1  4638 129 NEURON-SPECIFIC METHYLOME ANALYSIS REVEALS EPIGENETIC REGULATION AND TAU-RELATED DYSFUNCTION OF BRCA1 IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE CHARACTERIZED BY PATHOLOGY OF ACCUMULATED AMYLOID BETA (ABETA) AND PHOSPHORYLATED TAU PROTEINS IN THE BRAIN. POSTMORTEM DEGRADATION AND CELLULAR COMPLEXITY WITHIN THE BRAIN HAVE LIMITED APPROACHES TO MOLECULARLY DEFINE THE CAUSAL RELATIONSHIP BETWEEN PATHOLOGICAL FEATURES AND NEURONAL DYSFUNCTION IN AD. TO OVERCOME THESE LIMITATIONS, WE ANALYZED THE NEURON-SPECIFIC DNA METHYLOME OF POSTMORTEM BRAIN SAMPLES FROM AD PATIENTS, WHICH ALLOWED DIFFERENTIALLY HYPOMETHYLATED REGION OF THE BRCA1 PROMOTER TO BE IDENTIFIED. EXPRESSION OF BRCA1 WAS SIGNIFICANTLY UP-REGULATED IN AD BRAINS, CONSISTENT WITH ITS HYPOMETHYLATION. BRCA1 PROTEIN LEVELS WERE ALSO ELEVATED IN RESPONSE TO DNA DAMAGE INDUCED BY ABETA. BRCA1 BECAME MISLOCALIZED TO THE CYTOPLASM AND HIGHLY INSOLUBLE IN A TAU-DEPENDENT MANNER, RESULTING IN DNA FRAGMENTATION IN BOTH IN VITRO CELLULAR AND IN VIVO MOUSE MODELS. BRCA1 DYSFUNCTION UNDER ABETA BURDEN IS CONSISTENT WITH CONCOMITANT DETERIORATION OF GENOMIC INTEGRITY AND SYNAPTIC PLASTICITY. THE BRCA1 PROMOTER REGION OF AD MODEL MICE BRAIN WAS SIMILARLY HYPOMETHYLATED, INDICATING AN EPIGENETIC MECHANISM UNDERLYING BRCA1 REGULATION IN AD. OUR RESULTS SUGGEST DETERIORATION OF DNA INTEGRITY AS A CENTRAL CONTRIBUTING FACTOR IN AD PATHOGENESIS. MOREOVER, THESE DATA DEMONSTRATE THE TECHNICAL FEASIBILITY OF USING NEURON-SPECIFIC DNA METHYLOME ANALYSIS TO FACILITATE DISCOVERY OF ETIOLOGICAL CANDIDATES IN SPORADIC NEURODEGENERATIVE DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  3393  43 HOST DETERMINANTS OF PRION STRAIN DIVERSITY INDEPENDENT OF PRION PROTEIN GENOTYPE. PHENOTYPIC DIVERSITY IN PRION DISEASES CAN BE SPECIFIED BY PRION STRAINS IN WHICH BIOLOGICAL TRAITS ARE PROPAGATED THROUGH AN EPIGENETIC MECHANISM MEDIATED BY DISTINCT PRP(SC) CONFORMATIONS. WE INVESTIGATED THE ROLE OF HOST-DEPENDENT FACTORS ON PHENOTYPIC DIVERSITY OF CHRONIC WASTING DISEASE (CWD) IN DIFFERENT HOST SPECIES THAT EXPRESS THE SAME PRION PROTEIN GENE (PRNP). TWO CWD STRAINS THAT HAVE DISTINCT BIOLOGICAL, BIOCHEMICAL, AND PATHOLOGICAL FEATURES WERE IDENTIFIED IN TRANSGENIC MICE THAT EXPRESS THE SYRIAN GOLDEN HAMSTER (SGH) PRNP. THE CKY STRAIN OF CWD HAD A SHORTER INCUBATION PERIOD THAN THE WST STRAIN OF CWD, BUT AFTER TRANSMISSION TO SGH, THE INCUBATION PERIOD OF CKY CWD WAS APPROXIMATELY 150 DAYS LONGER THAN WST CWD. LIMITED PROTEINASE K DIGESTION REVEALED STRAIN-SPECIFIC PRP(SC) POLYPEPTIDE PATTERNS THAT WERE MAINTAINED IN BOTH HOSTS, BUT THE SOLUBILITY AND CONFORMATIONAL STABILITY OF PRP(SC) DIFFERED FOR THE CWD STRAINS IN A HOST-DEPENDENT MANNER. WST CWD PRODUCED PRP(SC) AMYLOID PLAQUES IN THE BRAIN OF THE SGH THAT WERE PARTIALLY INSOLUBLE AND STABLE AT A HIGH CONCENTRATION OF PROTEIN DENATURANT. HOWEVER, IN TRANSGENIC MICE, PRP(SC) FROM WST CWD DID NOT ASSEMBLE INTO PLAQUES, WAS HIGHLY SOLUBLE, AND HAD LOW CONFORMATIONAL STABILITY. SIMILAR STUDIES USING THE HY AND DY STRAINS OF TRANSMISSIBLE MINK ENCEPHALOPATHY RESULTED IN MINOR DIFFERENCES IN PRION BIOLOGICAL AND PRP(SC) PROPERTIES BETWEEN TRANSGENIC MICE AND SGH. THESE FINDINGS INDICATE THAT HOST-SPECIFIC PATHWAYS THAT ARE INDEPENDENT OF PRNP CAN ALTER THE PRP(SC) CONFORMATION OF CERTAIN PRION STRAINS, LEADING TO CHANGES IN THE BIOPHYSICAL PROPERTIES OF PRP(SC), NEUROPATHOLOGY, AND CLINICAL PRION DISEASE. IMPORTANCE: PRIONS ARE MISFOLDED PATHOGENIC PROTEINS THAT CAUSE NEURODEGENERATION IN HUMANS AND ANIMALS. TRANSMISSIBLE PRION DISEASES EXHIBIT A SPECTRUM OF DISEASE PHENOTYPES AND THE BASIS OF THIS DIVERSITY IS ENCODED IN THE STRUCTURE OF THE PATHOGENIC PRION PROTEIN AND PROPAGATED BY AN EPIGENETIC MECHANISM. IN THE PRESENT STUDY, WE INVESTIGATED PRION DIVERSITY IN TWO HOSTS SPECIES THAT EXPRESS THE SAME PRION PROTEIN GENE. WHILE PRIOR REPORTS HAVE DEMONSTRATED THAT PRION STRAIN PROPERTIES ARE STABLE UPON INFECTION OF THE SAME HOST SPECIES AND PRION PROTEIN GENOTYPE, OUR FINDINGS INDICATE THAT CERTAIN PRION STRAINS CAN UNDERGO DRAMATIC CHANGES IN BIOLOGICAL PROPERTIES THAT ARE NOT DEPENDENT ON THE PRION PROTEIN. THEREFORE, HOST FACTORS INDEPENDENT OF THE PRION PROTEIN CAN AFFECT PRION DIVERSITY. UNDERSTANDING HOW HOST PATHWAYS CAN MODIFY PRION DISEASE PHENOTYPES MAY PROVIDE CLUES ON HOW TO ALTER PRION FORMATION AND LEAD TO TREATMENTS FOR PRION, AND OTHER, HUMAN NEURODEGENERATIVE DISEASES OF PROTEIN MISFOLDING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  4963  38 PATHOGENESIS OF THYROID NODULES: HISTOLOGICAL CLASSIFICATION? THYROID NODULE GENESIS MAY BE CONSIDERED AS AN AMPLIFICATION OF THYROID HETEROGENEITY DUE TO GENETIC AND/OR EPIGENETIC MECHANISMS. WE CLASSIFIED THE THYROID NODULES IN FIVE TYPES WITH DISTINCT HISTOLOGICAL FEATURES: HYPERPLASTIC, NEOPLASTIC, COLLOID, CYSTIC AND THYROIDITIC NODULES. HYPERPLASTIC: THYROCYTE PROLIFERATION IS UNDER THE CONTROL OF TSH BUT SEVERAL OTHER PARACRINE AND AUTOCRINE FACTORS ARE SECRETED BY FOLLICULAR CELLS, THE STROMAL APPARATUS AND THE LYMPHOCYTES, WHICH ARE IMPLICATED IN INITIATION AND PERPETUATION OF THYROID HYPERPLASIA. GROWTH OCCURS MAINLY THROUGH TSHR, CAMP AND PKA. CONSTITUTIVE CAMP OVERPRODUCTION HAS BEEN SHOWN TO BE DUE TO POINT MUTATION OF THE TSHR OR GS PROTEIN, PRODUCING OVERGROWTH AND HYPERFUNCTION. NEOPLASTIC: SEVERAL ACTIVATED ONCOGENES HAVE BEEN IDENTIFIED IN THYROID MALIGNANCIES. ONCOGENES RELEVANT TO THE THYROID CARCINOGENESIS ARE: MUTATED TSHR AND GSP (CONSTITUTIVE ACTIVATION OF CAMP); TRK (RECEPTOR FOR NGF); RET/PTC (PHOSPHORYLATION OF TYROSINE KINASE RECEPTOR)--AN ISOFORM OF THIS ONCOGENE IS INDUCED BY RADIATION: RAS (IT ENCODES GS PROTEINS TRANSDUCING MITOGENIC SIGNALS); AND C-MET (RECEPTOR FOR HEPATOCYTE GROWTH FACTOR). THE EVOLUTION OF A DIFFERENTIATED THYROID CANCER TOWARDS AN UNDIFFERENTIATED CANCER IS DUE TO A MUTATION OF A FAMILY OF PROTEINS (I.E., P53), WHICH ACTS AS A BRAKE, PREVENTING THE GENOMIC INSTABILITY OF CANCER. IT IS SUGGESTED THAT A TUMOR INITIATES BY RET OR RAS AND POSSIBLY PROGRESSES--AS A RESULT OF ADDITIONAL MUTATIONS AND BY P53 MUTATION--TO ANAPLASTIC CARCINOMA. COLLOID: FLATTENING OF THE EPITHELIUM AND DILATATION OF FOLLICLES CONTAINING VISCOUS MATERIAL--MADE UP BY A CONCENTRATED SOLUTION OF THYROGLOBULIN (HTG)--IS THE CHARACTERISTIC OF THE COLLOID NODULE. A DEFECT OF INTRALUMINAL REABSORPTION OF HTG HAS BEEN SUGGESTED BUT NOT PROVEN. EXPERIMENTALLY, A LOAD OF IODINE IS ABLE TO CHANGE THYROID HYPERPLASIA TO A COLLOID FEATURE; HOWEVER, A LOAD OF IODINE IS RARELY FOUND IN THE CLINICAL HISTORY OF PATIENTS. A NEW CLUE TO THE PATHOGENESIS COMES FROM THE FINDING THAT A RELEVANT PART OF THE COLLOID (10-20%) IS MADE UP OF INSOLUBLE GLOBULES, WHERE HTG IS COMPACTED IN A POLYMERIC FORM. IT IS SUGGESTED THAT STOCKING HTG INTO GLOBULES IS DEFECTIVE IN COLLOID NODULES, LEADING TO ENORMOUS ENLARGEMENT OF THE FOLLICLE. CYSTIC: IT IS ESTIMATED THAT BETWEEN 15 AND 40% OF THYROID NODULES ARE PARTLY OR ENTIRELY CYSTIC. THE 'TRUE CYST' IS RARE; MOST OF THE SO-CALLED CYSTIC NODULES ARE 'PSEUDOCYSTS', WHICH FOLLOW NECROSIS AND COLLIQUATION. NECROSIS ISSUES AS AN IMBALANCE BETWEEN GROWTH AND THE PRECISELY REGULATED PROCESS OF ANGIOGENESIS. MORE RECENTLY, THE VEGF/VPF HAS BEEN FOUND TO BE AT THE ORIGIN OF RECENT AND RECURRENT CYSTS. IMMUNOTOXIC AND APOPTOTIC MECHANISMS HAVE ALSO BEEN SUGGESTED. CHEMICAL ANALYSIS OF CYSTIC FLUID SHOWED A 'DENATURED' AND 'SERUM-LIKE' PATTERN SUGGESTING DIFFERENT MECHANISMS IN THE PATHOGENESIS OF THE PSEUDOCYSTIC THYROID NODULES. THYROIDITIC: NODULAR LYMPHOCYTIC THYROIDITIS (NLT) INCLUDES TWO DIFFERENT ENTITIES: 1) LYMPHOCYTE THYROIDITIS GROWING AS A NODULE IN A HYPERPLASTIC OR NORMAL GLAND, AND 2) LYMPHOCYTE THYROIDITIS ASSOCIATED IN THE SAME NODULE WITH OTHER NODULAR DISEASES OF THE THYROID: PAPILLARY THYROID CARCINOMA AND LYMPHOMA HAVE BEEN FOUND TO BE ASSOCIATED TO CHRONIC LYMPHOCYTIC THYROIDITIS.	2001	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  3934  33 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS.	1982	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  1156  24 CONSIDERING THE USE OF THE TERMS STRAIN AND ADAPTATION IN PRION RESEARCH. EVOLUTIONARY BIOLOGISTS AND DISEASE BIOLOGISTS USE THE TERMS STRAIN AND ADAPTATION IN CHRONIC WASTING DISEASE (CWD) RESEARCH IN DIFFERENT WAYS. IN EVOLUTIONARY BIOLOGY, A STRAIN IS A NASCENT GENETIC LINEAGE THAT CAN BE DESCRIBED BY A GENEALOGY, AND A PHYLOGENETIC NOMENCLATURE CONSTRUCTED TO REFLECT THAT GENEALOGY. PRION STRAINS ARE DESCRIBED AS SHOWING DISTINCT HOST RANGE, CLINICAL PRESENTATION, DISEASE PROGRESSION, AND NEUROPATHOLOGICAL AND PRP BIOCHEMICAL PROFILES, AND LACK INFORMATION THAT WOULD PERMIT PHYLOGENETIC RECONSTRUCTION OF THEIR HISTORY. PRION STRAINS ARE ALTERNATIVE PROTEIN CONFORMATIONS, SOMETIMES DERIVED FROM THE SAME GENOTYPE. I SUGGEST REFERRING TO PRION STRAINS AS ECOTYPES, BECAUSE THE VARIANT PHENOTYPIC CONFORMATIONS ("STRAINS") ARE A FUNCTION OF THE INTERACTION BETWEEN PRNP AMINO ACID GENOTYPE AND THE HOST ENVIRONMENT. IN THE CASE OF CWD, A PRION ECOTYPE IN WHITE-TAILED DEER WOULD BE DESCRIBED BY ITS GENOTYPE AND THE HOST IN WHICH IT OCCURS, SUCH AS THE H95 + ECOTYPE. HOWEVER, AN EVOLUTIONARY NOMENCLATURE IS DIFFICULT BECAUSE NOT ALL INDIVIDUALS WITH THE SAME PRNP GENOTYPE SHOW SIGNS OF CWD, THEREFORE CREATING A NOMENCLATURE REFLECTING AND ONE-TO-ONE RELATIONSHIP BETWEEN PRNP GENEALOGY AND CWD PRESENCE IS DIFFICULT. FURTHERMORE, VERY LITTLE INFORMATION EXISTS ON THE PHYLOGENETIC DISTRIBUTION OF CWD ECOTYPES IN WILD DEER POPULATIONS. ADAPTATION HAS A CLEAR MEANING IN EVOLUTIONARY BIOLOGY, THE DIFFERENTIAL SURVIVAL AND REPRODUCTION OF INDIVIDUAL GENOTYPES. IF A NEW PRION ECOTYPE ARISES IN A PARTICULAR HOST AND KILLS MORE HOSTS OR KILLS AT AN EARLIER AGE, IT IS THE ANTITHESIS OF THE EVOLUTIONARY DEFINITION OF ADAPTATION. HOWEVER, PRION STRAINS MIGHT BE TRANSMITTED ACROSS GENERATIONS EPIGENETICALLY, BUT WHETHER THIS REPRESENTS ADAPTATION DEPENDS ON THE FITNESS CONSEQUENCES OF THE STRAIN. PROTEIN PHENOTYPES OF PRNP THAT CAUSE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSES), AND CWD, ARE MALADAPTIVE AND WOULD NOT BE PROPAGATED GENETICALLY OR EPIGENETICALLY VIA A PROCESS CONSISTENT WITH AN EVOLUTIONARY VIEW OF ADAPTATION. I SUGGEST TERMING THE PROCESS OF PRION STRAIN ORIGINATION "PHENOTYPIC TRANSFORMATION", AND ONLY ADAPTATION IF EVIDENCE SHOWS THEY ARE NOT MALADAPTIVE AND PERSIST OVER EVOLUTIONARY TIME PERIODS (E.G., THOUSANDS OF GENERATIONS) AND ACROSS DISTINCT SPECIES BOUNDARIES (VIA INHERITANCE). THUS, PRION BIOLOGISTS USE STRAIN AND ADAPTATION, HISTORICALLY EVOLUTIONARY TERMS, IN QUITE DIFFERENT WAYS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6  3736  35 INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT IMPACT ON CENTRAL NERVOUS SYSTEM PRION DISEASE. PRION DISEASES SUCH AS CREUTZFELDT-JAKOB DISEASE IN HUMANS, BOVINE SPONGIFORM ENCEPHALOPATHY IN CATTLE, AND SCRAPIE IN SHEEP, ARE INFECTIOUS AND CHRONIC NEURODEGENERATIVE DISEASES TO WHICH THERE ARE NO CURES. INFECTION WITH PRIONS IN THE CENTRAL NERVOUS SYSTEM (CNS) ULTIMATELY CAUSES EXTENSIVE NEURODEGENERATION, AND THIS IS ACCOMPANIED BY PROMINENT MICROGLIAL AND ASTROCYTIC ACTIVATION IN AFFECTED REGIONS. THE MICROGLIA ARE THE CNS MACROPHAGES AND HELP MAINTAIN NEURONAL HOMEOSTASIS, CLEAR DEAD OR DYING CELLS AND PROVIDE DEFENSE AGAINST PATHOGENS. THE MICROGLIA ALSO PROVIDE NEUROPROTECTION DURING CNS PRION DISEASE, BUT THEIR PRO-INFLAMMATORY ACTIVATION MAY EXACERBATE THE DEVELOPMENT OF THE NEUROPATHOLOGY. INNATE IMMUNE TOLERANCE INDUCED BY CONSECUTIVE SYSTEMIC BACTERIAL LIPOPOLYSACCHARIDE (LPS) TREATMENT CAN INDUCE LONG-TERM EPIGENETIC CHANGES IN THE MICROGLIA IN THE BRAIN THAT SEVERAL MONTHS LATER CAN DAMPEN THEIR RESPONSIVENESS TO SUBSEQUENT LPS TREATMENT AND IMPEDE THE DEVELOPMENT OF NEURITIC DAMAGE IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE-LIKE PATHOLOGY. WE THEREFORE REASONED THAT INNATE IMMUNE TOLERANCE IN MICROGLIA MIGHT SIMILARLY IMPEDE THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. TO TEST THIS HYPOTHESIS GROUPS OF MICE WERE FIRST INFECTED WITH PRIONS BY INTRACEREBRAL INJECTION, AND 35 DAYS LATER GIVEN FOUR CONSECUTIVE SYSTEMIC INJECTIONS WITH LPS TO INDUCE INNATE IMMUNE TOLERANCE. OUR DATA SHOW THAT CONSECUTIVE SYSTEMIC LPS TREATMENT DID NOT AFFECT THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. OUR DATA SUGGESTS INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT INFLUENCE THE SUBSEQUENT ONSET OF PRION DISEASE-INDUCED NEUROPATHOLOGY IN MICE, DESPITE PREVIOUSLY PUBLISHED EVIDENCE OF THIS EFFECT IN AN ALZHEIMER'S DISEASE MOUSE MODEL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  4015  36 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  5010  26 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID.	1994	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  6742  34 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  3056  29 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  6743  34 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? INCORPORATING PRESENTATIONS ON SCOLIOGENY AT THE 2012 IRSSD AND SRS MEETINGS. THIS PAPER AIMS TO INTEGRATE INTO CURRENT UNDERSTANDING OF AIS CAUSATION, ETIOPATHOGENETIC INFORMATION PRESENTED AT TWO MEETINGS DURING 2012 NAMELY, THE INTERNATIONAL RESEARCH SOCIETY OF SPINAL DEFORMITIES (IRSSD) AND THE SCOLIOSIS RESEARCH SOCIETY (SRS). THE ULTIMATE HOPE IS TO PREVENT THE OCCURRENCE OR PROGRESSION OF THE SPINAL DEFORMITY OF AIS WITH NON-INVASIVE TREATMENT, POSSIBLY MEDICAL. THIS MIGHT BE ATTAINED BY PERSONALISED POLYMECHANISTIC PREVENTIVE THERAPY TARGETING THE APPROPRIATE ETIOLOGY AND/OR ETIOPATHOGENETIC PATHWAYS, TO AVOID FUSION AND MAINTAIN SPINAL MOBILITY. ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  5580  35 ROLE OF NEUROTOXICANTS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE: A MECHANISTIC INSIGHT. ALZHEIMER'S DISEASE (AD) IS THE MOST CONSPICUOUS CHRONIC NEURODEGENERATIVE SYNDROME, WHICH HAS BECOME A SIGNIFICANT CHALLENGE FOR THE GLOBAL HEALTHCARE SYSTEM. MULTIPLE STUDIES HAVE CORROBORATED A CLEAR ASSOCIATION OF NEUROTOXICANTS WITH AD PATHOGENICITY, SUCH AS AMYLOID BETA (ABETA) PROTEINS AND NEUROFIBRILLARY TANGLES (NFTS), SIGNALLING PATHWAY MODIFICATIONS, CELLULAR STRESS, COGNITIVE DYSFUNCTIONS, NEURONAL APOPTOSIS, NEUROINFLAMMATION, EPIGENETIC MODIFICATION, AND SO ON. THIS REVIEW, THEREFORE, AIMED TO ADDRESS SEVERAL ESSENTIAL MECHANISMS AND SIGNALLING CASCADES, INCLUDING WNT (WINGLESS AND INT.) SIGNALLING PATHWAY, AUTOPHAGY, MAMMALIAN TARGET OF RAPAMYCIN (MTOR), PROTEIN KINASE C (PKC) SIGNALLING CASCADES, CELLULAR REDOX STATUS, ENERGY METABOLISM, GLUTAMATERGIC NEUROTRANSMISSIONS, IMMUNE CELL STIMULATIONS (E.G. MICROGLIA, ASTROCYTES) AS WELL AS AN AMYLOID PRECURSOR PROTEIN (APP), PRESENILIN-1 (PSEN1), PRESENILIN-2 (PSEN2) AND OTHER AD-RELATED GENE EXPRESSIONS THAT HAVE BEEN PRETENTIOUS AND MODULATED BY THE VARIOUS NEUROTOXICANTS. THIS REVIEW CONCLUDED THAT NEUROTOXICANTS PLAY A MOMENTOUS ROLE IN DEVELOPING AD THROUGH MODULATING VARIOUS SIGNALLING CASCADES. NEVERTHELESS, COMPREHENSION OF THIS RISK AGENT-INDUCED NEUROTOXICITY IS FAR TOO LITTLE. MORE IN-DEPTH EPIDEMIOLOGICAL AND SYSTEMATIC INVESTIGATIONS ARE NEEDED TO UNDERSTAND THE POTENTIAL MECHANISMS BETTER TO ADDRESS THESE NEUROTOXICANTS AND IMPROVE APPROACHES TO THEIR RISK EXPOSURE THAT AID IN AD PATHOGENESIS.KEY MESSAGESINEVITABLE CASCADE MECHANISMS OF HOW ALZHEIMER'S DISEASE-RELATED (AD-RELATED) GENE EXPRESSIONS ARE MODULATED BY NEUROTOXICANTS HAVE BEEN DISCUSSED.INVOLVEMENT OF THE NEUROTOXICANTS-INDUCED PATHWAYS CAUSED AN EXTENDED RISK OF AD IS EXPLICITED.INTEGRATION OF CELL CULTURE, ANIMALS AND POPULATION-BASED ANALYSIS ON THE CLINICAL SEVERITY OF AD IS ADDRESSED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   745  39 CANNABIS ALTERS EPIGENETIC INTEGRITY AND ENDOCANNABINOID SIGNALLING IN THE HUMAN FOLLICULAR NICHE. STUDY QUESTION: DO PHYTOCANNABINOIDS (PCS) AFFECT FOLLICULAR ENDOCANNABINOID SIGNALLING AND THE EPIGENOME IN THE SURROUNDING GRANULOSA CELLS (GCS)? SUMMARY ANSWER: EXPOSURE TO PCS INCREASES THE EXPRESSION OF ENDOCANNABINOID RECEPTORS AND REDUCES DNA METHYLATION ENZYME EXPRESSION AND GLOBAL DNA METHYLATION IN NAIVE GCS. WHAT IS KNOWN ALREADY: CANNABIS PLANT DERIVATIVES, KNOWN AS PCS, ARE USED FOR MEDICINAL AND RECREATIONAL PURPOSES. THE MAIN PC, TETRAHYDROCANNABINOL (THC), IS THE THIRD MOST COMMONLY USED SUBSTANCE BY WOMEN OF CHILDBEARING AGE, HENCE KNOWLEDGE OF THE EFFECT IT HAS ON REPRODUCTION IS OF UTMOST IMPORTANCE. THC EXERTS ITS EFFECTS VIA RECEPTORS OF THE ENDOCANNABINOID SYSTEM (ECS) AND CAN INTERFERE WITH FOLLICULOGENESIS, OOCYTE DEVELOPMENT AND OVULATION. ENDOCANNABINOIDS HAVE BEEN MEASURED IN FOLLICULAR FLUID (FF) OBTAINED DURING OOCYTE RETRIEVAL AND ARE IMPLICATED IN CONTROLLING FOLLICULOGENESIS. IT HAS BEEN ESTABLISHED THAT IN THE PLACENTA, PCS DISRUPT ENDOCANNABINOID HOMEOSTASIS VIA IMPAIRMENT OF THE SYNTHETIC AND DEGRADING ENZYMES, LEADING TO A NET INCREASE OF ENDOCANNABINOID LEVELS. FINALLY, PREVIOUS STUDIES HAVE SHOWN THAT THC ALTERS METHYLATION AND HISTONE MODIFICATIONS IN SPERM, BRAIN AND BLOOD CELLS. STUDY DESIGN, SIZE, DURATION: THIS STUDY INCLUDED AN IN VIVO COHORT ASSESSMENT OF CANNABIS EXPOSURE AND ITS EFFECTS ON THE FOLLICLE AND IN VITRO ASSAYS CONDUCTED TO VALIDATE THE IN VIVO FINDINGS AND TO EXPLORE POSSIBLE MECHANISMS OF ACTION. PARTICIPANTS/MATERIALS, SETTING, METHODS: A TOTAL OF 318 FF SAMPLES, FROM 261 PATIENTS UNDERGOING IVF TREATMENT AT A PRIVATE FERTILITY CLINIC WHO CONSENTED FOR BIOBANKING BIOLOGICAL WASTE MATERIAL BETWEEN JANUARY 2018 AND JULY 2019, WERE INCLUDED IN THIS STUDY. CONCENTRATIONS OF PCS AND ENDOCANNABINOIDS WERE ASSESSED IN FF BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY (LC-MS/MS). EXPOSURE TO PCS WAS DETERMINED BASED ON THESE MEASURED LEVELS. LEVELS OF BOTH ENDOCANNABINOID RECEPTORS (CB1R, CB2R) AND THE DE NOVO DNA METHYLATING ENZYME, DNMT3B, IN GCS WERE ASSESSED BY FLOW CYTOMETRY BOTH IN VITRO AND IN VIVO AND GLOBAL DNA METHYLATION WAS ASSESSED IN VITRO BY ELISA. IN VIVO EFFECTS WERE ASSESSED BY COMPARING SAMPLES POSITIVE FOR AT LEAST ONE PC, WITH SAMPLES NEGATIVE FOR ALL MEASURED PCS. IN VITRO EFFECTS WERE DETERMINED IN NAIVE GCS, OBTAINED CONCURRENTLY WITH FF SAMPLES THAT HAD TESTED NEGATIVE FOR ALL PCS. THESE GCS WERE TREATED WITH DIFFERENT COMBINATIONS OF THE MAIN THREE PCS. MAIN RESULTS AND THE ROLE OF CHANCE: OVERALL, 17 PATIENTS (6.4%) WERE POSITIVE FOR CANNABIS CONSUMPTION. FURTHERMORE, THE PREVALENCE OF CANNABIS POSITIVITY IN THE FF INCREASED FROM 4% OF THE TESTED SAMPLES THAT WERE COLLECTED PRIOR TO NATIONAL LEGALISATION IN OCTOBER 2018 TO 12% OF THOSE COLLECTED FOLLOWING LEGALISATION. OF NOTE, 59% OF PATIENTS WHO TESTED POSITIVE FOR PCS (10 OF 17) REPORTED PREVIOUS OR ONGOING EXPOSURE TO CANNABIS UPON THEIR INITIAL INTAKE. ENDOCANNABINOID LEVELS WERE NOT AFFECTED BY THE PRESENCE OF PCS. CB2R WAS MORE PREVALENT THAN CB1R IN GCS AND ITS EXPRESSION INCREASED FOLLOWING ACUTE AND CHRONIC IN VITRO EXPOSURE TO PCS. THE EXPRESSION OF DNMT3B AND GLOBAL METHYLATION DECREASED FOLLOWING EXPOSURE, SUGGESTING THAT CANNABIS MAY AFFECT THE EPIGENOME IN THE FOLLICULAR NICHE. THE ACUTE CHANGES WERE SUSTAINED THROUGHOUT CHRONIC TREATMENT. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: OUR STUDY IS LIMITED BY LACK OF DETAILS REGARDING MODE, FREQUENCY AND TIMING OF PC CONSUMPTION. MOREOVER, WE WERE NOT ABLE TO ADEQUATELY ASSESS THE EFFECT OF PCS ON IMMEDIATE OR LONG-TERM CLINICAL OUTCOMES, DUE TO THE SMALL SAMPLE SIZE AND THE LACK OF FOLLOW UP. FUTURE, LARGE-SCALE STUDIES SHOULD FOCUS ON ASSESS THE CLINICAL IMPLICATIONS OF CANNABIS EXPOSURE, VALIDATE OUR FINDINGS, AND DETERMINE TO WHAT EXTENT CANNABIS AFFECTS THE EPIGENOME OVARIAN FOLLICLE AND THE DEVELOPING OOCYTE. WIDER IMPLICATIONS OF THE FINDINGS: TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY MEASURING PCS IN FF BY LC-MS/MS. WE SHOW THAT CONSUMING CANNABIS ALTERS THE ECS IN THE DEVELOPING FOLLICLE, AND DIRECTLY AFFECTS DNMT EXPRESSION AND GLOBAL DNA METHYLATION LEVELS. CANNABIS LEGALISATION AND USE IS INCREASING WORLDWIDE, THEREFORE FURTHER UNDERSTANDING ITS ROLE IN FEMALE FERTILITY AND FOLLICULOGENESIS IS CRITICAL. STUDY FUNDING/COMPETING INTEREST(S): ALL FUNDING WAS PROVIDED BY CREATE FERTILITY CENTRE THROUGH THE REINVESTMENT OF CLINICAL EARNINGS. THE AUTHORS DECLARE NO COMPETING INTERESTS.	2021	

14   355  33 ALTERED MITOCHONDRIAL DNA METHYLATION AND MITOCHONDRIAL DNA COPY NUMBER IN AN APP/PS1 TRANSGENIC MOUSE MODEL OF ALZHEIMER DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE AND MITOCHONDRIAL IMPAIRMENT IS A KEY FEATURE OF AD. THE MITOCHONDRIAL DNA (MTDNA) EPIGENETIC MECHANISM IS A RELATIVELY NEW FIELD COMPARED TO NUCLEAR DNA. THE RELATIONSHIP BETWEEN MTDNA EPIGENETIC MECHANISM AND AD HASN'T BEEN ESTABLISHED. SO WE ANALYZED THE MTDNA METHYLATION IN D-LOOP REGION AND 12 S RRNA GENE IN THE HIPPOCAMPI IN AMYLOID PRECURSOR PROTEIN/PRESENILIN 1 (APP/PS1) TRANSGENIC MICE BY BISULFITE PYROSEQUENCING. MITOCHONDRIAL DNA COPY NUMBER AND GENE EXPRESSION WERE STUDIED BY QUANTITATIVE REAL-TIME PCR (QRT-PCR). WE OBSERVED A DECREASE IN THE DISPLACEMENT LOOP (D-LOOP) METHYLATION AND AN INCREASE IN 12 S RRNA GENE METHYLATION, WHILE BOTH THE MTDNA COPY NUMBER AND THE MITOCHONDRIAL GENE EXPRESSION WERE REDUCED IN APP/PS1 TRANSGENIC MICE. IN SUMMARY, THE PRESENT FINDING SUGGEST THAT MTDNA METHYLATION MAY PLAY A ROLE IN AD PATHOLOGY, WHICH WARRANTS LARGER FUTURE INVESTIGATIONS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15   718  25 CALCIUM-DEPENDENT INTRACELLULAR SIGNAL PATHWAYS IN PRIMARY CULTURED ADIPOCYTES AND ANK3 GENE VARIATION IN PATIENTS WITH BIPOLAR DISORDER AND HEALTHY CONTROLS. BIPOLAR DISORDER (BD) IS A CHRONIC PSYCHIATRIC DISORDER OF PUBLIC HEALTH IMPORTANCE AFFECTING >1% OF THE SWEDISH POPULATION. DESPITE PROGRESS, PATIENTS STILL SUFFER FROM CHRONIC MOOD SWITCHES WITH POTENTIAL SEVERE CONSEQUENCES. THUS, EARLY DETECTION, DIAGNOSIS AND INITIATION OF CORRECT TREATMENT ARE CRITICAL. CULTURED ADIPOCYTES FROM 35 PATIENTS WITH BD AND 38 HEALTHY CONTROLS WERE ANALYSED USING SIGNAL PATHWAY REPORTER ASSAYS, THAT IS, PROTEIN KINASE C (PKC), PROTEIN KINASE A (PKA), MITOGEN-ACTIVATED PROTEIN KINASES (EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) AND C-JUN N-TERMINAL KINASE (JNK)), MYC, WNT AND P53. THE LEVELS OF ACTIVATED TARGET TRANSCRIPTIONAL FACTORS WERE MEASURED IN ADIPOCYTES BEFORE AND AFTER STIMULATION WITH LITHIUM AND ESCITALOPRAM. VARIATIONS WERE ANALYSED IN THE LOCI OF 25 DIFFERENT SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS). ACTIVATION OF INTRACELLULAR SIGNALS IN SEVERAL PATHWAYS ANALYSED WERE SIGNIFICANTLY HIGHER IN PATIENTS THAN IN HEALTHY CONTROLS UPON DRUG STIMULATION, ESPECIALLY WITH ESCITALOPRAM STIMULATION OF PKC, JNK AND MYC, AS WELL AS LITHIUM-STIMULATED PKC, WHEREAS NO MEANINGFUL DIFFERENCE WAS OBSERVED BEFORE STIMULATION. UNIVARIATE ANALYSES OF CONTINGENCY TABLES FOR 80 CATEGORICAL SNP RESULTS VERSUS DIAGNOSES SHOWED A SIGNIFICANT LINK WITH THE ANK3 GENE (RS10761482; LIKELIHOOD RATIO CHI(2)=4.63; P=0.031). IN A MULTIVARIATE ORDINAL LOGISTIC FIT FOR DIAGNOSIS, A BACKWARD STEPWISE PROCEDURE SELECTED ANK3 AS THE REMAINING SIGNIFICANT PREDICTOR. COMPARISON OF THE ESCITALOPRAM-STIMULATED PKC ACTIVITY AND THE ANK3 GENOTYPE SHOWED THEM TO ADD THEIR SHARE OF THE DIAGNOSTIC VARIANCE, WITH NO INTERACTION (15% OF VARIANCE EXPLAINED, P<0.002). THE STUDY IS CROSS-SECTIONAL WITH NO LONGITUDINAL FOLLOW-UP. COHORTS ARE RELATIVELY SMALL WITH NO MEDICATION-FREE PATIENTS, AND THERE ARE NO 'ILL PATIENT' CONTROLS. IT TAKES 3 TO 4 WEEKS OF CULTURE TO EXPAND ADIPOCYTES THAT MAY CHANGE EPIGENETIC PROFILES BUT REMOVE THE POSSIBILITY OF MEDICATION EFFECTS. ABNORMALITIES IN THE REACTIVITY OF INTRACELLULAR SIGNAL PATHWAYS TO STIMULATION AND THE ANK3 GENOTYPE MAY BE ASSOCIATED WITH PATHOGENESIS OF BD. ALGORITHMS USING BIOLOGICAL PATTERNS SUCH AS PATHWAY REACTIVITY TOGETHER WITH STRUCTURAL GENETIC SNP DATA MAY PROVIDE OPPORTUNITIES FOR EARLIER DETECTION AND EFFECTIVE TREATMENT OF BD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16   244  33 ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), ENVIRONMENT, EXPOSOME AND EPIGENETICS: A MOLECULAR PERSPECTIVE OF POSTNATAL NORMAL SPINAL GROWTH AND THE ETIOPATHOGENESIS OF AIS WITH CONSIDERATION OF A NETWORK APPROACH AND POSSIBLE IMPLICATIONS FOR MEDICAL THERAPY. GENETIC FACTORS ARE BELIEVED TO PLAY AN IMPORTANT ROLE IN THE ETIOLOGY OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS). DISCORDANT FINDINGS FOR MONOZYGOTIC (MZ) TWINS WITH AIS SHOW THAT ENVIRONMENTAL FACTORS INCLUDING DIFFERENT INTRAUTERINE ENVIRONMENTS ARE IMPORTANT IN ETIOLOGY, BUT WHAT THESE ENVIRONMENTAL FACTORS MAY BE IS UNKNOWN. RECENT EVIDENCE FOR COMMON CHRONIC NON-COMMUNICABLE DISEASES SUGGESTS EPIGENETIC DIFFERENCES MAY UNDERLIE MZ TWIN DISCORDANCE, AND BE THE LINK BETWEEN ENVIRONMENTAL FACTORS AND PHENOTYPIC DIFFERENCES. DNA METHYLATION IS ONE IMPORTANT EPIGENETIC MECHANISM OPERATING AT THE INTERFACE BETWEEN GENOME AND ENVIRONMENT TO REGULATE PHENOTYPIC PLASTICITY WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. THE WORD EXPOSOME REFERS TO THE TOTALITY OF ENVIRONMENTAL EXPOSURES FROM CONCEPTION ONWARDS, COMPRISING FACTORS IN EXTERNAL AND INTERNAL ENVIRONMENTS. THE WORD EXPOSOME IS USED HERE ALSO IN RELATION TO PHYSIOLOGIC AND ETIOPATHOGENETIC FACTORS THAT AFFECT NORMAL SPINAL GROWTH AND MAY INDUCE THE DEFORMITY OF AIS. IN NORMAL POSTNATAL SPINAL GROWTH WE PROPOSE A NEW TERM AND CONCEPT, PHYSIOLOGIC GROWTH-PLATE EXPOSOME FOR THE NORMAL PROCESSES PARTICULARLY OF THE INTERNAL ENVIRONMENTS THAT MAY HAVE EPIGENETIC EFFECTS ON GROWTH PLATES OF VERTEBRAE. IN AIS, WE PROPOSE A NEW TERM AND CONCEPT PATHOPHYSIOLOGIC SCOLIOGENIC EXPOSOME FOR THE ABNORMAL PROCESSES IN MOLECULAR PATHWAYS PARTICULARLY OF THE INTERNAL ENVIRONMENT CURRENTLY EXPRESSED AS ETIOPATHOGENETIC HYPOTHESES; THESE ARE SUGGESTED TO HAVE DEFORMING EFFECTS ON THE GROWTH PLATES OF VERTEBRAE AT CELL, TISSUE, STRUCTURE AND/OR ORGAN LEVELS THAT ARE CONSIDERED TO BE EPIGENETIC. NEW RESEARCH IS REQUIRED FOR CHROMATIN MODIFICATIONS INCLUDING DNA METHYLATION IN AIS SUBJECTS AND VERTEBRAL GROWTH PLATES EXCISED AT SURGERY. IN ADDITION, CONSIDERATION IS NEEDED FOR A POSSIBLE NETWORK APPROACH TO ETIOPATHOGENESIS BY CONSTRUCTING AIS DISEASOMES. THESE APPROACHES MAY LEAD THROUGH SCREENING, GENETIC, EPIGENETIC, BIOCHEMICAL, METABOLIC PHENOTYPES AND PHARMACOGENOMIC RESEARCH TO IDENTIFY SUSCEPTIBLE INDIVIDUALS AT RISK AND MODULATE ABNORMAL MOLECULAR PATHWAYS OF AIS. THE POTENTIAL OF EPIGENETIC-BASED MEDICAL THERAPY FOR AIS CANNOT BE ASSESSED AT PRESENT, AND MUST AWAIT NEW RESEARCH DERIVED FROM THE EVALUATION OF EPIGENETIC CONCEPTS OF SPINAL GROWTH IN HEALTH AND DEFORMITY. THE TENETS OUTLINED HERE FOR AIS ARE APPLICABLE TO OTHER MUSCULOSKELETAL GROWTH DISORDERS INCLUDING INFANTILE AND JUVENILE IDIOPATHIC SCOLIOSIS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17   849  35 CHILDHOOD TRAUMATIZATION IS ASSOCIATED WITH DIFFERENCES IN TRPA1 PROMOTER METHYLATION IN FEMALE PATIENTS WITH MULTISOMATOFORM DISORDER WITH PAIN AS THE LEADING BODILY SYMPTOM. BACKGROUND: THE CONSTRUCT OF MULTISOMATOFORM DISORDER (MSD) IS A COMMON POINT OF REFERENCE FOR PATIENTS IN DIFFERENT SOMATIC AND PSYCHOSOMATIC SPECIALTIES AND THEREFORE USEFUL IN STUDYING LARGE WELL-CHARACTERIZED COHORTS OF A PROTOTYPE OF A SOMATOFORM DISORDER AND IN PARALLEL AS A FUNCTIONAL SOMATIC SYNDROME (FSS). THIS DISORDER IS CHARACTERIZED BY DISTRESSING AND FUNCTIONALLY DISABLING SOMATIC SYMPTOMS WITH CHRONIC PAIN AS THE MOST FREQUENT AND CLINICALLY RELEVANT COMPLAINT. PAIN IS PERCEIVED BY NOCICEPTIVE NERVE FIBERS AND TRANSFERRED THROUGH THE GENERATION OF ACTION POTENTIALS BY DIFFERENT RECEPTOR MOLECULES KNOWN TO DETERMINE PAIN SENSITIVITY IN PATHOPHYSIOLOGICAL PROCESSES. PREVIOUS STUDIES HAVE SHOWN THAT FOR THE TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), RECEPTOR METHYLATION OF A PARTICULAR CPG DINUCLEOTIDE IN THE PROMOTER REGION IS INVERSELY ASSOCIATED WITH BOTH HEAT PAIN AND PRESSURE PAIN THRESHOLDS. IN THIS STUDY, WE HYPOTHESIZED THAT TRPA1 PROMOTER METHYLATION REGULATES PAIN SENSITIVITY OF PATIENTS WITH MULTISOMATOFORM DISORDER (MSD). A COHORT OF 151 PATIENTS WITH MSD AND 149 MATCHED HEALTHY VOLUNTEERS WERE EVALUATED USING QUANTITATIVE SENSORY TESTING, CLINICAL AND PSYCHOMETRIC ASSESSMENT, AND METHYLATION ANALYSIS USING DNA ISOLATED FROM WHOLE BLOOD. RESULTS: WE FOUND CPG -628 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD AND CPG -411 TO BE CORRELATED WITH MECHANICAL PAIN THRESHOLD IN FEMALE VOLUNTEERS, I.E., HIGHER METHYLATION LEVELS LEAD TO HIGHER PAIN THRESHOLDS. A NOVEL FINDING IS THAT METHYLATION LEVELS WERE SIGNIFICANTLY DIFFERENT BETWEEN PATIENTS WITH NO AND SEVERE LEVELS OF CHILDHOOD TRAUMA. CPG METHYLATION ALSO CORRELATED WITH PSYCHOMETRIC ASSESSMENT OF PAIN AND PAIN LEVELS RATED ON A VISUAL ANALOG SCALE. CONCLUSION: OUR FINDINGS SUPPORT THE HYPOTHESIS THAT EPIGENETIC REGULATION OF TRPA1 PLAYS A ROLE IN MECHANICAL PAIN SENSITIVITIES IN HEALTHY VOLUNTEERS. THEY FURTHER PROVIDE EVIDENCE FOR THE POSSIBLE INFLUENCE OF CHILDHOOD TRAUMATIC EXPERIENCES ON THE EPIGENETIC REGULATION OF TRPA1 IN PATIENTS WITH MSD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18  4491  31 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS.	1992	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19   930  31 CHRONIC IRRADIATION OF HUMAN CELLS REDUCES HISTONE LEVELS AND DEREGULATES GENE EXPRESSION. OVER THE PAST DECADES, THERE HAVE BEEN HUGE ADVANCES IN UNDERSTANDING CELLULAR RESPONSES TO IONISING RADIATION (IR) AND DNA DAMAGE. THESE STUDIES, HOWEVER, WERE MOSTLY EXECUTED WITH CELL LINES AND MICE USING SINGLE OR MULTIPLE ACUTE DOSES OF RADIATION. HENCE, RELATIVELY LITTLE IS KNOWN ABOUT HOW CONTINUOUS EXPOSURE TO LOW DOSE IONISING RADIATION AFFECTS NORMAL CELLS AND ORGANISMS, EVEN THOUGH OUR CELLS ARE CONSTANTLY EXPOSED TO LOW LEVELS OF RADIATION. WE ADDRESSED THIS ISSUE BY EXAMINING THE CONSEQUENCES OF EXPOSING HUMAN PRIMARY CELLS TO CONTINUOUS IONISING GAMMA-RADIATION DELIVERED AT 6-20 MGY/H. ALTHOUGH THESE DOSE RATES ARE ESTIMATED TO INFLICT FEWER THAN A SINGLE DNA DOUBLE-STRAND BREAK (DSB) PER HOUR PER CELL, THEY STILL CAUSED DOSE-DEPENDENT REDUCTIONS IN CELL PROLIFERATION AND INCREASED CELLULAR SENESCENCE. WE CONCOMITANTLY OBSERVED HISTONE PROTEIN LEVELS TO REDUCE BY UP TO 40%, WHICH IN CONTRAST TO PREVIOUS OBSERVATIONS, WAS NOT MAINLY DUE TO PROTEIN DEGRADATION BUT INSTEAD CORRELATED WITH REDUCED HISTONE GENE EXPRESSION. HISTONE REDUCTIONS WERE ACCOMPANIED BY ENLARGED NUCLEAR SIZE PARALLELED BY AN INCREASE IN GLOBAL TRANSCRIPTION, INCLUDING THAT OF PRO-INFLAMMATORY GENES. THUS, CHRONIC IRRADIATION, EVEN AT LOW DOSE-RATES, CAN INDUCE CELL SENESCENCE AND ALTER GENE EXPRESSION VIA A HITHERTO UNCHARACTERISED EPIGENETIC ROUTE. THESE FEATURES OF CHRONIC RADIATION REPRESENT A NEW ASPECT OF RADIATION BIOLOGY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  5766  38 SPECIAL ISSUE: ALZHEIMER'S DISEASE. MORE THAN 45 MILLION PEOPLE WORLDWIDE HAVE ALZHEIMER'S DISEASE (AD), A DETERIORATION OF MEMORY AND OTHER COGNITIVE DOMAINS THAT LEADS TO DEATH WITHIN 3 TO 9 YEARS AFTER DIAGNOSIS. THE PRINCIPAL RISK FACTOR FOR AD IS AGE. AS THE AGING POPULATION INCREASES, THE PREVALENCE WILL APPROACH 131 MILLION CASES WORLDWIDE IN 2050. AD IS THEREFORE A GLOBAL PROBLEM CREATING A RAPIDLY GROWING EPIDEMIC AND BECOMING A MAJOR THREAT TO HEALTHCARE IN OUR SOCIETIES. IT HAS BEEN MORE THAN 20 YEARS SINCE IT WAS FIRST PROPOSED THAT THE NEURODEGENERATION IN AD MAY BE CAUSED BY DEPOSITION OF AMYLOID-BETA (ABETA) PEPTIDES IN PLAQUES IN BRAIN TISSUE. ACCORDING TO THE AMYLOID HYPOTHESIS, ACCUMULATION OF ABETA PEPTIDES, RESULTING FROM A CHRONIC IMBALANCE BETWEEN ABETA PRODUCTION AND ABETA CLEARANCE IN THE BRAIN, IS THE PRIMARY INFLUENCE DRIVING AD PATHOGENESIS. CURRENT AVAILABLE MEDICATIONS APPEAR TO BE ABLE TO PRODUCE MODERATE SYMPTOMATIC BENEFITS BUT NOT TO STOP DISEASE PROGRESSION. THE SEARCH FOR BIOMARKERS AS WELL AS NOVEL THERAPEUTIC APPROACHES FOR AD HAS BEEN A MAJOR FOCUS OF RESEARCH. RECENT FINDINGS, HOWEVER, SHOW THAT NEURONAL-INJURY BIOMARKERS ARE INDEPENDENT OF ABETA SUGGESTING EPIGENETIC MODIFICATIONS, GENE-GENE AND/OR GENE-ENVIRONMENT INTERACTIONS IN THE DISEASE ETIOLOGY, AND CALLING FOR RECONSIDERATION OF THE PATHOLOGICAL CASCADE AND ASSESSMENT OF ALTERNATIVE THERAPEUTIC STRATEGIES. IN ADDITION, RECENT RESEARCH RESULTS REGARDING THE EXPRESSION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP) GENE RESULTING IN THE PRESENCE OF VARIOUS APP-MRNA ISOFORMS AND THEIR QUANTIFICATION, ESPECIALLY FOR IDENTIFYING THE MOST ABUNDANT ONE THAT MAY DECISIVE FOR THE NORMAL STATUS OR DISEASE RISK, HAVE BEEN REPORTED. AS SUCH, A MORE COMPLETE UNDERSTANDING OF AD PATHOGENESIS WILL LIKELY REQUIRE GREATER INSIGHTS INTO THE PHYSIOLOGICAL FUNCTION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP).	2018