1 6579 136 TREFOIL FACTORS AND HUMAN GASTRIC CANCER (REVIEW). TFF1/PS2, TFF2/SP AND TFF3/ITF ARE SOLUBLE PEPTIDES WITH TREFOIL DOMAIN(S) AND C-TERMINAL DIMERIZATION DOMAIN, WHICH ARE CONSERVED AMONG HUMAN, COW, MOUSE AND RAT. TFF1 MRNA IS EXPRESSED IN STOMACH (MUCOUS CELLS IN FUNDUS AND ANTRUM), TFF2 MRNA IN STOMACH (MUCOUS NECK CELLS IN FUNDUS AND BASAL CELLS IN ANTRAL AND PYLORIC GLANDS) AND DUODENUM (BRUNNER'S GLAND), TFF3 MRNA IN SMALL INTESTINE AND LARGE INTESTINE (GOBLET CELLS). EXPRESSION OF TFF1, TFF2 AND TFF3 MRNAS ARE DIFFERENTIALLY REGULATED BY FGF2/BFGF, FGF7/KGF, ESTROGEN, ASPIRIN, ARACHIDONIC ACID, X-RAY IRRADIATION, AND HYDROGEN PEROXIDE. GASTRIC CANCER IS CLASSIFIED INTO THE INTESTINAL TYPE AND THE DIFFUSE TYPE. TFF MRNAS ARE PREFERENTIALLY EXPRESSED IN DIFFUSE-TYPE GASTRIC CANCER CELLS. CUSTOM-MADE MICROARRAY (TFF MRNAS) AND ELISA (TFF PROTEINS) MIGHT BE APPLICABLE FOR SCREENING METHODS OF PERITONEAL AND BONE MARROW DISSEMINATION FROM DIFFUSE-TYPE GASTRIC CANCER. TFF1 AND TFF2 MRNAS ARE FREQUENTLY DOWN-REGULATED IN INTESTINAL-TYPE GASTRIC CANCER. TFF1 GENE, INACTIVATED BY DELETION, MISSENSE MUTATION AND PROMOTER HYPERMETHYLATION, IS A TUMOR SUPPRESSOR GENE IMPLICATED IN GASTRIC CANCER. TFF2 IS A CANDIDATE TUMOR SUPPRESSOR GENE; HOWEVER, GENETIC AND EPIGENETIC ALTERATIONS OF TFF2 GENE IN HUMAN GASTRIC CANCER REMAIN UNCLEAR. TFF1, TFF2 AND TFF3 PLAY KEY ROLES IN MUCOSAL PROTECTION THROUGH MUCOUS-BARRIER FORMATION, AND ALSO IN MUCOSAL REPAIR THROUGH PROMOTION OF RESTITUTION AFTER INJURY. PATIENTS WITH CHRONIC ATROPHIC GASTRITIS AND THOSE WITH ULCERATIVE COLITIS ARE AT RISK OF GASTRIC CANCER AND COLORECTAL CANCER, RESPECTIVELY. TFF1, TFF2 AND TFF3 PROTEINS MIGHT BE APPLICABLE FOR CHEMOPREVENTION OF GASTROINTESTINAL CANCER ASSOCIATED WITH CHRONIC PERSISTENT INFLAMMATION. 2003 2 6871 23 [PATHOGENETIC IMPORTANCE OF HELICOBACTER PYLORI INFECTION]. H. PYLORI ARE ETIOLOGICAL FACTOR OF HUMAN ACUTE AND CHRONIC GASTRITIS. DEPENDING ON PATHOGENIC FACTORS OF MICROORGANISM AND POLYMORPHISM OF HUMAN GENES, CHRONIC GASTRITIS CAN BE A CAUSE FOR ULCERATIVE ENTERITIS OF THE DUODENUM OR STOMACH, GASTRIC ADENOCARCINOMA AND MALT-LYMPHOMA DEVELOPMENT. WE REVEALED GENETIC FEATURES OF BACTERIA, DETERMINED THE INTENSITY OF INFLAMMATION, SUCH AS PATHOGENIC FACTORS--CAG, PLASTIC REGION OF THE GENOME AND ADHESIN CODING GENES. EPIGENETIC CHANGES, FOR EXAMPLE THE METHYLATION OF E-CADHERIN GENE ASSOCIATED WITH H PYLORI, ARE CRUCIAL FOR CARCINOGENESIS. THEREBY, PREDISPOSITION OF CHRONIC GASTRITIS ASSOCIATED WITH H. PYLORI TO ULCERATIVE ENTERITIS OF THE DUODENUM, ULCERATIVE STOMACH DISEASE OR GASTRIC ADENOCARCINOMA DEPENDS ON TOPOGRAPHY, THE INTENSITY OF INFLAMMATION AND CHANGES OF ACID PRODUCTION IN THE STOMACH. 2012 3 1798 38 EFFECT OF HELICOBACTER PYLORI INFECTION ON GATA-5 AND TFF1 REGULATION, COMPARISON BETWEEN PEDIATRIC AND ADULT PATIENTS. BACKGROUND: GATA FACTORS, WHICH CONSTITUTE A FAMILY OF TRANSCRIPTION REGULATORY PROTEINS, PARTICIPATE IN GASTROINTESTINAL DEVELOPMENT. TREFOIL FACTOR 1 (TFF1) PLAYS A CRUCIAL ROLE IN MUCOSAL DEFENSE AND HEALING, AND EVIDENCE SUGGESTS THAT GATA-5 MEDIATED ITS REGULATION. GASTRIC CANCER IS A MULTIPLE-STEP PROCESS TRIGGERED BY HELICOBACTER PYLORI AND IS CHARACTERIZED BY ACCUMULATION OF MOLECULAR AND EPIGENETIC ALTERATION. THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECT OF H. PYLORI INFECTION ON THE REGULATION OF GATA-5 AND TFF1 IN VITRO AND IN VIVO. RESULTS: INFECTED CELLS EXHIBITED UPREGULATION OF GATA-5 AND TFF1 AFTER 48 H. AN INCREASE IN GATA-5 AND TFF1 MRNA LEVELS WAS ALSO FOUND IN MICE SAMPLES AFTER 6 AND 12 MONTHS OF INFECTION, RESPECTIVELY. IN HUMAN SAMPLES, WE FOUND AN ASSOCIATION BETWEEN H. PYLORI INFECTION AND GATA-5 UPREGULATION. IN FACT, AMONG H. PYLORI-INFECTED PATIENTS, HYPERMETHYLATION WAS OBSERVED IN 45.5% OF PEDIATRIC SAMPLES, IN 62.6% OF CHRONIC GASTRITIS SAMPLES, AND IN 63% OF GASTRIC CANCER SAMPLES. REGARDING TFF1, THE EXPRESSION LEVELS WERE SIMILAR IN PEDIATRICS AND ADULTS PATIENTS, AND WERE INDEPENDENT OF H. PYLORI INFECTION, AND THE EXPRESSION OF THESE FACTORS WAS DOWNREGULATED IN GASTRIC CANCER SAMPLES. GATA-5 PROMOTER METHYLATION WAS ASSOCIATED WITH A DECREASE IN TFF1 MRNA LEVELS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE UPREGULATION OF GATA-5 AND TFF1 OBSERVED IN VITRO AND IN VIVO MAY BE CORRELATED WITH A PROTECTIVE EFFECT OF THE MUCOSA IN RESPONSE TO INFECTION. THE EPIGENETIC INACTIVATION OF GATA-5 OBSERVED IN HUMAN BIOPSIES FROM INFECTED PATIENTS MAY SUGGEST THAT THIS ALTERATION IS AN EARLY EVENT OCCURRING IN ASSOCIATION WITH H. PYLORI INFECTION. 2018 4 4521 29 MULTI?LAYERED PREVENTION AND TREATMENT OF CHRONIC INFLAMMATION, ORGAN FIBROSIS AND CANCER ASSOCIATED WITH CANONICAL WNT/BETA?CATENIN SIGNALING ACTIVATION (REVIEW). BETA?CATENIN/CTNNB1 IS AN INTRACELLULAR SCAFFOLD PROTEIN THAT INTERACTS WITH ADHESION MOLECULES (E?CADHERIN/CDH1, N?CADHERIN/CDH2, VE?CADHERIN/CDH5 AND ALPHA?CATENINS), TRANSMEMBRANE?TYPE MUCINS (MUC1/CD227 AND MUC16/CA125), SIGNALING REGULATORS (APC, AXIN1, AXIN2 AND NHERF1/EBP50) AND EPIGENETIC OR TRANSCRIPTIONAL REGULATORS (BCL9, BCL9L, CREBBP/CBP, EP300/P300, FOXM1, MED12, SMARCA4/BRG1 AND TCF/LEF). GAIN?OF?FUNCTION CTTNB1 MUTATIONS ARE DETECTED IN BLADDER CANCER, COLORECTAL CANCER, GASTRIC CANCER, LIVER CANCER, LUNG CANCER, PANCREATIC CANCER, PROSTATE CANCER AND UTERINE CANCER, WHEREAS LOSS?OF?FUNCTION CTNNB1 MUTATIONS ARE ALSO DETECTED IN HUMAN CANCER. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA AND ZNRF3 ARE REPRESENTATIVE BETA?CATENIN TARGET GENES. BETA?CATENIN SIGNALING IS INVOLVED IN MYOFIBROBLAST ACTIVATION AND SUBSEQUENT PULMONARY FIBROSIS, IN ADDITION TO OTHER TYPES OF FIBROSIS. BETA?CATENIN AND NF?KAPPAB SIGNALING ACTIVATION ARE INVOLVED IN FIELD CANCERIZATION IN THE STOMACH ASSOCIATED WITH HELICOBACTER PYLORI (H. PYLORI) INFECTION AND IN THE LIVER ASSOCIATED WITH HEPATITIS C VIRUS (HCV) INFECTION AND OTHER ETIOLOGIES. BETA?CATENIN?TARGETED THERAPEUTICS ARE FUNCTIONALLY CLASSIFIED INTO BETA?CATENIN INHIBITORS TARGETING UPSTREAM REGULATORS (AZ1366, ETC?159, G007?LK, GNF6231, IPAFRICEPT, NVP?TNKS656, ROSMANTUZUMAB, VANTICTUMAB, WNT?C59, WNT974 AND XAV939), BETA?CATENIN INHIBITORS TARGETING PROTEIN?PROTEIN INTERACTIONS (CGP049090, CWP232228, E7386, ICG?001, LF3 AND PRI?724), BETA?CATENIN INHIBITORS TARGETING EPIGENETIC REGULATORS (PKF118?310), BETA?CATENIN INHIBITORS TARGETING MEDIATOR COMPLEXES (CCT251545 AND CORTISTATIN A) AND BETA?CATENIN INHIBITORS TARGETING TRANSMEMBRANE?TYPE TRANSCRIPTIONAL OUTPUTS, INCLUDING CD44V6, FZD7 AND LGR5. ERADICATING H. PYLORI AND HCV IS THE OPTIMAL APPROACH FOR THE FIRST?LINE PREVENTION OF GASTRIC CANCER AND HEPATOCELLULAR CARCINOMA (HCC), RESPECTIVELY. HOWEVER, BETA?CATENIN INHIBITORS MAY BE APPLICABLE FOR THE PREVENTION OF ORGAN FIBROSIS, SECOND?LINE HCC PREVENTION AND TREATING BETA?CATENIN?DRIVEN CANCER. THE MULTI?LAYERED PREVENTION AND TREATMENT STRATEGY OF BETA?CATENIN?RELATED HUMAN DISEASES IS NECESSARY FOR THE PRACTICE OF PERSONALIZED MEDICINE AND IMPLEMENTATION OF PRECISION MEDICINE. 2018 5 3805 25 INTESTINE-SPECIFIC HOMEOBOX (ISX) INDUCES INTESTINAL METAPLASIA AND CELL PROLIFERATION TO CONTRIBUTE TO GASTRIC CARCINOGENESIS. BACKGROUND: HELICOBACTER PYLORI INDUCES CHRONIC INFLAMMATION AND INTESTINAL METAPLASIA (IM) THROUGH GENETIC AND EPIGENETIC CHANGES AND ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS THAT CONTRIBUTE TO GASTRIC CARCINOGENESIS. HOWEVER, THE PRECISE MECHANISM OF IM IN GASTRIC CARCINOGENESIS HAS NOT BEEN FULLY ELUCIDATED. WE PREVIOUSLY FOUND THAT INTESTINE-SPECIFIC HOMEOBOX (ISX) MRNA EXPRESSION INCREASED IN ORGANOIDS CULTURED FROM HELICOBACTER-INFECTED MOUSE MUCOSA. IN THIS STUDY, WE ELUCIDATE THE ROLE OF ISX IN THE DEVELOPMENT OF IM AND GASTRIC CARCINOGENESIS. METHODS: ISX EXPRESSION WAS ASSESSED IN HELICOBACTER-INFECTED MOUSE AND HUMAN GASTRIC MUCOSA. MKN45 GASTRIC CANCER CELLS WERE CO-CULTURED WITH H. PYLORI TO DETERMINE WHETHER HELICOBACTER INFECTION INDUCED ISX EXPRESSION. WE ESTABLISHED STABLE MKN45 TRANSFECTED CELLS EXPRESSING ISX (STABLE-ISX MKN45) AND PERFORMED A SPHEROID COLONY FORMATION ASSAY AND A XENOGRAFT MODEL. WE PERFORMED ISX IMMUNOHISTOCHEMISTRY IN CANCER AND ADJACENT GASTRIC TISSUES. RESULTS: ISX EXPRESSION WAS INCREASED IN MOUSE AND HUMAN GASTRIC MUCOSA INFECTED WITH HELICOBACTER. THE PRESENCE OF IM AND H. PYLORI INFECTION IN HUMAN STOMACH WAS CORRELATED WITH ISX EXPRESSION. H. PYLORI INDUCED ISX MRNA AND PROTEIN EXPRESSION. CDX1/2, CYCLIND1, AND MUC2 WERE UPREGULATED IN STABLE-ISX MKN45, WHEREAS MUC5AC WAS DOWNREGULATED. STABLE-ISX MKN45 CELLS FORMED MORE SPHEROID COLONIES, AND HAD HIGH TUMORIGENIC ABILITY. ISX EXPRESSION IN GASTRIC CANCER AND ADJACENT MUCOSA WERE CORRELATED. CONCLUSIONS: ISX EXPRESSION INDUCED BY H. PYLORI INFECTION MAY LEAD TO IM AND HYPERPROLIFERATION OF GASTRIC MUCOSA THROUGH CDX1/2 AND CYCLIND1 EXPRESSION, CONTRIBUTING TO GASTRIC CARCINOGENESIS. 2016 6 4048 20 MAINTENANCE AND PHARMACOLOGIC TARGETING OF ROR1 PROTEIN LEVELS VIA UHRF1 IN T(1;19) PRE-B-ALL. EXPRESSION OF THE TRANSMEMBRANE PSEUDOKINASE ROR1 IS REQUIRED FOR SURVIVAL OF T(1;19)-PRE-B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T(1;19) PRE-B-ALL), CHRONIC LYMPHOCYTIC LEUKEMIA, AND MANY SOLID TUMORS. HOWEVER, TARGETING ROR1 WITH SMALL-MOLECULES HAS BEEN CHALLENGING DUE TO THE ABSENCE OF ROR1 KINASE ACTIVITY. TO IDENTIFY GENES THAT REGULATE ROR1 EXPRESSION AND MAY, THEREFORE, SERVE AS SURROGATE DRUG TARGETS, WE EMPLOYED AN SIRNA SCREENING APPROACH AND DETERMINED THAT THE EPIGENETIC REGULATOR AND E3 UBIQUITIN LIGASE, UHRF1, IS REQUIRED FOR T(1;19) PRE-B-ALL CELL VIABILITY IN A ROR1-DEPENDENT MANNER. UPON UHRF1 SILENCING, ROR1 PROTEIN IS REDUCED WITHOUT ALTERING ROR1 MRNA, AND ECTOPICALLY EXPRESSED UHRF1 IS SUFFICIENT TO INCREASE ROR1 LEVELS. ADDITIONALLY, PROTEASOME INHIBITION RESCUES LOSS OF ROR1 PROTEIN AFTER UHRF1 SILENCING, SUGGESTING A ROLE FOR THE PROTEASOME IN THE UHRF1-ROR1 AXIS. FINALLY, WE SHOW THAT ROR1-POSITIVE CELLS ARE TWICE AS SENSITIVE TO THE UHRF1-TARGETING DRUG, NAPHTHAZARIN, AND UNDERGO INCREASED APOPTOSIS COMPARED TO ROR1-NEGATIVE CELLS. NAPHTHAZARIN ELICITS REDUCED EXPRESSION OF UHRF1 AND ROR1, AND COMBINATION OF NAPHTHAZARIN WITH INHIBITORS OF PRE-B CELL RECEPTOR SIGNALING RESULTS IN FURTHER REDUCTION OF CELL SURVIVAL COMPARED WITH EITHER INHIBITOR ALONE. THEREFORE, OUR WORK REVEALS A MECHANISM BY WHICH UHRF1 STABILIZES ROR1, SUGGESTING A POTENTIAL TARGETING STRATEGY TO INHIBIT ROR1 IN T(1;19) PRE-B-ALL AND OTHER MALIGNANCIES. 2018 7 600 19 BETA-DEFENSINS AND ANALOGS IN HELICOBACTER PYLORI INFECTIONS: MRNA EXPRESSION LEVELS, DNA METHYLATION, AND ANTIBACTERIAL ACTIVITY. ANTIMICROBIAL PEPTIDES CAN PROTECT THE GASTRIC MUCOSA FROM BACTERIA, BUT HELICOBACTER PYLORI (H. PYLORI) CAN EQUALLY COLONIZE THE GASTRIC APPARATUS. TO UNDERSTAND BETA-DEFENSIN FUNCTION IN H. PYLORI-ASSOCIATED CHRONIC GASTRITIS, WE INVESTIGATED SUSCEPTIBILITY, HUMAN BETA-DEFENSIN MRNA EXPRESSION, AND DNA METHYLATION CHANGES TO PROMOTERS IN THE GASTRIC MUCOSA WITH OR WITHOUT H. PYLORI INFECTION. WE STUDIED THE EXPRESSION OF HBD2 (GENE NAME DEFB4A), HBD3 (DEFB103A), AND HBD4 (DEFB104) USING REAL-TIME PCR IN 15 CONTROL AND 10 H. PYLORI INFECTION PATIENT GASTRIC SPECIMENS. THIS STUDY DEMONSTRATES THAT H. PYLORI INFECTION IS RELATED TO GASTRIC ENHANCEMENT OF INDUCIBLE HBD2, BUT INDUCIBLE HBD3 AND HBD4 EXPRESSION LEVELS REMAINED UNCHANGED. HBD2 GENE METHYLATION LEVELS WERE OVERALL HIGHER IN H. PYLORI-NEGATIVE SAMPLES THAN IN H. PYLORI-POSITIVE SAMPLES. WE ALSO ASSESSED ANTIMICROBIAL SUSCEPTIBILITY USING GROWTH ON BLOOD AGAR. THE H. PYLORI STRAIN TOX+ WAS SUSCEPTIBLE TO ALL DEFENSINS TESTED AND THEIR ANALOGS (3N, 3NI). THESE RESULTS SHOW THAT HBD2 IS INVOLVED IN GASTRITIS DEVELOPMENT DRIVEN BY H. PYLORI, WHICH FACILITATES THE CREATION OF AN EPIGENETIC FIELD DURING H. PYLORI-ASSOCIATED GASTRIC TUMORIGENESIS. 2019 8 6463 23 TISSUE METHYLATION AND DEMETHYLATION INFLUENCE TRANSLESION SYNTHESIS DNA POLYMERASES (TLS) CONTRIBUTING TO THE GENESIS OF CHROMOSOMAL ABNORMALITIES IN MYELODYSPLASTIC SYNDROME. AIMS: DNA METHYLATION HAS ITS DISTRIBUTION INFLUENCED BY DNA DEMETHYLATION PROCESSES WITH THE CATALYTIC CONVERSION OF 5-METHYLCYTOSINE (5MC) INTO 5-HYDROXYMETHYLCYTOSINE (5HMC). MYELODYSPLASTIC SYNDROME (MDS) HAS BEEN ASSOCIATED WITH EPIGENETIC DYSREGULATION OF GENES RELATED TO DNA REPAIR SYSTEM, CHRONIC IMMUNE RESPONSE AND CELL CYCLE. METHODS: WE EVALUATED THE TISSUE DNA METHYLATION/HYDROXYMETHYLATION IN BONE MARROW TREPHINE BIOPSIES OF 73 PATIENTS WITH MDS, TRYING TO CORRELATE WITH THE MRNA EXPRESSION OF 21 GENES (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB AND TPX2). RESULTS: THE M-SCORE (5MC) WAS SIGNIFICANTLY HIGHER IN PATIENTS WITH CHROMOSOMAL ABNORMALITIES THAN PATIENTS WITH NORMAL KARYOTYPE (95% CI -27.127779 TO -2.368020; P=0.022). WE OBSERVED A HIGHER 5MC/5HMC RATIO IN PATIENTS CLASSIFIED AS HIGH-RISK SUBTYPES COMPARED WITH LOW-RISK SUBTYPES (95% CI -72.922115 TO -1.855662; P=0.040) AS WELL AS PATIENTS WITH HYPERCELLULAR BONE MARROW COMPARED WITH PATIENTS WITH NORMOCELLULAR/HYPOCELLULAR BONE MARROW (95% CI -69.189259 TO -0.511828; P=0.047) AND WITH THE PRESENCE OF DYSERYTHROPOIESIS (95% CI 17.077703 TO 51.331388; P=0.001). DNA POLS WITH TRANSLESION ACTIVITY ARE SIGNIFICANTLY INFLUENCED BY METHYLATION. AS 5MC IMMUNOEXPRESSION INCREASES, THE EXPRESSIONS OF POLH (R=-0.816; R(2) =0.665; P=0.000), POLQ (R=-0.790; R(2)=0.624; P=0.001), PCNA (R=-0.635; R(2)=0.403; P=0.020), POLK (R=-0.633; R(2)=0.400; P=0.036 AND REV1 (R=-0.578; R(2)=0.334; P=0.049) DECREASE. CONCLUSIONS: OUR RESULTS CONFIRM THAT THERE IS AN IMBALANCE IN THE DNA METHYLATION IN MDS, INFLUENCING THE DEVELOPMENT OF CHROMOSOMAL ABNORMALITIES WHICH MAY BE ASSOCIATED WITH THE LOW EXPRESSION OF DNA POLYMERASES WITH TRANSLESION SYNTHESIS POLYMERASES ACTIVITY. 2022 9 2649 21 EPIGENOMIC, GENOMIC, AND TRANSCRIPTOMIC LANDSCAPE OF SCHWANNOMATOSIS. SCHWANNOMATOSIS (SWNTS) IS A GENETIC CANCER PREDISPOSITION SYNDROME THAT MANIFESTS AS MULTIPLE AND OFTEN PAINFUL NEURONAL TUMORS CALLED SCHWANNOMAS (SWNS). WHILE GERMLINE MUTATIONS IN SMARCB1 OR LZTR1, PLUS SOMATIC MUTATIONS IN NF2 AND LOSS OF HETEROZYGOSITY IN CHROMOSOME 22Q HAVE BEEN IDENTIFIED IN A SUBSET OF PATIENTS, LITTLE IS KNOWN ABOUT THE EPIGENOMIC AND GENOMIC ALTERATIONS THAT DRIVE SWNTS-RELATED SWNS (SWNTS-SWNS) IN A MAJORITY OF THE CASES. WE PERFORMED MULTIPLATFORM GENOMIC ANALYSIS AND ESTABLISHED THE MOLECULAR SIGNATURE OF SWNTS-SWNS. WE SHOW THAT SWNTS-SWNS HARBOR DISTINCT GENOMIC FEATURES RELATIVE TO THE HISTOLOGICALLY IDENTICAL NON-SYNDROMIC SPORADIC SWNS (NS-SWNS). WE DEMONSTRATE THE EXISTENCE OF FOUR DISTINCT DNA METHYLATION SUBGROUPS OF SWNTS-SWNS THAT ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTIONAL PROGRAMS AND TUMOR LOCATION. WE SHOW SEVERAL NOVEL RECURRENT NON-22Q DELETIONS AND STRUCTURAL REARRANGEMENTS. WE DETECTED THE SH3PXD2A-HTRA1 GENE FUSION IN SWNTS-SWNS, WITH PREDOMINANCE IN LZTR1-MUTANT TUMORS. IN ADDITION, WE IDENTIFIED SPECIFIC GENETIC, EPIGENETIC, AND ACTIONABLE TRANSCRIPTIONAL PROGRAMS ASSOCIATED WITH PAINFUL SWNTS-SWNS INCLUDING PIGF, VEGF, MEK, AND MTOR PATHWAYS, WHICH MAY BE HARNESSED FOR MANAGEMENT OF THIS SYNDROME. 2021 10 967 16 CHRONIC NICOTINE EXPOSURE AUGMENTS RENAL OXIDATIVE STRESS AND INJURY THROUGH TRANSCRIPTIONAL ACTIVATION OF P66SHC. BACKGROUND: CHRONIC NICOTINE (CH-NIC) EXPOSURE EXACERBATES ISCHEMIA/REPERFUSION (I/R)-INDUCED OXIDATIVE STRESS AND ACUTE KIDNEY INJURY (AKI), AND MITOCHONDRIAL PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS) IN CULTURED RENAL PROXIMAL TUBULE CELLS (RPTCS). BECAUSE SER36-PHOSPHORYLATED P66SHC MODULATES MITOCHONDRIAL ROS PRODUCTION AND INJURY OF RPTCS, WE HYPOTHESIZED THAT CH-NIC EXACERBATES AKI BY INCREASING STRESS-INDUCED PHOSPHORYLATION OF P66SHC. METHODS: WE FIRST TESTED WHETHER CH-NIC AUGMENTS I/R-AKI-INDUCED EXPRESSION AND PHOSPHORYLATION OF P66SHC IN VIVO. WE THEN EXAMINED WHETHER KNOCKING DOWN P66SHC, OR IMPAIRING ITS SER36 PHOSPHORYLATION OR BINDING TO CYTOCHROME C, ALTERS THE EFFECTS OF CH-NIC ON OXIDATIVE STRESS (H(2)O(2))-INDUCED PRODUCTION OF ROS, MITOCHONDRIAL DEPOLARIZATION AND INJURY IN RPTCS IN VITRO. RESULTS: WE FOUND THAT CH-NIC INCREASED THE EXPRESSION OF P66SHC IN THE CONTROL AND ISCHEMIC KIDNEYS, BUT ONLY INCREASED ITS SER36 PHOSPHORYLATION AFTER RENAL I/R. KNOCKING DOWN P66SHC OR IMPAIRING PHOSPHORYLATION OF ITS SER36 RESIDUE, VIA THE S36A MUTATION (BUT NOT THE PHOSPHOMIMETIC S36D MUTATION), BLUNTED CH-NIC + H2O2-DEPENDENT ROS PRODUCTION, MITOCHONDRIAL DEPOLARIZATION AND INJURY IN RPTCS. ADDITIONALLY, CH-NIC + H2O2-DEPENDENT BINDING OF P66SHC TO MITOCHONDRIAL CYTOCHROME C WAS ATTENUATED BY S36A MUTATION OF P66SHC, AND IMPAIRING CYTOCHROME C BINDING (VIA W134F MUTATION) ABOLISHED ROS PRODUCTION, MITOCHONDRIAL DEPOLARIZATION AND INJURY, WHILE ECTOPIC OVEREXPRESSION OF P66SHC (WHICH MIMICS CH-NIC TREATMENT) AUGMENTED OXIDANT INJURY. WE DETERMINED THAT CH-NIC STIMULATES THE P66SHC PROMOTER THROUGH P53- AND EPIGENETIC MODIFICATION (PROMOTER HYPOMETHYLATION). CONCLUSIONS: CH-NIC WORSENS OXIDATIVE STRESS-DEPENDENT ACUTE RENAL INJURY BY INCREASING EXPRESSION AND CONSEQUENT OXIDATIVE STRESS-DEPENDENT SER36 PHOSPHORYLATION OF P66SHC. THUS, TARGETING THIS PATHWAY MAY HAVE THERAPEUTIC RELEVANCE IN PREVENTING/AMELIORATING TOBACCO-RELATED KIDNEY INJURY. 2013 11 1171 19 CONTRIBUTION OF MATURE HEPATOCYTES TO BILIARY REGENERATION IN RATS WITH ACUTE AND CHRONIC BILIARY INJURY. WHETHER HEPATOCYTES CAN CONVERT INTO BILIARY EPITHELIAL CELLS (BECS) DURING BILIARY INJURY IS MUCH DEBATED. TO TEST THIS CONCEPT, WE TRACED THE FATE OF GENETICALLY LABELED [DIPEPTIDYL PEPTIDASE IV (DPPIV)-POSITIVE] HEPATOCYTES IN HEPATOCYTE TRANSPLANTATION MODEL FOLLOWING ACUTE HEPATO-BILIARY INJURY INDUCED BY 4,4'-METHYLENE-DIANILINE (DAPM) AND D-GALACTOSAMINE (DAPM+D-GAL) AND IN DPPIV-CHIMERIC LIVER MODEL SUBJECTED TO ACUTE (DAPM+D-GAL) OR CHRONIC BILIARY INJURY CAUSED BY DAPM AND BILE DUCT LIGATION (DAPM+BDL). IN BOTH MODELS BEFORE BILIARY INJURY, BECS ARE UNIFORMLY DPPIV-DEFICIENT AND PROLIFERATION OF DPPIV-DEFICIENT HEPATOCYTES IS RESTRICTED BY RETRORSINE. WE FOUND THAT MATURE HEPATOCYTES UNDERWENT A STEPWISE CONVERSION INTO BECS AFTER BILIARY INJURY. IN THE HEPATOCYTE TRANSPLANTATION MODEL, DPPIV-POSITIVE HEPATOCYTES ENTRAPPED PERIPORTALLY PROLIFERATED, AND FORMED TWO-LAYERED PLATES ALONG PORTAL VEINS. WITHIN THE TWO-LAYERED PLATES, THE HEPATOCYTES GRADUALLY LOST THEIR HEPATOCYTIC IDENTITY, PROCEEDED THROUGH AN INTERMEDIATE STATE, ACQUIRED A BILIARY PHENOTYPE, AND SUBSEQUENTLY FORMED BILE DUCTS ALONG THE HILUM-TO-PERIPHERY AXIS. IN DPPIV-CHIMERIC LIVER MODEL, PERIPORTAL HEPATOCYTES EXPRESSING HEPATOCYTE NUCLEAR FACTOR-1BETA (HNF-1BETA) WERE EXCLUSIVELY DPPIV-POSITIVE AND WERE IN CONTINUITY TO DPPIV-POSITIVES BILE DUCTS. INHIBITION OF HEPATOCYTE PROLIFERATION BY ADDITIONAL DOSES OF RETRORSINE IN DPPIV-CHIMERIC LIVERS PREVENTED THE APPEARANCE OF DPPIV-POSITIVE BECS AFTER BILIARY INJURY. MOREOVER, ENRICHED DPPIV-POSITIVE BEC/HEPATIC OVAL CELL TRANSPLANTATION PRODUCED DPPIV-POSITIVE BECS OR BILE DUCTS IN UNEXPECTEDLY LOW FREQUENCY AND IN MID-LOBULAR REGIONS. THESE RESULTS TOGETHER SUGGEST THAT MATURE HEPATOCYTES BUT NOT CONTAMINATING BECS/HEPATIC OVAL CELLS ARE THE SOURCES OF PERIPORTAL DPPIV-POSITIVE BECS. WE CONCLUDE THAT MATURE HEPATOCYTES CONTRIBUTE TO BILIARY REGENERATION IN THE ENVIRONMENT OF ACUTE AND CHRONIC BILIARY INJURY THROUGH A DUCTAL PLATE CONFIGURATION WITHOUT THE NEED OF EXOGENOUSLY GENETIC OR EPIGENETIC MANIPULATION. 2015 12 3416 21 HTR1A, HTR1B, HTR2A, HTR2C AND HTR6 GENE POLYMORPHISMS AND EXTRAPYRAMIDAL SIDE EFFECTS IN HALOPERIDOL-TREATED PATIENTS WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A SERIOUS, CHRONIC PSYCHIATRIC DISORDER REQUIRING LIFELONG TREATMENT. EXTRAPYRAMIDAL SIDE EFFECTS (EPS) ARE COMMON ADVERSE REACTIONS TO ANTIPSYCHOTIC MEDICATIONS. IN ADDITION TO THE DOPAMINERGIC SYSTEM, SEROTONERGIC MECHANISMS, INCLUDING SEROTONIN (5-HT) RECEPTORS, MIGHT BE INVOLVED IN EPS DEVELOPMENT. THIS STUDY AIMED TO EXAMINE MOLECULAR ASSOCIATIONS OF HTR1A, HTR1B, HTR2A, HTR2C AND HTR6 GENE POLYMORPHISMS WITH ACUTE EPS IN 229 MALE SCHIZOPHRENIA PATIENTS, FOLLOWING TWO WEEKS OF HALOPERIDOL MONOTHERAPY. THE SIMPSON-ANGUS RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS (SAS), BARNES AKATHISIA RATING SCALE (BARS) AND EXTRAPYRAMIDAL SYMPTOM RATING SCALE (ESRS) WERE USED TO EVALUATE EPS SEVERITY. GENOTYPING WAS PERFORMED USING REAL-TIME PCR, FOLLOWING EXTRACTION OF BLOOD DNA. SIGNIFICANT ACUTE EPS APPEARED IN 48.03% OF SCHIZOPHRENIA PATIENTS. FOR THE RS13212041 HTR1B GENE POLYMORPHISM, AFFECTING MICRORNA REGULATION OF HTR1B GENE EXPRESSION, A HIGHER FREQUENCY OF TT CARRIERS WAS FOUND AMONG HALOPERIDOL-TREATED PATIENTS WITH AKATHISIA WHEN COMPARED TO THE GROUP WITHOUT AKATHISIA SYMPTOMS. IN COMPARISON TO C-ALLELE CARRIERS, PATIENTS CARRYING THE TT GENOTYPE HAD HIGHER AKATHISIA SEVERITY, AS DETERMINED BY THE SAS, BARS AND ESRS SCALES. THESE MOLECULAR FINDINGS SUGGEST POTENTIAL INVOLVEMENT OF 5-HT(1B) RECEPTORS IN AKATHISIA DEVELOPMENT FOLLOWING HALOPERIDOL TREATMENT, AS WELL AS POSSIBLE EPIGENETIC MECHANISMS OF SEROTONERGIC MODULATION ASSOCIATED WITH ANTIPSYCHOTIC-INDUCED EPS. 2020 13 2134 27 EPIGENETIC INACTIVATION OF THE MIR129-2 IN HEMATOLOGICAL MALIGNANCIES. BACKGROUND: MIR129-2 HAS BEEN SHOWN TO BE A TUMOR SUPPRESSOR MICRORNA HYPERMETHYLATED IN EPITHELIAL CANCERS. PATIENTS AND METHODS: EPIGENETIC INACTIVATION OF MIR129-2 WAS STUDIED BY METHYLATION-SPECIFIC PCR (MSP) IN 13 CELL LINES (EIGHT MYELOMA AND FIVE LYMPHOMA), 15 NORMAL CONTROLS AND 344 PRIMARY SAMPLES INCLUDING ACUTE MYELOID LEUKEMIA (AML), ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC MYELOID LEUKEMIA (CML), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), NON-HODGKIN'S LYMPHOMA (NHL), MULTIPLE MYELOMA (MM) AT DIAGNOSIS, MM AT RELAPSE/PROGRESSION, AND MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS). EXPRESSION OF MIR129 AND ITS TARGET, SOX4, IN CELL LINES WAS MEASURED BEFORE AND AFTER HYPOMETHYLATING TREATMENT AND MIR129 OVEREXPRESSION. MIR129 EXPRESSION WAS CORRELATED WITH MIR129-2 METHYLATION STATUS IN PRIMARY LYMPHOMA SAMPLES. TUMOR SUPPRESSOR FUNCTION OF MIR129 WAS DEMONSTRATED BY MTT AND TRYPAN BLUE EXCLUSION ASSAY AFTER MIR129 OVEREXPRESSION. RESULTS: THE SENSITIVITY OF THE METHYLATED-MSP WAS ONE IN 10(3). DIFFERENT MSP STATUSES, INCLUDING COMPLETE METHYLATION, PARTIAL METHYLATION, AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE PYROSEQUENCING. ALL FIVE LYMPHOMA AND SEVEN OF EIGHT MYELOMA CELL LINES SHOWED COMPLETE AND PARTIAL MIR129-2 METHYLATION. IN PRIMARY SAMPLES, MIR129-2 METHYLATION WAS ABSENT IN AML AND CML, BUT DETECTED IN 5% ALL, 45.9% CLL, 49.5% MM AT DIAGNOSIS, AND 59.1% NHL. IN CLL, MIR129-2 METHYLATION ADVERSELY IMPACTED ON SURVIVAL (P=0.004). IN MM, MIR129-2 METHYLATION INCREASED FROM 27.5% MGUS TO 49.5% MM AT DIAGNOSIS AND 41.5% AT RELAPSE/PROGRESSION (P=0.023). IN NHL, MIR129-2 METHYLATION WAS ASSOCIATED WITH MIR124-1 AND MIR203 METHYLATION (P<0.001), AND LOWER MIR129 EXPRESSION (P=0.009). HYPOMETHYLATION TREATMENT OF JEKO-1, HOMOZYGOUSLY METHYLATED FOR MIR129-2, LED TO MIR129-2 DEMETHYLATION AND MIR129 RE-EXPRESSION, WITH DOWNREGULATION OF SOX4 MRNA. MOREOVER, MIR129 OVEREXPRESSION IN BOTH MANTLE CELL LINES, JEKO-1 AND GRANTA-519, INHIBITED CELLULAR PROLIFERATION AND ENHANCED CELL DEATH, WITH CONCOMITANT SOX4 MRNA DOWNREGULATION. CONCLUSIONS: MIR129-2 IS A TUMOR SUPPRESSIVE MICRORNA FREQUENTLY METHYLATED IN LYMPHOID BUT NOT MYELOID MALIGNANCIES, LEADING TO REVERSIBLE MIR129-2 SILENCING. IN CLL, MIR129-2 METHYLATION WAS ASSOCIATED WITH AN INFERIOR SURVIVAL. IN MM, MIR129-2 METHYLATION MIGHT BE ACQUIRED DURING PROGRESSION FROM MGUS TO SYMPTOMATIC MM. IN NHL, MIR129-2 METHYLATION MIGHT COLLABORATE WITH MIR124-1 AND MIR203 METHYLATION IN LYMPHOMAGENESIS. 2013 14 3216 36 HEDGEHOG SIGNALING PATHWAY AND GASTROINTESTINAL STEM CELL SIGNALING NETWORK (REVIEW). HEDGEHOG, BMP/TGFBETA, FGF, WNT AND NOTCH SIGNALING PATHWAYS CONSTITUTE THE STEM CELL SIGNALING NETWORK, WHICH PLAYS A KEY ROLE IN A VARIETY OF PROCESSES, SUCH AS EMBRYOGENESIS, MAINTENANCE OF ADULT TISSUE HOMEOSTASIS, TISSUE REPAIR DURING CHRONIC PERSISTENT INFLAMMATION, AND CARCINOGENESIS. SONIC HEDGEHOG (SHH), INDIAN HEDGEHOG (IHH) AND DESERT HEDGEHOG (DHH) BIND TO PTCH1/PTCH OR PTCH2 RECEPTOR TO RELEASE SMOOTHENED (SMO) SIGNAL TRANSDUCER FROM PATCHED-DEPENDENT SUPPRESSION. SMO THEN ACTIVATES STK36 SERINE/THREONINE KINASE TO STABILIZE GLI FAMILY MEMBERS AND TO PHOSPHORYLATE SUFU FOR NUCLEAR ACCUMULATION OF GLI. HEDGEHOG SIGNALING ACTIVATION LEADS TO GLI-DEPENDENT TRANSCRIPTIONAL ACTIVATION OF TARGET GENES, SUCH AS GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1. GLI1-DEPENDENT POSITIVE FEEDBACK LOOP COMBINED WITH PTCH1-DEPENDENT NEGATIVE FEEDBACK LOOP GIVES RISE TO TRANSIENT PROLIFERATION OF HEDGEHOG TARGET CELLS. IGUANA HOMOLOGS (DZIP1 AND DZIP1L) AND COSTAL-2 HOMOLOGS (KIF7 AND KIF27) ARE IDENTIFIED BY COMPARATIVE INTEGROMICS. SHH-DEPENDENT PARIETAL CELL PROLIFERATION IS IMPLICATED IN GASTRIC MUCOSAL REPAIR DURING CHRONIC HELICOBACTER PYLORI INFECTION. BMP-RUNX3 SIGNALING INDUCES IHH EXPRESSION IN SURFACE DIFFERENTIATED EPITHELIAL CELLS OF STOMACH AND INTESTINE. HEDGEHOG SIGNALS FROM EPITHELIAL CELLS THEN INDUCES FOXL1-MEDIATED BMP4 UPREGULATION IN MESENCHYMAL CELLS. HEDGEHOG SIGNALING IS FREQUENTLY ACTIVATED IN ESOPHAGEAL CANCER, GASTRIC CANCER AND PANCREATIC CANCER DUE TO TRANSCRIPTIONAL UPREGULATION OF HEDGEHOG LIGANDS AND EPIGENETIC SILENCING OF HHIP1/HHIP GENE, ENCODING THE HEDGEHOG INHIBITOR. HOWEVER, HEDGEHOG SIGNALING IS RARELY ACTIVATED IN COLORECTAL CANCER DUE TO NEGATIVE REGULATION BY THE CANONICAL WNT SIGNALING PATHWAY. HEDGEHOG SIGNALING MOLECULES OR TARGETS, SUCH AS SHH, IHH, HHIP1, PTCH1 AND GLI1, ARE APPLIED AS BIOMARKERS FOR CANCER DIAGNOSTICS, PROGNOSTICS AND THERAPEUTICS. SMALL-MOLECULE INHIBITORS FOR SMO OR STK36 ARE SUITABLE TO BE USED FOR TREATMENT OF HEDGEHOG-DEPENDENT CANCER. 2006 15 2880 24 FUSOBACTERIUM NUCLEATUM INFECTION IN COLORECTAL CANCER: LINKING INFLAMMATION, DNA MISMATCH REPAIR AND GENETIC AND EPIGENETIC ALTERATIONS. IT HAS BEEN RECENTLY REPORTED THAT THE POPULATION OF FUSOBACTERIUM, PARTICULARLY FUSOBACTERIUM NUCLEATUM (FN), IS OVERREPRESENTED IN COLORECTAL CANCERS AND ADENOMAS. THE PROMOTING EFFECTS OF FN INFECTION ON ADENOMA AND/OR CARCINOMA FORMATION HAVE BEEN SHOWN IN APC(MIN/+)MICE. CHARACTERISTICS OF FN-ASSOCIATED CRC WERE IDENTIFIED THROUGH STUDIES USING HUMAN CRC COHORTS, AND INCLUDE RIGHT-SIDED COLON LOCATION, CPG ISLAND METHYLATION PHENOTYPE-HIGH (CIMP-H), HIGH LEVEL OF MICROSATELLITE INSTABILITY (MSI-H), AND POOR PATIENT PROGNOSIS. A SUBSET OF FN-ASSOCIATED CRC EXHIBITS A LOW LEVEL OF MICROSATELLITE INSTABILITY (MSI-L) AND ELEVATED MICROSATELLITE ALTERATIONS IN SELECTED TETRA-NUCLEOTIDE REPEATS (EMAST) INDUCED BY TRANSLOCATION OF MSH3 FROM THE NUCLEUS TO THE CYTOPLASM IN RESPONSE TO OXIDATIVE DNA DAMAGE OR INFLAMMATORY SIGNALS. THE ASSOCIATION BETWEEN CIMP/MSI-H AND FN-INFECTION CAN BE EXPLAINED BY THE ROLE OF THE MISMATCH REPAIR (MMR) PROTEIN COMPLEX FORMED BETWEEN MSH2 AND MSH6 (MUTSALPHA) TO REPAIR ABERRANT BASES GENERATED BY ROS TO FORM 7,8-DIHYDRO-8-OXO-GUANINE (8-OXOG). CLUSTERED 8-OXOGS FORMED AT CPG-RICH REGIONS INCLUDING PROMOTERS BY ROS IS REFRACTORY TO BASE EXCISION REPAIR (BER). UNDER THESE CONDITIONS, MUTSALPHA INITIATES REPAIR IN COOPERATION WITH DNA METHYLTRANSFERASES (DNMTS) AND THE POLYCOMB REPRESSIVE COMPLEX 4 (PRC4). DNMTS AT DAMAGED SITES METHYLATE CPG ISLANDS TO REPRESS TRANSCRIPTION OF TARGET GENES AND PROMOTE REPAIR REACTIONS. THUS, CONTINUOUS GENERATION OF ROS THROUGH CHRONIC FN INFECTION MAY INITIATE 1) CIMP-POSITIVE ADENOMA AND CARCINOMA IN AN MSH2/MSH6-DEPENDENT MANNER, AND/OR 2) MSI-L/EMAST CRC IN AN MSH3-DEPENDENT MANNER. THE POOR PROGNOSIS OF FN-ASSOCIATED CRC CAN BE EXPLAINED BY FN-INDUCED IMMUNE-EVASION AND/OR CHEMO-RESISTANCE. 2018 16 3303 21 HIGH-FREQUENCY P16(INK) (4A) PROMOTER METHYLATION IS ASSOCIATED WITH HISTONE METHYLTRANSFERASE SETDB1 EXPRESSION IN SPORADIC CUTANEOUS MELANOMA. EPIGENETIC MECHANISMS PARTICIPATE IN MELANOMA DEVELOPMENT AND PROGRESSION. THE EFFECT OF HISTONE MODIFICATIONS AND THEIR CATALYSING ENZYMES OVER EUCHROMATIC PROMOTER DNA METHYLATION IN MELANOMA REMAINS UNCLEAR. THIS STUDY INVESTIGATED THE POTENTIAL ASSOCIATION OF P16(INK) (4A) PROMOTER METHYLATION WITH HISTONE METHYLTRANSFERASE SETDB1 EXPRESSION IN GREEK PATIENTS WITH SPORADIC MELANOMA AND THEIR CORRELATION WITH CLINICOPATHOLOGICAL CHARACTERISTICS. PROMOTER METHYLATION WAS DETECTED BY METHYLATION-SPECIFIC PCR IN 100 PERIPHERAL BLOOD SAMPLES AND 58 MELANOMA TISSUES FROM THE SAME PATIENTS. CELL PROLIFERATION (KI-67 INDEX), P16(INK) (4A) AND SETDB1 EXPRESSION WERE EVALUATED BY IMMUNOHISTOCHEMISTRY. HIGH-FREQUENCY PROMOTER METHYLATION (25.86%) WAS OBSERVED IN TISSUE SAMPLES AND CORRELATED WITH INCREASED CELL PROLIFERATION (P = 0.0514). P16(INK) (4A) PROMOTER METHYLATION WAS HIGHER IN VERTICAL GROWTH-PHASE (60%) MELANOMAS THAN IN RADIAL (40%, P = 0.063) AND THOSE DISPLAYING EPIDERMAL INVOLVEMENT (P = 0.046). IMPORTANTLY, P16(INK) (4A) METHYLATION CORRELATED WITH INCREASED MELANOMA THICKNESS ACCORDING TO BRESLOW INDEX (P = 0.0495) AND MARGINALLY WITH INCREASED CLARK LEVEL (I/II VS III/IV/V, P = 0.070). LOW (1-30%) P16(INK) (4A) EXPRESSION WAS DETECTED AT THE MAJORITY (19 OF 54) OF MELANOMA CASES (35.19%), BEING MARGINALLY CORRELATED WITH TUMOR LYMPHOCYTIC INFILTRATION (P = 0.078). SETDB1 NUCLEAR IMMUNOREACTIVITY WAS OBSERVED IN 47 OF 57 (82.46%) CASES, WHEREAS 27 OF 57 (47.37%) SHOWED CYTOPLASMIC IMMUNOEXPRESSION. CYTOPLASMIC SETDB1 EXPRESSION CORRELATED WITH HIGHER FREQUENCY OF P16(INK) (4A) METHYLATION AND P16(INK) (4A) EXPRESSION (P = 0.033, P = 0.011, RESPECTIVELY). INCREASED NUCLEAR SETDB1 LEVELS WERE ASSOCIATED WITH HIGHER MITOTIC COUNT (0-5/MM(2) VS >5/MM(2) , P = 0.0869), ADVANCED CLARK LEVEL (III-V, P = 0.0380), EPIDERMAL INVOLVEMENT (P = 0.0331) AND THE NON-CHRONIC SUN EXPOSURE-ASSOCIATED MELANOMA TYPE (P = 0.0664). OUR DATA DEMONSTRATE FOR THE FIRST TIME THE ASSOCIATION OF HISTONE METHYLTRANSFERASE SETDB1 WITH FREQUENT METHYLATION OF THE EUCHROMATIC P16(INK) (4A) PROMOTER AND SEVERAL PROGNOSTIC PARAMETERS IN MELANOMAS. 2014 17 2867 25 FUNCTIONAL AND CANCER GENOMICS OF ASXL FAMILY MEMBERS. ADDITIONAL SEX COMBS-LIKE (ASXL)1, ASXL2 AND ASXL3 ARE HUMAN HOMOLOGUES OF THE DROSOPHILA ASX GENE THAT ARE INVOLVED IN THE REGULATION OR RECRUITMENT OF THE POLYCOMB-GROUP REPRESSOR COMPLEX (PRC) AND TRITHORAX-GROUP (TRXG) ACTIVATOR COMPLEX. ASXL PROTEINS CONSIST OF ASXN, ASXH, ASXM1, ASXM2 AND PHD DOMAINS. ASXL1 DIRECTLY INTERACTS WITH BAP1, KDM1A (LSD1), NCOA1 AND NUCLEAR HORMONE RECEPTORS (NHRS), SUCH AS RETINOIC ACID RECEPTORS, OESTROGEN RECEPTOR AND ANDROGEN RECEPTOR. ASXL FAMILY MEMBERS ARE EPIGENETIC SCAFFOLDING PROTEINS THAT ASSEMBLE EPIGENETIC REGULATORS AND TRANSCRIPTION FACTORS TO SPECIFIC GENOMIC LOCI WITH HISTONE MODIFICATIONS. ASXL1 IS INVOLVED IN TRANSCRIPTIONAL REPRESSION THROUGH AN INTERACTION WITH PRC2 AND ALSO CONTRIBUTES TO TRANSCRIPTIONAL REGULATION THROUGH INTERACTIONS WITH BAP1 AND/OR NHR COMPLEXES. GERM-LINE MUTATIONS OF HUMAN ASXL1 AND ASXL3 OCCUR IN BOHRING-OPITZ AND RELATED SYNDROMES. AMPLIFICATION AND OVEREXPRESSION OF ASXL1 OCCUR IN CERVICAL CANCER. TRUNCATION MUTATIONS OF ASXL1 OCCUR IN COLORECTAL CANCERS WITH MICROSATELLITE INSTABILITY (MSI), MALIGNANT MYELOID DISEASES, CHRONIC LYMPHOCYTIC LEUKAEMIA, HEAD AND NECK SQUAMOUS CELL CARCINOMA, AND LIVER, PROSTATE AND BREAST CANCERS; THOSE OF ASXL2 OCCUR IN PROSTATE CANCER, PANCREATIC CANCER AND BREAST CANCER AND THOSE OF ASXL3 ARE OBSERVED IN MELANOMA. EPC1-ASXL2 GENE FUSION OCCURS IN ADULT T-CELL LEUKAEMIA/LYMPHOMA. THE PROGNOSIS OF MYELOID MALIGNANCIES WITH MISREGULATING TRUNCATION MUTATIONS OF ASXL1 IS POOR. ASXL FAMILY MEMBERS ARE ASSUMED TO BE TUMOUR SUPPRESSIVE OR ONCOGENIC IN A CONTEXT-DEPENDENT MANNER. 2013 18 1950 26 EPIGENETIC ACTIVATION OF TENSIN 4 PROMOTES GASTRIC CANCER PROGRESSION. GASTRIC CANCER (GC) IS A COMPLEX DISEASE INFLUENCED BY MULTIPLE GENETIC AND EPIGENETIC FACTORS. CHRONIC INFLAMMATION CAUSED BY HELICOBACTER PYLORI INFECTION AND DIETARY RISK FACTORS CAN RESULT IN THE ACCUMULATION OF ABERRANT DNA METHYLATION IN GASTRIC MUCOSA, WHICH PROMOTES GC DEVELOPMENT. TENSIN 4 (TNS4), A MEMBER OF THE TENSIN FAMILY OF PROTEINS, IS LOCALIZED TO FOCAL ADHESION SITES, WHICH CONNECT THE EXTRACELLULAR MATRIX AND CYTOSKELETAL NETWORK. WE IDENTIFIED UPREGULATION OF TNS4 IN GC USING QUANTITATIVE REVERSE TRANSCRIPTION PCR WITH 174 PAIRED SAMPLES OF GC TUMORS AND ADJACENT NORMAL TISSUES. TRANSCRIPTIONAL ACTIVATION OF TNS4 OCCURRED EVEN DURING THE EARLY STAGE OF TUMOR DEVELOPMENT. TNS4 DEPLETION IN GC CELL LINES THAT EXPRESSED HIGH TO MODERATE LEVELS OF TNS4, I.E., SNU-601, KATO III, AND MKN74, REDUCED CELL PROLIFERATION AND MIGRATION, WHEREAS ECTOPIC EXPRESSION OF TNS4 IN THOSE LINES THAT EXPRESSED LOWER LEVELS OF TNS4, I.E., SNU-638, MKN1, AND MKN45 INCREASED COLONY FORMATION AND CELL MIGRATION. THE PROMOTER REGION OF TNS4 WAS HYPOMETHYLATED IN GC CELL LINES THAT SHOWED UPREGULATION OF TNS4. WE ALSO FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN TNS4 EXPRESSION AND CPG METHYLATION IN 250 GC TUMORS BASED ON THE CANCER GENOME ATLAS (TCGA) DATA. THIS STUDY ELUCIDATES THE EPIGENETIC MECHANISM OF TNS4 ACTIVATION AND FUNCTIONAL ROLES OF TNS4 IN GC DEVELOPMENT AND PROGRESSION AND SUGGESTS A POSSIBLE APPROACH FOR FUTURE GC TREATMENTS. 2023 19 3009 24 GENETICS AND EPIGENETICS IN NEOPLASMS WITH PLASMACYTOID DENDRITIC CELLS. PLASMACYTOID DENDRITIC CELLS (PDC) ARE TYPE I INTERFERON (IFN)-PRODUCING CELLS THAT PLAY A KEY ROLE IN IMMUNE RESPONSES. TWO MAJOR TYPES OF NEOPLASTIC COUNTERPARTS FOR PDC ARE NOW DISCRIMINATED: BLASTIC PDC NEOPLASM (BPDCN) AND MATURE PDC PROLIFERATION (MPDCP), ASSOCIATED WITH MYELOID NEOPLASM. TWO TYPES OF MPDCP ARE NOW BETTER DESCRIBED: CHRONIC MYELOMONOCYTIC LEUKEMIA WITH PDC EXPANSION (PDC-CMML) AND ACUTE MYELOID LEUKEMIA WITH PDC EXPANSION (PDC-AML). DIFFERENTIAL DIAGNOSIS BETWEEN PDC-AML AND BPDCN IS PARTICULARLY CHALLENGING, AND GENOMIC FEATURES CAN HELP FOR DIAGNOSIS. HERE, WE SYSTEMATICALLY REVIEW THE CYTOGENETIC, MOLECULAR, AND TRANSCRIPTIONAL CHARACTERISTICS OF BPDCN AND PDC-AML. BPDCN ARE CHARACTERIZED BY FREQUENT COMPLEX KARYOTYPES WITH RECURRENT MYB/MYC REARRANGEMENTS AS WELL AS RECURRENT DELETIONS INVOLVING ETV6, IKZF1, RB1, AND TP53 LOCI. EPIGENETIC AND SPLICING PATHWAYS ARE ALSO PARTICULARLY MUTATED, WHILE ORIGINAL PROCESSES ARE DYSREGULATED, SUCH AS NF-KB, TCF4, BCL2, AND IFN PATHWAYS; NEUTROPHIL-SPECIFIC RECEPTORS; AND CHOLINERGIC SIGNALING. IN CONTRAST, CYTOGENETIC ABNORMALITIES ARE LIMITED IN PDC-AML AND ARE QUITE SIMILAR TO OTHER AML. INTERESTINGLY, RUNX1 IS THE MOST FREQUENTLY MUTATED GENE (70% OF CASES). THESE TYPICAL GENOMIC FEATURES ARE OF POTENTIAL INTEREST FOR DIAGNOSIS, AND ALSO FROM A PROGNOSTIC OR THERAPEUTIC PERSPECTIVE. 2022 20 2042 22 EPIGENETIC CHARACTERISTICS IN INFLAMMATORY CANDIDATE GENES IN AGGRESSIVE PERIODONTITIS. BACKGROUND: PERIODONTITIS IS A CHRONIC INFLAMMATORY DISEASE TRIGGERED BY THE HOST IMMUNE RESPONSE. EPIGENETIC MODIFICATIONS ALSO AFFECT THE IMMUNE RESPONSE. WE ASSESSED CPG METHYLATION IN 22 INFLAMMATORY CANDIDATE GENES (ATF2, CCL25, CXCL14, CXCL3, CXCL5, CXCL6, FADD, GATA3, IL10RA, IL12A, IL12B, IL13, IL13RA1, IL15, IL17C, IL17RA, IL4R, IL6R, IL6ST, IL7, INHA, AND TYK2) WITH RESPECT TO THE OCCURRENCE OF AGGRESSIVE PERIODONTITIS (AGP). PATIENTS AND METHODS: IN THIS STUDY 15 AGP PATIENTS (53.3% MALES, 41.4+/-10.5 YEARS) AND 10 CONTROLS (40.0% MALES, 36.9+/-17.5 YEARS) WERE INCLUDED. THE METHYLATION PATTERNS OF GINGIVAL BIOPSIES WERE QUANTIFIED USING EPITECT(R) METHYL SIGNATURE PCR ARRAY HUMAN INFLAMMATORY RESPONSE. RESULTS: IN GINGIVAL BIOPSIES TAKEN FROM PATIENTS WITH AGP, CPG METHYLATION OF CCL25 (1.73% VS. 2.59%, P=0.015) AND IL17C (6.89% VS. 19.27%, P=0.002) WAS SIGNIFICANTLY REDUCED AS COMPARED WITH PERIODONTALLY HEALTHY TISSUES. DISCUSSION: WE SHOWED FOR THE FIRST TIME A DIFFERENTIAL METHYLATION PATTERN FOR CCL25 AND IL17C IN PERIODONTITIS. CCL25 PLAYS AN IMPORTANT ROLE IN T-CELL DEVELOPMENT, WHEREAS IL17C REGULATES INNATE EPITHELIAL IMMUNE RESPONSES. THE DECREASE IN CPG METHYLATION IS PRESUMABLY ACCOMPANIED BY AN INCREASE IN GENE EXPRESSION. THIS COULD LEAD TO A GREATER AVAILABILITY OF CCL25 AND INTERLEUKIN 17C AND SUPPORT PERIODONTAL LOSS OF ATTACHMENT. 2016