1 6579 136 TREFOIL FACTORS AND HUMAN GASTRIC CANCER (REVIEW). TFF1/PS2, TFF2/SP AND TFF3/ITF ARE SOLUBLE PEPTIDES WITH TREFOIL DOMAIN(S) AND C-TERMINAL DIMERIZATION DOMAIN, WHICH ARE CONSERVED AMONG HUMAN, COW, MOUSE AND RAT. TFF1 MRNA IS EXPRESSED IN STOMACH (MUCOUS CELLS IN FUNDUS AND ANTRUM), TFF2 MRNA IN STOMACH (MUCOUS NECK CELLS IN FUNDUS AND BASAL CELLS IN ANTRAL AND PYLORIC GLANDS) AND DUODENUM (BRUNNER'S GLAND), TFF3 MRNA IN SMALL INTESTINE AND LARGE INTESTINE (GOBLET CELLS). EXPRESSION OF TFF1, TFF2 AND TFF3 MRNAS ARE DIFFERENTIALLY REGULATED BY FGF2/BFGF, FGF7/KGF, ESTROGEN, ASPIRIN, ARACHIDONIC ACID, X-RAY IRRADIATION, AND HYDROGEN PEROXIDE. GASTRIC CANCER IS CLASSIFIED INTO THE INTESTINAL TYPE AND THE DIFFUSE TYPE. TFF MRNAS ARE PREFERENTIALLY EXPRESSED IN DIFFUSE-TYPE GASTRIC CANCER CELLS. CUSTOM-MADE MICROARRAY (TFF MRNAS) AND ELISA (TFF PROTEINS) MIGHT BE APPLICABLE FOR SCREENING METHODS OF PERITONEAL AND BONE MARROW DISSEMINATION FROM DIFFUSE-TYPE GASTRIC CANCER. TFF1 AND TFF2 MRNAS ARE FREQUENTLY DOWN-REGULATED IN INTESTINAL-TYPE GASTRIC CANCER. TFF1 GENE, INACTIVATED BY DELETION, MISSENSE MUTATION AND PROMOTER HYPERMETHYLATION, IS A TUMOR SUPPRESSOR GENE IMPLICATED IN GASTRIC CANCER. TFF2 IS A CANDIDATE TUMOR SUPPRESSOR GENE; HOWEVER, GENETIC AND EPIGENETIC ALTERATIONS OF TFF2 GENE IN HUMAN GASTRIC CANCER REMAIN UNCLEAR. TFF1, TFF2 AND TFF3 PLAY KEY ROLES IN MUCOSAL PROTECTION THROUGH MUCOUS-BARRIER FORMATION, AND ALSO IN MUCOSAL REPAIR THROUGH PROMOTION OF RESTITUTION AFTER INJURY. PATIENTS WITH CHRONIC ATROPHIC GASTRITIS AND THOSE WITH ULCERATIVE COLITIS ARE AT RISK OF GASTRIC CANCER AND COLORECTAL CANCER, RESPECTIVELY. TFF1, TFF2 AND TFF3 PROTEINS MIGHT BE APPLICABLE FOR CHEMOPREVENTION OF GASTROINTESTINAL CANCER ASSOCIATED WITH CHRONIC PERSISTENT INFLAMMATION.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 1950  26 EPIGENETIC ACTIVATION OF TENSIN 4 PROMOTES GASTRIC CANCER PROGRESSION. GASTRIC CANCER (GC) IS A COMPLEX DISEASE INFLUENCED BY MULTIPLE GENETIC AND EPIGENETIC FACTORS. CHRONIC INFLAMMATION CAUSED BY HELICOBACTER PYLORI INFECTION AND DIETARY RISK FACTORS CAN RESULT IN THE ACCUMULATION OF ABERRANT DNA METHYLATION IN GASTRIC MUCOSA, WHICH PROMOTES GC DEVELOPMENT. TENSIN 4 (TNS4), A MEMBER OF THE TENSIN FAMILY OF PROTEINS, IS LOCALIZED TO FOCAL ADHESION SITES, WHICH CONNECT THE EXTRACELLULAR MATRIX AND CYTOSKELETAL NETWORK. WE IDENTIFIED UPREGULATION OF TNS4 IN GC USING QUANTITATIVE REVERSE TRANSCRIPTION PCR WITH 174 PAIRED SAMPLES OF GC TUMORS AND ADJACENT NORMAL TISSUES. TRANSCRIPTIONAL ACTIVATION OF TNS4 OCCURRED EVEN DURING THE EARLY STAGE OF TUMOR DEVELOPMENT. TNS4 DEPLETION IN GC CELL LINES THAT EXPRESSED HIGH TO MODERATE LEVELS OF TNS4, I.E., SNU-601, KATO III, AND MKN74, REDUCED CELL PROLIFERATION AND MIGRATION, WHEREAS ECTOPIC EXPRESSION OF TNS4 IN THOSE LINES THAT EXPRESSED LOWER LEVELS OF TNS4, I.E., SNU-638, MKN1, AND MKN45 INCREASED COLONY FORMATION AND CELL MIGRATION. THE PROMOTER REGION OF TNS4 WAS HYPOMETHYLATED IN GC CELL LINES THAT SHOWED UPREGULATION OF TNS4. WE ALSO FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN TNS4 EXPRESSION AND CPG METHYLATION IN 250 GC TUMORS BASED ON THE CANCER GENOME ATLAS (TCGA) DATA. THIS STUDY ELUCIDATES THE EPIGENETIC MECHANISM OF TNS4 ACTIVATION AND FUNCTIONAL ROLES OF TNS4 IN GC DEVELOPMENT AND PROGRESSION AND SUGGESTS A POSSIBLE APPROACH FOR FUTURE GC TREATMENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
3 1798  38 EFFECT OF HELICOBACTER PYLORI INFECTION ON GATA-5 AND TFF1 REGULATION, COMPARISON BETWEEN PEDIATRIC AND ADULT PATIENTS. BACKGROUND: GATA FACTORS, WHICH CONSTITUTE A FAMILY OF TRANSCRIPTION REGULATORY PROTEINS, PARTICIPATE IN GASTROINTESTINAL DEVELOPMENT. TREFOIL FACTOR 1 (TFF1) PLAYS A CRUCIAL ROLE IN MUCOSAL DEFENSE AND HEALING, AND EVIDENCE SUGGESTS THAT GATA-5 MEDIATED ITS REGULATION. GASTRIC CANCER IS A MULTIPLE-STEP PROCESS TRIGGERED BY HELICOBACTER PYLORI AND IS CHARACTERIZED BY ACCUMULATION OF MOLECULAR AND EPIGENETIC ALTERATION. THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECT OF H. PYLORI INFECTION ON THE REGULATION OF GATA-5 AND TFF1 IN VITRO AND IN VIVO. RESULTS: INFECTED CELLS EXHIBITED UPREGULATION OF GATA-5 AND TFF1 AFTER 48 H. AN INCREASE IN GATA-5 AND TFF1 MRNA LEVELS WAS ALSO FOUND IN MICE SAMPLES AFTER 6 AND 12 MONTHS OF INFECTION, RESPECTIVELY. IN HUMAN SAMPLES, WE FOUND AN ASSOCIATION BETWEEN H. PYLORI INFECTION AND GATA-5 UPREGULATION. IN FACT, AMONG H. PYLORI-INFECTED PATIENTS, HYPERMETHYLATION WAS OBSERVED IN 45.5% OF PEDIATRIC SAMPLES, IN 62.6% OF CHRONIC GASTRITIS SAMPLES, AND IN 63% OF GASTRIC CANCER SAMPLES. REGARDING TFF1, THE EXPRESSION LEVELS WERE SIMILAR IN PEDIATRICS AND ADULTS PATIENTS, AND WERE INDEPENDENT OF H. PYLORI INFECTION, AND THE EXPRESSION OF THESE FACTORS WAS DOWNREGULATED IN GASTRIC CANCER SAMPLES. GATA-5 PROMOTER METHYLATION WAS ASSOCIATED WITH A DECREASE IN TFF1 MRNA LEVELS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE UPREGULATION OF GATA-5 AND TFF1 OBSERVED IN VITRO AND IN VIVO MAY BE CORRELATED WITH A PROTECTIVE EFFECT OF THE MUCOSA IN RESPONSE TO INFECTION. THE EPIGENETIC INACTIVATION OF GATA-5 OBSERVED IN HUMAN BIOPSIES FROM INFECTED PATIENTS MAY SUGGEST THAT THIS ALTERATION IS AN EARLY EVENT OCCURRING IN ASSOCIATION WITH H. PYLORI INFECTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4 2080  31 EPIGENETIC DNA METHYLATION OF EBI3 MODULATES HUMAN INTERLEUKIN-35 FORMATION VIA NFKB SIGNALING: A PROMISING THERAPEUTIC OPTION IN ULCERATIVE COLITIS. ULCERATIVE COLITIS (UC), A SEVERE CHRONIC DISEASE WITH UNCLEAR ETIOLOGY THAT IS ASSOCIATED WITH INCREASED RISK FOR COLORECTAL CANCER, IS ACCOMPANIED BY DYSREGULATION OF CYTOKINES. EPSTEIN-BARR VIRUS-INDUCED GENE 3 (EBI3) ENCODES A SUBUNIT IN THE UNIQUE HETERODIMERIC IL-12 CYTOKINE FAMILY OF EITHER PRO- OR ANTI-INFLAMMATORY FUNCTION. AFTER HAVING RECENTLY DEMONSTRATED THAT UPREGULATION OF EBI3 BY HISTONE ACETYLATION ALLEVIATES DISEASE SYMPTOMS IN A DEXTRAN SULFATE SODIUM (DSS)-TREATED MOUSE MODEL OF CHRONIC COLITIS, WE NOW AIMED TO EXAMINE A POSSIBLE FURTHER EPIGENETIC REGULATION OF EBI3 BY DNA METHYLATION UNDER INFLAMMATORY CONDITIONS. TREATMENT WITH THE DNA METHYLTRANSFERASE INHIBITOR (DNMTI) DECITABINE (DAC) AND TNFALPHA LED TO SYNERGISTIC UPREGULATION OF EBI3 IN HUMAN COLON EPITHELIAL CELLS (HCEC). USE OF DIFFERENT SIGNALING PATHWAY INHIBITORS INDICATED NFKAPPAB SIGNALING WAS NECESSARY AND PROPORTIONAL TO THE SYNERGISTIC EBI3 INDUCTION. MALDI-TOF/MS AND HPLC-ESI-MS/MS ANALYSIS OF DAC/TNFALPHA-TREATED HCEC IDENTIFIED IL-12P35 AS THE MOST PROBABLE BINDING PARTNER TO FORM A FUNCTIONAL PROTEIN. EBI3/IL-12P35 HETERODIMERS (IL-35) INDUCE THEIR OWN GENE UPREGULATION, SOMETHING THAT WAS INDEED OBSERVED IN HCEC CULTURED WITH MEDIA FROM PREVIOUSLY DAC/TNFALPHA-TREATED HCEC. THESE RESULTS SUGGEST THAT UNDER INFLAMMATORY AND DEMETHYLATING CONDITIONS THE UPREGULATION OF EBI3 RESULTS IN THE FORMATION OF ANTI-INFLAMMATORY IL-35, WHICH MIGHT BE CONSIDERED AS A THERAPEUTIC TARGET IN COLITIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5 3805  25 INTESTINE-SPECIFIC HOMEOBOX (ISX) INDUCES INTESTINAL METAPLASIA AND CELL PROLIFERATION TO CONTRIBUTE TO GASTRIC CARCINOGENESIS. BACKGROUND: HELICOBACTER PYLORI INDUCES CHRONIC INFLAMMATION AND INTESTINAL METAPLASIA (IM) THROUGH GENETIC AND EPIGENETIC CHANGES AND ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS THAT CONTRIBUTE TO GASTRIC CARCINOGENESIS. HOWEVER, THE PRECISE MECHANISM OF IM IN GASTRIC CARCINOGENESIS HAS NOT BEEN FULLY ELUCIDATED. WE PREVIOUSLY FOUND THAT INTESTINE-SPECIFIC HOMEOBOX (ISX) MRNA EXPRESSION INCREASED IN ORGANOIDS CULTURED FROM HELICOBACTER-INFECTED MOUSE MUCOSA. IN THIS STUDY, WE ELUCIDATE THE ROLE OF ISX IN THE DEVELOPMENT OF IM AND GASTRIC CARCINOGENESIS. METHODS: ISX EXPRESSION WAS ASSESSED IN HELICOBACTER-INFECTED MOUSE AND HUMAN GASTRIC MUCOSA. MKN45 GASTRIC CANCER CELLS WERE CO-CULTURED WITH H. PYLORI TO DETERMINE WHETHER HELICOBACTER INFECTION INDUCED ISX EXPRESSION. WE ESTABLISHED STABLE MKN45 TRANSFECTED CELLS EXPRESSING ISX (STABLE-ISX MKN45) AND PERFORMED A SPHEROID COLONY FORMATION ASSAY AND A XENOGRAFT MODEL. WE PERFORMED ISX IMMUNOHISTOCHEMISTRY IN CANCER AND ADJACENT GASTRIC TISSUES. RESULTS: ISX EXPRESSION WAS INCREASED IN MOUSE AND HUMAN GASTRIC MUCOSA INFECTED WITH HELICOBACTER. THE PRESENCE OF IM AND H. PYLORI INFECTION IN HUMAN STOMACH WAS CORRELATED WITH ISX EXPRESSION. H. PYLORI INDUCED ISX MRNA AND PROTEIN EXPRESSION. CDX1/2, CYCLIND1, AND MUC2 WERE UPREGULATED IN STABLE-ISX MKN45, WHEREAS MUC5AC WAS DOWNREGULATED. STABLE-ISX MKN45 CELLS FORMED MORE SPHEROID COLONIES, AND HAD HIGH TUMORIGENIC ABILITY. ISX EXPRESSION IN GASTRIC CANCER AND ADJACENT MUCOSA WERE CORRELATED. CONCLUSIONS: ISX EXPRESSION INDUCED BY H. PYLORI INFECTION MAY LEAD TO IM AND HYPERPROLIFERATION OF GASTRIC MUCOSA THROUGH CDX1/2 AND CYCLIND1 EXPRESSION, CONTRIBUTING TO GASTRIC CARCINOGENESIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
6 1843  19 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7 1668  28 DOWNREGULATION OF SOCS1 INCREASES INTERFERON-INDUCED ISGYLATION DURING DIFFERENTIATION OF INDUCED-PLURIPOTENT STEM CELLS TO HEPATOCYTES. BACKGROUND & AIMS: INCREASED EXPRESSION OF IFN-STIMULATED GENE 15 (ISG15) AND SUBSEQUENTLY INCREASED ISGYLATION ARE KEY FACTORS IN THE HOST RESPONSE TO VIRAL INFECTION. IN THIS STUDY, WE SOUGHT TO CHARACTERIZE THE EXPRESSION OF ISG15, ISGYLATION, AND ASSOCIATED ENZYMES AT EACH STAGE OF DIFFERENTIATION FROM INDUCED PLURIPOTENT STEM CELLS (IPSCS) TO HEPATOCYTES. METHODS: TO STUDY THE REGULATION OF ISGYLATION, WE UTILIZED PATIENT SAMPLES AND IN VITRO CELL CULTURE MODELS INCLUDING IPSCS, HEPATOCYTES-LIKE CELLS, IMMORTALIZED CELL LINES, AND PRIMARY HUMAN HEPATOCYTES. PROTEIN/MRNA EXPRESSION WERE MEASURED FOLLOWING TREATMENT WITH POLY(I:C), IFNALPHA AND HCV INFECTION. RESULTS: WHEN COMPARED TO HLCS, WE OBSERVED SEVERAL NOVEL ASPECTS OF THE ISGYLATION PATHWAY IN IPSCS. THESE INCLUDE A LOWER BASELINE EXPRESSION OF THE ISGYLATION-ACTIVATING ENZYME, UBE1L, A LACK OF IFN-INDUCED EXPRESSION OF THE ISGYLATION-CONJUGATION ENZYME UBE2L6, AN ATTENUATED ACTIVATION OF THE TRANSCRIPTION FACTOR STAT1 AND CONSTITUTIVE EXPRESSION OF SOCS1. ISGYLATION WAS OBSERVED IN IPSCS FOLLOWING DOWNREGULATION OF SOCS1, WHICH FACILITATED STAT1 ACTIVATION AND SUBSEQUENTLY INCREASED EXPRESSION OF UBE2L6. INTRIGUINGLY, HCV PERMISSIVE TRANSFORMED HEPATOMA CELL LINES DEMONSTRATED HIGHER INTRINSIC EXPRESSION OF SOCS1 AND WEAKER ISGYLATION FOLLOWING IFN TREATMENT. SOCS1 DOWNREGULATION IN HCV-INFECTED HUH 7.5.1 CELLS LED TO INCREASED ISGYLATION. CONCLUSIONS: HEREIN, WE SHOW THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. FURTHERMORE, AS IPSCS DIFFERENTIATE INTO HEPATOCYTES, EPIGENETIC MECHANISMS REGULATE ISGYLATION BY MODIFYING UBE1L AND SOCS1 EXPRESSION LEVELS. OVERALL, THIS STUDY DEMONSTRATES THAT THE DEVELOPMENT OF CELL-INTRINSIC INNATE IMMUNITY DURING THE DIFFERENTIATION OF IPSCS TO HEPATOCYTES PROVIDES INSIGHT INTO CELL TYPE-SPECIFIC REGULATION OF HOST DEFENSE RESPONSES AND RELATED ONCOGENIC PROCESSES. IMPACT AND IMPLICATIONS: TO ELUCIDATE THE MECHANISM UNDERLYING REGULATION OF ISGYLATION, A KEY PROCESS IN THE INNATE IMMUNE RESPONSE, WE STUDIED CHANGES IN ISGYLATION-ASSOCIATED GENES AT THE DIFFERENT STAGES OF DIFFERENTIATION FROM IPSCS TO HEPATOCYTES. WE FOUND THAT HIGH BASAL LEVELS OF SOCS1 INHIBIT STAT1 ACTIVATION AND SUBSEQUENTLY IFN-INDUCED UBE2L6 AND ISGYLATION IN IPSCS. IMPORTANTLY, EPIGENETIC REGULATION OF SOCS1 AND SUBSEQUENTLY ISGYLATION MAY BE IMPORTANT FACTORS IN THE DEVELOPMENT OF CELL TYPE-SPECIFIC HOST DEFENSE RESPONSES IN HEPATOCYTES THAT SHOULD BE CONSIDERED WHEN STUDYING CHRONIC INFECTIONS AND ONCOGENIC PROCESSES IN THE LIVER.	2022	
                                                                                                                                                                                                                                              
8 5775  25 SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE ACTIVITY ASSOCIATES WITH WHITE BLOOD CELL COUNT IN MYELOID LEUKEMIAS. THE METABOLISM OF POLYAMINES, THE CATIONIC SMALL MOLECULES ESSENTIAL FOR CELL PROLIFERATION AND DIFFERENTIATION, IS ALTERED IN CANCER CELLS AND CAN BE EXPLOITED IN CANCER DIAGNOSIS AND THERAPY. SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE (SSAT), WHICH REGULATES INTRACELLULAR LEVELS OF POLYAMINES BY CATABOLIZING SPERMIDINE AND SPERMINE, HAS A CONTROVERSIAL ROLE IN THE DEVELOPMENT OF CANCERS. IN THIS STUDY, THE POLYAMINE METABOLISM AND FUNCTION OF SSAT WERE CHARACTERIZED IN ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOID LEUKEMIA (CML), AND ACUTE LYMPHOID LEUKEMIA PATIENT SAMPLES. ALSO, MICE OVEREXPRESSING SSAT AND HAVING A MYELOPROLIFERATIVE PHENOTYPE WERE ANALYZED FOR THEIR RESPONSE TO DECITABINE AND HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A. THE PRESENCE OF EPIGENETIC FACTORS IN THE BONE MARROW CELLS OF SSAT MICE WAS ANALYZED. ELEVATED LEVELS OF SPERMIDINE AND SPERMINE, AS WELL AS INCREASED ACTIVITY OF SSAT, WERE DETECTED IN AML, CML, AND ACUTE LYMPHOID LEUKEMIA PATIENTS COMPARED WITH THE CONTROLS. HOWEVER, WE FOUND SSAT ACTIVITY TO BE ASSOCIATED WITH WHITE BLOOD CELL COUNT ONLY IN AML AND CML PATIENTS. DECITABINE TREATMENT BROUGHT THE PERIPHERAL BLOOD AND BONE MARROW CELL COUNTS OF SSAT MICE TO THE LEVEL OF WILD-TYPE MICE. SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE MICE HAD INCREASED HISTONE METHYLATION AND AN INCREASED LEVEL OF HISTONE DEACETYLASE 1 IN THEIR BONE MARROW CELLS. THE STUDY SUGGESTS THAT SSAT INFLUENCES THE DEVELOPMENT OF MYELOID MALIGNANCIES, AND EPIGENETIC FACTORS PARTLY CONTRIBUTE TO THE SSAT OVEREXPRESSION-INDUCED MYELOPROLIFERATIVE DISEASE IN MICE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  768  26 CD47 (CLUSTER OF DIFFERENTIATION 47). CD47, ALSO KNOWN AS INTEGRIN-ASSOCIATED PROTEIN, IS A CONSTITUTIVELY AND UBIQUITOUSLY EXPRESSED TRANSMEMBRANE RECEPTOR. CD47 IS CONSERVED ACROSS AMNIOTES INCLUDING MAMMALS, REPTILES, AND BIRDS. EXPRESSION IS INCREASED IN MANY CANCERS AND, IN NON-MALIGNANT CELLS, BY STRESS AND WITH AGING. THE UP-REGULATION OF CD47 EXPRESSION IS GENERALLY EPIGENETIC, WHEREAS GENE AMPLIFICATION OCCURS WITH LOW FREQUENCY IN SOME CANCERS. CD47 IS A HIGH AFFINITY SIGNALING RECEPTOR FOR THE SECRETED PROTEIN THROMBOSPONDIN-1 (THBS1) AND THE COUNTER-RECEPTOR FOR SIGNAL REGULATORY PROTEIN-ALPHA (SIRPA, SIRPALPHA) AND SIRPGAMMA (SIRPG). CD47 INTERACTION WITH SIRPALPHA SERVES AS A MARKER OF SELF TO INNATE IMMUNE CELLS AND THEREBY PROTECTS CANCER CELLS FROM PHAGOCYTIC CLEARANCE. CONSEQUENTLY, HIGHER CD47 CORRELATES WITH A POOR PROGNOSIS IN SOME CANCERS, AND THERAPEUTIC BLOCKADE CAN SUPPRESS TUMOR GROWTH BY ENHANCING INNATE ANTITUMOR IMMUNITY. CD47 EXPRESSED ON CYTOTOXIC T CELLS, DENDRITIC CELLS, AND NK CELLS MEDIATES INHIBITORY THBS1 SIGNALING THAT FURTHER LIMITS ANTITUMOR IMMUNITY. CD47 LATERALLY ASSOCIATES WITH SEVERAL INTEGRINS AND THEREBY REGULATES CELL ADHESION AND MIGRATION. CD47 HAS ADDITIONAL LATERAL BINDING PARTNERS IN SPECIFIC CELL TYPES, AND LIGATION OF CD47 IN SOME CASES MODULATES THEIR FUNCTION. THBS1-CD47 SIGNALING IN NON-MALIGNANT CELLS INHIBITS NITRIC OXIDE/CGMP, CALCIUM, AND VEGF SIGNALING, MITOCHONDRIAL HOMEOSTASIS, STEM CELL MAINTENANCE, PROTECTIVE AUTOPHAGY, AND DNA DAMAGE RESPONSE, AND PROMOTES NADPH OXIDASE ACTIVITY. CD47 SIGNALING IS A PHYSIOLOGICAL REGULATOR OF PLATELET ACTIVATION, ANGIOGENESIS AND BLOOD FLOW. THBS1/CD47 SIGNALING IS FREQUENTLY DYSREGULATED IN CHRONIC DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 2974  26 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11 6593  23 TUMOR-ASSOCIATED MACROPHAGES PROMOTE EPIGENETIC SILENCING OF GELSOLIN THROUGH DNA METHYLTRANSFERASE 1 IN GASTRIC CANCER CELLS. EPIGENETIC REPRESSION OF THE TUMOR SUPPRESSOR GELSOLIN (GSN) IS FREQUENTLY OBSERVED IN CANCERS. CHRONIC INFLAMMATION CAN PROMOTE TUMOR PROGRESSION VIA ABERRANT DNA METHYLATION. IN THIS STUDY, WE INVESTIGATED THE ROLE OF TUMOR-ASSOCIATED MACROPHAGES (TAMS) IN DNA METHYLATION OF THE GSN GENE DURING GASTRIC CANCER PROGRESSION. IMMUNOFLUORESCENCE STAINING OF 121 GASTRIC CANCER TISSUES SHOWED ABERRANT LOCALIZATION OF GSN AND DNA METHYLTRANSFERASE 1 (DNMT1) AND JUXTAPOSITION OF DNMT1 AND M2 TAMS. DECREASED GSN PROTEIN AND MRNA EXPRESSION AND INCREASED DNA METHYLATION IN THE GSN PROMOTER WERE OBSERVED IN GASTRIC CANCER CELL LINES AND CLINICAL SPECIMENS. TO EXAMINE THE EFFECT OF TAMS ON DNA METHYLATION IN GASTRIC CANCER CELLS, WE PERFORMED IN VITRO COCULTURE ASSAYS AND FOUND INCREASED DNMT1 EXPRESSION BUT DECREASED GSN EXPRESSION IN GASTRIC CANCER CELLS AFTER COCULTURE WITH U937 CELLS. KNOCKDOWN OF DNMT1 EXPRESSION IN GASTRIC CANCER CELLS COULD ABORT U937 COCULTURE-MEDIATED GSN DOWNREGULATION. MEANWHILE, CCL5 WAS THE MAIN CHEMOKINE UPREGULATED IN COCULTURE MEDIUM. TREATMENT WITH CCL5 COULD INDUCE DNMT1 EXPRESSION IN GASTRIC CANCER CELLS VIA STAT3 SIGNALING. INHIBITING DNMT1 ACTIVITY WITH PROCAINAMIDE, INHIBITING DNA METHYLATION WITH 5-AZA, OR INHIBITING CCL5/CCR5 SIGNALING WITH MARAVIROC REDUCED TUMOR GROWTH IN VIVO IN CONCLUSION, UPREGULATION OF DNMT1 BY CCL5/CCR5/STAT3 SIGNALING IS CRITICAL FOR TAM-MEDIATED GSN SILENCING IN GASTRIC CANCER. THIS STUDY IDENTIFIED POTENTIAL TARGETS FOR GASTRIC CANCER THERAPY. CANCER IMMUNOL RES; 5(10); 885-97. (C)2017 AACR.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12 1067  31 CLINICAL UTILITY OF PDSS2 EXPRESSION TO STRATIFY PATIENTS AT RISK FOR RECURRENCE OF HEPATOCELLULAR CARCINOMA. IDENTIFICATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS IS REQUIRED FOR OPTIMAL STRATIFICATION OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AT RISK FOR RECURRENCE AND ADVERSE PROGNOSIS. COENZYME Q10 (COQ10), WHICH MEDIATES APOPTOSIS, IS SYNTHESIZED BY PRENYL DIPHOSPHATE SYNTHASE SUBUNIT 2 (PDSS2). IN THE PRESENT STUDY WE EVALUATED THE CLINICAL SIGNIFICANCE AND REGULATORY MECHANISMS OF PDSS2 EXPRESSION IN HCC. PDSS2 EXPRESSION LEVELS AND THOSE OF GENES ENCODING POTENTIALLY INTERACTING PROTEINS AS WELL AS THE METHYLATION STATUS OF THE PDSS2 PROMOTER REGION WERE ANALYZED IN HCC CELL LINES. PDSS2 MRNA LEVELS IN 151 PAIRS OF RESECTED SPECIMENS WERE DETERMINED TO EVALUATE THE ASSOCIATION OF PDSS2 EXPRESSION AND CLINICOPATHOLOGICAL FACTORS. THE EXPRESSION AND DISTRIBUTION OF PDSS2 WERE DETERMINED USING IMMUNOHISTOCHEMISTRY. PDSS2 MRNA EXPRESSION WAS DECREASED IN SIX OF NINE HCC CELL LINES AND SIGNIFICANTLY CORRELATED WITH THOSE OF HEPATOCYTE NUCLEAR FACTOR 4ALPHA. PDSS2 TRANSCRIPTION IN HCC CELLS WITH DECREASED PDSS2 EXPRESSION ACCOMPANYING HYPERMETHYLATION WAS REACTIVATED AFTER TREATING THESE CELLS WITH A METHYLATION INHIBITOR. MEAN EXPRESSION LEVELS OF PDSS2 MRNA RELATIVE TO THAT OF UNINVOLVED LIVER DIMINISHED GRADUALLY IN THE ORDER OF CHRONIC HEPATITIS TO CIRRHOSIS, AND EACH WAS SIGNIFICANTLY HIGHER THAN THOSE OF HCCS. PDSS2 AND PDSS2 MRNA LEVELS WERE CONSISTENT. DECREASED PDSS2 MRNA LEVELS WERE DETECTED IN HCC TISSUES OF 56 PATIENTS, CORRELATED WITH SHORTER DISEASE-SPECIFIC SURVIVAL, AND WAS IDENTIFIED AS AN INDEPENDENT PROGNOSTIC FACTOR. PDSS2 IS A PUTATIVE TUMOR SUPPRESSOR, AND PROMOTER HYPERMETHYLATION IS A KEY REGULATORY MECHANISM IN HCC. DECREASED LEVELS OF PDSS2 MRNA EXPRESSION MAY REPRESENT A NOVEL BIOMARKER OF HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  460  24 ARACHIDONIC ACID 15-LIPOXYGENASE: EFFECTS OF ITS EXPRESSION, METABOLITES, AND GENETIC AND EPIGENETIC VARIATIONS ON AIRWAY INFLAMMATION. ARACHIDONIC ACID 15-LIPOXYGENASE (ALOX15) IS AN ENZYME THAT CAN OXIDIZE POLYUNSATURATED FATTY ACIDS. ALOX15 IS STRONGLY EXPRESSED IN AIRWAY EPITHELIAL CELLS, WHERE IT CATALYZES THE CONVERSION OF ARACHIDONIC ACID TO 15-HYDROXYEICOSATETRAENOIC ACID (15-HETE) INVOLVED IN VARIOUS AIRWAY INFLAMMATORY DISEASES. INTERLEUKIN (IL)-4 AND IL-13 INDUCE ALOX15 EXPRESSION BY ACTIVATING JAK2 AND TYK2 KINASES AS WELL AS SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATS) 1/3/5/6. ALOX15 UP-REGULATION AND SUBSEQUENT ASSOCIATION WITH PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 (PEBP1) ACTIVATE THE MITOGEN-ACTIVATED EXTRACELLULAR SIGNAL-REGULATED KINASE (MEK)-EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) PATHWAY, THUS INDUCING EOSINOPHIL-MEDIATED AIRWAY INFLAMMATION. IN ADDITION, ALOX15 PLAYS A SIGNIFICANT ROLE IN PROMOTING THE MIGRATION OF IMMUNE CELLS, SUCH AS IMMATURE DENDRITIC CELLS, ACTIVATED T CELLS, AND MAST CELLS, AND AIRWAY REMODELING, INCLUDING GOBLET CELL DIFFERENTIATION. GENOME-WIDE ASSOCIATION STUDIES HAVE REVEALED MULTIPLE ALOX15 VARIANTS AND THEIR SIGNIFICANT CORRELATION WITH THE RISK OF DEVELOPING AIRWAY DISEASES. THE EPIGENETIC MODIFICATIONS OF THE ALOX15 GENE, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, HAVE BEEN SHOWN TO CLOSELY RELATE WITH AIRWAY INFLAMMATION. THIS REVIEW SUMMARIZES THE ROLE OF ALOX15 IN DIFFERENT PHENOTYPES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CHRONIC RHINOSINUSITIS, ASPIRIN-EXACERBATED RESPIRATORY DISEASE, AND NASAL POLYPS, SUGGESTING NEW TREATMENT STRATEGIES FOR THESE AIRWAY INFLAMMATORY DISEASES WITH COMPLEX ETIOLOGY AND POOR TREATMENT RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14   35  24 A CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC APPROACH REVEALS A TRANSCRIPTIONAL REPRESSOME FOR GENE-SPECIFIC SILENCING. IMMUNE CELLS DEVELOP ENDOTOXIN TOLERANCE (ET) AFTER PROLONGED STIMULATION. ET INCREASES THE LEVEL OF A REPRESSION MARK H3K9ME2 IN THE TRANSCRIPTIONALLY SILENT CHROMATIN SPECIFICALLY ASSOCIATED WITH PRO-INFLAMMATORY GENES. HOWEVER, IT IS NOT CLEAR WHAT PROTEINS ARE FUNCTIONALLY INVOLVED IN THIS PROCESS. HERE WE SHOW THAT A NOVEL CHROMATIN ACTIVITY-BASED CHEMOPROTEOMIC (CHAC) APPROACH CAN DISSECT THE FUNCTIONAL CHROMATIN PROTEIN COMPLEXES THAT REGULATE ET-ASSOCIATED INFLAMMATION. USING UNC0638 THAT BINDS THE ENZYMATICALLY ACTIVE H3K9-SPECIFIC METHYLTRANSFERASE G9A/GLP, CHAC REVEALS THAT G9A IS CONSTITUTIVELY ACTIVE AT A G9A-DEPENDENT MEGA-DALTON REPRESSOME IN PRIMARY ENDOTOXIN-TOLERANT MACROPHAGES. G9A/GLP BROADLY IMPACTS THE ET-SPECIFIC REPROGRAMMING OF THE HISTONE CODE LANDSCAPE, CHROMATIN REMODELLING AND THE ACTIVITIES OF SELECT TRANSCRIPTION FACTORS. WE DISCOVER THAT THE G9A-DEPENDENT EPIGENETIC ENVIRONMENT PROMOTES THE TRANSCRIPTIONAL REPRESSION ACTIVITY OF C-MYC FOR GENE-SPECIFIC CO-REGULATION OF CHRONIC INFLAMMATION. CHAC MAY ALSO BE APPLICABLE TO DISSECT OTHER FUNCTIONAL PROTEIN COMPLEXES IN THE CONTEXT OF PHENOTYPIC CHROMATIN ARCHITECTURES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15 5017  21 PERSISTENT INFECTION OF CULTURED CELLS WITH MOUSE HEPATITIS VIRUS (MHV) RESULTS FROM THE EPIGENETIC EXPRESSION OF THE MHV RECEPTOR. THE A59 STRAIN OF MURINE CORONAVIRUS MOUSE HEPATITIS VIRUS (MHV) CAN CAUSE PERSISTENT INFECTION OF 17C1-1 CELLS AND OTHER MURINE CELL LINES. PERSISTENTLY INFECTED CULTURES RELEASED LARGE AMOUNTS OF VIRUS (10(7) TO 10(8) PFU/ML) AND WERE RESISTANT TO SUPERINFECTION WITH MHV BUT NOT TO INFECTION WITH UNRELATED SEMLIKI FOREST AND VESICULAR STOMATITIS VIRUSES. THE CULTURE MEDIUM FROM PERSISTENTLY INFECTED CULTURES DID NOT CONTAIN A SOLUBLE INHIBITOR SUCH AS INTERFERON THAT PROTECTED UNINFECTED CELLS FROM INFECTION BY MHV OR VESICULAR STOMATITIS VIRUS. THE PERSISTENT INFECTION WAS CURED IF FEWER THAN 100 CELLS WERE TRANSFERRED DURING SUBCULTURING, AND SUCH CURED CULTURES WERE SUSCEPTIBLE TO REINFECTION AND THE REESTABLISHMENT OF PERSISTENT INFECTION. CULTURES OF 17C1-1 CELLS THAT HAD BEEN NEWLY CLONED FROM SINGLE CELLS CONSISTED OF A MIXTURE OF MHV-RESISTANT AND -SUSCEPTIBLE CELLS. 17C1-1/#97 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 97 PASSAGES OF A PERSISTENTLY INFECTED CULTURE OVER A 1-YEAR PERIOD, CONTAINED 5 TO 10% OF THEIR POPULATION AS SUSCEPTIBLE CELLS, WHILE 17C1-1/#402 CELLS, WHICH WERE CURED BY SUBCLONING AFTER 402 PASSAGES OVER A 3-YEAR PERIOD, HAD LESS THAN 1% SUSCEPTIBLE CELLS. SUSCEPTIBILITY TO INFECTION CORRELATED WITH THE EXPRESSION OF MHV RECEPTOR GLYCOPROTEIN (MHVR [BGP1A]). FLUORESCENCE-ACTIVATED CELL SORTER ANALYSIS WITH ANTIBODY TO MHVR SHOWED THAT 17C1-1/#97 CELLS CONTAINED A SMALL FRACTION OF MHVR-EXPRESSING CELLS. THESE MHVR-EXPRESSING CELLS WERE SELECTIVELY ELIMINATED WITHIN 24 H AFTER CHALLENGE WITH MHV-A59, AND PRETREATMENT OF 17C1-1/#97 CELLS WITH MONOCLONAL ANTIBODY CC1, WHICH BINDS TO THE N-TERMINAL DOMAIN OF MHVR, BLOCKED INFECTION. WE CONCLUDE THAT THE SUBPOPULATION OF MHVR-EXPRESSING CELLS WERE INFECTED AND KILLED IN ACUTELY OR PERSISTENTLY INFECTED CULTURES, WHILE THE SUBPOPULATION OF MHVR-NONEXPRESSING CELLS SURVIVED AND PROLIFERATED. THE SUBPOPULATION OF MHVR-NEGATIVE CELLS PRODUCED A SMALL PROPORTION OF PROGENY CELLS THAT EXPRESSED MHVR AND BECAME INFECTED, THEREBY MAINTAINING THE PERSISTENT INFECTION AS A STEADY-STATE CARRIER CULTURE. THUS, IN 17C1-1 CELL CULTURES, THE UNSTABLE OR EPIGENETIC EXPRESSION OF MHVR PERMITTED THE ESTABLISHMENT OF A PERSISTENT, CHRONIC INFECTION.	1995	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 6636  31 UNRAVELING A NEW PLAYER IN MULTIPLE SCLEROSIS PATHOGENESIS: THE RNA-BINDING PROTEIN HUR. BACKGROUND: ELAV-LIKE PROTEINS ARE A SMALL FAMILY OF RNA-BINDING PROTEINS THAT ARE FUNDAMENTAL PLAYERS IN POST-TRANSCRIPTIONAL MECHANISMS AND ARE INVOLVED IN THE PATHOGENESIS OF NEUROLOGIC AND PSYCHIATRIC DISORDERS. HUR, THE UBIQUITOUSLY EXPRESSED MEMBER OF THE FAMILY, IS ALSO IMPLICATED IN SUSTAINING INFLAMMATION AND INFLAMMATORY DISEASES, SUPPORTING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. INFLAMMATION PLAYS A CENTRAL ROLE IN MULTIPLE SCLEROSIS (MS), WHICH REPRESENTS THE MOST COMMON CAUSE OF PERMANENT PHYSICAL DISABILITY IN YOUNG ADULTS. MS IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING THE CENTRAL NERVOUS SYSTEM, WITH A COMPLEX AETIOLOGY INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. NO DATA ARE AVAILABLE ON THE POTENTIAL ENTANGLEMENT OF HUR IN MS PATHOGENESIS IN PATIENTS. IN THE PRESENT WORK, WE AIMED AT EXPLORING HUR PROTEIN LEVELS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM MS PATIENTS, COMPARED TO HEALTHY CONTROLS. TO FURTHER ELUCIDATE THE POSSIBLE INVOLVEMENT OF HUR IN MS, WE ALSO INVESTIGATED THE RELATIONSHIP BETWEEN THIS SPECIFIC RNA-BINDING PROTEIN AND HSP70-2 PROTEIN, ALSO CONSIDERING THE HSP70-2 RS1061581 POLYMORPHISM, GIVEN THAT HSP70-2 MRNA HAS BEEN REPORTED AS A HUR TARGET AND THIS SPECIFIC POLYMORPHISM TO BE ASSOCIATED WITH MS RISK. METHODS: ALLELES AND GENOTYPES FOR HSP70-2 RS1061581 POLYMORPHISM WERE ASSESSED, BY USING A POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM, FOLLOWED BY DIGESTION WITH RESTRICTION ENZYME, IN MS PATIENTS AND HEALTHY CONTROLS. PBMCS FROM A SUBGROUP OF PATIENTS AND CONTROLS WERE USED TO EVALUATE HUR AND HSP70-2 PROTEIN CONTENT BY WESTERN BLOT. RESULTS: PBMCS FROM 52 MS PATIENTS HAD A LOWER HUR AND HIGHER HSP70-2 PROTEIN CONTENT COMPARED TO 43 HEALTHY CONTROLS. AN INCREASE OF 100 UNITS OF HUR SIGNIFICANTLY DECREASED THE RISK OF DEVELOPING MS BY 9.8% (OR: 0.902, 95% CI: 0.83-0.98), CONTROLLING FOR HSP70-2 PROTEIN EXPRESSION, HSP70-2 RS1061581 GENOTYPE, AGE AND SEX. MOREOVER, HOLDING HUR LEVELS, AN INCREASE OF 100 UNITS OF HSP70-2 PROTEIN SIGNIFICANTLY INCREASED THE MS RISK BY 18.1% (OR: 1.181, 95% CI: 1.03-1.36) AND THE GENETIC SUSCEPTIBILITY OF DEVELOPING MS FOR HSP70-2 RS1061581 GG CARRIERS IS CONFIRMED. OF INTEREST, MS PATIENTS WITH A MODERATE TO SEVERE FORM OF MS (MSSS >/= 3) SHOWED A TREND TOWARDS A REDUCTION OF HUR PROTEIN LEVELS COMPARED TO PATIENTS WITH MILD DISEASE SEVERITY (MSSS < 3). CONCLUSIONS: HUR PROTEIN LEVELS ARE REDUCED IN MS PATIENTS COMPARED TO HEALTHY SUBJECTS, AND THE PROTEIN AMOUNT MAY CONTINUE TO DECLINE WITH DISEASE PROGRESSION, SUGGESTING A PUTATIVE ROLE OF THIS RNA-BINDING PROTEIN. MOREOVER, OUR RESULTS SUGGEST THAT MS PATHOLOGY MAY HAVE DISRUPTED THE LINK BETWEEN HUR AND ITS TARGET TRANSCRIPT HSP70-2. IT WILL BE IMPORTANT TO FURTHER EXPLORE THE EXACT ROLE OF HUR IN MS, CONSIDERING THE COMPLEX INTERPLAY WITH OTHER RNA-BINDING FACTORS AND TARGET MRNAS.	2020	

17 1951  25 EPIGENETIC ACTIVATION OF THE TUSC3 GENE AS A POTENTIAL THERAPY FOR XMEN DISEASE. BACKGROUND: X-LINKED MAGT1 DEFICIENCY WITH INCREASED SUSCEPTIBILITY TO EPSTEIN-BARR VIRUS INFECTION AND N-LINKED GLYCOSYLATION DEFECT (XMEN) DISEASE IS A RARE COMBINED IMMUNODEFICIENCY CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE MAGNESIUM TRANSPORTER 1 (MAGT1) GENE. MAGT1 DEFICIENCY IMPAIRS MAGNESIUM TRANSPORT AND THE N-LINKED GLYCOSYLATION OF A PANEL OF PROTEINS, WHICH SUBSEQUENTLY ABOLISHES THE EXPRESSION OF KEY IMMUNE RECEPTORS SUCH AS NATURAL KILLER GROUP 2, MEMBER D (AKA NKG2D). THESE EFFECTS INDUCE IMMUNE SYSTEM ABNORMALITIES, CHRONIC EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA. RECENT RESEARCH SHOWS THAT MAGT1 AND TUMOR CANDIDATE SUPPRESSOR 3 (TUSC3) SHARE HIGH SEQUENCE AND FUNCTIONAL SIMILARITY. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE FEASIBILITY OF ACTIVATING TUSC3 EXPRESSION TO PROVIDE A POTENTIAL THERAPEUTIC STRATEGY FOR XMEN DISEASE. METHODS: THE EXPRESSION PROFILES OF MAGT1 AND TUSC3 WERE ANALYZED USING MULTIPLE DATABASES, REAL-TIME QUANTITATIVE PCR, AND WESTERN BLOT. THE EFFECTS OF DECITABINE AND PANOBINOSTAT ON THE REGULATION OF TUSC3 EXPRESSION WERE EXPLORED IN BOTH MAGT1 KNOCKOUT (KO)/PATIENT-DERIVED LYMPHOCYTES AND MAGT1 KO HEPATOCYTES. RESULTS: ALTHOUGH TUSC3 IS WIDELY EXPRESSED, IT IS UNDETECTABLE SPECIFICALLY IN THE IMMUNE SYSTEM AND LIVER, CONSISTENT WITH THE MAIN DISEASED TISSUES IN PATIENTS WITH XMEN DISEASE. CRISPR/CAS9-MEDIATED KO OF MAGT1 IN THE NKL CELL LINE SUCCESSFULLY MIMICKED THE PHENOTYPES OF XMEN PATIENT-DERIVED LYMPHOCYTES, AND EXOGENOUS EXPRESSION OF TUSC3 RESCUED THE DEFICIENCIES IN KO NKL CELLS. USING THIS IN VITRO MODEL, WE IDENTIFIED 2 EPIGENETIC DRUGS, DECITABINE AND PANOBINOSTAT, BY SCREENING. COMBINATION TREATMENT USING THESE 2 DRUGS SIGNIFICANTLY UPREGULATED TUSC3 EXPRESSION AND RESCUED THE IMMUNE AND LIVER ABNORMALITIES. CONCLUSIONS: EPIGENETIC ACTIVATION OF TUSC3 EXPRESSION CONSTITUTES AN EFFECTIVE THERAPEUTIC STRATEGY FOR XMEN DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18 5640  26 SERUM TUMOR MARKERS AND MOLECULAR BIOLOGICAL DIAGNOSIS IN PANCREATIC CANCER. RECENT STUDIES ON GENETIC ABNORMALITIES IN PANCREATIC DUCTAL CANCER HAVE LED TO THE INVESTIGATION OF TUMOR MARKERS AND GENETIC MARKERS IN BOTH SERUM AND PANCREATIC JUICE (PJ). SERUM TYPE 1 CHAIN CARBOHYDRATE ANTIGENS SUCH AS CA19-9 ARE POSITIVE IN NEARLY 80% OF PATIENTS WITH PANCREATIC CANCER (PCA), OF WHICH MOST ARE IN ADVANCED STAGE, WHEREAS FALSE-POSITIVE RATES ARE RELATIVELY HIGH AT 20%-30% IN BENIGN HEPATOBILIARY AND PANCREATIC DISEASES. ALTHOUGH THE PREVALENCE OF TYPE 2 CHAIN CARBOHYDRATE ANTIGENS, SUCH AS SLX, IS RELATIVELY LOW, CANCER SPECIFICITY OF THESE ANTIGENS IS HIGH. HOWEVER, SERUM TUMOR MARKERS HAVE LIMITED DIAGNOSTIC VALUE FOR EARLY DETECTION OF PCA. IN PJ COLLECTED ENDOSCOPICALLY FROM PATIENTS WITH PCA, K-RAS MUTATIONS (KRM) ARE DETECTABLE IN > 80%, WHEREAS KRM ARE OBSERVED IN 20%-30% OF PJ FROM PATIENTS WITH CHRONIC PANCREATITIS (CP), REFLECTING BENIGN MUCOUS CELL HYPERPLASIA HARBORING KRM. THUS, A QUALITATIVE ANALYSIS OF KRM IN PJ IS UNSUITABLE FOR DIAGNOSIS OF PCA. ON THE OTHER HAND, USING AN HYBRIDIZATION PROTECTION ASSAY THAT CAN QUANTITATIVELY DETERMINE KRM, KRM WERE POSITIVE IN 66% OF PCA BUT ONLY IN 40% OF CP CASES, INDICATING THAT QUALITATIVE ANALYSIS OF KRM IN PJ MAY BE USEFUL FOR DIFFERENTIATING PCA FROM CP. P53 MUTATIONS ARE FOUND IN 4%-50% IN PJ FROM PATIENTS WITH PCA BUT ARE NOT DETECTABLE IN PJ FROM CP, SUGGESTING THAT THE SPECIFICITY OF P53 MUTATIONS IS VERY HIGH FOR PCA. FURTHERMORE, P53 MUTATIONS WERE DETECTED IN 7 OF 15 (47%) PATIENTS WITH PCA IN WHICH THE PJ CYTOLOGIC DIAGNOSIS WAS NEGATIVE. TELOMERASE (TE) ACTIVITY OR ITS CATALYTIC SUBUNIT, H-TERT, WAS REPORTEDLY POSITIVE >80% IN PJ FROM PCA BUT WAS DETECTED IN <20% OF PJ FROM CP. TE ACTIVITY IN PJ FROM CP ORIGINATES FROM LYMPHOCYTES. THE DEVELOPMENT AND APPLICATION OF THESE NEW GENETIC AND EPIGENETIC MARKERS WITH HIGH SPECIFICITY AND SENSITIVITY FOR PCA IN SERUM AND PJ WILL SIGNIFICANTLY IMPROVE OUR DIAGNOSTIC ACCURACY.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 5601  18 RORALPHA IS CRUCIAL FOR ATTENUATED INFLAMMATORY RESPONSE TO MAINTAIN INTESTINAL HOMEOSTASIS. RETINOIC ACID-RELATED ORPHAN RECEPTOR ALPHA (RORALPHA) FUNCTIONS AS A TRANSCRIPTION FACTOR FOR VARIOUS BIOLOGICAL PROCESSES, INCLUDING CIRCADIAN RHYTHM, CANCER, AND METABOLISM. HERE, WE GENERATE INTESTINAL EPITHELIAL CELL (IEC)-SPECIFIC RORALPHA-DEFICIENT (RORALPHA(DELTAIEC)) MICE AND FIND THAT RORALPHA IS CRUCIAL FOR MAINTAINING INTESTINAL HOMEOSTASIS BY ATTENUATING NUCLEAR FACTOR KAPPAB (NF-KAPPAB) TRANSCRIPTIONAL ACTIVITY. RORALPHA(DELTAIEC) MICE EXHIBIT EXCESSIVE INTESTINAL INFLAMMATION AND HIGHLY ACTIVATED INFLAMMATORY RESPONSES IN THE DEXTRAN SULFATE SODIUM (DSS) MOUSE COLITIS MODEL. TRANSCRIPTOME ANALYSIS REVEALS THAT DELETION OF RORALPHA LEADS TO UP-REGULATION OF NF-KAPPAB TARGET GENES IN IECS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALS CORECRUITMENT OF RORALPHA AND HISTONE DEACETYLASE 3 (HDAC3) ON NF-KAPPAB TARGET PROMOTERS AND SUBSEQUENT DISMISSAL OF CREB BINDING PROTEIN (CBP) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) FOR TRANSCRIPTIONAL REPRESSION. TOGETHER, WE DEMONSTRATE THAT RORALPHA/HDAC3-MEDIATED ATTENUATION OF NF-KAPPAB SIGNALING CONTROLS THE BALANCE OF INFLAMMATORY RESPONSES, AND THERAPEUTIC STRATEGIES TARGETING THIS EPIGENETIC REGULATION COULD BE BENEFICIAL TO THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES, INCLUDING INFLAMMATORY BOWEL DISEASE (IBD).	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20 1016  22 CIITA EXPRESSION IS REGULATED BY HISTONE DEACETYLASE ENZYMES AND HAS A ROLE IN ALPHA-SYNUCLEIN PRE-FORMED FIBRIL-INDUCED ANTIGEN PRESENTATION IN MURINE MICROGLIAL CELL LINE. AIM: PARKINSON'S DISEASE (PD) IS A CHRONIC NEURODEGENERATIVE DISORDER RELATED WITH SEVERAL GENETIC AND EPIGENETIC FACTORS. IN THE CONTEXT OF EPIGENETIC FACTORS, HISTONE ACETYLATION IS ONE OF THE MOST ASSOCIATED MECHANISMS WITH PARKINSON'S DISEASE PROGRESSION. THIS STUDY INVESTIGATES THE EFFECTS OF THE INCREASED HISTONE ACETYLATION ON ANTIGEN PRESENTATION IN MICROGLIAL CELLS WHICH WERE INDUCED BY PRE-FORMED FIBRILS OF ALPHA-SYNUCLEIN (PFF ALPHA-SYNUCLEIN). METHODS: PARKINSON'S DISEASE MODEL WAS CREATED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION TO THE BV-2 MICROGLIAL CELLS. BV-2 CELLS WERE CO-TREATED WITH CUDC-907 AND TMP-195 TO INCREASE HISTONE ACETYLATION IN THE PRESENCE OF ALPHA-SYNUCLEIN. ANTIGEN REPRESENTATION WAS EVALUATED BY DETERMINING EXPRESSION LEVELS OF MAJOR HISTOCOMPATIBILITY COMPLEX-II (MHC-II) AND CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX (CIITA). RESULTS: OUR RESULTS SHOWED THAT PFF ALPHA-SYNUCLEIN SIGNIFICANTLY INCREASED MHC-II EXPRESSION, AND THAT EFFECT WAS MOST SEVERE AT 6 H OF ADMINISTRATION OF ALPHA-SYNUCLEIN. INCREASING HISTONE ACETYLATION VIA CUDC-907 AND TMP-195 ENHANCED MHC-II LEVELS EXPRESSION, WHICH WAS MORE SEVERE IN CUDC-907. ADDITIONALLY, CIITA EXPRESSION LEVELS WERE SIGNIFICANTLY INCREASED WITH PFF ALPHA-SYNUCLEIN ADMINISTRATION AND INTENSIFIED WITH THE CO-TREATMENT OF CUDC-907 AND TMP-195. FURTHERMORE, PFF ALPHA-SYNUCLEIN CAUSED A TIME-DEPENDENT INCREASE IN THE IFN-GAMMA (IFN-?) AND INTERLEUKIN-16(IL-16) LEVELS, AND THAT INCREASE WAS POTENTIATED WITH CUDC-907 AND TMP-195. CONCLUSION: CHANGES IN MHC-II AND CIITA EXPRESSION INDICATE THAT HISTONE ACETYLATION INCREASES THE ANTIGEN PRESENTATION PROPERTIES OF MICROGLIAL CELLS AFTER PFF ALPHA-SYNUCLEIN OR HISTONE DEACETYLASE INHIBITOR (HDACI) ADMINISTRATION. OUR RESULTS SHOW THAT MICROGLIAL ANTIGEN PRESENTATION MIGHT HAVE AN ESSENTIAL ROLE IN THE PATHOLOGY OF PARKINSON'S DISEASE, AND ALPHA-SYNUCLEIN LIKELY TO PLAY A PRIMARY ROLE IN THIS MECHANISM.	2022