1  2959 133 GENETIC AND EPIGENETIC INSTABILITY INDUCED BY BETEL QUID ASSOCIATED CHEMICALS. OVER THE YEARS, BETEL QUID CHEWING AND TOBACCO USE HAVE ATTRACTED CONSIDERABLE INTEREST AS THEY ARE IMPLICATED AS THE MOST LIKELY CAUSATIVE RISK FACTORS OF ORAL AND ESOPHAGEAL CANCERS. ALTHOUGH ARECA NUT USE AND BETEL QUID CHEWING MAY LEAD TO APOPTOSIS, CHRONIC EXPOSURE TO ARECA NUT AND SLAKED LIME MAY PROMOTE PRE-MALIGNANT AND MALIGNANT TRANSFORMATION OF ORAL CELLS. THE PUTATIVE MUTAGENIC AND CARCINOGENIC MECHANISMS MAY INVOLVE ENDOGENOUS NITROSATION OF ARECA AND TOBACCO ALKALOIDS AS WELL AS THE PRESENCE OF DIRECT ALKYLATING AGENTS IN BETEL QUID AND SMOKELESS TOBACCO. METABOLIC ACTIVATION OF CARCINOGENIC N-NITROSAMINES BY PHASE-I ENZYMES IS REQUIRED NOT ONLY TO ELICIT THE GENOTOXICITY VIA THE REACTIVE INTERMEDIATES BUT ALSO TO POTENTIATE THE MUTAGENICITY WITH THE SPORADIC ALKYLATIONS OF NUCLEOTIDE BASES, RESULTING IN THE FORMATION OF DIVERSE DNA ADDUCTS. PERSISTENT DNA ADDUCTS PROVIDES THE IMPETUS FOR GENETIC AND EPIGENETIC LESIONS. THE GENETIC AND EPIGENETIC FACTORS CUMULATIVELY INFLUENCE THE DEVELOPMENT AND PROGRESSION OF DISORDERS SUCH AS CANCER. ACCUMULATION OF NUMEROUS GENETIC AND EPIGENETIC ABERRATIONS DUE TO LONG-TERM BETEL QUID (WITH OR WITHOUT TOBACCO) CHEWING AND TOBACCO USE CULMINATES INTO THE DEVELOPMENT OF HEAD AND NECK CANCERS. WE REVIEW RECENT EVIDENCE THAT SUPPORTS PUTATIVE MECHANISMS FOR MUTAGENICITY AND CARCINOGENICITY OF BETEL QUID CHEWING ALONG WITH TOBACCO (SMOKING AND SMOKELESS) USE. THE DETAILED MOLECULAR MECHANISMS OF THE EXTENT OF ACCUMULATION AND PATTERNS OF GENETIC ALTERATIONS, INDICATIVE OF THE PRIOR EXPOSURE TO CARCINOGENS AND ALKYLATING AGENTS BECAUSE OF BQ CHEWING AND TOBACCO USE, HAVE NOT YET BEEN ELUCIDATED.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  3142  25 GLOBAL METHYLATION PROFILES IN BUCCAL CELLS OF LONG-TERM SMOKERS AND MOIST SNUFF CONSUMERS. PURPOSE: ALTERNATIONS IN GENE METHYLATION AND OTHER EPIGENETIC CHANGES REGULATE NORMAL DEVELOPMENT AS WELL AS DRIVE DISEASE PROGRESSION. THE AIM OF THIS STUDY IS TO INVESTIGATE GLOBAL METHYLATION CHANGES IN THE BUCCAL CELLS OF SMOKERS AND SMOKELESS TOBACCO USERS. MATERIALS AND METHODS: GENERALLY HEALTHY ADULT MALE SUBJECTS WERE RECRUITED INTO SMOKER (SMK), MOIST SNUFF CONSUMER (MSC) AND NON-TOBACCO CONSUMER (NTC) COHORTS (40 SUBJECTS/COHORT) (CLINICALTRIALS.GOV IDENTIFIER: NCT01923402). GLOBAL METHYLATION PROFILING WAS PERFORMED ON ILLUMINA 450 K METHYLATION ARRAYS USING BUCCAL CELL DNAS. RESULTS: THE SMK COHORT EXHIBITED LARGER QUALITATIVE AND QUANTITATIVE CHANGES RELATIVE TO MSC. APPROXIMATELY HALF OF THE DIFFERENTIALLY METHYLATED 1252 GENE LOCI WERE GROUPED AS COMBUSTIBLE TOBACCO-RELATED (CTR) SIGNATURES AND A THIRD OF THE CHANGES, TOBACCO-RELATED (TR) SIGNATURES, WERE ASSOCIATED WITH SMOKING. VERY FEW (41) DIFFERENTIALLY METHYLATED GENE LOCI WERE EXCLUSIVELY ASSOCIATED WITH MOIST SNUFF USE AND WERE DESIGNATED AS MOIST SNUFF-RELATED (MSR) SIGNATURE. PATHWAY ENRICHMENT ANALYSES REVEALED THAT DEVELOPMENTAL AND IMMUNE RESPONSE PATHWAYS, AMONG OTHERS, WERE IMPACTED DUE TO TOBACCO USE. CONCLUSIONS: CHRONIC CIGARETTE SMOKING CAUSES HYPER- AND HYPO-METHYLATION OF GENES THAT COULD CONTRIBUTE TO SMOKING-RELATED DISEASES. THESE RESULTS HELP PLACE COMBUSTIBLE AND NON-COMBUSTIBLE TOBACCO PRODUCTS ALONG A RISK CONTINUUM AND PROVIDE ADDITIONAL INSIGHTS INTO THE EFFECTS OF TOBACCO CONSUMPTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  1941  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  5380  35 RECENT UPDATES ON BIOMARKERS OF EXPOSURE AND SYSTEMIC TOXICITY IN E-CIGARETTE USERS AND EVALI. ELECTRONIC NICOTINE DELIVERY SYSTEMS (ENDS), OR E-CIGARETTES, ARE EMERGING TOBACCO PRODUCTS THAT PRODUCE AEROSOLS BY HEATING E-LIQUIDS, WHICH MOST OFTEN CONSIST OF PROPYLENE GLYCOL AND VEGETABLE GLYCERIN ALONG WITH VARIOUS FLAVORING COMPOUNDS, BYPASSING THE COMBUSTION THAT OCCURS IN THE USE OF TRADITIONAL TOBACCO CIGARETTES. THESE PRODUCTS HAVE SEEN A DRASTIC INCREASE IN POPULARITY IN RECENT YEARS BOTH AS SMOKING CESSATION DEVICES AS WELL AS AMONG YOUNGER GENERATIONS, DUE IN LARGE PART TO THE WIDESPREAD PERCEPTION AMONG CONSUMERS THAT E-CIGS ARE SIGNIFICANTLY LESS HARMFUL TO HEALTH THAN TRADITIONAL TOBACCO CIGARETTES. DUE TO THE NOVELTY OF ENDS AS WELL AS THEIR RAPIDLY INCREASING USE, RESEARCH INTO BIOMARKERS OF E-CIG EXPOSURE AND TOXICITY HAVE LAGGED BEHIND THEIR POPULARITY, LEAVING IMPORTANT QUESTIONS ABOUT THEIR POTENTIAL TOXICITY UNANSWERED. RESEARCH INTO POTENTIAL BIOMARKERS OF ACUTE AND CHRONIC E-CIG USE, AND E-CIGARETTE- OR VAPING-ASSOCIATED LUNG INJURY IS NECESSARY FOR INFORMING BOTH CLINICAL AND REGULATORY DECISION-MAKING. WE AIM TO PROVIDE AN UPDATED REVIEW OF RECENT RESEARCH INTO POTENTIAL CIRCULATING, GENOMIC, TRANSCRIPTOMIC, AND EPIGENETIC BIOMARKERS OF EXPOSURE TO AND TOXICITY OF E-CIGS. WE ADDITIONALLY HIGHLIGHT RESEARCH AREAS THAT WARRANT ADDITIONAL STUDY TO GAIN A BETTER UNDERSTANDING OF HEALTH RISKS ASSOCIATED WITH ENDS USE, AS WELL AS TO PROVIDE VALIDATION OF EXISTING DATA AND METHODS FOR MEASURING AND ANALYZING E-CIG-ASSOCIATED BIOMARKERS IN HUMAN AND ANIMAL BIOFLUIDS, TISSUES, AND CELLS. THIS REVIEW ALSO HIGHLIGHTS ONGOING EFFORTS WITHIN THE WNY CENTER FOR RESEARCH ON FLAVORED TOBACCO FOR RESEARCH INTO NOVEL BIOMARKERS IN EXTRACELLULAR VESICLES THAT MAY BE ASSOCIATED WITH SHORT- AND LONG-TERM ENDS USE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  1775  35 EBV IN T-/NK-CELL TUMORIGENESIS. EPSTEIN-BARR VIRUS (EBV), WHICH IS ASSOCIATED WITH B-CELL PROLIFERATIVE DISORDERS, ALSO TRANSFORMS T- OR NATURAL KILLER (NK)-LINEAGE CELLS AND HAS BEEN CONNECTED WITH VARIOUS T- OR NK (T/NK)-CELL MALIGNANCIES, SUCH AS EXTRANODAL NK/T-CELL LYMPHOMA-NASAL TYPE AND AGGRESSIVE NK-CELL LEUKEMIA. CHRONIC ACTIVE EBV (CAEBV) DISEASE , WHICH OCCURS MOST OFTEN IN CHILDREN AND YOUNG ADULTS IN EAST ASIA, IS AN EBV-ASSOCIATED T-/NK-CELL LYMPHOPROLIFERATIVE DISEASE. PATIENTS WITH CAEBV OFTEN PROGRESS TO OVERT LYMPHOMA OR LEUKEMIA OVER A LONG-TERM CLINICAL COURSE. EBV'S TRANSFORMING CAPACITY IN B CELLS IS WELL CHARACTERIZED, BUT THE MOLECULAR PATHOGENESIS OF CLONAL EXPANSION CAUSED BY EBV IN T/NK CELLS HAS NOT YET BEEN CLARIFIED. IN THE PRIMARY INFECTION, EBV INFECTS B CELLS AND EPITHELIAL CELLS AND MAY ALSO INFECT SOME T/NK CELLS. IN SOME INDIVIDUALS, BECAUSE OF POOR PRESENTATION BY SPECIFIC HUMAN LEUKOCYTE ANTIGENS OR THE GENETIC BACKGROUND, EBV-INFECTED T/NK CELLS EVADE HOST IMMUNITY AND SURVIVE. OCCASIONALLY, WITH THE HELP OF VIRAL ONCOGENES, EBV-ASSOCIATED T/NK LYMPHOPROLIFERATIVE DISEASES, SUCH AS CAEBV, MAY DEVELOP. THE SUBSEQUENT ACCUMULATION OF GENETIC MUTATIONS AND/OR EPIGENETIC MODIFICATIONS IN DRIVER GENES, SUCH AS DDX3X AND TP53, MAY LEAD TO OVERT LYMPHOMA AND LEUKEMIA. ACTIVATION-INDUCED CYTIDINE DEAMINASE AND THE APOBEC3 FAMILY, DRIVEN BY EBV INFECTION, MAY INDUCE CHROMOSOMAL RECOMBINATION AND SOMATIC MUTATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  5400  30 REDUCING TOBACCO-RELATED DISABILITY IN CHRONIC SMOKERS. TOBACCO CONSUMPTION (PREDOMINANTLY CIGARETTES) IS THE LEADING PREVENTABLE CAUSE OF MORTALITY WORLDWIDE. ALTHOUGH THE MAJOR FOCUS OF STRATEGIES TO REDUCE MORTALITY FROM TOBACCO MUST INCLUDE PREVENTION OF FUTURE GENERATIONS FROM INITIALLY GAINING ACCESS, SOME SMOKERS ARE UNWILLING OR UNABLE TO QUIT. CAN THE HIGHER RISK CHRONIC SMOKER BE IDENTIFIED AND CAN THEIR RISK BE REDUCED? THE RISK OF ADVERSE EVENTS IN CIGARETTE SMOKERS IS INFLUENCED BY THE INTENSITY AND DURATION OF CIGARETTE SMOKING OR SECONDHAND EXPOSURE, ASSOCIATED CONVENTIONAL RISK FACTORS, ENVIRONMENTAL STRESSORS, AND CERTAIN GENETIC VARIANTS AND EPIGENETIC MODIFIERS. RECENT DATA SUGGEST THAT INFLAMMATORY MARKERS SUCH AS HIGH-SENSITIVITY C-REACTIVE PROTEIN (HS CRP) AND TARGETED IMAGING CAN IDENTIFY SOME SMOKERS AT HIGHER RISK. AS SMOKING IS PROTHROMBOTIC, ASPIRIN INITIATION AND EXPANDED STATIN USE MIGHT REDUCE CARDIOVASCULAR RISK IN THOSE WHO DO NOT PRESENTLY MEET CRITERIA FOR THESE THERAPIES, BUT FURTHER STUDY IS REQUIRED. THUS, ALTHOUGH ADVOCACY FOR SMOKING CESSATION SHOULD ALWAYS BE THE PRIMARY APPROACH, INCREASED EFFORTS ARE NEEDED TO IDENTIFY AND POTENTIALLY TREAT THOSE WHO ARE UNABLE OR UNWILLING TO QUIT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  1852  37 ELECTRONIC CIGARETTES: THEIR CONSTITUENTS AND POTENTIAL LINKS TO ASTHMA. PURPOSE OF REVIEW: VAPING IS GAINING POPULARITY IN THE USA, PARTICULARLY AMONG TEENS AND YOUNG ADULTS. WHILE E-CIGS ARE COMMONLY REPRESENTED AS SAFER ALTERNATIVES TO TOBACCO CIGARETTES, LITTLE IS KNOWN REGARDING THE HEALTH EFFECTS OF THEIR SHORT- OR LONG-TERM USE, ESPECIALLY IN INDIVIDUALS WITH PRE-EXISTING RESPIRATORY DISEASES SUCH AS ASTHMA. FLAVORED E-CIG LIQUIDS (E-LIQUIDS) AND E-CIG AEROSOLS CONTAIN AIRWAY IRRITANTS AND TOXICANTS THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS AND WORSENING OF LUNG DISEASES. IN THIS REVIEW, WE WILL SUMMARIZE EXISTING DATA ON POTENTIAL HEALTH EFFECTS OF COMPONENTS PRESENT IN E-CIG AEROSOLS, SUCH AS PROPYLENE GLYCOL, VEGETABLE GLYCERIN, NICOTINE, AND FLAVORINGS, AND DISCUSS THEIR RELEVANCE IN THE CONTEXT OF ASTHMA. RECENT FINDINGS: RECENT SURVEY DATA INDICATE THAT ADOLESCENTS WITH ASTHMA HAD A HIGHER PREVALENCE OF CURRENT E-CIG USE (12.4%) COMPARED TO THEIR NON-ASTHMATICS PEERS (10.2%) AND CONVEYED POSITIVE BELIEFS ABOUT TOBACCO PRODUCTS, ESPECIALLY E-CIGS. SIMILARLY, A STUDY CONDUCTED AMONG HIGH SCHOOL STUDENTS FROM ONTARIO, CANADA, INDICATED A GREATER LIKELIHOOD OF E-CIG USE IN ASTHMATICS AS COMPARED TO THEIR NON-ASTHMATIC PEERS. AVAILABILITY OF DIFFERENT FLAVORINGS IS OFTEN CITED AS THE MAIN REASON AMONG YOUTH/ADOLESCENTS FOR TRYING E-CIGS OR SWITCHING FROM CIGARETTES TO E-CIGS. OCCUPATIONAL INHALATION OF SOME COMMON FOOD-SAFE FLAVORING AGENTS IS REPORTED TO CAUSE OCCUPATIONAL ASTHMA AND WORSEN ASTHMATIC SYMPTOMS. MOREOVER, WORKPLACE INHALATION EXPOSURES TO THE FLAVORING AGENT DIACETYL HAVE CAUSED IRREVERSIBLE OBSTRUCTIVE AIRWAY DISEASE IN HEALTHY WORKERS. ADDITIONALLY, RECENT STUDIES REPORT THAT THERMAL DECOMPOSITION OF PROPYLENE GLYCOL (PG) AND VEGETABLE GLYCERIN (VG), THE BASE CONSTITUENTS OF E-LIQUIDS, PRODUCES REACTIVE CARBONYLS, INCLUDING ACROLEIN, FORMALDEHYDE, AND ACETALDEHYDE, WHICH HAVE KNOWN RESPIRATORY TOXICITIES. FURTHERMORE, RECENT NICOTINE STUDIES IN RODENTS REVEAL THAT PRENATAL NICOTINE EXPOSURES LEAD TO EPIGENETIC REPROGRAMMING IN THE OFFSPRING, ABNORMAL LUNG DEVELOPMENT, AND MULTIGENERATIONAL TRANSMISSION OF ASTHMATIC-LIKE SYMPTOMS. COMPARISONS OF THE TOXICITY AND HEALTH EFFECTS OF E-CIGS AND CONVENTIONAL CIGARETTES OFTEN FOCUS ON TOXICANTS KNOWN TO BE PRESENT IN CIGARETTE SMOKE (CS) (I.E., FORMALDEHYDE, NITROSAMINES, ETC.), AS WELL AS SMOKING-ASSOCIATED CLINICAL ENDPOINTS, SUCH AS CANCER, BRONCHITIS, AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HOWEVER, THIS APPROACH DISREGARDS POTENTIAL TOXICITY OF COMPONENTS UNIQUE TO FLAVORED E-CIGS, SUCH AS PG, VG, AND THE MANY DIFFERENT FLAVORING CHEMICALS, WHICH LIKELY INDUCE RESPIRATORY EFFECTS NOT USUALLY OBSERVED IN CIGARETTE SMOKERS.	2017	

8  5903  42 T3/TRS AXIS IN HEPATOCELLULAR CARCINOMA: NEW CONCEPTS FOR AN OLD PAIR. HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE, AND ITS BURDEN IS EXPECTED TO FURTHER INCREASE IN THE NEXT YEARS. CHRONIC INFLAMMATION, INDUCED BY MULTIPLE VIRUSES OR METABOLIC ALTERATIONS, AND EPIGENETIC AND GENETIC MODIFICATIONS, COOPERATE IN CANCER DEVELOPMENT VIA A COMBINATION OF COMMON AND DISTINCT AETIOLOGY-SPECIFIC PATHWAYS. IN SPITE OF THE ADVANCES OF CLASSICAL THERAPIES, THE PROGNOSIS OF THIS NEOPLASM HAS NOT CONSIDERABLY IMPROVED OVER THE PAST FEW YEARS. THE ADVENT OF TARGETED THERAPIES AND THE APPROVAL OF THE SYSTEMIC TREATMENT OF ADVANCED HCC WITH THE KINASE INHIBITOR SORAFENIB HAVE PROVIDED SOME HOPE FOR THE FUTURE. HOWEVER, THE BENEFITS OBTAINED FROM THIS TREATMENT ARE STILL DISAPPOINTING, AS IT EXTENDS THE MEDIAN LIFE EXPECTANCY OF PATIENTS BY ONLY FEW MONTHS. IT IS THUS MANDATORY TO FIND ALTERNATIVE EFFECTIVE TREATMENTS. ALTHOUGH THE ROLE PLAYED BY THYROID HORMONES (THS) AND THEIR NUCLEAR RECEPTORS (TRS) IN HUMAN CANCER IS STILL UNCLEAR, MOUNTING EVIDENCE INDICATES THAT THEY BEHAVE AS ONCOSUPPRESSORS IN HCC. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH THEY EXERT THIS EFFECT AND THE CONSEQUENCE OF THEIR ACTIVATION FOLLOWING LIGAND BINDING ON HCC PROGRESSION REMAIN ELUSIVE. IN THIS REVIEW, WE RE-EVALUATE THE EXISTING EVIDENCE OF THE ROLE OF TH/TRS IN HCC DEVELOPMENT; WE WILL ALSO DISCUSS HOW TR ALTERATIONS COULD AFFECT FUNDAMENTAL BIOLOGICAL PROCESSES, SUCH AS HEPATOCYTE PROLIFERATION AND DIFFERENTIATION, AND CONSEQUENTLY HCC PROGRESSION. FINALLY, WE WILL DISCUSS IF AND HOW TRS CAN BE FORESEEN AS THERAPEUTIC TARGETS IN HCC AND WHETHER SELECTIVE TR MODULATION BY TH ANALOGUES MAY HOLD PROMISE FOR HCC TREATMENT.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9  3229  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10   401  26 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  3232  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12  2903  25 GENDER-SPECIFIC METHYLATION DIFFERENCES IN RELATION TO PRENATAL EXPOSURE TO CIGARETTE SMOKE. EPIGENETIC ALTERATIONS MAY MECHANISTICALLY EXPLAIN THE DEVELOPMENTAL ORIGINS OF ADULT DISEASE, NAMELY THE HYPOTHESIS THAT MANY COMPLEX ADULT CHRONIC DISEASES ORIGINATE AS A RESULT OF CONDITIONS ENCOUNTERED IN UTERO. IF TRUE, EPIGENETICALLY REGULATED IMPRINTED GENES, CRITICAL TO NORMAL GROWTH AND DEVELOPMENT, MAY PARTIALLY MEDIATE THESE OUTCOMES. WE DETERMINED THE INFLUENCE OF IN UTERO EXPOSURE TO CIGARETTE SMOKING ON METHYLATION AT TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) REGULATING INSULIN-LIKE GROWTH FACTOR 2 (IGF2) AND H19, AND HOW THIS MIGHT RELATE TO BIRTH WEIGHT OF INFANTS BORN TO 418 PREGNANT WOMEN. SMOKING STATUS WAS ASCERTAINED THROUGH SELF-REPORT AND MEDICAL RECORDS. BISULFITE PYROSEQUENCING WAS USED TO MEASURE METHYLATION IN UMBILICAL CORD BLOOD DNAS. LEAST SQUARES DNA METHYLATION MEANS AT EACH DMR AND BIRTH WEIGHT WERE COMPARED BETWEEN INFANTS OF SMOKERS AND NON-SMOKERS, USING GENERALIZED LINEAR MODELS. WHILE THERE WERE NO SIGNIFICANT DIFFERENCES AT THE H19 DMR, INFANTS BORN TO SMOKERS HAD HIGHER METHYLATION AT THE IGF2 DMR THAN THOSE BORN TO NEVER SMOKERS OR THOSE WHO QUIT DURING PREGNANCY (49.5%, SD=8.0 VERSUS 46.6%, SD=5.6 AND 45.8%, SD=6.3, RESPECTIVELY; P=0.0002). THE SMOKING-RELATED INCREASE IN METHYLATION WAS MOST PRONOUNCED IN MALE OFFSPRING (P FOR SEX INTERACTION=0.03), FOR WHOM APPROXIMATELY 20% OF SMOKING-RELATED LOW BIRTH WEIGHT WAS MEDIATED BY DNA METHYLATION AT THE IGF2 DMR. OUR FINDINGS SUGGEST THAT IGF2 DMR PLASTICITY IS AN IMPORTANT MECHANISM BY WHICH IN UTERO ADJUSTMENTS TO ENVIRONMENTAL TOXICANTS ARE CONFERRED. LARGER STUDIES TO REPLICATE THESE FINDINGS ARE REQUIRED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13  5744  17 SMOKING-INDUCED EXPRESSION OF THE GPR15 GENE INDICATES ITS POTENTIAL ROLE IN CHRONIC INFLAMMATORY PATHOLOGIES. DESPITE THE DESCRIBED CLEAR EPIGENETIC EFFECTS OF SMOKING, THE EFFECT OF SMOKING ON GENOME-WIDE GENE EXPRESSION IN THE BLOOD IS OBSCURE. WE THEREFORE STUDIED THE SMOKING-INDUCED CHANGES IN THE GENE-EXPRESSION PROFILE OF THE PERIPHERAL BLOOD. RNA WAS EXTRACTED FROM THE WHOLE BLOOD OF 48 INDIVIDUALS WITH A DETAILED SMOKING HISTORY (24 NEVER-SMOKERS, 16 SMOKERS, AND 8 EX-SMOKERS). GENE-EXPRESSION PROFILES WERE EVALUATED WITH RNA SEQUENCING, AND RESULTS WERE ANALYZED SEPARATELY IN 24 MEN AND 24 WOMEN. IN THE MALE SMOKERS, 13 GENES WERE STATISTICALLY SIGNIFICANTLY (FALSE-DISCOVERY RATE <0.1) DIFFERENTIALLY EXPRESSED; IN FEMALE SMOKERS, 5 GENES. ALTHOUGH MOST OF THE DIFFERENTIALLY EXPRESSED GENES WERE DIFFERENT BETWEEN THE MALE AND FEMALE SMOKERS, THE G-PROTEIN-COUPLED RECEPTOR 15 GENE (GPR15) WAS DIFFERENTIALLY EXPRESSED IN BOTH MALE AND FEMALE SMOKERS COMPARED WITH NEVER-SMOKERS. ANALYSIS OF GPR15 METHYLATION IDENTIFIED SIGNIFICANTLY GREATER HYPOMETHYLATION IN SMOKERS COMPARED WITH THAT IN NEVER-SMOKERS. GPR15 IS THE CHEMOATTRACTANT RECEPTOR THAT REGULATES T-CELL MIGRATION AND IMMUNITY. UP-REGULATION OF GPR15 COULD EXPLAIN TO SOME EXTENT THE HEALTH HAZARDS OF SMOKING WITH REGARD TO CHRONIC INFLAMMATORY DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  4725  26 NORMAL GASTRIC TISSUE HELICOBACTER PYLORI INFECTION IS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION, INCREASED MITOTIC TICK RATE, TISSUE CELL COMPOSITION, AND NATURAL KILLER CELL METHYLATION ALTERATIONS. BACKGROUND: GASTRIC ADENOCARCINOMAS ARE A LEADING CAUSE OF GLOBAL MORTALITY, ASSOCIATED WITH CHRONIC INFECTION WITH HELICOBACTER PYLORI . THE MECHANISMS BY WHICH INFECTION WITH H. PYLORI CONTRIBUTES TO CARCINOGENESIS ARE NOT WELL UNDERSTOOD. RECENT STUDIES FROM SUBJECTS WITH AND WITHOUT GASTRIC CANCER HAVE IDENTIFIED SIGNIFICANT DNA METHYLATION ALTERATIONS IN NORMAL GASTRIC MUCOSA ASSOCIATED WITH H. PYLORI INFECTION AND GASTRIC CANCER RISK. HERE WE FURTHER INVESTIGATED DNA METHYLATION ALTERATIONS IN NORMAL GASTRIC MUCOSA IN GASTRIC CANCER CASES (N = 42) AND CONTROL SUBJECTS (N = 42) WITH H. PYLORI INFECTION DATA. WE ASSESSED TISSUE CELL TYPE COMPOSITION, DNA METHYLATION ALTERATIONS WITHIN CELL POPULATIONS, EPIGENETIC AGING, AND REPETITIVE ELEMENT METHYLATION. RESULTS: IN NORMAL GASTRIC MUCOSA OF BOTH GASTRIC CANCER CASES AND CONTROL SUBJECTS, WE OBSERVED INCREASED EPIGENETIC AGE ACCELERATION ASSOCIATED WITH H. PYLORI INFECTION. WE ALSO OBSERVED AN INCREASED MITOTIC TICK RATE ASSOCIATED WITH H. PYLORI INFECTION IN BOTH GASTRIC CANCER CASES AND CONTROLS. SIGNIFICANT DIFFERENCES IN IMMUNE CELL POPULATIONS ASSOCIATED WITH H. PYLORI INFECTION IN NORMAL TISSUE FROM CANCER CASES AND CONTROLS WERE IDENTIFIED USING DNA METHYLATION CELL TYPE DECONVOLUTION. WE ALSO FOUND NATURAL KILLER CELL-SPECIFIC METHYLATION ALTERATIONS IN NORMAL MUCOSA FROM GASTRIC CANCER PATIENTS WITH H. PYLORI INFECTION. CONCLUSIONS: OUR FINDINGS FROM NORMAL GASTRIC MUCOSA PROVIDE INSIGHT INTO UNDERLYING CELLULAR COMPOSITION AND EPIGENETIC ASPECTS OF H. PYLORI ASSOCIATED GASTRIC CANCER ETIOLOGY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  1011  22 CIGARETTE SMOKE CONDENSATE INDUCES DIFFERENTIAL EXPRESSION AND PROMOTER METHYLATION PROFILES OF CRITICAL GENES INVOLVED IN LUNG CANCER IN NL-20 LUNG CELLS IN VITRO: SHORT-TERM AND CHRONIC EXPOSURE. ESTABLISHING EARLY DIAGNOSTIC MARKERS OF HARM IS CRITICAL FOR EFFECTIVE PREVENTION PROGRAMS AND REGULATION OF TOBACCO PRODUCTS. THIS STUDY EXAMINED EFFECTS OF CIGARETTE SMOKE CONDENSATE (CSC) ON EXPRESSION AND PROMOTER METHYLATION PROFILE OF CRITICAL GENES (DAPK, ECAD, MGMT, AND RASSF1A) INVOLVED IN LUNG CANCER DEVELOPMENT IN DIFFERENT HUMAN LUNG CELL LINES. NL-20 CELLS WERE TREATED WITH 0.1-100 MUG/ML OF CSC FOR 24 TO 72 HRS FOR SHORT-TERM EXPOSURES. DAPK EXPRESSION OR METHYLATION STATUS WAS NOT SIGNIFICANTLY AFFECTED. HOWEVER, CSC TREATMENT RESULTED IN CHANGES IN EXPRESSION AND PROMOTER METHYLATION PROFILE OF ECAD, MGMT, AND RASSF1A. FOR CHRONIC STUDIES, CELLS WERE EXPOSED TO 1 OR 10 MUG/ML CSC UP TO 28 DAYS. CELLS SHOWED MORPHOLOGICAL CHANGES ASSOCIATED WITH TRANSFORMATION AND CHANGES IN INVASION CAPACITIES AND GLOBAL METHYLATION STATUS. THIS STUDY PROVIDES CRITICAL DATA SUGGESTING THAT EPIGENETIC CHANGES COULD SERVE AS AN EARLY BIOMARKER OF HARM DUE TO EXPOSURE TO CIGARETTE SMOKE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  6633  31 UNHEALTHY SMOKERS: SCOPES FOR PROPHYLACTIC INTERVENTION AND CLINICAL TREATMENT. BACKGROUND: GLOBALLY, TOBACCO USE CAUSES APPROXIMATELY 6 MILLION DEATHS PER YEAR, AND PREDICTIONS REPORT THAT WITH CURRENT TRENDS; MORE THAN 8 MILLION DEATHS ARE EXPECTED ANNUALLY BY 2030. CIGARETTE SMOKINGS IS CURRENTLY ACCOUNTABLE FOR MORE THAN 480,000 DEATHS EACH YEAR IN UNITED STATES (US) AND IS THE LEADING CAUSE OF PREVENTABLE DEATH IN THE US. ON AVERAGE, SMOKERS DIE 10 YEARS EARLIER THAN NONSMOKERS AND IF SMOKING CONTINUES AT ITS CURRENT PROPORTION AMONG ADOLESCENTS, ONE IN EVERY 13 AMERICANS AGED 17 YEARS OR YOUNGER IS EXPECTED TO DIE PREMATURELY FROM A SMOKING-RELATED ILLNESS. EVEN THOUGH THERE HAS BEEN A MARGINAL SMOKING DECLINE OF AROUND 5% IN RECENT YEARS (2005 VS 2015), SMOKERS STILL ACCOUNT FOR 15% OF THE US ADULT POPULATION. WHAT IS ALSO CONCERNING IS THAT 41,000 OUT OF 480,000 DEATHS RESULTS FROM SECONDHAND SMOKE (SHS) EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE FOR THE SCOPE OF CLINICAL TREATMENT. CONCLUSIONS: CONSIDERING THESE PREMISES, IT IS EVIDENT THAT MUCH DETAILED TRANSLATIONAL AND CLINICAL STUDIES ARE NEEDED. FACTORS SUCH AS THE LENGTH OF SMOKING CESSATION FOR EX-SMOKERS, THE LEVEL OF SMOKE EXPOSURE IN CASE OF SHS, PRE-ESTABLISHED HEALTH CONDITIONS, GENETICS (AND EPIGENETICS MODIFICATION CAUSED BY CHRONIC SMOKING) ARE FEW OF THE CRITERIA THAT NEED TO BE EVALUATED TO BEGIN ASSESSING THE PROPHYLACTIC AND/OR THERAPEUTIC IMPACT OF TREATMENTS AIMED AT CHRONIC AND FORMER SMOKERS (ESPECIALLY EARLY STAGE EX-SMOKERS) INCLUDING THOSE FREQUENTLY SUBJECTED TO SECOND HAND TOBACCO SMOKE EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS ABOUT PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE AND SCOPE FOR CLINICAL TREATMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  4984  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  1540  32 DNA METHYLATION IN GASTRIC CANCER, RELATED TO HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS. GASTRIC CANCER IS A LEADING CAUSE OF CANCER DEATH WORLDWIDE, AND SIGNIFICANT EFFORT HAS BEEN FOCUSED ON CLARIFYING THE PATHOLOGY OF GASTRIC CANCER. IN PARTICULAR, THE DEVELOPMENT OF GENOME-WIDE ANALYSIS TOOLS HAS ENABLED THE DETECTION OF GENETIC AND EPIGENETIC ALTERATIONS IN GASTRIC CANCER; FOR EXAMPLE, ABERRANT DNA METHYLATION IN GENE PROMOTER REGIONS IS THOUGHT TO PLAY A CRUCIAL ROLE IN GASTRIC CARCINOGENESIS. THE ETIOLOGICAL VIEWPOINT IS ALSO ESSENTIAL FOR THE STUDY OF GASTRIC CANCERS, AND TWO DISTINCT PATHOGENS, HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV), ARE KNOWN TO PARTICIPATE IN GASTRIC CARCINOGENESIS. CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM DUE TO H. PYLORI INFECTION INDUCES ABERRANT POLYCLONAL METHYLATION THAT MAY LEAD TO AN INCREASED RISK OF GASTRIC CANCER. IN ADDITION, EBV INFECTION IS KNOWN TO CAUSE EXTENSIVE METHYLATION, AND EBV-POSITIVE GASTRIC CANCERS DISPLAY A HIGH METHYLATION EPIGENOTYPE, IN WHICH ABERRANT METHYLATION EXTENDS TO NOT ONLY POLYCOMB REPRESSIVE COMPLEX (PRC)-TARGET GENES IN EMBRYONIC STEM CELLS BUT ALSO NON-PRC-TARGET GENES. HERE, WE REVIEW ABERRANT DNA METHYLATION IN GASTRIC CANCER AND THE ASSOCIATION BETWEEN METHYLATION AND INFECTION WITH H. PYLORI AND EBV.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19   974  31 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20  3221  29 HELICOBACTER PYLORI AND THE MOLECULAR PATHOGENESIS OF INTESTINAL-TYPE GASTRIC CARCINOMA. GASTRIC CARCINOMA IS AN INFLAMMATION-RELATED CANCER CAUSED BY LONG-TERM INFECTION WITH THE HUMAN BACTERIAL PATHOGEN, HELICOBACTER PYLORI. THE PATTERN OF ACUTE-ON-CHRONIC INFLAMMATION CAUSES PROGRESSIVE MUCOSAL DAMAGE WHICH MAY RESULT IN ATROPHY WITH METAPLASTIC EPITHELIA AND EVENTUALLY GASTRIC CANCER. RECENTLY, IT HAS BEEN RECOGNIZED THAT H. PYLORI CAN ALSO CAUSE GENETIC INSTABILITY SUCH AS DOUBLE-STRANDED DNA BREAKS AND CAN PRODUCE GENE ACTIVATION AND SILENCING VIA EPIGENETIC PATHWAYS. AS GENETIC INSTABILITY IS THE HALLMARK OF CANCER, WE HIGHLIGHT RECENT PROGRESS IN UNDERSTANDING THE GASTRIC CARCINOGENESIS IN RELATION TO H. PYLORI-RELATED INFLAMMATION, H. PYLORI-INDUCED DOUBLE-STRANDED DNA BREAKAGE AND ABERRANT GENE EXPRESSION AS WELL AS THE MECHANISMS AND ROLE OF H. PYLORI-ASSOCIATED EPIGENETIC CHANGE IN GENE EXPRESSION.	2014