPITHELIAL CELL IS A POTENTIAL SOURCE OF SECRETED ATP. TOGETHER WITH FILTERED ATP AND ITS METABOLITES DERIVED FROM THE GLOMERULUS, SECRETED ATP AND ADENOSINE DERIVED FROM CELLS ALONG THE NEPHRON ARE LIKELY THE PRINCIPAL TWO OF SEVERAL NUCLEOTIDE AND NUCLEOSIDE CANDIDATES FOR RENAL AUTOCRINE AND PARACRINE LIGANDS WITHIN THE TUBULAR FLUID OF THE NEPHRON. THIS MINIREVIEW DISCUSSES THE FIRST PRINCIPLES OF PURINERGIC SIGNALING AS THEY RELATE TO THE NEPHRON AND THE URINARY BLADDER. THE REVIEW DISCUSSES HOW THE LUMEN OF A RENAL TUBULE PRESENTS AN IDEAL PURINERGIC SIGNALING MICROENVIRONMENT. THE REVIEW ALSO ILLUSTRATES HOW REMODELED AND ENCAPSULATED CYSTS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) AND REMODELED PSEUDOCYSTS IN AUTOSOMAL RECESSIVE PKD (ARPKD) OF THE RENAL COLLECTING DUCT LIKELY CREATE AN EVEN MORE IDEAL MICROENVIRONMENT FOR PURINERGIC SIGNALING. ONCE TRAPPED IN THESE CLOSED MICROENVIRONMENTS, PURINERGIC SIGNALING BECOMES CHRONIC AND LIKELY PLAYS A SIGNIFICANT EPIGENETIC AND DETRIMENTAL ROLE IN THE SECONDARY PROGRESSION OF PKD, ONCE THE REMODELING OF THE RENAL TISSUE HAS BEGUN. IN PKD CYSTIC MICROENVIRONMENTS, WE ARGUE THAT NORMAL PURINERGIC SIGNALING WITHIN THE LUMEN OF THE NEPHRON PROVIDES DETRIMENTAL ACCELERATION OF ADPKD ONCE REMODELING IS COMPLETE. 2008 11 837 47 CHEMICALLY INDUCED RENAL TUBULE TUMORS IN THE LABORATORY RAT AND MOUSE: REVIEW OF THE NCI/NTP DATABASE AND CATEGORIZATION OF RENAL CARCINOGENS BASED ON MECHANISTIC INFORMATION. THE INCIDENCE OF RENAL TUBULE CARCINOGENESIS IN MALE AND FEMALE RATS OR MICE WITH 69 CHEMICALS FROM THE 513 BIOASSAYS CONDUCTED TO DATE BY THE NCI/NTP HAS BEEN COLLATED, THE CHEMICALS CATEGORIZED, AND THE RELATIONSHIP BETWEEN CARCINOGENESIS AND RENAL TUBULE HYPERPLASIA AND EXACERBATION OF THE SPONTANEOUS, AGE-RELATED RODENT DISEASE CHRONIC PROGRESSIVE NEPHROPATHY (CPN) EXAMINED. WHERE INFORMATION ON MECHANISM OR MODE OF ACTION EXISTS, THE CHEMICALS HAVE BEEN CATEGORIZED BASED ON THEIR ABILITY TO DIRECTLY OR INDIRECTLY INTERACT WITH RENAL DNA, OR ON THEIR ACTIVITY VIA EPIGENETIC PATHWAYS INVOLVING EITHER DIRECT OR INDIRECT CYTOTOXICITY WITH REGENERATIVE HYPERPLASIA, OR EXACERBATION OF CPN. NINE CHEMICALS WERE IDENTIFIED AS DIRECTLY INTERACTING WITH DNA, WITH SIX OF THESE PRODUCING RENAL TUBULE TUMORS AT HIGH INCIDENCE IN RATS OF BOTH SEXES, AND IN SOME CASES ALSO IN MICE. OCHRATOXIN A WAS THE MOST POTENT COMPOUND IN THIS GROUP, PRODUCING A HIGH TUMOR INCIDENCE AT VERY LOW DOSES, OFTEN WITH METASTASIS. THREE CHEMICALS WERE DISCUSSED IN THE CONTEXT OF INDIRECT DNA DAMAGE MEDIATED BY AN OXIDATIVE FREE RADICAL MECHANISM, ONE OF THESE BEING FROM THE NTP DATABASE. A THIRD CATEGORY INCLUDED FOUR CHEMICALS THAT HAD THE POTENTIAL TO CAUSE DNA DAMAGE FOLLOWING CONJUGATION WITH GLUTATHIONE AND SUBSEQUENT ENZYMATIC ACTIVATION TO A REACTIVE SPECIES, USUALLY A THIOL-CONTAINING ENTITY. TWO CHEMICALS WERE ALLOCATED INTO THE CATEGORY INVOLVING A DIRECT CYTOTOXIC ACTION ON THE RENAL TUBULE FOLLOWED BY SUSTAINED COMPENSATORY CELL PROLIFERATION, WHILE NINE WERE INCLUDED IN A GROUP WHERE THE CELL LOSS AND SUSTAINED INCREASE IN RENAL TUBULE CELL TURNOVER WERE DEPENDENT ON LYSOSOMAL ACCUMULATION OF THE MALE RAT-SPECIFIC PROTEIN, ALPHA2MU-GLOBULIN. IN A SIXTH CATEGORY, MORPHOLOGIC EVIDENCE ON TWO CHEMICALS INDICATED THAT THE RENAL TUMORS WERE A CONSEQUENCE OF EXACERBATED CPN. FOR THE REMAINING CHEMICALS, THERE WERE NO PERTINENT DATA ENABLING ASSIGNMENT TO A MECHANISTIC CATEGORY. ACCORDINGLY, THESE CHEMICALS, ACTING THROUGH AN AS YET UNKNOWN MECHANISM, WERE GROUPED AS EITHER BEING ASSOCIATED WITH AN ENHANCEMENT OF CPN (CATEGORY 7, 16 CHEMICALS), OR NOT ASSOCIATED WITH ENHANCED CPN (CATEGORY 8, 4 CHEMICALS). A NINTH CATEGORY DEALT WITH 11 CHEMICALS THAT WERE REGARDED AS PRODUCING INCREASES IN RENAL TUBULE TUMORS THAT DID NOT REACH STATISTICAL SIGNIFICANCE. A 10TH CATEGORY DISCUSSED 6 CHEMICALS THAT INDUCED RENAL TUMORS IN MICE BUT NOT IN RATS, PLUS 8 CHEMICALS THAT PRODUCED A LOW INCIDENCE OF RENAL TUBULE TUMORS IN MICE THAT DID NOT REACH STATISTICAL SIGNIFICANCE. AS MORE MECHANISTIC DATA ARE GENERATED, SOME CHEMICALS WILL INEVITABLY BE PLACED IN DIFFERENT GROUPS, PARTICULARLY THOSE FROM CATEGORIES 7 AND 8. A LARGE NUMBER OF CHEMICALS IN THE SERIES EXACERBATED CPN, BUT THOSE IN CATEGORY 7 ESPECIALLY MAY BE CANDIDATES FOR INCLUSION IN CATEGORY 6 WHEN FURTHER INFORMATION IS GLEANED FROM THE RELEVANT NTP STUDIES. ALSO, NEW DATA ON SPECIFIC CHEMICALS WILL PROBABLY EXPAND CATEGORY 5 AS CYTOTOXICITY AND CELL REGENERATION ARE IDENTIFIED AS OBLIGATORY STEPS IN RENAL CARCINOGENESIS IN MORE CASES. ADDITIONAL CONFIRMATORY OUTCOMES ARISING FROM THIS REVIEW ARE THAT METASTASES FROM RENAL TUBULE TUMORS, WHILE ENCOUNTERED WITH CHEMICALS CAUSING DNA DAMAGE, ARE RARE WITH THOSE ACTING THROUGH AN EPIGENETIC PATHWAY, WITH THE EXCEPTION BEING FUMONISIN B1; THAT MALE RATS AND MICE ARE GENERALLY MORE SUSCEPTIBLE THAN FEMALE RATS AND MICE TO CHEMICAL INDUCTION OF RENAL TUBULE TUMORS; AND THAT A BACKGROUND OF ATYPICAL TUBULE HYPERPLASIA IS A USEFUL INDICATOR REFLECTING A CHEMICALLY ASSOCIATED RENAL TUBULE TUMOR RESPONSE. WITH RESPECT TO RENAL TUBULE TUMORS AND HUMAN RISK ASSESSMENT, CHEMICALS IN CATEGORIES 1 AND 2, AND POSSIBLY 3, WOULD CURRENTLY BE JUDGED BY LINEAR DEFAULT METHODS; CHEMICALS IN CATEGORY 4 (AND PROBABLY SOME IN CATEGORY 3) AS EXHIBITING A THRESHOLD OF ACTIVITY WARRANTING THE BENCHMARK APPROACH; AND THOSE IN CATEGORIES 5 AND 6 AS REPRESENTING MECHANISMS THAT HAVE NO RELEVANCE FOR EXTRAPOLATION TO HUMANS. 2004 12 4052 27 MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET) CHARACTERIZED BY GENOME-WIDE METHYLATION ANALYSIS. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET) ARE CONSIDERED TO BE RARE, BENIGN, AND ASSOCIATED WITH CHRONIC EPILEPSY. WE PRESENT THE CASE OF A 28-YEAR-OLD MAN WITH A HISTORY OF EPILEPSY SINCE AGE 12. SURGERY OF AN OCCIPITAL CORTICAL LESION IN 2009 REVEALED A DNET. FIVE YEARS LATER, A RECURRENT TUMOR AT THE EDGE OF THE RESECTION CAVITY WAS REMOVED, AND THE TISSUE UNDERWENT AN INTENSIVE DIAGNOSTIC WORKUP. THE FIRST TUMOR WAS UNEQUIVOCALLY CHARACTERIZED AS A DNET, BUT NEUROPATHOLOGICAL DIAGNOSTICS OF THE RECURRENT TUMOR REVEALED A GLIOBLASTOMA. AFTER 6 MONTHS, ANOTHER RECURRENT TUMOR WAS DETECTED NEXT TO THE LOCATION OF THE ORIGINAL TUMOR, AND THIS WAS ALSO RESECTED. AN ILLUMINA 450 K BEADCHIP METHYLATION ARRAY WAS PERFORMED TO CHARACTERIZE ALL OF THE TUMORS. THE METHYLATION PROFILE OF THESE TUMORS SIGNIFICANTLY DIFFERED FROM OTHER GLIOBLASTOMA AND EPILEPSY-ASSOCIATED TUMOR PROFILES AND REVEALED A DNET-LIKE METHYLATION PROFILE. THUS, MOLECULAR CHARACTERIZATION OF THESE RECURRENT TUMORS SUGGESTS MALIGNANT TRANSFORMATION OF A PREVIOUSLY BENIGN DNET. WE FOUND INCREASED COPY NUMBER CHANGES IN THE RECURRENT DNET TUMORS AFTER MALIGNANT TRANSFORMATION. MODERN HIGH-THROUGHPUT ANALYSIS ADDS ESSENTIAL MOLECULAR INFORMATION IN ADDITION TO STANDARD HISTOPATHOLOGY FOR PROPER IDENTIFICATION OF RARE BRAIN TUMORS THAT PRESENT WITH AN UNUSUAL CLINICAL COURSE. 2016 13 708 30 BYSTANDER EFFECTS IN RADIATION-INDUCED GENOMIC INSTABILITY. EXPOSURE OF GM10115 HAMSTER-HUMAN HYBRID CELLS TO X-RAYS CAN RESULT IN THE INDUCTION OF CHROMOSOMAL INSTABILITY IN THE PROGENY OF SURVIVING CELLS. THIS INSTABILITY MANIFESTS AS THE DYNAMIC PRODUCTION OF NOVEL SUB-POPULATIONS OF CELLS WITH UNIQUE CYTOGENETIC REARRANGEMENTS INVOLVING THE "MARKER" HUMAN CHROMOSOME. WE HAVE USED THE COMET ASSAY TO INVESTIGATE WHETHER THERE WAS AN ELEVATED LEVEL OF ENDOGENOUS DNA BREAKS IN CHROMOSOMALLY UNSTABLE CLONES THAT COULD PROVIDE A SOURCE FOR THE CHROMOSOMAL REARRANGEMENTS AND THUS ACCOUNT FOR THE PERSISTENT INSTABILITY OBSERVED. OUR RESULTS INDICATE NO SIGNIFICANT DIFFERENCE IN COMET TAIL MEASUREMENT BETWEEN NON-IRRADIATED AND RADIATION-INDUCED CHROMOSOMALLY UNSTABLE CLONES. USING TWO-COLOR FLUORESCENCE IN SITU HYBRIDIZATION WE ALSO INVESTIGATED WHETHER RECOMBINATIONAL EVENTS INVOLVING THE INTERSTITIAL TELOMERE REPEAT-LIKE SEQUENCES IN GM10115 CELLS WERE INVOLVED AT FREQUENCIES HIGHER THAN RANDOM PROCESSES WOULD OTHERWISE PREDICT. NINE OF 11 CLONES DEMONSTRATED A SIGNIFICANTLY HIGHER THAN EXPECTED INVOLVEMENT OF THESE INTERSTITIAL TELOMERE REPEAT-LIKE SEQUENCES AT THE RECOMBINATION JUNCTION BETWEEN THE HUMAN AND HAMSTER CHROMOSOMES. SINCE ELEVATED LEVELS OF ENDOGENOUS BREAKS WERE NOT DETECTED IN UNSTABLE CLONES WE PROPOSE THAT EPIGENETIC OR BYSTANDER EFFECTS (BSES) LEAD TO THE ACTIVATION OF RECOMBINATIONAL PATHWAYS THAT PERPETUATE THE UNSTABLE PHENOTYPE. SPECIFICALLY, WE EXPAND UPON THE HYPOTHESIS THAT RADIATION INDUCES CONDITIONS AND/OR FACTORS THAT STIMULATE THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS). THESE REACTIVE INTERMEDIATES THEN CONTRIBUTE TO A CHRONIC PRO-OXIDANT ENVIRONMENT THAT CYCLES OVER MULTIPLE GENERATIONS, PROMOTING CHROMOSOMAL RECOMBINATION AND OTHER PHENOTYPES ASSOCIATED WITH GENOMIC INSTABILITY. 2002 14 818 21 CHARACTERISTICS OF THE SPECTRUM OF PROLIFERATIVE LESIONS OBSERVED IN THE KIDNEY AND URINARY BLADDER OF FISCHER 344 RATS AND B6C3F1 MICE. MANY RODENT RENAL AND BLADDER CARCINOGENS RELY UPON EPIGENETIC MECHANISMS OF CARCINOGENESIS; SUCH MECHANISMS ARE LIKELY TO INFLUENCE THE SPECTRUM OF URINARY TRACT TUMORS OBSERVED IN CONTROL AND TREATED ANIMALS. THIS IS REFLECTED IN SEVERAL FEATURES OF CHEMICALLY INDUCED RODENT URINARY TRACT NEOPLASMS, INCLUDING A LOW OVERALL TUMOR INCIDENCE, AN INCREASED PREVALENCE OF URINARY TRACT TUMORS IN RATS COMPARED TO MICE AND MALES COMPARED TO FEMALES, THE TENDENCY FOR EPITHELIAL TUMORS TO PREDOMINATE OVER NONEPITHELIAL TYPES, AND DEMONSTRATED LINKS TO CHRONIC PROGRESSIVE NEPHROPATHY AND UROLITHIASIS. SUCH TENDENCIES ARE ALSO CHARACTERISTIC OF SPONTANEOUS URINARY TRACT TUMORS IN RODENTS. DATA TO SUPPORT THESE OBSERVATIONS CAN BE DERIVED FROM LARGE HISTORICAL DATABASES SUCH AS THE TOXICOLOGY DATA MANAGEMENT SYSTEM, MAINTAINED BY NATIONAL TOXICOLOGY PROGRAM. 2002 15 865 30 CHRONIC ACRYLAMIDE EXPOSURE IN MALE MICE RESULTS IN ELEVATED DNA DAMAGE IN THE GERMLINE AND HERITABLE INDUCTION OF CYP2E1 IN THE TESTES. ACUTE ACRYLAMIDE EXPOSURE IN MALE RODENTS RESULTS IN REDUCED REPRODUCTIVE PERFORMANCE AND DOMINANT LETHALITY. HOWEVER, THE REPRODUCTIVE EFFECTS OF LOW DOSE CHRONIC EXPOSURE, WHICH BETTER REFLECTS THE NATURE OF HUMAN EXPOSURE, REMAIN FAR LESS CERTAIN. HUMAN DIETARY CONSUMPTION OF ACRYLAMIDE HAS BEEN ESTIMATED AT AN AVERAGE OF 1-4 MICROG/KG BW/DAY. IN ORDER TO SIMULATE THIS EXPOSURE, MALE MICE WERE PROVIDED WITH ACRYLAMIDE (1 MICROG/ML) VIA THEIR DRINKING WATER CONTINUOUSLY FOR SIX MONTHS, WHICH WAS EQUIVALENT TO A HUMAN DOSE OF 10.5 MICROG/ KG BW/DAY. THIS EXPOSURE REGIME INCREASED DNA DAMAGE IN THE SPERMATOZOA, WITHOUT AFFECTING A CONCOMITANT REDUCTION IN OVERALL FERTILITY. THE OFFSPRING OF ACRYLAMIDE TREATED MICE DID NOT HAVE AN INCREASED INCIDENCE OF SKIN PAPILLOMA FORMATION FOLLOWING THE TWO-STAGE TUMOR INDUCTION PROTOCOL. HOWEVER, THE MALE OFFSPRING OF ACRYLAMIDE TREATED FATHERS HAD SIGNIFICANTLY INCREASED LEVELS OF DNA DAMAGE IN THEIR SPERMATOZOA, DESPITE HAVING HAD NO DIRECT TOXICANT EXPOSURE. IT WAS ALSO FOUND THAT THE F0, AND MOST CRUCIALLY, F1 MICE HAD INCREASED LEVELS OF CYP2E1 PROTEIN IN THEIR GERM CELLS. THIS IS SIGNIFICANT AS CYP2E1 IS THE SOLE ENZYME RESPONSIBLE FOR CONVERSION OF ACRYLAMIDE TO ITS HARMFUL METABOLITE GLYCIDAMIDE. THIS ALTERED EXPRESSION MAY BE DUE TO EPIGENETIC ALTERATIONS. ADDITIONALLY, THE F0 AND F1 MICE HAD INCREASED OXIDATIVE ADDUCTS IN THE DNA OF THEIR GERM CELLS, WHICH WAS HYPOTHESIZED TO ARISE AS A BYPRODUCT OF INCREASED CYP2E1 ACTIVITY. THEREFORE, CHRONIC PATERNAL ACRYLAMIDE EXPOSURE IN MICE HAS CONSEQUENCES FOR THEIR OFFSPRING, AND RAISES CONCERNS FOR THE EFFECTS OF ACRYLAMIDE EXPOSURE IN THE HUMAN POPULATION AND THE ACCUMULATED EFFECTS WITH MULTIPLE GENERATIONS OF EXPOSURE. 2016 16 1599 32 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 17 1918 40 ENVIRONMENTAL CARCINOGENESIS AND TRANSGENERATIONAL TRANSMISSION OF CARCINOGENIC RISK: FROM GENETICS TO EPIGENETICS. THE DOMINANT PATHOGENIC MODEL, SOMATIC MUTATION THEORY (SMT), CONSIDERS CARCINOGENESIS AS A 'GENETIC ACCIDENT' DUE TO THE ACCUMULATION OF 'STOCHASTIC' DNA MUTATIONS. THIS MODEL WAS PROPOSED AND ACCEPTED BY THE SCIENTIFIC COMMUNITY WHEN CANCER MAINLY AFFECTED THE ELDERLY, BUT IT DOES NOT EXPLAIN THE EPIDEMIOLOGICAL OBSERVATION OF THE CONTINUOUS INCREASE IN CANCER INCIDENCE AMONG CHILDREN AND YOUNG ADULTS. SOMATIC MUTATION THEORY HAS BEEN PROPOSED FOR A REVISION BASED ON THE EMERGING EXPERIMENTAL EVIDENCE, AS IT DOES NOT FULLY ADDRESS SOME ISSUES THAT HAVE PROVEN TO BE CRUCIAL FOR CARCINOGENESIS, NAMELY: THE INFLAMMATORY CONTEXT OF CANCER; THE KEY ROLE PLAYED BY THE STROMA, MICROENVIRONMENT, ENDOTHELIAL CELLS, ACTIVATED MACROPHAGES, AND SURROUNDING TISSUES; AND THE DISTORTED DEVELOPMENTAL COURSE FOLLOWED BY THE NEOPLASTIC TISSUE. FURTHERMORE, SMT IS OFTEN NOT ABLE TO CONSIDER EITHER THE EXISTENCE OF SPECIFIC MUTATIONS RESULTING IN A WELL-DEFINED CANCER TYPE, OR A CLEAR RELATIONSHIP BETWEEN MUTATIONS AND TUMOR PROGRESSION. MOREOVER, IT DOES NOT EXPLAIN THE MECHANISM OF ACTION OF THE NON-MUTAGENIC AND ENVIRONMENTAL CARCINOGENS. IN THE LAST DECADE, CANCER RESEARCH HAS HIGHLIGHTED THE PROMINENT ROLE OF AN ALTERED REGULATION OF GENE EXPRESSION, SUGGESTING THAT CANCER SHOULD BE CONSIDERED AS A RESULT OF A POLYCLONAL EPIGENETIC DISRUPTION OF STEM/PROGENITOR CELLS, MEDIATED BY TUMOUR-INDUCING GENES. THE MATERNAL AND FETAL EXPOSURE TO A WIDE RANGE OF CHEMICALS AND ENVIRONMENTAL CONTAMINANTS IS RAISING THE ATTENTION OF THE SCIENTIFIC COMMUNITY. INDEED, THE MOST POWERFUL PROCARCINOGENIC MECHANISMS OF ENDOCRINE DISRUPTORS AND OTHER POLLUTANTS IS LINKED TO THEIR POTENTIAL TO INTERFERE EPIGENETICALLY WITH THE EMBRYO-FETAL PROGRAMMING OF TISSUES AND ORGANS, ALTERING THE REGULATION OF THE GENES INVOLVED IN THE CELL CYCLE, CELL PROLIFERATION, APOPTOSIS, AND OTHER KEY SIGNALING PATHWAYS. THE EMBRYO-FETAL EXPOSURE TO ENVIRONMENTAL, STRESSFUL, AND PROINFLAMMATORY TRIGGERS (FIRST HIT), SEEMS TO ACT AS A 'DISEASE PRIMER', MAKING FETAL CELLS AND TISSUES MORE SUSCEPTIBLE TO THE SUBSEQUENT ENVIRONMENTAL EXPOSURES (SECOND HIT), TRIGGERING THE CARCINOGENIC PATHWAYS. FURTHERMORE, EVEN AT THE MOLECULAR LEVEL, IN CARCINOGENESIS, 'EPIGENETICS PRECEDES GENETICS' AS GLOBAL DNA HYPOMETHYLATION, AND THE HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES ARE COMMON BOTH IN CANCEROUS AND IN PRECANCEROUS CELLS, AND GENERALLY PRECEDE MUTATIONS. THESE EPIGENETIC MODELS MAY BETTER EXPLAIN THE INCREASE OF CANCER AND CHRONIC/DEGENERATIVE DISEASES IN THE LAST DECADES AND COULD BE USEFUL TO ADOPT APPROPRIATE PRIMARY PREVENTION MEASURES, ESSENTIALLY BASED ON THE REDUCTION OF MATERNAL-FETAL AND CHILD EXPOSURE TO SEVERAL PROCARCINOGENIC AGENTS AND FACTORS DISPERSED IN THE ENVIRONMENT AND IN THE FOOD-CHAINS, AS RECENTLY SUGGESTED BY THE WORLD HEALTH ORGANIZATION. 2018 18 3623 35 IN VIVO COMET ASSAY ON ISOLATED KIDNEY CELLS TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS OR CYTOTOXIC COMPOUNDS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE THE ABILITY OF THE ALKALINE IN VIVO COMET ASSAY (PH>13) TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS WHEN PERFORMED ON FRESHLY ISOLATED KIDNEY CELLS AND TO DETERMINE THE POSSIBLE INTERFERENCE OF CYTOTOXICITY BY ASSESSING DNA DAMAGE INDUCED BY RENAL GENOTOXIC, EPIGENETIC OR TOXIC COMPOUNDS AFTER ENZYMATIC ISOLATION OF KIDNEY CELLS FROM OFA SPRAGUE-DAWLEY MALE RATS. THE ABILITY OF THE COMET ASSAY TO DISTINGUISH (1) GENOTOXICITY VERSUS CYTOTOXICITY AND (2) GENOTOXIC VERSUS NON-GENOTOXIC (EPIGENETIC) CARCINOGENS, WAS THUS INVESTIGATED BY STUDYING FIVE KNOWN GENOTOXIC RENAL CARCINOGENS ACTING THROUGH DIVERSE MECHANISMS OF ACTION, I.E. STREPTOZOTOCIN, ARISTOLOCHIC ACIDS, 2-NITROANISOLE, POTASSIUM BROMATE AND CISPLATIN, TWO RODENT RENAL EPIGENETIC CARCINOGENS: D-LIMONENE AND CICLOSPORINE AND TWO NEPHROTOXIC COMPOUNDS: STREPTOMYCIN AND INDOMETHACIN. ANIMALS WERE TREATED ONCE WITH THE TEST COMPOUND BY THE APPROPRIATE ROUTE OF ADMINISTRATION AND GENOTOXIC EFFECTS WERE MEASURED AT THE TWO SAMPLING TIMES OF 3-6 AND 22-26H AFTER TREATMENT. REGARDING THE TISSUE PROCESSING, THE LIMITED BACKGROUND LEVEL OF DNA MIGRATION OBSERVED IN THE NEGATIVE CONTROL GROUPS THROUGHOUT ALL EXPERIMENTS DEMONSTRATED THAT THE ENZYMATIC ISOLATION METHOD IMPLEMENTED IN THE CURRENT STUDY IS APPROPRIATE. ON THE OTHER HAND, STREPTOZOTOCIN, 20MG/KG, USED AS POSITIVE REFERENCE CONTROL CONCURRENTLY TO EACH ASSAY, CAUSED A CLEAR INCREASE IN THE MEAN OLIVE TAIL MOMENT MEDIAN VALUE, WHICH ALLOWS VALIDATING THE CURRENT METHODOLOGY. UNDER THESE EXPERIMENTAL CONDITIONS, THE IN VIVO RODENT COMET ASSAY DEMONSTRATED GOOD SENSITIVITY AND GOOD SPECIFICITY: ALL THE FIVE RENAL GENOTOXIC CARCINOGENS WERE CLEARLY DETECTED IN AT LEAST ONE EXPRESSION PERIOD EITHER DIRECTLY OR INDIRECTLY, AS IN THE CASE OF CISPLATIN: FOR THIS CROSS-LINKING AGENT, THE SIGNIFICANT DECREASE IN DNA MIGRATION OBSERVED UNDER STANDARD ELECTROPHORESIS CONDITIONS WAS CLEARLY AMPLIFIED WHEN THE DURATION OF ELECTROPHORESIS WAS INCREASED UP TO 40MIN. IN CONTRAST, EPIGENETIC AND NEPHROTOXIC COMPOUNDS FAILED TO INDUCE ANY SIGNIFCANT INCREASE IN DNA MIGRATION. IN CONCLUSION, THE IN VIVO RODENT COMET ASSAY PERFORMED ON ISOLATED KIDNEY CELLS COULD BE USED AS A TOOL TO INVESTIGATE THE GENOTOXIC POTENTIAL OF A TEST COMPOUND IF NEOPLASIC/PRENEOPLASIC CHANGES OCCUR AFTER SUBCHRONIC OR CHRONIC TREATMENTS, IN ORDER TO DETERMINE THE ROLE OF GENOTOXICITY IN TUMOR INDUCTION. MOREOVER, THE EPIGENETIC CARCINOGENS AND CYTOTOXIC COMPOUNDS DISPLAYED CLEARLY NEGATIVE RESPONSES IN THIS STUDY. THESE RESULTS ALLOW EXCLUDING A DNA DIRECT-ACTING MECHANISM OF ACTION AND CAN THUS SUGGEST THAT A THRESHOLD EXISTS. THEREFORE, THE CURRENT IN VIVO RODENT COMET ASSAY COULD CONTRIBUTE TO ELUCIDATE AN EPIGENETIC MECHANISM AND THUS, TO UNDERTAKE A RISK ASSESSMENT ASSOCIATED WITH HUMAN USE, DEPENDING ON THE EXPOSURE LEVEL. 2007 19 3803 34 INTESTINAL METAPLASIA OF THE STOMACH. A STATUS REPORT. INTESTINAL METAPLASIA IN THE STOMACH INCREASES THE RISK OF GASTRIC CANCER, AND THE INCREASED RISK IS PROPORTIONAL TO THE EXTENT OF THE METAPLASIA. THIS RISK COULD BE GENERATED BY ONE OR MORE MECHANISMS: (1) THE METAPLASTIC TISSUE IS AN EARLY STEP IN A MULTISTEP INDUCTION PROCESS; (2) THE METAPLASTIC TISSUE IS AN EPIGENETIC CHANGE THAT RAISES THE PH OF GASTRIC JUICE BY REPLACING OXYNTIC MUCOSA, FAVORING THE GROWTH OF A BACTERIA CAPABLE OF GENERATING ENDOGENOUS MUTAGENS; AND/OR (3) THE METAPLASIA IS ONLY A MARKER FOR CHRONIC GASTRITIS DUE TO H. PYLORI INFECTION OR PERNICIOUS ANEMIA. WITH THE LAST MECHANISM, THE INFLAMMATORY RESPONSE FAVORS INTRAMURAL MUTAGENESIS THAT MIGHT RESULT IN METAPLASIA OR NEOPLASIA AS INDEPENDENT EVENTS. FINDING GENE REARRANGEMENTS COMMON TO BOTH METAPLASTIC AND NEOPLASTIC TISSUE MAY ESTABLISH A DIRECT LINK BETWEEN THEM, BUT TOO FEW HAVE BEEN IDENTIFIED TO ACCOUNT FOR THE LARGE NUMBER OF STOMACH CANCERS THAT DEVELOP IN HIGH RISK POPULATIONS. HISTOCHEMICAL AND IMMUNOCHEMICAL STAINS THAT IDENTIFY ENZYMES OR MUCOSUBSTANCES MAY SUGGEST THAT METAPLASTIC EPITHELIAL CELLS RESEMBLE SMALL OR LARGE INTESTINAL CELLS, BUT THEY ARE DISTINCTLY DIFFERENT FROM BOTH. MOREOVER, THESE STAINS DO NOT INDICATE WHETHER A GIVEN CYTOLOGIC CHANGE IS GENETIC OR EPIGENETIC; THEREFORE, THEY CANNOT BE USED TO DEFINE THE RELATIONSHIP BETWEEN METAPLASIA AND NEOPLASIA. IT IS UNNECESSARY FOR PRACTICING PHYSICIANS TO AWAIT RESOLUTION OF THIS QUESTION. IT CAN BE ASSUMED THAT ANY PERSON WITH EXTENSIVE METAPLASIA IS AT HIGH RISK FOR GASTRIC CANCER AND SHOULD BE SUBJECT TO PERIODIC SCREENING. THE EXTENT OF THE METAPLASTIC PROCESS IS PROBABLY MORE IMPORTANT THAN THE METAPLASTIC SUBTYPE. 1994 20 3934 38 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982