1 3803 151 INTESTINAL METAPLASIA OF THE STOMACH. A STATUS REPORT. INTESTINAL METAPLASIA IN THE STOMACH INCREASES THE RISK OF GASTRIC CANCER, AND THE INCREASED RISK IS PROPORTIONAL TO THE EXTENT OF THE METAPLASIA. THIS RISK COULD BE GENERATED BY ONE OR MORE MECHANISMS: (1) THE METAPLASTIC TISSUE IS AN EARLY STEP IN A MULTISTEP INDUCTION PROCESS; (2) THE METAPLASTIC TISSUE IS AN EPIGENETIC CHANGE THAT RAISES THE PH OF GASTRIC JUICE BY REPLACING OXYNTIC MUCOSA, FAVORING THE GROWTH OF A BACTERIA CAPABLE OF GENERATING ENDOGENOUS MUTAGENS; AND/OR (3) THE METAPLASIA IS ONLY A MARKER FOR CHRONIC GASTRITIS DUE TO H. PYLORI INFECTION OR PERNICIOUS ANEMIA. WITH THE LAST MECHANISM, THE INFLAMMATORY RESPONSE FAVORS INTRAMURAL MUTAGENESIS THAT MIGHT RESULT IN METAPLASIA OR NEOPLASIA AS INDEPENDENT EVENTS. FINDING GENE REARRANGEMENTS COMMON TO BOTH METAPLASTIC AND NEOPLASTIC TISSUE MAY ESTABLISH A DIRECT LINK BETWEEN THEM, BUT TOO FEW HAVE BEEN IDENTIFIED TO ACCOUNT FOR THE LARGE NUMBER OF STOMACH CANCERS THAT DEVELOP IN HIGH RISK POPULATIONS. HISTOCHEMICAL AND IMMUNOCHEMICAL STAINS THAT IDENTIFY ENZYMES OR MUCOSUBSTANCES MAY SUGGEST THAT METAPLASTIC EPITHELIAL CELLS RESEMBLE SMALL OR LARGE INTESTINAL CELLS, BUT THEY ARE DISTINCTLY DIFFERENT FROM BOTH. MOREOVER, THESE STAINS DO NOT INDICATE WHETHER A GIVEN CYTOLOGIC CHANGE IS GENETIC OR EPIGENETIC; THEREFORE, THEY CANNOT BE USED TO DEFINE THE RELATIONSHIP BETWEEN METAPLASIA AND NEOPLASIA. IT IS UNNECESSARY FOR PRACTICING PHYSICIANS TO AWAIT RESOLUTION OF THIS QUESTION. IT CAN BE ASSUMED THAT ANY PERSON WITH EXTENSIVE METAPLASIA IS AT HIGH RISK FOR GASTRIC CANCER AND SHOULD BE SUBJECT TO PERIODIC SCREENING. THE EXTENT OF THE METAPLASTIC PROCESS IS PROBABLY MORE IMPORTANT THAN THE METAPLASTIC SUBTYPE. 1994 2 1112 38 COMMON PATHOGENETIC MECHANISMS UNDERLYING AGING AND TUMOR AND MEANS OF INTERVENTIONS. RECENTLY, THERE HAS BEEN AN INCREASE IN THE INCIDENCE OF MALIGNANT TUMORS AMONG THE OLDER POPULATION. MOREOVER, THERE IS AN ASSOCIATION BETWEEN AGING AND CANCER. DURING THE PROCESS OF SENESCENCE, THE HUMAN BODY SUFFERS FROM A SERIES OF IMBALANCES, WHICH HAVE BEEN SHOWN TO FURTHER ACCELERATE AGING, TRIGGER TUMORIGENESIS, AND FACILITATE CANCER PROGRESSION. THEREFORE, EXPLORING THE JUNCTIONS OF AGING AND CANCER AND SEARCHING FOR NOVEL METHODS TO RESTORE THE JUNCTIONS IS OF GREAT IMPORTANCE TO INTERVENE AGAINST AGING-RELATED CANCERS. IN THIS REVIEW, WE HAVE IDENTIFIED THE UNDERLYING PATHOGENETIC MECHANISMS OF AGING-RELATED CANCERS BY COMPARING ALTERATIONS IN THE HUMAN BODY CAUSED BY AGING AND THE FACTORS THAT TRIGGER CANCERS. WE FOUND THAT THE COMMON MECHANISMS OF AGING AND CANCER INCLUDE CELLULAR SENESCENCE, ALTERATIONS IN PROTEOSTASIS, MICROBIOTA DISORDERS (DECREASED PROBIOTICS AND INCREASED PERNICIOUS BACTERIA), PERSISTENT CHRONIC INFLAMMATION, EXTENSIVE IMMUNOSENESCENCE, INORDINATE ENERGY METABOLISM, ALTERED MATERIAL METABOLISM, ENDOCRINE DISORDERS, ALTERED GENETIC EXPRESSION, AND EPIGENETIC MODIFICATION. FURTHERMORE, WE HAVE PROPOSED THAT AGING AND CANCER HAVE COMMON MEANS OF INTERVENTION, INCLUDING NOVEL USES OF COMMON MEDICINE (METFORMIN, RESVERATROL, AND RAPAMYCIN), DIETARY RESTRICTION, AND ARTIFICIAL MICROBIOTA INTERVENTION OR SELECTIVELY REPLENISHING SCARCE METABOLITES. IN ADDITION, WE HAVE SUMMARIZED THE RESEARCH PROGRESS OF EACH INTERVENTION AND REVEALED THEIR BIDIRECTIONAL EFFECTS ON CANCER PROGRESSION TO COMPARE THEIR RELIABILITY AND FEASIBILITY. THEREFORE, THE STUDY FINDINGS PROVIDE VITAL INFORMATION FOR ADVANCED RESEARCH STUDIES ON AGE-RELATED CANCERS. HOWEVER, THERE IS A NEED FOR FURTHER OPTIMIZATION OF THE DESCRIBED METHODS AND MORE SUITABLE METHODS FOR COMPLICATED CLINICAL PRACTICES. IN CONCLUSION, TARGETING AGING MAY HAVE POTENTIAL THERAPEUTIC EFFECTS ON AGING-RELATED CANCERS. 2022 3 3229 38 HELICOBACTER PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. HELICOBACTER PYLORI (H. PYLORI) INFECT OVER HALF OF THE WORLD'S POPULATION. THE PREVALENCE OF H. PYLORI INFECTION AND THE PREDOMINANT GENOTYPE OF H. PYLORI VIRULENCE FACTORS VARY CONSIDERABLY ACROSS DIFFERENT GEOGRAPHICAL REGIONS. H. PYLORI COULD UNIQUELY PERSIST FOR DECADES IN THE HARSH STOMACH ENVIRONMENT, WHERE IT DAMAGES THE GASTRIC MUCOSA AND CHANGES THE PATTERN OF GASTRIC HORMONE RELEASE, THEREBY AFFECTS GASTRIC PHYSIOLOGY. BY UTILIZING VARIOUS VIRULENCE FACTORS, H. PYLORI TARGETS DIFFERENT CELLULAR PROTEINS TO MODULATE THE HOST INFLAMMATORY RESPONSE AND INITIATE MULTIPLE "HITS" ON THE GASTRIC MUCOSA, RESULTING IN CHRONIC GASTRITIS AND PEPTIC ULCERATION. AMONG THE LONG-TERM CONSEQUENCES OF H. PYLORI INFECTION IS GASTRIC MALIGNANCIES, PARTICULARLY GASTRIC CANCER (GC) AND GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA. AS SUCH, H. PYLORI HAS BEEN RECOGNIZED AS A CLASS I CARCINOGEN BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. DESPITE A CLOSE CAUSAL LINK BETWEEN H. PYLORI INFECTION AND THE DEVELOPMENT OF GASTRIC MALIGNANCIES, THE PRECISE MECHANISMS INVOLVED IN THIS PROCESS ARE STILL OBSCURE. STUDIES OVER THE PAST TWO DECADES HAVE REVEALED THAT H. PYLORI EXERT ONCOGENIC EFFECTS ON GASTRIC MUCOSA THROUGH A COMPLEX INTERACTION BETWEEN BACTERIAL FACTORS, HOST FACTORS, AND ENVIRONMENTAL FACTORS. NUMEROUS SIGNALING PATHWAYS CAN BE ACTIVATED BY H. PYLORI. IN THIS REVIEW, WE AIM TO ELABORATE ON THE RECENT DEVELOPMENTS IN THE PATHOPHYSIOLOGICAL MECHANISMS OF H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC CANCER. 2014 4 3232 33 HELICOBACTER PYLORI-INDUCED SIGNALING PATHWAYS CONTRIBUTE TO INTESTINAL METAPLASIA AND GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (H. PYLORI) INDUCES CHRONIC GASTRIC INFLAMMATION, ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND CANCER. ALTHOUGH THE RISK OF GASTRIC CANCER INCREASES EXPONENTIALLY WITH THE EXTENT OF ATROPHIC GASTRITIS, THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS HAVE NOT BEEN FULLY ELUCIDATED. H. PYLORI INDUCES GENETIC AND EPIGENETIC CHANGES IN GASTRIC EPITHELIAL CELLS THROUGH ACTIVATING INTRACELLULAR SIGNALING PATHWAYS IN A CAGPAI-DEPENDENT MANNER. H. PYLORI EVENTUALLY INDUCES GASTRIC CANCER WITH CHROMOSOMAL INSTABILITY (CIN) OR MICROSATELLITE INSTABILITY (MSI), WHICH ARE CLASSIFIED AS TWO MAJOR SUBTYPES OF GASTRIC CANCER. ELUCIDATION OF THE PRECISE MECHANISMS OF GASTRIC CARCINOGENESIS WILL ALSO BE IMPORTANT FOR CANCER THERAPY. 2015 5 4984 34 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 6 495 44 ASSESSMENT OF THE HEALTH EFFECTS OF TRICHLOROETHYLENE. THE EPIDEMIOLOGICAL STUDIES PERFORMED THUS FAR HAVE PRESENTED ONLY LIMITED EVIDENCE FOR THE CARCINOGENICITY OF TRICHLOROETHYLENE (TRI) TO HUMANS. HOWEVER, THESE STUDIES HAD DRAWBACKS SUCH AS INSUFFICIENT SIZE OF COHORT, SHORT OBSERVATION PERIOD, AND INADEQUATE TRI EXPOSURE ASSESSMENT; THEREFORE, NO CONCRETE CONCLUSION HAS BEEN REACHED CONCERNING TRI CARCINOGENICITY TO HUMANS. DESPITE THE LIMITED EPIDEMIOLOGICAL EVIDENCE AS TO THE CARCINOGENICITY OF TRI, THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS CHANGED THE CARCINOGENICITY CLASSIFICATION OF TRI FROM GROUP 3 (NOT CLASSIFIABLE AS TO CARCINOGENICITY TO HUMANS) TO GROUP 2A (PROBABLY CARCINOGENIC TO HUMANS). IN REGARD TO THE NEW CLASSIFICATION BY THE IARC, THE COMMITTEE FOR OCCUPATIONAL EXPOSURE LIMITS OF THE JAPAN SOCIETY FOR OCCUPATIONAL HEALTH HAS MADE A PROPOSAL THAT IT IS TOO EARLY TO CLASSIFY THE CARCINOGENICITY OF TRI AS GROUP 2A AND THAT IT IS PROPER TO PROMOTE EXPOSURE CONTROL WITH THE CARCINOGENICITY BEING CLASSIFIED AS 2B FOR THE MOMENT. THERE ARE SPECIES DIFFERENCES IN TRI CARCINOGENICITY, PARTICULARLY BETWEEN RATS AND MICE. ALTHOUGH EXPERIMENTAL STUDIES HAVE FOUND NO EVIDENCE THAT TRI INDUCES LIVER CANCER IN RATS, THERE IS AMPLE EVIDENCE THAT TRI PROMOTES THE DEVELOPMENT OF LIVER CANCER IN MICE, PARTICULARLY IN B6C3F1 MICE. THE CARCINOGENICITY OF TRI IN THIS STRAIN OF MICE MAY BE BASED ON AN EPIGENETIC MECHANISM RATHER ON A GENOTOXIC MECHANISM AND THE LIVER CANCER MAY BE INDUCED ONLY AFTER TRI HAS BEEN INHALED FOR A LONG PERIOD OF TIME AT CONCENTRATIONS HIGH ENOUGH TO CAUSE CYTOTOXICITY. CONVERSELY, WITH NO REPORTS SHOWING TRI-INDUCED RENAL TUMORS IN MICE, THE POSSIBILITY HAS BEEN SUGGESTED THAT THIS CHEMICAL INDUCES SUCH TUMORS IN MALE RATS. THE SPECIES DIFFERENCES ARE MAINLY ACCOUNTED FOR BY DIFFERENCES IN THE METABOLISM OF TRI BETWEEN RATS AND MICE. FROM A GENERAL SURVEY OF THE LITERATURE, IT CAN BE CONCLUDED THAT TRI ITSELF IS NOT MUTAGENIC. HOWEVER, THE CONJUGATION OF TRI WITH GLUTATHIONE (GSH), A MINOR PATHWAY OF TRI METABOLISM, RESULTS IN MUTAGENIC METABOLITES IN THE KIDNEY OF RATS. THE ACUTE TOXICITY OF TRI IS NEUROTOXICITY BASED ON ITS ANESTHETIC ACTION. AN EXPOSURE TO EXTREMELY HIGH LEVELS OF TRI MAY CAUSE THE LIVER AND KIDNEY DISORDERS. REPEATED EXPOSURES TO HIGH LEVELS OF TRI MAY RESULT IN NEURO-, HEPATO-, AND/OR NEPHROTOXICITY. THE MAIN SYMPTOMS APPEARING AFTER CHRONIC EXPOSURE AT LOW LEVELS ARE NEUROLOGICAL CHANGES REPRESENTED BY SUBJECTIVE SYMPTOMS RELATING TO CENTRAL AND AUTONOMIC NERVOUS SYSTEMS, OR BY A LOWERED CONDUCTION VELOCITY OF THE NERVES OR A PROLONGED LATENCY OF THE NERVE RESPONSES. FOR THE PRESENT, IT IS REASONABLE TO USE THE NEUROLOGICAL FINDINGS FOR ESTABLISHING THE REFERENCE VALUES OF TRI FOR BOTH WORK AND GENERAL ENVIRONMENTS. A VALUE OF 25 PPM (135 MG/M3) IS PROPOSED AS A REFERENCE VALUE FOR WORK ENVIRONMENTS, AND 25-50 PPB (135-270 MICROGRAMS/M3) FOR THE GENERAL ENVIRONMENT (1/1,000 OF THE VALUE FOR WORK ENVIRONMENT). 1997 7 3222 43 HELICOBACTER PYLORI ASSOCIATED CHRONIC GASTRITIS, CLINICAL SYNDROMES, PRECANCEROUS LESIONS, AND PATHOGENESIS OF GASTRIC CANCER DEVELOPMENT. HELICOBACTER PYLORI (H. PYLORI) INFECTION IS WELL KNOWN TO BE ASSOCIATED WITH THE DEVELOPMENT OF PRECANCEROUS LESIONS SUCH AS CHRONIC ATROPHIC GASTRITIS (AG), OR GASTRIC INTESTINAL METAPLASIA (GIM), AND CANCER. VARIOUS MOLECULAR ALTERATIONS ARE IDENTIFIED NOT ONLY IN GASTRIC CANCER (GC) BUT ALSO IN PRECANCEROUS LESIONS. H. PYLORI TREATMENT SEEMS TO IMPROVE AG AND GIM, BUT STILL REMAINS CONTROVERSIAL. IN CONTRAST, MANY STUDIES, INCLUDING META-ANALYSIS, SHOW THAT H. PYLORI ERADICATION REDUCES GC. MOLECULAR MARKERS DETECTED BY GENETIC AND EPIGENETIC ALTERATIONS RELATED TO CARCINOGENESIS REVERSE FOLLOWING H. PYLORI ERADICATION. THIS INDICATES THAT THESE CHANGES MAY BE AN IMPORTANT FACTOR IN THE IDENTIFICATION OF HIGH RISK PATIENTS FOR CANCER DEVELOPMENT. PATIENTS WHO UNDERWENT ENDOSCOPIC TREATMENT OF GC ARE AT HIGH RISK FOR DEVELOPMENT OF METACHRONOUS GC. A RANDOMIZED CONTROLLED TRIAL FROM JAPAN CONCLUDED THAT PROPHYLACTIC ERADICATION OF H. PYLORI AFTER ENDOSCOPIC RESECTION SHOULD BE USED TO PREVENT THE DEVELOPMENT OF METACHRONOUS GC, BUT RECENT RETROSPECTIVE STUDIES DID NOT SHOW THE TENDENCY. PATIENTS WITH PRECANCEROUS LESIONS (MOLECULAR ALTERATIONS) THAT DO NOT REVERSE AFTER H. PYLORI TREATMENT, REPRESENT THE "POINT OF NO RETURN" AND MAY BE AT HIGH RISK FOR THE DEVELOPMENT OF GC. THEREFORE, EARLIER H. PYLORI ERADICATION SHOULD BE CONSIDERED FOR PREVENTING GC DEVELOPMENT PRIOR TO THE APPEARANCE OF PRECANCEROUS LESIONS. 2014 8 1799 39 EFFECT OF HELICOBACTER PYLORI INFECTION ON THE COMPOSITION OF GASTRIC MICROBIOTA IN THE DEVELOPMENT OF GASTRIC CANCER. BACKGROUND: GASTRIC CANCER IS ONE OF THE MOST COMMON CANCER TYPES WORLDWIDE. IN CHINA, GASTRIC CANCER HAS BECOME ONE OF THE MAJOR THREATS FOR PUBLIC HEALTH, RANKING SECOND ON INCIDENCE AND THIRD ON CAUSE OF CANCER DEATH. DESPITE THE COMMON RISK FACTORS THAT PROMOTE THE DEVELOPMENT OF GASTRIC CANCER, THE HUGE QUANTITY OF MICROORGANISM COLONIES WITHIN THE GASTROINTESTINAL TRACT, PARTICULARLY HELICOBACTER PYLORI INFECTION, DEMONSTRATES A CORRELATION WITH CHRONIC INFLAMMATION AND GASTRIC CARCINOGENESIS, AS EPIDEMIOLOGICAL STUDIES HAVE DETERMINED THAT H. PYLORI INFECTION CONFERS APPROXIMATELY 75% OF THE ATTRIBUTABLE RISK FOR GASTRIC CANCER. SUMMARY: THE CURRENT ARTICLE DRAWS AN OVERVIEW ON THE CORRELATION BETWEEN THE MICROBIOTA, INFLAMMATION AND GASTRIC TUMORIGENESIS. H. PYLORI INFECTION HAS BEEN IDENTIFIED AS THE MAIN RISK FACTOR AS IT TRIGGERS EPITHELIAL BARRIER DISRUPTION, SURVIVAL SIGNALING AS WELL AS GENETIC/EPIGENETIC MODULATION. APART FROM H. PYLORI, THE EXISTENCE OF A DIVERSE AND COMPLEX COMPOSITION OF MICROBIOTA IN THE STOMACH HAS BEEN IDENTIFIED, WHICH SUPPORTS A ROLE OF MICROBIOTA IN THE DEVELOPMENT OF GASTRIC CANCER. MOREOVER, METAGENOMICS STUDIES FOCUSED ON THE COMPOSITION AND FUNCTION OF THE MICROBIOTA HAVE ASSOCIATED MICROBIOTA WITH GASTRIC METABOLIC DISEASES AND EVEN TUMORIGENESIS. APART FROM THE GASTRIC MICROBIOTA, INFLAMMATION IS ANOTHER IDENTIFIED CONTRIBUTOR TO CANCER DEVELOPMENT AS WELL. KEY MESSAGE: THOUGH H. PYLORI INFECTION AND THE NON-H. PYLORI MICROBIOTA PLAY A ROLE IN GASTRIC CANCER, THE PROPERTIES OF GASTRIC MICROBIOTA AND MECHANISMS BY WHICH THEY PARTICIPATE IN THE GENESIS OF GASTRIC CANCER ARE STILL NOT CLEARLY DEPICTED. MOREOVER, IT REMAINS TO BE UNDERSTOOD HOW THE PRESENCE OF MICROBIOTA ALONG WITH H. PYLORI INFECTION AFFECTS THE PROGRESS FROM GASTRIC DISEASE TO CANCER. PRACTICAL IMPLICATIONS: THIS ARTICLE SUMMARIZED A CLUE OF THE CURRENT STUDIES ON MICROBIOTA, H. PYLORI INFECTION AND THE PROGRESSION FROM GASTRIC DISEASE TO CANCER. 2015 9 5181 31 PREMALIGNANT LESIONS IN GASTRIC CANCER. DESPITE A PLATEAU IN INCIDENCE, GASTRIC CANCER IS ONE OF THE MOST COMMON CANCERS WORLDWIDE AND CAUSES CONSIDERABLE MORBIDITY AND MORTALITY. PREMALIGNANT GASTRIC LESIONS ARE WELL KNOWN RISK FACTORS FOR THE DEVELOPMENT OF INTESTINAL-TYPE GASTRIC ADENOCARCINOMAS. IN THIS MULTISTEP MODEL OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI CAUSES CHRONIC ACTIVE INFLAMMATION OF THE GASTRIC MUCOSA, WHICH SLOWLY PROGRESSES THROUGH THE PREMALIGNANT STAGES OF ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, AND ADENOMA/DYSPLASIA TO GASTRIC CARCINOMA. THIS PROGRESSION IS PARALLELED BY A STEPWISE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. DETECTION, TREATMENT, AND MOLECULAR ANALYSES OF PREMALIGNANT LESIONS MAY THUS PROVIDE A BASIS FOR GASTRIC CANCER PREVENTION. THIS REVIEW DESCRIBES AN OVERVIEW OF CURRENT KNOWLEDGE ON PREMALIGNANT GASTRIC LESIONS. IT ALSO REVIEWS THE ISSUE OF SURVEILLANCE OF PATIENTS WITH PREMALIGNANT LESIONS IN ORDER TO IMPROVE THE SURVIVAL OF PATIENTS WITH GASTRIC CANCER. 2010 10 3849 31 IS ERADICATION OF HELICOBACTER PYLORI THE FEASIBLE WAY TO PREVENT GASTRIC CANCER? NEW EVIDENCE AND PROGRESS, BUT STILL A LONG WAY TO GO. EPIDEMIOLOGICAL, ANIMAL AND BIOLOGICAL STUDIES PROVIDE COMPELLING EVIDENCE FOR THE ROLE OF HELICOBACTER PYLORI INFECTION IN GASTRIC CARCINOGENESIS. THE FINDING THAT H. PYLORI-INDUCED CHRONIC ATROPHIC GASTRITIS IS THE MAJOR CAUSE OF GASTRIC CANCER SUGGESTS THAT ERADICATION OF THE BACTERIUM MAY PREVENT THIS MALIGNANCY. COMPUTER-SIMULATION STUDIES HAVE CONFIRMED THE COST-EFFECTIVENESS OF ERADICATION IN HIGH-RISK SUBJECTS; HOWEVER, UNRESOLVED ISSUES COMPLICATE ACTIVE TESTING FOR AND TREATMENT OF H. PYLORI INFECTION AMONG ASYMPTOMATIC CARRIERS. CONCERNS INCLUDE THE ENORMOUS COSTS FOR DEVELOPING COUNTRIES TO IMPLEMENT STRATEGIES, THE INCONCLUSIVENESS OF DATA FROM RANDOMIZED CONTROLLED STUDIES, THE POTENTIAL INDUCTION OF ANTIMICROBIAL RESISTANCE, AND THE UNCERTAIN EFFECT OF ELIMINATING THIS ORGANISM ON THE SPECTRUM OF MODERN DISEASE. ALTHOUGH CURRENT EVIDENCE IS INSUFFICIENT TO RECOMMEND UNIVERSAL TESTING AND TREATMENT, IT IS POSSIBLE TO IDENTIFY HIGHLY SUSCEPTIBLE INDIVIDUALS WHO ARE MOST LIKELY TO BENEFIT FROM TREATMENT. NOVEL BIOMARKERS FOR PREDICTING RISK ARE UNDER EXTENSIVE INVESTIGATION, INCLUDING GENETIC, EPIGENETIC AND PROTEINOMIC FACTORS. THE EMERGING EVIDENCE SUGGESTS THAT TREATMENT OF H. PYLORI INFECTION IN ASYMPTOMATIC CARRIERS MAY DECREASE THE BURDEN OF GASTRIC CANCER. HOWEVER, CONFIRMATION OF LONG-TERM BENEFITS REMAINS A LONG WAY OFF. 2008 11 3233 27 HELICOBACTER, INFLAMMATION, AND GASTRIC CANCER. HELICOBACTER PYLORI INFECTION LEADS TO LONG-LASTING CHRONIC INFLAMMATION AND REPRESENTS THE MOST COMMON RISK FACTOR UNDERLYING GASTRIC CANCER. RECENTLY, NEW INSIGHTS INTO THE MECHANISMS THROUGH WHICH H. PYLORI AND MUCOSAL INFLAMMATION LEAD TO CANCER DEVELOPMENT HAVE EMERGED. H. PYLORI VIRULENCE FACTORS, IN PARTICULAR SPECIFIC CAGA GENOTYPES, REPRESENT MAIN FACTORS IN GASTRIC CANCER, INDUCING ALTERED INTRACELLULAR SIGNALING IN EPITHELIAL CELLS. THE CHRONIC NATURE OF H. PYLORI INFECTION APPEARS TO RELATE TO THE VACA VIRULENCE FACTOR AND TH17/TREG MECHANISMS. A ROLE OF H. PYLORI INFECTION IN EPIGENETIC AND MICRORNA DEREGULATION HAS BEEN SHOWN. MUTATION OF THE EPITHELIAL CELL GENOME, A HALLMARK OF CANCER, WAS DEMONSTRATED TO ACCUMULATE IN H. PYLORI INFECTED STOMACH PARTLY DUE TO INADEQUATE DNA REPAIR. GASTRIC STEM CELLS WERE SHOWN TO BE TARGETS OF OXIDATIVE INJURY IN THE HELICOBACTER-INFLAMMATORY MILIEU. RECENT ADVANCES EMPHASIZING THE CONTRIBUTION OF BACTERIAL FACTORS, INFLAMMATORY MEDIATORS, AND THE HOST EPITHELIAL RESPONSE IN GASTRIC CARCINOGENESIS ARE REVIEWED. 2013 12 6169 31 THE GUT MICROBIOTA AND HEALTHY AGING: A MINI-REVIEW. THE GUT MICROBIOTA SHOWS A WIDE INTER-INDIVIDUAL VARIATION, BUT ITS WITHIN-INDIVIDUAL VARIATION IS RELATIVELY STABLE OVER TIME. A FUNCTIONAL CORE MICROBIOME, PROVIDED BY ABUNDANT BACTERIAL TAXA, SEEMS TO BE COMMON TO VARIOUS HUMAN HOSTS REGARDLESS OF THEIR GENDER, GEOGRAPHIC LOCATION, AND AGE. WITH ADVANCING CHRONOLOGICAL AGE, THE GUT MICROBIOTA BECOMES MORE DIVERSE AND VARIABLE. HOWEVER, WHEN MEASURES OF BIOLOGICAL AGE ARE USED WITH ADJUSTMENT FOR CHRONOLOGICAL AGE, OVERALL RICHNESS DECREASES, WHILE A CERTAIN GROUP OF BACTERIA ASSOCIATED WITH FRAILTY INCREASES. THIS HIGHLIGHTS THE IMPORTANCE OF CONSIDERING BIOLOGICAL OR FUNCTIONAL MEASURES OF AGING. STUDIES USING MODEL ORGANISMS INDICATE THAT AGE-RELATED GUT DYSBIOSIS MAY CONTRIBUTE TO UNHEALTHY AGING AND REDUCED LONGEVITY. THE GUT MICROBIOME DEPENDS ON THE HOST NUTRIENT SIGNALING PATHWAYS FOR ITS BENEFICIAL EFFECTS ON HOST HEALTH AND LIFESPAN, AND GUT DYSBIOSIS DISRUPTING THE INTERDEPENDENCE MAY DIMINISH THE BENEFICIAL EFFECTS OR EVEN HAVE REVERSE EFFECTS. GUT DYSBIOSIS CAN TRIGGER THE INNATE IMMUNE RESPONSE AND CHRONIC LOW-GRADE INFLAMMATION, LEADING TO MANY AGE-RELATED DEGENERATIVE PATHOLOGIES AND UNHEALTHY AGING. THE GUT MICROBIOTA COMMUNICATES WITH THE HOST THROUGH VARIOUS BIOMOLECULES, NUTRIENT SIGNALING-INDEPENDENT PATHWAYS, AND EPIGENETIC MECHANISMS. DISTURBANCE OF THESE COMMUNICATIONS BY AGE-RELATED GUT DYSBIOSIS CAN AFFECT THE HOST HEALTH AND LIFESPAN. THIS MAY EXPLAIN THE IMPACT OF THE GUT MICROBIOME ON HEALTH AND AGING. 2018 13 3219 41 HELICOBACTER PYLORI AND GASTRIC CANCER. INFECTION WITH HELICOBACTER PYLORI IS ESTABLISHED AS THE MAJOR RISK FACTOR FOR GASTRIC CANCER DEVELOPMENT. DAMAGE OF THE MUCOSAL BARRIER DUE TO H. PYLORI-INDUCED INFLAMMATION ENHANCES THE CARCINOGENIC EFFECT OF OTHER RISK FACTORS SUCH AS SALT INTAKE OR TOBACCO SMOKING. THE GENETIC DISPOSITION OF BOTH THE BACTERIAL STRAIN AND THE HOST CAN INCREASE THE POTENTIAL TOWARDS GASTRIC CANCER FORMATION. GENETIC VARIANCE OF THE BACTERIAL PROTEINS CAGA AND VACA IS ASSOCIATED WITH A HIGHER GASTRIC CANCER RISK, AS ARE POLYMORPHISMS AND EPIGENETIC CHANGES IN HOST GENE CODING FOR INTERLEUKINS (IL1BETA, IL8), TRANSCRIPTION FACTORS (CDX2, RUNX3) AND DNA REPAIR ENZYMES. APPLICATION OF HIGH-THROUGHPUT ASSAYS FOR GENOME-WIDE ASSESSMENT OF EITHER GENETIC STRUCTURAL VARIANCE OR GENE EXPRESSION PATTERNS MAY LEAD TO A BETTER UNDERSTANDING OF THE PATHOBIOLOGICAL BACKGROUND OF THESE PROCESSES, INCLUDING THE UNDERLYING SIGNALING PATHWAYS. UNDERSTANDING OF THE STEPWISE ALTERATIONS THAT TAKE PLACE IN THE TRANSITION FROM CHRONIC ATROPHIC GASTRITIS, VIA METAPLASTIC CHANGES, TO INVASIVE NEOPLASIA IS VITAL TO DEFINE THE 'POINT OF NO RETURN' BEFORE WHICH ERADICATION OF H. PYLORI HAS THE POTENTIAL TO PREVENT GASTRIC CANCER. CURRENTLY, ERADICATION AS PREVENTIVE STRATEGY IS ONLY RECOMMENDED FOR HIGH-INCIDENCE REGIONS IN ASIA; LARGE POPULATION STUDIES WITH AN ADEQUATE FOLLOW-UP ARE REQUIRED TO DEMONSTRATE THE EFFECTIVENESS OF SUCH AN APPROACH IN WESTERN POPULATIONS. 2014 14 6841 37 [MECHANISMS OF H. PYLORI INFECTION-INDUCED GASTRIC CARCINOGENESIS]. MANY EPIDEMIOLOGICAL STUDIES HAVE DEMONSTRATED A STRONG ASSOCIATION BETWEEN H. PYLORI (HELICOBACTER PYLORI) INFECTION AND HUMAN GASTRIC CANCER DEVELOPMENT. THE PRECISE MECHANISMS ACCOUNTING FOR GASTRIC CANCER DEVELOPMENT INDUCED BY H. PYLORI INFECTION ARE STILL NOT COMPLETELY UNDERSTOOD. HOWEVER, IT SHOULD BE REASONABLE TO ASSUME THAT THERE ARE TWO DISTINCT MOLECULAR PATHWAYS FOR GASTRIC CARCINOGENESIS BY H. PYLORI INFECTION; THE DIRECT ACTION OF THE BACTERIA ITSELF ON GASTRIC EPITHELIAL CELLS, AND THE ACCUMULATION OF GENETIC CHANGES CAUSED BY PROLONGED BACTERIAL INFECTION AND CHRONIC INFLAMMATION. AS A DIRECT ACTION OF H. PYLORI, BACTERIAL PROTEINS SUCH AS CAGA COULD BE DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE TYPE IV SECRETION APPARATUS AND MODIFY THE HOST CELL FUNCTIONS RELATED TO CELL PROLIFERATION. IN ADDITION TO THE DIRECT BACTERIAL ACTION, H. PYLORI INFECTION AND THE RESULTANT INFLAMMATORY RESPONSE CAUSE VARIOUS GENETIC AND EPIGENETIC CHANGES IN TUMOR-RELATED GENES OF THE GASTRIC EPITHELIAL CELLS. NOTABLY, EXPRESSION OF AID (ACTIVATION-INDUCED CYTIDINE DEAMINASE), A DNA EDITING ENZYME THAT UNDERGOES SOMATIC HYPERMUTATION ON HUMAN GENES, IS INDUCED IN RESPONSE TO H. PYLORI INFECTION AND PROINFLAMMATORY CYTOKINE STIMULATION IN HUMAN GASTRIC EPITHELIAL CELLS. AS A RESULT, THE ACCUMULATION OF GENETIC ALTERATIONS WOULD PERSIST UNTIL THE CLINICAL STAGE OF ATROPHIC GASTRITIS AND EVENTUALLY TRIGGER THE MALIGNANT TRANSFORMATION OF GASTRIC CELLS. 2010 15 3804 25 INTESTINAL MICROBIOTA, CHRONIC INFLAMMATION, AND COLORECTAL CANCER. IN ADDITION TO GENETIC AND EPIGENETIC FACTORS, VARIOUS ENVIRONMENTAL FACTORS, INCLUDING DIET, PLAY IMPORTANT ROLES IN THE DEVELOPMENT OF COLORECTAL CANCER (CRC). RECENTLY, THERE IS INCREASING INTEREST IN THE INTESTINAL MICROBIOTA AS AN ENVIRONMENTAL RISK FACTOR FOR CRC, BECAUSE DIET ALSO INFLUENCES THE COMPOSITION OF THE INTESTINAL MICROBIOTA. THE HUMAN INTESTINAL MICROBIOTA COMPRISES ABOUT 100 TRILLION MICROBES. THIS MICROBIOME THRIVES ON UNDIGESTED DIETARY RESIDUES IN THE INTESTINAL LUMEN AND PRODUCES VARIOUS METABOLITES. IT IS WELL KNOWN THAT THE DIETARY RISK FACTORS FOR CRC ARE MEDIATED BY DYSBIOSIS OF THE INTESTINAL MICROBIOTA AND THEIR METABOLITES. IN THIS REVIEW, WE DESCRIBE THE BACTERIAL TAXA ASSOCIATED WITH CRC, INCLUDING FUSOBACTERIUM NUCLEATUM, ENTEROTOXIGENIC BACTEROIDES FRAGILIS, ESCHERICHIA COLI, AND BUTYRATE-PRODUCING BACTERIA. WE ALSO DISCUSS THE HOST-DIET INTERACTION IN COLORECTAL CARCINOGENESIS. 2018 16 5180 28 PREMALIGNANT CONDITIONS OF GASTRIC CANCER. PREMALIGNANT LESIONS OF GASTRIC CANCER ENCOMPASS A VARIETY OF CONDITIONS SUCH AS CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND DYSPLASIA, IN WHICH ELEVATED RISK OF DEVELOPING GASTRIC CANCER HAVE BEEN DOCUMENTED. AMONG THEM, INTESTINAL METAPLASIA IS FREQUENTLY ENCOUNTERED IN OUR DAILY ENDOSCOPIC EXAMINATION, YET ITS CLINICAL SIGNIFICANCE IS OFTEN UNDERESTIMATED DESPITE OF A NUMBER OF REPORTS DEMONSTRATING GENETIC AND EPIGENETIC ALTERATIONS IN THE INTESTINAL METAPLASTIC MUCOSA. IN THIS REVIEW, I WILL DESCRIBE THE MOLECULAR MECHANISMS OF PHENOTYPIC CHANGES FROM GASTRIC MUCOSA TO INTESTINAL METAPLASIA BASED ON OUR ANALYSIS OF MOUSE MODEL OF INTESTINAL METAPLASIA GENERATED BY ECTOPIC EXPRESSION OF CDX2 IN CONJUNCTION WITH THE STUDIES WITH HUMAN INTESTINAL METAPLASIA. 2013 17 1398 31 DIET, GUT MICROBIOME AND EPIGENETICS: EMERGING LINKS WITH INFLAMMATORY BOWEL DISEASES AND PROSPECTS FOR MANAGEMENT AND PREVENTION. INFLAMMATORY BOWEL DISEASES (IBD) REPRESENT A GROWING PUBLIC HEALTH CONCERN DUE TO INCREASING INCIDENCE WORLDWIDE. THE CURRENT NOTION ON THE PATHOGENESIS OF IBD IS THAT GENETICALLY SUSCEPTIBLE INDIVIDUALS DEVELOP INTOLERANCE TO DYSREGULATED GUT MICROFLORA (DYSBIOSIS) AND CHRONIC INFLAMMATION DEVELOPS AS A RESULT OF ENVIRONMENTAL TRIGGERS. AMONG THE ENVIRONMENTAL FACTORS ASSOCIATED WITH IBD, DIET PLAYS AN IMPORTANT ROLE IN MODULATING THE GUT MICROBIOME, INFLUENCING EPIGENETIC CHANGES, AND, THEREFORE, COULD BE APPLIED AS A THERAPEUTIC TOOL TO IMPROVE THE DISEASE COURSE. NEVERTHELESS, THE CURRENT DIETARY RECOMMENDATIONS FOR DISEASE PREVENTION AND MANAGEMENT ARE SCARCE AND HAVE WEAK EVIDENCE. THIS REVIEW SUMMARISES THE CURRENT KNOWLEDGE ON THE COMPLEX INTERACTIONS BETWEEN DIET, MICROBIOME AND EPIGENETICS IN IBD. WHEREAS AN OVERABUNDANCE OF CALORIES AND SOME MACRONUTRIENTS INCREASE GUT INFLAMMATION, SEVERAL MICRONUTRIENTS HAVE THE POTENTIAL TO MODULATE IT. IMMUNONUTRITION HAS EMERGED AS A NEW CONCEPT PUTTING FORWARD THE IMPORTANCE OF VITAMINS SUCH AS VITAMINS A, C, E, AND D, FOLIC ACID, BETA CAROTENE AND TRACE ELEMENTS SUCH AS ZINC, SELENIUM, MANGANESE AND IRON. HOWEVER, WHEN ASSESSED IN CLINICAL TRIALS, SPECIFIC MICRONUTRIENTS EXERTED A LIMITED BENEFIT. BEYOND NUTRIENTS, AN ANTI-INFLAMMATORY DIETARY PATTERN AS A COMPLEX INTERVENTION APPROACH HAS BECOME POPULAR IN RECENT YEARS. HENCE, EXCLUSIVE ENTERAL NUTRITION IN PAEDIATRIC CROHN'S DISEASE IS THE ONLY NUTRITIONAL INTERVENTION CURRENTLY RECOMMENDED AS A FIRST-LINE THERAPY. OTHER NUTRITIONAL INTERVENTIONS OR SPECIFIC DIETS INCLUDING THE SPECIFIC CARBOHYDRATE DIET (SCD), THE LOW FERMENTABLE OLIGOSACCHARIDES, DISACCHARIDES, MONOSACCHARIDES, AND POLYOL (FODMAP) DIET AND, MOST RECENTLY, THE MEDITERRANEAN DIET HAVE SHOWN STRONG ANTI-INFLAMMATORY PROPERTIES AND SHOW PROMISE FOR IMPROVING DISEASE SYMPTOMS. MORE WORK IS REQUIRED TO EVALUATE THE ROLE OF INDIVIDUAL FOOD COMPOUNDS AND COMPLEX NUTRITIONAL INTERVENTIONS WITH THE POTENTIAL TO DECREASE INFLAMMATION AS A MEANS OF PREVENTION AND MANAGEMENT OF IBD. 2017 18 4663 36 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 19 3934 60 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982 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