1 2996 79 GENETIC PROFILE AND MICROSATELLITE INSTABILITY IN A CASE OF SECONDARY ESOPHAGEAL SQUAMOUS CELL CARCINOMA 12 YEARS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR APLASTIC ANEMIA. WE REPORT ON A 16-YEAR-OLD JAPANESE BOY IN WHOM AN ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) DEVELOPED 12 YEARS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WAS PERFORMED FOR APLASTIC ANEMIA. A HIGH FREQUENCY OF MICROSATELLITE INSTABILITY WAS DETECTED IN SAMPLES OF ESCC. MOREOVER, THE DETECTION OF PATHOGENIC VARIANTS, INCLUDING SINGLE NUCLEOTIDE SUBSTITUTION OF TP53 (C.346C>T) AND BRCA2 (C.6952C>T) AND SPLICING OF KDM6A (C.1194+2T>G), SUGGEST THAT THE DEVELOPMENT OF ESCC IN THE PATIENT WAS TRIGGERED BY IMPAIRMENT OF CHECKPOINT AND REPAIR FOR DNA DAMAGE AND EPIGENETIC MODIFICATION THROUGH ACCUMULATION OF GENE MUTATIONS INDUCED BY CHRONIC GRAFT-VERSUS-HOST DISEASE AND PROLONGED ADMINISTRATION OF TACROLIMUS. 2020 2 5087 16 PIMECROLIMUS FOR THE TREATMENT OF ATOPIC DERMATITIS IN INFANTS: AN ASIAN PERSPECTIVE. ATOPIC DERMATITIS (AD) IS A COMMON CHRONIC, MULTISYSTEM INFLAMMATORY SKIN DISEASE IN PEDIATRIC PATIENTS. THERE HAS BEEN AN INCREASE IN THE INCIDENCE OF AD IN THE PEDIATRIC POPULATION OF THE ASIA-PACIFIC REGION. STUDIES HAVE SHOWN THAT GENETIC, EPIGENETIC, ENVIRONMENTAL AND CULTURAL FACTORS MAY LEAD TO DIFFERENCES IN THE CLINICAL MANIFESTATION AND PREVALENCE OF AD BETWEEN RACES. EARLY TREATMENT OF AD IS NECESSARY TO PREVENT THE ATOPIC MARCH LEADING TO COMORBIDITIES SUCH AS ASTHMA AND ALLERGIC RHINITIS. TOPICAL CORTICOSTEROIDS (TCS) ARE USED AS FIRST-LINE THERAPY FOR THE TREATMENT OF AD, BUT THEIR LONG-TERM USAGE POSES A RISK TO THE PATIENT'S HEALTH. PIMECROLIMUS (1%) IS A TOPICAL CALCINEURIN INHIBITOR (TCI) THAT IS INDICATED FOR THE TREATMENT OF MILD TO MODERATE AD. PIMECROLIMUS HAS NO APPARENT INCREASE IN ADVERSE EVENTS COMPARED TO TCS, AND IT CAUSES LESS OF A BURNING SENSATION THAN TACROLIMUS. THE SAFETY AND EFFICACY OF PIMECROLIMUS HAS BEEN ESTABLISHED THROUGH VARIOUS CLINICAL TRIALS; YET, IN MANY ASIAN COUNTRIES, THE USE OF PIMECROLIMUS IN INFANTS IS STILL RESTRICTED DUE TO SAFETY CONCERNS. BASED ON THE AVAILABLE EVIDENCE, THE EXPERT PANEL RECOMMENDS PIMECROLIMUS IN INFANTS BETWEEN 3 MONTHS AND 2 YEARS OF AGE IN THE ASIAN POPULATION. 2023 3 56 17 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 4 1401 8 DIETARY AND PHARMACOLOGICAL TREATMENT OF ABDOMINAL PAIN IN IBS. THIS REVIEW INTRODUCES THE PRINCIPLES OF VISCERAL SENSATION AND APPRAISES THE CURRENT APPROACHES TO MANAGEMENT OF VISCERAL PAIN IN FUNCTIONAL GI DISEASES, PRINCIPALLY IBS. THESE APPROACHES INCLUDE DIETARY MEASURES INCLUDING FIBRE SUPPLEMENTATION, LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS DIET, AND PHARMACOLOGICAL APPROACHES SUCH AS ANTISPASMODICS, PEPPERMINT OIL, ANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS), 5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON), NON-ABSORBED ANTIBIOTIC (RIFAXIMIN), SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE), MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST, DELTA-OR ANTAGONIST (ELUXADOLINE), HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE), NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT) AND GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). EFFICACY AND SAFETY ARE DISCUSSED BASED ON PIVOTAL TRIALS OR PUBLISHED SYSTEMATIC REVIEWS AND META-ANALYSIS, EXPRESSING ORS OR RELATIVE RISKS AND THEIR 95% CIS. POTENTIAL NEW APPROACHES MAY BE BASED ON RECENT INSIGHTS ON MUCOSAL EXPRESSION OF GENES, AND MICRORNA AND EPIGENETIC MARKERS IN HUMAN BIOPSIES AND IN ANIMAL MODELS OF VISCERAL HYPERSENSITIVITY.THE OBJECTIVES OF THIS REVIEW ARE TO APPRAISE THE PHYSIOLOGY AND ANATOMY OF GUT SENSATION AND THE EFFICACY IN THE RELIEF OF VISCERAL PAIN (TYPICALLY IN IBS) OF SEVERAL CLASSES OF THERAPIES. THESE INCLUDE FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES AND POLYOLS (FODMAPS) AND DIFFERENT CLASSES OF MEDICATIONS (BOX 1). BOX 1CLASSES OF PHARMACOLOGICAL AGENTS FOR VISCERAL PAINANTIDEPRESSANTS (TRICYCLIC AGENTS, SELECTIVE SEROTONIN REUPTAKE INHIBITORS)PEPPERMINT OIL5-HT(3) RECEPTOR ANTAGONISTS (ALOSETRON, ONDANSETRON, RAMOSETRON)NON-ABSORBED ANTIBIOTIC (RIFAXIMIN)SECRETAGOGUES (LUBIPROSTONE, LINACLOTIDE)MU-OPIOID RECEPTOR (OR) AND KAPPA-OR AGONIST AND DELTA-OR ANTAGONIST (ELUXADOLINE)HISTAMINE H1 RECEPTOR ANTAGONIST (EBASTINE)NEUROKININ-2 RECEPTOR ANTAGONIST (IBODUTANT)GABAERGIC AGENTS (GABAPENTIN AND PREGABALIN). 2017 5 2649 16 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 6 5763 10 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS. 1991 7 81 7 A NEW TYPE OF DENTAL ANOMALY: MOLAR-INCISOR MALFORMATION (MIM). A MOLAR-INCISOR MALFORMATION (MIM) IS A NEWLY DISCOVERED TYPE OF DENTAL ANOMALY OF THE PERMANENT FIRST MOLARS, DECIDUOUS SECOND MOLARS, AND PERMANENT MAXILLARY CENTRAL INCISORS. MIM ANOMALIES OF THE PERMANENT FIRST MOLARS AND DECIDUOUS SECOND MOLARS MAY INCLUDE NORMAL CROWNS WITH A CONSTRICTED CERVICAL REGION AND THIN, NARROW, AND SHORT ROOTS, WHEREAS THE AFFECTED MAXILLARY CENTRAL INCISORS MAY EXHIBIT A HYPOPLASTIC ENAMEL NOTCH NEAR THE CERVICAL THIRD OF THE CLINICAL CROWN. ALTHOUGH THE ETIOLOGY OF MIM REMAINS TO BE DETERMINED, IT IS THOUGHT TO BE ATTRIBUTABLE TO AN EPIGENETIC FACTOR LINKED TO BRAIN- AND CENTRAL NERVOUS SYSTEM-RELATED SYSTEMIC DISEASES AT AROUND AGE 1 TO 2 YEARS. MIM TEETH ARE ASSOCIATED WITH CLINICAL PROBLEMS SUCH AS IMPACTION, EARLY EXFOLIATION, SPACE LOSS, SPONTANEOUS PAIN, PERIAPICAL ABSCESS, AND POOR INCISOR ESTHETICS. CHILDREN WITH MIM TEETH SHOULD BE OBSERVED CLOSELY WITH RESPECT TO THEIR MEDICAL HISTORY, AND DENTISTS SHOULD FORMULATE A WIDER-RANGING TREATMENT PLAN. 2014 8 3903 20 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 9 1171 20 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 10 31 19 A CASE OF INFECTION-ASSOCIATED ANTIPROTEINASE-3-NEGATIVE CYTOPLASMIC ANTINEUTROPHIL CYTOPLASMIC ANTIBODY PAUCI-IMMUNE FOCAL NECROTIZING GLOMERULONEPHRITIS. WE PRESENT THE CASE OF A MAN WITH GRAM-NEGATIVE SEPSIS AND EXPOSURE TO ORAL SILICA WHO DEVELOPED PAUCI-IMMUNE FOCAL NECROTIZING GLOMERULONEPHRITIS (PI-FNGN) IN THE SETTING OF A SUBACUTE POLYMICROBIAL CENTRAL VENOUS LINE (CVL) INFECTION. HE DEVELOPED A CYTOPLASMIC ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY (C-ANCA) THAT WAS ANTIPROTEINASE-3 (PR-3) AND ANTIMYELOPEROXIDASE (MPO) ANTIBODY NEGATIVE. WE BELIEVE THIS IS THE FIRST REPORTED CASE OF GRAM-NEGATIVE SEPSIS-ASSOCIATED PI-FNGN. CHRONIC SILICA EXPOSURE IS A LEADING ENVIRONMENTAL RISK FACTOR IN THE DEVELOPMENT OF ANCA VASCULITIS. ORAL SILICA IS A COMMON PHARMACEUTICAL ADDITIVE AND ITS BIOAVAILABILITY IS BEING RECOGNIZED. ORAL SILICA, THEREFORE, MAY ALSO BE A RISK FOR DEVELOPMENT OF AUTOREACTIVITY. THE PI-FNGN RESOLVED WITH ANTIBIOTIC THERAPY ALONE. THE C-ANCA TITER DECLINED AS THE PI-FNGN RESOLVED. THE CASE SUPPORTS EXPERIMENTAL AND OBSERVATIONAL RESEARCH THAT ENVIRONMENTAL EXPOSURES ACT AS ADJUVANTS FOR AN IMMUNE RESPONSE AND ALSO PROVIDE EPIGENETIC TRIGGERS FOR AUTOREACTIVITY. THE C-ANCA WAS NEGATIVE FOR PR-3, ITS MAJOR ANTIGEN. C-ANCA ANTIGEN SPECIFICITY MAY DEPEND ON THE PATHOGENESIS OF THE UNDERLYING DISEASE, POTENTIALLY ELICITED BY A CROSS-REACTION OF AN ANTIBODY TO FOREIGN AND SELF TARGET ANTIGEN SEQUENCE HOMOLOGY OR ALTERNATIVELY ELICITED BY ANTIGENIC EPITOPE SPREAD. 2010 11 2977 19 GENETIC AND PHENOTYPIC CHARACTERIZATION OF IN-HOST DEVELOPED AZOLE-RESISTANT ASPERGILLUS FLAVUS ISOLATES. ASPERGILLUS FLAVUS IS A PATHOGENIC FUNGAL SPECIES THAT CAN CAUSE PULMONARY ASPERGILLOSIS, AND TRIAZOLE COMPOUNDS ARE USED FOR THE TREATMENT OF THESE INFECTIONS. PROLONGED EXPOSURE TO AZOLES MAY SELECT FOR COMPENSATORY MUTATIONS IN THE A. FLAVUS GENOME, RESULTING IN AZOLE RESISTANCE. HERE, WE CHARACTERIZE A SERIES OF 11 ISOGENIC A. FLAVUS STRAINS ISOLATED FROM A PATIENT WITH PULMONARY ASPERGILLOSIS. OVER A PERIOD OF THREE MONTHS, THE INITIALLY AZOLE-SUSCEPTIBLE STRAIN DEVELOPED ITRACONAZOLE AND VORICONAZOLE RESISTANCE. SHORT TANDEM REPEAT ANALYSIS AND WHOLE-GENOME SEQUENCING REVEALED THE HIGH GENETIC RELATEDNESS OF ALL ISOLATES, INDICATING AN INFECTION WITH ONE SINGLE ISOLATE. IN CONTRAST, THE ISOLATES WERE MACROSCOPICALLY HIGHLY DIVERSE, SUGGESTING AN ADAPTATION TO THE ENVIRONMENT DUE TO (EPI)GENETIC CHANGES. THE WHOLE-GENOME SEQUENCING OF SUSCEPTIBLE AND AZOLE-RESISTANT STRAINS SHOWED A NUMBER OF MUTATIONS THAT MIGHT BE ASSOCIATED WITH AZOLE RESISTANCE. THE MAJORITY OF RESISTANT STRAINS CONTAIN A Y119F MUTATION IN THE CYP51A GENE, WHICH CORRESPONDS TO THE Y121F MUTATION FOUND IN A. FUMIGATUS. ONE AZOLE-RESISTANT STRAIN DEMONSTRATED A DIVERGENT SET OF MUTATIONS, INCLUDING A V99A MUTATION IN A MAJOR FACILITATOR SUPERFAMILY (MSF) MULTIDRUG TRANSPORTER (AFLA 083950). 2021 12 760 17 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 13 890 13 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 14 5640 19 SERUM TUMOR MARKERS AND MOLECULAR BIOLOGICAL DIAGNOSIS IN PANCREATIC CANCER. RECENT STUDIES ON GENETIC ABNORMALITIES IN PANCREATIC DUCTAL CANCER HAVE LED TO THE INVESTIGATION OF TUMOR MARKERS AND GENETIC MARKERS IN BOTH SERUM AND PANCREATIC JUICE (PJ). SERUM TYPE 1 CHAIN CARBOHYDRATE ANTIGENS SUCH AS CA19-9 ARE POSITIVE IN NEARLY 80% OF PATIENTS WITH PANCREATIC CANCER (PCA), OF WHICH MOST ARE IN ADVANCED STAGE, WHEREAS FALSE-POSITIVE RATES ARE RELATIVELY HIGH AT 20%-30% IN BENIGN HEPATOBILIARY AND PANCREATIC DISEASES. ALTHOUGH THE PREVALENCE OF TYPE 2 CHAIN CARBOHYDRATE ANTIGENS, SUCH AS SLX, IS RELATIVELY LOW, CANCER SPECIFICITY OF THESE ANTIGENS IS HIGH. HOWEVER, SERUM TUMOR MARKERS HAVE LIMITED DIAGNOSTIC VALUE FOR EARLY DETECTION OF PCA. IN PJ COLLECTED ENDOSCOPICALLY FROM PATIENTS WITH PCA, K-RAS MUTATIONS (KRM) ARE DETECTABLE IN > 80%, WHEREAS KRM ARE OBSERVED IN 20%-30% OF PJ FROM PATIENTS WITH CHRONIC PANCREATITIS (CP), REFLECTING BENIGN MUCOUS CELL HYPERPLASIA HARBORING KRM. THUS, A QUALITATIVE ANALYSIS OF KRM IN PJ IS UNSUITABLE FOR DIAGNOSIS OF PCA. ON THE OTHER HAND, USING AN HYBRIDIZATION PROTECTION ASSAY THAT CAN QUANTITATIVELY DETERMINE KRM, KRM WERE POSITIVE IN 66% OF PCA BUT ONLY IN 40% OF CP CASES, INDICATING THAT QUALITATIVE ANALYSIS OF KRM IN PJ MAY BE USEFUL FOR DIFFERENTIATING PCA FROM CP. P53 MUTATIONS ARE FOUND IN 4%-50% IN PJ FROM PATIENTS WITH PCA BUT ARE NOT DETECTABLE IN PJ FROM CP, SUGGESTING THAT THE SPECIFICITY OF P53 MUTATIONS IS VERY HIGH FOR PCA. FURTHERMORE, P53 MUTATIONS WERE DETECTED IN 7 OF 15 (47%) PATIENTS WITH PCA IN WHICH THE PJ CYTOLOGIC DIAGNOSIS WAS NEGATIVE. TELOMERASE (TE) ACTIVITY OR ITS CATALYTIC SUBUNIT, H-TERT, WAS REPORTEDLY POSITIVE >80% IN PJ FROM PCA BUT WAS DETECTED IN <20% OF PJ FROM CP. TE ACTIVITY IN PJ FROM CP ORIGINATES FROM LYMPHOCYTES. THE DEVELOPMENT AND APPLICATION OF THESE NEW GENETIC AND EPIGENETIC MARKERS WITH HIGH SPECIFICITY AND SENSITIVITY FOR PCA IN SERUM AND PJ WILL SIGNIFICANTLY IMPROVE OUR DIAGNOSTIC ACCURACY. 2004 15 4576 15 MYOGENIC POTENTIAL OF CANINE CRANIOFACIAL SATELLITE CELLS. THE SKELETAL FIBERS HAVE DIFFERENT EMBRYOLOGICAL ORIGIN; THE EXTRAOCULAR AND JAW-CLOSER MUSCLES DEVELOP FROM PRECHORDAL MESODERM WHILE THE LIMB AND TRUNK MUSCLES FROM SOMITES. THESE DIFFERENT ORIGINS CHARACTERIZE ALSO THE ADULT MUSCLE STEM CELLS, KNOWN AS SATELLITE CELLS (SCS) AND RESPONSIBLE FOR THE FIBER GROWTH AND REGENERATION. THE PHYSIOLOGICAL PROPERTIES OF PRESOMITIC SCS AND THEIR EPIGENETICS ARE POORLY STUDIED DESPITE THEIR PECULIAR CHARACTERISTICS TO PRESERVE MUSCLE INTEGRITY DURING CHRONIC MUSCLE DEGENERATION. HERE, WE ISOLATED SCS FROM CANINE SOMITIC [SOMITE-DERIVED MUSCLE (SDM): VASTUS LATERALIS, RECTUS ABDOMINIS, GLUTEUS SUPERFICIALIS, BICEPS FEMORIS, PSOAS] AND PRESOMITIC [PRE-SOMITE-DERIVED MUSCLE (PSDM): LATERAL RECTUS, TEMPORALIS, AND RETRACTOR BULBI] MUSCLES AS MYOGENIC PROGENITOR CELLS FROM YOUNG AND OLD ANIMALS. IN ADDITION, SDM AND PSDM-SCS WERE OBTAINED ALSO FROM GOLDEN RETRIEVERS AFFECTED BY MUSCULAR DYSTROPHY (GRMD). WE CHARACTERIZED THE LIFESPAN, THE MYOGENIC POTENTIAL AND FUNCTIONS, AND OXIDATIVE STRESS OF BOTH SOMITIC AND PRESOMITIC SCS WITH THE AIM TO REVEAL DIFFERENCES WITH AGING AND BETWEEN HEALTHY AND DYSTROPHIC ANIMALS. THE DIFFERENT PROLIFERATION RATE WAS CONSISTENT WITH HIGHER TELOMERASE ACTIVITY IN PSDM-SCS COMPARED TO SDM-SCS, ALTHOUGH RESTRICTED AT EARLY PASSAGES. SDM-SCS EXPRESS EARLY (PAX7, MYOD) AND LATE (MYOSIN HEAVY CHAIN, MYOGENIN) MYOGENIC MARKERS DIFFERENTLY FROM PSDM-SCS RESULTING IN A MORE EFFICIENT AND FASTER CELL DIFFERENTIATION. TAKEN TOGETHER, OUR RESULTS SHOWED THAT PSDM-SCS ELICIT A STRONGER STEM CELL PHENOTYPE COMPARED TO SDM ONES. FINALLY, MYOMIR EXPRESSION PROFILE REVEALS A UNIQUE EPIGENETIC SIGNATURE IN GRMD SCS AND MIR-206, HIGHLY EXPRESSED IN DYSTROPHIC SCS, SEEMS TO PLAY A CRITICAL ROLE IN MUSCLE DEGENERATION. THUS, MIR-206 COULD REPRESENT A POTENTIAL TARGET FOR NOVEL THERAPEUTIC APPROACHES. 2014 16 4048 14 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 17 608 12 BEYOND HOMEOSTASIS: UNDERSTANDING THE IMPACT OF PSYCHOSOCIAL FACTORS ON APPETITE USING NONHUMAN PRIMATE MODELS. ANIMAL MODELS HAVE PROVEN TO BE EXCEPTIONALLY INFORMATIVE IN DEFINING NEUROPEPTIDE REGULATION OF APPETITE AND ENERGY HOMEOSTASIS (GAO AND HORVATH 2007, BERTHOUD 2012, WILLIAMS AND ELMQUIST 2012). MORE RECENT STUDIES USING A RANGE OF ANIMAL MODELS AND MOLECULAR TOOLS ARE ELUCIDATING HOW EPIGENETIC CHANGES RESULTING FROM SPECIFIC PRENATAL AND POSTNATAL DIETARY ENVIRONMENTS OR EXPERIENCES AFFECT METABOLIC PROCESSES AND APPETITE REGULATION (LEVIN 2008, ZAMBRANO AND NATHANIELSZ 2013, BURDGE AND LILLYCROP 2014). TAKEN TOGETHER, THESE APPROACHES ARE HELPING TO DEFINE POSSIBLE TREATMENT INTERVENTIONS FOR EATING DISORDERS IN PEOPLE (CASPER, SULLIVAN, AND TECOTT 2008, FOLTIN 2012, VAN GESTEL ET AL. 2014, LUTTER, CROGHAN, AND CUI 2016). THE CHOICE OF ANIMAL USED IS BEST DICTATED BY THE QUESTION BEING ADDRESSED. BECAUSE OF SIMILARITIES IN PHYSIOLOGY AND NEUROBIOLOGY, STUDIES OF CAPTIVE NONHUMAN PRIMATES HAVE BEGUN TO CONTRIBUTE SIGNIFICANTLY TO OUR UNDERSTANDING OF APPETITE REGULATION (SEE WILSON ET AL. 2014 FOR A REVIEW). IMPORTANTLY, THE USE OF NONHUMAN PRIMATE MODELS PROVIDES THE UNIQUE OPPORTUNITY TO EXTEND ANALYSES BEYOND A FOCUS ON THE HOMEOSTATIC REGULATION OF APPETITE. THIS IS PARTICULARLY RELEVANT GIVEN THE WELL-ESTABLISHED NOTION THAT A NUMBER OF PSYCHOSOCIAL FACTORS INFLUENCE FOOD INTAKE IN PEOPLE (BRUCE AND RICCIARDELLI 2015), INCLUDING CHRONIC STRESSOR EXPOSURE (TSENKOVA, BOYLAN, AND RYFF 2013), EVEN IN CHILDREN (NGUYEN-RODRIGUEZ, UNGER, AND SPRUIJT-METZ 2009). WHILE THE IMPORTANCE OF PSYCHOSOCIAL FACTORS CAN BE MODELED IN NONPRIMATE ANIMALS (TAMASHIRO, HEGEMAN, AND SAKAI 2006), SOCIALLY HOUSED NONHUMAN PRIMATES SHARE MANY CHARACTERISTICS IN ADDITION TO PHYSIOLOGY AND NEUROBIOLOGY, WITH HUMANS INCREASING THE TRANSLATIONAL VALUE OF THESE PRE-CLINICAL STUDIES. 2017 18 2998 14 GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE CONTRIBUTE TO SOLAR LENTIGINES. SOLAR LENTIGINES (SLS) ARE A HALLMARK OF HUMAN SKIN AGING. THEY RESULT FROM CHRONIC EXPOSURE TO SUNLIGHT AND OTHER ENVIRONMENTAL STRESSORS. RECENT STUDIES ALSO IMPLY GENETIC FACTORS, BUT FINDINGS ARE PARTIALLY CONFLICTING AND LACK OF REPLICATION. THROUGH A MULTI-TRAIT BASED ANALYSIS STRATEGY, WE DISCOVERED THAT GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE WERE SIGNIFICANTLY ASSOCIATED WITH NON-FACIAL SL IN TWO EAST ASIAN (TAIZHOU LONGITUDINAL COHORT, N = 2,964 AND NATIONAL SURVEY OF PHYSICAL TRAITS, N = 2,954) AND ONE CAUCASIAN POPULATION (SALIA, N = 462), TOP SNP RS2853672 (P-VALUE FOR TAIZHOU LONGITUDINAL COHORT = 1.32 X 10(?28) AND P-VALUE FOR NATIONAL SURVEY OF PHYSICAL TRAITS = 3.66 X 10(?17) AND P-VALUE FOR SALIA = 0.0007 AND P(META) = 4.93 X 10(?44)). THE SAME VARIANTS WERE NOMINALLY ASSOCIATED WITH FACIAL SL BUT NOT WITH OTHER SKIN AGING OR SKIN PIGMENTATION TRAITS. THE SL-ENHANCED ALLELE/HAPLOTYPE UPREGULATED THE TRANSCRIPTION OF THE TELOMERASE REVERSE TRANSCRIPTASE GENE. OF NOTE, WELL-KNOWN TELOMERASE REVERSE TRANSCRIPTASE?RELATED AGING MARKERS SUCH AS LEUKOCYTE TELOMERE LENGTH AND INTRINSIC EPIGENETIC AGE ACCELERATION WERE NOT ASSOCIATED WITH SL. OUR RESULTS INDICATE A PREVIOUSLY UNRECOGNIZED ROLE OF TELOMERASE REVERSE TRANSCRIPTASE IN SKIN AGING?RELATED LENTIGINES FORMATION. 2023 19 1791 19 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 20 2819 17 FILARIAL AND WOLBACHIA GENOMICS. FILARIAL NEMATODE PARASITES, THE CAUSATIVE AGENTS FOR A SPECTRUM OF ACUTE AND CHRONIC DISEASES INCLUDING LYMPHATIC FILARIASIS AND RIVER BLINDNESS, THREATEN THE WELL-BEING AND LIVELIHOOD OF HUNDREDS OF MILLIONS OF PEOPLE IN THE DEVELOPING REGIONS OF THE WORLD. THE 2007 PUBLICATION ON A DRAFT ASSEMBLY OF THE 95-MB GENOME OF THE HUMAN FILARIAL PARASITE BRUGIA MALAYI- REPRESENTING THE FIRST HELMINTH PARASITE GENOME TO BE SEQUENCED - HAS BEEN FOLLOWED IN RAPID SUCCESSION BY PROJECTS THAT HAVE RESULTED IN THE GENOME SEQUENCING OF SIX ADDITIONAL FILARIAL SPECIES, SEVEN NONFILARIAL NEMATODE PARASITES OF ANIMALS AND NEARLY 30 PLANT PARASITIC AND FREE-LIVING SPECIES. PARALLEL TO THE GENOMIC SEQUENCING, TRANSCRIPTOMIC AND PROTEOMIC PROJECTS HAVE FACILITATED GENOME ANNOTATION, EXPANDED OUR UNDERSTANDING OF STAGE-ASSOCIATED GENE EXPRESSION AND PROVIDED A FIRST LOOK AT THE ROLE OF EPIGENETIC REGULATION OF FILARIAL GENOMES THROUGH MICRORNAS. THE EXPANSION IN FILARIAL GENOMICS WILL ALSO PROVIDE A SIGNIFICANT ENRICHMENT IN OUR KNOWLEDGE OF THE DIVERSITY AND VARIABILITY IN THE GENOMES OF THE ENDOSYMBIOTIC BACTERIUM WOLBACHIA LEADING TO A BETTER UNDERSTANDING OF THE GENETIC PRINCIPLES THAT GOVERN FILARIAL-WOLBACHIA MUTUALISM. THE GOAL HERE IS TO PROVIDE AN OVERVIEW OF THE TRENDS AND ADVANCES IN FILARIAL AND WOLBACHIA GENOMICS. 2012