1 2814 188 FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: MIDDLE-AGE ONSET OF HETEROTOPIC OSSIFICATION FROM A UNIQUE MISSENSE MUTATION (C.974G>C, P.G325A) IN ACVR1. FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (FOP) IS THE RARE MENDELIAN DISEASE CHARACTERIZED BY CONGENITAL MALFORMATION OF THE GREAT TOES PRECEDING HETEROTOPIC OSSIFICATION (HO) AND CAUSED BY HETEROZYGOUS ACTIVATING MUTATION OF THE ACVR1 GENE, WHICH ENCODES THE ALK2 RECEPTOR FOR BONE MORPHOGENETIC PROTEINS. EARLY ADULT LIFE IS THE LATEST REPORTED PRESENTATION FOR THE HO OF FOP. THE PATIENT OF OUR REPORT FIRST DEVELOPED HO FROM FOP AT 47 YEARS OF AGE. SHE HAD CONGENITAL HALLUX VALGUS DEFORMITY BUT DESPITE VARIOUS TRAUMAS WAS PREVIOUSLY WELL. HO BEGAN SEVERAL MONTHS AFTER A BRIEF, SEEMINGLY VIRAL, ILLNESS. SUDDEN AND PROGRESSIVE PAIN, REDNESS, WARMTH, AND SWELLING APPEARED OVER A SCAPULA. COMPUTED TOMOGRAPHY WAS REMARKABLE FOR ASYMMETRICAL THICKENING OF MUSCLES AND FASCIAL PLANES. AT FIRST, THE SIGNIFICANCE OF THE GREAT TOE ABNORMALITIES WENT UNRECOGNIZED ELSEWHERE, AND BIOPSY FOR SUSPECTED INFLAMMATORY FASCIITIS REVEALED PROLIFERATING FIBROBLASTS WITH SCATTERED INFLAMMATORY CELLS. PREDNISONE IMPROVED HER SYMPTOMS BUT, WHEN TAPERED, SWELLINGS DEVELOPED ON HER CHEST, POSTERIOR THORAX, AND FLANK, AND FOP WAS DIAGNOSED. METHYLPREDNISOLONE, METHOTREXATE, AND ALENDRONATE SEEMED TO HELP HER SYMPTOMS, BUT THE LESIONS WORSENED AND HO APPEARED AND RAPIDLY PROGRESSED. MUTATION ANALYSIS OF THE ACVR1 GENE REVEALED HETEROZYGOSITY FOR A UNIQUE MISSENSE DEFECT (C.974G>C, P.G325A) THAT PREDICTED A CONSERVATIVE (MILD) AMINO ACID CHANGE WITHIN THE KINASE DOMAIN OF ALK2. HENCE, HO IN FOP CAN BE DELAYED UNTIL MIDDLE-AGE, AND PERHAPS PROVOKED BY A VIRAL ILLNESS. NEVERTHELESS, PROGRESSION OF HO CAN THEN BE RAPID DESPITE BISPHOSPHONATE AND HIGH-DOSE IMMUNOSUPPRESSIVE THERAPY. POSSIBLY, OUR PATIENT'S LATE-ONSET HO REFLECTS HER MILD ALTERATION OF ALK2 OR SOME PROTECTIVE AND THERAPEUTICALLY USEFUL GENETIC, EPIGENETIC, OR NONGENETIC FACTOR. RECOGNITION OF PRESYMPTOMATIC INDIVIDUALS OR LATE-ONSET HO IN FOP SHOULD HAVE THESE PATIENTS AVOID TRAUMAS, TREATMENTS, AND MAYBE VIRAL ILLNESSES THAT CAN INITIATE OR EXACERBATE THE HO. IF THE DIAGNOSIS OF FOP IS UNCLEAR, ACVR1 MUTATION ANALYSIS IS AVAILABLE AT CERTIFIED LABORATORIES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 4492  39 MONOZYGOTIC TWINS DISCORDANT FOR ROHHAD PHENOTYPE. RAPID-ONSET OBESITY WITH HYPOTHALAMIC DYSFUNCTION, HYPOVENTILATION, AND AUTONOMIC DYSREGULATION (ROHHAD) FALLS WITHIN A GROUP OF PEDIATRIC DISORDERS WITH BOTH RESPIRATORY CONTROL AND AUTONOMIC NERVOUS SYSTEM DYSREGULATION. CHILDREN WITH ROHHAD TYPICALLY PRESENT AFTER 1.5 YEARS OF AGE WITH RAPID WEIGHT GAIN AS THE INITIAL SIGN. SUBSEQUENTLY, THEY DEVELOP ALVEOLAR HYPOVENTILATION, AUTONOMIC NERVOUS SYSTEM DYSREGULATION, AND, IF UNTREATED, CARDIORESPIRATORY ARREST. TO OUR KNOWLEDGE, THIS IS THE FIRST REPORT OF DISCORDANT PRESENTATION OF ROHHAD IN MONOZYGOTIC TWINS. TWIN GIRLS, BORN AT TERM, HAD CONCORDANT GROWTH AND DEVELOPMENT UNTIL 8 YEARS OF AGE. FROM 8 TO 12 YEARS OF AGE, THE AFFECTED TWIN DEVELOPED FEATURES CHARACTERISTIC OF ROHHAD INCLUDING OBESITY, ALVEOLAR HYPOVENTILATION, SCOLIOSIS, HYPOTHALAMIC DYSFUNCTION (CENTRAL DIABETES INSIPIDUS, HYPOTHYROIDISM, PREMATURE PUBARCHE, AND GROWTH HORMONE DEFICIENCY), RIGHT PARASPINAL/THORACIC GANGLIONEUROBLASTOMA, SEIZURES, AND AUTONOMIC DYSREGULATION INCLUDING ALTERED PAIN PERCEPTION, LARGE AND SLUGGISHLY REACTIVE PUPILS, HYPOTHERMIA, AND PROFOUND BRADYCARDIA THAT REQUIRED A CARDIAC PACEMAKER. RESULTS OF GENETIC TESTING FOR PHOX2B (CONGENITAL CENTRAL HYPOVENTILATION SYNDROME DISEASE-DEFINING GENE) MUTATIONS WERE NEGATIVE. WITH EARLY RECOGNITION AND CONSERVATIVE MANAGEMENT, THE AFFECTED TWIN HAD EXCELLENT NEUROCOGNITIVE OUTCOME THAT MATCHED THAT OF THE UNAFFECTED TWIN. THE UNAFFECTED TWIN DEMONSTRATED RAPID WEIGHT GAIN LATER IN AGE BUT NOT DEVELOPMENT OF SIGNS/SYMPTOMS CONSISTENT WITH ROHHAD. THIS DISCORDANT TWIN PAIR DEMONSTRATES KEY FEATURES OF ROHHAD INCLUDING THE IMPORTANCE OF EARLY RECOGNITION (ESPECIALLY HYPOVENTILATION), COMPLEXITY OF SIGNS/SYMPTOMS AND CLINICAL COURSE, AND IMPORTANCE OF INITIATING COMPREHENSIVE, MULTISPECIALTY CARE. THESE CASES CONFOUND THE HYPOTHESIS OF A MONOGENIC ETIOLOGY FOR ROHHAD AND INDICATE ALTERNATIVE ETIOLOGIES INCLUDING AUTOIMMUNE OR EPIGENETIC PHENOMENON OR A COMBINATION OF GENETIC PREDISPOSITION AND ACQUIRED PRECIPITANT.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3 5356  26 REAC-INDUCED ENDOGENOUS BIOELECTRIC CURRENTS IN THE TREATMENT OF VENOUS ULCERS: A THREE-ARM RANDOMIZED CONTROLLED PROSPECTIVE STUDY. INTRODUCTION: ENDOGENOUS BIOELECTRIC FIELDS (EBFS) PLAY A FUNDAMENTAL ROLE IN PROMOTING REPAIR AND REGENERATION PROCESSES, INCLUDING IN LEG VENOUS ULCERS (LVUS). UNFORTUNATELY, THE MECHANISM UNDERLYING THE PRODUCTION OF EBFS IS EASILY ALTERED BY INFECTIOUS, TRAUMATIC, AND EPIGENETIC FACTORS. THIS ALTERATION IS ONE OF THE DETERMINING FACTORS FOR THE CHRONICITY OF LVUS. THIS STUDY INVESTIGATES HOW RADIOELECTRIC ASYMMETRIC CONVEYER (REAC) TECHNOLOGY TREATMENTS, SPECIFICALLY DESIGNED TO OPTIMIZE EBFS, AND IN PARTICULAR TISSUE OPTIMIZATION-REPARATIVE (TO-RPR) TREATMENT, CAN IMPROVE THE RESULTS OF STANDARD DRESSING WITH AND WITHOUT ELASTIC COMPRESSION IN LVU PATIENTS. METHODS: A TOTAL OF 30 PATIENTS WERE ENROLLED (12 MALES AND 18 FEMALES) AND RANDOMIZED INTO THREE GROUPS. ALL PATIENTS COMPLETED THE STUDY. GROUP A WAS TREATED WITH STANDARD DRESSING, ELASTIC COMPRESSION, AND REAC TO-RPR TREATMENT; GROUP B WAS TREATED WITH STANDARD DRESSING AND REAC TO-RPR TREATMENT; AND GROUP C WAS TREATED WITH STANDARD DRESSING AND ELASTIC COMPRESSION. RESULTS: THE RESULTS SHOW THAT THE COMBINATION OF REAC TREATMENT AND STANDARD DRESSING ASSOCIATED WITH ELASTIC COMPRESSION HAS THE GREATEST THERAPEUTIC EFFICACY IN PROMOTING THE HEALING PROCESS FOR ULCERS, REDUCING PERCEIVED PAIN, AND IMPROVING THE QUALITY OF LIFE OF THE PATIENTS TREATED. CONCLUSIONS: FURTHER STUDIES WILL BE USEFUL TO INVESTIGATE THESE PROSPECTIVE RESULTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4 5511  21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5 5353  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
6 2818  15 FIBROSIS UNDER ARREST. APPROXIMATELY 5% OF PEOPLE THAT ARE HOSPITALIZED FOR ANY REASON DEVELOP ACUTE KIDNEY FAILURE, WHICH, IN SOME CASES, PROGRESSES TO A CHRONIC CONDITION RESULTING IN FIBROSIS OF THE KIDNEY AND PERMANENT CHANGES IN THE ORGAN'S FUNCTION. TWO NEW STUDIES SUGGEST THAT CELL CYCLE ARREST OF EPITHELIAL CELLS AND EPIGENETIC MODIFICATIONS HAVE KEY ROLES IN THE SWITCH TO CHRONIC DISEASE (PAGES 535-543 AND 544-550).	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  820  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8 6636  35 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	

9 1448  34 DIPEPTIDYL PEPTIDASE-4 INHIBITION AND NARROW-BAND ULTRAVIOLET-B LIGHT IN PSORIASIS (DINUP): STUDY PROTOCOL FOR A RANDOMISED CONTROLLED TRIAL. BACKGROUND: MODERATE TO SEVERE PSORIASIS IS A SYSTEMIC INFLAMMATORY DISEASE ASSOCIATED WITH INSULIN RESISTANCE, OBESITY AND TYPE 2 DIABETES (T2DM). SITAGLIPTIN IS A DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR THAT IMPROVES GLYCAEMIA AND HAS A MARKETING AUTHORISATION FOR THE TREATMENT OF T2DM. NON-IMMUNOSUPPRESSIVE THERAPIES THAT ARE EFFECTIVE FOR PSORIASIS AND ITS ASSOCIATED COMORBIDITIES WOULD BE A SIGNIFICANT ADVANCE IN THE TREATMENT OF THIS CHRONIC DISEASE. METHODS/DESIGN: THIS IS A SINGLE CENTRE, 39-WEEK, PROSPECTIVE, RANDOMISED, OPEN LABEL, CLINICAL TRIAL OF ORAL SITAGLIPTIN (JANUVIA((R))) IN PSORIASIS PATIENTS WHO ARE DUE TO UNDERGO A COURSE OF NARROW-BAND ULTRAVIOLET-B (NB-UVB) PHOTOTHERAPY. WE PLAN TO ENROL 120 PARTICIPANTS AND ALLOCATE PARTICIPANTS ON A RANDOM AND 1:1 BASIS TO RECEIVE SITAGLIPTIN 100 MG DAILY FOR 24 WEEKS COMBINED WITH NB-UVB OR NB-UVB MONOTHERAPY. PARTICIPANTS WILL BE FOLLOWED UP FOR 12 WEEKS AFTER SITAGLIPTIN THERAPY IS DISCONTINUED. THE PRIMARY ENDPOINT IS THE CHANGE IN PSORIASIS AREA AND SEVERITY INDEX (PASI) 24 WEEKS AFTER TREATMENT INITIATION. SECONDARY ENDPOINTS INCLUDE CUMULATIVE NB-UVB DOSE, NUMBER OF NB-UVB TREATMENTS REQUIRED TO CLEAR PSORIASIS, PROPORTIONS OF PARTICIPANTS WHO ACHIEVE PASI-50 (50 % REDUCTION IN PASI FROM BASELINE), PASI-75, PASI-90 AND THE PROPORTION OF PARTICIPANTS WHO RELAPSE IN EACH GROUP. WE WILL ALSO ANALYSE CHANGES IN CARDIOVASCULAR DISEASE RISK FACTORS, SERUM CYTOKINE AND HORMONE LEVELS AND PERIPHERAL BLOOD MONONUCLEAR EXPRESSION OF IMMUNE PROTEINS AT 24 AND 36 WEEKS. A SUBGROUP OF PARTICIPANTS WILL HAVE SKIN BIOPSIES TAKEN AND ANALYSED FOR SKIN LEVELS AND EXPRESSION OF IMMUNE CELLS, RECEPTORS, HORMONES AND IMMUNE PROTEINS. THE GENETIC OR EPIGENETIC PROFILE THAT PREDICTS BEST RESPONSE TO DPP-4 INHIBITOR THERAPY WILL BE ANALYSED. THE SAFETY ENDPOINTS INCLUDE THE RATE AND SEVERITY OF ADVERSE EVENTS. DISCUSSION: THIS IS THE FIRST RANDOMISED CLINICAL TRIAL ASSESSING DIPEPTIDYL PEPTIDASE-4 INHIBITION THERAPY IN PSORIASIS. WE HYPOTHESISE THAT SITAGLIPTIN THERAPY IN COMBINATION WITH NB-UVB IMPROVES PSORIASIS SEVERITY COMPARED TO NB-UVB MONOTHERAPY. TRIAL REGISTRATION: CLINICALTRIALS.GOV IDENTIFIER NCT02347501 (DATE OF REGISTRATION: 27 JANUARY 2015).	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  238  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11 5640  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 3381  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13 6484  23 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC).	1998	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 1109  25 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 5340  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 6603  28 TWO SISTERS WITH FAMILIAL MEDITERRANEAN FEVER: LACK OF CORRELATION BETWEEN GENOTYPE AND PHENOTYPE? FAMILIAL MEDITERRANEAN FEVER (FMF) IS AN AUTOSOMAL RECESSIVE DISORDER CHARACTERIZED BY ATTACKS OF FEVER AND SEROSITIS. THE MOST IMPORTANT COMPLICATION OF FMF IS RENAL AMYLOIDOSIS, WHICH DETERMINES THE PROGNOSIS. THE GENE CODING THE DISEASE (MEFV) IS IDENTIFIED ON THE 16TH CHROMOSOME. THE MOST COMMON MEFV MUTATIONS ARE M694V, M680I, V726A AND M694I LOCATED ON EXON 10 AND E148Q LOCATED ON EXON 2. UNFORTUNATELY, GENOTYPE-PHENOTYPE CORRELATION IS NOT WELL ESTABLISHED AND THERE ARE UNEXPLAINED ETHNIC DIFFERENCES IN AMYLOIDOSIS RATES. WE REPORT TWO SISTERS WITH A COMMON GENOTYPE (M694V/M694V) PRESENTING WITH DIFFERENT PHENOTYPIC CHARACTERISTICS: ONE COMPLAINING OF INTERMITTENT ABDOMINAL PAIN, ARTHRITIS AND FEVER, WHILE THE OTHER WAS SUFFERING FROM INTERMITTENT PLEURITIS AND FEVER DURING ATTACKS. THE OBSERVATION OF DIFFERENT PHENOTYPIC PRESENTATIONS WITH A COMMON GENOTYPE IN TWO FAMILY MEMBERS SHOWS THAT DIFFERENT PHENOTYPES CANNOT BE EXPLAINED BY PARTICULAR MUTATIONS. TO UNDERSTAND THE CORRELATION BETWEEN GENOTYPIC AND PHENOTYPIC FMF VARIANTS THE EXISTENCE OF COMPLEX ALLELES, MODIFIER LOCI, GENETIC HETEROGENEITY AND POSSIBLE EPIGENETIC FACTORS SHOULD BE STUDIED EXTENSIVELY.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17 6835  22 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 3883  25 KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. BACKGROUND: A RECENT REVIEW BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) UPDATED THE ASSESSMENTS OF THE > 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 1679  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  399  33 ANABOLIC STEROIDS-DRIVEN REGULATION OF PORCINE OVARIAN PUTATIVE STEM CELLS FAVORS THE ONSET OF THEIR NEOPLASTIC TRANSFORMATION. NANDROLONE (NDN) AND BOLDENONE (BDN), THE SYNTHETIC TESTOSTERONE ANALOGUES WITH STRONG ANABOLIC EFFECTS, DESPITE BEING RECOGNIZED AS POTENTIALLY CARCINOGENIC COMPOUNDS, ARE COMMONLY ABUSED BY ATHLETES AND BODYBUILDERS, WHICH INCLUDES WOMEN, WORLDWIDE. THIS STUDY TESTED THE HYPOTHESIS THAT DIFFERENT DOSES OF NDN AND BDN CAN INITIATE NEOPLASTIC TRANSFORMATION OF PORCINE OVARIAN PUTATIVE STEM CELLS (POPSCS). IMMUNOMAGNETICALLY ISOLATED POPSCS WERE EXPANDED EX VIVO IN THE PRESENCE OF NDN OR BDN, FOR 7 AND 14 DAYS. RESULTS SHOW THAT PHARMACOLOGICAL DOSES OF BOTH NDN AND BDN, ALREADY AFTER 7 DAYS OF POPSCS CULTURE, CAUSED A SIGNIFICANT INCREASE OF SELECTED, STEMNESS-RELATED MARKERS OF CANCER CELLS: CD44 AND CD133. NOTABLY, NDN ALSO NEGATIVELY AFFECTED POPSCS GROWTH NOT ONLY BY SUPPRESSING THEIR PROLIFERATION AND MITOCHONDRIAL RESPIRATION BUT ALSO BY INDUCING APOPTOSIS. THIS OBSERVATION SHOWS, FOR THE FIRST TIME, THAT CHRONIC EXPOSURE TO NDN OR BDN REPRESENTS A PRECONDITION THAT MIGHT ENHANCE RISK OF POPSCS NEOPLASTIC TRANSFORMATION. THESE STUDIES CARRIED OUT TO ACCOMPLISH DETAILED MOLECULAR CHARACTERIZATION OF THE EX VIVO EXPANDED POPSCS AND THEIR POTENTIALLY CANCEROUS DERIVATIVES (PCDS) MIGHT BE HELPFUL TO DETERMINE THEIR SUITABILITY AS NUCLEAR DONOR CELLS (NDCS) FOR FURTHER INVESTIGATIONS FOCUSED ON CLONING BY SOMATIC CELL NUCLEAR TRANSFER (SCNT). SUCH INVESTIGATIONS MIGHT ALSO BE INDISPENSABLE TO ESTIMATE THE CAPABILITIES OF NUCLEAR GENOMES INHERITED FROM POPSCS AND THEIR PCDS TO BE EPIGENETICALLY REPROGRAMMED (DEDIFFERENTIATED) IN CLONED PIG EMBRYOS GENERATED BY SCNT. THIS MIGHT OPEN UP NEW POSSIBILITIES FOR BIOMEDICAL RESEARCH AIMED AT MORE COMPREHENSIVELY RECOGNIZING GENETIC AND EPIGENETIC MECHANISMS UNDERLYING NOT ONLY TUMORIGENESIS BUT ALSO REVERSAL/RETARDATION OF PRO-TUMORIGENIC INTRACELLULAR EVENTS.	2021