1 1260 135 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021 2 6584 28 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 3 2461 34 EPIGENETIC THERAPY AS A PUTATIVE MOLECULAR TARGET TO MODULATE B CELL BIOLOGY AND BEHAVIOR IN THE CONTEXT OF IMMUNOLOGICAL DISORDERS. HISTONE DEACETYLASE- (HDAC-) DEPENDENT EPIGENETIC MECHANISMS HAVE BEEN WIDELY EXPLORED IN THE LAST DECADE IN DIFFERENT TYPES OF MALIGNANCIES IN PRECLINICAL STUDIES. THIS EFFORT LED TO THE DISCOVERY AND DEVELOPMENT OF A RANGE OF NEW HDAC INHIBITORS (IHDAC) WITH DIFFERENT CHEMICAL PROPERTIES AND SELECTIVE ABILITIES. IN FACT, HEMATOLOGICAL MALIGNANCIES WERE THE FIRST ONES TO HAVE NEW IHDACS APPROVED FOR CLINICAL USE, SUCH AS VORINOSTAT AND ROMIDEPSIN FOR CUTANEOUS T CELL LYMPHOMA AND PANOBINOSTAT FOR MULTIPLE MYELOMA. BESIDES THESE PROMISING ALREADY APPROVED IHDACS, WE HIGHLIGHT A RANGE OF STUDIES FOCUSING ON THE HDAC-DEPENDENT EPIGENETIC CONTROL OF B CELL DEVELOPMENT, BEHAVIOR, AND/OR FUNCTION. HERE, WE HIGHLIGHT 21 IHDACS WHICH HAVE BEEN STUDIED IN THE LITERATURE IN THE CONTEXT OF B CELL DEVELOPMENT AND/OR DYSFUNCTION MOSTLY FOCUSED ON B CELL LYMPHOMAGENESIS. REGARDLESS, WE HAVE IDENTIFIED 55 CLINICAL TRIALS USING 6 OUT OF 21 IHDACS TO APPROACH THEIR PUTATIVE ROLES ON B CELL MALIGNANCIES; NONE OF THEM FOCUSES ON PERITONEAL B CELL POPULATIONS. SINCE CELLS BELONGING TO THIS PECULIAR BODY COMPARTMENT, NAMED B1 CELLS, MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTOIMMUNE PATHOLOGIES, SUCH AS LUPUS, A BETTER UNDERSTANDING OF THE HDAC-DEPENDENT EPIGENETIC MECHANISMS THAT CONTROL ITS BIOLOGY AND BEHAVIOR MIGHT SHED LIGHT ON IHDAC USE TO MANAGE THESE IMMUNOLOGICAL DYSFUNCTIONS. IN THIS SENSE, IHDACS MIGHT EMERGE AS A PROMISING NEW APPROACH FOR TRANSLATIONAL STUDIES IN THIS FIELD. IN THIS REVIEW, WE DISCUSS A PUTATIVE ROLE OF IHDACS IN THE MODULATION OF PERITONEAL B CELL SUBPOPULATION'S BALANCE AS WELL AS THEIR ROLE AS THERAPEUTIC AGENTS IN THE CONTEXT OF CHRONIC DISEASES MEDIATED BY PERITONEAL B CELLS. 2020 4 2446 21 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020 5 5688 40 SILENCING EFFECTS OF MUTANT RAS SIGNALLING ON TRANSCRIPTOMES. MUTATED GENES OF THE RAS FAMILY ENCODING SMALL GTP-BINDING PROTEINS DRIVE NUMEROUS CANCERS, INCLUDING PANCREATIC, COLON AND LUNG TUMORS. BESIDES THE NUMEROUS EFFECTS OF MUTANT RAS GENE EXPRESSION ON ABERRANT PROLIFERATION, TRANSFORMED PHENOTYPES, METABOLISM, AND THERAPY RESISTANCE, THE MOST STRIKING CONSEQUENCES OF CHRONIC RAS ACTIVATION ARE CHANGES OF THE GENETIC PROGRAM. BY PERFORMING SYSTEMATIC GENE EXPRESSION STUDIES IN CELLULAR MODELS THAT ALLOW COMPARISONS OF PRE-NEOPLASTIC WITH RAS-TRANSFORMED CELLS, WE AND OTHERS HAVE ESTIMATED THAT 7 PERCENT OR MORE OF ALL TRANSCRIPTS ARE ALTERED IN CONJUNCTION WITH THE EXPRESSION OF THE ONCOGENE. IN THIS CONTEXT, THE NUMBER OF UP-REGULATED TRANSCRIPTS APPROXIMATES THAT OF DOWN-REGULATED TRANSCRIPTS. WHILE UP-REGULATED TRANSCRIPTION FACTORS SUCH AS MYC, FOSL1, AND HMGA2 HAVE BEEN IDENTIFIED AND CHARACTERIZED AS RAS-RESPONSIVE DRIVERS OF THE ALTERED TRANSCRIPTOME, THE SUPPRESSED FACTORS HAVE BEEN LESS WELL STUDIED AS POTENTIAL REGULATORS OF THE GENETIC PROGRAM AND TRANSFORMED PHENOTYPE IN THE BREADTH OF THEIR OCCURRENCE. WE THEREFORE HAVE COLLECTED INFORMATION ON DOWNREGULATED RAS-RESPONSIVE FACTORS AND DISCUSS THEIR POTENTIAL ROLE AS TUMOR SUPPRESSORS THAT ARE LIKELY TO ANTAGONIZE ACTIVE CANCER DRIVERS. TO BETTER UNDERSTAND THE ACTIVE MECHANISMS THAT ENTAIL ANTI-RAS FUNCTION AND THOSE THAT LEAD TO LOSS OF TUMOR SUPPRESSOR ACTIVITY, WE FOCUS ON THE TUMOR SUPPRESSOR HREV107 (ALIAS PLAAT3 [PHOSPHOLIPASE A AND ACYLTRANSFERASE 3], PLA2G16 [PHOSPHOLIPASE A2, GROUP XVI] AND HRASLS3 [HRAS-LIKE SUPPRESSOR 3]). INACTIVATING HREV107 MUTATIONS IN TUMORS ARE EXTREMELY RARE, HENCE EPIGENETIC CAUSES MODULATED BY THE RAS PATHWAY ARE LIKELY TO LEAD TO DOWN-REGULATION AND LOSS OF FUNCTION. 2023 6 5899 39 T-CELL DYSFUNCTION IN CHRONIC LYMPHOCYTIC LEUKEMIA FROM AN EPIGENETIC PERSPECTIVE. CELLULAR IMMUNOTHERAPEUTIC APPROACHES SUCH AS CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) THUS FAR HAVE NOT MET THE HIGH EXPECTATIONS. THEREFORE IT IS ESSENTIAL TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS OF CLLINDUCED T-CELL DYSFUNCTION. EVEN THOUGH A SIGNIFICANT NUMBER OF STUDIES ARE AVAILABLE ON T-CELL FUNCTION AND DYSFUNCTION IN CLL PATIENTS, NONE EXAMINE DYSFUNCTION AT THE EPIGENOMIC LEVEL. IN NON-MALIGNANT T-CELL RESEARCH, EPIGENOMICS IS WIDELY EMPLOYED TO DEFINE THE DIFFERENTIATION PATHWAY INTO T-CELL EXHAUSTION. ADDITIONALLY, METABOLIC RESTRICTIONS IN THE TUMOR MICROENVIRONMENT THAT CAUSE T-CELL DYSFUNCTION ARE OFTEN MEDIATED BY EPIGENETIC CHANGES. WITH THIS REVIEW PAPER WE ARGUE THAT UNDERSTANDING THE EPIGENETIC (DYS)REGULATION IN T CELLS OF CLL PATIENTS SHOULD BE LEVELED TO THE KNOWLEDGE WE CURRENTLY HAVE OF THE NEOPLASTIC B CELLS THEMSELVES. THIS WILL PERMIT A COMPLETE UNDERSTANDING OF HOW THESE IMMUNE CELL INTERACTIONS REGULATE T- AND B-CELL FUNCTION. HERE WE RELATE THE CELLULAR AND PHENOTYPIC CHARACTERISTICS OF CLL-INDUCED T-CELL DYSFUNCTION TO EPIGENETIC STUDIES OF T-CELL REGULATION EMERGING FROM CHRONIC VIRAL INFECTION AND TUMOR MODELS. THIS PAPER PROPOSES A FRAMEWORK FOR FUTURE STUDIES INTO THE EPIGENETIC REGULATION OF CLL-INDUCED TCELL DYSFUNCTION, KNOWLEDGE THAT WILL HELP TO GUIDE IMPROVEMENTS IN THE UTILITY OF AUTOLOGOUS T-CELL BASED THERAPIES IN CLL. 2021 7 4558 30 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 8 3599 42 IMPORTANCE OF EPIGENETIC CHANGES IN CANCER ETIOLOGY, PATHOGENESIS, CLINICAL PROFILING, AND TREATMENT: WHAT CAN BE LEARNED FROM HEMATOLOGIC MALIGNANCIES? EPIGENETIC ALTERATIONS REPRESENT A KEY CANCER HALLMARK, EVEN IN HEMATOLOGIC MALIGNANCIES (HMS) OR BLOOD CANCERS, WHOSE CLINICAL FEATURES DISPLAY A HIGH INTER-INDIVIDUAL VARIABILITY. EVIDENCE ACCUMULATED IN RECENT YEARS INDICATES THAT INACTIVATING DNA HYPERMETHYLATION PREFERENTIALLY TARGETS THE SUBSET OF POLYCOMB GROUP (PCG) GENES THAT ARE REGULATORS OF DEVELOPMENTAL PROCESSES. CONVERSELY, ACTIVATING DNA HYPOMETHYLATION TARGETS ONCOGENIC SIGNALING PATHWAY GENES, BUT OUTCOMES OF BOTH EVENTS LEAD IN THE OVEREXPRESSION OF ONCOGENIC SIGNALING PATHWAYS THAT CONTRIBUTE TO THE STEM-LIKE STATE OF CANCER CELLS. ON THE BASIS OF RECENT EVIDENCE FROM POPULATION-BASED, CLINICAL AND EXPERIMENTAL STUDIES, WE HYPOTHESIZE THAT FACTORS ASSOCIATED WITH RISK FOR DEVELOPING A HM, SUCH AS METABOLIC SYNDROME AND CHRONIC INFLAMMATION, TRIGGER EPIGENETIC MECHANISMS TO INCREASE THE TRANSCRIPTIONAL EXPRESSION OF ONCOGENES AND ACTIVATE ONCOGENIC SIGNALING PATHWAYS. AMONG OTHERS, SIGNALING PATHWAYS ASSOCIATED WITH SUCH RISK FACTORS INCLUDE PRO-INFLAMMATORY NUCLEAR FACTOR KAPPAB (NF-KAPPAB), AND MITOGENIC, GROWTH, AND SURVIVAL JANUS KINASE (JAK) INTRACELLULAR NON-RECEPTOR TYROSINE KINASE-TRIGGERED PATHWAYS, WHICH INCLUDE SIGNALING PATHWAYS SUCH AS TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT), RAS GTPASES/MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS)/EXTRACELLULAR SIGNAL-RELATED KINASES (ERKS), PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR), AND BETA-CATENIN PATHWAYS. RECENT FINDINGS ON EPIGENETIC MECHANISMS AT WORK IN HMS AND THEIR IMPORTANCE IN THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES ARE HEREIN SUMMARIZED AND DISCUSSED. FURTHERMORE, THE ROLE OF EPIGENETIC PROCESSES IN THE DETERMINATION OF BIOLOGICAL IDENTITY, THE CONSEQUENCES FOR INTERINDIVIDUAL VARIABILITY IN DISEASE CLINICAL PROFILE, AND THE POTENTIAL OF EPIGENETIC DRUGS IN HMS ARE ALSO CONSIDERED. 2013 9 4837 27 ONCOGENIC GENE EXPRESSION AND EPIGENETIC REMODELING OF CIS-REGULATORY ELEMENTS IN ASXL1-MUTANT CHRONIC MYELOMONOCYTIC LEUKEMIA. MYELOID NEOPLASMS ARE CLONAL HEMATOPOIETIC STEM CELL DISORDERS DRIVEN BY THE SEQUENTIAL ACQUISITION OF RECURRENT GENETIC LESIONS. TRUNCATING MUTATIONS IN THE CHROMATIN REMODELER ASXL1 (ASXL1(MT)) ARE ASSOCIATED WITH A HIGH-RISK DISEASE PHENOTYPE WITH INCREASED PROLIFERATION, EPIGENETIC THERAPEUTIC RESISTANCE, AND POOR SURVIVAL OUTCOMES. WE PERFORMED A MULTI-OMICS INTERROGATION TO DEFINE GENE EXPRESSION AND CHROMATIN REMODELING ASSOCIATED WITH ASXL1(MT) IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). ASXL1(MT) ARE ASSOCIATED WITH A LOSS OF REPRESSIVE HISTONE METHYLATION AND INCREASE IN PERMISSIVE HISTONE METHYLATION AND ACETYLATION IN PROMOTER REGIONS. ASXL1(MT) ARE FURTHER ASSOCIATED WITH DE NOVO ACCESSIBILITY OF DISTAL ENHANCERS BINDING ETS TRANSCRIPTION FACTORS, TARGETING IMPORTANT LEUKEMOGENIC DRIVER GENES. CHROMATIN REMODELING OF PROMOTERS AND ENHANCERS IS STRONGLY ASSOCIATED WITH GENE EXPRESSION AND HETEROGENOUS AMONG OVEREXPRESSED GENES. THESE RESULTS PROVIDE A COMPREHENSIVE MAP OF THE TRANSCRIPTOME AND CHROMATIN LANDSCAPE OF ASXL1(MT) CMML, FORMING AN IMPORTANT FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES TARGETING ONCOGENIC CIS INTERACTIONS. 2022 10 1902 33 ENHANCED EXPRESSION OF THE NUCLEAR ENVELOPE LAP2 TRANSCRIPTIONAL REPRESSORS IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. EXTENSIVE RESEARCH IN RECENT YEARS HAS BROADENED THE FUNCTIONS OF NUCLEAR ENVELOPE PROTEINS BEYOND SIMPLY STABILIZING THE NUCLEUS ARCHITECTURE. PARTICULARLY, INTEGRAL NUCLEAR MEMBRANE PROTEINS, SUCH AS THE ALTERNATIVE SPLICED ISOFORMS OF LAMINA-ASSOCIATED POLYPEPTIDE 2 (LAP2), HAVE BEEN SHOWN TO BE IMPORTANT FOR THE INITIATION OF REPLICATION AND REPRESSION OF TRANSCRIPTION. THE LATTER IS REGULATED BY EPIGENETIC CHANGES, INDUCED BY THE BINDING OF LAP2BETA TO HISTONE DEACETYLASE-3 (HDAC3), RESULTING IN HISTONE H4 DEACETYLATION. INVOLVEMENT OF NUCLEAR ENVELOPE PROTEINS IN PATHOLOGICAL PROLIFERATIVE CONDITIONS, MAINLY THOSE INVOLVING ABNORMAL RECRUITMENT AND ACTIVATION OF HDACS, IS STILL UNKNOWN. IN THIS PAPER, WE SHOW THAT VARIOUS NUCLEAR ENVELOPE PROTEINS ARE HIGHLY EXPRESSED IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. SPECIFICALLY, RAPIDLY REPLICATING CELLS OF VARIOUS HEMATOLOGICAL MALIGNANCIES HIGHLY EXPRESS LAP2BETA, WHILE SLOWLY PROLIFERATING MALIGNANT CELLS OF CHRONIC MALIGNANT HEMATOLOGICAL DISEASES DO NOT. TAKING TOGETHER THE ELEVATED EXPRESSION OF LAP2BETA IN HIGHLY PROLIFERATIVE MALIGNANT CELLS WITH ITS KNOWN ABILITY TO MODIFY HISTONES THROUGH BINDING WITH HDAC3 RAISES THE POSSIBILITY OF ITS ROLE IN HEMATOLOGICAL MALIGNANCIES INVOLVING ABERRANT ACTIVITY OF HDAC3. BASED ON OUR PRESENTED RESULTS, WE BELIEVE THAT THE LAP2-HDAC REGULATORY PATHWAY SHOULD BE STUDIED AS A NEW TARGET FOR RATIONAL THERAPY. 2007 11 6595 29 TUMOR-SPECIFIC GROWTH FACTOR (TSGF): A FUTURISTIC TUMOR BIOMARKER IN EARLY DIAGNOSIS OF CANCER. DESPITE THE SIGNIFICANT IMPROVEMENT IN THE TREATMENT MODALITIES, CANCER IS ONE OF THE FASTEST-GROWING CHRONIC DISEASE CONDITIONS ALL OVER THE WORLD. GENETIC AND EPIGENETIC ALTERATIONS IN THE NORMAL PHYSIOLOGY OF THE CELL ARE THE KEY FACTOR FOR TUMOR DEVELOPMENT. THESE CHANGES CAN TRIGGER THE PRODUCTION OF ABNORMAL PROTEIN EXPRESSIONS THROUGH STIMULATION OF DIFFERENT SIGNALING PATHWAYS AND CAN DEEPLY AFFECT NORMAL CELL GROWTH AND PROLIFERATION. ANY ALTERED PROTEIN EXPRESSION, GENETIC VARIATION, MICRO-RNA OR POST-TRANSLATIONAL PROTEIN MODIFICATIONS THAT INDICATE TUMORIGENESIS CAN ACT AS AN EARLY SIGNAL TERMED AS BIOMARKER. CANCER, BEING A MULTISTEP PROCESS WITH ACCUMULATING GENETIC AND EPIGENETIC ALTERATIONS, COULD BE DETECTED EARLY WITH SUITABLE BIOMARKERS. THERE ARE SEVERAL PROTEINS SUCH AS AFP, CA-125, PSA, TROPONIN, CEA, OSTEOPONTIN, CA 19-9 THAT ACT AS BIOMARKERS WHICH HELP IN EARLY DETECTION, PROGNOSIS, AND MONITORING OF DISEASE PROGRESSION, A HUNT FOR NEWER BIOMARKERS WITH HIGHER SPECIFICITY AND SENSITIVITY IS STILL ONGOING. TUMOR-SPECIFIC GROWTH FACTOR (TSGF) IS ONE SUCH BUDDING AND PREVAILING TUMOR BIOMARKER USED FOR THE EARLY-STAGE DETECTION OF SEVERAL TYPES OF CARCINOMAS. TSGF IS A GENE THAT HELPS IN TUMOR ANGIOGENESIS AND GETS RELEASED DURING THE PRELIMINARY STAGES FROM CANCER CELLS THAT ENSURE THE VASCULAR PROLIFERATION OF THE SAME. IN THIS REVIEW, THE CLINICAL INVESTIGATIONS OF TSGF IN DIFFERENT KINDS OF MALIGNANCY IS DISCUSSED IN DETAIL AND SUGGESTS THE POSSIBILITY OF USING TSGF AS A BIOMARKER IN EARLY DIAGNOSIS OF CANCER. 2023 12 3823 33 INVESTIGATING THE EFFECTS OF A SYNTHETIC CANNABINOID ON THE PATHOGENESIS OF LEUKEMIA AND LEUKEMIC STEM CELLS: A NEW THERAPEUTIC APPROACH. THE POPULARITY AND USAGE OF SYNTHETIC CANNABINOIDS (SCS) ARE INCREASING DUE TO THEIR EASY ACCESSIBILITY AND PSYCHOACTIVE EFFECTS WORLDWIDE. STUDIES ON CANNABINOIDS ON LEUKEMIC STEM CELLS (LSC) AND HEMATOPOIETIC STEM CELLS (HSCS), WHICH ARE THE PRECURSORS OF LEUKEMIA CELLS, GENERALLY DEPEND ON THE NATURAL CANNABINOID DELTA-9-THC. AS THERE IS ONLY A LIMITED NUMBER OF STUDIES FOCUSING ON THE RESULTS OF SC APPLICATIONS, THE REFLECTIONS UPON LSCS HAVE TO BE CLARIFIED. IN THIS STUDY, BIOLOGICAL RESPONSES AND ANTILEUKEMIC EFFECTS OF JWH-018-ONE OF THE FIRST PRODUCED AND WIDELY USED SCS-WERE EVALUATED UPON LEUKEMIA CELLS. WHETHER JWH-018 EXHIBITED A PREVENTIVE EFFECT ON BOTH LEUKEMIC AND HSCS WAS EVALUATED BY PRESENTING A THERAPEUTIC APPROACH FOR THE FIRST TIME IN THE LITERATURE. CELLS WERE ANALYZED IN CASE OF CELL PROLIFERATION, APOPTOSIS, AND TRANSCRIPTIONAL EXPRESSION PROFILING OF SOME SIGNIFICANT JAK/STAT AND AKT/MTOR PATHWAYS, APOPTOTIC, CELL CYCLE REGULATION, AND EPIGENETIC CHROMATIN REMODELING-RELATED GENES FOLLOWING JWH-018 TREATMENT. IN CONCLUSION, HOWEVER, FURTHER STUDIES ARE STILL NEEDED UPON BOTH HSCS AND LSCS TO ILLUMINATE THE EFFECTS OF SCS ON LEUKEMOGENESIS ON CHRONIC MYELOID LEUKEMIA (CML) MORE CLEARLY; WE CONSIDER THAT THE JWH-018 CAN PROVIDE A THERAPEUTIC EFFECT ON THE PATHOGENESIS OF LEUKEMIA AND PARTICULARLY UPON LSCS AND SCS MIGHT HAVE THERAPEUTIC POTENTIAL IN ADDITION TO CURRENT THERAPY. 2022 13 2533 32 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 14 5433 25 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION. 2002 15 5288 21 PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE. THERE IS GROWING EVIDENCE FOR A ROLE FOR EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN MOST CASES OFAUTOIMMUNE DISEASE THE PRECISE EPIGENETIC MECHANISM INVOLVED REMAINS TO BE RESOLVED, HOWEVER DNA HYPOMETHYLATION ACCOMPANIED BY HYPOACETYLATION OFHISTONE H3/H4 IS COMMONLY OBSERVED. DUE TO THE REVERSIBLE NATURE OF EPIGENETIC MARKS THEIR MAINTENANCE ENZYMES SUCH AS DNA METHYLTRANSFERASES (DNMTS), HISTONE DEACETYLASES (HDACS) AND HISTONE LYSINE METHYLTRANSFERASES (HKMT) ARE ATTRACTIVE DRUG TARGETS. SMALL MOLECULE INHIBITORS OF HISTONE MODIFICATION AND DNA METHYLATION MAINTENANCE ARE INCREASINGLY BECOMING AVAILABLE AND WILL BE USEFUL CHEMICAL BIOLOGICAL TOOLS TO DISSECT EPIGENETIC MECHANISMS IN THESE DISEASES. HOWEVER, ALTHOUGH EPIGENETIC THERAPIES USED IN CANCER TREATMENT ARE A PROMISING STARTING POINT FOR THE EXPLORATION OF AUTOIMMUNE DISEASE TREATMENT, THERE IS A REQUIREMENT FOR MORE SPECIFIC AND LESS TOXIC AGENTS FOR THESE CHRONIC DISEASES OR FOR USE AS CHEMOPREVENTATIVE AGENTS. 2011 16 4414 28 MOLECULAR AND CELLULAR MECHANISMS OF PROPOLIS AND ITS POLYPHENOLIC COMPOUNDS AGAINST CANCER. IN RECENT YEARS, INTEREST IN NATURAL PRODUCTS SUCH AS ALTERNATIVE SOURCES OF PHARMACEUTICALS FOR NUMEROUS CHRONIC DISEASES, INCLUDING TUMORS, HAS BEEN RENEWED. PROPOLIS, A NATURAL PRODUCT COLLECTED BY HONEYBEES, AND POLYPHENOLIC/FLAVONOID PROPOLIS-RELATED COMPONENTS MODULATE ALL STEPS OF THE CANCER PROGRESSION PROCESS. ANTICANCER ACTIVITY OF PROPOLIS AND ITS COMPOUNDS RELIES ON VARIOUS MECHANISMS: CELL-CYCLE ARREST AND ATTENUATION OF CANCER CELLS PROLIFERATION, REDUCTION IN THE NUMBER OF CANCER STEM CELLS, INDUCTION OF APOPTOSIS, MODULATION OF ONCOGENE SIGNALING PATHWAYS, INHIBITION OF MATRIX METALLOPROTEINASES, PREVENTION OF METASTASIS, ANTI-ANGIOGENESIS, ANTI-INFLAMMATORY EFFECTS ACCOMPANIED BY THE MODULATION OF THE TUMOR MICROENVIRONMENT (BY MODIFYING MACROPHAGE ACTIVATION AND POLARIZATION), EPIGENETIC REGULATION, ANTIVIRAL AND BACTERICIDAL ACTIVITIES, MODULATION OF GUT MICROBIOTA, AND ATTENUATION OF CHEMOTHERAPY-INDUCED DELETERIOUS SIDE EFFECTS. INGREDIENTS FROM PROPOLIS ALSO "SENSITIZE" CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS, LIKELY BY BLOCKING THE ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB). IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE RELATED TO THE THE EFFECTS OF FLAVONOIDS AND OTHER POLYPHENOLIC COMPOUNDS FROM PROPOLIS ON TUMOR GROWTH AND METASTASIZING ABILITY, AND DISCUSS POSSIBLE MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE MODULATION OF INFLAMMATORY PATHWAYS AND CELLULAR PROCESSES THAT AFFECT SURVIVAL, PROLIFERATION, INVASION, ANGIOGENESIS, AND METASTASIS OF THE TUMOR. 2022 17 5785 28 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 18 3762 34 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER. 2022 19 1309 41 DEFINING AND TARGETING PATTERNS OF T CELL DYSFUNCTION IN INBORN ERRORS OF IMMUNITY. INBORN ERRORS OF IMMUNITY (IEIS) ARE A GROUP OF MORE THAN 450 MONOGENIC DISORDERS THAT IMPAIR IMMUNE DEVELOPMENT AND FUNCTION. A SUBSET OF IEIS BLEND INCREASED SUSCEPTIBILITY TO INFECTION, AUTOIMMUNITY, AND MALIGNANCY AND ARE KNOWN COLLECTIVELY AS PRIMARY IMMUNE REGULATORY DISORDERS (PIRDS). WHILE MANY ASPECTS OF IMMUNE FUNCTION ARE ALTERED IN PIRDS, ONE KEY IMPACT IS ON T-CELL FUNCTION. BY THEIR NATURE, PIRDS PROVIDE UNIQUE INSIGHTS INTO HUMAN T-CELL SIGNALING; ALTERATIONS IN INDIVIDUAL SIGNALING MOLECULES TUNE DOWNSTREAM SIGNALING PATHWAYS AND EFFECTOR FUNCTION. QUANTIFYING T-CELL DYSFUNCTION IN PIRDS AND THE UNDERLYING CAUSATIVE MECHANISMS IS CRITICAL TO IDENTIFYING EXISTING THERAPIES AND POTENTIAL NOVEL THERAPEUTIC TARGETS TO TREAT OUR RARE PATIENTS AND GAIN DEEPER INSIGHT INTO THE BASIC MECHANISMS OF T-CELL FUNCTION. THOUGH THERE ARE MANY TYPES OF T-CELL DYSFUNCTION, HERE WE WILL FOCUS ON T-CELL EXHAUSTION, A KEY PATHOPHYSIOLOGICAL STATE. EXHAUSTION HAS BEEN DESCRIBED IN BOTH HUMAN AND MOUSE MODELS OF DISEASE, WHERE THE CHRONIC PRESENCE OF ANTIGEN AND INFLAMMATION (E.G., CHRONIC INFECTION OR MALIGNANCY) INDUCES A STATE OF ALTERED IMMUNE PROFILE, TRANSCRIPTIONAL AND EPIGENETIC STATES, AS WELL AS IMPAIRED T-CELL FUNCTION. SINCE A SUBSET OF PIRDS AMPLIFY T-CELL RECEPTOR (TCR) SIGNALING AND/OR INFLAMMATORY CYTOKINE SIGNALING CASCADES, IT IS POSSIBLE THAT THEY COULD INDUCE T-CELL EXHAUSTION BY GENETICALLY MIMICKING CHRONIC INFECTION. HERE, WE REVIEW THE FUNDAMENTALS OF T-CELL EXHAUSTION AND ITS POSSIBLE ROLE IN IEIS IN WHICH GENETIC MUTATIONS MIMIC PROLONGED OR AMPLIFIED T-CELL RECEPTOR AND/OR CYTOKINE SIGNALING. GIVEN THE POTENTIAL INSIGHT FROM THE MANY FORMS OF PIRDS IN UNDERSTANDING T-CELL FUNCTION AND THE CHALLENGES IN OBTAINING PRIMARY CELLS FROM THESE RARE DISORDERS, WE ALSO DISCUSS ADVANCES IN CRISPR-CAS9 GENOME-EDITING TECHNOLOGIES AND POTENTIAL APPLICATIONS TO EDIT HEALTHY DONOR T CELLS THAT COULD FACILITATE FURTHER STUDY OF MECHANISMS OF IMMUNE DYSFUNCTIONS IN PIRDS. EDITING T CELLS TO MATCH PIRD PATIENT GENETIC VARIANTS WILL ALLOW INVESTIGATIONS INTO THE MECHANISMS UNDERPINNING STATES OF DYSREGULATED T-CELL FUNCTION, INCLUDING T-CELL EXHAUSTION. 2022 20 6421 29 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES. 2018