1 6463 150 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 2 967 19 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 3 2796 18 FBW7 MEDIATES SENESCENCE AND PULMONARY FIBROSIS THROUGH TELOMERE UNCAPPING. TISSUE STEM CELLS UNDERGO PREMATURE SENESCENCE UNDER STRESS, PROMOTING AGE-RELATED DISEASES; HOWEVER, THE ASSOCIATED MECHANISMS REMAIN UNCLEAR. HERE, WE REPORT THAT IN RESPONSE TO RADIATION, OXIDATIVE STRESS, OR BLEOMYCIN, THE E3 UBIQUITIN LIGASE FBW7 MEDIATES CELL SENESCENCE AND TISSUE FIBROSIS THROUGH TELOMERE UNCAPPING. FBW7 BINDING TO TELOMERE PROTECTION PROTEIN 1 (TPP1) FACILITATES TPP1 MULTISITE POLYUBIQUITINATION AND ACCELERATES DEGRADATION, TRIGGERING TELOMERE UNCAPPING AND DNA DAMAGE RESPONSE. OVEREXPRESSING TPP1 OR INHIBITING FBW7 BY GENETIC ABLATION, EPIGENETIC INTERFERENCE, OR PEPTIDOMIMETIC TELOMERE DYSFUNCTION INHIBITOR (TELODIN) REDUCES TELOMERE UNCAPPING AND SHORTENING, EXPANDING THE PULMONARY ALVEOLAR AEC2 STEM CELL POPULATION IN MICE. TELODIN, SYNTHESIZED FROM THE SEVENTH BETA STRAND BLADE OF FBW7 WD40 PROPELLER DOMAIN, INCREASES TPP1 STABILITY, LUNG RESPIRATORY FUNCTION, AND RESISTANCE TO SENESCENCE AND FIBROSIS IN ANIMALS CHRONICALLY EXPOSED TO ENVIRONMENTAL STRESS. OUR FINDINGS ELUCIDATE A PIVOTAL MECHANISM UNDERLYING STRESS-INDUCED PULMONARY EPITHELIAL STEM CELL SENESCENCE AND FIBROSIS, PROVIDING A FRAMEWORK FOR AGING-RELATED DISORDER INTERVENTIONS. 2020 4 2649 23 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 5 3303 27 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 6 1791 23 EFFECT OF CHRONIC RADIATION ON THE FLAX (LINUM USITATISSIMUM L.) GENOME GROWN FOR SIX CONSECUTIVE GENERATIONS IN THE RADIOACTIVE CHERNOBYL AREA. THE GROWTH OF PLANTS UNDER CHRONIC RADIATION STRESS IN THE CHERNOBYL AREA MAY CAUSE CHANGES IN THE GENOME OF PLANTS. TO ASSESS THE EXTENT OF GENETIC AND EPIGENETIC CHANGES IN NUCLEAR DNA, SEEDS OF THE ANNUAL CROP FLAX (LINUM USITATISSIMUM L.) OF THE KYIVSKYI VARIETY, SOWN 21 YEARS AFTER THE ACCIDENT AND GROWN FOR SIX GENERATIONS IN RADIOACTIVE (RAD) AND REMEDIATED (REM) FIELDS WERE ANALYSED. FLAXSEED USED FOR SOWING FIRST GENERATION, WHICH SERVED AS A REFERENCE (REF), WAS ALSO ANALYSED. THE AFLP (AMPLIFIED FRAGMENT LENGTH POLYMORPHISM) REVEALED A HIGHER NUMBER OF SPECIFIC ECORI-MSEI LOCI (3.4-FOLD) IN POOLED FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH THE REM FIELD, INDICATING A LINK BETWEEN THE MUTATION PROCESS IN THE FLAX GENOME AND THE ONGOING ADAPTATION PROCESS. MSAP (METHYLATION-SENSITIVE AMPLIFIED POLYMORPHISM) DETECTING ECORI-MSPI AND ECORI-HPAII LOCI IN FLAX NUCLEAR DNA GENOME SHOWED NO SIGNIFICANT DIFFERENCES IN METHYLATION LEVEL, REACHING ABOUT 33% IN EACH OF THE GROUPS STUDIED. ON THE OTHER HAND, SIGNIFICANT CHANGES IN THE DNA METHYLATION PATTERN OF FLAXSEED SAMPLES HARVESTED FROM THE RAD FIELD COMPARED WITH CONTROLS WERE DETECTED. PAIRWISE F(ST) COMPARISON REVEALED WITHIN BOTH, ECORI-MSPI AND TRANSFORMED METHYLATION-SENSITIVE DATA SETS MORE THAN A 3-FOLD INCREASE OF GENETIC DIVERGENCE IN THE RAD FIELD COMPARED WITH BOTH CONTROLS. THESE RESULTS INDICATE THAT THE NUCLEAR GENOME OF FLAX EXPOSED TO CHRONIC RADIATION FOR SIX GENERATIONS HAS MORE MUTATIONS AND USES DNA METHYLATION AS ONE OF THE ADAPTATION MECHANISMS FOR SUSTAINABILITY UNDER ADVERSE CONDITIONS. 2022 7 2042 28 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 8 56 21 A GENOME-WIDE ASSOCIATION META-ANALYSIS OF CIRCULATING SEX HORMONE-BINDING GLOBULIN REVEALS MULTIPLE LOCI IMPLICATED IN SEX STEROID HORMONE REGULATION. SEX HORMONE-BINDING GLOBULIN (SHBG) IS A GLYCOPROTEIN RESPONSIBLE FOR THE TRANSPORT AND BIOLOGIC AVAILABILITY OF SEX STEROID HORMONES, PRIMARILY TESTOSTERONE AND ESTRADIOL. SHBG HAS BEEN ASSOCIATED WITH CHRONIC DISEASES INCLUDING TYPE 2 DIABETES (T2D) AND WITH HORMONE-SENSITIVE CANCERS SUCH AS BREAST AND PROSTATE CANCER. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) META-ANALYSIS OF 21,791 INDIVIDUALS FROM 10 EPIDEMIOLOGIC STUDIES AND VALIDATED THESE FINDINGS IN 7,046 INDIVIDUALS IN AN ADDITIONAL SIX STUDIES. WE IDENTIFIED TWELVE GENOMIC REGIONS (SNPS) ASSOCIATED WITH CIRCULATING SHBG CONCENTRATIONS. LOCI NEAR THE IDENTIFIED SNPS INCLUDED SHBG (RS12150660, 17P13.1, P = 1.8 X 10(-106)), PRMT6 (RS17496332, 1P13.3, P = 1.4 X 10(-11)), GCKR (RS780093, 2P23.3, P = 2.2 X 10(-16)), ZBTB10 (RS440837, 8Q21.13, P = 3.4 X 10(-09)), JMJD1C (RS7910927, 10Q21.3, P = 6.1 X 10(-35)), SLCO1B1 (RS4149056, 12P12.1, P = 1.9 X 10(-08)), NR2F2 (RS8023580, 15Q26.2, P = 8.3 X 10(-12)), ZNF652 (RS2411984, 17Q21.32, P = 3.5 X 10(-14)), TDGF3 (RS1573036, XQ22.3, P = 4.1 X 10(-14)), LHCGR (RS10454142, 2P16.3, P = 1.3 X 10(-07)), BAIAP2L1 (RS3779195, 7Q21.3, P = 2.7 X 10(-08)), AND UGT2B15 (RS293428, 4Q13.2, P = 5.5 X 10(-06)). THESE GENES ENCOMPASS MULTIPLE BIOLOGIC PATHWAYS, INCLUDING HEPATIC FUNCTION, LIPID METABOLISM, CARBOHYDRATE METABOLISM AND T2D, ANDROGEN AND ESTROGEN RECEPTOR FUNCTION, EPIGENETIC EFFECTS, AND THE BIOLOGY OF SEX STEROID HORMONE-RESPONSIVE CANCERS INCLUDING BREAST AND PROSTATE CANCER. WE FOUND EVIDENCE OF SEX-DIFFERENTIATED GENETIC INFLUENCES ON SHBG. IN A SEX-SPECIFIC GWAS, THE LOCI 4Q13.2-UGT2B15 WAS SIGNIFICANT IN MEN ONLY (MEN P = 2.5 X 10(-08), WOMEN P = 0.66, HETEROGENEITY P = 0.003). ADDITIONALLY, THREE LOCI SHOWED STRONG SEX-DIFFERENTIATED EFFECTS: 17P13.1-SHBG AND XQ22.3-TDGF3 WERE STRONGER IN MEN, WHEREAS 8Q21.12-ZBTB10 WAS STRONGER IN WOMEN. CONDITIONAL ANALYSES IDENTIFIED ADDITIONAL SIGNALS AT THE SHBG GENE THAT TOGETHER ALMOST DOUBLE THE PROPORTION OF VARIANCE EXPLAINED AT THE LOCUS. USING AN INDEPENDENT STUDY OF 1,129 INDIVIDUALS, ALL SNPS IDENTIFIED IN THE OVERALL OR SEX-DIFFERENTIATED OR CONDITIONAL ANALYSES EXPLAINED ~15.6% AND ~8.4% OF THE GENETIC VARIATION OF SHBG CONCENTRATIONS IN MEN AND WOMEN, RESPECTIVELY. THE EVIDENCE FOR SEX-DIFFERENTIATED EFFECTS AND ALLELIC HETEROGENEITY HIGHLIGHT THE IMPORTANCE OF CONSIDERING THESE FEATURES WHEN ESTIMATING COMPLEX TRAIT VARIANCE. 2012 9 760 23 CASZ1: CURRENT IMPLICATIONS IN CARDIOVASCULAR DISEASES AND CANCERS. CASTOR ZINC FINGER 1 (CASZ1) IS A C2H2 ZINC FINGER FAMILY PROTEIN THAT HAS TWO SPLICING VARIANTS, CASZ1A AND CASZ1B. IT IS INVOLVED IN MULTIPLE PHYSIOLOGICAL PROCESSES, SUCH AS TISSUE DIFFERENTIATION AND ALDOSTERONE ANTAGONISM. GENETIC AND EPIGENETIC ALTERNATIONS OF CASZ1 HAVE BEEN CHARACTERIZED IN MULTIPLE CARDIOVASCULAR DISORDERS, SUCH AS CONGENITAL HEART DISEASES, CHRONIC VENOUS DISEASES, AND HYPERTENSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CASZ1 MECHANICALLY PARTICIPATES IN THE PATHOGENESIS OF THESE DISEASES. OVER THE PAST DECADES, AT FIRST GLANCE, PARADOXICAL INFLUENCES ON CELL BEHAVIORS AND PROGRESSIONS OF DIFFERENT CANCER TYPES HAVE BEEN DISCOVERED FOR CASZ1, WHICH MAY BE EXPLAINED BY A "DOUBLE-AGENT" ROLE FOR CASZ1. IN THIS REVIEW, WE DISCUSS THE PHYSIOLOGICAL FUNCTION OF CASZ1, AND FOCUS ON THE ASSOCIATION OF CASZ1 ABERRATIONS WITH THE PATHOGENESIS OF CARDIOVASCULAR DISEASES AND CANCERS. 2023 10 4048 29 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 11 3903 31 LEP, LDLR AND APOA4 GENE POLYMORPHISMS AND THEIR RELATIONSHIP WITH THE RISK OF OVERWEIGHT, OBESITY AND CHRONIC DISEASES IN ADULTS OF THE STATE OF SUCRE, VENEZUELA. INTRODUCTION: OVERWEIGHT, OBESITY AND SOME CHRONIC DISEASES HAVE BECOME MORE PREVALENT RECENTLY. IT IS WELL KNOWN THAT THEIR CAUSES MAY BE GENETIC, EPIGENETIC, ENVIRONMENTAL, OR A MIXTURE OF THESE. OBJECTIVE: TO ANALYZE THE RELATIONSHIP BETWEEN NINE SINGLE NUCLEOTIDE POLYMORPHISMS OF GENES LEP (RS2167270), LDLR (RS885765, RS688, RS5925, RS55903358, RS5742911) AND APOA4 (RS5095, RS675, RS5110) WITH OBESITY-RELATED PHENOTYPES AND OTHER COMORBIDITIES. MATERIAL AND METHODS: WE RECRUITED 144 ADULTS (76 MALES AND 68 FEMALES, WITH AVERAGE AGES OF 29.93+/-8.29 AND 32.49+/-11.15 YEARS, RESPECTIVELY) IN THE STATE OF SUCRE, VENEZUELA. CLINICAL AND ANTHROPOMETRIC PARAMETERS WERE OBTAINED. GENOTYPE-RISK ASSOCIATIONS WERE STUDIED. WE THEN COMPARED THE AVERAGES REGISTERED FOR ANTHROPOMETRIC AND BIOCHEMICAL VARIABLES PREVIOUSLY ADJUSTED FOR BIOLOGICAL AND ENVIRONMENTAL FACTORS. RESULTS: ACCORDING TO THE BODY MASS INDEX, 38.9% OF THE INDIVIDUALS IN THE SAMPLE WERE OVERWEIGHT (25/=30 KG/M2). GENOTYPE AND ALLELE FREQUENCIES DID NOT DIFFER STATISTICALLY FOR GROUPS WITH NORMAL AND HIGH BODY MASS INDEX (OVERWEIGHT PLUS OBESITY). THE ASSOCIATION BETWEEN LDLR RS5742911 ANCESTRAL GENOTYPE A/A AND HIGH RISK CONDITION RELATED TO HDL-CHOLESTEROL WAS THE ONLY ONE FOUND TO BE SIGNIFICANT (OR=2.944, 95% CI: 1.446-5.996; P=0.003). THE DIFFERENCE IN ADJUSTED MEAN HDL-CHOLESTEROL FOR LDLR RS5742911 GENOTYPES WAS STATISTICALLY SIGNIFICANT (P=0.005) (A/A: 41.50+/-14.81 MG/DL; A/G: 45.00+/-12.07 MG/DL; G/G: 47.17+/-9.43 MG/DL). CONCLUSIONS: FOR MOST OF THE GENETIC VARIANTS STUDIED, THERE WAS AN ASSOCIATION WITH THE PRESENCE OF OVERWEIGHT AND OBESITY AMONG ANCESTRAL GENOTYPE CARRIERS, ALTHOUGH THIS WAS NOT STATISTICALLY SIGNIFICANT. THE RS5742911 POLYMORPHISM MAY BE USEFUL AS AN INDICATOR OF A RISK OF CHRONIC DISEASES. 2016 12 890 21 CHRONIC DIETARY EXPOSURE OF ROOSTERS TO A GLYPHOSATE-BASED HERBICIDE INCREASES SEMINAL PLASMA GLYPHOSATE AND AMPA CONCENTRATIONS, ALTERS SPERM PARAMETERS, AND INDUCES METABOLIC DISORDERS IN THE PROGENY. THE EFFECTS OF CHRONIC DIETARY ROUNDUP (RU) EXPOSURE ON ROOSTER SPERM PARAMETERS, FERTILITY, AND OFFSPRING ARE UNKNOWN. WE INVESTIGATED THE EFFECTS OF CHRONIC RU DIETARY EXPOSURE (46.8 MG KG(-1) DAY(-1) GLYPHOSATE) FOR 5 WEEKS IN 32-WEEK-OLD ROOSTERS (N = 5 RU-EXPOSED AND N = 5 CONTROL (CT)). ALTHOUGH THE CONCENTRATIONS OF GLYPHOSATE AND ITS MAIN METABOLITE AMPA (AMINOMETHYLPHOSPHONIC ACID) INCREASED IN BLOOD PLASMA AND SEMINAL FLUID DURING EXPOSURE, NO SIGNIFICANT DIFFERENCES IN TESTIS WEIGHT AND SPERM CONCENTRATIONS WERE OBSERVED BETWEEN RU AND CT ROOSTERS. HOWEVER, SPERM MOTILITY WAS SIGNIFICANTLY REDUCED, ASSOCIATED WITH DECREASED CALCIUM AND ATP CONCENTRATIONS IN RU SPERMATOZOA. PLASMA TESTOSTERONE AND OESTRADIOL CONCENTRATIONS INCREASED IN RU ROOSTERS. THESE NEGATIVE EFFECTS CEASED 14 DAYS AFTER RU REMOVAL FROM THE DIET. EPIGENETIC ANALYSIS SHOWED A GLOBAL DNA HYPOMETHYLATION IN RU ROOSTERS. AFTER ARTIFICIAL INSEMINATION OF HENS (N = 40) WITH SPERM FROM CT OR RU ROOSTERS, EGGS WERE COLLECTED AND ARTIFICIALLY INCUBATED. EMBRYO VIABILITY DID NOT DIFFER, BUT CHICKS FROM RU ROOSTERS (N = 118) HAD A HIGHER FOOD CONSUMPTION, BODY WEIGHT AND SUBCUTANEOUS ADIPOSE TISSUE CONTENT. CHRONIC DIETARY RU EXPOSURE IN ROOSTERS REDUCES SPERM MOTILITY AND INCREASES PLASMA TESTOSTERONE LEVELS, GROWTH PERFORMANCE, AND FATTENING IN OFFSPRING. 2021 13 3279 24 HERITABLE ALTERATION IN DNA METHYLATION INDUCED BY NITROGEN-DEFICIENCY STRESS ACCOMPANIES ENHANCED TOLERANCE BY PROGENIES TO THE STRESS IN RICE (ORYZA SATIVA L.). CYTOSINE METHYLATION IS RESPONSIVE TO VARIOUS BIOTIC- AND ABIOTIC-STRESSES, WHICH MAY PRODUCE HERITABLE EPIALLELES. NITROGEN (N)-DEFICIENCY IS AN ABIOTIC STRESS BEING REPEATEDLY EXPERIENCED BY PLANTS. TO ADDRESS POSSIBLE EPIGENETIC CONSEQUENCES OF N-DEFICIENCY-STRESS, WE INVESTIGATED THE STABILITY OF CYTOSINE METHYLATION IN RICE (ORYZA SATIVA L.) SUBSEQUENT TO A CHRONIC (A WHOLE-GENERATION) N-DEFICIENCY AT TWO LEVELS, MODERATE (20MG/L) AND SEVERE (10MG/L), UNDER HYDROPONIC CULTURE. MSAP ANALYSIS REVEALED THAT LOCUS-SPECIFIC METHYLATION ALTERATION OCCURRED IN LEAF-TISSUE OF THE STRESSED PLANTS (S(0)) EXPERIENCING EITHER LEVEL OF N-DEFICIENCY, WHICH WAS VALIDATED BY GEL-BLOTTING. ANALYSIS ON THREE NON-STRESSED SELF-FED PROGENIES (S(1), S(2) AND S(3)) BY GEL-BLOTTING INDICATED THAT CA. 50% OF THE ALTERED METHYLATION PATTERNS IN SOMATIC CELLS (LEAF) OF THE STRESSED S(0) PLANTS WERE RECAPTURED IN S(1), WHICH WERE THEN STABLY INHERITED TO S(2) AND S(3). BISULFITE SEQUENCING OF TWO VARIANT MSAP LOCI WITH HOMOLOGY TO LOW-COPY RETROTRANSPOSONS ON ONE STRESSED PLANT (S(0)) AND ITS NON-STRESSED PROGENIES (S(1) AND S(2)) SHOWED THAT WHEREAS ONE LOCUS EXHIBITED LIMITED AND NON-HERITABLE CHH METHYLATION ALTERATION, THE OTHER LOCUS MANIFESTED DRAMATIC HERITABLE HYPERMETHYLATION AT NEARLY ALL CYTOSINE SITES WITHIN THE ASSAYED REGION. INTRIGUINGLY, WHEN TWO GROUPS OF S(2) PLANTS DESCENDED FROM THE SAME N-DEFICIENCY-STRESSED S(0) PLANT WERE RE-SUBJECTED TO THE STRESS, THE GROUP INHERITING THE MODIFIED METHYLATION PATTERNS SHOWED ENHANCED TOLERANCE TO THE N-DEFICIENCY-STRESS COMPARED WITH THE GROUP BEARING THE ORIGINAL PATTERNS. OUR RESULTS THUS DEMONSTRATE HERITABILITY OF AN ACQUIRED ADAPTIVE TRAIT IN RICE, WHICH WAS ACCOMPANIED BY EPIGENETIC INHERITANCE OF MODIFIED CYTOSINE METHYLATION PATTERNS, IMPLICATING AN EPIGENETIC BASIS UNDERLYING THE INHERITANCE OF AN ACQUIRED TRAIT IN PLANTS. 2011 14 3305 27 HIGH-LEVEL EXPRESSION OF BCL3 DIFFERENTIATES T(2;5)(P23;Q35)-POSITIVE ANAPLASTIC LARGE CELL LYMPHOMA FROM HODGKIN DISEASE. ANAPLASTIC LARGE CELL LYMPHOMA (ALCL) WITH T(2;5)(P23;Q35) AND HODGKIN DISEASE (HD) SHARE MANY CELLULAR FEATURES, INCLUDING EXPRESSION OF CD30. WE COMPARED GENE EXPRESSION PROFILES OF 4 ALCL (KARPAS 299, SU-DHL-1, DEL, SR-786) AND 3 HD CELL LINES AND FOUND THAT BCL3, WHICH ENCODES A NUCLEAR PROTEIN BELONGING TO THE I KAPPA B FAMILY OF INHIBITORS OF NUCLEAR FACTOR-KAPPA B (NF-KAPPA B) TRANSCRIPTIONAL FACTORS, WAS EXPRESSED AT HIGHER LEVELS IN ALCL THAN HD. NORTHERN AND WESTERN BLOTTING ANALYSES CONFIRMED THE HIGH-LEVEL EXPRESSION OF BCL3 IN ALCL AT BOTH MRNA AND PROTEIN LEVELS. WE ESTABLISHED A REAL-TIME REVERSE TRANSCRIPTASE-MEDIATED POLYMERASE CHAIN REACTION ASSAY TO MEASURE THE BCL3 MRNA LEVEL AND FOUND A PREDOMINANT LEVEL OF BCL3 EXPRESSION IN T(2;5)(+) ALCL; THE LEVELS OF CELL LINES AND CLINICAL MATERIALS WERE COMPARABLE TO OR HIGHER THAN THAT OF A B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA CARRYING T(14;19)(Q32;Q13). SOUTHERN BLOTTING AND FLUORESCENCE IN SITU HYBRIDIZATION DISCLOSED THAT THE BCL3 GENE COPIES WERE AMPLIFIED IN SU-DHL-1, WHEREAS KARPAS 299 CARRIED 4 BCL3 GENE LOCI. THE BCL3 GENE CONTAINS 2 CYTOSINE-GUANINE DINUCLEOTIDE (CPG) ISLANDS, AND THE INTRAGENIC 3' CPG WAS ENTIRELY DEMETHYLATED IN SU-DHL-1 AND DEL. IN CONTRAST TO HD, IN WHICH NF-KAPPA B WAS CONSTITUTIVELY ACTIVATED, ALCL CELLS CONSISTENTLY SHOWED (P50)(2) HOMODIMER BINDING ACTIVITY ON ELECTROPHORETIC MOBILITY SHIFT ASSAY. IT IS SUGGESTED THAT THE HIGH-LEVEL NUCLEAR BCL-3 SEQUESTERS THE (P50)(2) HOMODIMER TO THE NUCLEUS, WHICH MAY ACCOUNT FOR THE CONTRADICTORY EFFECT OF CD30 STIMULATION ON ALCL AND HD. WE PROPOSE THAT BCL3 IS OVEREXPRESSED BY GENETIC AND EPIGENETIC MODIFICATIONS, POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF T(2;5)(+) ALCL. 2003 15 3570 26 IMPACT OF JUVENILE HORMONE ANALOGUE INSECTICIDES ON THE WATER FLEA MOINA MACROCOPA: GROWTH, REPRODUCTION AND TRANSGENERATIONAL EFFECT. THE INCREASING QUANTITIES OF INSECTICIDES THAT LEACH INTO WATER BODIES SEVERELY AFFECT THE HEALTH OF THE AQUATIC ENVIRONMENT. JUVENILE HORMONE ANALOGUE (JHA) INSECTICIDES ARE ENDOCRINE DISRUPTERS THAT INTERFERE WITH HORMONAL ACTIVITY IN INSECTS BY MIMICKING JUVENILE HORMONES (JHS). BECAUSE THE STRUCTURE AND FUNCTIONS OF METHYL FARNESOATE IN CRUSTACEANS ARE SIMILAR TO THE INSECT JHS, EXOGENOUS JHA INSECTICIDES MAY CAUSE ADVERSE EFFECTS ON THE GROWTH AND REPRODUCTION IN CRUSTACEANS SIMILAR TO THOSE OBSERVED IN INSECTS. THIS STUDY EXAMINED THE TOXIC EFFECTS OF TWO JHA INSECTICIDES, METHOPRENE AND FENOXYCARB, ON THE WATER FLEA MOINA MACROCOPA. THE 24-H AND 48-H LC(50) VALUES FOR FENOXYCARB AND METHOPRENE WERE 0.53 AND 0.32 MG/L AND 0.70 AND 0.54 MG/L, RESPECTIVELY. CHRONIC EXPOSURE TO THE TWO JHAS CAUSED A SERIES OF TOXIC EFFECTS IN M. MACROCOPA, INCLUDING SHORTENING OF LIFE EXPECTANCY, REPRESSION OF BODY GROWTH, REDUCTION IN FECUNDITY, AND DISTURBED THE EXPRESSION OF GENES INVOLVED IN THE JH SIGNALING PATHWAY, IN CUTICLE DEVELOPMENT, AND IN THE CARBOHYDRATE, AMINO ACID, AND ATP METABOLIC PROCESSES. MOREOVER, JHA EXPOSURE IMPAIRED THE GROWTH AND REPRODUCTION OF THE OFFSPRING OF M. MACROCOPA EXPOSED TO JHAS, EVEN WHEN THE NEONATES WERE NOT EXPOSED TO THE CHEMICALS. IN ADDITION, CHANGES IN THE EXPRESSION OF GENES RELATED TO HISTONE METHYLATION INDICATE THAT EPIGENETIC CHANGES MAY PROMOTE TRANSGENERATIONAL IMPAIRMENT IN M. MACROCOPA. THESE RESULTS DEMONSTRATE THE TOXIC EFFECTS OF FENOXYCARB AND METHOPRENE ON NON-TARGET AQUATIC ORGANISMS. THE DAMAGES DONE BY THESE JHA INSECTICIDES TO THE AQUATIC ENVIRONMENT IS WORTHY OF OUR ATTENTION AND FURTHER STUDIES. 2020 16 1422 28 DIFFERENTIAL CPG DNA METHYLATION OF PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES IN IGG4-RELATED DISEASE. OBJECTIVES: IMMUNOGLOBULIN-G4-RELATED DISEASE (IGG4-RD) IS A DISTINCT SYSTEMIC AUTOIMMUNE-MEDIATED DISEASE MANIFESTING AS CHRONIC INFLAMMATION AND TISSUE FIBROSIS. SINCE THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF IGG4-RD IS STILL UNCLEAR, WE CONDUCT THIS STUDY TO INVESTIGATE EPIGENETIC MODIFICATIONS IN IGG4-RD. METHODS: A GENOME-WIDE DNA METHYLATION STUDY WAS CONDUCTED WITH B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS AND MATCHED CONTROLS BY USING THE ILLUMINA HUMANMETHYLATION 850K BEADCHIP. WE FURTHER PERFORMED PYROSEQUENCING AND IMMUNOHISTOCHEMISTRY ASSAYS TO VALIDATE THE METHYLATION STATUS OF SOME TARGETS OF INTEREST. RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES INCLUDING 44 HYPOMETHYLATED AND 166 HYPERMETHYLATED DIFFERENTIALLY METHYLATED PROBES (DMPS) IN B CELLS AND 260 HYPOMETHYLATED AND 112 HYPERMETHYLATED DMPS IN CD4(+) T CELLS FROM 10 IGG4-RD PATIENTS COMPARED WITH 10 HEALTHY CONTROLS. WE ALSO IDENTIFIED 36945 HYPOMETHYLATED AND 78380 HYPERMETHYLATED DMPS IN SALIVARY GLAND TISSUES OF 4 IGG4-RD PATIENTS COMPARED WITH 4 CONTROLS. DPM2 (CG21181453), IQCK (CG10266221), AND ABCC13 (CG05699681, CG04985582) WERE HYPERMETHYLATED AND MBP (CG18455083) WAS HYPOMETHYLATED IN B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS. WE ALSO OBSERVED THE HYPOMETHYLATED HLA-DQB2 IN CD4(+) T CELLS FROM IGG4-RD PATIENTS. KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSIS OF DMPS IN SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS REVEALED ENRICHMENT OF PATHWAYS INVOLVED IN THE REGULATION OF IMMUNE CELL RESPONSES AND FIBROSIS. CONCLUSION: THIS IS THE FIRST DNA METHYLATION STUDY IN PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS. OUR FINDINGS HIGHLIGHTED THE ROLE OF EPIGENETIC MODIFICATION OF DNA METHYLATION AND IDENTIFIED SEVERAL GENES AND PATHWAYS POSSIBLY INVOLVED IN IGG4-RD PATHOGENESIS. 2023 17 3862 24 ISOPATHIC USE OF AUTO-SARCODE OF DNA AS ANTI-MIASMATIC HOMEOPATHIC MEDICINE AND MODULATOR OF GENE EXPRESSION? INTRODUCTION: IN ADDITION TO THE FOUR PILLARS OF HOMEOPATHY, VITALISM AND THE MIASMATIC THEORY ARE OFTEN USED TO EXPLAIN THE HEALTH-DISEASE PROCESS. ACCORDING TO HAHNEMANN'S CONCEPTS, HOMEOPATHIC MIASMS ARE THE MAIN OBSTACLE TO THE CURE OF CHRONIC DISEASES, WITH PSORA BEING THE FUNDAMENTAL CAUSE OF ALL FORMS OF DISEASES. ACCORDING TO MODERN GENETICS, THE DISEASE-PROMOTING EPIGENETIC ALTERATIONS ARE THE FUNDAMENTAL CAUSE OF THE MANIFESTATION OF CHRONIC DISEASES. OBJECTIVE: THIS ARTICLE DEVELOPS A PHILOSOPHICAL-SCIENTIFIC CORRELATION BETWEEN CHRONIC MIASMS AND DISEASE-PROMOTING EPIGENETIC MODIFICATIONS, AIMING TO JUSTIFY THE ISOPATHIC USE OF AUTO-SARCODE OF AN INDIVIDUAL'S DNA AS HOMEOPATHIC MEDICINE. RESULTS: BASED ON THE STUDY OF HOMEOPATHIC DOCTRINE AND EPIGENETICS, A CONCEPTUAL AND FUNCTIONAL CORRELATION IS OBSERVED BETWEEN HOMEOPATHIC CHRONIC MIASMS AND DISEASE-PROMOTING EPIGENETIC MODIFICATIONS. ADDITIONALLY, SEVERAL EXPERIMENTAL STUDIES SUGGEST THAT HOMEOPATHY'S MECHANISM OF ACTION MAY BE BY MODULATING GENE EXPRESSION. CONCLUSIONS: BY THE PHILOSOPHICAL-SCIENTIFIC CORRELATIONS DESCRIBED, IT IS INFERRED THAT DISEASE-PROMOTING EPIGENETIC ALTERATIONS ARE THE BIOLOGICAL REPRESENTATION OF THE CHRONIC MIASMS, SUGGESTING THE ISOPATHIC USE OF AUTO-SARCODE OF DNA AS HOMEOPATHIC THERAPEUTIC MODULATOR OF GENE EXPRESSION FOR THE MANAGEMENT OF CHRONIC DISEASES. 2019 18 1171 22 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 19 5483 21 RETRACTION. RETRACTION: "AGING IS ASSOCIATED WITH ALTERED INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC MARKERS, INFLUENCED BY EPIGENETIC MODIFICATIONS, IN THE HUMAN FRONTAL CORTEX" BY KELESHIAN VL, MODI HR, RAPOPORT SI, RAO JS. THE ABOVE ARTICLE FROM JOURNAL OF NEUROCHEMISTRY, PUBLISHED ONLINE ON 17 FEBRUARY 2013 IN WILEY ONLINE LIBRARY (WILEYONLINELIBRARY.COM) AND IN VOLUME 121, ISSUE 1, PP. 63-73, HAS BEEN RETRACTED BY AGREEMENT BETWEEN THE CORRESPONDING AUTHOR STANLEY RAPOPORT, THE JOURNAL'S EDITOR-IN-CHIEF, JORG SCHULZ, AND JOHN WILEY & SONS LTD. THE EDITORIAL OFFICE WAS CONTACTED BY THE AUTHOR STANLEY RAPOPORT WITH THE REQUEST TO RETRACT THIS AND A RELATED PUBLICATION (SEE BELOW), INFORMING THE EDITOR-IN-CHIEF THAT THE NATIONAL INSTITUTES OF HEALTH (NIH) HAD FOUND DR. JAGADEESH S. RAO GUILTY OF RESEARCH MISCONDUCT BY FALSIFYING DATA IN THE REFERENCED PAPER. THE EDITORIAL OFFICE WAS FORWARDED A LETTER, SIGNED BY INVESTIGATION COMMITTEE MEMBERS ON BEHALF OF NIH AND NIA, WHICH STATES: "[...] THE NATIONAL INSTITUTES OF HEALTH (NIH) INVESTIGATED ALLEGATIONS OF RESEARCH MISCONDUCT INVOLVING THE FALSIFICATION OF DATA IN "AGING IS ASSOCIATED WITH ALTERED INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC MARKERS, INFLUENCED BY EPIGENETIC MODIFICATIONS, IN THE HUMAN FRONTAL CORTEX." KELESHIAN VL, MODI HR, RAPOPORT SI, RAO JS. JOURNAL OF NEUROCHEMISTRY 2013 APR; 125(1): 63-73. BASED ON THE UNANIMOUS DECISION OF A FIVE MEMBER COMMITTEE, COMPOSED OF NIH INVESTIGATORS, NIH FOUND THAT DR. JAGADEESH RAO, CORRESPONDING AUTHOR, KNOWINGLY AND INTENTIONALLY COMMITTED RESEARCH MISCONDUCT BY FALSIFYING DATA IN FIGURES 1A, 1G, 3G, AND 4D IN THE MANUSCRIPT(S) LISTED ABOVE. DR. RAO WAS SOLELY RESPONSIBLE FOR THE FALSIFICATION AND ALL OTHER AUTHORS WERE UNINVOLVED. THE REPORT WAS SUBMITTED TO THE HHS OFFICE OF RESEARCH INTEGRITY FOR ITS REVIEW. BECAUSE DR. RAO WAS THE CORRESPONDING AUTHOR, DR. STANLEY I. RAPOPORT, SENIOR ADVISOR FOR THE FORMER LABORATORY OF BRAIN PHYSIOLOGY AND METABOLISM SECTION, IS ACTING FOR DR. RAO, WHO WAS HIS REPRESENTATIVE, AND APPROVES THIS REQUEST TO RETRACT THIS PUBLICATION USING THE RECOMMENDED LANGUAGE, IN ITALICS ABOVE." A RELATED PAPER HAS ALSO BEEN RETRACTED: RAO JS, ERTLEY RN, RAPOPORT SI, BAZINET RP, LEE HJ. (2007) CHRONIC NMDA ADMINISTRATION TO RATS UP-REGULATES FRONTAL CORTEX CYTOSOLIC PHOSPHOLIPASE A(2) AND ITS TRANSCRIPTION FACTOR, ACTIVATOR PROTEIN-2. J. NEUROCHEM. 102: 1918-1927. REFERENCES KELESHIAN V. L., MODI H. R., RAPOPORT S. I. AND RAO J. S. (2013) AGING IS ASSOCIATED WITH ALTERED INFLAMMATORY, ARACHIDONIC ACID CASCADE, AND SYNAPTIC MARKERS, INFLUENCED BY EPIGENETIC MODIFICATIONS, IN THE HUMAN FRONTAL CORTEX. J. NEUROCHEM. 125, 63-73. RAO J. S., ERTLEY R. N., RAPOPORT S. I., BAZINET R. P. AND LEE H. J. (2007) CHRONIC NMDA ADMINISTRATION TO RATS UP-REGULATES FRONTAL CORTEX CYTOSOLIC PHOSPHOLIPASE A(2) AND ITS TRANSCRIPTION FACTOR, ACTIVATOR PROTEIN-2. J. NEUROCHEM. 102, 1918-1927. 2017 20 6072 32 THE DNA METHYLOME OF HUMAN VASCULAR ENDOTHELIUM AND ITS USE IN LIQUID BIOPSIES. BACKGROUND: VASCULAR ENDOTHELIAL CELLS (VECS) ARE AN ESSENTIAL COMPONENT OF EACH TISSUE, CONTRIBUTE TO MULTIPLE PATHOLOGIES, AND ARE TARGETED BY IMPORTANT DRUGS. YET, THERE IS A SHORTAGE OF BIOMARKERS TO ASSESS VEC TURNOVER. METHODS: TO DEVELOP DNA METHYLATION-BASED LIQUID BIOPSIES FOR VECS, WE DETERMINED THE METHYLOME OF VECS ISOLATED FROM FRESHLY DISSOCIATED HUMAN TISSUES. FINDINGS: A COMPARISON WITH A HUMAN CELL-TYPE METHYLOME ATLAS YIELDED THOUSANDS OF LOCI THAT ARE UNIQUELY UNMETHYLATED IN VECS. THESE SITES ARE TYPICALLY GENE ENHANCERS, OFTEN RESIDING ADJACENT TO VEC-SPECIFIC GENES. WE ALSO IDENTIFIED HUNDREDS OF GENOMIC LOCI THAT ARE DIFFERENTIALLY METHYLATED IN ORGANOTYPIC VECS, INDICATING THAT VECS FEEDING SPECIFIC ORGANS ARE DISTINCT CELL TYPES WITH A STABLE EPIGENETIC IDENTITY. WE ESTABLISHED UNIVERSAL AND LUNG-SPECIFIC VEC MARKERS AND EVALUATED THEIR PRESENCE IN CIRCULATING CELL-FREE DNA (CFDNA). NEARLY 2.5% OF CFDNA IN THE PLASMA OF HEALTHY INDIVIDUALS ORIGINATES FROM VECS. SEPSIS, GRAFT VERSUS HOST DISEASE, AND CARDIAC CATHETERIZATION ARE ASSOCIATED WITH ELEVATED LEVELS OF VEC-DERIVED CFDNA, INDICATIVE OF VASCULAR DAMAGE. LUNG-SPECIFIC VEC CFDNA IS SELECTIVELY ELEVATED IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OR LUNG CANCER, REVEALING TISSUE-SPECIFIC VASCULAR TURNOVER. CONCLUSIONS: VEC CFDNA BIOMARKERS INFORM VASCULAR DYNAMICS IN HEALTH AND DISEASE, POTENTIALLY CONTRIBUTING TO EARLY DIAGNOSIS AND MONITORING OF PATHOLOGIES, AND ASSESSMENT OF DRUG ACTIVITY. FUNDING: THIS WORK WAS SUPPORTED BY THE BEUTLER RESEARCH PROGRAM, HELMSLEY CHARITABLE TRUST, JDRF, GRAIL AND THE DON FOUNDATION (TO Y.D.). Y.D HOLDS THE WALTER & GRETA STIEL CHAIR IN HEART STUDIES. B.G., R.S., J.M., D.N., T.K., AND Y.D. FILED PATENTS ON CFDNA ANALYSIS. 2023