1 3934 260 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 2 3380 37 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY. 2023 3 3811 42 INTRATUMORAL HETEROGENEITY: CLONAL COOPERATION IN EPITHELIAL-TO-MESENCHYMAL TRANSITION AND METASTASIS. ALTHOUGH PHENOTYPIC INTRATUMORAL HETEROGENEITY WAS FIRST DESCRIBED MANY DECADES AGO, THE ADVENT OF NEXT-GENERATION SEQUENCING HAS PROVIDED CONCLUSIVE EVIDENCE THAT IN ADDITION TO PHENOTYPIC DIVERSITY, SIGNIFICANT GENOTYPIC DIVERSITY EXISTS WITHIN TUMORS. TUMOR HETEROGENEITY LIKELY ARISES BOTH FROM CLONAL EXPANSIONS, AS WELL AS FROM DIFFERENTIATION HIERARCHIES EXISTENT IN THE TUMOR, SUCH AS THAT ESTABLISHED BY CANCER STEM CELLS (CSCS) AND NON-CSCS. THESE DIFFERENTIATION HIERARCHIES MAY ARISE DUE TO GENETIC MUTATIONS, EPIGENETIC ALTERATIONS, OR MICROENVIRONMENTAL INFLUENCES. AN ADDITIONAL DIFFERENTIATION HIERARCHY WITHIN EPITHELIAL TUMORS MAY ARISE WHEN ONLY A FEW TUMOR CELLS TRANS-DIFFERENTIATE INTO MESENCHYMAL-LIKE CELLS, A PROCESS KNOWN AS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). AGAIN, THIS PROCESS CAN BE INFLUENCED BY BOTH GENETIC AND NON-GENETIC FACTORS. IN THIS REVIEW WE DISCUSS THE EVIDENCE FOR CLONAL INTERACTION AND COOPERATION FOR TUMOR MAINTENANCE AND PROGRESSION, PARTICULARLY WITH RESPECT TO EMT, AND FURTHER ADDRESS THE FAR-REACHING EFFECTS THAT TUMOR HETEROGENEITY MAY HAVE ON CANCER THERAPY. 2015 4 2697 35 EX VIVO MODELS OF CHRONIC GRANULOMATOUS DISEASE. INDUCED PLURIPOTENT STEM CELLS (IPSCS) ARE PLURIPOTENT STEM CELLS THAT CAN BE ESTABLISHED FROM DEDIFFERENTIATION OF ALL SOMATIC CELL TYPES BY EPIGENETIC PHENOMENA. IPSCS CAN BE DIFFERENTIATED INTO ANY MATURE CELLS LIKE NEURONS, HEPATOCYTES, OR PANCREATIC CELLS THAT HAVE NOT BEEN EASILY AVAILABLE TO DATE. THUS, IPSCS ARE WIDELY USED FOR DISEASE MODELING, DRUG DISCOVERY, AND CELL THERAPY DEVELOPMENT. HERE, WE DESCRIBE A PROTOCOL TO OBTAIN HUMAN MATURE AND FUNCTIONAL NEUTROPHILS AND MACROPHAGES AS EX VIVO MODELS OF X-LINKED CHRONIC GRANULOMATOUS DISEASE (X-CGD). THIS METHOD CAN BE APPLIED TO MODEL THE OTHER GENETIC FORMS OF CGD. WE ALSO DESCRIBE METHODS FOR TESTING THE CHARACTERISTICS AND FUNCTIONS OF NEUTROPHILS AND MACROPHAGES BY MORPHOLOGY, PHAGOCYTOSIS ASSAY, RELEASE OF GRANULE MARKERS OR CYTOKINES, CELL SURFACE MARKERS, AND NADPH OXIDASE ACTIVITY. 2019 5 6044 44 THE COMPLEX BIOLOGY OF HUMAN CYTOMEGALOVIRUS LATENCY. WHILE MANY VIRAL INFECTIONS ARE LIMITED AND EVENTUALLY RESOLVED BY THE HOST IMMUNE RESPONSE OR BY DEATH OF THE HOST, OTHER VIRUSES ESTABLISH LONG-TERM RELATIONSHIPS WITH THE HOST BY WAY OF A PERSISTENT INFECTION, THAT RANGE FROM CHRONIC VIRUSES THAT MAY BE EVENTUALLY CLEARED TO THOSE THAT ESTABLISH LIFE-LONG PERSISTENT OR LATENT INFECTION. VIRUSES INFECTING HOSTS FROM BACTERIA TO HUMANS ESTABLISH QUIESCENT INFECTIONS THAT MUST BE REACTIVATED TO PRODUCE PROGENY. FOR MAMMALIAN VIRUSES, MOST NOTABLY HERPESVIRUSES, THIS QUIESCENT MAINTENANCE OF VIRAL GENOMES IN THE ABSENCE OF VIRUS REPLICATION IS REFERRED TO AS LATENCY. THE LATENT STRATEGY ALLOWS THE VIRUS TO PERSIST QUIESCENTLY WITHIN A SINGLE HOST UNTIL CONDITIONS INDICATE A NEED TO REACTIVATE TO REACH A NEW HOST OR, TO RE-SEED A RESERVOIR WITHIN THE HOST. HERE, I REVIEW COMMON THEMES IN VIRAL STRATEGIES TO REGULATE THE LATENT CYCLE AND REACTIVATE FROM IT RANGING FROM BACTERIOPHAGE TO HERPESVIRUSES WITH A FOCUS ON HUMAN CYTOMEGALOVIRUS (HCMV). THEMES CENTRAL TO HERPESVIRUS LATENCY INCLUDE, EPIGENETIC REPRESSION OF VIRAL GENE EXPRESSION AND MECHANISMS TO REGULATE HOST SIGNALING AND SURVIVAL. CRITICAL TO THE SUCCESS OF A LATENT PROGRAM ARE MECHANISMS BY WHICH THE VIRUS CAN "SENSE" FLUCTUATIONS IN HOST BIOLOGY (WITHIN THE HOST) OR ENVIRONMENT (OUTSIDE THE HOST) AND MAKE APPROPRIATE "DECISIONS" TO MAINTAIN LATENCY OR RE-INITIATE THE REPLICATIVE PROGRAM. THE SIGNALS OR ENVIRONMENTS THAT INDICATE THE ESTABLISHMENT OF A LATENT STATE, THE VERY NATURE OF THE LATENT STATE, AS WELL AS THE SIGNALS DRIVING REACTIVATION HAVE BEEN TOPICS OF INTENSE STUDY FROM BACTERIOPHAGE TO HUMAN VIRUSES, AS THESE QUESTIONS ENCOMPASS THE HEIGHT OF COMPLEXITY IN VIRUS-HOST INTERACTIONS-WHERE THE HOST AND THE VIRUS COEXIST. 2022 6 6296 71 THE PROSPECTS FOR A SIMPLIFIED AND INTERNATIONALLY HARMONIZED APPROACH TO THE DETECTION OF POSSIBLE HUMAN CARCINOGENS AND MUTAGENS. IT IS PROPOSED THAT THE MANY SETS OF REGULATORY GUIDELINES FOR THE ASSESSMENT OF CHEMICAL CARCINOGENICITY AND MUTAGENICITY SHOULD BE SIMPLIFIED AND HARMONIZED IN LIGHT OF CURRENT EXPERIMENTAL DATA. DATA ARE DISCUSSED WHICH ILLUSTRATE THAT AN ABSOLUTE DISTINCTION WOULD BE DRAWN BETWEEN ASSAYS CONDUCTED IN VITRO FROM THOSE IN VIVO, AND THAT THE GENOTOXICITY OF A CHEMICAL CAN BE ADEQUATELY DEFINED USING A COMBINATION OF THE SALMONELLA MUTATION ASSAY AND ONE FOR THE ASSESSMENT OF CHROMOSOME ABERRATIONS IN VITRO. IT IS SPECIFICALLY RECOMMENDED THAT ONCE A CHEMICAL HAS SHOWN A CLEAR POSITIVE RESPONSE IN VITRO, FURTHER SHORT-TERM ASSAYS SHOULD BE CONDUCTED IN VIVO; THIS AVOIDS CONSIDERING THE 'WEIGHT OF EVIDENCE' OF IN VITRO DATA, THE DANGERS OF WHICH ARE ILLUSTRATED. IT HAS NOW BEEN UNEQUIVOCALLY ESTABLISHED THAT NOT ALL IN VITRO GENOTOXINS PROVE CARCINOGENIC TO MAMMALS. IT IS THEREFORE RECOMMENDED THAT ALL NEW IN VITRO GENOTOXINS SHOULD BE ASSESSED IN VIVO USING THE MOUSE BONE MARROW MICRONUCLEUS ASSAY, AND IF A NEGATIVE RESPONSE IS OBSERVED, A LIVER GENOTOXICITY TEST. AT PRESENT AN ASSAY FOR THE INDUCTION OF UNSCHEDULED DNA SYNTHESIS (UDS) IN THE LIVER IS THE MOST WELL DEVELOPED FOR THIS PURPOSE. CURRENT DATA INDICATE THAT AN IN VITRO GENOTOXIN FOUND TO BE INACTIVE IN THESE TWO IN VIVO ASSAYS WILL BE NEITHER CARCINOGENIC NOR MUTAGENIC TO THE GERM CELLS OF MAMMALS. EQUALLY, GENOTOXICITY PRODUCED IN MAMMALS INDICATES A CARCINOGENIC AND MUTAGENIC POTENTIAL WHICH CAN USUALLY ONLY BE COUNTERED BY APPROPRIATE CHRONIC BIOASSAYS. THE USE OF SHORT-TERM IN VIVO ASSAYS IN THIS CRITICAL ROLE REQUIRES ATTENTION TO THE SELECTION OF APPROPRIATE DOSE-LEVELS AND ROUTES OF EXPOSURE - THESE ISSUES ARE DISCUSSED. THE ABOVE TESTING STRATEGY WILL NOT DETECT CERTAIN ANIMAL CARCINOGENS, SOME OF WHICH ARE SPECIFICALLY DISCUSSED. THESE CARCINOGENS HAVE BEEN VARIOUSLY REFERRED TO IN THE LITERATURE AS EPIGENETIC/NON-GENOTOXIC/HORMONAL/TOXIC/AMBIGUOUS OR AMBIVALENT CARCINOGENS. IT IS SUGGESTED THAT THEY PRESENT A MINOR POTENTIAL HAZARD TO MAN WHEN COMPARED WITH THAT OF GENOTOXIC CARCINOGENS AND THAT THEIR SHORT-TERM DETECTION CAN ONLY BE ACHIEVED BY THE DEVELOPMENT OF NEW WHOLE MAMMAL ASSAYS EMPLOYING NON-GENETIC ENDPOINTS. THIS IS IN CONTRAST TO THE PRESENT TENDENCY TO EMPLOY ADDITIONAL GENOTOXICITY ASSAYS FOR THEIR DETECTION IN THE UNJUSTIFIED BELIEF THAT THEY POSSESS AN EXQUISITE SPECIFICITY OF GENOTOXIC ACTION. THIS ARTICLE REPRESENTS A PERSONAL VIEW, BUT THE TESTING STRATEGY PROPOSED IS BASED TO A LARGE EXTENT ON THE ORIGINAL THREE-TIER APPROACH OF BRIDGES.(ABSTRACT TRUNCATED AT 400 WORDS) 1986 7 1010 38 CHRONICALLY ELEVATED PROLIFERATION AS A RISK FACTOR FOR NEOPLASIA. CHRONIC DISEASE CONDITIONS THAT ARE ASSOCIATED WITH ELEVATED PROLIFERATION ARE WELL ESTABLISHED AS RISK FACTORS FOR CANCER DEVELOPMENT. THESE MAY BE DUE TO VIRUSES (FOR EXAMPLE, IN THE CASE OF HEPATITIS AND LIVER CANCER), BACTERIAL INFECTIONS, PARASITE INFESTATION OR PHYSICAL TRAUMA. IN ADDITION TO THESE EXOGENOUS AGENTS THERE ARE ALSO METABOLIC ABNORMALITIES THAT CAN CONTRIBUTE, CAUSED BY GENETIC OR EPIGENETIC INFLUENCE. IN THE LATTER CASE, AN INCREASE IN SERUM LEVELS OF THE HORMONES OESTROGEN, TESTOSTERONE AND INSULIN MAY BE OF SPECIAL IMPORTANCE. THE PRESENT REVIEW CONCENTRATES ATTENTION ON FACTORS THAT INDUCE ELEVATED CELL TURNOVER AND FOR WHICH THERE IS EPIDEMIOLOGICAL AND/OR EXPERIMENTAL EVIDENCE OF A LINK WITH NEOPLASIA, WITH PARTICULAR STRESS ON THE INDIVIDUAL ORGAN OR TISSUE LEVEL. 1998 8 2770 45 EXTENDING INJURY- AND DISEASE-RESISTANT CNS PHENOTYPES BY REPETITIVE EPIGENETIC CONDITIONING. SIGNIFICANT REDUCTIONS IN THE EXTENT OF ACUTE INJURY IN THE CNS CAN BE ACHIEVED BY EXPOSURE TO DIFFERENT PRECONDITIONING STIMULI, BUT THE DURATION OF THE INDUCED PROTECTIVE PHENOTYPE IS TYPICALLY SHORT-LASTING, AND THUS IS DEEMED AS LIMITING ITS CLINICAL APPLICABILITY. EXTENDING THE PERIOD OVER WHICH SUCH ADAPTIVE EPIGENETIC CHANGES PERSIST - IN EFFECT, EXPANDING CONDITIONING'S "THERAPEUTIC WINDOW" - WOULD SIGNIFICANTLY BROADEN THE POTENTIAL APPLICATIONS OF SUCH A TREATMENT APPROACH IN PATIENTS. THE FREQUENCY OF THE CONDITIONING STIMULUS MAY HOLD THE KEY. WHILE TRANSIENT (1-3 DAYS) PROTECTION AGAINST CNS ISCHEMIC INJURY IS WELL ESTABLISHED PRECLINICALLY FOLLOWING A SINGLE PRECONDITIONING STIMULUS, REPETITIVELY PRESENTING PRECONDITIONING STIMULI EXTENDS THE DURATION OF ISCHEMIC TOLERANCE BY MANY WEEKS. MOREOVER, REPETITIVE INTERMITTENT POSTCONDITIONING ENHANCES POST-ISCHEMIC RECOVERY METRICS AND IMPROVES LONG-TERM SURVIVAL. INTERMITTENT CONDITIONING IS ALSO EFFICACIOUS FOR PREVENTING OR DELAYING INJURY IN PRECLINICAL MODELS OF CHRONIC NEURODEGENERATIVE DISEASE, AND FOR PROMOTING LONG-LASTING FUNCTIONAL IMPROVEMENTS IN A NUMBER OF OTHER PATHOLOGIES AS WELL. ALTHOUGH THE DETAILED MECHANISMS UNDERLYING THESE PROTRACTED KINDS OF NEUROPLASTICITY REMAIN LARGELY UNSTUDIED, ACCUMULATING EMPIRICAL EVIDENCE SUPPORTS THE CONTENTION THAT ALL OF THESE ADAPTIVE PHENOTYPES ARE EPIGENETICALLY MEDIATED. GOING FORWARD, ADDITIONAL PRECLINICAL DEMONSTRATIONS OF THE ABILITY TO INDUCE SUSTAINED BENEFICIAL PHENOTYPES THAT REDUCE THE BURDEN OF ACUTE AND CHRONIC NEURODEGENERATION, AND EXPERIMENTAL INTERROGATIONS OF THE REGULATORY CONSTRUCTS RESPONSIBLE FOR THESE EPIGENETIC RESPONSES, WILL ACCELERATE THE IDENTIFICATION OF NOT ONLY EFFICACIOUS BUT ALSO PRACTICAL, ADAPTIVE EPIGENETICS-BASED TREATMENTS FOR INDIVIDUALS WITH NEUROLOGICAL DISEASE. 2015 9 4791 50 NUTRITIONAL CATCH-UP GROWTH. MALNUTRITION, MARKED BY VARIANT NUTRIENT DEFICIENCIES, IS CONSIDERED A LEADING CAUSE OF STUNTED GROWTH WORLDWIDE. IN DEVELOPING COUNTRIES, MALNUTRITION IS CAUSED MAINLY BY FOOD SHORTAGE AND INFECTIOUS DISEASES. MALNUTRITION MAY ALSO BE FOUND IN THE DEVELOPED WORLD, WHERE IT IS DUE MOSTLY TO PREMATURITY, CHRONIC DISEASES, AND ANOREXIA NERVOSA. IN MOST CASES, WHEN FOOD CONSUMPTION IS CORRECTED, SPONTANEOUS CATCH-UP (CU) GROWTH OCCURS. HOWEVER, CU GROWTH IS NOT ALWAYS COMPLETE, LEADING TO GROWTH DEFICITS. THEREFORE, IT IS IMPORTANT TO UNDERSTAND THE MECHANISMS THAT GOVERN THIS PROCESS. USING A RAT MODEL OF FOOD RESTRICTION FOLLOWED BY REFEEDING, WE ESTABLISHED A NUTRITION-INDUCED CU GROWTH MODEL. LEVELS OF LEPTIN AND INSULIN-LIKE GROWTH FACTOR-1 WERE FOUND TO SIGNIFICANTLY DECREASE WHEN FOOD WAS RESTRICTED AND TO INCREASE ALREADY 1 DAY AFTER REFEEDING. GENE EXPRESSION ANALYSIS OF THE GROWTH PLATE REVEALED THAT FOOD RESTRICTION SPECIFICALLY AFFECTS TRANSCRIPTION FACTORS SUCH AS THE HYPOXIA INDUCIBLE FACTOR-1 AND ITS DOWNSTREAM TARGETS ON THE ONE HAND, AND GLOBAL GENE EXPRESSION, INDICATING EPIGENETIC REGULATION, ON THE OTHER. FOOD RESTRICTION ALSO REDUCED THE LEVEL OF SEVERAL MICRORNAS, INCLUDING THE CHONDROCYTE-SPECIFIC MIR-140, WHICH LED TO AN INCREASE IN ITS TARGET, SIRT1, A CLASS III HISTONE DEACETYLASE. THESE FINDINGS MAY EXPLAIN THE GLOBAL CHANGES IN GENE EXPRESSION OBSERVED UNDER NUTRITIONAL MANIPULATION. WE SUGGEST THAT MULTIPLE LEVELS OF REGULATION, INCLUDING TRANSCRIPTION FACTORS, EPIGENETIC MECHANISMS, AND MICRORNAS RESPOND TO NUTRITIONAL CUES AND OFFER A POSSIBLE EXPLANATION FOR SOME OF THE EFFECTS OF FOOD RESTRICTION ON EPIPHYSEAL GROWTH PLATE GROWTH. THE MEANS WHEREBY THESE COMPONENTS SENSE CHANGES IN NUTRITIONAL STATUS ARE STILL UNKNOWN. DECIPHERING THE ROLE OF EPIGENETIC REGULATION IN GROWTH MAY PAVE THE WAY FOR THE DEVELOPMENT OF NEW TREATMENTS FOR CHILDREN WITH GROWTH DISORDERS. 2013 10 2608 28 EPIGENETICS: A KEY PARADIGM IN REPRODUCTIVE HEALTH. IT IS WELL ESTABLISHED THAT THERE IS A HERITABLE ELEMENT OF SUSCEPTIBILITY TO CHRONIC HUMAN AILMENTS, YET THERE IS COMPELLING EVIDENCE THAT SOME COMPONENTS OF SUCH HERITABILITY ARE TRANSMITTED THROUGH NON-GENETIC FACTORS. DUE TO THE COMPLEXITY OF REPRODUCTIVE PROCESSES, IDENTIFYING THE INHERITANCE PATTERNS OF THESE FACTORS IS NOT EASY. BUT LITTLE DOUBT EXISTS THAT BESIDES THE GENOMIC BACKBONE, A RANGE OF EPIGENETIC CUES AFFECT OUR GENETIC PROGRAMME. THE INTER-GENERATIONAL TRANSMISSION OF EPIGENETIC MARKS IS BELIEVED TO OPERATE VIA FOUR PRINCIPAL MEANS THAT DRAMATICALLY DIFFER IN THEIR INFORMATION CONTENT: DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS AND NUCLEOSOME POSITIONING. THESE EPIGENETIC SIGNATURES INFLUENCE THE CELLULAR MACHINERY THROUGH POSITIVE AND NEGATIVE FEEDBACK MECHANISMS EITHER ALONE OR INTERACTIVELY. UNDERSTANDING HOW THESE MECHANISMS WORK TO ACTIVATE OR DEACTIVATE PARTS OF OUR GENETIC PROGRAMME NOT ONLY ON A DAY-TO-DAY BASIS BUT ALSO OVER GENERATIONS IS AN IMPORTANT AREA OF REPRODUCTIVE HEALTH RESEARCH. 2016 11 2914 52 GENE REGULATORY NETWORK UNDERLYING THE IMMORTALIZATION OF EPITHELIAL CELLS. BACKGROUND: TUMORIGENIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS IN VITRO HAS BEEN DESCRIBED EXPERIMENTALLY AS THE POTENTIAL RESULT OF SPONTANEOUS IMMORTALIZATION. THIS PROCESS IS CHARACTERIZED BY A SERIES OF CELL-STATE TRANSITIONS, IN WHICH NORMAL EPITHELIAL CELLS ACQUIRE FIRST A SENESCENT STATE WHICH IS LATER SURPASSED TO ATTAIN A MESENCHYMAL STEM-LIKE PHENOTYPE WITH A POTENTIALLY TUMORIGENIC BEHAVIOR. IN THIS PAPER WE AIM TO PROVIDE A SYSTEM-LEVEL MECHANISTIC EXPLANATION TO THE EMERGENCE OF THESE CELL TYPES, AND TO THE TIME-ORDERED TRANSITION PATTERNS THAT ARE COMMON TO NEOPLASIAS OF EPITHELIAL ORIGIN. TO THIS END, WE FIRST INTEGRATE PUBLISHED FUNCTIONAL AND WELL-CURATED MOLECULAR DATA OF THE COMPONENTS AND INTERACTIONS THAT HAVE BEEN FOUND TO BE INVOLVED IN SUCH CELL STATES AND TRANSITIONS INTO A NETWORK OF 41 MOLECULAR COMPONENTS. WE THEN REDUCE THIS INITIAL NETWORK BY REMOVING SIMPLE MEDIATORS (I.E., LINEAR PATHWAYS), AND FORMALIZE THE RESULTING REGULATORY CORE INTO LOGICAL RULES THAT GOVERN THE DYNAMICS OF EACH OF THE NETWORK COMPONENTS AS A FUNCTION OF THE STATES OF ITS REGULATORS. RESULTS: COMPUTATIONAL DYNAMIC ANALYSIS SHOWS THAT OUR PROPOSED GENE REGULATORY NETWORK MODEL RECOVERS EXACTLY THREE ATTRACTORS, EACH OF THEM DEFINED BY A SPECIFIC GENE EXPRESSION PROFILE THAT CORRESPONDS TO THE EPITHELIAL, SENESCENT, AND MESENCHYMAL STEM-LIKE CELLULAR PHENOTYPES, RESPECTIVELY. WE SHOW THAT ALTHOUGH A MESENCHYMAL STEM-LIKE STATE CAN BE ATTAINED EVEN UNDER UNPERTURBED PHYSIOLOGICAL CONDITIONS, THE LIKELIHOOD OF CONVERGING TO THIS STATE IS INCREASED WHEN PRO-INFLAMMATORY CONDITIONS ARE SIMULATED, PROVIDING A SYSTEMS-LEVEL MECHANISTIC EXPLANATION FOR THE CARCINOGENIC ROLE OF CHRONIC INFLAMMATORY CONDITIONS OBSERVED IN THE CLINIC. WE ALSO FOUND THAT THE REGULATORY CORE YIELDS AN EPIGENETIC LANDSCAPE THAT RESTRICTS TEMPORAL PATTERNS OF PROGRESSION BETWEEN THE STEADY STATES, SUCH THAT RECOVERED PATTERNS RESEMBLE THE TIME-ORDERED TRANSITIONS OBSERVED DURING THE SPONTANEOUS IMMORTALIZATION OF EPITHELIAL CELLS, BOTH IN VIVO AND IN VITRO. CONCLUSION: OUR STUDY STRONGLY SUGGESTS THAT THE IN VITRO TUMORIGENIC TRANSFORMATION OF EPITHELIAL CELLS, WHICH STRONGLY CORRELATES WITH THE PATTERNS OBSERVED DURING THE PATHOLOGICAL PROGRESSION OF EPITHELIAL CARCINOGENESIS IN VIVO, EMERGES FROM UNDERLYING REGULATORY NETWORKS INVOLVED IN EPITHELIAL TRANS-DIFFERENTIATION DURING DEVELOPMENT. 2017 12 925 37 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 13 737 59 CANCER STEM CELLS. THERE IS AN INCREASING EVIDENCE SUPPORTING THE CANCER STEM CELL HYPOTHESIS. NORMAL STEM CELLS IN THE ADULT ORGANISM ARE RESPONSIBLE FOR TISSUE RENEWAL AND REPAIR OF AGED OR DAMAGED TISSUE. A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS IS THEIR ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. THE STEM CELLS ARE IMMORTAL, AND RATHER RESISTANT TO ACTION OF DRUGS. THEY ARE ABLE TO DIFFERENTIATE AND FORM SPECIFIC TYPES OF TISSUE DUE TO THE INFLUENCE OF MICROENVIRONMENTAL AND SOME OTHER FACTORS. STEM CELLS DIVIDE ASYMMETRICALLY PRODUCING TWO DAUGHTER CELLS -- ONE IS A NEW STEM CELL AND THE SECOND IS PROGENITOR CELL, WHICH HAS THE ABILITY FOR DIFFERENTIATION AND PROLIFERATION, BUT NOT THE CAPABILITY FOR SELF-RENEWAL. CANCER STEM CELLS ARE IN MANY ASPECTS SIMILAR TO THE STEM CELLS. IT HAS BEEN PROVEN THAT TUMOR CELLS ARE HETEROGENEOUS COMPRISING RARE TUMOR INITIATING CELLS AND ABUNDANT NON-TUMOR INITIATING CELLS. TUMOR INITIATING CELLS -- CANCER STEM CELLS HAVE THE ABILITY OF SELF-RENEWAL AND PROLIFERATION, ARE RESISTANT TO DRUGS, AND EXPRESS TYPICAL MARKERS OF STEM CELLS. IT IS NOT CLEAR WHETHER CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR BY REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS. PROBABLY BOTH MECHANISMS ARE INVOLVED IN THE ORIGIN OF CANCER STEM CELLS. DYSREGULATION OF STEM CELL SELF-RENEWAL IS A LIKELY REQUIREMENT FOR THE DEVELOPMENT OF CANCER. ISOLATION AND IDENTIFICATION OF CANCER STEM CELLS IN HUMAN TUMORS AND IN TUMOR CELL LINES HAS BEEN SUCCESSFUL. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. CANCER STEM CELL MODEL IS ALSO CONSISTENT WITH SOME CLINICAL OBSERVATIONS. ALTHOUGH STANDARD CHEMOTHERAPY KILLS MOST CELLS IN A TUMOR, CANCER STEM CELLS REMAIN VIABLE. DESPITE THE SMALL NUMBER OF SUCH CELLS, THEY MIGHT BE THE CAUSE OF TUMOR RECURRENCE, SOMETIMES MANY YEARS AFTER THE "SUCCESSFUL" TREATMENT OF PRIMARY TUMOR. GROWTH OF METASTASES IN DISTINCT AREAS OF BODY AND THEIR CELLULAR HETEROGENEITY MIGHT BE CONSEQUENCE OF CANCER STEM CELL DIFFERENTIATION AND/OR DEDIFFERENTIATION AND ASYMMETRIC DIVISION OF CANCER STEM CELLS. FURTHER CHARACTERIZATION OF CANCER STEM CELLS IS NEEDED IN ORDER TO FIND WAYS TO DESTROY THEM, WHICH MIGHT CONTRIBUTE SIGNIFICANTLY TO THE THERAPEUTIC MANAGEMENT OF MALIGNANT TUMORS. 2005 14 6142 51 THE EVALUATION OF CYTOKINES TO HELP ESTABLISH DIAGNOSIS AND GUIDE TREATMENT OF AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES. OUR KNOWLEDGE OF THE ROLE OF CYTOKINES IN PATHOLOGIC CONDITIONS HAS INCREASED CONSIDERABLY WITH THE EMERGENCE OF MOLECULAR AND GENETIC STUDIES, PARTICULARLY IN THE CASE OF AUTOINFLAMMATORY MONOGENIC DISEASES. MANY RARE DISORDERS, CONSIDERED ORPHAN UNTIL RECENTLY, ARE DIRECTLY RELATED TO ABNORMAL GENE REGULATION, AND THE TREATMENT WITH BIOLOGIC AGENTS (BIOLOGICS) TARGETING CYTOKINE RECEPTORS, INTRACELLULAR SIGNALING OR SPECIFIC CYTOKINES IMPROVE THE SYMPTOMS OF AN INCREASING NUMBER OF CHRONIC INFLAMMATORY DISEASES. AS IT IS CURRENTLY IMPOSSIBLE TO SYSTEMATICALLY CONDUCT GENETIC STUDIES FOR ALL PATIENTS WITH AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, THE EVALUATION OF CYTOKINES CAN BE SEEN AS A SIMPLE, LESS TIME CONSUMING, AND LESS EXPENSIVE ALTERNATIVE. THIS APPROACH COULD BE ESPECIALLY USEFUL WHEN THE DIAGNOSIS OF SYNDROMES OF DISEASES OF UNKNOWN ETIOLOGY REMAINS PROBLEMATIC. THE EVALUATION OF CYTOKINES COULD ALSO HELP AVOID THE CURRENT TRIAL-AND-ERROR APPROACH, WHICH HAS THE DISADVANTAGES OF EXPOSING PATIENTS TO INEFFECTIVE DRUGS WITH POSSIBLE UNNECESSARY SIDE EFFECTS AND PERMANENT ORGAN DAMAGES. IN THIS REVIEW, WE DISCUSS THE VARIOUS POSSIBILITIES, AS WELL AS THE LIMITATIONS OF EVALUATING THE CYTOKINE PROFILES OF PATIENTS SUFFERING FROM AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, WITH METHODS SUCH AS DIRECT DETECTION OF CYTOKINES IN THE PLASMA/SERUM OR FOLLOWING EX VIVO STIMULATION OF PBMCS LEADING TO THE PRODUCTION OF THEIR CYTOKINE SECRETOME. THE PATIENTS' SECRETOME, COMBINED WITH BIOMARKERS RANGING FROM GENETIC AND EPIGENETIC ANALYSES TO IMMUNOLOGIC BIOMARKERS, MAY HELP NOT ONLY THE DIAGNOSIS BUT ALSO GUIDE THE CHOICE OF BIOLOGICS FOR MORE EFFICIENT AND RAPID TREATMENTS. 2020 15 1006 45 CHRONIC VIRAL INFECTION AND PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCY. PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS CAUSE SIGNIFICANT MORBIDITY AND MORTALITY IN BOTH ADULTS AND CHILDREN. WHILE SOME OF THE GENETIC AND MOLECULAR MECHANISMS OF NEURO-ONCOGENESIS ARE KNOWN, MUCH LESS IS KNOWN ABOUT POSSIBLE EPIGENETIC CONTRIBUTIONS TO DISEASE PATHOPHYSIOLOGY. OVER THE LAST SEVERAL DECADES, CHRONIC VIRAL INFECTIONS HAVE BEEN ASSOCIATED WITH A NUMBER OF HUMAN MALIGNANCIES. IN PRIMARY CNS MALIGNANCIES, TWO FAMILIES OF VIRUSES, NAMELY POLYOMAVIRUS AND HERPESVIRUS, HAVE BEEN DETECTED WITH VARIED FREQUENCIES IN A NUMBER OF PEDIATRIC AND ADULT HISTOLOGICAL TUMOR SUBTYPES. HOWEVER, ESTABLISHING A LINK BETWEEN CHRONIC VIRAL INFECTION AND PRIMARY CNS MALIGNANCY HAS BEEN AN AREA OF CONSIDERABLE CONTROVERSY, DUE IN PART TO VARIATIONS IN DETECTION FREQUENCIES AND METHODOLOGIES USED AMONG RESEARCHERS. SINCE A LATENT VIRAL NEUROTROPISM CAN BE SEEN WITH A VARIETY OF VIRUSES AND A WIDESPREAD SEROPOSITIVITY EXISTS AMONG THE POPULATION, IT HAS BEEN DIFFICULT TO ESTABLISH AN ASSOCIATION BETWEEN VIRAL INFECTION AND CNS MALIGNANCY BASED ON EPIDEMIOLOGY ALONE. WHILE DIRECT EVIDENCE OF A ROLE OF VIRUSES IN NEURO-ONCOGENESIS IN HUMANS IS LACKING, A MORE PLAUSIBLE HYPOTHESIS OF NEURO-ONCOMODULATION HAS BEEN PROPOSED. THE OVERALL GOALS OF THIS REVIEW ARE TO SUMMARIZE THE MANY HUMAN INVESTIGATIONS THAT HAVE STUDIED VIRAL INFECTION IN PRIMARY CNS TUMORS, DISCUSS POTENTIAL NEURO-ONCOMODULATORY MECHANISMS OF VIRAL-ASSOCIATED CNS DISEASE AND PROPOSE FUTURE RESEARCH DIRECTIONS TO ESTABLISH A MORE FIRM ASSOCIATION BETWEEN CHRONIC VIRAL INFECTIONS AND PRIMARY CNS MALIGNANCIES. 2010 16 6054 44 THE CURRENT STATE AND FUTURE OF T-CELL EXHAUSTION RESEARCH. 'EXHAUSTION' IS A TERM USED TO DESCRIBE A STATE OF NATIVE AND REDIRECTED T-CELL HYPO-RESPONSIVENESS RESULTING FROM PERSISTENT ANTIGEN EXPOSURE DURING CHRONIC VIRAL INFECTIONS OR CANCER. ALTHOUGH A WELL-ESTABLISHED PHENOTYPE ACROSS MICE AND HUMANS, EXHAUSTION AT THE MOLECULAR LEVEL REMAINS POORLY DEFINED AND INCONSISTENT ACROSS THE LITERATURE. THIS IS, IN PART, DUE TO AN OVERRELIANCE ON SURFACE RECEPTORS TO DEFINE THESE CELLS AND EXPLAIN EXHAUSTIVE BEHAVIOURS, AN INCOMPLETE UNDERSTANDING OF HOW EXHAUSTION ARISES, AND A LACK OF CLARITY OVER WHETHER EXHAUSTION IS THE SAME ACROSS CONTEXTS, E.G. CHRONIC VIRAL INFECTIONS VERSUS CANCER. WITH THE DEVELOPMENT OF SYSTEMS-BASED GENETIC APPROACHES SUCH AS SINGLE-CELL RNA-SEQ AND CRISPR SCREENS APPLIED TO IN VIVO DATA, WE ARE MOVING CLOSER TO A CONSENSUS VIEW OF EXHAUSTION, ALTHOUGH UNDERSTANDING HOW IT ARISES REMAINS CHALLENGING GIVEN THE DIFFICULTY IN MANIPULATING THE IN VIVO SETTING. ACCORDINGLY, PRODUCING AND STUDYING EXHAUSTED T-CELLS EX VIVO ARE BURGEONING, ALLOWING EXPERIMENTS TO BE CONDUCTED AT SCALE UP AND WITH HIGH THROUGHPUT. HERE, WE FIRST REVIEW WHAT IS CURRENTLY KNOWN ABOUT T-CELL EXHAUSTION AND HOW IT'S BEING STUDIED. WE THEN DISCUSS HOW IMPROVEMENTS IN THEIR METHOD OF ISOLATION/PRODUCTION AND EXAMINING THE IMPACT OF DIFFERENT MICROENVIRONMENTAL SIGNALS AND CELL INTERACTIONS HAVE NOW BECOME AN ACTIVE AREA OF RESEARCH. FINALLY, WE DISCUSS WHAT THE FUTURE HOLDS FOR THE ANALYSIS OF THIS PHYSIOLOGICAL CONDITION AND, GIVEN THE DIVERSITY OF WAYS IN WHICH EXHAUSTED CELLS ARE NOW BEING GENERATED, PROPOSE THE ADOPTION OF A UNIFIED APPROACH TO CLEARLY DEFINING EXHAUSTION USING A SET OF METABOLIC-, EPIGENETIC-, TRANSCRIPTIONAL-, AND ACTIVATION-BASED PHENOTYPIC MARKERS, THAT WE CALL 'M.E.T.A'. 2023 17 1844 55 EFFECTS OF THE LIFESTYLE HABITS IN BREAST CANCER TRANSCRIPTIONAL REGULATION. THROUGH RESEARCH CARRIED OUT IN THE LAST 25 YEARS ABOUT THE BREAST CANCER ETIOLOGY, IT HAS BEEN POSSIBLE TO ESTIMATE THAT LESS THAN 10 % OF PATIENTS WHO ARE DIAGNOSED WITH THE CONDITION ARE CARRIERS OF SOME GERMLINE OR SOMATIC MUTATION. THE CLINICAL REPORTS OF BREAST CANCER PATIENTS WITH HEALTHY TWINS AND THE DEVELOPMENT OF DISEASE IN WOMEN WITHOUT HIGH PENETRANCE MUTATIONS DETECTED, WARN THE PARTICIPATION MORE FACTORS IN THE TRANSFORMATION PROCESS. THE HIGH INCIDENCE OF MAMMARY ADENOCARCINOMA IN THE MODERN WOMAN AND THE URGENT NEED FOR NEW METHODS OF PREVENTION AND EARLY DETECTION HAVE DEMANDED MORE INFORMATION ABOUT THE ROLE THAT ENVIRONMENT AND LIFESTYLE HAVE ON THE TRANSFORMATION OF MAMMARY GLAND EPITHELIAL CELLS. OBESITY, ALCOHOLISM AND SMOKING ARE FACTORS THAT HAVE SHOWN A CLOSE CORRELATION WITH THE RISK OF DEVELOPING BREAST CANCER. AND ALTHOUGH THESE CONDITIONS AFFECT DIFFERENT CELL REGULATION LEVELS, THE STUDY OF ITS EFFECTS IN THE MECHANISMS OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION IS CONSIDERED CRITICAL FOR A BETTER UNDERSTANDING OF THE LOSS OF IDENTITY OF EPITHELIAL CELLS DURING CARCINOGENESIS OF THIS TISSUE. THE MAIN OBJECTIVE OF THIS REVIEW WAS TO ESTABLISH THE IMPORTANCE OF CHANGES OCCURRING TO TRANSCRIPTIONAL LEVEL IN THE MAMMARY GLAND AS A CONSEQUENCE OF ACUTE OR CHRONIC EXPOSURE TO HARMFUL PRODUCTS SUCH AS OBESITY-CAUSING FOODS, ETHANOL AND CIGARETTE SMOKE COMPONENTS. AT ANALYZE THE MAIN STUDIES RELATED TO TOPIC, IT HAS CONCLUDED THAT THE UNDERSTANDING OF EFFECTS CAUSED BY THE LIFESTYLE FACTORS IN PERFORMANCE OF THE TRANSCRIPTIONAL MECHANISMS THAT DETERMINE GENE EXPRESSION OF THE MAMMARY GLAND EPITHELIAL CELLS, MAY HELP EXPLAIN THE DEVELOPMENT OF THIS DISEASE IN WOMEN WITHOUT GENETIC PROPENSITY AND DIFFERENT PHENOTYPIC MANIFESTATIONS OF THIS CANCER TYPE. 2016 18 2541 37 EPIGENETICS IN KIDNEY DEVELOPMENT AND RENAL DISEASE. THE STUDY OF EPIGENETICS IS INTIMATELY LINKED AND INSEPARABLE FROM DEVELOPMENTAL BIOLOGY. MANY OF THE GENES THAT IMPRINT EPIGENETIC INFORMATION ON CHROMATIN FUNCTION DURING THE SPECIFICATION OF CELL LINEAGES IN THE DEVELOPING EMBRYO. THESE INCLUDE THE HISTONE METHYLTRANSFERASES AND THEIR COFACTORS OF THE POLYCOMB AND TRITHORAX GENE FAMILIES. HOW HISTONE METHYLATION IS ESTABLISHED AND WHAT REGULATES THE TISSUE AND LOCUS SPECIFICITY OF HISTONE METHYLATION IS AN EMERGING AREA OF RESEARCH. THE EMBRYONIC KIDNEY IS USED AS A MODEL TO UNDERSTAND HOW DNA-BINDING PROTEINS CAN SPECIFY CELL LINEAGES AND HOW SUCH PROTEINS INTERACT DIRECTLY WITH THE HISTONE METHYLATION MACHINERY TO GENERATE A UNIQUE EPIGENOME FOR PARTICULAR TISSUES AND CELL TYPES. IN ADULT TISSUES, HISTONE METHYLATION MARKS MUST BE MAINTAINED FOR NORMAL GENE EXPRESSION PATTERNS. IN CHRONIC AND ACUTE RENAL DISEASE, EPIGENETIC MARKS ARE BEING CHARACTERIZED AND CORRELATED WITH THE ESTABLISHMENT OF METABOLIC MEMORY, IN PART TO EXPLAIN THE PERSISTENCE OF PATHOLOGIES EVEN WHEN OPTIMAL TREATMENT MODALITIES ARE USED. THUS, THE STATE OF THE EPIGENOME IN ADULT CELLS MUST BE CONSIDERED WHEN ATTEMPTING TO ALLEVIATE OR ALTER GENE EXPRESSION PATTERNS IN DISEASE. 2015 19 1928 54 ENVIRONMENTAL EXPOSURE MEASUREMENT IN CANCER EPIDEMIOLOGY. ENVIRONMENTAL EXPOSURES, USED IN THE BROADEST SENSE OF LIFESTYLE, INFECTIONS, RADIATION, NATURAL AND MAN-MADE CHEMICALS AND OCCUPATION, ARE A MAJOR CAUSE OF HUMAN CANCER. HOWEVER, THE PRECISE CONTRIBUTION OF SPECIFIC RISK FACTORS AND THEIR INTERACTION, BOTH WITH EACH OTHER AND WITH GENOTYPE, CONTINUES TO BE DIFFICULT TO ELUCIDATE. THIS IS PARTIALLY DUE TO LIMITATIONS IN ACCURATELY MEASURING EXPOSURE WITH THE SUBSEQUENT RISK OF MISCLASSIFICATION. ONE OF THE PRIMARY CHALLENGES OF MOLECULAR CANCER EPIDEMIOLOGY THEREFORE IS TO IMPROVE EXPOSURE ASSESSMENT. PROGRESS HAS BEEN MADE WITH BIOMARKERS SUCH AS CARCINOGENS AND THEIR METABOLITES, DNA AND PROTEIN ADDUCTS AND MUTATIONS MEASURED IN VARIOUS TISSUES AND BODY FLUIDS. NEVERTHELESS, MUCH REMAINS TO BE ACCOMPLISHED IN ORDER TO ESTABLISH AETIOLOGY AND PROVIDE THE EVIDENCE BASE FOR PUBLIC HEALTH DECISIONS. THIS REVIEW CONSIDERS SOME OF THE PRINCIPLES BEHIND THE APPLICATION OF EXPOSURE BIOMARKERS IN CANCER EPIDEMIOLOGY. IT ALSO DEMONSTRATES HOW THE SAME BIOMARKERS CAN CONTRIBUTE BOTH TO ESTABLISHING THE BIOLOGICAL PLAUSIBILITY OF ASSOCIATIONS BETWEEN EXPOSURE AND DISEASE AND BE VALUABLE ENDPOINTS IN INTERVENTION STUDIES. THE POTENTIAL OF NEW TECHNOLOGIES SUCH AS TRANSCRIPTOMICS, PROTEOMICS AND METABONOMICS TO PROVIDE A STEP CHANGE IN ENVIRONMENTAL EXPOSURE ASSESSMENT IS DISCUSSED. AN INCREASING RECOGNITION OF THE ROLE OF EPIGENETIC CHANGES IN CARCINOGENESIS PRESENTS A FRESH CHALLENGE AS ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA IN RESPONSE TO ENVIRONMENTAL EXPOSURES DEMAND A NEW GENERATION OF EXPOSURE BIOMARKER. THE OVERALL IMPORTANCE OF THIS AREA OF RESEARCH IS BROUGHT INTO SHARP RELIEF BY THE LARGE PROSPECTIVE COHORT STUDIES (E.G. UK BIOBANK) WHICH NEED ACCURATE EXPOSURE MEASUREMENT IN ORDER TO SHED LIGHT ON THE COMPLEX GENE:ENVIRONMENT INTERACTIONS UNDERLYING COMMON CHRONIC DISORDERS INCLUDING CANCER. IT IS SUGGESTED THAT A CONCERTED EFFORT IS NOW REQUIRED, WITH APPROPRIATE FUNDING, TO DEVELOP AND VALIDATE THE REQUIRED EXPOSURE ASSESSMENT METHODOLOGY BEFORE THESE COHORTS COME TO MATURITY. 2009 20 3803 60 INTESTINAL METAPLASIA OF THE STOMACH. A STATUS REPORT. INTESTINAL METAPLASIA IN THE STOMACH INCREASES THE RISK OF GASTRIC CANCER, AND THE INCREASED RISK IS PROPORTIONAL TO THE EXTENT OF THE METAPLASIA. THIS RISK COULD BE GENERATED BY ONE OR MORE MECHANISMS: (1) THE METAPLASTIC TISSUE IS AN EARLY STEP IN A MULTISTEP INDUCTION PROCESS; (2) THE METAPLASTIC TISSUE IS AN EPIGENETIC CHANGE THAT RAISES THE PH OF GASTRIC JUICE BY REPLACING OXYNTIC MUCOSA, FAVORING THE GROWTH OF A BACTERIA CAPABLE OF GENERATING ENDOGENOUS MUTAGENS; AND/OR (3) THE METAPLASIA IS ONLY A MARKER FOR CHRONIC GASTRITIS DUE TO H. PYLORI INFECTION OR PERNICIOUS ANEMIA. WITH THE LAST MECHANISM, THE INFLAMMATORY RESPONSE FAVORS INTRAMURAL MUTAGENESIS THAT MIGHT RESULT IN METAPLASIA OR NEOPLASIA AS INDEPENDENT EVENTS. FINDING GENE REARRANGEMENTS COMMON TO BOTH METAPLASTIC AND NEOPLASTIC TISSUE MAY ESTABLISH A DIRECT LINK BETWEEN THEM, BUT TOO FEW HAVE BEEN IDENTIFIED TO ACCOUNT FOR THE LARGE NUMBER OF STOMACH CANCERS THAT DEVELOP IN HIGH RISK POPULATIONS. HISTOCHEMICAL AND IMMUNOCHEMICAL STAINS THAT IDENTIFY ENZYMES OR MUCOSUBSTANCES MAY SUGGEST THAT METAPLASTIC EPITHELIAL CELLS RESEMBLE SMALL OR LARGE INTESTINAL CELLS, BUT THEY ARE DISTINCTLY DIFFERENT FROM BOTH. MOREOVER, THESE STAINS DO NOT INDICATE WHETHER A GIVEN CYTOLOGIC CHANGE IS GENETIC OR EPIGENETIC; THEREFORE, THEY CANNOT BE USED TO DEFINE THE RELATIONSHIP BETWEEN METAPLASIA AND NEOPLASIA. IT IS UNNECESSARY FOR PRACTICING PHYSICIANS TO AWAIT RESOLUTION OF THIS QUESTION. IT CAN BE ASSUMED THAT ANY PERSON WITH EXTENSIVE METAPLASIA IS AT HIGH RISK FOR GASTRIC CANCER AND SHOULD BE SUBJECT TO PERIODIC SCREENING. THE EXTENT OF THE METAPLASTIC PROCESS IS PROBABLY MORE IMPORTANT THAN THE METAPLASTIC SUBTYPE. 1994