1 3464 231 HYPOTHESIS. BYSTANDERS OR BAD SEEDS? MANY AUTOIMMUNE-TARGET CELLS MAY BE TRANSFORMING TO CANCER AND SIGNALLING "DANGER" TO THE IMMUNE SYSTEM. AUTOIMMUNE-TARGET CELLS IN AUTOIMMUNE DISEASE (AID) ARE USUALLY CONSTRUED AS CONSTITUTIONALLY NORMAL HEALTHY CELLS. A RELATED ASSUMPTION IS THAT OTHER CELLS IN THE BODY OF AID PATIENTS, EXCEPT FOR CERTAIN IMMUNOCYTES, ARE HEALTHY CELLS. AN IMPLICATION OF THAT VIEW IS THAT ANY SYSTEMIC PATHOLOGY IN ORGAN-SPECIFIC AID IS RELATED TO METABOLIC DERANGEMENTS SECONDARY TO TISSUE DESTRUCTION. HOWEVER, MUCH DATA ON TARGET AND OTHER CELLS IN AID SUGGEST WIDESPREAD PRIMARY CELLULAR DEFECTS. IN INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), FOR EXAMPLE, MANY "COMPLICATIONS" SUCH AS ATHEROSCLEROSIS, PREMATURE ARTERIAL STIFFENING, SENESCENCE OF FIBROBLASTS IN VITRO, AND EXUBERANT GROWTH OF SMOOTH MUSCLE AND MESANGIAL CELLS IN VIVO ARE NOT STRICTLY ATTRIBUTABLE TO GLUCOSE ELEVATION. ALSO UNEXPLAINED IS THE SIMILAR APPEARANCE OF IDDM BETA-CELLS AND CELLS FROM INSULINOMA AND WHY THE PRODROMAL PHASE OF IDDM HAS MANY INSULINOMA-LIKE FEATURES. WHILE AID TARGET CELLS HAVE OFTEN BEEN LIKENED TO NEOPLASTIC CELLS, INVESTIGATORS HAVE RARELY EXPLORED THE POSSIBILITY THAT AUTOIMMUNITY IN AID IS FUNDAMENTALLY ANTINEOPLASTIC. THIS IS LIKELY BECAUSE THE DOMINANT IDEAS IN ONCOLOGY AND IMMUNOLOGY-SOMATIC MUTATION AND CLONAL DELETION, RESPECTIVELY-HAVE PREVENTED EXPLANATIONS FOR HOW NORMAL IMMUNITY COULD DETECT TRANSFORMING CELLS NOT EXPRESSING NON-SELF ANTIGENS. NEW AND LESS CONVENTIONAL THEORIES OF CANCER AND IMMUNITY HAVE FACILITATED SUCH AN EXPLANATION. I USE RUBIN'S "EPIGENETIC" AGING MODEL OF CARCINOGENESIS AND MATZINGER'S "DANGER" MODEL OF IMMUNITY TO INTEGRATE THE IMMUNOLOGICAL AND ONCOLOGICAL SIDES OF AID. IN PARTICULAR, I POSTULATE THAT INDIVIDUALS SUFFERING FROM AID HAVE INHERITED MANY FOCI OF PREMATURELY AGING CELLS. THOSE INHERENTLY DAMAGED CELLS ADAPT TO IN VIVO CHALLENGES BY BEGINNING TO TRANSFORM INTO CANCER CELLS. HOWEVER, AS LONG AS THOSE STRESSED CELLS HAVE NOT FULLY TRANSFORMED, THEY WILL CONTINUE TO SIGNAL "DANGER" TO THE INNATE IMMUNE SYSTEM. THE CLINICAL OUTCOME OF THAT STRUGGLE BETWEEN INCIPIENT NEOPLASIA AND IMMUNITY WILL VARY DEPENDING UPON THE DEGREE OF TUMOR-PRONENESS AND RESISTANCE OF THE INDIVIDUAL. BORROWING FROM CANCER GENETICIST HENRY LYNCH, I POSTULATE THAT TUMOR-RESISTANCE IS INHERITED AS A QUANTITATIVE POLYGENIC TRAIT IN DIRECT PROPORTION TO TUMOR-PRONENESS. I FURTHER CONTEND THAT TUMOR-PRONENESS AND IMMUNITY ARE LINKED POLYGENIC TRAITS SUCH THAT THE GREATER ONE'S TUMOR-PRONENESS, THE MORE POWERFUL HIS/HER ANTITUMOR IMMUNITY. I POINT TO THE SHARED DNA REPAIR DEFICIENCY OF CERTAIN CANCER-PRONE SYNDROMES AND HLA-LINKED AID, THEIR OCCASIONAL CO-OCCURRENCE, AND THEIR DEMONSTRABLY EXCEPTIONAL IMMUNITY AGAINST SOLID TUMORS. I PROPOSE THAT HLA-LINKED AID CONSTITUTE "CHRONIC HYPERSENSITIVITY SYNDROMES" DUE TO IMMUNITY'S LARGELY HIDDEN BATTLE TO SUPPRESS MULTIPLE INCIPIENT NEOPLASTIC MICROFOCI. MUCH OF THE PHYSIOPATHOLOGY OF AID IS EXPLICABLE AS A SUSTAINED SYSTEMIC RESPONSE TO THREATENED NEOPLASTIC TRANSFORMATION. 2001 2 389 33 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 3 5281 38 PROMOTION AND SELECTION BY SERUM GROWTH FACTORS DRIVE FIELD CANCERIZATION, WHICH IS ANTICIPATED IN VIVO BY TYPE 2 DIABETES AND OBESITY. INDIVIDUALS SUFFERING FROM TYPE 2 DIABETES OR OBESITY EXHIBIT A SIGNIFICANT INCREASE IN THE INCIDENCE OF VARIOUS TYPES OF CANCER. IT IS GENERALLY ACCEPTED THAT THOSE CONDITIONS ARISE FROM OVERNUTRITION AND A SEDENTARY LIFESTYLE, WHICH LEAD TO INSULIN RESISTANCE CHARACTERIZED BY OVERPRODUCTION OF INSULIN ACTING AS A GROWTH FACTOR. THERE IS A CONSENSUS BASED LARGELY ON EPIDEMIOLOGICAL DATA THAT CHRONIC OVERPRODUCTION OF INSULIN IS RESPONSIBLE FOR THE INCREASED INCIDENCE OF CANCER. A MODEL SYSTEM IN CULTURE OF NIH 3T3 CELLS INDUCES THE COLLECTIVE EFFECTS OF SERUM GROWTH FACTORS ON PROGRESSION THROUGH THE STAGES OF FIELD CANCERIZATION. IT SHOWS THAT THE DRIVING FORCE OF PROGRESSION IS PROMOTION OF CELL GROWTH UNDER SELECTION AT HIGH CELL DENSITY, WITH NO REQUIREMENT FOR EXOGENOUS CARCINOGENIC AGENTS. THE EARLY EFFECT IS GRADUAL SELECTION AMONG MANY PREEXISTING, LOW-PENETRANCE PRENEOPLASTIC MUTATIONS OR STABLE EPIGENETIC VARIANTS, FOLLOWED BY SPORADIC, HIGH-PENETRANCE TRANSFORMING VARIANTS, ALL DEPENDENT ON ENDOGENOUS PROCESSES. THE SIGNIFICANCE OF THE RESULTS FOR CANCER IN DIABETIC AND OBESE INDIVIDUALS IS THAT THE INITIAL STAGES OF THE PROCESS INVOLVE MULTIORGAN METABOLIC INTERACTIONS THAT PRODUCE A SYSTEMIC INSULIN RESISTANCE WITH CHRONIC OVERPRODUCTION OF INSULIN AND LOCALIZED FIELD CANCERIZATION. HYPOMAGNESEMIA IS PREVALENT IN THE FOREGOING METABALO/SYSTEMIC DISORDERS, AND MAY ALSO PROVIDE A SELECTIVE MICROENVIRONMENT FOR TUMOR DEVELOPMENT. 2013 4 6906 33 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 5 3801 41 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 6 3418 26 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 7 705 31 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 8 6496 55 TRAINED IMMUNITY CONTRIBUTION TO AUTOIMMUNE AND INFLAMMATORY DISORDERS. A DYSREGULATED IMMUNE RESPONSE TOWARD SELF-ANTIGENS CHARACTERIZES AUTOIMMUNE AND AUTOINFLAMMATORY (AIF) DISORDERS. AUTOANTIBODIES OR AUTOREACTIVE T CELLS CONTRIBUTE TO AUTOIMMUNE DISEASES, WHILE AUTOINFLAMMATION RESULTS FROM A HYPER-FUNCTIONAL INNATE IMMUNE SYSTEM. ASIDE FROM THEIR DIFFERENCES, MANY STUDIES SUGGEST THAT MONOCYTES AND MACROPHAGES (MO/MA) SIGNIFICANTLY CONTRIBUTE TO THE DEVELOPMENT OF BOTH TYPES OF DISEASE. MO/MA ARE INNATE IMMUNE CELLS THAT PROMOTE AN IMMUNE-MODULATORY, PRO-INFLAMMATORY, OR REPAIR RESPONSE DEPENDING ON THE MICROENVIRONMENT. HOWEVER, UNDERSTANDING THE CONTRIBUTION OF THESE CELLS TO DIFFERENT IMMUNE DISORDERS HAS BEEN DIFFICULT DUE TO THEIR HIGH FUNCTIONAL AND PHENOTYPIC PLASTICITY. SEVERAL FACTORS CAN INFLUENCE THE FUNCTION OF MO/MA UNDER THE LANDSCAPE OF AUTOIMMUNE/AUTOINFLAMMATORY DISEASES, SUCH AS GENETIC PREDISPOSITION, EPIGENETIC CHANGES, OR INFECTIONS. FOR INSTANCE, SOME VACCINES AND MICROORGANISMS CAN INDUCE EPIGENETIC CHANGES IN MO/MA, MODIFYING THEIR FUNCTIONAL RESPONSES. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY. TRAINED IMMUNITY CAN BE MEDIATED BY MO/MA AND NK CELLS INDEPENDENTLY OF T AND B CELL FUNCTION. IT IS DEFINED AS THE ALTERED INNATE IMMUNE RESPONSE TO THE SAME OR DIFFERENT MICROORGANISMS DURING A SECOND ENCOUNTER. THE IMPROVEMENT IN CELL FUNCTION IS RELATED TO EPIGENETIC AND METABOLIC CHANGES THAT MODIFY GENE EXPRESSION. ALTHOUGH THE BENEFITS OF IMMUNE TRAINING HAVE BEEN HIGHLIGHTED IN A VACCINATION CONTEXT, THE EFFECTS OF THIS TYPE OF IMMUNE RESPONSE ON AUTOIMMUNITY AND CHRONIC INFLAMMATION STILL REMAIN CONTROVERSIAL. INDUCTION OF TRAINED IMMUNITY REPROGRAMS CELLULAR METABOLISM IN HEMATOPOIETIC STEM CELLS (HSCS), TRANSMITTING A MEMORY-LIKE PHENOTYPE TO THE CELLS. THUS, TRAINED MO/MA DERIVED FROM HSCS TYPICALLY PRESENT A METABOLIC SHIFT TOWARD GLYCOLYSIS, WHICH LEADS TO THE MODIFICATION OF THE CHROMATIN ARCHITECTURE. DURING TRAINED IMMUNITY, THE EPIGENETIC CHANGES FACILITATE THE SPECIFIC GENE EXPRESSION AFTER SECONDARY CHALLENGE WITH OTHER STIMULI. CONSEQUENTLY, THE ENHANCED PRO-INFLAMMATORY RESPONSE COULD CONTRIBUTE TO DEVELOPING OR MAINTAINING AUTOIMMUNE/AUTOINFLAMMATORY DISEASES. HOWEVER, THE PREDICTION OF THE OUTCOME IS NOT SIMPLE, AND OTHER STUDIES PROPOSE THAT TRAINED IMMUNITY CAN INDUCE A BENEFICIAL RESPONSE BOTH IN AIF AND AUTOIMMUNE CONDITIONS BY INDUCING ANTI-INFLAMMATORY RESPONSES. THIS ARTICLE DESCRIBES THE METABOLIC AND EPIGENETIC MECHANISMS INVOLVED IN TRAINED IMMUNITY THAT AFFECT MO/MA, CONTRAPOSING THE CONTROVERSIAL EVIDENCE ON HOW IT MAY IMPACT AUTOIMMUNE/AUTOINFLAMMATION CONDITIONS. 2022 9 461 40 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 10 4399 40 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 11 796 48 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 12 761 35 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 13 3917 40 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 14 5447 42 REPOSITIONING LIDOCAINE AS AN ANTICANCER DRUG: THE ROLE BEYOND ANESTHESIA. WHILE CANCER TREATMENT HAS IMPROVED DRAMATICALLY, IT HAS ALSO ENCOUNTERED MANY CRITICAL CHALLENGES, SUCH AS DISEASE RECURRENCE, METASTASIS, AND DRUG RESISTANCE, MAKING NEW DRUGS WITH NOVEL MECHANISMS AN URGENT CLINICAL NEED. THE TERM "DRUG REPOSITIONING," ALSO KNOWN AS OLD DRUGS FOR NEW USES, HAS EMERGED AS ONE PRACTICAL STRATEGY TO DEVELOP NEW ANTICANCER DRUGS. ANESTHETICS HAVE BEEN WIDELY USED IN SURGICAL PROCEDURES TO REDUCE THE EXCRUCIATING PAIN. LIDOCAINE, ONE OF THE MOST-USED LOCAL ANESTHETICS IN CLINICAL SETTINGS, HAS BEEN FOUND TO SHOW MULTI-ACTIVITIES, INCLUDING POTENTIAL IN CANCER TREATMENT. GROWING EVIDENCE SHOWS THAT LIDOCAINE MAY NOT ONLY WORK AS A CHEMOSENSITIZER THAT SENSITIZES OTHER CONVENTIONAL CHEMOTHERAPEUTICS TO CERTAIN RESISTANT CANCER CELLS, BUT ALSO COULD SUPPRESS CANCER CELLS GROWTH BY SINGLE USE AT DIFFERENT DOSES OR CONCENTRATIONS. LIDOCAINE COULD SUPPRESS CANCER CELL GROWTH IN VITRO AND IN VIVO VIA MULTIPLE MECHANISMS, SUCH AS REGULATING EPIGENETIC CHANGES AND PROMOTING PRO-APOPTOSIS PATHWAYS, AS WELL AS REGULATING ABC TRANSPORTERS, METASTASIS, AND ANGIOGENESIS, ETC., PROVIDING VALUABLE INFORMATION FOR ITS FURTHER APPLICATION IN CANCER TREATMENT AND FOR NEW DRUG DISCOVERY. IN ADDITION, LIDOCAINE IS NOW UNDER CLINICAL TRIALS TO TREAT CERTAIN TYPES OF CANCER. IN THE CURRENT REVIEW, WE SUMMARIZE THE RESEARCH AND ANALYZE THE UNDERLYING MECHANISMS, AND ADDRESS KEY ISSUES IN THIS AREA. 2020 15 4505 27 MOUSE MODELS AND THE GENETICS OF DIABETES: IS THERE EVIDENCE FOR GENETIC OVERLAP BETWEEN TYPE 1 AND TYPE 2 DIABETES? IN HUMANS, BOTH TYPE 1 AND TYPE 2 DIABETES EXEMPLIFY GENETICALLY HETEROGENEOUS COMPLEX DISEASES IN WHICH EPIGENETIC FACTORS CONTRIBUTE TO UNDERLYING GENETIC SUSCEPTIBILITY. EXTENDED HUMAN PEDIGREES OFTEN SHOW INHERITANCE OF BOTH DIABETES TYPES. A COMMON PATHOPHYSIOLOGICAL DENOMINATOR IN BOTH DISEASE FORMS IS PANCREATIC BETA-CELL EXPOSURE TO PROINFLAMMATORY CYTOKINES. HENCE, IT IS INTUITIVE THAT SYSTEMICALLY EXPRESSED GENES REGULATING BETA-CELL ABILITY TO WITHSTAND CHRONIC DIABETOGENIC STRESS MAY REPRESENT A COMPONENT OF SHARED SUSCEPTIBILITY TO BOTH MAJOR DISEASE FORMS. IN THIS REVIEW, THE AUTHORS ASSEMBLE EVIDENCE FROM GENETIC EXPERIMENTS USING ANIMAL MODELS DEVELOPING CLEARLY DISTINCT DIABETES SYNDROMES TO INQUIRE WHETHER SOME DEGREE OF OVERLAP IN GENES CONTRIBUTING SUSCEPTIBILITY CAN BE DEMONSTRATED. THE CONCLUSION IS THAT ALTHOUGH OVERLAP EXISTS IN THE PATHOPHYSIOLOGICAL INSULTS LEADING TO BETA-CELL DESTRUCTION IN THE CURRENTLY STUDIED RODENT MODELS, THE GENETIC BASES SEEM QUITE DISTINCT. 2005 16 5905 31 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 17 4 37 "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 18 5134 43 POTENTIAL HEALTH RISKS OF MRNA-BASED VACCINE THERAPY: A HYPOTHESIS. THERAPEUTIC APPLICATIONS OF SYNTHETIC MRNA WERE PROPOSED MORE THAN 30 YEARS AGO, AND ARE CURRENTLY THE BASIS OF ONE OF THE VACCINE PLATFORMS USED AT A MASSIVE SCALE AS PART OF THE PUBLIC HEALTH STRATEGY TO GET COVID-19 UNDER CONTROL. TO DATE, THERE ARE NO PUBLISHED STUDIES ON THE BIODISTRIBUTION, CELLULAR UPTAKE, ENDOSOMAL ESCAPE, TRANSLATION RATES, FUNCTIONAL HALF-LIFE AND INACTIVATION KINETICS OF SYNTHETIC MRNA, RATES AND DURATION OF VACCINE-INDUCED ANTIGEN EXPRESSION IN DIFFERENT CELL TYPES. FURTHERMORE, DESPITE THE ASSUMPTION THAT THERE IS NO POSSIBILITY OF GENOMIC INTEGRATION OF THERAPEUTIC SYNTHETIC MRNA, ONLY ONE RECENT STUDY HAS EXAMINED INTERACTIONS BETWEEN VACCINE MRNA AND THE GENOME OF TRANSFECTED CELLS, AND REPORTED THAT AN ENDOGENOUS RETROTRANSPOSON, LINE-1 IS UNSILENCED FOLLOWING MRNA ENTRY TO THE CELL, LEADING TO REVERSE TRANSCRIPTION OF FULL LENGTH VACCINE MRNA SEQUENCES, AND NUCLEAR ENTRY. THIS FINDING SHOULD BE A MAJOR SAFETY CONCERN, GIVEN THE POSSIBILITY OF SYNTHETIC MRNA-DRIVEN EPIGENETIC AND GENOMIC MODIFICATIONS ARISING. WE PROPOSE THAT IN SUSCEPTIBLE INDIVIDUALS, CYTOSOLIC CLEARANCE OF NUCLEOTIDE MODIFIED SYNTHETIC (NMS-MRNAS) IS IMPEDED. SUSTAINED PRESENCE OF NMS-MRNA IN THE CYTOPLASM DEREGULATES AND ACTIVATES ENDOGENOUS TRANSPOSABLE ELEMENTS (TES), CAUSING SOME OF THE MRNA COPIES TO BE REVERSE TRANSCRIBED. THE CYTOSOLIC ACCUMULATION OF THE NMS-MRNA AND THE REVERSE TRANSCRIBED CDNA MOLECULES ACTIVATES RNA AND DNA SENSORY PATHWAYS. THEIR CONCURRENT ACTIVATION INITIATES A SYNCHRONIZED INNATE RESPONSE AGAINST NON-SELF NUCLEIC ACIDS, PROMPTING TYPE-I INTERFERON AND PRO-INFLAMMATORY CYTOKINE PRODUCTION WHICH, IF UNREGULATED, LEADS TO AUTOINFLAMMATORY AND AUTOIMMUNE CONDITIONS, WHILE ACTIVATED TES INCREASE THE RISK OF INSERTIONAL MUTAGENESIS OF THE REVERSE TRANSCRIBED MOLECULES, WHICH CAN DISRUPT CODING REGIONS, ENHANCE THE RISK OF MUTATIONS IN TUMOUR SUPPRESSOR GENES, AND LEAD TO SUSTAINED DNA DAMAGE. SUSCEPTIBLE INDIVIDUALS WOULD THEN EXPECTEDLY HAVE AN INCREASED RISK OF DNA DAMAGE, CHRONIC AUTOINFLAMMATION, AUTOIMMUNITY AND CANCER. IN LIGHT OF THE CURRENT MASS ADMINISTRATION OF NMS-MRNA VACCINES, IT IS ESSENTIAL AND URGENT TO FULLY UNDERSTAND THE INTRACELLULAR CASCADES INITIATED BY CELLULAR UPTAKE OF SYNTHETIC MRNA AND THE CONSEQUENCES OF THESE MOLECULAR EVENTS. 2023 19 49 29 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 20 2533 31 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014