1 6040 153 THE CHRONIC MYELOPROLIFERATIVE DISORDERS: CLONALITY AND CLINICAL HETEROGENEITY. THE CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD), POLYCYTHEMIA VERA (PV), CHRONIC IDIOPATHIC MYELOFIBROSIS (IMF), ESSENTIAL THROMBOCYTOSIS (ET), AND CHRONIC MYELOGENOUS LEUKEMIA (CML), ARE THOUGHT TO BE CLONAL DISORDERS ARISING IN A MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL. HOWEVER, ESTABLISHING THE DIAGNOSIS OF AN MPD OTHER THAN CML IS PROBLEMATIC DUE TO A LACK OF CLINICALLY APPLICABLE CLONAL MARKERS. FURTHERMORE, IN SOME PATIENTS, IN WHOM A CLASSICAL MPD PHENOTYPE IS PRESENT, THE HEMATOPOIETIC STEM CELLS APPEAR TO BE POLYCLONAL, SUGGESTING THAT THE CHRONIC MPD OTHER THAN CML MAY ACTUALLY BE A GENETICALLY HETEROGENEOUS GROUP OF DISORDERS. FURTHERMORE, SINCE THE ABERRANT CLONE IS BELIEVED TO ARISE FROM A MULTIPOTENT HEMATOPOIETIC STEM CELL, THE NON-CML CHRONIC MPD-ET, PV, AND IMF-COULD BE RELATED. ADDITIONAL UNRESOLVED ISSUES REGARDING THE MPD INCLUDE: IDENTIFICATION OF THE MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL INVOLVED, THE MOLECULAR BASIS FOR THE CLINICAL HETEROGENEITY AMONGST THE INDIVIDUAL MPD, THE CLINICAL SIGNIFICANCE OF CLONALITY IN NON-CML MPD, AND RECONCILIATION OF THERAPY WITH THE CLONAL AND CLINICAL HETEROGENEITY OF THESE DISORDERS. DETERMINATION OF CLONALITY HAS LARGELY BEEN CARRIED OUT USING X CHROMOSOME-LINKED POLYMORPHISMS, BUT SUCH STUDIES ARE LIMITED TO WOMEN AND WITH INCREASING PATIENT AGE ARE COMPROMISED BY SKEWING OF ALLELIC EXPRESSION IN BOTH NEUTROPHILS AND T LYMPHOCYTES, MAKING THE RESULTS DIFFICULT TO INTERPRET. X CHROMOSOME-LINKED POLYMORPHISM STUDIES HAVE INDICATED THAT IN PV THE TARGET STEM CELL IS ONE THAT GIVES RISE TO BOTH LYMPHOID AND MYELOID PROGENITORS. RECENTLY, TWO EPIGENETIC MARKERS HAVE BEEN IDENTIFIED IN THE MPD: IMPAIRED EXPRESSION OF THE THROMBOPOIETIN RECEPTOR, MPL, IN PLATELETS AND MEGAKARYOCYTES, AND OVEREXPRESSION IN NEUTROPHILS OF THE MRNA OF A GENE DESIGNATED POLYCYTHEMIA RUBRA VERA-1 (PRV-1). THE ROLE OF THESE EPIGENETIC ABNORMALITIES IN THE DIAGNOSIS OF THE MPD REMAINS TO BE ESTABLISHED. CURRENTLY, GIVEN THE UNRESOLVED ISSUES WITH RESPECT TO THE CLINICAL AND CLONAL HETEROGENEITY OF THE MPD, TREATMENT NEEDS TO BE TAILORED INDIVIDUALLY IN PATIENTS WITH AN MPD. 2004 2 1540 33 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 3 3223 32 HELICOBACTER PYLORI INFECTION AND AUTOIMMUNE DISEASES; IS THERE AN ASSOCIATION WITH SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AUTOIMMUNE ATROPHY GASTRITIS AND AUTOIMMUNE PANCREATITIS? A SYSTEMATIC REVIEW AND META-ANALYSIS STUDY. AUTOIMMUNE DISEASES ARE CONSIDERED AS ONE OF THE MOST IMPORTANT DISORDERS OF THE IMMUNE SYSTEM, IN WHICH THE PROLONGED AND CHRONIC PROCESSES ELIMINATE SELF-TOLERANCE TO THE AUTO-ANTIGENS. THE PREVALENCE OF AUTOIMMUNE DISEASES HAS BEEN INCREASING WORLDWIDE IN THE RECENT YEARS. ACCORDING TO THE LITERATURE, BIOLOGICAL PROCESSES SUCH AS THE HOST GENOME, EPIGENETIC EVENTS, ENVIRONMENTAL CONDITION, DRUG CONSUMPTION, AND INFECTIOUS AGENTS ARE THE MOST IMPORTANT RISK FACTORS THAT MAKE THE HOST SUSCEPTIBLE TO THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THE RECENT YEARS, THE ROLE OF HELICOBACTER PYLORI IN THE INDUCTION OF AUTOIMMUNE DISEASES HAS ATTRACTED EXTENSIVE ATTENTION. VIA MOLECULAR MIMICRY, EPITOPE SPREADING, BYSTANDER ACTIVATION, POLYCLONAL ACTIVATION, DYSREGULATION IN IMMUNE RESPONSE, AND HIGHLY IMMUNE-DOMINANT VIRULENCE, SUCH AS CAGA, H. PYLORI CAUSES TISSUE DAMAGE, POLARITY, AND PROLIFERATION OF THE HOST CELLS LEADING TO THE MODULATION OF HOST IMMUNE RESPONSES. MOREOVER, GIVEN THE LARGE POPULATION WORLDWIDE INFECTED WITH H. PYLORI, IT SEEMS LIKELY THAT THE BACTERIUM MAY DEVELOP INTO AUTOIMMUNE DISEASES THROUGH DYSREGULATION OF THE IMMUNE RESPONSE. THE FREQUENCY AND RELATIONSHIP BETWEEN H. PYLORI INFECTION AND SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AUTOIMMUNE ATROPHY GASTRITIS, AND AUTOIMMUNE PANCREATITIS WERE EVALUATED USING THE DATA FROM 43 STUDIES INVOLVING 5052 PATIENTS. ACCORDING TO STATISTICAL ANALYSIS IT IS PROBABLE THAT INFECTION WITH MORE VIRULENT STRAINS OF H. PYLORI (SUCH AS H. PYLORI CAGA POSITIVE) CAN INCREASE THE RISK OF AUTOIMMUNE DISEASES. IN ADDITION, IT WAS SHOWN THAT INFECTION WITH H. PYLORI CAN PREVENT THE DEVELOPMENT OF ATROPHIC GASTRITIS BY STIMULATING INFLAMMATION IN THE GASTRIC ANTRUM. HOWEVER, FUTURE STUDIES SHOULD CONFIRM THE VALIDITY OF THIS STUDY. 2021 4 3229 21 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 5 4994 28 PERFORMANCE OF DNA METHYLATION ON THE MOLECULAR PATHOGENESIS OF HELICOBACTER PYLORI IN GASTRIC CANCER; TARGETED THERAPY APPROACH. GASTRIC CANCER (GC) IS A SIGNIFICANT CAUSE OF CANCER MORTALITY WHICH HAS LED TO FOCUSED EXPLORATION OF THE PATHOLOGY OF GC. THE ADVENT OF GENOME-WIDE ANALYSIS METHODS HAS MADE IT POSSIBLE TO UNCOVER GENETIC AND EPIGENETIC FLUCTUATION SUCH AS ABNORMAL DNA METHYLATION IN GENE PROMOTER REGIONS THAT IS EXPECTED TO PLAY A KEY ROLE IN GC. THE STUDY OF GASTRIC MALIGNANCIES REQUIRES AN ETIOLOGICAL PERSPECTIVE, AND HELICOBACTER PYLORI (H. PYLORI) WAS IDENTIFIED TO PLAY A ROLE IN GC. H. PYLORI INFECTION CAUSES CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM CAUSING ABNORMAL POLYCLONAL METHYLATION, WHICH MIGHT RAISE THE RISK OF GC. IN THE LAST TWO DECADES, VARIOUS PATHOGENIC FACTORS BY WHICH H. PYLORI INFECTION CAUSES GC HAVE BEEN DISCOVERED. ABNORMAL DNA METHYLATION IS TRIGGERED IN SEVERAL GENES, RENDERING THEM INACTIVE. IN GC, METHYLATION PATTERNS ARE LINKED TO CERTAIN SUBTYPES INCLUDING MICROSATELLITE INSTABILITY. MULTIPLE CANCER-RELATED PROCESSES ARE MORE USUALLY CHANGED BY ABNORMAL DNA METHYLATION THAN THROUGH MUTATIONS, ACCORDING TO CURRENT GENERAL AND COMBINED INVESTIGATIONS. FURTHERMORE, THE AMOUNT OF ACQUIRED ABNORMAL DNA METHYLATION IS HEAVILY LINKED TO THE CHANCES OF DEVELOPING GC. THEREFORE, WE INVESTIGATED ABNORMAL DNA METHYLATION IN GC AND THE LINK BETWEEN METHYLATION AND H. PYLORI INFECTION. 2022 6 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 7 3222 31 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 6841 26 [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 9 64 36 A HIGH-THROUGHPUT SCREENING ASSAY FOR SILENCING ESTABLISHED HIV-1 MACROPHAGE INFECTION IDENTIFIES NUCLEOSIDE ANALOGS THAT PERTURB H3K9ME3 ON PROVIRAL GENOMES. HIV-INFECTED MACROPHAGES ARE LONG-LIVED CELLS THAT REPRESENT A BARRIER TO FUNCTIONAL CURE. ADDITIONALLY, LOW-LEVEL VIRAL EXPRESSION BY CENTRAL NERVOUS SYSTEM (CNS) MACROPHAGES CONTRIBUTES TO NEUROCOGNITIVE DEFICITS THAT DEVELOP DESPITE ANTIRETROVIRAL THERAPY (ART). WE RECENTLY IDENTIFIED H3K9ME3 AS AN ATYPICAL EPIGENETIC MARK ASSOCIATED WITH CHRONIC HIV INFECTION IN MACROPHAGES. THUS, STRATEGIES ARE NEEDED TO SUPPRESS HIV-1 EXPRESSION IN MACROPHAGES, BUT THE UNIQUE MYELOID ENVIRONMENT AND THE RESPONSIBLE MACROPHAGE/CNS-TROPIC STRAINS REQUIRE CELL/STRAIN-SPECIFIC APPROACHES. HERE, WE GENERATED AN HIV-1 REPORTER VIRUS FROM A CNS-DERIVED STRAIN WITH INTACT AUXILIARY GENES EXPRESSING DESTABILIZED LUCIFERASE. WE EMPLOYED THIS REPORTER VIRUS IN POLYCLONAL INFECTION OF PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES (MDM) FOR A HIGH-THROUGHPUT SCREEN (HTS) TO IDENTIFY COMPOUNDS THAT SUPPRESS VIRUS EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. SCREENING ~6,000 KNOWN DRUGS AND COMPOUNDS YIELDED 214 HITS. A SECONDARY SCREEN WITH 10-DOSE TITRATION IDENTIFIED 24 MEETING CRITERIA FOR HIV-SELECTIVE ACTIVITY. USING THREE REPLICATION-COMPETENT CNS-DERIVED MACROPHAGE-TROPIC HIV-1 ISOLATES AND VIRAL GENE EXPRESSION READOUT IN MDM, WE CONFIRMED THE EFFECT OF THREE PURINE ANALOGS, NELARABINE, FLUDARABINE, AND ENTECAVIR, SHOWING THE SUPPRESSION OF HIV-1 EXPRESSION FROM ESTABLISHED MACROPHAGE INFECTION. NELARABINE INHIBITED THE FORMATION OF H3K9ME3 ON HIV GENOMES IN MACROPHAGES. THUS, THIS NOVEL HTS ASSAY CAN IDENTIFY SUPPRESSORS OF HIV-1 TRANSCRIPTION IN ESTABLISHED MACROPHAGE INFECTION, SUCH AS NUCLEOSIDE ANALOGS AND HDAC INHIBITORS, WHICH MAY BE LINKED TO H3K9ME3 MODIFICATION. THIS SCREEN MAY BE USEFUL TO IDENTIFY NEW METABOLIC AND EPIGENETIC AGENTS THAT AMELIORATE HIV-DRIVEN NEUROINFLAMMATION IN PEOPLE ON ART OR PREVENT VIRAL RECRUDESCENCE FROM MACROPHAGE RESERVOIRS IN STRATEGIES TO ACHIEVE ART-FREE REMISSION. IMPORTANCE MACROPHAGES INFECTED BY HIV-1 ARE A LONG-LIVED RESERVOIR AND A BARRIER IN CURRENT EFFORTS TO ACHIEVE HIV CURE AND ALSO CONTRIBUTE TO NEUROCOGNITIVE COMPLICATIONS IN PEOPLE DESPITE ANTIRETROVIRAL THERAPY (ART). SILENCING HIV EXPRESSION IN THESE CELLS WOULD BE OF GREAT VALUE, BUT THE REGULATION OF HIV-1 IN MACROPHAGES DIFFERS FROM T CELLS. WE DEVELOPED A NOVEL HIGH-THROUGHPUT SCREEN FOR COMPOUNDS THAT CAN SILENCE ESTABLISHED INFECTION OF PRIMARY MACROPHAGES, AND IDENTIFIED AGENTS THAT DOWNREGULATE VIRUS EXPRESSION AND ALTER PROVIRUS EPIGENETIC PROFILES. THE SIGNIFICANCE OF THIS ASSAY IS THE POTENTIAL TO IDENTIFY NEW DRUGS THAT ACT IN THE UNIQUE MACROPHAGE ENVIRONMENT ON RELEVANT VIRAL STRAINS, WHICH MAY CONTRIBUTE TO ADJUNCTIVE TREATMENT FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS AND/OR PREVENT VIRAL REBOUND IN EFFORTS TO ACHIEVE ART-FREE REMISSION OR CURE. 2023 10 1918 41 ENVIRONMENTAL CARCINOGENESIS AND TRANSGENERATIONAL TRANSMISSION OF CARCINOGENIC RISK: FROM GENETICS TO EPIGENETICS. THE DOMINANT PATHOGENIC MODEL, SOMATIC MUTATION THEORY (SMT), CONSIDERS CARCINOGENESIS AS A 'GENETIC ACCIDENT' DUE TO THE ACCUMULATION OF 'STOCHASTIC' DNA MUTATIONS. THIS MODEL WAS PROPOSED AND ACCEPTED BY THE SCIENTIFIC COMMUNITY WHEN CANCER MAINLY AFFECTED THE ELDERLY, BUT IT DOES NOT EXPLAIN THE EPIDEMIOLOGICAL OBSERVATION OF THE CONTINUOUS INCREASE IN CANCER INCIDENCE AMONG CHILDREN AND YOUNG ADULTS. SOMATIC MUTATION THEORY HAS BEEN PROPOSED FOR A REVISION BASED ON THE EMERGING EXPERIMENTAL EVIDENCE, AS IT DOES NOT FULLY ADDRESS SOME ISSUES THAT HAVE PROVEN TO BE CRUCIAL FOR CARCINOGENESIS, NAMELY: THE INFLAMMATORY CONTEXT OF CANCER; THE KEY ROLE PLAYED BY THE STROMA, MICROENVIRONMENT, ENDOTHELIAL CELLS, ACTIVATED MACROPHAGES, AND SURROUNDING TISSUES; AND THE DISTORTED DEVELOPMENTAL COURSE FOLLOWED BY THE NEOPLASTIC TISSUE. FURTHERMORE, SMT IS OFTEN NOT ABLE TO CONSIDER EITHER THE EXISTENCE OF SPECIFIC MUTATIONS RESULTING IN A WELL-DEFINED CANCER TYPE, OR A CLEAR RELATIONSHIP BETWEEN MUTATIONS AND TUMOR PROGRESSION. MOREOVER, IT DOES NOT EXPLAIN THE MECHANISM OF ACTION OF THE NON-MUTAGENIC AND ENVIRONMENTAL CARCINOGENS. IN THE LAST DECADE, CANCER RESEARCH HAS HIGHLIGHTED THE PROMINENT ROLE OF AN ALTERED REGULATION OF GENE EXPRESSION, SUGGESTING THAT CANCER SHOULD BE CONSIDERED AS A RESULT OF A POLYCLONAL EPIGENETIC DISRUPTION OF STEM/PROGENITOR CELLS, MEDIATED BY TUMOUR-INDUCING GENES. THE MATERNAL AND FETAL EXPOSURE TO A WIDE RANGE OF CHEMICALS AND ENVIRONMENTAL CONTAMINANTS IS RAISING THE ATTENTION OF THE SCIENTIFIC COMMUNITY. INDEED, THE MOST POWERFUL PROCARCINOGENIC MECHANISMS OF ENDOCRINE DISRUPTORS AND OTHER POLLUTANTS IS LINKED TO THEIR POTENTIAL TO INTERFERE EPIGENETICALLY WITH THE EMBRYO-FETAL PROGRAMMING OF TISSUES AND ORGANS, ALTERING THE REGULATION OF THE GENES INVOLVED IN THE CELL CYCLE, CELL PROLIFERATION, APOPTOSIS, AND OTHER KEY SIGNALING PATHWAYS. THE EMBRYO-FETAL EXPOSURE TO ENVIRONMENTAL, STRESSFUL, AND PROINFLAMMATORY TRIGGERS (FIRST HIT), SEEMS TO ACT AS A 'DISEASE PRIMER', MAKING FETAL CELLS AND TISSUES MORE SUSCEPTIBLE TO THE SUBSEQUENT ENVIRONMENTAL EXPOSURES (SECOND HIT), TRIGGERING THE CARCINOGENIC PATHWAYS. FURTHERMORE, EVEN AT THE MOLECULAR LEVEL, IN CARCINOGENESIS, 'EPIGENETICS PRECEDES GENETICS' AS GLOBAL DNA HYPOMETHYLATION, AND THE HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES ARE COMMON BOTH IN CANCEROUS AND IN PRECANCEROUS CELLS, AND GENERALLY PRECEDE MUTATIONS. THESE EPIGENETIC MODELS MAY BETTER EXPLAIN THE INCREASE OF CANCER AND CHRONIC/DEGENERATIVE DISEASES IN THE LAST DECADES AND COULD BE USEFUL TO ADOPT APPROPRIATE PRIMARY PREVENTION MEASURES, ESSENTIALLY BASED ON THE REDUCTION OF MATERNAL-FETAL AND CHILD EXPOSURE TO SEVERAL PROCARCINOGENIC AGENTS AND FACTORS DISPERSED IN THE ENVIRONMENT AND IN THE FOOD-CHAINS, AS RECENTLY SUGGESTED BY THE WORLD HEALTH ORGANIZATION. 2018 11 4984 25 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 12 4960 27 PATHOGENESIS OF PRE-NEOPLASTIC LESIONS OF THE STOMACH: TARGETS FOR PREVENTION. GASTRIC ATROPHY AND INTESTINAL METAPLASIA ARE GENERALLY CONSIDERED TO BE PRECANCEROUS LESIONS OF THE STOMACH. CHRONIC HELICOBACTER PYLORI INFECTION IS ONE THE MOST IMPORTANT FACTORS IN THE DEVELOPMENT OF THESE PRE-MALIGNANT GASTRIC LESIONS. IN ADDITION TO BACTERIAL FACTORS, POLYMORPHISMS IN THE CYTOKINE GENES OF THE HOST THAT MODULATE INFLAMMATORY RESPONSES ARE FOUND TO HAVE A SYNERGISTIC EFFECT IN THE DEVELOPMENT OF GASTRIC CANCER AS WELL AS PRE-NEOPLASTIC LESIONS. RECENTLY, INAPPROPRIATE ACTIVATION OF THE INTESTINE-SPECIFIC TRANSCRIPTION FACTOR LIKE THE HOMEOBOX GENE COMPLEX CDX1 AND CDX2 ARE FOUND TO BE AN IMPORTANT CONTRIBUTING FACTOR IN THE INDUCTION OF INTESTINAL METAPLASIA IN THE STOMACH. ABERRANT EXPRESSION OF CYCLOOXYGENASE-2 AND EPIGENETIC CHANGES ARE ALSO FREQUENTLY DETECTED IN PRE-NEOPLASTIC GASTRIC LESIONS. ONE OF THE MOST IMPORTANT QUESTIONS RELATING TO THESE PRE-NEOPLASTIC GASTRIC LESIONS IS THAT WHETHER H. PYLORI ERADICATION COULD REVERSE THESE CHANGES. HOWEVER, MOST CONTROLLED STUDIES SHOWED NO OR JUST MODEST IMPROVEMENT IN INTESTINAL METAPLASIA AFTER H. PYLORI ERADICATION. FURTHER STUDIES SHOULD EVALUATE THE ROLE OF OTHER CHEMOPREVENTIVE AGENTS, PARTICULARLY CYCLOOXYGENASE-2 INHIBITOR, ON REGRESSION OF PRE-NEOPLASTIC LESIONS. 2004 13 3233 19 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 14 3219 29 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 15 3803 32 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 16 3226 25 HELICOBACTER PYLORI INFECTION, ONCOGENIC PATHWAYS AND EPIGENETIC MECHANISMS IN GASTRIC CARCINOGENESIS. CHRONIC COLONIZATION OF THE HUMAN STOMACH BY HELICOBACTER PYLORI, A GRAM-NEGATIVE BACTERIUM, IS THE MAJOR CAUSE OF CHRONIC GASTRITIS, PEPTIC ULCERS AND GASTRIC CANCER. RECENT PROGRESS HAS ELUCIDATED IMPORTANT BACTERIAL AND HOST FACTORS THAT ARE RESPONSIBLE FOR H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC MALIGNANCY. H. PYLORI CYTOTOXIN-ASSOCIATED ANTIGEN A IS THE MAJOR ONCOGENIC FACTOR INJECTED INTO HOST CELLS FROM BACTERIA AND IT DISRUPTS EPITHELIAL CELL FUNCTIONS. TOGETHER WITH H. PYLORI CAG PATHOGENICITY ISLAND, IT CAUSES GENERAL INFLAMMATORY STRESS WITHIN GASTRIC MUCOSA AND ACTIVATES MULTIPLE ONCOGENIC PATHWAYS IN EPITHELIAL CELLS. A GROWING LIST OF THESE PATHWAYS INCLUDES NF-KAPPAB, ACTIVATOR PROTEIN-1, PI3K, SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3, WNT/BETA-CATENIN AND CYCLOOXYGENASE 2. H. PYLORI INDUCES EPIGENETIC ALTERATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, WHICH PLAY CRITICAL ROLES IN ONCOGENIC TRANSFORMATION. IN ADDITION, INVESTIGATIONS INTO GASTRIC STEM CELL OR PROGENITOR CELL BIOLOGY HAVE SHED LIGHT ON THE MECHANISMS THROUGH WHICH GASTRIC CANCER MAY ORIGINATE. CONTINUED INVESTIGATION IN THESE AREAS WILL YIELD NOVEL INSIGHTS AND HELP TO ELUCIDATE THE MECHANISMS OF BACTERIA-INDUCED CARCINOGENESIS. 2010 17 6272 24 THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS. RECENT MOLECULAR GENETIC FINDINGS ON ENDOMETRIOSIS AND NORMAL ENDOMETRIUM SUGGEST A MODIFIED MODEL IN WHICH CIRCULATING EPITHELIAL PROGENITOR OR STEM CELLS INTENDED TO REGENERATE UTERINE ENDOMETRIUM AFTER MENSTRUATION MAY BECOME OVERREACTIVE AND TRAPPED OUTSIDE THE UTERUS. THESE TRAPPED EPITHELIUM-COMMITTED PROGENITOR CELLS FORM NASCENT GLANDS THROUGH CLONAL EXPANSION AND RECRUIT POLYCLONAL STROMAL CELLS, LEADING TO THE ESTABLISHMENT OF DEEP INFILTRATING ENDOMETRIOSIS. ONCE FORMED, THE ECTOPIC TISSUE BECOMES SUBJECT TO IMMUNE SURVEILLANCE, RESULTING IN CHRONIC INFLAMMATION. THE INFLAMMATORY RESPONSE ORCHESTRATED BY NUCLEAR FACTOR-KAPPAB SIGNALING IS EXACERBATED BY ABERRATIONS IN THE ESTROGEN RECEPTOR-BETA AND PROGESTERONE RECEPTOR PATHWAYS, WHICH ARE ALSO AFFECTED BY LOCAL INFLAMMATION, FORMING A DYSREGULATED INFLAMMATION-HORMONAL LOOP. GLANDULAR EPITHELIUM WITHIN ENDOMETRIOTIC TISSUE HARBORS CANCER-ASSOCIATED MUTATIONS THAT ARE FREQUENTLY DETECTED IN ENDOMETRIOSIS-RELATED OVARIAN CANCERS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES THAT HAVE ILLUMINATED THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS AND HAVE PROVIDED NEW AVENUES FOR RESEARCH THAT PROMISE TO IMPROVE THE EARLY DIAGNOSIS AND MANAGEMENT OF ENDOMETRIOSIS. 2020 18 2392 26 EPIGENETIC REPRESSION OF INTERLEUKIN 2 EXPRESSION IN SENESCENT CD4+ T CELLS DURING CHRONIC HIV TYPE 1 INFECTION. THE MOLECULAR MECHANISMS FOR IL2 GENE-SPECIFIC DYSREGULATION DURING CHRONIC HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) INFECTION ARE UNKNOWN. HERE, WE INVESTIGATED THE ROLE OF DNA METHYLATION IN SUPPRESSING INTERLEUKIN 2 (IL-2) EXPRESSION IN MEMORY CD4(+) T CELLS DURING CHRONIC HIV-1 INFECTION. WE OBSERVED THAT CPG SITES IN THE IL2 PROMOTER OF CD4(+) T CELLS WERE FULLY METHYLATED IN NAIVE CD4(+) T CELLS AND SIGNIFICANTLY DEMETHYLATED IN THE MEMORY POPULATIONS. INTERESTINGLY, WE FOUND THAT THE MEMORY CELLS THAT HAD A TERMINALLY DIFFERENTIATED PHENOTYPE AND EXPRESSED CD57 HAD INCREASED IL2 PROMOTER METHYLATION RELATIVE TO LESS DIFFERENTIATED MEMORY CELLS IN HEALTHY INDIVIDUALS. IMPORTANTLY, EARLY EFFECTOR MEMORY SUBSETS FROM HIV-1-INFECTED SUBJECTS EXPRESSED HIGH LEVELS OF CD57 AND WERE HIGHLY METHYLATED AT THE IL2 LOCUS. FURTHERMORE, THE INCREASED CD57 EXPRESSION ON MEMORY CD4(+) T CELLS WAS INVERSELY CORRELATED WITH IL-2 PRODUCTION. THESE DATA SUGGEST THAT DNA METHYLATION AT THE IL2 LOCUS IN CD4(+) T CELLS IS COUPLED TO IMMUNOSENESCENCE AND PLAYS A CRITICAL ROLE IN THE BROAD DYSFUNCTION THAT OCCURS IN POLYCLONAL T CELLS DURING HIV-1 INFECTION. 2015 19 762 26 CAUSAL ROLE OF HELICOBACTER PYLORI INFECTION AND ERADICATION THERAPY IN GASTRIC CARCINOGENESIS. MANY EPIDEMIOLOGICAL REPORTS INDICATE THAT HELICOBACTER PYLORI (H PYLORI) INFECTION PLAYS AN IMPORTANT ROLE IN GASTRIC CARCINOGENESIS. SEVERAL GENETIC AND EPIGENETIC ALTERATIONS CONTRIBUTE TO THE INITIATION, PROMOTION, AND PROGRESSION OF THE CANCER CELLS IN A MULTI-STEP MANNER. H PYLORI IS KNOWN TO INDUCE CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA. ITS PRODUCTS, INCLUDING SUPEROXIDES, PARTICIPATE IN THE DNA DAMAGE FOLLOWED BY INITIATION, AND THE INFLAMMATION-DERIVED CYTOKINES AND GROWTH FACTORS CONTRIBUTE TO THE PROMOTION OF GASTRIC CARCINOGENESIS. BY ERADICATING H PYLORI, GASTRIC INFLAMMATION CAN BE CURED; THE THERAPY DIMINISHES THE LEVELS NOT ONLY OF INFLAMMATORY CELL INFILTRATION, BUT ALSO ATROPHY/INTESTINAL METAPLASIA IN PART. A RANDOMIZED CONTROLLED TRIAL REVEALED THAT THE ERADICATION THERAPY DIMINISHED THE GASTRIC CANCER PREVALENCE IN CASES WITHOUT PRE-CANCEROUS CONDITIONS. IN ADDITION, RECENT EPIDEMIOLOGICAL STUDIES FROM JAPANESE GROUPS DEMONSTRATED THAT THE DEVELOPMENT OF GASTRIC CANCER, ESPECIALLY OF THE INTESTINAL TYPE, WAS DECREASED BY SUCCESSFUL ERADICATION THERAPY, ALTHOUGH THESE WERE DESIGNED IN A NON-RANDOMIZED MANNER. HOWEVER, IT SHOULD BE MENTIONED THAT ENDOSCOPIC DETECTION IS THE ONLY WAY TO EVALUATE THE DEGREE OF GASTRIC CARCINOGENESIS. WE HAVE REPORTED THAT THE ENDOSCOPIC AND HISTOLOGICAL MORPHOLOGIES COULD BE MODIFIED BY ERADICATION THERAPY AND IT MIGHT CONTRIBUTE TO THE PREVALENCE OF GASTRIC CANCER DEVELOPMENT. CONSIDERING THE BIOLOGICAL NATURE OF CANCER CELL PROLIFERATION, IT IS CONSIDERED THAT A SUFFICIENTLY LONG-TERM FOLLOW-UP WOULD BE ESSENTIAL TO DISCUSS THE ANTICANCER EFFECT OF ERADICATION THERAPY. 2006 20 2377 28 EPIGENETIC REGULATION OF TUMOR SUPPRESSORS BY HELICOBACTER PYLORI ENHANCES EBV-INDUCED PROLIFERATION OF GASTRIC EPITHELIAL CELLS. HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS (EBV) ARE TWO WELL-KNOWN CONTRIBUTORS TO CANCER AND CAN ESTABLISH LIFELONG PERSISTENT INFECTION IN THE HOST. THIS LEADS TO CHRONIC INFLAMMATION, WHICH ALSO CONTRIBUTES TO DEVELOPMENT OF CANCER. ASSOCIATION WITH H. PYLORI INCREASES THE RISK OF GASTRIC CARCINOMA, AND COEXISTENCE WITH EBV ENHANCES PROLIFERATION OF INFECTED CELLS. FURTHER, H. PYLORI-EBV COINFECTION CAUSES CHRONIC INFLAMMATION IN PEDIATRIC PATIENTS. WE HAVE ESTABLISHED AN H. PYLORI-EBV COINFECTION MODEL SYSTEM USING HUMAN GASTRIC EPITHELIAL CELLS. WE SHOWED THAT H. PYLORI INFECTION CAN INCREASE THE ONCOGENIC PHENOTYPE OF EBV-INFECTED CELLS AND THAT THE CYTOTOXIN-ASSOCIATED GENE (CAGA) PROTEIN ENCODED BY H. PYLORI STIMULATED EBV-MEDIATED CELL PROLIFERATION IN THIS COINFECTION MODEL SYSTEM. THIS LED TO INCREASED EXPRESSION OF DNA METHYL TRANSFERASES (DNMTS), WHICH REPROGRAMMED CELLULAR TRANSCRIPTIONAL PROFILES, INCLUDING THOSE OF TUMOR SUPPRESSOR GENES (TSGS), THROUGH HYPERMETHYLATION. THESE FINDINGS PROVIDE NEW INSIGHTS INTO A MOLECULAR MECHANISM WHEREBY COOPERATIVITY BETWEEN TWO ONCOGENIC AGENTS LEADS TO ENHANCED ONCOGENIC ACTIVITY OF GASTRIC CANCER CELLS.IMPORTANCE WE HAVE STUDIED THE COOPERATIVITY BETWEEN H. PYLORI AND EBV, TWO KNOWN ONCOGENIC AGENTS. THIS LED TO AN ENHANCED ONCOGENIC PHENOTYPE IN GASTRIC EPITHELIAL CELLS. WE NOW DEMONSTRATE THAT EBV-DRIVEN EPIGENETIC MODIFICATIONS ARE ENHANCED IN THE PRESENCE OF H. PYLORI, MORE SPECIFICALLY, IN THE PRESENCE OF ITS CAGA SECRETORY ANTIGEN. THIS RESULTS IN INCREASED PROLIFERATION OF THE INFECTED GASTRIC CELLS. OUR FINDINGS NOW ELUCIDATE A MOLECULAR MECHANISM WHEREBY EXPRESSION OF CELLULAR DNA METHYL TRANSFERASES IS INDUCED INFLUENCING INFECTION BY EBV. HYPERMETHYLATION OF THE REGULATORY GENOMIC REGIONS OF TUMOR SUPPRESSOR GENES RESULTS IN THEIR SILENCING. THIS DRASTICALLY AFFECTS THE EXPRESSION OF CELL CYCLE, APOPTOSIS, AND DNA REPAIR GENES, WHICH DYSREGULATES THEIR ASSOCIATED PROCESSES, AND PROMOTION OF THE ONCOGENIC PHENOTYPE. 2018