1 1844 153 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 2 5643 45 SEX AND AUTOIMMUNITY: PROPOSED MECHANISMS OF DISEASE ONSET AND SEVERITY. CHRONIC AUTOIMMUNE DISEASES AFFECT 5-10% OF THE POPULATION WORLDWIDE AND ARE LARGELY PREDOMINANT IN WOMEN. SEX HORMONE CHANGES HAVE BEEN WIDELY INVESTIGATED BASED ON CHANGES IN THE CLINICAL PHENOTYPES OBSERVED DURING PREGNANCY AND MENOPAUSE. IT IS KNOWN THAT FEMALES WITH AUTOIMMUNE DISEASES MANIFEST A HIGHER RATE OF CIRCULATING LEUKOCYTES WITH A SINGLE X CHROMOSOME, AND THERE HAVE BEEN SEVERAL REPORTS ON THE ROLE OF X CHROMOSOME GENE DOSAGE THROUGH INACTIVATION OR DUPLICATION IN AUTOIMMUNITY. HOWEVER, IT IS ALSO IMPORTANT NOT TO OVERLOOK MEN WITH AUTOIMMUNE DISEASES, WHO MIGHT MANIFEST A MORE FREQUENT LOSS OF THE Y CHROMOSOME IN CIRCULATING LEUKOCYTES. AREAS COVERED: IN THE PRESENT REVIEW, WE WILL DISCUSS THE CURRENT EVIDENCE SUPPORTING THE MECHANISMS OF FEMALE PREDOMINANCE IN RHEUMATIC DISEASES, BY DISCUSSING THE ROLE OF REPRODUCTIVE HISTORY, SEX HORMONES AND ABNORMALITIES RELATED TO THEM, CLINICAL DIFFERENCES BETWEEN MALE AND FEMALE PATIENTS, AND EPIGENETIC CHANGES THAT HAVE BEEN EVALUATED THROUGH TWIN STUDIES ON GENETIC AND ENVIRONMENTAL CHANGES IN RHEUMATIC PATIENTS. EXPERT OPINION: THE INFLUENCE OF SEX HORMONES AND CHROMOSOMES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS NEEDS TO BE CLARIFIED, TO BETTER UNDERSTAND THE RISK OF AUTOIMMUNE DISEASES, EARLY DIAGNOSTIC TOOLS, AND THERAPEUTIC RESPONSE. 2019 3 6823 35 [GENERAL CONCEPTS OF EPIGENETICS: PROJECTIONS IN PAEDIATRICS]. CURRENT EVIDENCE SUPPORTS THE NOTION THAT ALTERATIONS IN INTRAUTERINE GROWTH AND DURING THE FIRST YEARS OF LIFE HAVE A SUBSTANTIAL EFFECT ON THE RISK FOR THE DEVELOPMENT OF CHRONIC DISEASE, WHICH IN SOME CASES IS EVEN HIGHER THAN THOSE DUE TO GENETIC FACTORS. THE PERSISTENCE AND REPRODUCIBILITY OF THE PHENOTYPES ASSOCIATED WITH ALTERED EARLY DEVELOPMENT SUGGEST THE PARTICIPATION OF MECHANISMS THAT WOULD RECORD ENVIRONMENTAL CUES, GENERATING A CELLULAR REPROGRAMMING (I.E., EPIGENETIC MECHANISMS). THIS REVIEW IS AN INTRODUCTION TO A SERIES OF FIVE ARTICLES FOCUSED ON THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF HIGHLY PREVALENT CHRONIC DISEASES (I.E., CARDIOVASCULAR, METABOLIC, ASTHMA/ALLERGIES AND CANCER) AND THEIR ORIGINS IN THE FOETAL AND NEONATAL PERIOD. THIS SERIES OF ARTICLES AIMS TO SHOW THE STATE OF THE ART IN THIS RESEARCH AREA AND PRESENT THE UPCOMING CLUES AND CHALLENGES, IN WHICH PAEDIATRICIANS HAVE A PROMINENT ROLE, DEVELOPING STRATEGIES FOR THE PREVENTION, EARLY DETECTION AND FOLLOW-UP. 2016 4 943 30 CHRONIC LYMPHOCYTIC LEUKEMIA. PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA CAN BE DIVIDED INTO THREE CATEGORIES: THOSE WHO ARE MINIMALLY AFFECTED BY THE PROBLEM, OFTEN NEVER REQUIRING THERAPY; THOSE THAT INITIALLY FOLLOW AN INDOLENT COURSE BUT SUBSEQUENTLY PROGRESS AND REQUIRE THERAPY; AND THOSE THAT FROM THE POINT OF DIAGNOSIS EXHIBIT AN AGGRESSIVE DISEASE NECESSITATING TREATMENT. LIKEWISE, SUCH PATIENTS PASS THROUGH THREE PHASES: DEVELOPMENT OF THE DISEASE, DIAGNOSIS, AND NEED FOR THERAPY. FINALLY, THE LEUKEMIC CLONES OF ALL PATIENTS APPEAR TO REQUIRE CONTINUOUS INPUT FROM THE EXTERIOR, MOST OFTEN THROUGH MEMBRANE RECEPTORS, TO ALLOW THEM TO SURVIVE AND GROW. THIS REVIEW IS PRESENTED ACCORDING TO THE TEMPORAL COURSE THAT THE DISEASE FOLLOWS, FOCUSING ON THOSE EXTERNAL INFLUENCES FROM THE TISSUE MICROENVIRONMENT (TME) THAT SUPPORT THE TIME LINES AS WELL AS THOSE INTERNAL INFLUENCES THAT ARE INHERITED OR DEVELOP AS GENETIC AND EPIGENETIC CHANGES OCCURRING OVER THE TIME LINE. REGARDING THE FORMER, SPECIAL EMPHASIS IS PLACED ON THE INPUT PROVIDED VIA THE B-CELL RECEPTOR FOR ANTIGEN AND THE C-X-C-MOTIF CHEMOKINE RECEPTOR-4 AND THE THERAPEUTIC AGENTS THAT BLOCK THESE INPUTS. REGARDING THE LATTER, PROMINENCE IS LAID UPON INHERITED SUSCEPTIBILITY GENES AND THE GENETIC AND EPIGENETIC ABNORMALITIES THAT LEAD TO THE DEVELOPMENTAL AND PROGRESSION OF THE DISEASE. 2021 5 6791 30 [DOES THE NUMBER OF PATIENTS WITH AUTOIMMUNE DISORDERS AND THE FREQUENCY OF AUTOIMMUNE DISEASES INCREASE?]. AUTOIMMUNE DISEASES GENERALLY BELONG TO THE RARE DISEASES, HOWEVER, SOME OF THEM ARE FREQUENT IN THE POPULATION. IN THE PRESENT WORK THE AUTHORS ANALYSE WHETHER CAN ANY INCREASE BE OBSERVED IN THE NUMBER OF PATIENTS SUFFERING FROM AUTOIMMUNE DISEASES AND WHETHER DO THE FREQUENCY OF CERTAIN AUTOIMMUNE DISORDERS INCREASE. DUE MAINLY TO EPIGENETIC FACTORS THE INCIDENCE OF AUTOIMMUNE DISEASES ARE INCREASING, THEREFORE THERE ARE MORE PATIENTS RECOGNISED WITH PARTICULAR DISORDERS. ON THE OTHER HAND THE INCIDENCE IS INCREASED BY IMPROVING DIAGNOSTIC POSSIBILITIES, BY THE USE OF MORE SPECIFIC AND SENSITIVE CLASSIFICATION CRITERIA AND MORE SOPHISTICATED LABORATORY TESTS, RESULTED IN THE RECOGNITION OF MILDER AND ATYPICAL DISEASE VARIANTS AS WELL. THE PREVALENCE IS ALSO INCREASING IN CONSEQUENCE OF NOVEL IMMUNE SUPPRESSIVE THERAPEUTIC POSSIBILITIES AND THE CONSEQUENT IMPROVEMENT OF SURVIVAL IN THE MOST OF THESE DISEASES. BESIDES, MORE AND MORE DISEASES HAVE BEEN REVEALED TO HAVE AUTOIMMUNE BACKGROUND, AND LOT OF NEW AUTOIMMUNE SYNDROMES, DISEASES HAVE BEEN CHARACTERISED RECENTLY. THIS INCREASES THE NUMBER OF THE KNOWN AUTOIMMUNE RHEUMATIC DISORDERS WITH A CONSEQUENT INCREASE IN THE NUMBER OF AUTOIMMUNE PATIENTS. ASSIGNED TO THE INCREASING NUMBER OF VARIABLE CHRONIC AUTOIMMUNE DISORDERS, AND THE INCREASING NUMBER OF DISABLED PATIENTS WITH SUCH DISEASES INCREASING MEDICAL AND SOCIAL ATTENTION HAS TO BE FOCUSED ON. 2007 6 6116 35 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS. 2022 7 2569 32 EPIGENETICS OF ANKYLOSING SPONDYLITIS: RECENT DEVELOPMENTS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE WHICH MAINLY AFFECTS THE SPINE, SACROILIAC JOINT AND PERIPHERAL JOINTS. TO DATE, THE EXACT CAUSES AND PATHOGENESIS OF AS STILL REMAIN UNKNOWN. IT IS CONSIDERED THAT THE PATHOGENESIS OF AS IS ASSOCIATED WITH GENETIC, INFECTION, ENVIRONMENT, IMMUNITY AND OTHER FACTORS. AMONG THEM, THE ROLE OF GENETIC FACTORS IN THE PATHOGENESIS OF AS HAS BEEN STUDIED MOST DEEPLY. HOWEVER, OVER THE PAST FEW YEARS, THE FUNCTION OF ENVIRONMENTAL PREDISPOSITION AND EPIGENETIC MODIFICATION IN THE PATHOGENESIS OF AS HAS RECEIVED EXTENSIVE ATTENTION. THIS PAPER SUMMARIZES THE RECENT PROGRESS IN THE EPIGENETICS OF AS, INCLUDING ABNORMAL EPIGENETIC MODIFICATIONS AT AS-ASSOCIATED GENOMIC LOCI, SUCH AS DNA METHYLATION, HISTONE MODIFICATION, MICRORNA, AND SO ON. IN SUMMARY, THE FINDINGS OF THIS REVIEW ATTEMPT TO EXPLAIN THE ROLE OF EPIGENETIC MODIFICATION IN THE OCCURRENCE AND DEVELOPMENT OF AS. NEVERTHELESS, THERE ARE STILL UNKNOWN AND COMPLICATED ASPECTS WORTH EXPLORING TO DEEPEN OUR UNDERSTANDING OF THE PATHOGENESIS OF AS. 2021 8 6892 25 [SIGNIFICANCE OF PREVENTING DEVELOPMENTAL ORIGINS OF DISEASES IN IMPROVING POPULATION QUALITY]. MORE STUDIES SHOW THAT VARIOUS DISEASES, ESPECIALLY CHRONIC NON-INFECTIOUS DISEASES, HAVE DEVELOPMENTAL ORIGIN. DEVELOPMENTAL ORIGINS OF DISEASES ARE MAINLY DUE TO GAMETES AND EARLY LIFE DEVELOPMENT STAGE BEING EXPOSED TO ADVERSE ENVIRONMENT, RESULTING IN ABNORMAL MODIFICATION OF EPIGENETIC AND STABLE INHERITANCE TO THE ADULT STAGE, WHICH COULD MAKE THE RISK OF VARIOUS LONG-TERM DISEASES OF INDIVIDUALS HIGH. THE THEORY OF DEVELOPMENTAL ORIGIN PROVIDES A NEW PERSPECTIVE FOR THE OCCURRENCE AND DEVELOPMENT OF DISEASES, AND ALSO PROVIDES A THEORETICAL BASIS FOR DISEASE PREVENTION. ATTACHING IMPORTANCE TO MATERNAL AND CHILD HEALTH CARE AND LIFE-CYCLE MANAGEMENT IS CONDUCIVE TO THE PREVENTION OF DEVELOPMENTAL DISEASES AND IS OF GREAT SIGNIFICANCE TO THE IMPROVEMENT OF POPULATION QUALITY. 2023 9 6905 34 [THE ROLE OF EPIGENETIC REGULATIONS IN EARLY CHILDHOOD DISEASES]. WITH THE ACCEPTANCE OF "THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" CONCEPT IN THE 1990S, IT BECAME CLEAR THAT EPIGENETIC INHERITANCE, WHICH DO NOT INVOLVE CHANGES IN THE DNA SEQUENCE HAS IMPORTANT ROLE IN THE PATHOGENESIS OF DISEASES. EPIGENETIC REGULATION SERVES THE ADAPTATION TO THE CHANGING ENVIRONMENT AND MAINTAINS THE REPRODUCTIVE FITNESS EVEN ON THE DRAWBACK OF INCREASED RISK OF DISEASES IN LATER LIFE. THE ROLE OF EPIGENETIC MECHANISMS IN CHRONIC NON-COMMUNICABLE DISEASES HAS BEEN WELL ESTABLISHED. RECENT STUDIES HAVE REVEALED THAT EPIGENETIC CHANGES HAVE ALSO CAUSAL ROLE IN CERTAIN PEDIATRIC DISEASES. THE REVIEW EVALUATES THE RECENT EPIGENETIC FINDINGS IN THE PATHOMECHANISM OF COMMON PEDIATRIC DISEASES. THE WIDE RANGE AND LONG-LASTING DURATION OF EPIGENETIC REGULATIONS GIVE IMPORTANCE TO THE SUBJECT. METHODS ARE ALREADY AVAILABLE TO EVALUATE A PART OF THE EPIGENETIC CHANGES IN THE CLINICAL PRACTICE, PRESENTLY AIMING PRIMARILY THE ESTIMATION OF THE DISEASE RISK OR DEFINITION OF DIAGNOSIS. FURTHERMORE, THERE ARE ALREADY AVAILABLE LIMITED MEANS TO INFLUENCE THE EPIGENETIC REGULATION. 2019 10 6842 28 [MECHANISTIC ISSUES AND PREVENTION STRATEGIES TARGETING OCCUPATIONAL CARCINOGENESIS]. CARCINOGENESIS CAN BE VISUALIZED EITHER AS A MULTISTEP PROCESS (INITIATION, PROMOTION, PROGRESSION, INVASION, AND METASTASIS) OR AS A CONTINUUM OF MUTAGENIC AND MITOGENIC EVENTS, WITH THE CONTRIBUTION OF EPIGENETIC MECHANISMS. THE EXPONENTIAL GROWTH OF THE NEOPLASTIC MASS EXPLAINS THE IMPORTANCE OF SECONDARY PREVENTION (EARLY DIAGNOSIS) AND OF TERTIARY PREVENTION. PRIMARY PREVENTION, WHICH WAS SUCCESSFUL IN CONTROLLING OCCUPATIONAL CANCERS, AIMS AT MINIMIZING EXPOSURES TO CARCINOGENS IN HEALTHY SUBJECTS AND AT FAVORING THE INTAKE OF CHEMOPREVENTIVE AGENTS WITH DIETARY AND PHARMACOLOGICAL AGENTS. BESIDES CHEMICAL CARCINOGENS, OFTEN IN THE FORM OF COMPLEX MIXTURES, THE WORKPLACE MAY INVOLVE EXPOSURES TO PHYSICAL AGENTS, SUCH AS SUNLIGHT AND ARTIFICIAL ILLUMINATION SYSTEMS DELIVERING UV RADIATION, OR TO BIOLOGICAL AGENTS, SUCH AS CHRONIC VIRAL INFECTIONS (HBV, HCV, AND HIV) ASSOCIATED WITH CANCERS. A CONTROVERSIAL ISSUE IS THE OCCURRENCE OF THRESHOLD DOSES FOR CARCINOGENS IN THE WORKPLACE AND THE ENVIRONMENT. 2011 11 186 41 ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL CELLS AND CANCER RISK. CANCERS DEVELOP DUE TO THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. GENETIC ALTERATIONS ARE INDUCED BY AGING, MUTAGENIC CHEMICALS, ULTRAVIOLET LIGHT, AND OTHER FACTORS; WHEREAS, EPIGENETIC ALTERATIONS ARE MAINLY BY AGING AND CHRONIC INFLAMMATION. THE ACCUMULATION AND PATTERNS OF ALTERATIONS IN NORMAL CELLS REFLECT OUR PAST EXPOSURE LEVELS AND LIFE HISTORY. MOST ACCUMULATED ALTERATIONS ARE CONSIDERED AS PASSENGERS, BUT THEIR ACCUMULATION IS CORRELATED WITH CANCER DRIVERS. THIS HAS BEEN SHOWN FOR ABERRANT DNA METHYLATION BUT HAS ONLY BEEN SPECULATED FOR GENETIC ALTERATIONS. HOWEVER, RECENT TECHNOLOGICAL ADVANCEMENTS HAVE ENABLED MEASUREMENT OF RARE POINT MUTATIONS, AND STUDIES HAVE SHOWN THAT THEIR ACCUMULATION LEVELS ARE INDEED CORRELATED WITH CANCER RISK. WHEN THE ACCUMULATION LEVELS OF ABERRANT DNA METHYLATION AND POINT MUTATIONS ARE COMBINED, RISK PREDICTION BECOMES EVEN MORE ACCURATE. WHEN HIGH LEVELS OF ALTERATIONS ACCUMULATE, THE TISSUE HAS A HIGH RISK OF DEVELOPING CANCER OR EVEN MULTIPLE CANCERS AND IS CONSIDERED AS A "CANCERIZATION FIELD", WITH OR WITHOUT EXPANSION OF PHYSIOLOGICAL PATCHES OF CLONAL CELLS. IN THIS REVIEW, WE DESCRIBE THE FORMATION OF A CANCERIZATION FIELD AND HOW WE CAN APPLY ITS DETECTION IN PRECISION CANCER RISK DIAGNOSIS. 2019 12 1010 35 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 13 1918 55 ENVIRONMENTAL CARCINOGENESIS AND TRANSGENERATIONAL TRANSMISSION OF CARCINOGENIC RISK: FROM GENETICS TO EPIGENETICS. THE DOMINANT PATHOGENIC MODEL, SOMATIC MUTATION THEORY (SMT), CONSIDERS CARCINOGENESIS AS A 'GENETIC ACCIDENT' DUE TO THE ACCUMULATION OF 'STOCHASTIC' DNA MUTATIONS. THIS MODEL WAS PROPOSED AND ACCEPTED BY THE SCIENTIFIC COMMUNITY WHEN CANCER MAINLY AFFECTED THE ELDERLY, BUT IT DOES NOT EXPLAIN THE EPIDEMIOLOGICAL OBSERVATION OF THE CONTINUOUS INCREASE IN CANCER INCIDENCE AMONG CHILDREN AND YOUNG ADULTS. SOMATIC MUTATION THEORY HAS BEEN PROPOSED FOR A REVISION BASED ON THE EMERGING EXPERIMENTAL EVIDENCE, AS IT DOES NOT FULLY ADDRESS SOME ISSUES THAT HAVE PROVEN TO BE CRUCIAL FOR CARCINOGENESIS, NAMELY: THE INFLAMMATORY CONTEXT OF CANCER; THE KEY ROLE PLAYED BY THE STROMA, MICROENVIRONMENT, ENDOTHELIAL CELLS, ACTIVATED MACROPHAGES, AND SURROUNDING TISSUES; AND THE DISTORTED DEVELOPMENTAL COURSE FOLLOWED BY THE NEOPLASTIC TISSUE. FURTHERMORE, SMT IS OFTEN NOT ABLE TO CONSIDER EITHER THE EXISTENCE OF SPECIFIC MUTATIONS RESULTING IN A WELL-DEFINED CANCER TYPE, OR A CLEAR RELATIONSHIP BETWEEN MUTATIONS AND TUMOR PROGRESSION. MOREOVER, IT DOES NOT EXPLAIN THE MECHANISM OF ACTION OF THE NON-MUTAGENIC AND ENVIRONMENTAL CARCINOGENS. IN THE LAST DECADE, CANCER RESEARCH HAS HIGHLIGHTED THE PROMINENT ROLE OF AN ALTERED REGULATION OF GENE EXPRESSION, SUGGESTING THAT CANCER SHOULD BE CONSIDERED AS A RESULT OF A POLYCLONAL EPIGENETIC DISRUPTION OF STEM/PROGENITOR CELLS, MEDIATED BY TUMOUR-INDUCING GENES. THE MATERNAL AND FETAL EXPOSURE TO A WIDE RANGE OF CHEMICALS AND ENVIRONMENTAL CONTAMINANTS IS RAISING THE ATTENTION OF THE SCIENTIFIC COMMUNITY. INDEED, THE MOST POWERFUL PROCARCINOGENIC MECHANISMS OF ENDOCRINE DISRUPTORS AND OTHER POLLUTANTS IS LINKED TO THEIR POTENTIAL TO INTERFERE EPIGENETICALLY WITH THE EMBRYO-FETAL PROGRAMMING OF TISSUES AND ORGANS, ALTERING THE REGULATION OF THE GENES INVOLVED IN THE CELL CYCLE, CELL PROLIFERATION, APOPTOSIS, AND OTHER KEY SIGNALING PATHWAYS. THE EMBRYO-FETAL EXPOSURE TO ENVIRONMENTAL, STRESSFUL, AND PROINFLAMMATORY TRIGGERS (FIRST HIT), SEEMS TO ACT AS A 'DISEASE PRIMER', MAKING FETAL CELLS AND TISSUES MORE SUSCEPTIBLE TO THE SUBSEQUENT ENVIRONMENTAL EXPOSURES (SECOND HIT), TRIGGERING THE CARCINOGENIC PATHWAYS. FURTHERMORE, EVEN AT THE MOLECULAR LEVEL, IN CARCINOGENESIS, 'EPIGENETICS PRECEDES GENETICS' AS GLOBAL DNA HYPOMETHYLATION, AND THE HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES ARE COMMON BOTH IN CANCEROUS AND IN PRECANCEROUS CELLS, AND GENERALLY PRECEDE MUTATIONS. THESE EPIGENETIC MODELS MAY BETTER EXPLAIN THE INCREASE OF CANCER AND CHRONIC/DEGENERATIVE DISEASES IN THE LAST DECADES AND COULD BE USEFUL TO ADOPT APPROPRIATE PRIMARY PREVENTION MEASURES, ESSENTIALLY BASED ON THE REDUCTION OF MATERNAL-FETAL AND CHILD EXPOSURE TO SEVERAL PROCARCINOGENIC AGENTS AND FACTORS DISPERSED IN THE ENVIRONMENT AND IN THE FOOD-CHAINS, AS RECENTLY SUGGESTED BY THE WORLD HEALTH ORGANIZATION. 2018 14 6812 39 [EPIGENETICS, INTERFACE BETWEEN ENVIRONMENT AND GENES: ROLE IN COMPLEX DISEASES]. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION OR CELLULAR PHENOTYPE CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE. EPIGENETICS IS ONE OF THE MAJOR MECHANISMS EXPLAINING THE "DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASES" (DOHAD). BESIDES GENETIC BACKGROUND INHERITED FROM PARENTS, WHICH CONFERS SUSCEPTIBILITY TO CERTAIN PATHOLOGIES, EPIGENETIC CHANGES CONSTITUTE THE MEMORY OF PREVIOUS EVENTS, EITHER POSITIVE OR NEGATIVE, ALONG THE LIFE CYCLE, INCLUDING AT THE IN UTERO STAGE. THE LATER EXPOSITION TO HOSTILE ENVIRONMENT MAY REVEAL SUCH SUSCEPTIBILITY, WITH THE DEVELOPMENT OF VARIOUS PATHOLOGIES, AMONG THEM NUMEROUS CHRONIC COMPLEX DISEASES. THE DEMONSTRATION OF SUCH A SEQUENCE OF EVENTS HAS BEEN SHOWN FOR METABOLIC DISEASES AS OBESITY, METABOLIC SYNDROME AND TYPE 2 DIABETES, CARDIOVASCULAR DISEASE AND CANCER. IN CONTRAST TO GENETIC PREDISPOSITION, WHICH IS IRREVERSIBLE, EPIGENETIC CHANGES ARE POTENTIALLY REVERSIBLE, THUS GIVING TARGETS NOT ONLY FOR PREVENTION, BUT POSSIBLY ALSO FOR THE TREATMENT OF CERTAIN COMPLEX DISEASES. 2012 15 3210 40 HEALTH EFFECTS ASSOCIATED WITH PRE- AND PERINATAL EXPOSURE TO ARSENIC. INORGANIC ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN, ABLE TO INDUCE GENETIC AND EPIGENETIC ALTERATIONS. MORE THAN 200 MILLION PEOPLE WORLDWIDE ARE EXPOSED TO ARSENIC CONCENTRATIONS IN DRINKING WATER EXCEEDING THE RECOMMENDED WHO THRESHOLD (10MUG/L). ADDITIONALLY, CHRONIC EXPOSURE TO LEVELS BELOW THIS THRESHOLD IS KNOWN TO RESULT IN LONG-TERM HEALTH EFFECTS IN HUMANS. THE ARSENIC-RELATED HEALTH EFFECTS IN HUMANS ARE ASSOCIATED WITH ITS BIOTRANSFORMATION PROCESS, WHEREBY THE RESULTING METABOLITES CAN INDUCE MOLECULAR DAMAGE THAT ACCUMULATES OVER TIME. THE EFFECTS DERIVED FROM THESE ALTERATIONS INCLUDE GENOMIC INSTABILITY ASSOCIATED WITH OXIDATIVE DAMAGE, ALTERATION OF GENE EXPRESSION (INCLUDING CODING AND NON-CODING RNAS), GLOBAL AND LOCALIZED EPIGENETIC REPROGRAMMING, AND HISTONE POSTTRANSLATIONAL MODIFICATIONS. THESE ALTERATIONS DIRECTLY AFFECT MOLECULAR PATHWAYS INVOLVED IN THE ONSET AND PROGRESSION OF MANY CONDITIONS THAT CAN ARISE EVEN DECADES AFTER THE EXPOSURE OCCURS. IMPORTANTLY, ARSENIC METABOLITES GENERATED DURING ITS BIOTRANSFORMATION CAN ALSO PASS THROUGH THE PLACENTAL BARRIER, RESULTING IN FETAL EXPOSURE TO THIS CARCINOGEN AT SIMILAR LEVELS TO THOSE OF THE MOTHER. AS SUCH, MORE IMMEDIATE EFFECTS OF THE ARSENIC-INDUCED MOLECULAR DAMAGE CAN BE OBSERVED AS DETRIMENTAL EFFECTS ON FETAL DEVELOPMENT, PREGNANCY, AND BIRTH OUTCOMES. IN THIS REVIEW, WE FOCUS ON THE GENETIC AND EPIGENETIC DAMAGE ASSOCIATED WITH EXPOSURE TO LOW LEVELS OF ARSENIC, PARTICULARLY THOSE AFFECTING EARLY DEVELOPMENTAL STAGES. WE ALSO PRESENT HOW THESE ALTERATIONS OCCURRING DURING EARLY LIFE CAN IMPACT THE DEVELOPMENT OF CERTAIN DISEASES IN ADULT LIFE. 2021 16 748 43 CAPITAL EM, CYRILLICSMALL O, CYRILLICLECULAR MECHANISMS OF INITIATION OF CARCINOGENESIS IN THE TESTIS. IN THIS REVIEW, LITERATURE DATA ON THE STUDY OF PRECANCEROUS CHANGES IN TESTICULAR TISSUE AND MOLECULAR CHANGES, AS WELL AS THE INFLUENCE OF ENVIRONMENTAL FACTORS THAT CAN INITIATE CARCINOGENESIS, WERE ANALYZED AND SUMMARIZED FOR THE FUTURE DETERMINATION OF EARLY DIAGNOSIS OF GERM CELL TUMORS OF THE TESTIS AND THE DEVELOPMENT OF PREVENTIVE MEASURES. THE REVIEW ALSO DISCUSSES THE SIGNIFICANT NEW CHANGES PRESENTED IN THE FOURTH EDITION OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF UROGENITAL TUMORS, PUBLISHED IN 2016, AND MODERN CONCEPTS OF THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES. AMONG THE ENVIRONMENTAL FACTORS THAT CAN INITIATE CARCINOGENESIS, THE MOST NOTEWORTHY ARE THE BIOLOGICAL EFFECTS OF LOW DOSES OF IONIZING RADIATION, SUCH AS THE EFFECT OF RADIATION-INDUCED GENOME INSTABILITY, WHICH INCREASES THE RISK OF CARCINOGENESIS, THE "BYSTANDER EFFECT", AND CHRONIC OXIDATIVE STRESS. DISRUPTION OF UBIQUITIN-PROTEASOMAL PROTEOLYSIS, IMPAIRED MOLECULAR-LEVEL COMPONENTS OF THE BLOOD-TESTIS BARRIER, AND IMPAIRED REGULATORY ACTION OF TGF-BETA ON THE CELL CYCLE CAN PLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF MALE INFERTILITY AND THE INITIATION OF CARCINOGENESIS IN THE TESTIS. THE EFFECT OF LOW DOSES OF IONIZING RADIATION AS AN ADDITIONAL ETIOLOGICAL FACTOR LEADS TO CHANGES IN THE STRUCTURAL, AS WELL AS MOLECULAR, COMPONENTS OF THE TESTIS, INCLUDING EPIGENETIC CHANGES, WHICH CAN BE CHARACTERIZED AS ENVIRONMENTAL PATHOMORPHOSIS, WHICH LEADS TO IMPAIRED SPERMATOGENESIS AND INCREASED RISK OF MALIGNANCY. SUMMARIZING THE LITERATURE REVIEW DATA, WE CAN STATE THAT PATIENTS WITH BLOCKED SPERMATOGENESIS, IN WHICH ATYPICAL GERM CELL NEOPLASIA IN SITU CELLS ARE DETECTED IN TESTICULAR TISSUE, CONSTITUTE A GROUP AT INCREASED RISK OF TESTICULAR CARCINOGENESIS. THE PRESENCE OF ADDITIONAL ETIOLOGICAL FACTORS, SUCH AS CHRONIC LOW DOSES OF IONIZING RADIATION, CAN INITIATE THE PROGRESSION OF CARCINOGENESIS IN THE TESTICLE. 2019 17 5183 39 PREMATURE AGING IN CHILDHOOD CANCER SURVIVORS. PROGRESS IN MEDICINE HAS INCREASED THE SURVIVAL TIME OF CHILDREN SUFFERING FROM CANCER; >80% OF PATIENTS SURVIVE FOR AT LEAST 5 YEARS FROM THE END OF TREATMENT. HOWEVER, THERE ARE LATE EFFECTS OF ANTICANCER THERAPY, WHICH ACCOMPANY THIS SUCCESS. TWO-THIRDS OF CHILDHOOD CANCER SURVIVORS (CCSS) HAVE AT LEAST ONE LATE EFFECT (ANY SIDE EFFECTS OR COMPLICATIONS OF ANTICANCER TREATMENT THAT APPEAR MONTHS TO YEARS AFTER THE COMPLETION OF TREATMENT), E.G. ENDOCRINOPATHIES, CARDIOVASCULAR DISEASES OR SUBSEQUENT CANCERS, AND HALF OF THESE LATE EFFECTS ARE SERIOUS OR LIFE THREATENING. THESE LATE CONSEQUENCES OF CHILDHOOD CANCER TREATMENT POSE A SERIOUS HEALTH, SOCIAL AND ECONOMIC PROBLEM. A COMMON MECHANISM FOR DEVELOPING A NUMBER OF LATE EFFECTS IS THE ONSET OF PREMATURE BIOLOGICAL AGING, WHICH IS ASSOCIATED WITH THE EARLY ONSET OF CHRONIC DISEASES AND DEATH. CELLULAR SENESCENCE IN CANCER SURVIVORS IS CAUSED BY THERAPY THAT CAN INDUCE CHROMOSOMAL ABERRATIONS, MUTATIONS, TELOMERE SHORTENING, EPIGENETIC ALTERATIONS AND MITOCHONDRIAL DYSFUNCTIONS. THE MECHANISMS OF ACCELERATED AGING IN CANCER SURVIVORS HAVE NOT YET BEEN FULLY CLARIFIED. THE MEASUREMENT OF BIOLOGICAL AGE IN SURVIVORS CAN HELP IMPROVE THE UNDERSTANDING OF AGING MECHANISMS AND IDENTIFY RISK FACTORS FOR PREMATURE AGING. HOWEVER, TO THE BEST OF OUR KNOWLEDGE, NO SINGLE MARKER FOR THE EVALUATION OF BIOLOGICAL OR FUNCTIONAL AGE IS KNOWN, SO IT IS THEREFORE NECESSARY TO MEASURE THE CONSEQUENCES OF ANTICANCER TREATMENT USING COMPLEX ASSESSMENTS. THE PRESENT REVIEW PRESENTS AN OVERVIEW OF PREMATURE AGING IN CCSS AND OF THE MECHANISMS INVOLVED IN ITS DEVELOPMENT, FOCUSING ON THE ASSOCIATION OF SENESCENCE AND LATE EFFECTS. 2023 18 6840 29 [MALE INFERTILITY AND UROLOGIC CANCERS: ADVANCES IN STUDIES]. MALE INFERTILITY IS ONE OF THE MOST COMMON DISEASES IN ANDROLOGY. STUDIES SHOW THAT MALE INFERTILITY IS SIGNIFICANTLY CORRELATED WITH THE INCIDENCE AND MORTALITY OF TUMORS, ESPECIALLY MALIGNANT TUMORS IN THE GENITOURINARY SYSTEM, SUCH AS TESTIS CANCER AND PROSTATE CANCER. THE RELATIONSHIP OF MALE INFERTILITY WITH GENITOURINARY SYSTEM TUMORS INVOLVES VARIOUS ASPECTS, MAINLY INCLUDING CHANGES IN CHROMOSOME MUTATIONS, EPIGENETIC MARKS, HORMONAL IMBALANCE, AND CONGENITAL DEFORMITY. BESIDES, SOME CHRONIC DISEASES ARE SHOWN TO BE SIGNIFICANTLY ASSOCIATED WITH MALE INFERTILITY, AND SEMEN QUALITY OR FERTILITY STATUS MAY BE BIOMARKERS OF THE OVERALL HEALTH OF MALES. IN-DEPTH STUDIES OF THE CORRELATION BETWEEN MALE INFERTILITY AND THESE FACTORS ARE VERY IMPORTANT FOR AN INSIGHT INTO THE PATHOGENESIS AND PREVENTION OF THE RELATED DISEASES. 2022 19 1958 39 EPIGENETIC AGING AND COLORECTAL CANCER: STATE OF THE ART AND PERSPECTIVES FOR FUTURE RESEARCH. ALTHOUGH TRANSLATIONAL RESEARCH HAS IDENTIFIED A LARGE NUMBER OF POTENTIAL BIOMARKERS INVOLVED IN COLORECTAL CANCER (CRC) CARCINOGENESIS, A BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS ASSOCIATED WITH BIOLOGICAL AGING IN COLORECTAL CELLS AND TISSUES IS NEEDED. HERE, WE AIM TO SUMMARIZE THE STATE OF THE ART ABOUT THE ROLE OF AGE ACCELERATION, DEFINED AS THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IN THE DEVELOPMENT AND PROGRESSION OF CRC. SOME STUDIES HAVE SHOWN THAT ACCELERATED BIOLOGICAL AGING IS POSITIVELY ASSOCIATED WITH THE RISK OF CANCER AND DEATH IN GENERAL. IN LINE WITH THESE FINDINGS, OTHER STUDIES HAVE SHOWN HOW THE ASSESSMENT OF EPIGENETIC AGE IN PEOPLE AT RISK FOR CRC COULD BE HELPFUL FOR MONITORING THE MOLECULAR RESPONSE TO PREVENTIVE INTERVENTIONS. MOREOVER, IT WOULD BE INTERESTING TO INVESTIGATE WHETHER ABERRANT EPIGENETIC AGING COULD HELP IDENTIFY CRC PATIENTS WITH A HIGH RISK OF RECURRENCE AND A WORST PROGNOSIS, AS WELL AS THOSE WHO RESPOND POORLY TO TREATMENT. YET, THE APPLICATION OF THIS NOVEL CONCEPT IS STILL IN ITS INFANCY, AND FURTHER RESEARCH SHOULD BE ENCOURAGED IN ANTICIPATION OF FUTURE APPLICATIONS IN CLINICAL PRACTICE. 2020 20 6809 39 [EPIGENETICS IN INFLAMMATORY SYSTEMIC DISEASES]. IN ADDITION TO ANALYSIS OF THE GENETIC CODE, IN RECENT YEARS MORE AND MORE STUDIES HAVE CONCENTRATED ON CHANGES IN THE EPIGENETIC CODE. EPIGENETIC MECHANISMS DETERMINE WHICH GENES IN A CELL ARE TRANSCRIBED AND THUS FORM THE PHENOTYPE OF A CELL. THE EPIGENETIC CODE CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES, WHICH ALLOWS CELLS TO ADAPT TO LONGSTANDING CHANGES IN THE ENVIRONMENT. THEREFORE, IT IS FEASIBLE TO ASSUME THAT EPIGENETIC CHANGES ARE THE MOLECULAR BASIS FOR LONG-TERM EFFECTS OF THE ENVIRONMENT ON DISEASE DEVELOPMENT. IN PARTICULAR IN TUMORS AND CHRONIC INFLAMMATORY DISEASES EPIGENETIC CHANGES WERE FOUND TO CORRELATE WITH DISEASE SEVERITY AND PROGRESSION. KNOWLEDGE ABOUT THESE EPIGENETIC CHANGES MIGHT HELP THAT EPIGENETIC MODIFICATIONS CAN BE USED IN THE FUTURE AS BIOMARKERS, PROGNOSTIC FACTORS AND THERAPEUTIC TARGETS. 2014