1 4718 103 NON-TYPEABLE HAEMOPHILUS INFLUENZAE ISOLATES FROM PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE CONTAIN NEW PHASE-VARIABLE MODA METHYLTRANSFERASE ALLELES CONTROLLING PHASEVARIONS. PHASEVARIONS (PHASE-VARIABLE REGULONS) ARE EMERGING AS AN IMPORTANT AREA OF BACTERIAL GENE REGULATION. MANY BACTERIAL PATHOGENS CONTAIN PHASEVARIONS, WITH GENE EXPRESSION CONTROLLED BY THE PHASE-VARIABLE EXPRESSION OF DNA METHYLTRANSFERASES VIA EPIGENETIC MECHANISMS. NON-TYPEABLE HAEMOPHILUS INFLUENZAE (NTHI) CONTAINS THE PHASE-VARIABLE METHYLTRANSFERASE MODA, OF WHICH MULTIPLE ALLELIC VARIANTS EXIST (MODA1-21). WE HAVE PREVIOUSLY DEMONSTRATED 5 OF 21 THESE MODA ALLELES ARE OVERREPRESENTED IN NTHI STRAINS ISOLATED FROM CHILDREN WITH MIDDLE EAR INFECTIONS. IN THIS STUDY WE INVESTIGATED THE MODA ALLELE DISTRIBUTION IN NTHI STRAINS ISOLATED FROM PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD. WE DEMONSTRATE THAT THE DISTRIBUTION OF MODA ALLELES IN A LARGE PANEL OF COPD ISOLATES IS DIFFERENT TO THE DISTRIBUTION SEEN IN MIDDLE EAR INFECTIONS, SUGGESTING DIFFERENT MODA ALLELES MAY PROVIDE DISTINCT ADVANTAGES IN THE DIFFERING NICHES OF THE MIDDLE EAR AND COPD AIRWAYS. WE ALSO IDENTIFIED TWO NEW PHASE-VARIABLE MODA ALLELES - MODA15 AND MODA18 - AND DEMONSTRATE THAT THESE ALLELES METHYLATE DISTINCT DNA SEQUENCES AND CONTROL UNIQUE PHASEVARIONS. THE MODA15 AND MODA18 ALLELES HAVE ONLY BEEN OBSERVED IN COPD ISOLATES, INDICATING THAT THESE TWO ALLELES MAY BE MARKERS FOR ISOLATES LIKELY TO CAUSE EXACERBATIONS OF COPD. 2019 2 6273 25 THE ORIGINS OF GASTRIC CANCER FROM GASTRIC STEM CELLS: LESSONS FROM MOUSE MODELS. THE CELLULAR ORIGIN OF DIGESTIVE CANCERS HAS BEEN A LONG-STANDING QUESTION IN THE CANCER FIELD. MOUSE MODELS HAVE IDENTIFIED LONG-LIVED STEM CELLS IN MOST ORGAN SYSTEMS, INCLUDING THE LUMINAL GASTROINTESTINAL TRACT, AND NUMEROUS STUDIES HAVE POINTED TO TISSUE RESIDENT STEM CELLS AS THE MAIN CELLULAR ORIGIN OF CANCER. DURING GASTRIC CARCINOGENESIS, CHRONIC INFLAMMATION INDUCES GENETIC AND EPIGENETIC ALTERATIONS IN LONG-LIVED STEM CELLS, ALONG WITH EXPANSION OF STEM CELL NICHES, EVENTUALLY LEADING TO INVASIVE CANCER. THE GASTRIC CORPUS AND ANTRUM HAVE DISTINCT STEM CELLS AND STEM CELL NICHES, SUGGESTING DIFFERENTIAL REGULATION OF CANCER INITIATION AT THE 2 SITES. IN THIS SHORT REVIEW, WE DISCUSS RECENT EXPERIMENTAL MODELS AND HUMAN STUDIES, WHICH PROVIDE IMPORTANT INSIGHTS INTO THE PATHOGENESIS OF GASTRIC CANCER. 2017 3 1863 24 EMERGENCE OF MUC1 IN MAMMALS FOR ADAPTATION OF BARRIER EPITHELIA. THE MUCIN 1 (MUC1) GENE WAS DISCOVERED BASED ON ITS OVEREXPRESSION IN HUMAN BREAST CANCERS. SUBSEQUENT WORK DEMONSTRATED THAT MUC1 IS ABERRANTLY EXPRESSED IN CANCERS ORIGINATING FROM OTHER DIVERSE ORGANS, INCLUDING SKIN AND IMMUNE CELLS. THESE FINDINGS SUPPORTED A ROLE FOR MUC1 IN THE ADAPTATION OF BARRIER TISSUES TO INFECTION AND ENVIRONMENTAL STRESS. OF FUNDAMENTAL IMPORTANCE FOR THIS EVOLUTIONARY ADAPTATION WAS INCLUSION OF A SEA DOMAIN, WHICH CATALYZES AUTOPROTEOLYSIS OF THE MUC1 PROTEIN AND FORMATION OF A NON-COVALENT HETERODIMERIC COMPLEX. THE RESULTING MUC1 HETERODIMER IS POISED AT THE APICAL CELL MEMBRANE TO RESPOND TO LOSS OF HOMEOSTASIS. DISRUPTION OF THE COMPLEX RELEASES THE MUC1 N-TERMINAL (MUC1-N) SUBUNIT INTO A PROTECTIVE MUCOUS GEL. CONVERSELY, THE TRANSMEMBRANE C-TERMINAL (MUC1-C) SUBUNIT ACTIVATES A PROGRAM OF LINEAGE PLASTICITY, EPIGENETIC REPROGRAMMING AND REPAIR. THIS MUC1-C-ACTIVATED PROGRAM APPARENTLY EVOLVED FOR BARRIER TISSUES TO MOUNT SELF-REGULATING PROLIFERATIVE, INFLAMMATORY AND REMODELING RESPONSES ASSOCIATED WITH WOUND HEALING. EMERGING EVIDENCE INDICATES THAT MUC1-C UNDERPINS INFLAMMATORY ADAPTATION OF TISSUE STEM CELLS AND IMMUNE CELLS IN THE BARRIER NICHE. THIS REVIEW FOCUSES ON HOW PROLONGED ACTIVATION OF MUC1-C BY CHRONIC INFLAMMATION IN THESE NICHES PROMOTES THE CANCER STEM CELL (CSC) STATE BY ESTABLISHING AUTO-INDUCTIVE NODES THAT DRIVE SELF-RENEWAL AND TUMORIGENICITY. 2022 4 2894 25 GASTRIC CANCER AS A STEM-CELL DISEASE: DATA AND HYPOTHESES. THE MAIN FUNCTION OF GASTRIC STEM CELLS IS TO MAINTAIN THE INTEGRITY OF THE GASTROINTESTINAL EPITHELIUM AND REPLENISH ALL THE MATURE CELL LINEAGES. IN ORDER TO ACCOMPLISH THIS, GASTRIC STEM CELLS PROLIFERATE AND SELF-RENEW, GIVING RISE TO TRANSIENT AMPLIFYING CELLS WHICH REPLACE THE CONSTANTLY RENEWING EPITHELIUM, ESPECIALLY AFTER INJURY INDUCED BY LONG-TERM INFLAMMATION. GASTRIC CANCER (GC) REMAINS THE FOURTH MOST COMMON CANCER AND THE SECOND LEADING CAUSE OF DEATH FOR CANCER IN THE WORLD. THE MOST ACCEPTED MODEL OF GASTRIC CARCINOGENESIS PROVIDES A MULTIFACTORIAL AND MULTISTEP PATHOGENESIS, INVOLVING A NUMBER OF INITIATORS AND OTHER CONTINUATOR AGENTS. HELICOBACTER PYLORI INFECTION IS RECOGNIZED AS A NECESSARY BUT INSUFFICIENT CAUSE OF GC. RECENT ADVANCES IN GASTRIC STEM CELL BIOLOGY POINT OUT TO TWO HYPOTHESES. IN THE FIRST, IT IS POSTULATED THAT RESIDENT STEM CELLS MAY, IN A CHRONICALLY INFLAMED ENVIRONMENT, AS IN THE CASE OF HELICOBACTER PYLORI-INDUCED GASTRITIS, ACCUMULATE OVER TIME A SERIES OF GENETIC AND EPIGENETIC CHANGES THAT LEAD TO THE EMERGENCE OF GC STEM CELLS. ALTERNATIVELY, THE SETTING OF CHRONIC INFLAMMATORY STRESS MAY LEAD TO LOSS OF THE INDIGENOUS GASTRIC STEM CELLS FROM THEIR NICHES, FOLLOWED BY RECRUITMENT AND ENGRAFTMENT OF BONE MARROW DERIVED STEM CELLS (BMDCS) INTO THE GASTRIC EPITHELIUM. IN THE MOUSE MODEL, INCREASING EVIDENCE SUPPORTS THE HYPOTHESIS THAT BMDCS ARE IMPORTANT CELLULAR SOURCE OF HELICOBACTER-INDUCED GC. THIS REVIEW HIGHLIGHTS DATA AND HYPOTHESES ABOUT GC AS A MODEL OF STEM-CELL DISEASE. 2014 5 1378 21 DEVELOPMENTAL PROGRAMS ARE KEPT ALIVE DURING ADULTHOOD BY STEM CELLS: THE AGING ASPECT. STEM CELLS ARE FUNDAMENTAL FOR LIFE-LONG PRESERVATION OF CELLULAR SOMATIC MAINTENANCE. TISSUE-BORNE STEM CELLS REPLENISH WORN-OUT CRITICAL ELEMENTS. PROVIDED THEY REMAIN FIT OVER LIFETIME, ENDURING STEM CELL ACTIVITIES AVERT THE EMERGENCE OF AGE-ASSOCIATED CHRONIC DEGENERATIVE DISEASES AND PATHOLOGIES. ALTHOUGH EXPERIMENTALLY STILL UNCLEAR, IT IS ASSUMED THAT STEM CELLS RESIDE IN PROTECTED NICHES. FRESHLY ISOLATED MESENCHYMAL STEM CELLS EXHIBIT DONOR-SPECIFIC ABERRATIONS, WHICH CANNOT SOLELY BE ASCRIBED TO DIFFERENCES IN GENETIC BACKGROUND. BESIDES INEVITABLY ACCUMULATING INTRINSIC MODIFICATIONS, THE SYSTEMIC ENVIRONMENT ALSO IMPACTS ON BASIC PROPERTIES OF MESENCHYMAL STEM CELLS SUCH AS THEIR INHERENT MULTI-LINEAGE DIFFERENTIATION POTENTIAL. CHRONIC SYSTEMIC ABERRATIONS OVER TIME COMPRISE UNWHOLESOME INFLUENCES, IN PARTICULAR IN TERMS OF REGENERATION AND REPAIR WHEN STEM CELLS RECAPITULATE DISTINCT DEVELOPMENTAL PROGRAMS. DURING OR THEREAFTER, STEM CELLS CAN DIVERSIFY EITHER BECAUSE OF INSUFFICIENTLY SILENCING ACTIVATED BUILDING CYCLES, OR BY ACQUIRING EPIGENETIC DEVIATIONS. 2013 6 1080 36 CLOSED COMPLETE GENOME SEQUENCES OF TWO NONTYPEABLE HAEMOPHILUS INFLUENZAE STRAINS CONTAINING NOVEL MODA ALLELES FROM THE SPUTUM OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. NONTYPEABLE HAEMOPHILUS INFLUENZAE (NTHI) IS AN IMPORTANT BACTERIAL PATHOGEN THAT CAUSES OTITIS MEDIA AND EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). HERE, WE REPORT THE COMPLETE GENOME SEQUENCES OF NTHI STRAINS 10P129H1 AND 84P36H1, ISOLATED FROM COPD PATIENTS, WHICH CONTAIN THE PHASE-VARIABLE EPIGENETIC REGULATORS MODA15 AND MODA18, RESPECTIVELY. 2018 7 6466 27 TISSUE STEM CELLS AND CANCER STEM CELLS: POTENTIAL IMPLICATIONS FOR GASTRIC CANCER. GASTRIC CANCER REMAINS THE SECOND LEADING CAUSE OF DEATH IN THE WORLD TODAY, MAKING THE SEARCH FOR ITS MOLECULAR AND CELLULAR BASIS AN IMPORTANT PRIORITY. THOUGH RECOGNITION OF THE TIGHT LINK BETWEEN INFLAMMATION AND TUMORIGENESIS IS CENTURIES OLD, ONLY RECENTLY ARE THE PIECES OF THE ETIOLOGICAL PUZZLE BEGINNING TO FALL TOGETHER. RECENT ADVANCES IN GASTRIC STEM CELL BIOLOGY APPEAR TO BE CENTRAL TO THIS SLOWLY RESOLVING PUZZLE. AT LEAST TWO TYPES OF STEM CELLS MAY BE IMPORTANT. RESIDENT ADULT OR TISSUE STEM CELLS MAY, IN A CHRONICALLY INFLAMED ENVIRONMENT, SLOWLY ACQUIRE A SERIES OF GENETIC AND EPIGENETIC CHANGES THAT LEAD TO THEIR EMERGENCE AS ''CANCER STEM CELLS''. THIS SCENARIO HAS NOT YET BEEN PROVEN EXPERIMENTALLY, ALTHOUGH THE FIRST STEP, PROSPECTIVE RECOGNITION OF A GASTRIC STEM CELL HAS RECENTLY BEEN CONQUERED. ALTERNATIVELY, THE SETTING OF CHRONIC INFLAMMATORY STRESS AND INJURY MAY LEAD TO LOSS OF THE INDIGENOUS GASTRIC STEM CELLS FROM THEIR NICHES; BONE MARROW DERIVED STEM CELLS MAY THEN BE RECRUITED TO AND ENGRAFT INTO THE GASTRIC EPITHELIUM. SUCH RECRUITED CELLS HAVE THE POTENTIAL TO CONTRIBUTE TO THE TUMOR MASS. INDEED, EVIDENCE SUPPORTING THIS SCENARIO HAS BEEN PUBLISHED. HERE, WE REVIEW THESE RECENT FINDINGS AND DISCUSS IMPLICATIONS FOR THE FUTURE. 2008 8 6782 19 [CHRONIC DISEASES, PRECANCER, AND CANCER OF THE LUNG, WHICH ARE ASSOCIATED WITH PATHOLOGY OF THE CLUB CELLS OF RESPIRATORY AND TERMINAL BRONCHIOLES]. THE REVIEW OF THE LITERATURE DEALS WITH THE PARTICIPATION OF CLARA CELLS NOW CALLED CLUB CELLS (CCS) OF THE EPITHELIUM IN THE RESPIRATORY AND TERMINAL BRONCHIOLES IN THE PATHOGENESIS AND MORPHOGENESIS OF CHRONIC INFLAMMATORY DISEASES, PRECANCER, AND CANCER OF THE LUNG, WHICH DEVELOP IN THE RESPIRATORY SEGMENTS. THE REVIEW SUMMARIZES DATA ON THE HISTOPHYSIOLOGY OF CCS AND THEIR PARTICIPATION IN THE PATHOGENESIS AND MORPHOGENESIS OF CHRONIC INTERSTITIAL LUNG DISEASES, PNEUMOCONIOSIS, CHRONIC OBSTRUCTIVE DISEASES, ADENOMATOSIS, AND ADENOCARCINOMA OF THE LUNG. IN THIS AREA, THERE IS A BRONCHIOLOALVEOLAR JUNCTION AREA (BAJA), ONE OF THE MOST IMPORTANT STEM CELL NICHES. CCS ARE LOCATED IN THE BAJA; THEY ARE PROGENITOR TISSUE STEM CELLS AND PLAY AN IMPORTANT ROLE IN THE REGENERATION OF THE EPITHELIUM OF THE RESPIRATORY BRONCHIOLES AND ALVEOLI. PATHOLOGY OF CCS IN THE BAJA LEADS TO THE MAINTENANCE OF CHRONIC INFLAMMATION, TO THE DESTRUCTION OF THE LUNG ELASTIC FRAME, AND TO IMPAIRED EPITHELIAL REGENERATION, INTERSTITIAL FIBROSIS, AND ADENOMATOSIS. IN THIS CASE, DECOMPENSATED INFLAMMATION, PATHOLOGICAL REGENERATION, AND FIBROSIS DEVELOP, WHICH, ALONG WITH THE ACTION OF CARCINOGENIC AGENTS, CAN CONTRIBUTE TO THE ACCUMULATION OF MUTATIONS AND EPIGENETIC REARRANGEMENTS IN THE CCS, WHICH SUBSEQUENTLY RESULTS IN ATYPICAL ADENOMATOUS HYPERPLASIA AND ADENOCARCINOMA OF THE LUNG. 2018 9 2383 30 EPIGENETIC REGULATOR G9A PROVIDES GLUCOSE AS A SWEET KEY TO STRESS RESISTANCE. THE ABILITY TO ADAPT TO ACUTE AND CHRONIC STRESS IS IMPORTANT FOR ORGANISMS TO THRIVE IN EVOLUTIONARY NICHES AND FOR CELLS TO SURVIVE IN ADVERSE CONDITIONS. THE REGULATORY NETWORKS THAT CONTROL STRESS RESPONSES ARE EVOLUTIONARILY CONSERVED, AND MANY FACTORS THAT SELECTIVELY ACTIVATE STRESS RESPONSES HAVE BEEN IDENTIFIED. LESS WELL UNDERSTOOD ARE MECHANISMS THAT GUARD AGAINST UNNECESSARY INDUCTION OF CYTOPROTECTIVE FACTORS AND THAT CONNECT STRESS RESPONSES WITH CELLULAR METABOLISM TO CONTROL ENERGY EXPENDITURE DURING STRESS. THE WORK OF RIAHI AND COLLEAGUES REPRESENTS IMPORTANT PROGRESS IN THIS REGARD BECAUSE IT IDENTIFIES THE HISTONE METHYLTRANSFERASE G9A AS A MODULATOR OF OXIDATIVE STRESS RESPONSES. G9A DAMPENS THE EXPRESSION OF ANTIOXIDANT GENES, THUS PREVENTING INAPPROPRIATE ENERGY CONSUMPTION. MOREOVER, G9A PROMOTES THE WELL-PACED CATABOLISM OF STORAGE GLYCOGEN AND FAT DURING STRESS. THE IMPORTANCE OF ENERGY AVAILABILITY DURING STRESS IS FURTHER EVIDENCED BY EXOGENOUS GLUCOSE RESCUING THE VULNERABILITY OF THE G9A MUTANT TO OXIDATIVE STRESS. PRIOR WORK IN MULTIPLE MODEL SYSTEMS HAS IMPLICATED G9A IN SEVERAL OTHER ADAPTIVE RESPONSES. THEREFORE, ITS ROLE IN PACING ENERGY CONSUMPTION AND IN RESTRAINING EXCESSIVE STRESS RESPONSE GENE EXPRESSION UNDER STRESS MAY EXTEND TO OTHER ADAPTIVE RESPONSES ACROSS SPECIES. 2019 10 3625 43 IN VIVO GENOME AND METHYLOME ADAPTATION OF CAG-NEGATIVE HELICOBACTER PYLORI DURING EXPERIMENTAL HUMAN INFECTION. MULTIPLE STUDIES HAVE DEMONSTRATED RAPID BACTERIAL GENOME EVOLUTION DURING CHRONIC INFECTION WITH HELICOBACTER PYLORI IN CONTRAST, LITTLE WAS KNOWN ABOUT GENETIC CHANGES DURING THE FIRST STAGES OF INFECTION, WHEN SELECTIVE PRESSURE IS LIKELY TO BE HIGHEST. USING SINGLE-MOLECULE, REAL-TIME (SMRT) AND ILLUMINA SEQUENCING TECHNOLOGIES, WE ANALYZED GENOME AND METHYLOME EVOLUTION DURING THE FIRST 10 WEEKS OF INFECTION BY COMPARING THE CAG PATHOGENICITY ISLAND (CAGPAI)-NEGATIVE H. PYLORI CHALLENGE STRAIN BCS 100 WITH PAIRS OF H. PYLORI REISOLATES FROM GASTRIC ANTRUM AND CORPUS BIOPSY SPECIMENS OF 10 HUMAN VOLUNTEERS WHO HAD BEEN INFECTED WITH THIS STRAIN AS PART OF A VACCINE TRIAL. MOST GENETIC CHANGES DETECTED IN THE REISOLATES AFFECTED GENES WITH A SURFACE-RELATED ROLE OR A PREDICTED FUNCTION IN PEPTIDE UPTAKE. APART FROM PHENOTYPIC CHANGES OF THE BACTERIAL ENVELOPE, A DUPLICATION OF THE CATALASE GENE WAS OBSERVED IN ONE REISOLATE, WHICH RESULTED IN HIGHER CATALASE ACTIVITY AND IMPROVED SURVIVAL UNDER OXIDATIVE STRESS CONDITIONS. THE METHYLOMES ALSO VARIED IN SOME OF THE REISOLATES, MOSTLY BY ACTIVITY SWITCHING OF PHASE-VARIABLE METHYLTRANSFERASE (MTASE) GENES. THE OBSERVED IN VIVO MUTATION SPECTRUM WAS REMARKABLE FOR A VERY HIGH PROPORTION OF NONSYNONYMOUS MUTATIONS. ALTHOUGH THE DATA SHOWED SUBSTANTIAL WITHIN-STRAIN GENOME DIVERSITY IN THE CHALLENGE STRAIN, MOST ANTRUM AND CORPUS REISOLATES FROM THE SAME VOLUNTEERS WERE HIGHLY SIMILAR TO EACH OTHER, INDICATING THAT THE CHALLENGE INFECTION REPRESENTS A MAJOR SELECTIVE BOTTLENECK SHAPING THE TRANSMITTED POPULATION. OUR FINDINGS SUGGEST RAPID IN VIVO SELECTION OF H. PYLORI DURING EARLY-PHASE INFECTION PROVIDING ADAPTATION TO DIFFERENT INDIVIDUALS BY COMMON MECHANISMS OF GENETIC AND EPIGENETIC ALTERATIONS.IMPORTANCE EXCEPTIONAL GENETIC DIVERSITY AND VARIABILITY ARE HALLMARKS OF HELICOBACTER PYLORI, BUT THE BIOLOGICAL ROLE OF THIS PLASTICITY REMAINS INCOMPLETELY UNDERSTOOD. HERE, WE HAD THE RARE OPPORTUNITY TO INVESTIGATE THE MOLECULAR EVOLUTION DURING THE FIRST WEEKS OF H. PYLORI INFECTION BY COMPARING THE GENOMES AND EPIGENOMES OF H. PYLORI STRAIN BCS 100 USED TO CHALLENGE HUMAN VOLUNTEERS IN A VACCINE TRIAL WITH THOSE OF BACTERIA REISOLATED FROM THE VOLUNTEERS 10 WEEKS AFTER THE CHALLENGE. THE DATA PROVIDE MOLECULAR INSIGHTS INTO THE PROCESS OF ESTABLISHMENT OF THIS HIGHLY VERSATILE PATHOGEN IN 10 DIFFERENT HUMAN INDIVIDUAL HOSTS, SHOWING, FOR EXAMPLE, SELECTION FOR CHANGES IN HOST-INTERACTION MOLECULES AS WELL AS CHANGES IN EPIGENETIC METHYLATION PATTERNS. THE DATA PROVIDE IMPORTANT CLUES TO THE EARLY ADAPTATION OF H. PYLORI TO NEW HOST NICHES AFTER TRANSMISSION, WHICH WE BELIEVE IS VITAL TO UNDERSTAND ITS SUCCESS AS A CHRONIC PATHOGEN AND DEVELOP MORE EFFICIENT TREATMENTS AND VACCINES. 2020 11 5404 25 REGENERATIVE INTESTINAL STEM CELLS INDUCED BY ACUTE AND CHRONIC INJURY: THE SAVING GRACE OF THE EPITHELIUM? THE INTESTINAL EPITHELIUM IS REPLENISHED EVERY 3-4 DAYS THROUGH AN ORDERLY PROCESS THAT MAINTAINS IMPORTANT SECRETORY AND ABSORPTIVE FUNCTIONS WHILE PRESERVING A CONTINUOUS MUCOSAL BARRIER. INTESTINAL EPITHELIAL CELLS (IECS) DERIVE FROM A STABLE POPULATION OF INTESTINAL STEM CELLS (ISCS) THAT RESIDE IN THE BASAL CRYPTS. WHEN INTESTINAL INJURY REACHES THE CRYPTS AND DAMAGES IECS, A MECHANISM TO REPLACE THEM IS NEEDED. RECENT RESEARCH HAS HIGHLIGHTED THE EXISTENCE OF DISTINCT POPULATIONS OF ACUTE AND CHRONIC DAMAGE-ASSOCIATED ISCS AND THEIR ROLES IN MAINTAINING HOMEOSTASIS IN SEVERAL INTESTINAL PERTURBATION MODELS. WHAT REMAINS UNKNOWN IS HOW THE DAMAGE-ASSOCIATED REGENERATIVE ISC POPULATION FUNCTIONS IN THE SETTING OF CHRONIC INFLAMMATION, AS OPPOSED TO ACUTE INJURY. WHAT LONG-TERM CONSEQUENCES RESULT FROM PERSISTENT INFLAMMATION AND OTHER CELLULAR INSULTS TO THE ISC NICHE? WHAT PARTICULAR "REGENERATIVE" CELL TYPES PROVIDE THE MOST EFFICACIOUS RESTORATIVE PROPERTIES? WHICH DIFFERENTIATED IECS MAINTAIN THE ABILITY TO DE-DIFFERENTIATE AND RESTORE THE ISC NICHE? THIS REVIEW WILL COVER THE LATEST RESEARCH ON DAMAGE-ASSOCIATED REGENERATIVE ISCS AND EPIGENETIC FACTORS THAT DETERMINE ISC FATE, AS WELL AS PROVIDE OPINIONS ON FUTURE STUDIES THAT NEED TO BE UNDERTAKEN TO UNDERSTAND THE REPERCUSSIONS OF THE EMERGENCE OF THESE CELLS, THEIR CONTRIBUTION TO RELAPSES IN INFLAMMATORY BOWEL DISEASE, AND THEIR POTENTIAL USE IN THERAPEUTICS FOR CHRONIC INTESTINAL DISEASES. 2020 12 2273 45 EPIGENETIC REGULATION ALTERS BIOFILM ARCHITECTURE AND COMPOSITION IN MULTIPLE CLINICAL ISOLATES OF NONTYPEABLE HAEMOPHILUS INFLUENZAE. BIOFILMS PLAY A CRITICAL ROLE IN THE COLONIZATION, PERSISTENCE, AND PATHOGENESIS OF MANY HUMAN PATHOGENS. MULTIPLE MUCOSA-ASSOCIATED PATHOGENS HAVE EVOLVED A MECHANISM OF RAPID ADAPTATION, TERMED THE PHASEVARION, WHICH FACILITATES A COORDINATED REGULATION OF NUMEROUS GENES THROUGHOUT THE BACTERIAL GENOME. THIS EPIGENETIC REGULATION OCCURS VIA PHASE VARIATION OF A DNA METHYLTRANSFERASE, MOD. THE PHASEVARION OF NONTYPEABLE HAEMOPHILUS INFLUENZAE (NTHI) SIGNIFICANTLY AFFECTS THE SEVERITY OF EXPERIMENTAL OTITIS MEDIA AND REGULATES SEVERAL DISEASE-RELATED PROCESSES. HOWEVER, THE ROLE OF THE NTHI PHASEVARION IN BIOFILM FORMATION IS UNCLEAR. THE PRESENT STUDY SHOWS THAT THE PHASEVARIONS OF MULTIPLE NTHI CLINICAL ISOLATES REGULATE IN VITRO BIOFILM FORMATION UNDER DISEASE-SPECIFIC MICROENVIRONMENTAL CONDITIONS. THE IMPACT OF PHASEVARION REGULATION WAS GREATEST UNDER ALKALINE CONDITIONS THAT MIMIC THOSE KNOWN TO OCCUR IN THE MIDDLE EAR DURING DISEASE. UNDER ALKALINE CONDITIONS, NTHI STRAINS THAT EXPRESS THE MODA2 METHYLTRANSFERASE FORMED BIOFILMS WITH SIGNIFICANTLY GREATER BIOMASS AND LESS DISTINCT ARCHITECTURE THAN THOSE FORMED BY A MODA2-DEFICIENT POPULATION. THE BIOFILMS FORMED BY NTHI STRAINS THAT EXPRESS MODA2 ALSO CONTAINED LESS EXTRACELLULAR DNA (EDNA) AND SIGNIFICANTLY LESS EXTRACELLULAR HU, A DNABII DNA-BINDING PROTEIN CRITICAL FOR BIOFILM STRUCTURAL STABILITY. STABLE BIOFILM STRUCTURE IS CRITICAL FOR BACTERIAL PATHOGENESIS AND PERSISTENCE IN MULTIPLE EXPERIMENTAL MODELS OF DISEASE. THESE RESULTS IDENTIFY A ROLE FOR THE PHASEVARION IN REGULATION OF BIOFILM FORMATION, A PROCESS INTEGRAL TO THE CHRONIC NATURE OF MANY INFECTIONS. UNDERSTANDING THE ROLE OF THE PHASEVARION IN BIOFILM FORMATION IS CRITICAL TO THE DEVELOPMENT OF PREVENTION AND TREATMENT STRATEGIES FOR THESE CHRONIC DISEASES.IMPORTANCE UPPER RESPIRATORY TRACT INFECTIONS ARE THE NUMBER ONE REASON FOR A CHILD TO VISIT THE EMERGENCY DEPARTMENT, AND OTITIS MEDIA (MIDDLE EAR INFECTION) RANKS THIRD OVERALL. BIOFILMS CONTRIBUTE SIGNIFICANTLY TO THE CHRONIC NATURE OF BACTERIAL RESPIRATORY TRACT INFECTIONS, INCLUDING OTITIS MEDIA, AND MAKE THESE DISEASES PARTICULARLY DIFFICULT TO TREAT. SEVERAL MUCOSA-ASSOCIATED HUMAN PATHOGENS UTILIZE A MECHANISM OF RAPID ADAPTATION TERMED THE PHASEVARION, OR PHASEVARIABLE REGULON, TO RESIST ENVIRONMENTAL AND HOST IMMUNE PRESSURES. IN THIS STUDY, WE ASSESSED THE ROLE OF THE PHASEVARION IN REGULATION OF BIOFILM FORMATION BY NONTYPEABLE HAEMOPHILUS INFLUENZAE (NTHI), WHICH CAUSES NUMEROUS RESPIRATORY TRACT DISEASES. WE FOUND THAT THE NTHI PHASEVARION REGULATES BIOFILM STRUCTURE AND CRITICAL BIOFILM MATRIX COMPONENTS UNDER DISEASE-SPECIFIC CONDITIONS. THE FINDINGS OF THIS WORK COULD BE SIGNIFICANT IN THE DESIGN OF IMPROVED STRATEGIES AGAINST NTHI INFECTIONS, AS WELL AS DISEASES DUE TO OTHER PATHOGENS THAT UTILIZE A PHASEVARION. 2018 13 4494 43 MORAXELLA CATARRHALIS RESTRICTION-MODIFICATION SYSTEMS ARE ASSOCIATED WITH PHYLOGENETIC LINEAGE AND DISEASE. MORAXELLA CATARRHALIS IS A HUMAN-ADAPTED PATHOGEN, AND A MAJOR CAUSE OF OTITIS MEDIA (OM) AND EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE SPECIES IS COMPRISED OF TWO MAIN PHYLOGENETIC LINEAGES, RB1 AND RB2/3. RESTRICTION-MODIFICATION (R-M) SYSTEMS ARE AMONG THE FEW LINEAGE-ASSOCIATED GENES IDENTIFIED IN OTHER BACTERIAL GENERA AND HAVE MULTIPLE FUNCTIONS INCLUDING DEFENSE AGAINST FOREIGN INVADING DNA, MAINTENANCE OF SPECIATION, AND EPIGENETIC REGULATION OF GENE EXPRESSION. HERE, WE DEFINE THE REPERTOIRE OF R-M SYSTEMS IN 51 PUBLICLY AVAILABLE M. CATARRHALIS GENOMES AND REPORT THEIR DISTRIBUTION AMONG M. CATARRHALIS PHYLOGENETIC LINEAGES. AN ASSOCIATION WITH PHYLOGENETIC LINEAGE (RB1 OR RB2/3) WAS OBSERVED FOR SIX R-M SYSTEMS, WHICH MAY CONTRIBUTE TO THE EVOLUTION OF THE LINEAGES BY RESTRICTING DNA TRANSFORMATION. IN ADDITION, WE OBSERVED A RELATIONSHIP BETWEEN A MUTUALLY EXCLUSIVE TYPE I R-M SYSTEM AND A TYPE III R-M SYSTEM AT A SINGLE LOCUS CONSERVED THROUGHOUT A GEOGRAPHICALLY AND CLINICALLY DIVERSE SET OF M. CATARRHALIS ISOLATES. THE TYPE III R-M SYSTEM AT THIS LOCUS CONTAINS THE PHASE-VARIABLE TYPE III DNA METHYLTRANSFERASE, MODM, WHICH CONTROLS A PHASEVARION (PHASE-VARIABLE REGULON). WE OBSERVED AN ASSOCIATION BETWEEN MODM PRESENCE AND OM-ASSOCIATED MIDDLE EAR ISOLATES, INDICATING A POTENTIAL ROLE FOR MODM-MEDIATED EPIGENETIC REGULATION IN OM PATHOBIOLOGY. 2018 14 5767 24 SPECIES-SPECIFIC ROLE OF GENE-ADJACENT RETROELEMENTS IN HUMAN AND MOUSE GASTRIC CARCINOGENESIS. HELICOBACTER PYLORI (HP) INFECTION PROMOTES THE RECRUITMENT OF BONE MARROW STEM CELLS INTO CHRONIC GASTRITIS LESIONS. SOME OF THESE MARROW STEM CELLS CAN DIFFERENTIATE INTO GASTRIC EPITHELIAL CELLS AND NEOPLASTIC CELLS. WE PROPOSE THAT HP-ASSOCIATED METHYLATION COULD STABILIZE TRANS-DIFFERENTIATION OF MARROW-DERIVED STEM CELLS AND THAT AN UNSTABLE METHYLATION STATUS IS ASSOCIATED WITH A RISK OF GASTRIC CANCER. PATHOBIOLOGIC BEHAVIOR OF EXPERIMENTAL MOUSE GASTRIC CANCER IS MILD COMPARED TO INVASIVE AND METASTATIC HUMAN GASTRIC CANCER. DIFFERENCES IN EPIGENETIC STABILIZATION OF ADULT CELL PHENOTYPES BETWEEN HUMANS AND MICE COULD PROVIDE A FOUNDATION TO EXPLORE THE DEVELOPMENT OF INVASIVE AND METASTATIC GASTRIC CANCER. RETROELEMENTS ARE HIGHLY REPETITIVE SEQUENCES THAT PLAY AN ESSENTIAL ROLE IN THE GENERATION OF SPECIES DIVERSITY. IN THIS REVIEW, WE ANALYZED RETROELEMENTS ADJACENT TO HUMAN AND MOUSE HOUSEKEEPING GENES AND PROPOSED A POSSIBLE EPIGENETIC MECHANISM FOR HP-ASSOCIATED CARCINOGENESIS. 2018 15 4512 20 MUC1-C IN CHRONIC INFLAMMATION AND CARCINOGENESIS; EMERGENCE AS A TARGET FOR CANCER TREATMENT. CHRONIC INFLAMMATION IS A HIGHLY PREVALENT CONSEQUENCE OF CHANGES IN ENVIRONMENTAL AND LIFESTYLE FACTORS THAT CONTRIBUTE TO THE DEVELOPMENT OF CANCER. THE BASIS FOR THIS CRITICAL ASSOCIATION HAS LARGELY REMAINED UNCLEAR. THE MUC1 GENE EVOLVED IN MAMMALS TO PROTECT EPITHELIA FROM THE EXTERNAL ENVIRONMENT. THE MUC1-C SUBUNIT PROMOTES RESPONSES FOUND IN WOUND HEALING AND CANCER. MUC1-C INDUCES EMT, EPIGENETIC REPROGRAMMING, DEDIFFERENTIATION AND PLURIPOTENCY FACTOR EXPRESSION, WHICH WHEN PROLONGED IN CHRONIC INFLAMMATION PROMOTE CANCER PROGRESSION. AS DISCUSSED IN THIS REVIEW, MUC1-C ALSO DRIVES DRUG RESISTANCE AND IMMUNE EVASION, AND IS AN IMPORTANT TARGET FOR CANCER THERAPEUTICS NOW UNDER DEVELOPMENT. 2020 16 4409 25 MOLECULAR ANATOMY AND PATHOGENIC ACTIONS OF HELICOBACTER PYLORI CAGA THAT UNDERPIN GASTRIC CARCINOGENESIS. CHRONIC INFECTION WITH HELICOBACTER PYLORI CAGA-POSITIVE STRAINS IS THE STRONGEST RISK FACTOR FOR GASTRIC CANCER. THE CAGA GENE PRODUCT, CAGA, IS DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE BACTERIAL TYPE IV SECRETION SYSTEM. DELIVERED CAGA THEN UNDERGOES TYROSINE PHOSPHORYLATION AT THE GLU-PRO-ILE-TYR-ALA (EPIYA) MOTIFS IN ITS C-TERMINAL REGION AND ACTS AS AN ONCOGENIC SCAFFOLD PROTEIN THAT PHYSICALLY INTERACTS WITH MULTIPLE HOST SIGNALING PROTEINS IN BOTH TYROSINE PHOSPHORYLATION-DEPENDENT AND -INDEPENDENT MANNERS. ANALYSIS OF CAGA USING IN VITRO CULTURED GASTRIC EPITHELIAL CELLS HAS INDICATED THAT THE NONPHYSIOLOGICAL SCAFFOLDING ACTIONS OF CAGA CELL-AUTONOMOUSLY PROMOTE THE MALIGNANT TRANSFORMATION OF THE CELLS BY ENDOWING THE CELLS WITH MULTIPLE PHENOTYPIC CANCER HALLMARKS: SUSTAINED PROLIFERATION, EVASION OF GROWTH SUPPRESSORS, INVASIVENESS, RESISTANCE TO CELL DEATH, AND GENOMIC INSTABILITY. TRANSGENIC EXPRESSION OF CAGA IN MICE LEADS TO IN VIVO ONCOGENIC ACTION OF CAGA WITHOUT ANY OVERT INFLAMMATION. THE IN VIVO ONCOGENIC ACTIVITY OF CAGA IS FURTHER POTENTIATED IN THE PRESENCE OF CHRONIC INFLAMMATION. SINCE HELICOBACTER PYLORI INFECTION TRIGGERS A PROINFLAMMATORY RESPONSE IN HOST CELLS, A FEEDFORWARD STIMULATION LOOP THAT AUGMENTS THE ONCOGENIC ACTIONS OF CAGA AND INFLAMMATION IS CREATED IN CAGA-INJECTED GASTRIC MUCOSA. GIVEN THAT HELICOBACTER PYLORI IS NO LONGER COLONIZED IN ESTABLISHED GASTRIC CANCER LESIONS, THE MULTISTEP NATURE OF GASTRIC CANCER DEVELOPMENT SHOULD INCLUDE A "HIT-AND-RUN" PROCESS OF CAGA ACTION. THUS, ACQUISITION OF GENETIC AND EPIGENETIC ALTERATIONS THAT COMPENSATE FOR CAGA-DIRECTED CANCER HALLMARKS MAY BE REQUIRED FOR COMPLETION OF THE "HIT-AND-RUN" PROCESS OF GASTRIC CARCINOGENESIS. 2020 17 3224 24 HELICOBACTER PYLORI INFECTION AND STEM CELLS AT THE ORIGIN OF GASTRIC CANCER. HELICOBACTER PYLORI INFECTION IS NOW RECOGNIZED AS THE MAIN AND SPECIFIC INFECTIOUS CAUSE OF CANCER IN THE WORLD. IT IS RESPONSIBLE FOR GASTRIC ADENOCARCINOMAS OF BOTH INTESTINAL AND DIFFUSE TYPES, WHICH ARE THE LONG-TERM CONSEQUENCES OF THE CHRONIC INFECTION OF THE GASTRIC MUCOSA. CASE-CONTROL STUDIES HAVE SHOWN AN ASSOCIATION BETWEEN THE TWO, RECOGNIZED AS EARLY AS 1994 AND FURTHER SUBSTANTIATED BY INTERVENTIONAL STUDIES IN WHICH H. PYLORI ERADICATION HAS LED TO THE PREVENTION OF AT LEAST PART OF THE GASTRIC CANCERS. EXPERIMENTAL STUDIES HAVE HIGHLIGHTED THE ROLE OF BONE MARROW-DERIVED CELLS (BMDCS) AND PARTICULARLY MESENCHYMAL STEM CELLS, IN THE NEOPLASTIC PROCESS IN ABOUT A QUARTER OF THE CASES AND POSSIBLY AN EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN THE OTHER CASES. DIFFERENT STUDIES HAVE CONFIRMED THAT CHRONIC INFECTION WITH H. PYLORI INDUCES A CHRONIC INFLAMMATION AND SUBSEQUENT DAMAGE OF THE GASTRIC EPITHELIAL MUCOSA, LEADING TO BMDC RECRUITMENT. ONCE RECRUITED, THESE CELLS HOME AND DIFFERENTIATE BY CELL-CELL FUSION WITH LOCAL GASTRIC EPITHELIAL CELLS, BEARING LOCAL STEM CELL FAILURE AND PARTICIPATING IN TISSUE REGENERATION. THE CONTEXT OF CHRONIC INFECTION AND INFLAMMATION LEADS TO AN EMT AND ALTERED TISSUE REGENERATION AND DIFFERENTIATION FROM BOTH LOCAL EPITHELIAL STEM CELLS AND BMDC. EMT INDUCES THE EMERGENCE OF CD44+ CELLS POSSESSING MESENCHYMAL AND STEM CELL PROPERTIES, RESULTING IN METAPLASTIC AND DYSPLASTIC LESIONS TO GIVE RISE, AFTER ADDITIONAL EPIGENETIC AND MUTATIONAL EVENTS, TO THE EMERGENCE OF CANCER STEM CELLS (CSCS) AND ADENOCARCINOMA. 2015 18 3232 20 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 19 5212 22 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC. 2018 20 4984 22 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