1 5341 118 RADIATION-HORMESIS PHENOTYPES, THE RELATED MECHANISMS AND IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY. HUMANS ARE CONTINUOUSLY EXPOSED TO IONIZING RADIATION THROUGHOUT LIFE FROM NATURAL SOURCES THAT INCLUDE COSMIC, SOLAR, AND TERRESTRIAL. MUCH HARSHER NATURAL RADIATION AND CHEMICAL ENVIRONMENTS EXISTED DURING OUR PLANET'S EARLY YEARS. MAMMALS SURVIVED THE HARSHER ENVIRONMENTS VIA EVOLUTIONARILY-CONSERVED GIFTS ? A CONTINUOUSLY EVOLVING SYSTEM OF STRESS-INDUCED NATURAL PROTECTIVE MEASURES (I.E., ACTIVATED NATURAL PROTECTION [ANP]). THE CURRENT PROTECTIVE SYSTEM IS DIFFERENTIALLY ACTIVATED BY STOCHASTIC (I.E., VARIABLE) LOW-RADIATION-DOSE THRESHOLDS AND WHEN OPTIMALLY ACTIVATED IN MAMMALS INCLUDES ANTIOXIDANTS, DNA DAMAGE REPAIR, P53-RELATED APOPTOSIS OF SEVERELY-DAMAGED CELLS, REACTIVE-OXYGEN-SPECIES (ROS)/REACTIVE-NITROGEN-SPECIES (RNS)- AND CYTOKINE-REGULATED AUXILIARY APOPTOSIS THAT SELECTIVELY REMOVES ABERRANT CELLS (E.G., PRECANCEROUS CELLS), SUPPRESSION OF DISEASE PROMOTING INFLAMMATION, AND IMMUNITY AGAINST CANCER CELLS. THE INTERCELLULAR-SIGNALING-BASED PROTECTIVE SYSTEM IS REGULATED AT LEAST IN PART VIA EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES. WHEN THE SYSTEM IS OPTIMALLY ACTIVATED, IT PROTECTS AGAINST CANCER AND SOME OTHER DISEASES, THEREBY LEADING TO HORMETIC PHENOTYPES (E.G., REDUCED DISEASE INCIDENCE TO BELOW THE BASELINE LEVEL; REDUCED PAIN FROM INFLAMMATION-RELATED PROBLEMS). HERE, SOME EXPRESSED RADIATION HORMESIS PHENOTYPES AND RELATED MECHANISMS ARE DISCUSSED ALONG WITH THEIR IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY. 2014 2 5343 61 RADIATION-STIMULATED EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES IN THE LUNG: AN EVOLUTIONARY GIFT FOR MOUNTING ADAPTIVE PROTECTION AGAINST LUNG CANCER. HUMANS ARE CONTINUOUSLY EXPOSED TO LOW-LEVEL IONIZING RADIATION FROM NATURAL SOURCES. HOWEVER, HARSHER RADIATION ENVIRONMENTS PERSISTED DURING OUR PLANET'S EARLY YEARS AND MAMMALS SURVIVED VIA AN EVOLUTIONARY GIFT--A SYSTEM OF RADIATION-INDUCED NATURAL PROTECTIVE MEASURES (ADAPTIVE PROTECTION). THIS SYSTEM INCLUDES ANTIOXIDANTS, DNA REPAIR, APOPTOSIS OF SEVERELY DAMAGED CELLS, EPIGENETICALLY REGULATED APOPTOSIS (EPIAPOPTOSIS) PATHWAYS THAT SELECTIVELY REMOVE PRECANCEROUS AND OTHER ABERRANT CELLS, AND IMMUNITY AGAINST CANCER. WE PROPOSE A NOVEL MODEL IN WHICH THE PROTECTIVE SYSTEM IS REGULATED AT LEAST IN PART VIA RADIATION-STRESS-STIMULATED EPIGENETIC REPROGRAMMING (EPIREPROGRAMMING) OF ADAPTIVE-RESPONSE GENES. HIGH-DOSE RADIATION CAN PROMOTE EPIGENETICALLY SILENCING OF ADAPTIVE-RESPONSE GENES (EPISILENCING), FOR EXAMPLE VIA PROMOTER-ASSOCIATED DNA AND/OR HISTONE METHYLATION AND/OR HISTONE DEACETYLATION. EVIDENCE IS PROVIDED FOR LOW LINEAR-ENERGY-TRANSFER (LET) RADIATION-ACTIVATED NATURAL PROTECTION (ANP) AGAINST HIGH-LET ALPHA-RADIATION-INDUCED LUNG CANCER IN PLUTONIUM-239 EXPOSED RATS AND RADON-PROGENY-EXPOSED HUMANS. USING A REVISED HORMETIC RELATIVE RISK MODEL FOR CANCER INDUCTION THAT ACCOUNTS FOR BOTH EPIGENETIC ACTIVATION (EPIACTIVATION) AND EPISILENCING OF GENES, WE DEMONSTRATE THAT, ON AVERAGE, >80% OF ALPHA-RADIATION-INDUCED RAT LUNG CANCERS WERE PREVENTED BY CHRONIC, LOW-RATE GAMMA-RAY ANP. INTERESTINGLY, LIFETIME EXPOSURE TO RESIDENTIAL RADON AT THE ENVIRONMENTAL PROTECTION AGENCY'S ACTION LEVEL OF 4 PCI L(-1) APPEARS TO BE ASSOCIATED WITH ON AVERAGE A > 60% REDUCTION IN LUNG CANCER CASES, RATHER THAN AN INCREASE. WE HAVE USED UNDERLINED ITALICS TO INDICATE NEWLY INTRODUCED TERMINOLOGY. 2009 3 4018 33 LOW-DOSE IONIZING RADIATION: INDUCTION OF DIFFERENTIAL INTRACELLULAR SIGNALLING POSSIBLY AFFECTING INTERCELLULAR COMMUNICATION. GIVEN THE COMPLEXITY OF THE CARCINOGENIC PROCESS AND THE LACK OF ANY MECHANISTIC UNDERSTANDING OF HOW IONIZING RADIATION AT LOW-LEVEL EXPOSURES AFFECTS THE MULTISTAGE, MULTIMECHANISM PROCESSES OF CARCINOGENESIS, IT IS IMPERATIVE THAT CONCEPTS AND PARADIGMS BE REEXAMINED WHEN EXTRAPOLATING FROM HIGH DOSE TO LOW DOSE. ANY HEALTH EFFECT DIRECTLY LINKED TO LOW-DOSE RADIATION EXPOSURE MUST HAVE MOLECULAR/BIOCHEMICAL AND BIOLOGICAL BASES. ON THE OTHER HAND, DEMONSTRATING SOME MOLECULAR/BIOCHEMICAL OR CELLULAR EFFECT, USING SURROGATE SYSTEMS FOR THE HUMAN BEING, DOES NOT NECESSARILY IMPLY A CORRESPONDING HEALTH EFFECT. GIVEN THE GENERAL ACCEPTANCE OF AN EXTRAPOLATED LNT MODEL, OUR CURRENT UNDERSTANDING OF CARCINOGENESIS CRIES OUT FOR A RESOLUTION OF A REAL PROBLEM. HOW CAN A LOW-LEVEL ACUTE, OR EVEN A CHRONIC, EXPOSURE OF IONIZING RADIATION BRING ABOUT ALL THE DIFFERENT MECHANISMS (MUTAGENIC, CYTOTOXIC, AND EPIGENETIC) AND GENOTYPIC/PHENOTYPIC CHANGES NEEDED TO CONVERT NORMAL CELLS TO AN INVASIVE, MALIGNANT CELL, GIVEN ALL THE PROTECTIVE, REPAIR, AND SUPPRESSIVE SYSTEMS KNOWN TO EXIST IN THE HUMAN BODY? UNTIL RECENTLY, THE PREVAILING PARADIGM THAT IONIZING RADIATION BRINGS ABOUT CANCER PRIMARILY BY DNA DAMAGE AND ITS CONVERSION TO GENE AND CHROMOSOMAL MUTATIONS, DROVE OUR INTERPRETATION OF RADIATION CARCINOGENESIS. TODAY, OUR KNOWLEDGE INCLUDES THE FACTS BOTH THAT EPIGENETIC EVENTS PLAY A MAJOR ROLE IN CARCINOGENESIS AND THAT LOW-DOSE RADIATION CAN ALSO INDUCE EPIGENETIC EVENTS IN AND BETWEEN CELLS IN TISSUES. THIS CHALLENGES ANY SIMPLE EXTRAPOLATION OF THE LNT MODEL. ALTHOUGH A RECENT DELINEATION OF "HALLMARKS" OF THE CANCER PROCESS HAS HELPED TO FOCUS ON HOW IONIZING RADIATION MIGHT CONTRIBUTE TO THE INDUCTION OF CANCERS, SEVERAL OTHER HALLMARKS, PREVIOUSLY IGNORED--NAMELY, THE STEM CELLS IN TISSUES AS TARGETS FOR CARCINOGENESIS AND THE ROLE OF CELL-CELL COMMUNICATION PROCESSES IN MODULATING THE RADIATION EFFECTS ON THE TARGET CELL--MUST BE CONSIDERED, PARTICULARLY FOR THE ADAPTIVE RESPONSE, BYSTANDER EFFECTS, AND GENOMIC INSTABILITY PHENOMENA. 2005 4 3418 23 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 5 5879 22 SYNTHETIC MITOCHONDRIA AS THERAPEUTICS AGAINST SYSTEMIC AGING: A HYPOTHESIS. WE HYPOTHESIZE HEREIN THAT SYNTHETIC MITOCHONDRIA, ENGINEERED, OR REPROGRAMMED TO BE MORE ENERGETICALLY EFFICIENT AND TO HAVE MILDLY ELEVATED LEVELS OF REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, WOULD BE AN EFFECTIVE FORM OF THERAPEUTICS AGAINST SYSTEMIC AGING. THE FREE RADICAL AND MITOCHONDRIA THEORIES OF AGING HOLD THAT MITOCHONDRIA-GENERATED ROS UNDERLIES CHRONIC ORGANELLE, CELL AND TISSUES DAMAGES THAT CONTRIBUTE TO SYSTEMIC AGING. MORE RECENT FINDINGS, HOWEVER, COLLECTIVELY SUGGEST THAT WHILE ACUTE AND MASSIVE ROS GENERATION DURING EVENTS SUCH AS TISSUE INJURY IS INDEED DETRIMENTAL, SUBACUTE STRESSES, AND CHRONIC ELEVATION IN ROS PRODUCTION MAY INSTEAD INDUCE A STATE OF MITOCHONDRIAL HORMESIS (OR "MITOHORMESIS") THAT COULD EXTEND LIFESPAN. MITOHORMESIS APPEARS TO BE A CONVERGENT MECHANISM FOR SEVERAL KNOWN ANTI-AGING SIGNALING PATHWAYS. IMPORTANTLY, MITOHORMETIC SIGNALING COULD ALSO OCCUR IN A NON-CELL AUTONOMOUS MANNER, WITH ITS INDUCTION IN NEURONS AFFECTING GUT CELLS, FOR EXAMPLE. TECHNOLOGIES ARE OUTLINED THAT COULD LEAD TOWARDS TESTING OF THE HYPOTHESIS, WHICH INCLUDE GENETIC AND EPIGENETIC ENGINEERING OF THE MITOCHONDRIA, AS WELL AS INTERCELLULAR TRANSFER OF MITOCHONDRIA FROM TRANSPLANTED HELPER CELLS TO TARGET TISSUES. 2015 6 266 33 ADVERSE OUTCOME PATHWAYS FOR IONIZING RADIATION AND BREAST CANCER INVOLVE DIRECT AND INDIRECT DNA DAMAGE, OXIDATIVE STRESS, INFLAMMATION, GENOMIC INSTABILITY, AND INTERACTION WITH HORMONAL REGULATION OF THE BREAST. KNOWLEDGE ABOUT ESTABLISHED BREAST CARCINOGENS CAN SUPPORT IMPROVED AND MODERNIZED TOXICOLOGICAL TESTING METHODS BY IDENTIFYING KEY MECHANISTIC EVENTS. IONIZING RADIATION (IR) INCREASES THE RISK OF BREAST CANCER, ESPECIALLY FOR WOMEN AND FOR EXPOSURE AT YOUNGER AGES, AND EVIDENCE OVERALL SUPPORTS A LINEAR DOSE-RESPONSE RELATIONSHIP. WE USED THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK TO OUTLINE AND EVALUATE THE EVIDENCE LINKING IONIZING RADIATION WITH BREAST CANCER FROM MOLECULAR INITIATING EVENTS TO THE ADVERSE OUTCOME THROUGH INTERMEDIATE KEY EVENTS, CREATING A QUALITATIVE AOP. WE IDENTIFIED KEY EVENTS BASED ON REVIEW ARTICLES, SEARCHED PUBMED FOR RECENT LITERATURE ON KEY EVENTS AND IR, AND IDENTIFIED ADDITIONAL PAPERS USING REFERENCES. WE MANUALLY CURATED PUBLICATIONS AND EVALUATED DATA QUALITY. IONIZING RADIATION DIRECTLY AND INDIRECTLY CAUSES DNA DAMAGE AND INCREASES PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES (RONS). RONS LEAD TO DNA DAMAGE AND EPIGENETIC CHANGES LEADING TO MUTATIONS AND GENOMIC INSTABILITY (GI). PROLIFERATION AMPLIFIES THE EFFECTS OF DNA DAMAGE AND MUTATIONS LEADING TO THE AO OF BREAST CANCER. SEPARATELY, RONS AND DNA DAMAGE ALSO INCREASE INFLAMMATION. INFLAMMATION CONTRIBUTES TO DIRECT AND INDIRECT EFFECTS (EFFECTS IN CELLS NOT DIRECTLY REACHED BY IR) VIA POSITIVE FEEDBACK TO RONS AND DNA DAMAGE, AND SEPARATELY INCREASES PROLIFERATION AND BREAST CANCER THROUGH PRO-CARCINOGENIC EFFECTS ON CELLS AND TISSUE. FOR EXAMPLE, GENE EXPRESSION CHANGES ALTER INFLAMMATORY MEDIATORS, RESULTING IN IMPROVED SURVIVAL AND GROWTH OF CANCER CELLS AND A MORE HOSPITABLE TISSUE ENVIRONMENT. ALL OF THESE EVENTS OVERLAP AT MULTIPLE POINTS WITH EVENTS CHARACTERISTIC OF "BACKGROUND" INDUCTION OF BREAST CARCINOGENESIS, INCLUDING HORMONE-RESPONSIVE PROLIFERATION, OXIDATIVE ACTIVITY, AND DNA DAMAGE. THESE OVERLAPS MAKE THE BREAST PARTICULARLY SUSCEPTIBLE TO IONIZING RADIATION AND REINFORCE THAT THESE BIOLOGICAL ACTIVITIES ARE IMPORTANT CHARACTERISTICS OF CARCINOGENS. AGENTS THAT INCREASE THESE BIOLOGICAL PROCESSES SHOULD BE CONSIDERED POTENTIAL BREAST CARCINOGENS, AND PREDICTIVE METHODS ARE NEEDED TO IDENTIFY CHEMICALS THAT INCREASE THESE PROCESSES. TECHNIQUES ARE AVAILABLE TO MEASURE RONS, DNA DAMAGE AND MUTATION, CELL PROLIFERATION, AND SOME INFLAMMATORY PROTEINS OR PROCESSES. IMPROVED ASSAYS ARE NEEDED TO MEASURE GI AND CHRONIC INFLAMMATION, AS WELL AS THE INTERACTION WITH HORMONALLY DRIVEN DEVELOPMENT AND PROLIFERATION. SEVERAL METHODS MEASURE DIVERSE EPIGENETIC CHANGES, BUT IT IS NOT CLEAR WHICH CHANGES ARE RELEVANT TO BREAST CANCER. IN ADDITION, MOST TOXICOLOGICAL ASSAYS ARE NOT CONDUCTED IN MAMMARY TISSUE, AND SO IT IS A PRIORITY TO EVALUATE IF RESULTS FROM OTHER TISSUES ARE GENERALIZABLE TO BREAST, OR TO CONDUCT ASSAYS IN BREAST TISSUE. DEVELOPING AND APPLYING THESE ASSAYS TO IDENTIFY EXPOSURES OF CONCERN WILL FACILITATE EFFORTS TO REDUCE SUBSEQUENT BREAST CANCER RISK. 2020 7 389 26 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 8 705 21 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 9 3917 25 LINK BETWEEN CHRONIC INFLAMMATION AND HUMAN PAPILLOMAVIRUS-INDUCED CARCINOGENESIS (REVIEW). INFLAMMATION IS A DEFENSE STRATEGY AGAINST INVADING AGENTS AND HARMFUL MOLECULES THAT IS ACTIVATED IMMEDIATELY FOLLOWING A STIMULUS, AND INVOLVES THE RELEASE OF CYTOKINES AND CHEMOKINES, WHICH ACTIVATE THE INNATE IMMUNE RESPONSE. THESE MEDIATORS ACT TOGETHER TO INCREASE BLOOD FLOW AND VASCULAR PERMEABILITY, FACILITATING RECRUITMENT OF EFFECTOR CELLS TO THE SITE OF INJURY. FOLLOWING RESOLUTION OF THE INJURY AND REMOVAL OF THE STIMULUS, INFLAMMATION IS DISABLED, BUT IF THE STIMULUS PERSISTS, INFLAMMATION BECOMES CHRONIC AND IS STRONGLY ASSOCIATED WITH CANCER. THIS IS LIKELY TO BE DUE TO THE FACT THAT THE INFLAMMATION LEADS TO A WOUND THAT DOES NOT HEAL, REQUIRING A CONSTANT RENEWAL OF CELLS, WHICH INCREASES THE RISK OF NEOPLASTIC TRANSFORMATION. DEBRIS FROM PHAGOCYTOSIS, INCLUDING THE REACTIVE SPECIES OF OXYGEN AND NITROGEN THAT CAUSE DAMAGE TO DNA ALREADY DAMAGED BY THE LEUKOTRIENES AND PROSTAGLANDINS, HAS AN IMPACT ON INFLAMMATION AND VARIOUS CARCINOGENIC ROUTES. THERE IS AN ASSOCIATION BETWEEN CHRONIC INFLAMMATION, PERSISTENT INFECTION AND CANCER, WHERE ONCOGENIC ACTION IS MEDIATED BY AUTOCRINE AND PARACRINE SIGNALS, CAUSING CHANGES IN SOMATIC CELLS UNDER THE INFLUENCE OF THE MICROBIAL GENOME OR OF EPIGENETIC FACTORS. AMONG THE INFECTIOUS AGENTS ASSOCIATED WITH CANCER, CERTAIN GENOTYPES OF HUMAN PAPILLOMAVIRUS (HPV) STAND OUT. HPV IS RESPONSIBLE FOR VIRTUALLY ALL CASES OF CERVICAL CANCER AND A LOWER PROPORTION OF CANCERS OF THE VAGINA, VULVA, ANUS, PENIS AND A NUMBER OF EXTRAGENITAL CANCERS. IN THE PRESENT REVIEW, RECENT ADVANCES IN THE MECHANISMS INVOLVED IN THE INFLAMMATORY RESPONSE ARE PRESENTED WITH THEIR PARTICIPATION IN THE PROCESS OF CARCINOGENESIS, EMPHASIZING THE ROLE OF CHRONIC INFLAMMATION IN THE DEVELOPMENT OF HPV-INDUCED CERVICAL CANCER. 2015 10 49 21 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 11 3287 40 HIERARCHICAL AND CYBERNETIC NATURE OF BIOLOGIC SYSTEMS AND THEIR RELEVANCE TO HOMEOSTATIC ADAPTATION TO LOW-LEVEL EXPOSURES TO OXIDATIVE STRESS-INDUCING AGENTS. DURING EVOLUTION IN AN AEROBIC ENVIRONMENT, MULTICELLULAR ORGANISMS SURVIVED BY ADAPTIVE RESPONSES TO BOTH THE ENDOGENOUS OXIDATIVE METABOLISM IN THE CELLS OF THE ORGANISM AND THE CHEMICALS AND LOW-LEVEL RADIATION TO WHICH THEY HAD BEEN EXPOSED. THE DEFENSE REPERTOIRE EXISTS AT ALL LEVELS OF THE BIOLOGICAL HIERARCHY--FROM THE MOLECULAR AND BIOCHEMICAL LEVEL TO THE CELLULAR AND TISSUE LEVEL TO THE ORGAN AND ORGAN SYSTEM LEVEL. CELLS CONTAIN PREVENTIVE ANTIOXIDANTS TO SUPPRESS OXIDATIVE DAMAGE TO MEMBRANES. CELLS ALSO CONTAIN PROTEINS AND DNA; BUILT-IN REDUNDANCIES FOR DAMAGED MOLECULES AND ORGANELLES; TIGHTLY COUPLED REDOX SYSTEMS; POOLS OF REDUCTANTS; ANTIOXIDANTS; DNA REPAIR MECHANISMS AND SENSITIVE SENSOR MOLECULES SUCH AS NUCLEAR FACTOR KAPPA BETA; AND SIGNAL TRANSDUCTION MECHANISMS AFFECTING BOTH TRANSCRIPTION AND POST-TRANSLATIONAL MODIFICATION OF PROTEINS NEEDED TO COPE WITH OXIDATIVE STRESS. THE BIOLOGIC CONSEQUENCES OF THE LOW-LEVEL RADIATION THAT EXCEEDS THE BACKGROUND LEVEL OF OXIDATIVE DAMAGE COULD BE NECROSIS OR APOPTOSIS, CELL PROLIFERATION, OR CELL DIFFERENTIATION. THESE EFFECTS ARE TRIGGERED BY OXIDATIVE STRESS-INDUCED SIGNAL TRANSDUCTION MECHANISMS--AN EPIGENETIC, NOT GENOTOXIC, PROCESS. IF THE END POINTS OF CELL PROLIFERATION, DIFFERENTIATION, OR CELL DEATH ARE NOT SEEN AT FREQUENCIES ABOVE BACKGROUND LEVELS IN AN ORGANISM, IT IS UNLIKELY THAT LOW-LEVEL RADIATION WOULD PLAY A ROLE IN THE MULTISTEP PROCESSES OF CHRONIC DISEASES SUCH AS CANCER. THE MECHANISM LINKED TO HOMEOSTATIC REGULATION OF PROLIFERATION AND ADAPTIVE FUNCTIONS IN A MULTICELLULAR ORGANISM COULD PROVIDE PROTECTION OF ANY ONE CELL RECEIVING DEPOSITED ENERGY BY THE RADIATION TRACT THROUGH THE SHARING OF REDUCTANTS AND BY TRIGGERING APOPTOSIS OF TARGET STEM CELLS. EXAMPLES OF THE ROLE OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN THE ADAPTIVE RESPONSE OF CELLS AND THE BYSTANDER EFFECT ILLUSTRATE HOW THE INTERACTION OF CELLS CAN MODULATE THE EFFECT OF RADIATION ON THE SINGLE CELL. 1998 12 3801 25 INTERPLAY OF VITAMIN D AND SIRT1 IN TISSUE-SPECIFIC METABOLISM-POTENTIAL ROLES IN PREVENTION AND TREATMENT OF NON-COMMUNICABLE DISEASES INCLUDING CANCER. THE IMPORTANCE OF THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES, INCLUDING OBESITY, METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES, AND CANCER, IS INCREASING AS A REQUIREMENT OF THE AGING POPULATION IN DEVELOPED COUNTRIES AND THE SUSTAINABILITY OF HEALTHCARE. SIMILARLY, THE 2013-2030 ACTION PLAN OF THE WHO FOR THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES SEEKS THESE ACHIEVEMENTS. ADEQUATE LIFESTYLE CHANGES, ALONE OR WITH THE NECESSARY TREATMENTS, COULD REDUCE THE RISK OF MORTALITY OR THE DETERIORATION OF QUALITY OF LIFE. IN OUR RECENT WORK, WE SUMMARIZED THE ROLE OF TWO CENTRAL FACTORS, I.E., APPROPRIATE LEVELS OF VITAMIN D AND SIRT1, WHICH ARE CONNECTED TO ADEQUATE LIFESTYLES WITH BENEFICIAL EFFECTS ON THE PREVENTION AND CONTROL OF NON-COMMUNICABLE DISEASES. BOTH OF THESE FACTORS HAVE RECEIVED INCREASED ATTENTION IN RELATION TO THE COVID-19 PANDEMIC AS THEY BOTH TAKE PART IN REGULATION OF THE MAIN METABOLIC PROCESSES, I.E., LIPID/GLUCOSE/ENERGY HOMEOSTASIS, OXIDATIVE STRESS, REDOX BALANCE, AND CELL FATE, AS WELL AS IN THE HEALTHY REGULATION OF THE IMMUNE SYSTEM. VITAMIN D AND SIRT1 HAVE DIRECT AND INDIRECT INFLUENCE OF THE REGULATION OF TRANSCRIPTION AND EPIGENETIC CHANGES AND ARE RELATED TO CYTOPLASMIC SIGNALING PATHWAYS SUCH AS PLC/DAG/IP3/PKC/MAPK, MEK/ERK, INSULIN/MTOR/CELL GROWTH, PROLIFERATION; LEPTIN/PI3K-AKT-MTORC1, AKT/NFKB/COX-2, NFKB/TNFALPHA, IL-6, IL-8, IL-1BETA, AND AMPK/PGC-1ALPHA/GLUT4, AMONG OTHERS. THROUGH THEIR PROPER REGULATION, THEY MAINTAIN NORMAL BODY WEIGHT, LIPID PROFILE, INSULIN SECRETION AND SENSITIVITY, BALANCE BETWEEN THE PRO- AND ANTI-INFLAMMATORY PROCESSES UNDER NORMAL CONDITIONS AND INFECTIONS, MAINTAIN ENDOTHELIAL HEALTH; BALANCE CELL DIFFERENTIATION, PROLIFERATION, AND FATE; AND BALANCE THE CIRCADIAN RHYTHM OF THE CELLULAR METABOLISM. THE ROLE OF THESE TWO MOLECULES IS INTERCONNECTED IN THE MOLECULAR NETWORK, AND THEY REGULATE EACH OTHER IN SEVERAL LAYERS OF THE HOMEOSTASIS OF ENERGY AND THE CELLULAR METABOLISM. BOTH HAVE A CENTRAL ROLE IN THE MAINTENANCE OF HEALTHY AND BALANCED IMMUNE REGULATION AND REDOX REACTIONS; THEREFORE, THEY COULD CONSTITUTE PROMISING TARGETS EITHER FOR PREVENTION OR AS COMPLEMENTARY THERAPIES TO ACHIEVE A BETTER QUALITY OF LIFE, AT ANY AGE, FOR HEALTHY PEOPLE AND PATIENTS UNDER CHRONIC CONDITIONS. 2023 13 761 27 CATEGORIZING THE CHARACTERISTICS OF HUMAN CARCINOGENS: A NEED FOR SPECIFICITY. THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS RECENTLY PROPOSED EMPLOYING "TEN KEY CHARACTERISTICS OF HUMAN CARCINOGENS" (TKCS) TO DETERMINE THE POTENTIAL OF AGENTS FOR HARMFUL EFFECTS. THE TKCS SEEM LIKELY TO CONFUSE THE UNSATISFACTORY CORRELATION FROM TESTING REGIMES THAT HAVE IGNORED THE DIFFERENCES EVIDENT WHEN CELLULAR CHANGES ARE COMPARED IN SHORT AND LONG-LIVED SPECIES, WITH THEIR VERY DIFFERENT STEM CELL AND SOMATIC CELL PHYLOGENIES. THE PROPOSED CHARACTERISTICS ARE SO BROAD THAT THEIR USE WILL LEAD TO AN INCREASE IN THE CURRENT UNACCEPTABLY HIGH RATE OF FALSE POSITIVES. IT COULD BE AN INFORMATIVE EXPERIMENT TO TAKE WELL-ESTABLISHED APPROVED THERAPEUTICS WITH WELL-KNOWN HUMAN SAFETY PROFILES AND TEST THEM AGAINST THIS NEW TKC PARADIGM. CANCERS ARE INITIATED AND DRIVEN BY HERITABLE AND TRANSIENT CHANGES IN GENE EXPRESSION, EXPAND CLONALLY, AND PROGRESS VIA ADDITIONAL ASSOCIATED ACQUIRED MUTATIONS AND EPIGENETIC ALTERATIONS THAT PROVIDE CELLS WITH AN EVOLUTIONARY ADVANTAGE. THE GENOTOXICITY TESTING PROTOCOLS CURRENTLY EMPLOYED AND REQUIRED BY REGULATION, EMPHASIZE TESTING FOR THE MUTATIONAL POTENTIAL OF THE TEST AGENT. TWO-YEAR, CHRONIC RODENT CANCER BIOASSAYS ARE INTENDED TO TEST FOR THE ENTIRE SPECTRUM OF CARCINOGENIC TRANSFORMATION. THE USE OF CYTOTOXIC DOSES CAUSING INCREASED, SUSTAINED CELL PROLIFERATION THAT FACILITATES ACCUMULATED GENETIC DAMAGE LEADS TO A HIGH FALSE-POSITIVE RATE OF TUMOR INDUCTION. CURRENT CANCER HAZARD ASSESSMENT PROTOCOLS AND WEIGHT-OF-THE-EVIDENCE ANALYSIS OF AGENT-SPECIFIC CANCER RISK ALIGN POORLY WITH THE PATHOGENESIS OF HUMAN CARCINOMA AND SO NEED MODERNIZATION AND IMPROVEMENT IN WAYS SUGGESTED HERE. 2021 14 3511 32 IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI): FROM MOLECULAR EPIDEMIOLOGY TO MOLECULAR MEDICINE. INHERITED OR ACQUIRED IMPAIRMENT OF XENOBIOTICS METABOLISM IS A POSTULATED MECHANISM UNDERLYING ENVIRONMENT-ASSOCIATED PATHOLOGIES SUCH AS MULTIPLE CHEMICAL SENSITIVITY, FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, DENTAL AMALGAM DISEASE, AND OTHERS, ALSO COLLECTIVELY NAMED IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI). IN VIEW OF THE POOR CURRENT KNOWLEDGE OF THEIR ETIOLOGY AND PATHOGENESIS, AND THE ABSENCE OF RECOGNISED GENETIC AND METABOLIC MARKERS OF THE DISEASES. THEY ARE OFTEN CONSIDERED "MEDICALLY UNEXPLAINED SYNDROMES",. THESE DISABLING CONDITIONS SHARE THE FEATURES OF POLYSYMPTOMATIC MULTI-ORGAN SYNDROMES, CONSIDERED BY PART OF THE MEDICAL COMMUNITY TO BE ABERRANT RESPONSES TRIGGERED BY EXPOSURE TO LOW-DOSE ORGANIC AND INORGANIC CHEMICALS AND METALS, IN CONCENTRATIONS FAR BELOW AVERAGE REFERENCE LEVELS ADMITTED FOR ENVIRONMENTAL TOXICANTS. A GENETIC PREDISPOSITION TO ALTERED BIOTRANSFORMATION OF ENVIRONMENTAL CHEMICALS, DRUGS, AND METALS, AND OF ENDOGENOUS LOW-MOLECULAR WEIGHT METABOLITES, CAUSED BY POLYMORPHISMS OF GENES CODING FOR XENOBIOTIC METABOLIZING ENZYMES, THEIR RECEPTORS AND TRANSCRIPTION FACTORS APPEARS TO BE INVOLVED IN THE SUSCEPTIBILITY TO THESE ENVIRONMENT-ASSOCIATED PATHOLOGIES, ALONG WITH EPIGENETIC FACTORS. FREE RADICAL/ANTIOXIDANT HOMEOSTASIS MAY ALSO BE HEAVILY IMPLICATED, INDIRECTLY BY AFFECTING THE REGULATION OF XENOBIOTIC METABOLIZING ENZYMES, AND DIRECTLY BY CAUSING INCREASED LEVELS OF OXIDATIVE PRODUCTS, IMPLICATED IN THE CHRONIC DAMAGE OF CELLS AND TISSUES, WHICH IS IN PART CORRELATED WITH CLINICAL SYMPTOMS. MORE SYSTEMATIC STUDIES OF MOLECULAR EPIDEMIOLOGY, TOXICO- AND PHARMACO-GENOMICS, ELUCIDATING THE MECHANISMS OF REGULATION, EXPRESSION, INDUCTION, AND ACTIVITY OF ANTIOXIDANT/DETOXIFYING ENZYMES, AND THE POSSIBLE ROLE OF INFLAMMATORY MEDIATORS, PROMISE A BETTER UNDERSTANDING OF THIS PATHOLOGICALLY INCREASED SENSITIVITY TO LOW-LEVEL CHEMICAL STIMULI, AND A SOLID BASIS FOR EFFECTIVE INDIVIDUALIZED ANTIOXIDANT- AND/OR CHELATOR-BASED TREATMENTS. 2010 15 5894 27 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 16 796 28 CELLULAR SENESCENCE IN CANCER: FROM MECHANISMS TO DETECTION. SENESCENCE REFERS TO A CELLULAR STATE FEATURING A STABLE CELL-CYCLE ARREST TRIGGERED IN RESPONSE TO STRESS. THIS RESPONSE ALSO INVOLVES OTHER DISTINCT MORPHOLOGICAL AND INTRACELLULAR CHANGES INCLUDING ALTERATIONS IN GENE EXPRESSION AND EPIGENETIC MODIFICATIONS, ELEVATED MACROMOLECULAR DAMAGE, METABOLISM DEREGULATION AND A COMPLEX PRO-INFLAMMATORY SECRETORY PHENOTYPE. THE INITIAL DEMONSTRATION OF ONCOGENE-INDUCED SENESCENCE IN VITRO ESTABLISHED SENESCENCE AS AN IMPORTANT TUMOUR-SUPPRESSIVE MECHANISM, IN ADDITION TO APOPTOSIS. SENESCENCE NOT ONLY HALTS THE PROLIFERATION OF PREMALIGNANT CELLS BUT ALSO FACILITATES THE CLEARANCE OF AFFECTED CELLS THROUGH IMMUNOSURVEILLANCE. FAILURE TO CLEAR SENESCENT CELLS OWING TO DEFICIENT IMMUNOSURVEILLANCE MAY, HOWEVER, LEAD TO A STATE OF CHRONIC INFLAMMATION THAT NURTURES A PRO-TUMORIGENIC MICROENVIRONMENT FAVOURING CANCER INITIATION, MIGRATION AND METASTASIS. IN ADDITION, SENESCENCE IS A RESPONSE TO POST-THERAPY GENOTOXIC STRESS. THEREFORE, TRACKING THE EMERGENCE OF SENESCENT CELLS BECOMES PIVOTAL TO DETECT POTENTIAL PRO-TUMORIGENIC EVENTS. CURRENT PROTOCOLS FOR THE IN VIVO DETECTION OF SENESCENCE REQUIRE THE ANALYSIS OF FIXED OR DEEP-FROZEN TISSUES, DESPITE A SIGNIFICANT CLINICAL NEED FOR REAL-TIME BIOIMAGING METHODS. ACCURACY AND EFFICIENCY OF SENESCENCE DETECTION ARE FURTHER HAMPERED BY A LACK OF UNIVERSAL AND MORE SPECIFIC SENESCENCE BIOMARKERS. RECENTLY, IN AN ATTEMPT TO OVERCOME THESE HURDLES, AN ASSORTMENT OF DETECTION TOOLS HAS BEEN DEVELOPED. THESE STRATEGIES ALL HAVE SIGNIFICANT POTENTIAL FOR CLINICAL UTILISATION AND INCLUDE FLOW CYTOMETRY COMBINED WITH HISTO- OR CYTOCHEMICAL APPROACHES, NANOPARTICLE-BASED TARGETED DELIVERY OF IMAGING CONTRAST AGENTS, OFF-ON FLUORESCENT SENOPROBES, POSITRON EMISSION TOMOGRAPHY SENOPROBES AND ANALYSIS OF CIRCULATING SASP FACTORS, EXTRACELLULAR VESICLES AND CELL-FREE NUCLEIC ACIDS ISOLATED FROM PLASMA. HERE, WE HIGHLIGHT THE OCCURRENCE OF SENESCENCE IN NEOPLASIA AND ADVANCED TUMOURS, ASSESS THE IMPACT OF SENESCENCE ON TUMORIGENESIS AND DISCUSS HOW THE ONGOING DEVELOPMENT OF SENESCENCE DETECTION TOOLS MIGHT IMPROVE EARLY DETECTION OF MULTIPLE CANCERS AND RESPONSE TO THERAPY IN THE NEAR FUTURE. 2021 17 4399 26 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 18 4 23 "MIX OF MICS"- PHENOTYPIC AND BIOLOGICAL HETEROGENEITY OF "MULTIPOTENT" MUSCLE INTERSTITIAL CELLS (MICS). THE CAPACITY OF ADULT SKELETAL MUSCLE FOR REGENERATION APPEARS TO BE LIMITED, WITH PROGRESSIVE IMPAIRMENT IN REPAIR EFFICIENCY OF INJURED MUSCLES OBSERVED IN CHRONIC MUSCULAR DISORDERS AND DURING AGING. WHILE SATELLITE CELLS, THE COMMITTED ADULT MUSCLE STEM CELLS, ARE THE MAIN DIRECT CELL SOURCE SUPPORTING THE REGENERATIVE POTENTIAL OF ADULT SKELETAL MUSCLES, THE CHARACTERIZATION OF THE CELL TYPES AND SIGNALS THAT CONSTITUTE THE FUNCTIONAL "NICHE" OF SATELLITE CELLS IS CURRENTLY THE OBJECT OF INTENSE INVESTIGATION. RECENT STUDIES HAVE IDENTIFIED A FUNCTIONAL RELATIONSHIP BETWEEN SATELLITE CELLS AND VARIOUS CELL TYPES LOCATED IN KEY ANATOMICAL POSITION, SUCH AS THE INTERSTITIUM OF SKELETAL MUSCLES. THIS HETEROGENEOUS POPULATION OF MUSCLE INTERSTITIAL CELLS (MICS) APPEARS TO RETAIN AN INTRINSIC MULTIPOTENCY WITHIN THE MESODERMAL LINEAGE, AND THEIR DIRECT OR INDIRECT CONTRIBUTION TO MYOFIBER TURNOVER, REPAIR AND DEGENERATION HAS BEEN SUGGESTED BY MANY STUDIES THAT WILL BE REVIEWED HERE. GIVEN THE EXISTING GAP OF KNOWLEDGE ON LINEAGE IDENTITY AND FUNCTIONAL PROPERTIES OF MICS, THEIR DETAILED CHARACTERIZATION AT THE SINGLE CELL LEVEL HOLDS THE PROMISE TO PROVIDE KEY INSIGHT INTO THE COMPOSITION OF THIS HETEROGENEOUS POPULATION AND THE DYNAMIC TRANSITION THROUGH DISTINCT SUB-POPULATIONS IN HEALTHY, DISEASED AND AGING MUSCLES. THIS REVIEW PROVIDES AN OVERVIEW OF THE RESULTS OF VARIOUS STUDIES DESCRIBING THE PHENOTYPE AND THE FUNCTION OF CELLS ISOLATED FROM SKELETAL MUSCLE INTERSTITIUM, AND DISCUSSES THE IMPORTANCE OF SINGLE CELL TRANSCRIPTION PROFILING IN ORDER TO DECIPHER THE FUNCTIONAL AND PHENOTYPICAL HETEROGENEITY OF MUSCLE INTERSTITIAL CELLS (MICS). 2012 19 6334 25 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 20 1162 28 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018