1 1941 94 EPIDEMIOLOGY AND POTENTIAL MECHANISMS OF TOBACCO SMOKING AND HEAVY ALCOHOL CONSUMPTION IN PANCREATIC CANCER. TOBACCO SMOKING REPRESENTS AN IMPORTANT KNOWN CAUSE OF DUCTAL PANCREATIC ADENOCARCINOMA. RECENT DATA FROM POOLED ANALYSES IN CONSORTIA INVOLVING MULTIPLE CASE-CONTROL AND COHORT STUDIES SUGGEST THAT HEAVY (BUT NOT MODERATE OR LIGHT) ALCOHOL CONSUMPTION ALSO MAY INCREASE PANCREATIC CANCER RISK. ANIMAL AND HUMAN EVIDENCE INDICATE THAT TOBACCO CARCINOGENS AND METABOLITES MAY ACT IN CONCERT AND HAVE BOTH GENETIC AND EPIGENETIC EFFECTS AT EARLY AND LATER STAGES IN PANCREATIC TUMORIGENESIS. ONE OF THE MORE IMPORTANT TOBACCO-RELATED CARCINOGENS, NNK, PROBABLY ACTS VIA MULTIPLE PATHWAYS. HEAVY ALCOHOL CONSUMPTION MAY INCREASE PANCREATIC CANCER RISK BY POTENTIATING THE EFFECTS OF OTHER RISK FACTORS SUCH AS TOBACCO SMOKING, POOR NUTRITION, AND INFLAMMATORY PATHWAYS RELATED TO CHRONIC PANCREATITIS, BUT ALSO MAY HAVE INDEPENDENT GENETIC AND EPIGENETIC EFFECTS. ANIMAL AND HUMAN STUDIES OF TOBACCO- AND ALCOHOL-RELATED PANCREATIC CARCINOGENESIS SUGGEST MULTI-MODAL, OVERLAPPING MECHANISTIC PATHWAYS. TOBACCO SMOKING AND HEAVY ALCOHOL CONSUMPTION ARE PREVENTABLE EXPOSURES, AND THEIR AVOIDANCE WOULD SUBSTANTIALLY DECREASE THE BURDEN OF PANCREATIC CANCER WORLDWIDE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 1844 33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3 1014 28 CIGARETTE SMOKING AND DNA METHYLATION. DNA METHYLATION IS THE MOST STUDIED EPIGENETIC MODIFICATION, CAPABLE OF CONTROLLING GENE EXPRESSION IN THE CONTEXTS OF NORMAL TRAITS OR DISEASES. IT IS HIGHLY DYNAMIC DURING EARLY EMBRYOGENESIS AND REMAINS RELATIVELY STABLE THROUGHOUT LIFE, AND SUCH PATTERNS ARE INTRICATELY RELATED TO HUMAN DEVELOPMENT. DNA METHYLATION IS A QUANTITATIVE TRAIT DETERMINED BY A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. GENETIC VARIANTS AT A SPECIFIC LOCUS CAN INFLUENCE BOTH REGIONAL AND DISTANT DNA METHYLATION. THE ENVIRONMENT CAN HAVE VARYING EFFECTS ON DNA METHYLATION DEPENDING ON WHEN THE EXPOSURE OCCURS, SUCH AS DURING PRENATAL LIFE OR DURING ADULTHOOD. IN PARTICULAR, CIGARETTE SMOKING IN THE CONTEXT OF BOTH CURRENT SMOKING AND PRENATAL EXPOSURE IS A STRONG MODIFIER OF DNA METHYLATION. EPIGENOME-WIDE ASSOCIATION STUDIES HAVE UNCOVERED CANDIDATE GENES ASSOCIATED WITH CIGARETTE SMOKING THAT HAVE BIOLOGICALLY RELEVANT FUNCTIONS IN THE ETIOLOGY OF SMOKING-RELATED DISEASES. AS SUCH, DNA METHYLATION IS A POTENTIAL MECHANISTIC LINK BETWEEN CURRENT SMOKING AND CANCER, AS WELL AS PRENATAL CIGARETTE-SMOKE EXPOSURE AND THE DEVELOPMENT OF ADULT CHRONIC DISEASES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 6790 29 [DNA METHYLATION ANALYSIS IN ENVIRONMENTAL AND OCCUPATIONAL CANCER RESEARCH]. THE PRESENT PAPER REVIEWS RECENT LABORATORY METHODS AND EXPERIMENTAL EVIDENCE CONCERNING EPIGENETIC BIOMARKERS INVOLVED IN CARCINOGENESIS MECHANISMS. WE INTRODUCE DNA METHYLATION AND ITS ROLE IN GENE EXPRESSION CONTROL. DNA METHYLATION ANALYSIS MAY ALLOW TO IDENTIFY EARLY CHANGES LEADING TO CANCER AND OTHER CHRONIC DISEASES. WE DESCRIBE HERE STRATEGIES FOR LABORATORY ANALYSES AND THEIR POSSIBLE APPLICATIONS. WE EXAMINE RESULTS FROM RECENT EXPERIMENTAL STUDIES SUGGESTING THAT THE EFFECTS OF CERTAIN OCCUPATIONAL AGENTS ARE MEDIATED BY ALTERATIONS IN DNA METHYLATION. PLANNING AND CONDUCTING INVESTIGATIONS ON EXPOSED HUMAN SUBJECTS WILL ALLOW TO VERIFY WHETHER DNA METHYLATION CHANGES IDENTIFIED IN ANIMAL AND IN-VITRO STUDIES MAY BE USED AS EARLY-EFFECT AND SUSCEPTIBILITY BIOMARKERS. DNA METHYLATION ANALYSIS HAS THE POTENTIAL FOR FUTURE APPLICATIONS IN RISK ASSESSMENT AND PREVENTION PROGRAMS CONDUCTED ON SUBJECTS EXPOSED TO HUMAN CARCINOGENS.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  318 31 ALCOHOL-INDUCED EPIGENETIC CHANGES IN CANCER. CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH SERIOUS NEGATIVE HEALTH EFFECTS, INCLUDING THE DEVELOPMENT OF SEVERAL CANCER TYPES. ONE OF THE PATHWAYS AFFECTED BY ALCOHOL TOXICITY IS THE ONE-CARBON METABOLISM. THE ALCOHOL-INDUCED IMPAIRMENT OF THIS METABOLIC PATHWAY RESULTS IN EPIGENETIC CHANGES ASSOCIATED WITH CANCER DEVELOPMENT. THESE EPIGENETIC CHANGES ARE INDUCED BY FOLATE DEFICIENCY AND BY PRODUCTS OF THE ETHANOL METABOLISM. THE CHANGES INDUCED BY LONG-TERM HEAVY ETHANOL CONSUMPTION RESULT IN ELEVATIONS OF HOMOCYSTEINE AND S-ADENOSYL-HOMOCYSTEINE (SAH) AND REDUCTIONS IN S-ADENOSYLMETHIONINE (SAM) AND ANTIOXIDANT GLUTATHIONE (GSH) LEVELS, LEADING TO ABNORMAL PROMOTER GENE HYPERMETHYLATION, GLOBAL HYPOMETHYLATION, AND METABOLIC INSUFFICIENCY OF ANTIOXIDANT DEFENSE MECHANISMS. IN ADDITION, REACTIVE OXYGEN SPECIES (ROS) GENERATED DURING THE ETHANOL METABOLISM INDUCE ALTERATIONS IN DNA METHYLATION PATTERNS THAT PLAY A CRITICAL ROLE IN CANCER DEVELOPMENT. SPECIFIC EPIGENETIC CHANGES IN ESOPHAGEAL, HEPATIC, AND COLORECTAL CANCERS HAVE BEEN DETECTED IN BLOOD SAMPLES AND PROPOSED TO BE USED CLINICALLY AS EPIGENETIC BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF THESE CANCERS. ALSO, GENETIC VARIANTS OF GENES INVOLVED IN ONE-CARBON METABOLISM AND ETHANOL METABOLISM WERE FOUND TO MODULATE THE RELATIONSHIP BETWEEN ALCOHOL-INDUCED EPIGENETIC CHANGES AND CANCER RISK. FURTHERMORE, ALCOHOL METABOLISM PRODUCTS HAVE BEEN ASSOCIATED WITH AN INCREASE IN NADH LEVELS, WHICH LEAD TO HISTONE MODIFICATIONS AND CHANGES IN GENE EXPRESSION THAT IN TURN INFLUENCE CANCER SUSCEPTIBILITY. CHRONIC EXCESSIVE USE OF ALCOHOL ALSO AFFECTS SELECTED MEMBERS OF THE FAMILY OF MICRORNAS, AND AS MIRNAS COULD ACT AS EPIGENETIC REGULATORS, THIS MAY PLAY AN IMPORTANT ROLE IN CARCINOGENESIS. IN CONCLUSION, TARGETING ALCOHOL-INDUCED EPIGENETIC CHANGES IN SEVERAL CANCER TYPES COULD MAKE AVAILABLE CLINICAL TOOLS FOR THE DIAGNOSIS, PROGNOSIS, AND TREATMENT OF THESE CANCERS, WITH AN IMPORTANT ROLE IN PRECISION MEDICINE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  315 29 ALCOHOL, DNA METHYLATION, AND CANCER. CANCER IS ONE OF THE MOST SIGNIFICANT DISEASES ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION, AND CHRONIC DRINKING IS A STRONG RISK FACTOR FOR CANCER, PARTICULARLY OF THE UPPER AERODIGESTIVE TRACT, LIVER, COLORECTUM, AND BREAST. SEVERAL FACTORS CONTRIBUTE TO ALCOHOL-INDUCED CANCER DEVELOPMENT (I.E., CARCINOGENESIS), INCLUDING THE ACTIONS OF ACETALDEHYDE, THE FIRST AND PRIMARY METABOLITE OF ETHANOL, AND OXIDATIVE STRESS. HOWEVER, INCREASING EVIDENCE SUGGESTS THAT ABERRANT PATTERNS OF DNA METHYLATION, AN IMPORTANT EPIGENETIC MECHANISM OF TRANSCRIPTIONAL CONTROL, ALSO COULD BE PART OF THE PATHOGENETIC MECHANISMS THAT LEAD TO ALCOHOL-INDUCED CANCER DEVELOPMENT. THE EFFECTS OF ALCOHOL ON GLOBAL AND LOCAL DNA METHYLATION PATTERNS LIKELY ARE MEDIATED BY ITS ABILITY TO INTERFERE WITH THE AVAILABILITY OF THE PRINCIPAL BIOLOGICAL METHYL DONOR, S-ADENOSYLMETHIONINE (SAME), AS WELL AS PATHWAYS RELATED TO IT. SEVERAL MECHANISMS MAY MEDIATE THE EFFECTS OF ALCOHOL ON DNA METHYLATION, INCLUDING REDUCED FOLATE LEVELS AND INHIBITION OF KEY ENZYMES IN ONE-CARBON METABOLISM THAT ULTIMATELY LEAD TO LOWER SAME LEVELS, AS WELL AS INHIBITION OF ACTIVITY AND EXPRESSION OF ENZYMES INVOLVED IN DNA METHYLATION (I.E., DNA METHYLTRANSFERASES). FINALLY, VARIATIONS (I.E., POLYMORPHISMS) OF SEVERAL GENES INVOLVED IN ONE-CARBON METABOLISM ALSO MODULATE THE RISK OF ALCOHOL-ASSOCIATED CARCINOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7 4458 29 MOLECULAR MECHANISMS OF ALCOHOL-INDUCED COLORECTAL CARCINOGENESIS. THE ETIOLOGY OF COLORECTAL CANCER (CRC) IS COMPLEX. APPROXIMATELY, 10% OF INDIVIDUALS WITH CRC HAVE PREDISPOSING GERMLINE MUTATIONS THAT LEAD TO FAMILIAL CANCER SYNDROMES, WHEREAS MOST CRC PATIENTS HAVE SPORADIC CANCER RESULTING FROM A COMBINATION OF ENVIRONMENTAL AND GENETIC RISK FACTORS. IT HAS BECOME INCREASINGLY CLEAR THAT CHRONIC ALCOHOL CONSUMPTION IS ASSOCIATED WITH THE DEVELOPMENT OF SPORADIC CRC; HOWEVER, THE EXACT MECHANISMS BY WHICH ALCOHOL CONTRIBUTES TO COLORECTAL CARCINOGENESIS ARE LARGELY UNKNOWN. SEVERAL PROPOSED MECHANISMS FROM STUDIES IN CRC MODELS SUGGEST THAT ALCOHOL METABOLITES AND/OR ENZYMES ASSOCIATED WITH ALCOHOL METABOLISM ALTER CELLULAR REDOX BALANCE, CAUSE DNA DAMAGE, AND EPIGENETIC DYSREGULATION. IN ADDITION, ALCOHOL METABOLITES CAN CAUSE A DYSBIOTIC COLORECTAL MICROBIOME AND INTESTINAL PERMEABILITY, RESULTING IN BACTERIAL TRANSLOCATION, INFLAMMATION, AND IMMUNOSUPPRESSION. ALL OF THESE EFFECTS CAN INCREASE THE RISK OF DEVELOPING CRC. THIS REVIEW AIMS TO OUTLINE SOME OF THE MOST SIGNIFICANT AND RECENT FINDINGS ON THE MECHANISMS OF ALCOHOL IN COLORECTAL CARCINOGENESIS. WE EXAMINE THE EFFECT OF ALCOHOL ON THE GENERATION OF REACTIVE OXYGEN SPECIES, THE DEVELOPMENT OF GENOTOXIC STRESS, MODULATION OF ONE-CARBON METABOLISM, DISRUPTION OF THE MICROBIOME, AND IMMUNOSUPPRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8 4767 31 NUCLEAR AND MITOCHONDRIAL DNA ALTERATIONS IN NEWBORNS WITH PRENATAL EXPOSURE TO CIGARETTE SMOKE. NEWBORNS EXPOSED TO MATERNAL CIGARETTE SMOKE (CS) IN UTERO HAVE AN INCREASED RISK OF DEVELOPING CHRONIC DISEASES, CANCER, AND ACQUIRING DECREASED COGNITIVE FUNCTION IN ADULTHOOD. ALTHOUGH THE LITERATURE REPORTS MANY DELETERIOUS EFFECTS ASSOCIATED WITH MATERNAL CIGARETTE SMOKING ON THE FETUS, THE MOLECULAR ALTERATIONS AND MECHANISMS OF ACTION ARE NOT YET CLEAR. SMOKING MAY ACT DIRECTLY ON NUCLEAR DNA BY INDUCING MUTATIONS OR EPIGENETIC MODIFICATIONS. RECENT STUDIES ALSO INDICATE THAT SMOKING MAY ACT ON MITOCHONDRIAL DNA BY INDUCING A CHANGE IN THE NUMBER OF COPIES TO MAKE UP FOR THE DAMAGE CAUSED BY SMOKING ON THE RESPIRATORY CHAIN AND LACK OF ENERGY. IN ADDITION, INDIVIDUAL GENETIC SUSCEPTIBILITY PLAYS A SIGNIFICANT ROLE IN DETERMINING THE EFFECTS OF SMOKING DURING DEVELOPMENT. FURTHERMORE, PRIOR EXPOSURE OF PATERNAL AND MATERNAL GAMETES TO CIGARETTE SMOKE MAY AFFECT THE HEALTH OF THE DEVELOPING INDIVIDUAL, NOT ONLY THE IN UTERO EXPOSURE. THIS REVIEW EXAMINES THE GENETIC AND EPIGENETIC ALTERATIONS IN NUCLEAR AND MITOCHONDRIAL DNA ASSOCIATED WITH SMOKE EXPOSURE DURING THE MOST SENSITIVE PERIODS OF DEVELOPMENT (PRIOR TO CONCEPTION, PRENATAL AND EARLY POSTNATAL) AND ASSESSES HOW SUCH CHANGES MAY HAVE CONSEQUENCES FOR BOTH FETAL GROWTH AND DEVELOPMENT.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9 4112 31 MECHANISMS CONTRIBUTING TO THE COMORBIDITY OF COPD AND LUNG CANCER. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OFTEN CO-OCCUR, AND INDIVIDUALS WITH COPD ARE AT A HIGHER RISK OF DEVELOPING LUNG CANCER. WHILE THE UNDERLYING MECHANISM FOR THIS RISK IS NOT WELL UNDERSTOOD, ITS MAJOR CONTRIBUTING FACTORS HAVE BEEN PROPOSED TO INCLUDE GENOMIC, IMMUNE, AND MICROENVIRONMENT DYSREGULATION. HERE, WE REVIEW THE EVIDENCE AND SIGNIFICANT STUDIES THAT EXPLORE THE MECHANISMS UNDERLYING THE HEIGHTENED LUNG CANCER RISK IN PEOPLE WITH COPD. GENETIC AND EPIGENETIC CHANGES, AS WELL AS THE ABERRANT EXPRESSION OF NON-CODING RNAS, PREDISPOSE THE LUNG EPITHELIUM TO CARCINOGENESIS BY ALTERING THE EXPRESSION OF CANCER- AND IMMUNE-RELATED GENES. OXIDATIVE STRESS GENERATED BY TOBACCO SMOKING PLAYS A ROLE IN REDUCING GENOMIC INTEGRITY, PROMOTING EPITHELIAL-MESENCHYMAL-TRANSITION, AND GENERATING A CHRONIC INFLAMMATORY ENVIRONMENT. THIS LEADS TO ABNORMAL IMMUNE RESPONSES THAT PROMOTE CANCER DEVELOPMENT, THOUGH NOT ALL SMOKERS DEVELOP LUNG CANCER. SEX DIFFERENCES IN THE METABOLISM OF TOBACCO SMOKE PREDISPOSE FEMALES TO DEVELOPING COPD AND ACCUMULATING DAMAGE FROM OXIDATIVE STRESS THAT POSES A RISK FOR THE DEVELOPMENT OF LUNG CANCER. DYSREGULATION OF THE LUNG MICROENVIRONMENT AND MICROBIOME CONTRIBUTES TO CHRONIC INFLAMMATION, WHICH IS OBSERVED IN COPD AND KNOWN TO FACILITATE CANCER INITIATION IN VARIOUS TUMOR TYPES. FURTHER, THERE IS A NEED TO BETTER CHARACTERIZE AND IDENTIFY THE PROPORTION OF INDIVIDUALS WITH COPD WHO ARE AT A HIGH RISK FOR DEVELOPING LUNG CANCER. WE EVALUATE POSSIBLE NOVEL AND INDIVIDUALIZED SCREENING STRATEGIES, INCLUDING BIOMARKERS IDENTIFIED IN GENETIC STUDIES AND EXHALED BREATH CONDENSATE ANALYSIS. WE ALSO DISCUSS THE USE OF CORTICOSTEROIDS AND STATINS AS CHEMOPREVENTIVE AGENTS TO PREVENT LUNG CANCER. IT IS CRUCIAL THAT WE OPTIMIZE THE CURRENT METHODS FOR THE EARLY DETECTION AND MANAGEMENT OF LUNG CANCER AND COPD IN ORDER TO IMPROVE THE HEALTH OUTCOMES FOR A LARGE AFFECTED POPULATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 1010 24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  396 28 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12 3210 28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13 2507 25 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 6653 37 UPDATE ON PANCREATIC CANCER AND ALCOHOL-ASSOCIATED RISK. DUCTAL ADENOCARCINOMA OF THE PANCREAS IS CHARACTERIZED BY EXTREMELY AGGRESSIVE BEHAVIOR, WITH AN OVERALL 5-YEAR SURVIVAL OF <4%. BECAUSE CONVENTIONAL AND SPECIFICALLY TAILORED THERAPEUTIC REGIMENS HAVE LITTLE IMPACT ON PATIENT SURVIVAL, EPIDEMIOLOGICAL AND MOLECULAR RESEARCH AIMS AT IDENTIFYING AND REDUCING RISK FACTORS. CIGARETTE SMOKING, OBESITY, DIABETES MELLITUS, AND CHRONIC PANCREATITIS ARE AMENABLE TO MEDICAL PREVENTION OR THERAPY. HEAVY ALCOHOL CONSUMPTION IS AN INCONSISTENT SINGLE RISK FACTOR FOR PANCREATIC CANCER BUT MAY PROMOTE CARCINOGENESIS BY INCREASING THE RISK OF DIABETES MELLITUS OR CHRONIC PANCREATITIS. FOR VARIOUS AGENTS, THE KEY CARCINOGENIC EFFECT IS PROBABLY AN INFLAMMATORY RESPONSE IN THE PANCREATIC TISSUE. ON THE MOLECULAR LEVEL, MUTATIONS OF ONCOGENES AND TUMOR SUPPRESSOR GENES, AS WELL AS VARIOUS EPIGENETIC ALTERATIONS, SUCH AS OVEREXPRESSION OF GROWTH FACTORS AND THEIR RECEPTORS, ARE IMPORTANT IN TUMORIGENESIS. COMPLETE AND SAFE SURGICAL RESECTION, TOGETHER WITH ADJUVANT THERAPY, OFFERS PROLONGED SURVIVAL, WITH 5-YEAR SURVIVAL RATES OF APPROXIMATELY 25%. HOWEVER, FOR UNRESECTABLE OR DISSEMINATED DISEASE, WHICH CONSTITUTES THE VAST MAJORITY OF CASES, TREATMENT IS PALLIATIVE. DESPITE INCREASING KNOWLEDGE ABOUT THE MOLECULAR PATHOLOGY OF PANCREATIC CANCER AND DESPITE ADVANCES IN TREATMENT, THE OVERALL COURSE OF THE DISEASE IS DISMAL, AND REINFORCED EFFORTS TO REDUCE INCIDENCE AND IMPROVE OUTCOME ARE NEEDED DESPERATELY.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 1958 19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 5373 32 RECENT ADVANCES IN UNDERSTANDING THE ROLE OF DIET AND OBESITY IN THE DEVELOPMENT OF COLORECTAL CANCER. COLORECTAL CANCER (CRC) IS A MAJOR CAUSE OF PREMATURE DEATH IN THE UK AND MANY DEVELOPED COUNTRIES. HOWEVER, THE RISK OF DEVELOPING CRC IS WELL RECOGNISED TO BE ASSOCIATED NOT ONLY WITH DIET BUT ALSO WITH OBESITY AND LACK OF EXERCISE. WHILE EPIDEMIOLOGICAL EVIDENCE SHOWS AN ASSOCIATION WITH FACTORS SUCH AS HIGH RED MEAT INTAKE AND LOW INTAKE OF VEGETABLES, FIBRE AND FISH, THE MECHANISMS UNDERLYING THESE EFFECTS ARE ONLY NOW BEING ELUCIDATED. CRC DEVELOPS OVER MANY YEARS AND IS TYPICALLY CHARACTERISED BY AN ACCUMULATION OF MUTATIONS, WHICH MAY ARISE AS A CONSEQUENCE OF INHERITED POLYMORPHISMS IN KEY GENES, BUT MORE COMMONLY AS A RESULT OF SPONTANEOUSLY ARISING MUTATIONS AFFECTING GENES CONTROLLING CELL PROLIFERATION, DIFFERENTIATION, APOPTOSIS AND DNA REPAIR. EPIGENETIC CHANGES ARE OBSERVED THROUGHOUT THE PROGRESS FROM NORMAL MORPHOLOGY THROUGH FORMATION OF ADENOMA, AND THE SUBSEQUENT DEVELOPMENT OF CARCINOMA. THE REASONS WHY THIS ACCUMULATION OF LOSS OF HOMOEOSTATIC CONTROLS ARISES ARE UNCLEAR BUT CHRONIC INFLAMMATION HAS BEEN PROPOSED TO PLAY A CENTRAL ROLE. OBESITY IS ASSOCIATED WITH INCREASED PLASMA LEVELS OF CHEMOKINES AND ADIPOKINES CHARACTERISTIC OF CHRONIC SYSTEMIC INFLAMMATION, AND DIETARY FACTORS SUCH AS FISH OILS AND PHYTOCHEMICALS HAVE BEEN SHOWN TO HAVE ANTI-INFLAMMATORY PROPERTIES AS WELL AS MODULATING ESTABLISHED RISK FACTORS SUCH AS APOPTOSIS AND CELL PROLIFERATION. THERE IS ALSO SOME EVIDENCE THAT DIET CAN MODIFY EPIGENETIC CHANGES. THIS PAPER BRIEFLY REVIEWS THE CURRENT STATE OF KNOWLEDGE IN RELATION TO CRC DEVELOPMENT AND CONSIDERS EVIDENCE FOR POTENTIAL MECHANISMS BY WHICH DIET MAY MODIFY RISK.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
17  266 36 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	

18 5119 30 POSSIBLE CONTRIBUTION OF CHRONIC INFLAMMATION IN THE INDUCTION OF CANCER IN RHEUMATIC DISEASES. SEVERAL CHRONIC INFLAMMATORY CONDITIONS AND AUTOIMMUNE DISEASES INVOLVING DIFFERENT ORGANS AND TISSUES HAVE BEEN FOUND AT RISK OF PROGRESSION TO CANCER. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE PRODUCTS, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT TRANSITION OF CELLS ALMOST ALWAYS IN A BACKGROUND OF CHRONIC INFLAMMATION. INTERESTINGLY, EPIGENETIC PERTURBATIONS (I.E. MIRNA ABERRATIONS, ALTERED DNA METHYLATION) TOGETHER WITH IMPORTANT STEROID HORMONE METABOLIC CHANGES (I.E. OESTROGENS), OR THE ALTERED VITAMIN D CONCENTRATIONS THAT MAY UNBALANCE THE IMMUNE / INFLAMMATORY RESPONSE, HAVE BEEN FOUND LINKED TO THE RISK AND SEVERITY IN SEVERAL CHRONIC INFLAMMATORY CONDITIONS, AS WELL AS IN CANCER. IN PARTICULAR, IT IS EVIDENT, THAT NOT ONLY THE PARENT OESTROGEN BUT ALSO OESTROGEN METABOLITES SHOULD BE TAKEN INTO ACCOUNT WHEN THIS PROCESS IS EVALUATED, SPECIALLY THE FORMATION OF CATECHOLOESTROGEN METABOLITES, THAT ARE CAPABLE OF FORMING EITHER STABLE OR DEPURINATING DNA ADDUCTS, WHICH CAN CAUSE EXTENSIVE DNA DAMAGE. IT IS INTERESTING THAT TODAY THE SUCCESSFUL TREATMENT OF SEVERAL CHRONIC IMMUNE/INFLAMMATORY RHEUMATIC DISEASES IS OBTAINED ALSO BY USING MEDICATIONS INITIALLY DEVELOPED FOR THEIR USE IN ONCOLOGY. THE CIRCADIAN INCREASE OF GROWTH FACTORS, SPECIALLY DURING THE LATE NIGHT, IN BOTH CHRONIC INFLAMMATION AND IN CANCER PATIENTS, AS WELL AS THE PRESENCE OF OESTROGEN-REGULATED CIRCADIAN MECHANISMS, SUGGESTS FURTHER IMPORTANT LINKS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 3848 21 IS EPIGENETICS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE? BACKGROUND: EPIGENETIC MECHANISMS PROVIDE ONE POTENTIAL EXPLANATION FOR HOW ENVIRONMENTAL INFLUENCES IN EARLY LIFE CAUSE LONG-TERM CHANGES IN CHRONIC DISEASE SUSCEPTIBILITY. WHEREAS EPIGENETIC DYSREGULATION IS INCREASINGLY IMPLICATED IN VARIOUS RARE DEVELOPMENTAL SYNDROMES AND CANCER, THE ROLE OF EPIGENETICS IN COMPLEX CHRONIC DISEASES, SUCH AS CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND OBESITY, REMAINS LARGELY UNCHARACTERIZED. EXTENSIVE WORK IN ANIMAL MODELS IS REQUIRED TO DEVELOP SPECIFIC HYPOTHESES THAT CAN BE PRACTICABLY TESTED IN HUMANS. ANIMAL MODELS: WE HAVE DEVELOPED A MOUSE MODEL SHOWING THAT METHYL DONOR SUPPLEMENTATION PREVENTS TRANSGENERATIONAL AMPLIFICATION OF OBESITY, SUGGESTING A ROLE FOR DNA METHYLATION IN THE DEVELOPMENTAL ESTABLISHMENT OF BODY WEIGHT REGULATION. CONCLUSIONS: COUPLING SUCH MODELS WITH RECENTLY DEVELOPED EPIGENOMIC TECHNOLOGIES SHOULD ULTIMATELY ENABLE US TO DETERMINE IF EPIGENETICS IS AN IMPORTANT LINK BETWEEN EARLY LIFE EVENTS AND ADULT DISEASE.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 1970 27 EPIGENETIC ALTERATIONS AND OCCUPATIONAL EXPOSURE TO BENZENE, FIBERS, AND HEAVY METALS ASSOCIATED WITH TUMOR DEVELOPMENT (REVIEW). THE CHRONIC OCCUPATIONAL EXPOSURE TO CONTAMINANTS AND CARCINOGENS LEADS TO THE DEVELOPMENT OF CANCER. OVER THE PAST DECADES, MANY CARCINOGENS HAVE BEEN FOUND IN THE OCCUPATIONAL ENVIRONMENT AND THEIR PRESENCE IS OFTEN ASSOCIATED WITH AN INCREASED INCIDENCE OF CANCER. ACCORDING TO THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), THE MAJORITY OF CARCINOGENS ARE CLASSIFIED AS 'PROBABLE' AND 'POSSIBLE' HUMAN CARCINOGENS, WHILE, DIRECT EVIDENCE OF CARCINOGENICITY IS PROVIDED IN EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES. ADDITIONALLY, ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS MAY BE EARLY INDICATORS OF GENOTOXIC AND NON-GENOTOXIC CARCINOGEN EXPOSURE. IN THE PRESENT REVIEW, THE RELATIONSHIP BETWEEN EXPOSURES TO BENZENE, MINERAL FIBERS, METALS AND EPIGENETIC ALTERATIONS ARE DISCUSSED AS THE MOST IMPORTANT CANCER RISK FACTORS DURING WORK ACTIVITIES.	2017