1 2977 115 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2 5340  29 QUORUM SENSING AND VIRULENCE OF PSEUDOMONAS AERUGINOSA DURING LUNG INFECTION OF CYSTIC FIBROSIS PATIENTS. PSEUDOMONAS AERUGINOSA IS THE PREDOMINANT MICROORGANISM IN CHRONIC LUNG INFECTION OF CYSTIC FIBROSIS PATIENTS. THE CHRONIC LUNG INFECTION IS PRECEDED BY INTERMITTENT COLONIZATION. WHEN THE CHRONIC INFECTION BECOMES ESTABLISHED, IT IS WELL ACCEPTED THAT THE ISOLATED STRAINS DIFFER PHENOTYPICALLY FROM THE INTERMITTENT STRAINS. DOMINATING CHANGES ARE THE SWITCH TO MUCOIDITY (ALGINATE OVERPRODUCTION) AND LOSS OF EPIGENETIC REGULATION OF VIRULENCE SUCH AS THE QUORUM SENSING (QS). TO ELUCIDATE THE DYNAMICS OF P. AERUGINOSA QS SYSTEMS DURING LONG TERM INFECTION OF THE CF LUNG, WE HAVE INVESTIGATED 238 ISOLATES OBTAINED FROM 152 CF PATIENTS AT DIFFERENT STAGES OF INFECTION RANGING FROM INTERMITTENT TO LATE CHRONIC. ISOLATES WERE CHARACTERIZED WITH REGARD TO QS SIGNAL MOLECULES, ALGINATE, RHAMNOLIPID AND ELASTASE PRODUCTION AND MUTANT FREQUENCY. THE GENETIC BASIS FOR CHANGE IN QS REGULATION WERE INVESTIGATED AND IDENTIFIED BY SEQUENCE ANALYSIS OF LASR, RHLR, LASI AND RHLI. THE FIRST QS SYSTEM TO BE LOST WAS THE ONE ENCODED BY LAS SYSTEM 12 YEARS (MEDIAN VALUE) AFTER THE ONSET OF THE LUNG INFECTION WITH SUBSEQUENT LOSS OF THE RHL ENCODED SYSTEM AFTER 17 YEARS (MEDIAN VALUE) SHOWN AS DEFICIENCIES IN PRODUCTION OF THE 3-OXO-C12-HSL AND C4-HSL QS SIGNAL MOLECULES RESPECTIVELY. THE CONCOMITANT DEVELOPMENT OF QS MALFUNCTION SIGNIFICANTLY CORRELATED WITH THE REDUCED PRODUCTION OF RHAMNOLIPIDS AND ELASTASE AND WITH THE OCCURRENCE OF MUTATIONS IN THE REGULATORY GENES LASR AND RHLR. ACCUMULATION OF MUTATIONS IN BOTH LASR AND RHLR CORRELATED WITH DEVELOPMENT OF HYPERMUTABILITY. INTERESTINGLY, A HIGHER NUMBER OF MUCOID ISOLATES WERE FOUND TO PRODUCE C4-HSL SIGNAL MOLECULES AND RHAMNOLIPIDS COMPARED TO THE NON-MUCOID ISOLATES. AS SEEN FROM THE PRESENT DATA, WE CAN CONCLUDE THAT P. AERUGINOSA AND PARTICULARLY THE MUCOID STRAINS DO NOT LOSE THE QS REGULATION OR THE ABILITY TO PRODUCE RHAMNOLIPIDS UNTIL THE LATE STAGE OF THE CHRONIC INFECTION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
3 3479  31 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	

4 5017  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5 6636  28 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                        
6 5511  18 RIBONUCLEASES IN TUMOR GROWTH. THIS REVIEW SUMMARIZES DATA ON AMBIGUOUS BIOLOGICAL FUNCTIONS OF RIBONUCLEASES (RNASES) AT TUMOR GROWTH. IN SOME CASES THE RAISED LEVEL OF ENZYME ACTIVITY IN BIOLOGICAL FLUIDS CAN BE REGARDED AS AN ADDITIONAL MARKER OF MALIGNANT GROWTH (PANCREAS CANCER, CHRONIC MYELOID LEUKEMIA, ETC.). AT THE SAME TIME THE ACTIVITY OF RNASES IS OFTEN LOWERED IN TUMOR TISSUE. HIGH SUBSTRATE SPECIFICITY OF PARTICULAR RNASES PROVIDES METABOLIC BALANCE BETWEEN VARIOUS KINDS OF RNAS WITH VARIOUS HALF-TIME EXCHANGE TURN. RNASES ARE THE IMPORTANT FACTORS OF EPIGENETIC REGULATION OF GENE ACTIVITY IN CELLS. THE ACTIVITY OF RNASES IS ADJUSTABLE BY INHIBITORS AND OTHER FACTORS, AND DEFINES TIME OF EXISTENCE OF DIFFERENT KINDS OF RNAS. RNASES (THE MODIFIED VARIANTS OF RNASE A, RNASES OF SEMEN FLUID OF THE CATTLE, RNASE OF AMPHIBIA OOCYTES) CAN BE USED AS ANTI-TUMOR THERAPEUTIC AGENTS. ON THE OTHER HAND, SOME INHIBITORS OF RNASES OF NATURAL OR SYNTHETIC ORIGIN WERE DEMONSTRATED TO BE PERSPECTIVE DRUGS THAT INHIBIT TUMOR GROWTH.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 1791  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 3381  22 HLA AND AUTOIMMUNE DISEASES: TYPE 1 DIABETES (T1D) AS AN EXAMPLE. AUTOIMMUNE DISEASES NEED TO BE CONSIDERED AT A GENETIC AND MECHANISTIC LEVEL. T1D IS AN AUTOIMMUNE, CHRONIC, MULTIFACTORIAL AND POLYGENIC DISEASE CHARACTERIZED BY THE DESTRUCTION OF THE PANCREATIC BETA-CELLS ASSOCIATED WITH LONG TERM DYSFUNCTION OF SEVERAL ORGANS AND TISSUES. MECHANISMS OF SUSCEPTIBILITY INCLUDE EPI-GENETIC AND POST-TRANSCRIPTIONAL EFFECTS THAT REGULATE TRANSMISSION AND EXPRESSION OF THE INHERITED GENES. THE HLA COMPLEX, CONSTITUTES THE MOST RELEVANT REGION CONTRIBUTING 50% OF THE INHERITED RISK FOR T1D. AN ADDITIONAL 17 GENES WITH VARIABLE BUT SMALL EFFECTS HAVE BEEN DESCRIBED. IN NON-CAUCASIANS, THE PRESENCE OF E-DRBETA1-74 AND/OR D-DRBETA1-57 ARE RELEVANT IN PREDISPOSITION. THE "DIABETOGENIC HAPLOTYPES" IN MEXICANS WERE DRB1*0301-DQA1*0501-DQB1*0201 (OR = 21.4); DRB1*0405-DQA1-*0301-DQB1*0302 (OR = 44.5) AND THE SAME DQA1/DQB1 WITH DRB1*0404/*0401 CONFERRING LOWER RISK, INCREASING (OR = 61.3) WITH AN EARLY AGE AT ONSET AND A HETEROZYGOTE DR3/DR4 GENOTYPE. IN MOST POPULATIONS, THE ABSENCE OF D-57 AND THE PRESENCE OF R-52 ARE IMPORTANT TO THE SUSCEPTIBILITY, BUT IN HISPANICS, ALL DR4S (INCLUDING THE PROTECTIVE DRB1*0403/*0407/*0411) ARE IN LINKAGE DISEQUILIBRIUM WITH DQA1/DQB1 SUSCEPTIBILITY ALLELES. THUS, SUSCEPTIBILITY ALLELES IN LATIN AMERICAN MESTIZOS ARE OF MEDITERRANEAN ANCESTRY WHEREAS PROTECTIVE ALLELES ARE OF AMERINDIAN ORIGIN. IN THIS REVIEW, WE DISCUSS THE COMPLEXITY OF T1D AND SOME ASPECTS OF PREVENTION/INTERVENTION BASED ON IMMUNOGENETICS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9 2819  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10 1679  24 DRUG RESISTANCE IN GIARDIA DUODENALIS. GIARDIA DUODENALIS IS A MICROAEROPHILIC PARASITE OF THE HUMAN GASTROINTESTINAL TRACT AND A MAJOR CONTRIBUTOR TO DIARRHEAL AND POST-INFECTIOUS CHRONIC GASTROINTESTINAL DISEASE WORLD-WIDE. TREATMENT OF G. DUODENALIS INFECTION CURRENTLY RELIES ON A SMALL NUMBER OF DRUG CLASSES. NITROHETEROCYCLICS, IN PARTICULAR METRONIDAZOLE, HAVE REPRESENTED THE FRONT LINE TREATMENT FOR THE LAST 40 YEARS. NITROHETEROCYCLIC-RESISTANT G. DUODENALIS HAVE BEEN ISOLATED FROM PATIENTS AND CREATED IN VITRO, PROMPTING CONSIDERABLE RESEARCH INTO THE BIOMOLECULAR MECHANISMS OF RESISTANCE. THESE COMPOUNDS ARE REDOX-ACTIVE AND ARE BELIEVED TO DAMAGE PROTEINS AND DNA AFTER BEING ACTIVATED BY OXIDOREDUCTASE ENZYMES IN METABOLICALLY ACTIVE CELLS. IN THIS REVIEW, WE EXPLORE THE MOLECULAR PHENOTYPES OF NITROHETEROCYCLIC-RESISTANT G. DUODENALIS DESCRIBED TO DATE IN THE CONTEXT OF THE PROTIST'S UNUSUAL GLYCOLYTIC AND ANTIOXIDANT SYSTEMS. WE PROPOSE THAT RESISTANCE MECHANISMS ARE LIKELY TO EXTEND WELL BEYOND CURRENTLY DESCRIBED RESISTANCE-ASSOCIATED ENZYMES (I.E., PYRUVATE FERREDOXIN OXIDOREDUCTASES AND NITROREDUCTASES), TO INCLUDE NAD(P)H- AND FLAVIN-GENERATING PATHWAYS, AND POSSIBLY REDOX-SENSITIVE EPIGENETIC REGULATION. MECHANISMS THAT ALLOW G. DUODENALIS TO TOLERATE OXIDATIVE STRESS MAY LEAD TO RESISTANCE AGAINST BOTH OXYGEN AND NITROHETEROCYCLICS, WITH IMPLICATIONS FOR CLINICAL CONTROL. THE PRESENT REVIEW HIGHLIGHTS THE POTENTIAL FOR SYSTEMS BIOLOGY TOOLS AND ADVANCED BIOINFORMATICS TO FURTHER INVESTIGATE THE MULTIFACETED MECHANISMS OF NITROHETEROCYCLIC RESISTANCE IN THIS IMPORTANT PATHOGEN.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  760  19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 5640  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13 1843  18 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 2080  21 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15 1951  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 2974  28 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 5353  29 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18 6036  28 THE CHARACTERISTICS OF EXTRACHROMOSOMAL CIRCULAR DNA IN PATIENTS WITH END-STAGE RENAL DISEASE. BACKGROUND: END-STAGE RENAL DISEASE (ESRD) IS THE FINAL STAGE OF CHRONIC KIDNEY DISEASE (CKD). IN ADDITION TO THE STRUCTURALLY INTACT CHROMOSOME GENOMIC DNA, THERE IS A DOUBLE-STRANDED CIRCULAR DNA CALLED EXTRACHROMOSOMAL CIRCULAR DNA (ECCDNA), WHICH IS THOUGHT TO BE INVOLVED IN THE EPIGENETIC REGULATION OF HUMAN DISEASE. HOWEVER, THE FEATURES OF ECCDNA IN ESRD PATIENTS ARE BARELY KNOWN. IN THIS STUDY, WE IDENTIFIED ECCDNA FROM ESRD PATIENTS AND HEALTHY PEOPLE, AS WELL AS REVEALED THE CHARACTERISTICS OF ECCDNA IN PATIENTS WITH ESRD. METHODS: USING THE HIGH-THROUGHPUT CIRCLE-SEQUENCING TECHNIQUE, WE EXAMINED THE ECCDNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY PEOPLE (NC) (N = 12) AND ESRD PATIENTS (N = 16). WE ANALYZED THE LENGTH DISTRIBUTION, GENOME ELEMENTS, AND MOTIFS FEATURE OF ECCDNA IN ESRD PATIENTS. THEN, AFTER IDENTIFYING THE SPECIFIC ECCDNA IN ESRD PATIENTS, WE EXPLORED THE POTENTIAL FUNCTIONS OF THE TARGET GENES OF THE SPECIFIC ECCDNA. FINALLY, WE INVESTIGATED THE PROBABLE HUB ECCDNA USING ALGORITHMS. RESULTS: IN TOTAL, 14,431 AND 11,324 ECCDNAS WERE FOUND IN THE ESRD AND NC GROUPS, RESPECTIVELY, WITH SIZES RANGING FROM 0.01 KB TO 60 KB AT MOST. ADDITIONALLY, THE ESRD GROUP HAD A GREATER DISTRIBUTION OF ECCDNA ON CHROMOSOMES 4, 11, 13, AND 20. IN TWO GROUPS, WE ALSO DISCOVERED SEVERAL MOTIFS OF SPECIFIC ECCDNAS. FURTHERMORE, WE IDENTIFIED 13,715 SPECIFIC ECCDNAS IN THE ESRD GROUP AND 10,585 SPECIFIC ECCDNAS IN THE NC GROUP, BOTH OF WHICH WERE LARGELY ANNOTATED AS MRNA CATALOG. PATHWAY STUDIES USING GENE ONTOLOGY (GO) AND THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) SHOWED THAT THE SPECIFIC ECCDNA IN ESRD WAS MARKEDLY ENRICHED IN CELL JUNCTION AND COMMUNICATION PATHWAYS. FURTHERMORE, WE IDENTIFIED POTENTIALLY 20 HUB ECCDNA-TARGETING GENES FROM ALL ESRD-SPECIFIC ECCDNA-TARGETING GENES. ALSO, WE FOUND THAT 39 ECCDNA-TARGETING GENES WERE ASSOCIATED WITH ESRD, AND SOME OF THESE ECCDNAS MAY BE RELATED TO THE PATHOGENESIS OF ESRD. CONCLUSIONS: OUR FINDINGS REVEALED THE CHARACTERISTICS OF ECCDNA IN ESRD PATIENTS AND DISCOVERED POTENTIALLY HUB AND ESRD-RELEVANT ECCDNA-TARGETING GENES, SUGGESTING A NOVEL PROBABLE MECHANISM OF ESRD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 1419  21 DIFFERENT CLINICAL FORMS OF HEREDITARY TYROSINEMIA (TYPE I) IN PATIENTS WITH IDENTICAL GENOTYPES. HEREDITARY TYROSINEMIA TYPE I (HTI, MCKUSICK 276700) IS AN AUTOSOMAL RECESSIVE DISEASE CAUSED BY DEFICIENT FUMARYLACETOACETATE HYDROLASE (FAH, EC 3.7.1.2) ACTIVITY. HTI IS CHARACTERIZED BY PROGRESSIVE LIVER DYSFUNCTION WITH NODULAR CIRRHOSIS OFTEN LEADING TO HEPATOCELLULAR CARCINOMA. TWO EXTREMES OF THE CLINICAL PHENOTYPE HAVE BEEN DESCRIBED: THE "ACUTE" (SEVERE, EARLY ONSET AND DEATH) AND "CHRONIC" (DELAYED ONSET AND SLOW COURSE) PHENOTYPE. ALLELIC HETEROGENEITY AND/OR MUTATION REVERSION IN HEPATIC CELLS HAVE BEEN PROPOSED EARLIER TO EXPLAIN THE CLINICAL HETEROGENEITY. TWO PROBANDS (ONE "ACUTE," ONE "CHRONIC") FROM THE FRENCH-CANADIAN ISOLATE WHERE HTI IS PREVALENT WERE STUDIED. BOTH WERE HOMOZYGOUS (GERM LINE) FOR THE SEVERE SPLICE MUTATION IVS12 + 5G --> A; BOTH SHOWED LIVER MOSAICISM FOR FAH IMMUNOREACTIVITY WITH EVIDENCE FOR MUTATION REVERSION TO HETEROZYGOSITY (IVS12 + 5G --> A/+) IN FAH-STAINED NODULES AS SHOWN BY AMPLIFICATION OF DNA EXTRACTED FROM MICRODISSECTED NODULES. WESTERN BLOT ANALYSIS OF PROTEINS FROM A REVERTED FAH-EXPRESSING NODULE SHOWED 29 +/- 3% FAH IMMUNOREACTIVE MATERIAL AS COMPARED TO AN AVERAGE NORMAL LIVER. THIS WAS CONSISTENT WITH THE MEASURED FAA HYDROLYTIC ACTIVITY (25%) IN THIS LARGE REGENERATING NODULE. THESE FINDINGS SHOW THAT GENOTYPIC HETEROGENEITY IS NOT A SUFFICIENT EXPLANATION FOR CLINICAL HETEROGENEITY AND IMPLICATE EPIGENETIC AND OTHER FACTORS MODIFYING THE PHENOTYPE IN HTI.	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  238  17 ADENOSINE KINASE: A KEY REGULATOR OF PURINERGIC PHYSIOLOGY. ADENOSINE (ADO) IS AN ESSENTIAL BIOMOLECULE FOR LIFE THAT PROVIDES CRITICAL REGULATION OF ENERGY UTILIZATION AND HOMEOSTASIS. ADENOSINE KINASE (ADK) IS AN EVOLUTIONARY ANCIENT RIBOKINASE DERIVED FROM BACTERIAL SUGAR KINASES THAT IS WIDELY EXPRESSED IN ALL FORMS OF LIFE, TISSUES AND ORGAN SYSTEMS THAT TIGHTLY REGULATES INTRACELLULAR AND EXTRACELLULAR ADO CONCENTRATIONS. THE FACILE ABILITY OF ADK TO ALTER ADO AVAILABILITY PROVIDES A "SITE AND EVENT" SPECIFICITY TO THE ENDOGENOUS PROTECTIVE EFFECTS OF ADO IN SITUATIONS OF CELLULAR STRESS. IN ADDITION TO MODULATING THE ABILITY OF ADO TO ACTIVATE ITS COGNATE RECEPTORS (P1 RECEPTORS), NUCLEAR ADK ISOFORM ACTIVITY HAS BEEN LINKED TO EPIGENETIC MECHANISMS BASED ON TRANSMETHYLATION PATHWAYS. PREVIOUS DRUG DISCOVERY RESEARCH HAS TARGETED ADK INHIBITION AS A THERAPEUTIC APPROACH TO MANAGE EPILEPSY, PAIN, AND INFLAMMATION. THESE EFFORTS GENERATED MULTIPLE CLASSES OF HIGHLY POTENT AND SELECTIVE INHIBITORS. HOWEVER, CLINICAL DEVELOPMENT OF EARLY ADK INHIBITORS WAS STOPPED DUE TO APPARENT MECHANISTIC TOXICITY AND THE LACK OF SUITABLE TRANSLATIONAL MARKERS. NEW INSIGHTS REGARDING THE POTENTIAL ROLE OF THE NUCLEAR ADK ISOFORM (ADK-LONG) IN THE EPIGENETIC MODULATION OF MALADAPTIVE DNA METHYLATION OFFERS THE POSSIBILITY OF IDENTIFYING NOVEL ADK-ISOFORM SELECTIVE INHIBITORS AND NEW INTERVENTIONAL STRATEGIES THAT ARE INDEPENDENT OF ADO RECEPTOR ACTIVATION.	2021