1   202 92 ACTIVATION INDUCED CYTIDINE DEAMINASE: AN OLD FRIEND WITH NEW FACES. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) PROTEIN IS A MEMBER OF APOBEC FAMILY. AID CONVERTS CYTIDINE TO URACIL, WHICH IS A KEY STEP FOR SOMATIC HYPERMUTATION (SHM) AND CLASS SWITCH RECOMBINATION (CSR). AID ALSO PLAYS CRITICAL ROLES IN B CELL PRECURSOR STAGES, REMOVING POLYREACTIVE B CELLS FROM IMMUNE REPERTOIRE. SINCE THE MAIN FUNCTION OF AID IS INDUCING POINT MUTATIONS, DYSREGULATION CAN LEAD TO INCREASED MUTATION LOAD, TRANSLOCATIONS, DISTURBED GENOMIC INTEGRITY, AND LYMPHOMAGENESIS. AS SUCH, EXPRESSION OF AID AS WELL AS ITS FUNCTION IS CONTROLLED STRICTLY AT VARIOUS MOLECULAR STEPS. OTHER MEMBERS OF THE APOBEC FAMILY ALSO PLAY CRUCIAL ROLES DURING CARCINOGENESIS. CONSIDERING ALL THESE FUNCTIONS, AID REPRESENTS A BRIDGE, LINKING CHRONIC INFLAMMATION TO CARCINOGENESIS AND IMMUNE DEFICIENCIES TO AUTOIMMUNE MANIFESTATIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  2215 14 EPIGENETIC MODIFICATIONS FOLLOWING NOXIOUS STIMULI IN INFANTS. PURPOSE: TO RECRUIT HEALTHY FULL- AND PRETERM INFANTS INTO GENETIC RESEARCH AND DETERMINE THE EFFECTIVENESS OF A NONINVASIVE DNA SAMPLING TECHNIQUE FOR COMPARING EPIGENETIC MODIFICATIONS. BACKGROUND: NOXIOUS STIMULI DURING A VULNERABLE PERIOD OF INFANT NEURONAL PLASTICITY MAY TRIGGER LONG-TERM EPIGENETIC CHANGES AFFECTING NEURODEVELOPMENT, PAIN MODULATION, AND REACTIVITY. RECOGNIZING EPIGENETIC PAIN FINDINGS IS PROBLEMATIC BECAUSE PARENTS ARE RELUCTANT TO ENROLL NEWBORNS INTO GENETIC RESEARCH. METHODS: DESIGN: WITHIN-SUBJECT CHANGE OVER TIME CANDIDATE-GENE DNA METHYLATION ASSOCIATION STUDY. SETTING/ SAMPLE: URBAN TEACHING HOSPITAL'S NEONATAL INTENSIVE CARE UNIT AND NEWBORN NURSERY. CONVENIENCE SAMPLE OF HEALTHY FULL- (>37 WEEKS, N = 6) AND PRETERM (<37 WEEKS, N = 6) INFANTS. PROCEDURE: PARENTS PARTICIPATED IN A GENETIC PRESENTATION PRIOR TO INFORMED CONSENT. INFANT BUCCAL SALIVA WAS COLLECTED AFTER ADMISSION TO THE UNIT AND PRIOR TO DISCHARGE. ANALYSIS: THE METHYLATION PATTERN AT THE 5' END OF MICRO-OPIOID RECEPTOR GENE ( OPRM1) WAS EXAMINED. DNA WAS TREATED WITH BISULFITE TO CONVERT ALL CYTOSINES TO URACIL RESIDUES, LEAVING METHYLATED CYTOSINES UNCHANGED. SEQUENCING OF UNTREATED AND BISULFITE-CONVERTED DNA WAS CARRIED OUT. THE SEQUENCES OF UNCONVERTED AND BISULFITE-CONVERTED DNA WERE ALIGNED WITH CLUSTALW, FIDELITY OF THE POLYMERASE CHAIN REACTION AND THE SEQUENCING REACTION EVALUATED, AND THE METHYLATION PATTERN IDENTIFIED. RESULTS: RECRUITMENT AND ASSESSMENT OF A NONINVASIVE DNA SAMPLING TECHNIQUE FOR COMPARING EPIGENETIC MODIFICATIONS WERE SUCCESSFUL; HOWEVER, INFANT STRESS DID NOT PRODUCE A CHANGE IN OPRM1 METHYLATION EXPRESSION. RELEVANCE: THIS STUDY ESTABLISHED THE FEASIBILITY OF RECRUITING HEALTHY FULL-TERM INFANTS INTO GENETIC RESEARCH AND THE EFFECTIVENESS OF NONINVASIVE DNA SAMPLING FOR COMPARING EPIGENETIC MODIFICATION IN INFANTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  2134 21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  1286 19 DECITABINE IN COMBINATION WITH DONOR LYMPHOCYTE INFUSIONS CAN INDUCE REMISSIONS IN RELAPSED MYELOID MALIGNANCIES WITH HIGHER LEUKEMIC BURDEN AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION. THE COMBINATION OF 5-AZACYTIDINE (AZA) WITH DONOR LYMPHOCYTE INFUSIONS (DLIS) CAN INDUCE REMISSIONS IN PATIENTS WITH RELAPSED MYELOID MALIGNANCIES AFTER ALLO-HCT. AS DECITABINE (DAC) IS KNOWN TO BE EFFECTIVE ALSO IN AML/MDS WITH LEUKOCYTOSIS, WE INVESTIGATED THE COMBINATION OF DAC WITH DLIS FOR RELAPSE AFTER ALLO-HCT. BETWEEN 2006 AND 2016, 26 PATIENTS (MEDIAN AGE 59 YEARS) WITH AML (N = 18), MDS (N = 6), OR MPN (N = 2) AND OVERT HEMATOLOGICAL RELAPSE AFTER ALLO-HCT WERE TREATED. MEDIAN DURATION FROM ALLO-HCT TO RELAPSE WAS 306 DAYS (RANGE, 76-4943). EIGHTEEN PATIENTS RECEIVED DAC + DLIS, 8 DAC-ONLY (MEDIAN NUMBER CYCLES OF DAC: 2, RANGE 1-13, MEDIAN NUMBER OF DLIS: 2, RANGE 1-10). THE INCIDENCE OF ACUTE AND CHRONIC GVHD IN PATIENTS RECEIVING DLI WAS 17% (3/18) AND 6% (1/18), RESPECTIVELY. CR/CRI WAS ACHIEVED IN 15% (4/26), PR IN 4% (1/26), AND STABLE DISEASE IN 58% (15/26) OF PATIENTS. EIGHT PATIENTS RECEIVED A SECOND ALLO-HCT. MEDIAN OVERALL SURVIVAL WAS 4.7 MONTHS. ELEVATED PD-L1 PROTEIN EXPRESSION IN BONE MARROW CELLS WAS DETECTED IN 4/8 PATIENTS WITH >20% BLAST INFILTRATION PRIOR TO DAC, WITHOUT A CLEAR ASSOCIATION WITH RESPONSE. IN CONCLUSION, THE DAC + DLI REGIMEN PROVED FEASIBLE AND EFFECTIVE IN RELAPSED MYELOID MALIGNANCIES AFTER ALLO-HCT, WITH EFFICACY NOT RESTRICTED TO PATIENTS WITH LOW LEUKEMIC BURDEN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  1496 10 DNA IS HYPOMETHYLATED IN CIRCADIAN MANIFESTATIONS OF BRUXISM. OBJECTIVE: THE AIM OF THIS STUDY WAS TO COMPARE THE GLOBAL DNA METHYLATION LEVELS IN PATIENTS UNDER BRUXISM TREATMENT AND A CONTROL GROUP. METHODS: SUBJECTS UNDERGOING BRUXISM TREATMENT WERE CLASSIFIED IN AWAKE BRUXISM (42 PATIENTS), SLEEP BRUXISM (32 PATIENTS) AND BOTH CONDITIONS (42 PATIENTS). THE CONTROL GROUP INCLUDED 42 INDIVIDUALS. A COLORIMETRIC ASSAY (METHYLFLASH METHYLATED DNA 5-MC QUANTIFICATION KIT, EPIGENETIC GROUP INC., NY, USA) WAS USED TO DETERMINE THE GLOBAL DNA METHYLATION LEVELS. RESULTS: STATISTICALLY SIGNIFICANT DIFFERENCES WERE FOUND IN AMOUNTS OF METHYLATED DNA IN ALL CIRCADIAN MANIFESTATIONS OF BRUXISM COMPARED WITH A CONTROL GROUP (SLEEP BRUXISM = 0.95% +/- 2.02%; AWAKE BRUXISM = 0.87% +/- 2.1%; SLEEP AND AWAKE BRUXISM = 0.17% +/- 0.25%; CONTROL = 1.69% +/- 1.6%; KRUSKAL-WALLIS TEST [P = .0001] FOLLOWED BY DUNN'S TEST [P < .05]). CONCLUSION: PATIENTS UNDERGOING BRUXISM TREATMENT EXHIBITED HYPOMETHYLATED DNA LEVELS WHEN COMPARED TO CONTROL GROUP. OUR RESULTS SUGGEST THAT DNA HYPOMETHYLATION MIGHT BE A NOVEL AETIOLOGIC FACTOR IN BRUXISM AETIOLOGY. FURTHER RESEARCHES MUST BE PERFORMED EXPLORING THE ROLE OF EPIGENETICS MODIFICATIONS IN CIRCADIAN MANIFESTATIONS OF BRUXISM.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  5017 19 PERSISTENT INFECTION OF CULTURED CELLS WITH MOUSE HEPATITIS VIRUS (MHV) RESULTS FROM THE EPIGENETIC EXPRESSION OF THE MHV RECEPTOR. THE A59 STRAIN OF MURINE CORONAVIRUS MOUSE HEPATITIS VIRUS (MHV) CAN CAUSE PERSISTENT INFECTION OF 17C1-1 CELLS AND OTHER MURINE CELL LINES. PERSISTENTLY INFECTED CULTURES RELEASED LARGE AMOUNTS OF VIRUS (10(7) TO 10(8) PFU/ML) AND WERE RESISTANT TO SUPERINFECTION WITH MHV BUT NOT TO INFECTION WITH UNRELATED SEMLIKI FOREST AND VESICULAR STOMATITIS VIRUSES. THE CULTURE MEDIUM FROM PERSISTENTLY INFECTED CULTURES DID NOT CONTAIN A SOLUBLE INHIBITOR SUCH AS INTERFERON THAT PROTECTED UNINFECTED CELLS FROM INFECTION BY MHV OR VESICULAR STOMATITIS VIRUS. THE PERSISTENT INFECTION WAS CURED IF FEWER THAN 100 CELLS WERE TRANSFERRED DURING SUBCULTURING, AND SUCH CURED CULTURES WERE SUSCEPTIBLE TO REINFECTION AND THE REESTABLISHMENT OF PERSISTENT INFECTION. CULTURES OF 17C1-1 CELLS THAT HAD BEEN NEWLY CLONED FROM SINGLE CELLS CONSISTED OF A MIXTURE OF MHV-RESISTANT AND -SUSCEPTIBLE CELLS. 17C1-1/#97 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 97 PASSAGES OF A PERSISTENTLY INFECTED CULTURE OVER A 1-YEAR PERIOD, CONTAINED 5 TO 10% OF THEIR POPULATION AS SUSCEPTIBLE CELLS, WHILE 17C1-1/#402 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 402 PASSAGES OVER A 3-YEAR PERIOD, HAD LESS THAN 1% SUSCEPTIBLE CELLS. SUSCEPTIBILITY TO INFECTION CORRELATED WITH THE EXPRESSION OF MHV RECEPTOR GLYCOPROTEIN (MHVR [BGP1A]). FLUORESCENCE-ACTIVATED CELL SORTER ANALYSIS WITH ANTIBODY TO MHVR SHOWED THAT 17C1-1/#97 CELLS CONTAINED A SMALL FRACTION OF MHVR-EXPRESSING CELLS. THESE MHVR-EXPRESSING CELLS WERE SELECTIVELY ELIMINATED WITHIN 24 H AFTER CHALLENGE WITH MHV-A59, AND PRETREATMENT OF 17C1-1/#97 CELLS WITH MONOCLONAL ANTIBODY CC1, WHICH BINDS TO THE N-TERMINAL DOMAIN OF MHVR, BLOCKED INFECTION. WE CONCLUDE THAT THE SUBPOPULATION OF MHVR-EXPRESSING CELLS WERE INFECTED AND KILLED IN ACUTELY OR PERSISTENTLY INFECTED CULTURES, WHILE THE SUBPOPULATION OF MHVR-NONEXPRESSING CELLS SURVIVED AND PROLIFERATED. THE SUBPOPULATION OF MHVR-NEGATIVE CELLS PRODUCED A SMALL PROPORTION OF PROGENY CELLS THAT EXPRESSED MHVR AND BECAME INFECTED, THEREBY MAINTAINING THE PERSISTENT INFECTION AS A STEADY-STATE CARRIER CULTURE. THUS, IN 17C1-1 CELL CULTURES, THE UNSTABLE OR EPIGENETIC EXPRESSION OF MHVR PERMITTED THE ESTABLISHMENT OF A PERSISTENT, CHRONIC INFECTION.	1995	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  4916 14 PAIN-RELATED INCREASE IN SEROTONIN TRANSPORTER GENE METHYLATION ASSOCIATES WITH EMOTIONAL REGULATION IN 4.5-YEAR-OLD PRETERM-BORN CHILDREN. AIM: THE MAIN GOAL OF THIS STUDY WAS TO ASSESS THE ASSOCIATION BETWEEN PAIN-RELATED INCREASE IN SEROTONIN TRANSPORTER GENE (SLC6A4) METHYLATION AND EMOTIONAL DYSREGULATION IN 4.5-YEAR-OLD PRETERM CHILDREN COMPARED WITH FULL-TERM MATCHED COUNTERPARTS. METHODS: PRETERM (N = 29) AND FULL-TERM (N = 26) CHILDREN RECRUITED FROM TWO ITALIAN HOSPITALS WERE FOLLOWED-UP FROM OCTOBER 2011 TO DECEMBER 2017. SLC6A4 METHYLATION WAS ASSESSED FROM CORD BLOOD AT BIRTH FROM BOTH GROUPS AND PERIPHERAL BLOOD AT DISCHARGE FOR PRETERM ONES. AT 4.5 YEARS, EMOTIONAL REGULATION (IE, ANGER, FEAR AND SADNESS) WAS ASSESSED THROUGH AN OBSERVATIONAL STANDARDISED PROCEDURE. RESULTS: PRETERM CHILDREN (18 FEMALES; MEAN AGE = 4.5, RANGE = 4.3-4.8) SHOWED GREATER ANGER DISPLAY COMPARED WITH FULL-TERM CONTROLS (14 FEMALES; MEAN AGE = 4.5, RANGE = 4.4-4.9) IN RESPONSE TO EMOTIONAL STRESS. CONTROLLING FOR ADVERSE LIFE EVENTS OCCURRENCE FROM DISCHARGE TO 4.5 YEARS AND SLC6A4 METHYLATION AT BIRTH, CPG-SPECIFIC SLC6A4 METHYLATION IN THE NEONATAL PERIOD WAS PREDICTIVE OF GREATER ANGER DISPLAY IN PRETERM CHILDREN BUT NOT IN FULL-TERM ONES. CONCLUSION: THESE FINDINGS CONTRIBUTE TO HIGHLIGHT HOW EPIGENETIC REGULATION OF SEROTONIN TRANSPORTER GENE IN RESPONSE TO NICU PAIN EXPOSURE CONTRIBUTES TO LONG-LASTING PROGRAMMING OF ANGER REGULATION IN PRETERM CHILDREN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  2042 19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  5487 24 REVERSIBLE ALTERATION IN THE EXPRESSION OF THE GAP JUNCTIONAL PROTEIN CONNEXIN 32 DURING TUMOR PROMOTION IN RAT LIVER AND ITS ROLE DURING CELL PROLIFERATION. ALTHOUGH NUMEROUS BIOCHEMICAL MARKERS CAN IDENTIFY PUTATIVE PRENEOPLASTIC ALTERED HEPATIC FOCI (AHF) IN RAT LIVER, NO CONSISTENT PATTERN OF EXPRESSION DURING HEPATOCARCINOGENESIS HAS EMERGED. USING QUANTITATIVE STEREOLOGIC ANALYSES WE DEMONSTRATED THAT DECREASED EXPRESSION OF THE MAJOR HEPATOCYTE GAP JUNCTION PROTEIN, CONNEXIN 32 (CX32), IN RAT AHF IS A CONSISTENT OBSERVATION IN SEVERAL PROTOCOLS OF MULTISTAGE HEPATOCARCINOGENESIS. THIS CHANGE WAS OBSERVED AFTER INITIATION BY EITHER ETHYLNITROSOUREA (ENU) OR DIETHYLNITROSAMINE (DEN), FOLLOWED BY PROMOTION WITH PHENOBARBITAL (PB), DIOXIN, CHLORENDIC ACID, C.I. SOLVENT YELLOW, OR TAMOXIFEN. AHF GENERATED BY WY-14,643, CIPROFIBRATE, AND A CHOLINE/METHIONINE-DEFICIENT DIETARY REGIMEN ALSO SHOWED DECREASED CX32 EXPRESSION. THE DECREASE OF CX32 IN AHF WAS RAPIDLY REVERSIBLE AFTER WITHDRAWAL OF PB, AND THIS CHANGE PRECEDED A REDUCTION IN PLACENTAL ISOZYME OF GLUTATHIONE-S-TRANSFERASE (GST) EXPRESSION IN THE SAME AHF. WITHIN 20 DAYS OF WITHDRAWAL, FEWER THAN 4% OF GST-POSITIVE AHF WERE CX32 DEFICIENT, WHILE THE VOLUME OF TOTAL AHF DECREASED 30%. CHRONIC PB TREATMENT ALSO RESULTED IN A REVERSIBLE DECREASE IN CX32 SPECIFICALLY IN MID- AND CENTRO-LOBULAR HEPATOCYTES. CONTINUOUS THYMIDINE LABELING DEMONSTRATED THAT CX32 COULD BE UNCOUPLED FROM THE CELL CYCLE, SUGGESTING THAT SOME LIVER PROMOTERS MAY ACT DIRECTLY TO ALTER THE EXPRESSION OF CX32. THESE OBSERVATIONS SUGGEST THAT A DECREASE IN CX32 CONTENT WAS A RELATIVELY COMMON EPIGENETIC CHANGE IN AHF INDUCED DURING HEPATOCARCINOGENESIS BY A NUMBER OF INITIATING AND PROMOTING AGENTS BUT THAT THIS CHANGE WAS NOT SUFFICIENT FOR CARCINOGENESIS. THIS CHANGE, HOWEVER, MAY BE NECESSARY FOR THE MECHANISM(S) OF TUMOR PROMOTION, SINCE CX32-POSITIVE AHF DID NOT PROLIFERATE AS READILY AS CX32-DEFICIENT AHF.	1990	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  1951 28 EPIGENETIC ACTIVATION OF THE TUSC3 GENE AS A POTENTIAL THERAPY FOR XMEN DISEASE. BACKGROUND: X-LINKED MAGT1 DEFICIENCY WITH INCREASED SUSCEPTIBILITY TO EPSTEIN-BARR VIRUS INFECTION AND N-LINKED GLYCOSYLATION DEFECT (XMEN) DISEASE IS A RARE COMBINED IMMUNODEFICIENCY CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE MAGNESIUM TRANSPORTER 1 (MAGT1) GENE. MAGT1 DEFICIENCY IMPAIRS MAGNESIUM TRANSPORT AND THE N-LINKED GLYCOSYLATION OF A PANEL OF PROTEINS, WHICH SUBSEQUENTLY ABOLISHES THE EXPRESSION OF KEY IMMUNE RECEPTORS SUCH AS NATURAL KILLER GROUP 2, MEMBER D (AKA NKG2D). THESE EFFECTS INDUCE IMMUNE SYSTEM ABNORMALITIES, CHRONIC EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA. RECENT RESEARCH SHOWS THAT MAGT1 AND TUMOR CANDIDATE SUPPRESSOR 3 (TUSC3) SHARE HIGH SEQUENCE AND FUNCTIONAL SIMILARITY. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE FEASIBILITY OF ACTIVATING TUSC3 EXPRESSION TO PROVIDE A POTENTIAL THERAPEUTIC STRATEGY FOR XMEN DISEASE. METHODS: THE EXPRESSION PROFILES OF MAGT1 AND TUSC3 WERE ANALYZED USING MULTIPLE DATABASES, REAL-TIME QUANTITATIVE PCR, AND WESTERN BLOT. THE EFFECTS OF DECITABINE AND PANOBINOSTAT ON THE REGULATION OF TUSC3 EXPRESSION WERE EXPLORED IN BOTH MAGT1 KNOCKOUT (KO)/PATIENT-DERIVED LYMPHOCYTES AND MAGT1 KO HEPATOCYTES. RESULTS: ALTHOUGH TUSC3 IS WIDELY EXPRESSED, IT IS UNDETECTABLE SPECIFICALLY IN THE IMMUNE SYSTEM AND LIVER, CONSISTENT WITH THE MAIN DISEASED TISSUES IN PATIENTS WITH XMEN DISEASE. CRISPR/CAS9-MEDIATED KO OF MAGT1 IN THE NKL CELL LINE SUCCESSFULLY MIMICKED THE PHENOTYPES OF XMEN PATIENT-DERIVED LYMPHOCYTES, AND EXOGENOUS EXPRESSION OF TUSC3 RESCUED THE DEFICIENCIES IN KO NKL CELLS. USING THIS IN VITRO MODEL, WE IDENTIFIED 2 EPIGENETIC DRUGS, DECITABINE AND PANOBINOSTAT, BY SCREENING. COMBINATION TREATMENT USING THESE 2 DRUGS SIGNIFICANTLY UPREGULATED TUSC3 EXPRESSION AND RESCUED THE IMMUNE AND LIVER ABNORMALITIES. CONCLUSIONS: EPIGENETIC ACTIVATION OF TUSC3 EXPRESSION CONSTITUTES AN EFFECTIVE THERAPEUTIC STRATEGY FOR XMEN DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  5934 18 TARGETING FEATURES OF CURAXIN CBL0137 ON HEMATOLOGICAL MALIGNANCIES IN VITRO AND IN VIVO. THE ANTICANCER ACTIVITY OF CURAXIN CBL0137, A DNA-BINDING SMALL MOLECULE WITH CHROMATIN REMODULATING EFFECT, HAS BEEN DEMONSTRATED IN DIFFERENT CANCERS. HEREIN, A COMPARATIVE EVALUATION OF CBL0137 ACTIVITY WAS PERFORMED IN RESPECT TO ACUTE MYELOID LEUKEMIA (AML), ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC MYELOID LEUKEMIA AND MULTIPLE MYELOMA (MM) CULTURED IN VITRO. MTT ASSAY SHOWED AML AND MM HIGHER SENSITIVITY TO CBL0137'S CYTOSTATIC EFFECT COMPARATIVELY TO OTHER HEMATOLOGICAL MALIGNANCY CELLS. FLOW CYTOMETRY CELL CYCLE ANALYSIS REVEALED AN INCREASE IN SUBG1 AND G2/M POPULATIONS AFTER CBL0137 CELL TREATMENT, BUT THE PREVALENT TYPE OF ARREST VARIED. APOPTOSIS ACTIVATION BY CBL0137 MEASURED BY ANNEXIN-V/PI DUAL STAINING WAS MORE ACTIVE IN AML AND MM CELLS. RT2 PCR ARRAY SHOWED THAT CHANGES CAUSED BY CBL0137 IN SIGNALING PATHWAYS INVOLVED IN CANCER PATHOGENESIS WERE MORE INTENSIVE IN AML AND MM CELLS. ON THE MURINE MODEL OF AML WEHI-3, CBL0137 SHOWED SIGNIFICANT ANTICANCER EFFECTS IN VIVO, WHICH WERE EVALUATED BY CORRESPONDING CHANGES IN SPLEEN AND LIVER. THUS, MORE PRONOUNCED ANTICANCER EFFECTS OF CBL0137 IN VITRO WERE OBSERVED IN RESPECT TO AML AND MM. EXPERIMENTS IN VIVO ALSO INDICATED THE PERSPECTIVE OF CBL0137 USE FOR AML TREATMENT. THIS IN ACCORDANCE WITH THE FRONTLINE TREATMENT APPROACH IN AML USING EPIGENETIC DRUGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  5001 17 PERINATAL RISK FACTORS IN TOURETTE'S AND CHRONIC TIC DISORDERS: A TOTAL POPULATION SIBLING COMPARISON STUDY. ADVERSE PERINATAL EVENTS MAY INCREASE THE RISK OF TOURETTE'S AND CHRONIC TIC DISORDERS (TD/CTD), BUT PREVIOUS STUDIES HAVE BEEN UNABLE TO CONTROL FOR UNMEASURED ENVIRONMENTAL AND GENETIC CONFOUNDING. WE AIMED TO PROSPECTIVELY INVESTIGATE POTENTIAL PERINATAL RISK FACTORS FOR TD/CTD, TAKING UNMEASURED FACTORS SHARED BETWEEN FULL SIBLINGS INTO ACCOUNT. A POPULATION-BASED BIRTH COHORT, CONSISTING OF ALL SINGLETONS BORN IN SWEDEN IN 1973-2003, WAS FOLLOWED UNTIL DECEMBER 2013. A TOTAL OF 3 026 861 INDIVIDUALS WERE IDENTIFIED, 5597 OF WHICH HAD A REGISTERED TD/CTD DIAGNOSIS. WE THEN STUDIED DIFFERENTIALLY EXPOSED FULL SIBLINGS FROM 947 942 FAMILIES; OF THESE, 3563 FAMILIES INCLUDED SIBLINGS THAT WERE DISCORDANT FOR TD/CTD. PERINATAL DATA WERE COLLECTED FROM THE MEDICAL BIRTH REGISTER AND TD/CTD DIAGNOSES WERE COLLECTED FROM THE NATIONAL PATIENT REGISTER, USING A PREVIOUSLY VALIDATED ALGORITHM. IN THE FULLY ADJUSTED MODELS, IMPAIRED FETAL GROWTH, PRETERM BIRTH, BREECH PRESENTATION AND CESAREAN SECTION WERE ASSOCIATED WITH A HIGHER RISK OF TD/CTD, LARGELY INDEPENDENT FROM SHARED FAMILY CONFOUNDERS AND MEASURED COVARIATES. MATERNAL SMOKING DURING PREGNANCY WAS ASSOCIATED WITH RISK OF TD/CTD IN A DOSE-RESPONSE MANNER BUT THE ASSOCIATION WAS NO LONGER STATISTICALLY SIGNIFICANT IN THE SIBLING COMPARISON MODELS OR AFTER THE EXCLUSION OF COMORBID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER. A DOSE-RESPONSE RELATIONSHIP BETWEEN THE NUMBER OF ADVERSE PERINATAL EVENTS AND INCREASED RISK FOR TD/CTD WAS ALSO OBSERVED, WITH HAZARD RATIOS RANGING FROM 1.41 (95% CONFIDENCE INTERVAL (CI): 1.33-1.50) FOR ONE EVENT TO 2.42 (95% CI: 1.65-3.53) FOR FIVE OR MORE EVENTS. THESE RESULTS PAVE THE WAY FOR FUTURE GENE BY ENVIRONMENT INTERACTION AND EPIGENETIC STUDIES IN TD/CTD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13  4465 17 MOLECULAR MECHANISMS OF POSTTRAUMATIC STRESS DISORDER (PTSD) AS A BASIS FOR INDIVIDUALIZED AND PERSONALIZED THERAPY: RATIONALE, DESIGN AND METHODS OF THE SOUTH EASTERN EUROPE (SEE)-PTSD STUDY. POSTTRAUMATIC STRESS DISORDER (PTSD) IS A MAJOR HEALTH PROBLEM IN SOUTH EASTERN EUROPE (SEE). AVAILABLE TREATMENT OPTIONS ARE NOT EFFICIENT ENOUGH AND THE COURSE IS OFTEN CHRONIC. LITTLE IS KNOWN ABOUT MOLECULAR MEDIATORS AND MODERATORS OF PATHOGENESIS AND THERAPY. GENETIC AND EPIGENETIC VARIATION MAY BE ONE CENTRAL MOLECULAR MECHANISM. WE THEREFORE ESTABLISHED A CONSORTIUM COMBINING CLINICAL EXPERTISE ON PTSD FROM SEE COUNTRIES BOSNIA-HERZEGOVINA (SARAJEVO, TUZLA AND MOSTAR), KOSOVO (PRISHTINA) AND CROATIA (ZAGREB) WITH GENETIC AND EPIGENETIC COMPETENCE FROM GERMANY (WURZBURG) IN 2011 WITHIN THE FRAMEWORK OF THE DAAD (DEUTSCHER AKADEMISCHER AUSTAUSCHDIENST)-FUNDED STABILITY PACT FOR SOUTH EASTERN EUROPE. AFTER OBTAINING ETHICAL VOTES AND PERFORMING RATER TRAININGS AS WELL AS TRAINING IN DNA EXTRACTION FROM EDTA BLOOD BETWEEN 2011 AND 2013, WE RECRUITED 747 INDIVIDUALS WHO HAD EXPERIENCED WAR-RELATED TRAUMA IN THE SEE CONFLICTS BETWEEN 1991 AND 1999. 236 PARTICIPANTS HAD CURRENT PTSD, 161 LIFETIME PTSD AND 350 DID NOT HAVE AND NEVER HAD PTSD. DEMOGRAPHIC AND CLINICAL DATA ARE CURRENTLY MERGED TOGETHER WITH GENETIC AND EPIGENETIC DATA IN A SINGLE DATABASE TO ALLOW FOR A COMPREHENSIVE ANALYSIS OF THE ROLE OF GENETIC AND EPIGENETIC VARIATION IN THE PATHOGENESIS AND THERAPY OF PTSD. ANALYSES WILL BE DONE TO A GREAT DEGREE BY PHD STUDENTS FROM PARTICIPATING SEE CENTERS WHO IN ADDITION TO PARTICIPATION IN THE PROJECT HAD AN OPPORTUNITY TO TAKE PART IN SPRING AND SUMMER SCHOOLS OF THE DFG (DEUTSCHE FORSCHUNGSGEMEINSCHAFT) FUNDED RESEARCH TRAINING GROUP (RTG) 1253 AND THUS MEET PHD STUDENTS FROM GERMANY AND OTHER COUNTRIES WE ARE CONFIDENT THAT OUR PROJECT WILL NOT ONLY CONTRIBUTE TO A BETTER UNDERSTANDING OF GENETIC AND EPIGENETIC MECHANISMS OF PTSD AS A BASIS FOR FUTURE INDIVIDUALIZED AND PERSONALIZED THERAPIES, BUT ALSO TO THE ACADEMIC DEVELOPMENT OF SOUTH EASTERN EUROPE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  6049 19 THE CONCURRENT DECLINE OF SOIL LEAD AND CHILDREN'S BLOOD LEAD IN NEW ORLEANS. LEAD (PB) IS EXTREMELY TOXIC AND A MAJOR CAUSE OF CHRONIC DISEASES WORLDWIDE. PB IS ASSOCIATED WITH HEALTH DISPARITIES, PARTICULARLY WITHIN LOW-INCOME POPULATIONS. IN BIOLOGICAL SYSTEMS, PB MIMICS CALCIUM AND, AMONG OTHER EFFECTS, INTERRUPTS CELL SIGNALING. FURTHERMORE, PB EXPOSURE RESULTS IN EPIGENETIC CHANGES THAT AFFECT MULTIGENERATIONAL GENE EXPRESSION. EXPOSURE TO PB HAS DECREASED THROUGH PRIMARY PREVENTION, INCLUDING REMOVAL OF PB SOLDER FROM CANNED FOOD, REGULATING LEAD-BASED PAINT, AND ESPECIALLY ELIMINATING PB ADDITIVES IN GASOLINE. WHILE RESEARCHERS OBSERVE A CONTINUOUS DECLINE IN CHILDREN'S BLOOD LEAD (BPB), RESERVOIRS OF EXPOSURE PERSIST IN TOPSOIL, WHICH STORES THE LEGACY DUST FROM LEADED GASOLINE AND OTHER SOURCES. OUR SURVEYS OF METROPOLITAN NEW ORLEANS REVEAL THAT MEDIAN TOPSOIL PB IN COMMUNITIES (N = 274) DECREASED 44% FROM 99 MG/KG TO 54 MG/KG (P VALUE OF 2.09 X 10(-08)), WITH A MEDIAN DEPLETION RATE OF APPROXIMATELY 2.4 MG?KG?Y(-1) OVER 15 Y. FROM 2000 THROUGH 2005 TO 2011 THROUGH 2016, CHILDREN'S BPB DECLINED FROM 3.6 MUG/DL TO 1.2 MUG/DL OR 64% (P VALUE OF 2.02 X 10(-85)), A DECREASE OF APPROXIMATELY 0.2 MUG?DL?Y(-1) DURING A MEDIAN OF 12 Y. HERE, WE EXPLORE THE DECLINE OF CHILDREN'S BPB BY EXAMINING A METABOLISM OF CITIES FRAMEWORK OF INPUTS, TRANSFORMATIONS, STORAGES, AND OUTPUTS. OUR FINDINGS INDICATE THAT DECREASING PB IN TOPSOIL IS AN IMPORTANT FACTOR IN THE CONTINUOUS DECLINE OF CHILDREN'S BPB. SIMILAR REDUCTIONS ARE EXPECTED IN OTHER MAJOR US CITIES. THE MOST CONTAMINATED URBAN COMMUNITIES, USUALLY INHABITED BY VULNERABLE POPULATIONS, REQUIRE FURTHER REDUCTIONS OF TOPSOIL PB TO FULFILL PRIMARY PREVENTION FOR THE NATION'S CHILDREN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15   820 18 CHARACTERIZATION OF A PORTUGUESE FAMILY WITH CHARCOT-MARIE-TOOTH DISEASE TYPE 1E DUE TO A NOVEL POINT MUTATION IN THE PMP22 GENE. INTRODUCTION: POINT MUTATIONS IN THE PERIPHERAL MYELIN PROTEIN 22 (PMP22) GENE COMPRISE LESS THAN 5% OF THE CHARCOT-MARIE-TOOTH (CMT) TYPE 1 CASES, AND INDIVIDUALIZE EITHER THE CMT 1E SUBTYPE, OR HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSY. THE PHENOTYPE OF CMT 1E PRESENTS WITH A SEVERE EARLY-ONSET POLYNEUROPATHY ASSOCIATED WITH DEAFNESS, ALTHOUGH THE CLINICAL SPECTRUM IS BROAD. CASE REPORT: WE DESCRIBE A NOVEL PMP22 GENE POINT MUTATION (C.84G>T;P.(TRP28CYS)) IN THREE PATIENTS OF A PORTUGUESE FAMILY WITH VARIABLE PHENOTYPES, RANGING FROM ASYMPTOMATIC TO MILD COMPLAINTS OF DISTAL LIMB NUMBNESS AND GAIT DIFFICULTIES, WITH THE AGE OF ONSET OF SYMPTOMS RANGING FROM MID-TWENTIES TO LATE-SIXTIES, AND NO ASSOCIATED DISABILITY. IN ALL AFFECTED PATIENTS, THERE WAS EVIDENCE OF DIFFUSE DEMYELINATING SENSORIMOTOR POLYNEUROPATHY. HEARING LOSS DOES NOT SEEM TO BE ASSOCIATED WITH THIS VARIANT, ALBEIT NEUROPATHIC PAIN WAS REPORTED. CONCLUSIONS: THESE FINDINGS SUGGEST THAT THIS PARTICULAR POINT MUTATION IN THE PMP22 GENE IS ASSOCIATED WITH A MILD PHENOTYPE, FURTHER EMPHASIZING THAT THERE ARE STILL UNKNOWN MECHANISMS (GENETIC AND/OR EPIGENETIC) THAT MAY PLAY A ROLE IN THE CLINICAL SPECTRUM OF CMT1E PATIENTS. NEXT GENERATION SEQUENCING PANELS INCLUDING COMMONLY MUTATED GENES IN CMT SHOULD BE CONSIDERED IN CMT1 CASES NEGATIVE FOR PMP22 GENE DUPLICATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  3879 14 KERATIN 19-EXPRESSING HEPATOCELLULAR CARCINOMA AND SMALL-DUCT TYPE INTRAHEPATIC CHOLANGIOCARCINOMA SHOW A SIMILAR POSTOPERATIVE CLINICAL COURSE BUT HAVE DISTINCT GENETIC FEATURES. AIMS: THE PRESENT STUDY AIMED TO SYSTEMATICALLY COMPARE CLINICOPATHOLOGICAL AND GENETIC FEATURES BETWEEN KERATIN 19 (K19)-EXPRESSING HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICCA). METHODS AND RESULTS: CONSECUTIVE CASES OF HCC (N = 430) WERE CLASSIFIED INTO K19(+) AND K19(-) USING IMMUNOHISTOCHEMISTRY. ICCA CASES WERE ALSO SEPARATED INTO SMALL-(S-ICCA; N = 36) AND LARGE-DUCT TYPES (N = 22) BASED ON RECENTLY PROPOSED CRITERIA, WITH THE FORMER BEING USED IN THE PRESENT STUDY. MUTATIONAL HOT-SPOTS IN TERT, CTNNB1, KRAS AND IDH1 WERE SEQUENCED. TWENTY-SIX CASES (6%) OF HCC EXPRESSED K19. K19(+) HCC WAS MORE STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B THAN K19(-) HCC AND S-ICCA (46% VERSUS 17% AND 6%; BOTH P < 0.001). LYMPH NODE METASTASIS WAS OBSERVED IN K19(+) HCC (8%) AND S-ICCA (22%), BUT WAS EXCEPTIONAL IN K19(-) HCC (1%). K19(+) HCC HAD TERT PROMOTER MUTATIONS LESS FREQUENTLY THAN K19(-) HCC (31% VERSUS 59%; P = 0.022), AND LACKED ALTERATIONS IN KRAS AND IDH1. CTNNB1 MUTATIONS WERE SIMILARLY OBSERVED IN K19(+) AND K19(-) HCC (23% AND 19%, RESPECTIVELY), BUT RARE IN S-ICCA (3%). THE POSTOPERATIVE SURVIVAL CURVE OF K19(+) HCC WAS ALMOST IDENTICAL TO THAT OF S-ICCA IN THE FIRST 5 YEARS (APPROXIMATELY 50% AT 5 YEARS), AND SIGNIFICANTLY WORSE THAN THAT OF K19(-) HCC (P = 0.040). EXTRAHEPATIC RECURRENCE WAS MORE COMMON IN K19(+) HCC (50%) AND S-ICCA (35%) THAN IN K19(-) HCC (15%) (P = 0.001). CONCLUSIONS: ALTHOUGH K19(+) HCC AND S-ICCA SHOWED SIMILAR BIOLOGICAL BEHAVIOURS, THEY DID NOT SHARE ANY DRIVER GENE MUTATIONS, SUGGESTING THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ICCA-LIKE FEATURES OF K19(+) HCC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17   511 18 ASSOCIATION OF RASSF1A HYPERMETHYLATION WITH RISK OF HBV/HCV-INDUCED HEPATOCELLULAR CARCINOMA: A META-ANALYSIS. BACKGROUND: RESEARCHERS HAVE DISCOVERED A LARGE NUMBER OF DNA METHYLATION PATTERNS IN HUMAN CANCER. THESE CANCER-SPECIFIC METHYLATION PATTERNS CAN PROVIDE INFORMATION FOR THE DIAGNOSIS, TREATMENT, AND PROGNOSIS OF CANCER. METHYLATION STUDIES CAN FIND NEW BIOMARKERS BASED ON EPIGENETIC ANALYSIS AND APPLY THESE BIOMARKERS TO CLINICAL ONCOLOGY. MANY STUDIES ON THE ASSOCIATION BETWEEN RAASF1A METHYLATION STATUS AND SUSCEPTIBILITY TO HEPATITIS B VIRUS (HBV)/HEPATITIS C VIRUS (HCV)-INDUCED HEPATOCELLULAR CARCINOMA (HCC) HAVE REACHED CONTROVERSIAL CONCLUSIONS. HENCE, THE CURRENT REVIEW COMPREHENSIVELY ASSESSED THE CORRELATION BETWEEN RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) METHYLATION AND THE RISK OF THE HCV/HBV-INDUCED HCC. METHODS: THE APPROPRIATED PUBLICATIONS WERE EXTRACTED IN EMBASE, PUBMED, WEB OF SCIENCE, COCHRANE LIBRARY, AND CHINA NATIONAL KNOWLEDGE INFRASTRUCTURE DATABASES USING STATA 5.0 SOFTWARE. THE ODDS RATIOS (ORS) WITH 95 % CONFIDENCE INTERVAL (95 % CI) OF RASSF1A METHYLATION WERE COMPUTED. RESULTS: A TOTAL OF 1015 HBV/HCV-RELATED HCC SAMPLES, 124 NON-HBV/HCV-RELATED HCC (NBNC-HCC) SAMPLES, AND 1225 NONTUMOROUS CONTROLS WERE EXTRACTED AND EXAMINED IN THIS RESEARCH. THE FREQUENCY OF THE METHYLATED RASSF1A IN THE HBV/HCV-RELATED TUMOR CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE OVERALL NONTUMOR SAMPLES (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). THE FREQUENCY OF THE METHYLATED RASSF1A IN HBV/HCV-RELATED NEOPLASM CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE NON-HBV/HCV-RELATED NEOPLASM (NBNC-NEOPLASM) SAMPLES (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). COMPARED WITH NORMAL, CHRONIC HEPATITIS B OR C, CIRRHOSIS, AND PARACANCEROUS SAMPLES, THE POOLED OR OF THE RASSF1A PROMOTER METHYLATION IN THE HBV/HCV-INDUCED HCC SAMPLES WAS 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) AND 9.02 (95 % CI = 0.91-89.80), RESPECTIVELY. THE RATE OF RASSF1A HYPERMETHYLATION WAS ROBUSTLY CORRELATED WITH TUMOR SIZE AND VASCULAR INVASION, AND THE POOLED OR WAS 0.346 (95 % CI = 0.210 - 0.569) AND 0.081 (95 % CI = 0.022 - 0.303), RESPECTIVELY. CONCLUSION: RESULTS SHOWED ROBUST ASSOCIATIONS BETWEEN RASSF1A GENE METHYLATION IN PROMOTER REGION AND ENHANCED HBV/HCV-RELATED HCC SUSCEPTIBILITY, THEREBY REVEALING THAT RASSF1A METHYLATION STATUS MAY SERVE AS AN IMPORTANT INDICATOR FOR HCC ONCOGENESIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  1791 16 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19   116 17 A STUDY OF DNA METHYLATION OF BLADDER CANCER BIOMARKERS IN THE URINE OF PATIENTS WITH NEUROGENIC LOWER URINARY TRACT DYSFUNCTION. BACKGROUND: BLADDER CANCER (BCA) IN PATIENTS SUFFERING FROM NEUROGENIC LOWER URINARY TRACT DYSFUNCTION (NLUTD) IS A SIGNIFICANT CONCERN DUE TO ITS ADVANCED STAGE AT DIAGNOSIS AND HIGH MORTALITY RATE. CURRENTLY, THERE IS A SCARCITY OF SPECIFIC GUIDELINES FOR BCA SCREENING IN THESE PATIENTS. THE DEVELOPMENT OF URINE BIOMARKERS FOR BCA SEEMS TO BE AN ATTRACTIVE NON-INVASIVE METHOD OF SCREENING OR RISK STRATIFICATION IN THIS PATIENT POPULATION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION, RESULTING IN THE TRANSCRIPTIONAL SILENCING OF TUMOR SUPPRESSION GENES, THAT IS FREQUENTLY DETECTED IN THE URINE OF BCA PATIENTS. OBJECTIVES: WE AIMED TO INVESTIGATE DNA HYPERMETHYLATION IN FIVE GENE PROMOTERS, PREVIOUSLY ASSOCIATED WITH BCA, IN THE URINE OF NLUTD PATIENTS, AND IN COMPARISON WITH HEALTHY CONTROLS. DESIGN, SETTING AND PARTICIPANTS: THIS WAS A PROSPECTIVE CASE-CONTROL STUDY THAT RECRUITED NEUROUROLOGY OUTPATIENTS FROM A PUBLIC TEACHING HOSPITAL WHO HAD SUFFERED FROM NLUTD FOR AT LEAST 5 YEARS. THEY ALL UNDERWENT CYSTOSCOPY COMBINED WITH BIOPSY FOR BCA SCREENING FOLLOWING WRITTEN INFORMED CONSENT. DNA WAS EXTRACTED AND DNA METHYLATION WAS ASSESSED FOR THE RASSF1, RARBETA, DAPK, TERT AND APC GENE PROMOTERS VIA QUANTITATIVE METHYLATION-SPECIFIC PCR IN URINE SPECIMENS FROM THE PATIENTS AND CONTROLS. RESULTS: FORTY-ONE PATIENTS OF MIXED NLUTD ETIOLOGY AND 35 CONTROLS WERE ENROLLED. DNA WAS DETECTED IN 36 PATIENTS' URINE SPECIMENS AND IN THOSE OF 22 CONTROLS. IN THE URINE SPECIMENS, DNA WAS HYPERMETHYLATED IN AT LEAST ONE OF FIVE GENE PROMOTERS IN 17/36 PATIENTS AND IN 3/22 CONTROLS (47.22% VS. 13.64%, RESPECTIVELY, P = 0.009). RASSF1 WAS HYPERMETHYLATED IN 10/17 (58.82%) SPECIMENS WITH DETECTED METHYLATION, APC IN 7/17 (41.18%), DAPK IN 4/17 (23.53%), RAR-BETA2 IN 3/17 (17.56%) AND TERT IN NONE. ACCORDING TO A MULTIVARIATE LOGISTIC REGRESSION ANALYSIS, NLUTD AND MALE GENDER WERE SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION (OR = 7.43, P = 0.007 AND OR = 4.21; P = 0.04, RESPECTIVELY). IN THE TISSUE SPECIMENS, HISTOLOGY REVEALED TALG BCA IN TWO PATIENTS AND UROTHELIAL SQUAMOUS METAPLASIA IN FIVE PATIENTS. CHRONIC BLADDER INFLAMMATION WAS PRESENT IN 35/41 BLADDER BIOPSIES. CONCLUSIONS: DNA HYPERMETHYLATION IN A PANEL OF FIVE BCA-ASSOCIATED GENES IN THE URINE WAS SIGNIFICANTLY MORE FREQUENT IN NLUTD PATIENTS THAN IN THE CONTROLS. OUR RESULTS WARRANT FURTHER EVALUATION IN LONGITUDINAL STUDIES ASSESSING THE CLINICAL IMPLICATIONS AND POSSIBLE ASSOCIATIONS BETWEEN DNA HYPERMETHYLATION, CHRONIC INFLAMMATION AND BCA IN THE NLUTD POPULATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20  3479 21 IDENTIFICATION OF BIOACTIVE METABOLITES AND EVALUATION OF IN VITRO ANTI-INFLAMMATORY AND IN VIVO ANTINOCICEPTIVE AND ANTIARTHRITIC ACTIVITIES OF ENDOPHYTE FUNGI ISOLATED FROM ELAEOCARPUS FLORIBUNDUS BLUME. ETHNOPHARMACOLOGICAL RELEVANCE: FUNCTIONAL DISABILITY ASSOCIATED WITH RHEUMATOID ARTHRITIS (RA), A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE IS A CHALLENGING CONCERN IN HEALTHCARE SYSTEMS. ALONG WITH ENVIRONMENTAL FACTORS AND EPIGENETIC DISORDERS, MULTIPLE PATHWAYS ARE REPORTED AS PROMINENT MECHANISM FOR THE PROGRESSION OF RA SYMPTOMS INCLUDING; PAIN, SWELLING AND STIFFNESS OF JOINTS. ELAEOCARPUS FLORIBUNDUS BLUME HAS BEEN USED AS A FOLKLORE MEDICINE FOR RA FROM ANCIENT TIMES. THIS PLANT HARBOURS A SUITE OF ENDOPHYTIC FUNGI THAT PRODUCE A RANGE OF METABOLITES OF POTENTIAL INTEREST. THUS, FOR THE ESTABLISHMENT OF A SCIENTIFIC BASIS FOR THIS FOLKLORE USE, IT IS ESSENTIAL TO FIND OUT THE INVOLVEMENT, IF ANY, OF THE ENDOPHYTIC FUNGI LIVING IN THIS PLANT AND THE METABOLITES THEY ELABORATE, FOR THE MANAGEMENT OF RA. AIM OF THE STUDY: THIS STUDY WAS DESIGNED TO ISOLATE, IDENTIFY AND EVALUATE THE IN VITRO ANTI-INFLAMMATORY AND IN VIVO ANTINOCICEPTIVE AND ANTIARTHRITIC ACTIVITIES OF THE COMPOUNDS PRODUCED BY THE ENDOPHYTIC FUNGI LIVING IN DIFFERENT PARTS OF ELAEOCARPUS FLORIBUNDUS BLUME. MATERIALS AND METHODS: ENDOPHYTIC FUNGI FROM DIFFERENT PARTS OF THE PLANT WERE ISOLATED AND CULTURED FOR THE PRODUCTION OF SECONDARY METABOLITES. CHROMATOGRAPHICALLY FRACTIONATED FUNGAL EXTRACTS WERE ASSESSED FOR ANTI-INFLAMMATORY AND ANTINOCICEPTIVE ACTIVITIES. FOR THE EVALUATION OF ANTI-INFLAMMATORY ACTIVITY, IN VITRO CYCLOOXYGENASE (COX1/COX2) AND 5-LIPOXYGENASE (5-LOX) INHIBITORY ASSAYS WERE PERFORMED. FOR THE EVALUATION OF IN VIVO ANTINOCICEPTIVE ACTIVITY, HOT PLATE ACETIC ACID INDUCED WRITHING, AND FORMALIN INDUCED PAW LICKING METHODS WERE ADOPTED, WHEREAS COMPLETE FREUND'S ADJUVANT (CFA) INDUCED POLY-ARTHRITIC METHOD WAS ADOPTED FOR THE EVALUATION OF ANTIARTHRITIC ACTIVITY. THE MOST EFFECTIVE FRACTION WAS ANALYZED BY LIQUID CHROMATOGRAPHY-MASS SPECTROSCOPY (LC-MS) IN SEARCH OF THE BIOACTIVE EXTRACELLULAR METABOLITES. RESULTS: FIVE ENDOPHYTIC FUNGI VIZ. ASPERGILLUS FUMIGATUS, ASPERGILLUS NIGER, RHIZOCTONIA ORYZAE, RHIZOPUS ORYZAE, AND SYNCEPHALASTRUM RACEMOSUM WERE ISOLATED. COX1/COX2 AND 5-LOX INHIBITORY ASSAYS STATE THAT THE ASPERGILLUS NIGER FRACTION POSSESSES THE GREATEST ACTIVITY AGAINST THESE ENZYMES OF INFLAMMATORY PROCESS. IN VIVO ANTINOCICEPTIVE SHOWED SIGNIFICANT (***P<0.001) REDUCTION OF PAIN IN A DOSE DEPENDENT MANNER. AS WELL, SIGNIFICANT (***P<0.001) REDUCTION OF PAW VOLUME WAS OBSERVED IN CFA INDUCE POLY-ARTHRITIC TEST. LC/MS ANALYSIS OF THE ASPERGILLUS NIGER FRACTION REVEALED THE PRESENCE OF BIOACTIVE COMPOUNDS INCLUDING TENSYUIC ACID, HEXYLITACONIC ACID, CHLOROGENIC ACID, NIGRAGILLIN, TMC-256C1, ASNIPYRONE B, ASPERENONE, FUMARIC ACID AND FUSARUBIN, ALL HAVING REPORTED PHARMACOLOGICAL ACTIVITIES. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT SECONDARY METABOLITES PRODUCED BY ENDOPHYTIC FUNGI LIVING IN VARIOUS PARTS OF ELAEOCARPUS FLORIBUNDUS BLUME HAD POTENTIAL TO RELIEF PAIN AND INFLAMMATION. THE ENDOPHYTES WERE FOUND TO CONTAIN MULTIPLE BIOMOLECULES EFFECTIVE IN RHEUMATOID ARTHRITIS. THESE FINDINGS PROVIDE A RATIONALE FOR THE FOLKLORE USE OF THE PLANT IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS.	2021