1 4521 192 MULTI?LAYERED PREVENTION AND TREATMENT OF CHRONIC INFLAMMATION, ORGAN FIBROSIS AND CANCER ASSOCIATED WITH CANONICAL WNT/BETA?CATENIN SIGNALING ACTIVATION (REVIEW). BETA?CATENIN/CTNNB1 IS AN INTRACELLULAR SCAFFOLD PROTEIN THAT INTERACTS WITH ADHESION MOLECULES (E?CADHERIN/CDH1, N?CADHERIN/CDH2, VE?CADHERIN/CDH5 AND ALPHA?CATENINS), TRANSMEMBRANE?TYPE MUCINS (MUC1/CD227 AND MUC16/CA125), SIGNALING REGULATORS (APC, AXIN1, AXIN2 AND NHERF1/EBP50) AND EPIGENETIC OR TRANSCRIPTIONAL REGULATORS (BCL9, BCL9L, CREBBP/CBP, EP300/P300, FOXM1, MED12, SMARCA4/BRG1 AND TCF/LEF). GAIN?OF?FUNCTION CTTNB1 MUTATIONS ARE DETECTED IN BLADDER CANCER, COLORECTAL CANCER, GASTRIC CANCER, LIVER CANCER, LUNG CANCER, PANCREATIC CANCER, PROSTATE CANCER AND UTERINE CANCER, WHEREAS LOSS?OF?FUNCTION CTNNB1 MUTATIONS ARE ALSO DETECTED IN HUMAN CANCER. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA AND ZNRF3 ARE REPRESENTATIVE BETA?CATENIN TARGET GENES. BETA?CATENIN SIGNALING IS INVOLVED IN MYOFIBROBLAST ACTIVATION AND SUBSEQUENT PULMONARY FIBROSIS, IN ADDITION TO OTHER TYPES OF FIBROSIS. BETA?CATENIN AND NF?KAPPAB SIGNALING ACTIVATION ARE INVOLVED IN FIELD CANCERIZATION IN THE STOMACH ASSOCIATED WITH HELICOBACTER PYLORI (H. PYLORI) INFECTION AND IN THE LIVER ASSOCIATED WITH HEPATITIS C VIRUS (HCV) INFECTION AND OTHER ETIOLOGIES. BETA?CATENIN?TARGETED THERAPEUTICS ARE FUNCTIONALLY CLASSIFIED INTO BETA?CATENIN INHIBITORS TARGETING UPSTREAM REGULATORS (AZ1366, ETC?159, G007?LK, GNF6231, IPAFRICEPT, NVP?TNKS656, ROSMANTUZUMAB, VANTICTUMAB, WNT?C59, WNT974 AND XAV939), BETA?CATENIN INHIBITORS TARGETING PROTEIN?PROTEIN INTERACTIONS (CGP049090, CWP232228, E7386, ICG?001, LF3 AND PRI?724), BETA?CATENIN INHIBITORS TARGETING EPIGENETIC REGULATORS (PKF118?310), BETA?CATENIN INHIBITORS TARGETING MEDIATOR COMPLEXES (CCT251545 AND CORTISTATIN A) AND BETA?CATENIN INHIBITORS TARGETING TRANSMEMBRANE?TYPE TRANSCRIPTIONAL OUTPUTS, INCLUDING CD44V6, FZD7 AND LGR5. ERADICATING H. PYLORI AND HCV IS THE OPTIMAL APPROACH FOR THE FIRST?LINE PREVENTION OF GASTRIC CANCER AND HEPATOCELLULAR CARCINOMA (HCC), RESPECTIVELY. HOWEVER, BETA?CATENIN INHIBITORS MAY BE APPLICABLE FOR THE PREVENTION OF ORGAN FIBROSIS, SECOND?LINE HCC PREVENTION AND TREATING BETA?CATENIN?DRIVEN CANCER. THE MULTI?LAYERED PREVENTION AND TREATMENT STRATEGY OF BETA?CATENIN?RELATED HUMAN DISEASES IS NECESSARY FOR THE PRACTICE OF PERSONALIZED MEDICINE AND IMPLEMENTATION OF PRECISION MEDICINE. 2018 2 1273 21 CYTOTOXIC PERIPHERAL T-CELL LYMPHOMAS AND EBV-POSITIVE T/NK-CELL LYMPHOPROLIFERATIVE DISEASES: EMERGING CONCEPTS, RECENT ADVANCES, AND THE PUTATIVE ROLE OF CLONAL HEMATOPOIESIS. A REPORT OF THE 2022 EA4HP/SH LYMPHOMA WORKSHOP. CYTOTOXIC PERIPHERAL T-CELL LYMPHOMAS AND EBV-POSITIVE T/NK-CELL LYMPHOPROLIFERATIVE DISEASES WERE DISCUSSED AT THE 2022 EUROPEAN ASSOCIATION FOR HAEMATOPATHOLOGY/SOCIETY FOR HEMATOPATHOLOGY LYMPHOMA WORKSHOP HELD IN FLORENCE, ITALY. THIS SESSION FOCUSED ON (I) PRIMARY NODAL EBV-POSITIVE T AND NK-CELL LYMPHOMAS (PRIMARY NODAL-EBV-TNKL), (II) EXTRANODAL EBV-POSITIVE T/NK LYMPHOPROLIFERATIVE DISEASES (LPD) IN CHILDREN AND ADULTS, (III) CYTOTOXIC PERIPHERAL T-CELL LYMPHOMAS, NOS (CPTCL-NOS), EBV-NEGATIVE, AND (IV) MISCELLANEOUS CASES. PRIMARY NODAL-EBV-TNKL IS A NEWLY RECOGNIZED ENTITY WHICH IS RARE, AGGRESSIVE, AND ASSOCIATED WITH UNDERLYING IMMUNE DEFICIENCY/IMMUNE DYSREGULATION. ALL CASES PRESENTED WITH LYMPHADENOPATHY BUT SOME DEMONSTRATED INVOLVEMENT OF TONSIL/WALDEYER'S RING AND EXTRANODAL SITES. THE MAJORITY OF TUMORS ARE OF T-CELL LINEAGE, AND THE MOST FREQUENT MUTATIONS INVOLVE THE EPIGENETIC MODIFIER GENES, SUCH AS TET2 AND DNMT3A, AND JAK-STAT GENES. A SPECTRUM OF EBV-POSITIVE T/NK LPD INVOLVING EXTRANODAL SITES WERE DISCUSSED AND HIGHLIGHT THE DIAGNOSTIC CHALLENGE WITH PRIMARY NODAL-EBV-TNKL WHEN THESE EXTRANODAL EBV-POSITIVE T/NK LPD CASES DEMONSTRATE PREDOMINANT NODAL DISEASE EITHER AT PRESENTATION OR DURING DISEASE PROGRESSION FROM CHRONIC ACTIVE EBV DISEASE. THE MAJORITY OF CPTCL-NOS DEMONSTRATED THE TBX21 PHENOTYPE. SOME CASES HAD A BACKGROUND OF IMMUNOSUPPRESSION OR IMMUNE DYSREGULATION. INTERESTINGLY, AN UNEXPECTED ASSOCIATION OF CPTCL-NOS, EBV-POSITIVE AND NEGATIVE, WITH TFH LYMPHOMAS/LPDS WAS OBSERVED IN THE WORKSHOP CASES. SIMILAR TO A PUBLISHED LITERATURE, THE GENETIC LANDSCAPE OF CPTCL-NOS FROM THE WORKSHOP SHOWED FREQUENT MUTATIONS IN EPIGENETIC MODIFIERS, INCLUDING TET2 AND DNMT3A, SUGGESTING A ROLE OF CLONAL HEMATOPOIESIS IN THE DISEASE PATHOGENESIS. 2023 3 1937 21 EOMES IS ESSENTIAL FOR ANTITUMOR ACTIVITY OF CD8(+) T CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA. GENOME-WIDE ASSOCIATION STUDIES IDENTIFIED A SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AFFECTING THE TRANSCRIPTION FACTOR EOMESODERMIN (EOMES) ASSOCIATED WITH A SIGNIFICANTLY INCREASED RISK TO DEVELOP CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). EPIGENETIC ANALYSES, RNA SEQUENCING, AND FLOW CYTOMETRY REVEALED THAT EOMES IS NOT EXPRESSED IN CLL CELLS, BUT IN CD8(+) T CELLS FOR WHICH EOMES IS A KNOWN MASTER REGULATOR. WE THUS HYPOTHESIZED THAT THE INCREASED CLL RISK ASSOCIATED WITH THE EOMES SNP MIGHT BE EXPLAINED BY ITS NEGATIVE IMPACT ON CD8(+) T-CELL-MEDIATED IMMUNE CONTROL OF CLL. FLOW CYTOMETRY ANALYSES REVEALED A HIGHER EOMES EXPRESSION IN CD8(+) T CELLS OF CLL PATIENTS COMPARED TO HEALTHY INDIVIDUALS, AND AN ACCUMULATION OF PD-1(+) EOMES(+) CD8(+) T CELLS IN LYMPH NODES RATHER THAN BLOOD OR BONE MARROW IN CLL. THIS WAS IN LINE WITH AN OBSERVED EXPANSION OF EOMES(+) CD8(+) T CELLS IN THE SPLEEN OF LEUKEMIC EMICRO-TCL1 MICE. AS EOMES EXPRESSION WAS HIGHEST IN CD8(+) T CELLS THAT EXPRESS INHIBITORY RECEPTORS, AN INVOLVEMENT OF EOMES IN T-CELL EXHAUSTION AND DYSFUNCTION SEEMS LIKELY. INTERESTINGLY, EOMES-DEFICIENCY IN CD8(+) T CELLS RESULTED IN THEIR IMPAIRED EXPANSION ASSOCIATED WITH DECREASED CLL CONTROL IN MICE. OVERALL, THESE OBSERVATIONS SUGGEST THAT EOMES IS ESSENTIAL FOR CD8(+) T-CELL EXPANSION AND/OR MAINTENANCE, AND THEREFORE INVOLVED IN ADAPTIVE IMMUNE CONTROL OF CLL. 2021 4 4338 20 MICROVASCULAR BARRIER PROTECTION BY MICRORNA-183 VIA FOXO1 REPRESSION: A PATHWAY DISTURBED IN NEUROPATHY AND COMPLEX REGIONAL PAIN SYNDROME. BLOOD NERVE BARRIER DISRUPTION AND EDEMA ARE COMMON IN NEUROPATHIC PAIN AS WELL AS IN COMPLEX REGIONAL PAIN SYNDROME (CRPS). MICRORNAS (MIRNA) ARE EPIGENETIC MULTITARGET SWITCHES CONTROLLING NEURONAL AND NON-NEURONAL CELLS IN PAIN. THE MIR-183 COMPLEX ATTENUATES HYPEREXCITABILITY IN NOCICEPTORS, BUT ADDITIONAL NON-NEURONAL EFFECTS VIA TRANSCRIPTION FACTORS COULD CONTRIBUTE AS WELL. THIS STUDY EXPLORED EXOSOMAL MIR-183 IN CRPS AND MURINE NEUROPATHY, ITS EFFECT ON THE MICROVASCULAR BARRIER VIA TRANSCRIPTION FACTOR FOXO1 AND TIGHT JUNCTION PROTEIN CLAUDIN-5, AND ITS ANTIHYPERALGESIC POTENTIAL. SCIATIC MIR-183 DECREASED AFTER CCI. SUBSTITUTION WITH PERINEURAL MIR-183 MIMIC ATTENUATED MECHANICAL HYPERSENSITIVITY AND RESTORED BLOOD NERVE BARRIER FUNCTION. IN VITRO, SERUM FROM CCI MICE UND CRPS PATIENTS WEAKENED THE MICROVASCULAR BARRIER OF MURINE CEREBELLAR ENDOTHELIAL CELLS, INCREASED ACTIVE FOXO1 AND REDUCED CLAUDIN-5, CONCOMITANT WITH A LACK OF EXOSOMAL MIR-183 IN CRPS PATIENTS. CELLULAR STRESS ALSO COMPROMISED THE MICROVASCULAR BARRIER WHICH WAS RESCUED EITHER BY MIR-183 MIMIC VIA FOXO1 REPRESSION OR BY PRIOR SILENCING OF FOXO1. PERSPECTIVE: LOW MIR-183 LEADING TO BARRIER IMPAIRMENT VIA FOXO1 AND SUBSEQUENT CLAUDIN-5 SUPPRESSION IS A NEW ASPECT IN THE PATHOPHYSIOLOGY OF CRPS AND NEUROPATHIC PAIN. THIS PATHWAY MIGHT HELP UNTANGLE THE WIDE SYMPTOMATIC RANGE OF CRPS AND NURTURE FURTHER RESEARCH INTO MIRNA MIMICS OR FOXO1 INHIBITORS. 2022 5 5967 21 TERMINATION OF ACUTE STRESS RESPONSE BY THE ENDOCANNABINOID SYSTEM IS REGULATED THROUGH LYSINE-SPECIFIC DEMETHYLASE 1-MEDIATED TRANSCRIPTIONAL REPRESSION OF 2-AG HYDROLASES ABHD6 AND MAGL. ACUTE ENVIRONMENTAL STRESS RARELY IMPLIES LONG-LASTING NEUROPHYSIOLOGICAL AND BEHAVIORAL ALTERATIONS. ON THE CONTRARY, CHRONIC STRESS EXERTS A POTENT TOXIC EFFECT AT THE GLUTAMATERGIC SYNAPSE WHOSE ALTERED PHYSIOLOGY HAS BEEN RECOGNIZED AS A CORE TRAIT OF NEUROPSYCHIATRIC DISORDERS. THE ENDOCANNABINOID SYSTEM (ECS) PLAYS AN IMPORTANT ROLE IN THE HOMEOSTATIC RESPONSE TO ACUTE STRESS. IN PARTICULAR, STRESS INDUCES SYNTHESIS OF ENDOCANNABINOID (ECB) 2-ARACHIDONYL GLYCEROL (2-AG). 2-AG STIMULATES PRESYNAPTIC CANNABINOID 1 (CB1) RECEPTOR CONTRIBUTING TO STRESS RESPONSE TERMINATION THROUGH INHIBITION OF GLUTAMATE RELEASE, RESTRAINING THEREAFTER ANXIETY AROUSAL. WE EMPLOY MOUSE MODELS OF STRESS RESPONSE COUPLED TO GENE EXPRESSION ANALYSES, UNRAVELLING THAT IN RESPONSE TO ACUTE PSYCHOSOCIAL STRESS IN THE MOUSE HIPPOCAMPUS, ECS-MEDIATED SYNAPTIC MODULATION IS ENHANCED VIA TRANSCRIPTIONAL REPRESSION OF TWO ENZYMES INVOLVED IN 2-AG DEGRADATION: ALPHA/BETA-HYDROLASE DOMAIN CONTAINING 6 (ABHD6) AND MONOACYLGLYCEROL LIPASE (MAGL). SUCH A PROCESS IS ORCHESTRATED BY THE EPIGENETIC COREPRESSOR LSD1 WHO DIRECTLY INTERACTS WITH PROMOTER REGULATORY REGIONS OF ABHD6 AND MAGL. REMARKABLY, NEGATIVE TRANSCRIPTIONAL CONTROL OF ABHD6 AND MAGL IS LOST IN THE HIPPOCAMPUS UPON CHRONIC PSYCHOSOCIAL STRESS, POSSIBLY CONTRIBUTING TO TRAUMA-INDUCED DRIFT OF SYNAPSE PHYSIOLOGY TOWARD UNCONTROLLED GLUTAMATE TRANSMISSION. WE PREVIOUSLY SHOWED THAT IN MICE LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INCREASES ITS HIPPOCAMPAL EXPRESSION IN RESPONSE TO PSYCHOSOCIAL STRESS PREVENTING EXCESSIVE CONSOLIDATION OF ANXIETY-RELATED PLASTICITY. IN THIS WORK, WE UNRAVEL A NODAL EPIGENETIC MODULATION OF ECB TURN OVER, SHEDDING NEW LIGHT ON THE MOLECULAR SUBSTRATE OF CONVERGING STRESS-TERMINATING EFFECTS DISPLAYED BY ECS AND LSD1. 2020 6 1693 21 DUSP4 DEFICIENCY CAUSED BY PROMOTER HYPERMETHYLATION DRIVES JNK SIGNALING AND TUMOR CELL SURVIVAL IN DIFFUSE LARGE B CELL LYMPHOMA. THE EPIGENETIC DYSREGULATION OF TUMOR SUPPRESSOR GENES IS AN IMPORTANT DRIVER OF HUMAN CARCINOGENESIS. WE HAVE COMBINED GENOME-WIDE DNA METHYLATION ANALYSES AND GENE EXPRESSION PROFILING AFTER PHARMACOLOGICAL DNA DEMETHYLATION WITH FUNCTIONAL SCREENING TO IDENTIFY NOVEL TUMOR SUPPRESSORS IN DIFFUSE LARGE B CELL LYMPHOMA (DLBCL). WE FIND THAT A CPG ISLAND IN THE PROMOTER OF THE DUAL-SPECIFICITY PHOSPHATASE DUSP4 IS ABERRANTLY METHYLATED IN NODAL AND EXTRANODAL DLBCL, IRRESPECTIVE OF ABC OR GCB SUBTYPE, RESULTING IN LOSS OF DUSP4 EXPRESSION IN 75% OF >200 EXAMINED CASES. THE DUSP4 GENOMIC LOCUS IS FURTHER DELETED IN UP TO 13% OF AGGRESSIVE B CELL LYMPHOMAS, AND THE LACK OF DUSP4 IS A NEGATIVE PROGNOSTIC FACTOR IN THREE INDEPENDENT COHORTS OF DLBCL PATIENTS. ECTOPIC EXPRESSION OF WILD-TYPE DUSP4, BUT NOT OF A PHOSPHATASE-DEFICIENT MUTANT, DEPHOSPHORYLATES C-JUN N-TERMINAL KINASE (JNK) AND INDUCES APOPTOSIS IN DLBCL CELLS. PHARMACOLOGICAL OR DOMINANT-NEGATIVE JNK INHIBITION RESTRICTS DLBCL SURVIVAL IN VITRO AND IN VIVO AND SYNERGIZES STRONGLY WITH THE BRUTON'S TYROSINE KINASE INHIBITOR IBRUTINIB. OUR RESULTS INDICATE THAT DLBCL CELLS DEPEND ON JNK SIGNALING FOR SURVIVAL. THIS FINDING PROVIDES A MECHANISTIC BASIS FOR THE CLINICAL DEVELOPMENT OF JNK INHIBITORS IN DLBCL, IDEALLY IN SYNTHETIC LETHAL COMBINATIONS WITH INHIBITORS OF CHRONIC ACTIVE B CELL RECEPTOR SIGNALING. 2015 7 2006 22 EPIGENETIC AUGMENTATION OF THE MACROPHAGE INFLAMMATORY PROTEIN 2/C-X-C CHEMOKINE RECEPTOR TYPE 2 AXIS THROUGH HISTONE H3 ACETYLATION IN INJURED PERIPHERAL NERVES ELICITS NEUROPATHIC PAIN. ALTHOUGH THERE IS GROWING EVIDENCE SHOWING THAT THE INVOLVEMENT OF CHEMOKINES IN THE PATHOGENESIS OF NEUROPATHIC PAIN IS ASSOCIATED WITH NEUROINFLAMMATION, THE DETAILS ARE UNCLEAR. WE INVESTIGATED THE C-X-C CHEMOKINE LIGAND TYPE 2 [MACROPHAGE INFLAMMATORY PROTEIN 2 (MIP-2)]/C-X-C CHEMOKINE RECEPTOR TYPE 2 (CXCR2) AXIS AND EPIGENETIC REGULATION OF THESE MOLECULES IN NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. EXPRESSION OF MIP-2 AND CXCR2 WERE UP-REGULATED AND LOCALIZED ON ACCUMULATED NEUTROPHILS AND MACROPHAGES IN THE INJURED SCIATIC NERVE (SCN) AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). PERINEURAL INJECTION OF MIP-2-NEUTRALIZING ANTIBODY (ANTI-MIP-2) OR THE CXCR2 ANTAGONIST N-(2-BROMOPHENYL)-N'-(2-HYDROXY-4-NITROPHENYL)UREA (SB225002) PREVENTED PSL-INDUCED TACTILE ALLODYNIA AND THERMAL HYPERALGESIA. PERINEURAL INJECTION OF RECOMBINANT MIP-2 ELICITED NEUROPATHIC PAIN-LIKE BEHAVIORS. ANTI-MIP-2 SUPPRESSED NEUTROPHIL ACCUMULATION IN THE SCN AFTER PSL. NEUTROPHIL DEPLETION BY INTRAPERITONEAL INJECTION OF LY6G ANTIBODY ATTENUATED PSL-INDUCED NEUROPATHIC PAIN. BOTH ANTI-MIP-2 AND SB225002 SUPPRESSED UP-REGULATION OF INFLAMMATORY CYTOKINES AND CHEMOKINES IN THE INJURED SCN. IN ADDITION, ACETYLATION OF HISTONE H3 [LYSINE (LYS9)-ACETYLATED HISTONE H3 (ACK9-H3)] ON THE PROMOTER REGION OF MIP-2 AND CXCR2 WAS INCREASED IN THE INJURED SCN AFTER PSL. EXPRESSION OF ACK9-H3 WAS OBSERVED IN THE NUCLEI OF NEUTROPHILS AND MACROPHAGES SURROUNDING THE EPINEURIUM. ADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID SUPPRESSED THE UP-REGULATION OF MIP-2 AND CXCR2 IN THE SCN AFTER PSL AND RESULTED IN THE PREVENTION OF PSL-INDUCED NEUROPATHIC PAIN. TAKEN TOGETHER, THESE RESULTS SHOW THAT AUGMENTATION OF THE MIP-2/CXCR2 AXIS BY HYPERACETYLATION OF HISTONE H3 ON THE PROMOTER REGION OF MIP-2 AND CXCR2 LOCATED IN THE INJURED PERIPHERAL NERVE ELICITS CHRONIC NEUROINFLAMMATION THROUGH NEUTROPHIL ACCUMULATION, LEADING TO NEUROPATHIC PAIN. 2012 8 201 26 ACTIVATING TRANSCRIPTION FACTOR 3 PROTECTS AGAINST PRESSURE-OVERLOAD HEART FAILURE VIA THE AUTOPHAGY MOLECULE BECLIN-1 PATHWAY. ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3), A CAMP RESPONSE ELEMENT-BINDING PROTEIN/ATF FAMILY TRANSCRIPTION FACTORS MEMBER, HAS BEEN IMPLICATED IN THE CARDIOVASCULAR AND INFLAMMATORY SYSTEM AND IS RAPIDLY INDUCED BY ISCHEMIC-REPERFUSION INJURIES. WE PERFORMED TRANSVERSE AORTIC BANDING (TAB) EXPERIMENTS USING ATF3 GENE-DELETED MICE (ATF3(-/-)) AND WILD-TYPE (WT) MICE TO DETERMINE WHAT EFFECT IT MIGHT HAVE ON HEART FAILURE INDUCED BY PRESSURE OVERLOADING. COMPARED WITH THE WT MICE, ATF3(-/-) MICE WERE FOUND BY ECHOCARDIOGRAPHY TO HAVE DECREASED LEFT VENTRICULAR CONTRACTILITY WITH LOSS OF NORMAL CARDIAC HYPERTROPHIC REMODELING. THE ATF3(-/-) MICE HAD GREATER NUMBERS OF TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE-MEDIATED DIGOXIGENIN-DEOXYURIDINE NICK-END LABELING-POSITIVE CELLS AND HIGHER LEVELS OF ACTIVATED CASPASE-3, AS WELL AS MORE APOPTOSIS. RESTORATION OF ATF3 EXPRESSION IN THE HEART OF ATF3(-/-) MICE BY ADENOVIRUS-INDUCED ATF3 TREATMENT SIGNIFICANTLY IMPROVED CARDIAC CONTRACTILITY AFTER TAB. THE RESULTS FROM MOLECULAR AND BIOCHEMICAL ANALYSES, INCLUDING CHROMATIN IMMUNE-PRECIPITATION AND IN VITRO /IN VIVO PROMOTER ASSAYS, SHOWED THAT ATF3 BOUND TO THE ATF/CAMP RESPONSE ELEMENT OF THE BECLIN-1 PROMOTER AND THAT ATF3 REDUCED AUTOPHAGY VIA SUPPRESSION OF THE BECLIN-1-DEPENDENT PATHWAY. FURTHERMORE, INFUSION OF TERT-BUTYLHYDROQUINONE (TBHQ), A SELECTIVE ATF3 INDUCER, INCREASED THE EXPRESSION OF ATF3 VIA THE NUCLEAR FACTOR ERYTHROID 2-RELATED TRANSCRIPTIONAL FACTOR, INHIBITED TAB-INDUCED CARDIAC DILATATION, AND INCREASED LEFT VENTRICULAR CONTRACTILITY, THEREBY RESCUING HEART FAILURE. OUR STUDY IDENTIFIED A NEW EPIGENETIC REGULATION MEDIATED BY THE STRESS-INDUCIBLE GENE ATF3 ON TAB-INDUCED CARDIAC DYSFUNCTION. THESE FINDINGS SUGGEST THAT THE ATF3 ACTIVATOR TBHQ MAY HAVE THERAPEUTIC POTENTIAL FOR THE TREATMENT OF PRESSURE-OVERLOAD HEART FAILURE INDUCED BY CHRONIC HYPERTENSION OR OTHER PRESSURE OVERLOAD MECHANISMS. 2014 9 1730 38 DYSREGULATION OF STEM CELL SIGNALING NETWORK DUE TO GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION IN GASTRIC CANCER. GENETIC FACTORS, HELICOBACTER PYLORI INFECTION, SALT OVER-UPTAKE, DECREASED VEGETABLE/FRUIT CONSUMPTION, SMOKING, AND METABOLIC SYNDROME ARE RISK FACTORS OF HUMAN GASTRIC CANCER. GERMLINE MUTATIONS OF CDH1 GENE, AND SNPS OF PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 AND RUNX3 GENES ARE ASSOCIATED WITH GASTRIC CANCER. HELICOBACTER PYLORI ACTIVATES CAGA-SHP2-ERK AND PEPTIDOGLYCAN-NOD1-NFKAPPAB SIGNALING CASCADES IN GASTRIC EPITHELIAL CELLS USING TYPE IV SECRETION SYSTEM, AND ALSO TRAF6-MAP3K7-NFKAPPAB AND TRAF6-MAP3K7-AP-1 SIGNALING CASCADES IN EPITHELIAL AND IMMUNE CELLS THROUGH LIPOPOLYSACCHARIDE RECOGNITION BY TLR2 OR TLR4. IL-1BETA, IL-6, IL-8, TNFALPHA AND IFNGAMMA ARE ELEVATED IN GASTRIC MUCOSA WITH HELICOBACTER PYLORI INFECTION. IL-6 AND TNFALPHA INDUCE UPREGULATION OF WNT5A AND WNT10B, RESPECTIVELY. WNT SIGNALS ARE TRANSDUCED TO BETA-CATENIN-TCF/LEF, RHOA, JNK, PKC, NFAT, AND NLK SIGNALING CASCADES. WNT-BETA-CATENIN-TCF/LEF SIGNALING INDUCES UPREGULATION OF MYC, CCND1, WISP1, FGF20, JAG1 AND DKK1 GENES. NOTCH SIGNALS ARE TRANSDUCED TO CSL-NICD-MAML AND NFKAPPAB SIGNALING CASCADES. FGF SIGNALS ARE TRANSDUCED TO ERK, PI3K-AKT, PKC, AND NFAT SIGNALING CASCADES. HELICOBACTER PYLORI INFECTION INDUCES SHH UPREGULATION IN PARIETAL CELL LINEAGE, WHILE BMP SIGNALS INDUCE IHH UPREGULATION IN PIT CELL LINEAGE. HEDGEHOG SIGNALS INDUCE UPREGULATION OF GLI1, PTCH1, CCND2, FOXL1, JAG2 AND SFRP1 GENES. JAG1 AND JAG2 ACTIVATE NOTCH SIGNALING, WHILE DKK1 AND SFRP1 INHIBIT WNT SIGNALING. STEM CELL SIGNALING NETWORK, CONSISTING OF WNT, NOTCH, FGF, HEDGEHOG AND BMP SIGNALING PATHWAYS, IS ACTIVATED DURING CHRONIC HELICOBACTER PYLORI INFECTION. EPIGENETIC SILENCING OF SFRP1 GENE OCCURS IN THE EARLIER STAGE OF CARCINOGENESIS IN THE STOMACH, WHILE AMPLIFICATION AND OVEREXPRESSION OF FGFR2 GENE IN THE LATER STAGE. DYSREGULATION OF THE STEM CELL SIGNALING NETWORK DUE TO THE ACCUMULATION OF GERMLINE MUTATION, SNP, HELICOBACTER PYLORI INFECTION, EPIGENETIC CHANGE AND GENETIC ALTERATION GIVES RISE TO GASTRIC CANCER. SNP TYPING AND CUSTOM-MADE MICROARRAY ANALYSES ON GENES ENCODING STEM CELL SIGNALING MOLECULES COULD BE UTILIZED FOR THE PERSONALIZED MEDICINE. 2007 10 864 24 CHROMOSOMAL INSTABILITY IN ORAL SQUAMOUS CELL CARCINOMA. ORAL SQUAMOUS CELL CARCINOMA (OSCC) DEMONSTRATES AN INCREASING RATE DUE TO HIGH RISK HUMAN PAPILLOMA VIRUS (HR-HPV) PERSISTENT INFECTION, AND ALSO TO CHRONIC CIGARETTE AND ALCOHOL CONSUMPTION. GROSS CHROMOSOMAL ALTERATIONS (POLYSOMY, ANEUPLOIDY, INTRA-CHROMOSOME REARRANGEMENTS) AND SPECIFIC GENE ABERRATIONS SUCH AS AMPLIFICATIONS, DELETIONS, POINT MUTATIONS COMBINED OR NOT WITH EPIGENETIC ONES (PROMOTER METHYLATIONS AND MIRNA DEREGULATIONS) ARE RESPONSIBLE FOR THE PROGRESSIVE TRANSFORMATION OF NORMAL SQUAMOUS CELL EPITHELIA TO THE CORRESPONDING MALIGNANT. CHROMOSOMAL INSTABILITY (CI) -BASED ON STRUCTURAL OR NUMERICAL ABNORMALITIES- LEADS TO SPECIFIC ABNORMAL KARYOTYPES COMBINED OR NOT WITH FUNCTIONAL SUPPRESSOR GENE INACTIVATION AND ONCOGENE OVERACTIVATION IN SOLID MALIGNANCIES, INCLUDING OSCC. EXTENSIVE CYTOGENETIC ANALYSES HAVE SHOWN THAT GROSS ALTERATIONS (GAINS/LOSSES) IN CHROMOSOMES 3, 4, 7, 8, 9, 11, 14, 17, 18, 19 AND ALSO 20 FORM DIFFERENT CI PATTERNS IN OSCC, WHICH IN CONJUNCTION WITH AN AGGRESSIVE PHENOTYPE (PRESENCE OF LYMPH NODAL METASTASIS) NEGATIVELY AFFECT THE PROGNOSIS IN THE CORRESPONDING PATIENTS. IN THE MAJORITY OF OSCC CASES, LOSS OF CHROMOSOMAL BANDS ARE ALMOST EQUALLY DETECTED COMPARED WITH GAINS REGARDING THE CHROMOSOMES REFERRED ABOVE. IN THE CURRENT SPECIAL MOLECULAR PAPER WE EXPLORED THE ROLE OF CI IN THE PROGRESSION AND BIOLOGICAL BEHAVIOR OF OSCCS. 2018 11 5867 34 SUPPRESSIVE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON HEPATITIS C VIRUS REPLICATION. THE HISTONE DEACETYLASE (HDAC) INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) HAS A CLINICAL PROMISE FOR TREATMENT OF CANCER INCLUDING HEPATOCELLULAR CARCINOMA (HCC). TO INVESTIGATE EFFECT OF SAHA ON HEPATITIS C VIRUS (HCV) REPLICATION, WE TREATED THE HCV REPLICON CELL OR6 WITH SAHA. HCV REPLICATION WAS SIGNIFICANTLY INHIBITED BY SAHA AT CONCENTRATIONS BELOW 1 MUM WITH NO CELLULAR TOXICITY. ANOTHER HDAC INHIBITOR, TRICOSTATIN A, ALSO SHOWED REDUCTION OF HCV REPLICATION. THE MICROARRAY ANALYSIS AND QUANTITATIVE RT-PCR DEMONSTRATED UP-REGULATION OF OSTEOPONTIN (OPN) AND DOWN-REGULATION OF APOLIPOPROTEIN-A1 (APO-A1) AFTER SAHA TREATMENT. DIRECT GENE INDUCTION OF OPN AND KNOCKDOWN OF APO-A1 ALSO SHOWED REDUCTION OF HCV REPLICATION. THE LIVER SPECIFIC MICRORNA-122, WHICH IS INVOLVED IN HCV REPLICATION, WAS NOT AFFECTED BY SAHA TREATMENT. THESE RESULTS SUGGEST THAT SAHA HAS SUPPRESSIVE EFFECT ON HCV REPLICATION THROUGH ALTERATIONS OF GENE EXPRESSION SUCH AS OPN AND APO-A1 IN HOST CELLS. EPIGENETIC TREATMENT WITH HDAC INHIBITORS MAY BE A NOVEL THERAPEUTIC APPROACH FOR DISEASES ASSOCIATED WITH HCV INFECTION SUCH AS CHRONIC HEPATITIS, LIVER CIRRHOSIS, AND HCC. 2013 12 1184 17 COOPERATIVE EPIGENETIC REMODELING BY TET2 LOSS AND NRAS MUTATION DRIVES MYELOID TRANSFORMATION AND MEK INHIBITOR SENSITIVITY. MUTATIONS IN EPIGENETIC MODIFIERS AND SIGNALING FACTORS OFTEN CO-OCCUR IN MYELOID MALIGNANCIES, INCLUDING TET2 AND NRAS MUTATIONS. CONCURRENT TET2 LOSS AND NRAS(G12D) EXPRESSION IN HEMATOPOIETIC CELLS INDUCED MYELOID TRANSFORMATION, WITH A FULLY PENETRANT, LETHAL CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), WHICH WAS SERIALLY TRANSPLANTABLE. TET2 LOSS AND NRAS MUTATION COOPERATIVELY LED TO DECREASE IN NEGATIVE REGULATORS OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) ACTIVATION, INCLUDING SPRY2, THEREBY CAUSING SYNERGISTIC ACTIVATION OF MAPK SIGNALING BY EPIGENETIC SILENCING. TET2/NRAS DOUBLE-MUTANT LEUKEMIA SHOWED PREFERENTIAL SENSITIVITY TO MAPK KINASE (MEK) INHIBITION IN BOTH MOUSE MODEL AND PATIENT SAMPLES. THESE DATA PROVIDE INSIGHTS INTO HOW EPIGENETIC AND SIGNALING MUTATIONS COOPERATE IN MYELOID TRANSFORMATION AND PROVIDE A RATIONALE FOR MECHANISM-BASED THERAPY IN CMML PATIENTS WITH THESE HIGH-RISK GENETIC LESIONS. 2018 13 2379 25 EPIGENETIC REGULATION OF WNT PATHWAY ANTAGONISTS IN HUMAN GLIOBLASTOMA MULTIFORME. EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES IS COMMON IN HUMAN CANCER. USING A LARGE-SCALE WHOLE-GENOME APPROACH IN AN EARLIER STUDY, THE AUTHORS IDENTIFIED EPIGENETICALLY SILENCED GENES WITH POTENTIAL TUMOR SUPPRESSOR FUNCTION IN GLIOBLASTOMA (GBM). THREE GENES IDENTIFIED IN THIS ANALYSIS-DKK1, SFRP1, AND WIF1-ARE POTENT INHIBITORS OF THE WNT SIGNAL TRANSDUCTION PATHWAY. HERE, THE AUTHORS CONFIRM DECREASED EXPRESSION OF THESE GENES IN GBM TUMOR TISSUE SAMPLES RELATIVE TO NONTUMOR BRAIN TISSUE SAMPLES USING REAL-TIME PCR. THEY THEN SHOW THAT EXPRESSION OF ALL 3 GENES IS RESTORED IN T98 GBM CELLS BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA), BUT ONLY DKK1 EXPRESSION IS RESTORED BY TREATMENT WITH THE DEMETHYLATING AGENT 5-AZACYTIDINE. BISULFITE SEQUENCING DID NOT REVEAL SIGNIFICANT METHYLATION IN THE PROMOTER REGION OF DKK1, WHEREAS HISTONE ACETYLATION AND CHROMATIN ACCESSIBILITY INCREASED SIGNIFICANTLY FOR ALL 3 GENES AFTER TSA TREATMENT. ECTOPIC EXPRESSION OF DKK1 SIGNIFICANTLY REDUCES COLONY FORMATION AND INCREASES CHEMOTHERAPY-INDUCED APOPTOSIS IN T98 CELLS. ECTOPIC EXPRESSION OF THE CANONICAL WNT PATHWAY INHIBITORS WIF1 AND SFRP1 SHOWS A RELATIVE LACK OF RESPONSE. CHRONIC WNT3A STIMULATION ONLY PARTIALLY REVERSES GROWTH SUPPRESSION AFTER DKK1 REEXPRESSION, WHEREAS A SPECIFIC INHIBITOR OF THE JNK PATHWAY SIGNIFICANTLY REVERSES THE EFFECT OF DKK1 REEXPRESSION ON COLONY FORMATION AND APOPTOSIS IN T98 CELLS. THESE RESULTS SUPPORT A POTENTIAL GROWTH-SUPPRESSIVE FUNCTION FOR EPIGENETICALLY SILENCED DKK1 IN GBM AND SUGGEST THAT DKK1 RESTORATION COULD MODULATE WNT SIGNALING THROUGH BOTH CANONICAL AND NONCANONICAL PATHWAYS. 2010 14 4918 23 PANCREATIC CANCER: FROM BENCH TO 5-YEAR SURVIVAL. PANCREATIC DUCTAL ADENOCARCINOMA IS ONE OF THE MOST AGGRESSIVE HUMAN MALIGNANCIES, WITH AN OVERALL 5-YEAR SURVIVAL RATE OF LESS THAN 4%. ON THE MOLECULAR LEVEL, AN INCREASING NUMBER OF GENETIC AND EPIGENETIC ALTERATIONS HAVE BEEN DISCOVERED, WITH A PARTICULAR FOCUS ON GROWTH FACTORS AND RELATED PATHWAYS. SMALL-MOLECULE TYROSINE KINASE INHIBITORS, ANTIBODIES, AND OTHER APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS TO TARGET THESE SIGNAL TRANSDUCTION PATHWAYS, AND FIRST CLINICAL TRIALS SHOW ENCOURAGING RESULTS. IN ADDITION, MOLECULAR ALTERATIONS HAVE BEEN IDENTIFIED THAT ENABLE THE CANCER CELLS TO INVADE THE PERINEURIUM AND THE RETROPERITONEAL SPACE, THUS EXPLAINING AT LEAST IN PART THE HIGH RATE OF LOCAL RECURRENCE AND THE SEVERE PAIN SYNDROME. TECHNICALLY, PANCREATIC SURGERY HAS ADVANCED, WITH ACCEPTABLE MORBIDITY AND MORTALITY RATES IN HIGH-VOLUME CENTERS. RANDOMIZED CONTROLLED TRIALS ARE INCREASINGLY CARRIED OUT TO DEFINE THE BEST PALLIATIVE AND ADJUVANT THERAPY FOR THIS DISEASE. TRANSLATIONAL RESEARCH COMBINED WITH CLINICAL TRIALS WILL HOPEFULLY LEAD TO IMPROVED SURVIVAL AND BETTER QUALITY OF LIFE FOR PANCREATIC CANCER PATIENTS IN THE FUTURE. 2006 15 604 23 BEYOND BROODING ON ONCOMETABOLIC HAVOC IN IDH-MUTANT GLIOMAS AND AML: CURRENT AND FUTURE THERAPEUTIC STRATEGIES. ISOCITRATE DEHYDROGENASES 1 AND 2 (IDH1,2), THE KEY KREBS CYCLE ENZYMES THAT GENERATE NADPH REDUCING EQUIVALENTS, UNDERGO HETEROZYGOUS MUTATIONS IN >70% OF LOW- TO MID-GRADE GLIOMAS AND ~20% OF ACUTE MYELOID LEUKEMIAS (AMLS) AND GAIN AN UNUSUAL NEW ACTIVITY OF REDUCING THE ALPHA-KETOGLUTARATE (ALPHA-KG) TO D-2 HYDROXYGLUTARATE (D-2HG) IN A NADPH-CONSUMING REACTION. THE ONCOMETABOLITE D-2HG, WHICH ACCUMULATES >35 MM, IS WIDELY ACCEPTED TO DRIVE A PROGRESSIVE ONCOGENESIS BESIDES EXACERBATING THE ALREADY INCREASED OXIDATIVE STRESS IN THESE CANCERS. MORE IMPORTANTLY, D-2HG COMPETES WITH ALPHA-KG AND INHIBITS A LARGE NUMBER OF ALPHA-KG-DEPENDENT DIOXYGENASES SUCH AS TET (TEN-ELEVEN TRANSLOCATION), JMJC DOMAIN-CONTAINING KDMS (HISTONE LYSINE DEMETHYLASES), AND THE ALKBH DNA REPAIR PROTEINS THAT ULTIMATELY LEAD TO HYPERMETHYLATION OF THE CPG ISLANDS IN THE GENOME. THE RESULTING CPG ISLAND METHYLATOR PHENOTYPE (CIMP) ACCOUNTS FOR MAJOR GENE EXPRESSION CHANGES INCLUDING THE SILENCING OF THE MGMT (O(6)-METHYLGUANINE DNA METHYLTRANSFERASE) REPAIR PROTEIN IN GLIOMAS. GLIOMA PATIENTS WITH IDH1 MUTATIONS ALSO SHOW BETTER THERAPEUTIC RESPONSES AND LONGER SURVIVAL, THE REASONS FOR WHICH ARE YET UNCLEAR. THERE HAS BEEN A GREAT SURGE IN DRUG DISCOVERY FOR CURTAILING THE MUTANT IDH ACTIVITIES, AND ARRESTING TUMOR PROLIFERATION; HOWEVER, GIVEN THE UNIQUE AND CHRONIC METABOLIC EFFECTS OF D-2HG, THE PROMISE OF THESE COMPOUNDS FOR GLIOMA TREATMENT IS UNCERTAIN. THIS COMPREHENSIVE REVIEW DISCUSSES THE BIOLOGY, CURRENT DRUG DESIGN AND OPPORTUNITIES FOR IMPROVED THERAPIES THROUGH EXPLOITABLE SYNTHETIC LETHALITY PATHWAYS, AND AN INTRIGUING ONCOMETABOLITE-INSPIRED STRATEGY FOR PRIMARY GLIOBLASTOMA. 2018 16 6758 36 WNT SIGNALING IN STEM CELL BIOLOGY AND REGENERATIVE MEDICINE. WNT FAMILY MEMBERS ARE SECRETED-TYPE GLYCOPROTEINS TO ORCHESTRATE EMBRYOGENESIS, TO MAINTAIN HOMEOSTASIS, AND TO INDUCE PATHOLOGICAL CONDITIONS. FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, AND ROR2 ARE TRANSMEMBRANE RECEPTORS TRANSDUCING WNT SIGNALS BASED ON LIGAND-DEPENDENT PREFERENTIALITY FOR CAVEOLIN- OR CLATHRIN-MEDIATED ENDOCYTOSIS. WNT SIGNALS ARE TRANSDUCED TO CANONICAL PATHWAY FOR CELL FATE DETERMINATION, AND TO NON-CANONICAL PATHWAYS FOR REGULATION OF PLANAR CELL POLARITY, CELL ADHESION, AND MOTILITY. MYC, CCND1, AXIN2, FGF20, WISP1, JAG1, DKK1 AND GLUCAGON ARE TARGET GENES OF CANONICAL WNT SIGNALING CASCADE, WHILE CD44, VIMENTIN AND STX5 ARE TARGET GENES OF NON-CANONICAL WNT SIGNALING CASCADES. HOWEVER, TARGET GENES OF WNT SIGNALING CASCADES ARE DETERMINED IN A CONTEXT-DEPENDENT MANNER DUE TO EXPRESSION PROFILE OF TRANSCRIPTION FACTORS AND EPIGENETIC STATUS. WNT SIGNALING CASCADES NETWORK WITH NOTCH, FGF, BMP AND HEDGEHOG SIGNALING CASCADES TO REGULATE THE BALANCE OF STEM CELLS AND PROGENITOR CELLS. HERE WNT SIGNALING IN EMBRYONIC STEM CELLS, NEURAL STEM CELLS, MESENCHYMAL STEM CELLS, HEMATOPOIETIC STEM CELLS, AND INTESTINAL STEM CELLS WILL BE REVIEWED. WNT3, WNT5A AND WNT10B ARE EXPRESSED IN UNDIFFERENTIATED HUMAN EMBRYONIC STEM CELLS, WHILE WNT6, WNT8B AND WNT10B IN ENDODERM PRECURSOR CELLS. WNT6 IS EXPRESSED IN INTESTINAL CRYPT REGION FOR STEM OR PROGENITOR CELLS. TNF/ALPHA-WNT10B SIGNALING IS A NEGATIVE FEEDBACK LOOP TO MAINTAIN HOMEOSTASIS OF ADIPOSE TISSUE AND GASTROINTESTINAL MUCOSA WITH CHRONIC INFLAMMATION. RECOMBINANT WNT PROTEIN OR WNT MIMETIC (CIRCULAR PEPTIDE, SMALL MOLECULE COMPOUND, OR RNA APTAMER) IN COMBINATION WITH NOTCH MIMETIC, FGF PROTEIN, AND BMP PROTEIN OPENS A NEW WINDOW TO TISSUE ENGINEERING FOR REGENERATIVE MEDICINE. 2008 17 1445 18 DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA ARISING IN AN OVARIAN MATURE CYSTIC TERATOMA. IMMATURE NEUROECTODERMAL TISSUE CAN BE FOUND IN THE OVARY AS PART OF AN IMMATURE TERATOMA OR AS PART OF A TERATOMA WITH MALIGNANT NEUROECTODERMAL TRANSFORMATION. SUCH LESIONS MAY CLOSELY RESEMBLE CENTRAL NERVOUS SYSTEM TUMORS, BUT THEIR BIOLOGIC SIMILARITY IS UNCLEAR. WE DESCRIBE AN 18-YR-OLD FEMALE WHO PRESENTED WITH ABDOMINAL PAIN CAUSED BY AN OVARIAN MASS WITH WIDESPREAD METASTASES. HISTOLOGY SHOWED A PRIMITIVE, HIGH-GRADE TUMOR ARISING IN THE BACKGROUND OF A MATURE TERATOMA. THE TUMOR WAS SOX10 POSITIVE, WITH FOCAL EXPRESSION OF GFAP, S100, NSE, AND SYNAPTOPHYSIN. MOLECULAR ANALYSIS DEMONSTRATED CO-AMPLIFICATION OF PDGFRA AND KIT, ALTERATIONS COMMON IN HIGH-GRADE GLIOMAS. BY WHOLE-GENOME METHYLATION PROFILING, IT CLUSTERED INTO THE "DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA, RTK1 SUBTYPE, SUBCLASS C" GROUP. DESPITE PROGRESSING THROUGH 2 LINES OF CHEMOTHERAPY WITH WIDESPREAD METASTATIC DISEASE, SHE ACHIEVED AN EXCELLENT RESPONSE TO CHEMOTHERAPY DIRECTED TOWARD AGGRESSIVE GERM CELL TUMORS. THIS CASE EMPHASIZES THE IMPORTANCE OF IMMUNOHISTOCHEMICAL, GENOMIC, AND EPIGENETIC ANALYSES TO ACCURATELY CLASSIFY THESE EXCEEDINGLY RARE TUMORS AND DETERMINE THE OPTIMAL THERAPY. 2023 18 1775 24 EBV IN T-/NK-CELL TUMORIGENESIS. EPSTEIN-BARR VIRUS (EBV), WHICH IS ASSOCIATED WITH B-CELL PROLIFERATIVE DISORDERS, ALSO TRANSFORMS T- OR NATURAL KILLER (NK)-LINEAGE CELLS AND HAS BEEN CONNECTED WITH VARIOUS T- OR NK (T/NK)-CELL MALIGNANCIES, SUCH AS EXTRANODAL NK/T-CELL LYMPHOMA-NASAL TYPE AND AGGRESSIVE NK-CELL LEUKEMIA. CHRONIC ACTIVE EBV (CAEBV) DISEASE , WHICH OCCURS MOST OFTEN IN CHILDREN AND YOUNG ADULTS IN EAST ASIA, IS AN EBV-ASSOCIATED T-/NK-CELL LYMPHOPROLIFERATIVE DISEASE. PATIENTS WITH CAEBV OFTEN PROGRESS TO OVERT LYMPHOMA OR LEUKEMIA OVER A LONG-TERM CLINICAL COURSE. EBV'S TRANSFORMING CAPACITY IN B CELLS IS WELL CHARACTERIZED, BUT THE MOLECULAR PATHOGENESIS OF CLONAL EXPANSION CAUSED BY EBV IN T/NK CELLS HAS NOT YET BEEN CLARIFIED. IN THE PRIMARY INFECTION, EBV INFECTS B CELLS AND EPITHELIAL CELLS AND MAY ALSO INFECT SOME T/NK CELLS. IN SOME INDIVIDUALS, BECAUSE OF POOR PRESENTATION BY SPECIFIC HUMAN LEUKOCYTE ANTIGENS OR THE GENETIC BACKGROUND, EBV-INFECTED T/NK CELLS EVADE HOST IMMUNITY AND SURVIVE. OCCASIONALLY, WITH THE HELP OF VIRAL ONCOGENES, EBV-ASSOCIATED T/NK LYMPHOPROLIFERATIVE DISEASES, SUCH AS CAEBV, MAY DEVELOP. THE SUBSEQUENT ACCUMULATION OF GENETIC MUTATIONS AND/OR EPIGENETIC MODIFICATIONS IN DRIVER GENES, SUCH AS DDX3X AND TP53, MAY LEAD TO OVERT LYMPHOMA AND LEUKEMIA. ACTIVATION-INDUCED CYTIDINE DEAMINASE AND THE APOBEC3 FAMILY, DRIVEN BY EBV INFECTION, MAY INDUCE CHROMOSOMAL RECOMBINATION AND SOMATIC MUTATIONS. 2018 19 1213 24 CPG ISLAND METHYLATION PATTERNS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON LEUKEMIA IN WESTERN COUNTRIES. IN CLL, A LARGE NUMBER OF GENES AFFECTING CANCER-RELATED PATHWAYS MAY BE DYSREGULATED BY EPIGENETIC SILENCING. WE ANALYSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION THE CPG ISLAND METHYLATION STATUS OF 15 WELL-CHARACTERISED CANCER-RELATED GENES IN 32 PATIENTS WITH CLL. ABERRANT METHYLATION IN THE SAMPLE OF PATIENTS WITH CLL WAS SHOWN FOR SECRETED FRIZZLED-RELATED PROTEIN 1 (68.8%), SECRETED FRIZZLED-RELATED PROTEIN 2 (65.6%), DEATH-ASSOCIATED PROTEIN KINASE 1 (50.0%), E-CADHERIN (21.9%), SECRETED FRIZZLED-RELATED PROTEIN 4 (15.6%), P15 (9.4%), P16 (6.3%), RETINOIC ACID RECEPTOR BETA2 (3.1%), SECRETED FRIZZLED-RELATED PROTEIN 5 (3.1%) AND TISSUE INHIBITOR OF MATRIX METALLOPROTEINASES 3 (3.1%). FOR HUMAN MUT-L HOMOLOG 1, O(6)-METHYLGUANINE DNA METHYLTRANSFERASE, P73, SUPPRESSOR OF CYTOKINE SIGNALLING 1 AND TISSUE INHIBITOR OF MATRIX METALLOPROTEINASES 2 NO HYPERMETHYLATION WAS DETECTED. HYPERMETHYLATION OF AT LEAST ONE GENE WAS OBSERVED IN 87.5% OF THE SAMPLES. OUR RESULTS SHOW THAT ABERRANT CPG ISLAND METHYLATION AFFECTING CANCER-RELATED PATHWAYS SUCH AS WNT SIGNALLING, REGULATION OF APOPTOSIS, CELL CYCLE CONTROL AND TISSUE INVASION IS A COMMON PHENOMENON IN CLL. EPIGENETIC DISTURBANCES MAY BE INVOLVED IN THE PATHOGENESIS OF CLL AND THUS MAY PROVIDE A MOLECULAR RATIONALE FOR THERAPEUTIC APPROACHES. 2009 20 4366 24 MIRNA-23A/CXCR4 REGULATES NEUROPATHIC PAIN VIA DIRECTLY TARGETING TXNIP/NLRP3 INFLAMMASOME AXIS. BACKGROUND: CHEMOKINE CXC RECEPTOR 4 (CXCR4) IN SPINAL GLIAL CELLS HAS BEEN IMPLICATED IN NEUROPATHIC PAIN. HOWEVER, THE REGULATORY CASCADES OF CXCR4 IN NEUROPATHIC PAIN REMAIN ELUSIVE. HERE, WE INVESTIGATED THE FUNCTIONAL REGULATORY ROLE OF MIRNAS IN THE PAIN PROCESS AND ITS INTERPLAY WITH CXCR4 AND ITS DOWNSTREAM SIGNALING. METHODS: MIRNAS AND CXCR4 AND ITS DOWNSTREAM SIGNALING MOLECULES WERE MEASURED IN THE SPINAL CORDS OF MICE WITH SCIATIC NERVE INJURY VIA PARTIAL SCIATIC NERVE LIGATION (PSNL). IMMUNOBLOTTING, IMMUNOFLUORESCENCE, IMMUNOPRECIPITATION, AND MAMMAL TWO-HYBRID AND BEHAVIORAL TESTS WERE USED TO EXPLORE THE DOWNSTREAM CXCR4-DEPENDENT SIGNALING PATHWAY. RESULTS: CXCR4 EXPRESSION INCREASED IN SPINAL GLIAL CELLS OF MICE WITH PSNL-INDUCED NEUROPATHIC PAIN. BLOCKING CXCR4 ALLEVIATED THE PAIN BEHAVIOR; CONTRARILY, OVEREXPRESSING CXCR4 INDUCED PAIN HYPERSENSITIVITY. MICRORNA-23A-3P (MIR-23A) DIRECTLY BOUNDS TO 3' UTR OF CXCR4 MRNA. PSNL-INDUCED NEUROPATHIC PAIN SIGNIFICANTLY REDUCED MRNA EXPRESSION OF MIR-23A. OVEREXPRESSION OF MIR-23A BY INTRATHECAL INJECTION OF MIR-23A MIMICS OR LENTIVIRUS REDUCED SPINAL CXCR4 AND PREVENTED PSNL-INDUCED NEUROPATHIC PAIN. IN CONTRAST, KNOCKDOWN OF MIR-23A BY INTRATHECAL INJECTION OF MIR-23A INHIBITOR OR LENTIVIRUS INDUCED PAIN-LIKE BEHAVIOR, WHICH WAS REDUCED BY CXCR4 INHIBITION. ADDITIONALLY, MIR-23A KNOCKDOWN OR CXCR4 OVEREXPRESSION IN NAIVE MICE COULD INCREASE THE THIOREDOXIN-INTERACTING PROTEIN (TXNIP), WHICH WAS ASSOCIATED WITH INDUCTION OF NOD-LIKE RECEPTOR PROTEIN 3 (NLRP3) INFLAMMASOME. INDEED, CXCR4 AND TXNIP WERE CO-EXPRESSED. THE MAMMAL TWO-HYBRID ASSAY REVEALED THE DIRECT INTERACTION BETWEEN CXCR4 AND TXNIP, WHICH WAS INCREASED IN THE SPINAL CORD OF PSNL MICE. IN PARTICULAR, INHIBITION OF TXNIP REVERSED PAIN BEHAVIOR ELICITED BY PSNL, MIR-23A KNOCKDOWN, OR CXCR4 OVEREXPRESSION. MOREOVER, MIR-23A OVEREXPRESSION OR CXCR4 KNOCKDOWN INHIBITED THE INCREASE OF TXNIP AND NLRP3 INFLAMMASOME IN PSNL MICE. CONCLUSIONS: MIR-23A, BY DIRECTLY TARGETING CXCR4, REGULATES NEUROPATHIC PAIN VIA TXNIP/NLRP3 INFLAMMASOME AXIS IN SPINAL GLIAL CELLS. EPIGENETIC INTERVENTIONS AGAINST MIR-23A, CXCR4, OR TXNIP MAY POTENTIALLY SERVE AS NOVEL THERAPEUTIC AVENUES IN TREATING PERIPHERAL NERVE INJURY-INDUCED NOCICEPTIVE HYPERSENSITIVITY. 2018