1 6002 115 THE ADAPTIVE BACTERIAL IMMUNE SYSTEM CRISPR-CAS AND ITS THERAPEUTIC POTENTIAL. THE BACTERIAL CRISPR-CAS-SYSTEM IS AN ADAPTIVE AND INHERITABLE IMMUNE SYSTEM FOR THE DEFENSE AGAINST INVASIVE GENETIC ELEMENTS SUCH AS VIRAL DNA OR PLASMIDS. CRISPR-CAS IMMUNITY ACTS BY INTEGRATING SHORT SEQUENCES OF NON-SELF DNA IN THE CELL'S CRISPR LOCUS WHICH ALLOWS THE CELL TO RECOGNIZE, TO REMEMBER AND TO DESTROY THE INVASIVE ELEMENT. IN THE LAST YEARS THE TYPE-II-SYSTEM CRISPR-CAS9 WAS DEVELOPED AS A POWERFUL AND UNIVERSAL TOOL FOR THE SEQUENCE-SPECIFIC MODIFICATION OF THE GENOME ALSO KNOWN AS GENOME EDITING. TYPE-II-SYSTEMS RELY SOLELY ON ONE SINGLE PROTEIN, CAS9, AND A NON-CODING, TRANS-ACTIVATING RNA THAT LEADS THE CAS9 PROTEIN TO ITS TARGET DNA. THE RNA-GUIDED MOLECULAR SCISSOR CAS9 IS PREDESTINATED TO CORRECT MUTATED GENES IN LINE WITH A GENE THERAPY AND TO HEAL CHRONIC DISEASES LIKE HIV INFECTIONS OR VIRUS-INDUCED FORMS OF CANCER VIA DELETING VIRAL DNA THAT IS INTEGRATED AS A PROVIRUS IN THE HOST'S GENOME. IN ADDITION, CATALYTICALLY INACTIVE CAS9 VARIANTS (DCAS9) FUSED TO EFFECTOR DOMAINS CAN BE USED TO SPECIFICALLY TAG GENOME SECTIONS, REGULATE GENE EXPRESSION AND MODIFY EPIGENETIC MARKERS. 2017 2 5433 21 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 3 6584 25 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 4 5153 25 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 5 102 24 A REGULATORY ROLE FOR CHD2 IN MYELOPOIESIS. THE TRANSCRIPTIONAL PROGRAM THAT DICTATES HAEMATOPOIETIC CELL FATE AND DIFFERENTIATION REQUIRES AN EPIGENETIC REGULATORY AND MEMORY FUNCTION, PROVIDED BY A NETWORK OF EPIGENETIC FACTORS THAT REGULATE DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS AND CHROMATIN STRUCTURE. DISTURBED EPIGENETIC REGULATION CAUSES PERTURBATIONS IN THE BLOOD CELL DIFFERENTIATION PROGRAM THAT RESULTS IN VARIOUS TYPES OF HAEMATOPOIETIC DISORDERS. THUS, ACCURATE EPIGENETIC REGULATION IS ESSENTIAL FOR FUNCTIONAL HAEMATOPOIESIS. IN THIS STUDY, WE USED A CRISPR-CAS9 SCREENING APPROACH TO IDENTIFY NEW EPIGENETIC REGULATORS IN MYELOID DIFFERENTIATION. WE DESIGNED A CHROMATIN-UMI CRISPR GUIDE LIBRARY TARGETING 1092 EPIGENETIC REGULATORS. PHORBOL 12-MYRISTATE 13-ACETATE (PMA) TREATMENT OF THE CHRONIC MYELOID LEUKAEMIA CELL LINE K-562 WAS USED AS A MEGAKARYOCYTIC MYELOID DIFFERENTIATION MODEL. BOTH PREVIOUSLY DESCRIBED DEVELOPMENTAL EPIGENETIC REGULATORS AND NOVEL FACTORS WERE IDENTIFIED IN OUR SCREEN. IN THIS STUDY, WE VALIDATED AND CHARACTERIZED A ROLE FOR THE CHROMATIN REMODELLER CHD2 IN MYELOID PROLIFERATION AND MEGAKARYOCYTIC DIFFERENTIATION. 2020 6 3762 30 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 7 2568 24 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022 8 6230 18 THE LONG NONCODING RNA LANDSCAPE IN HYPOXIC AND INFLAMMATORY RENAL EPITHELIAL INJURY. LONG NONCODING RNAS (LNCRNAS) ARE EMERGING AS KEY SPECIES-SPECIFIC REGULATORS OF CELLULAR AND DISEASE PROCESSES. TO IDENTIFY POTENTIAL LNCRNAS RELEVANT TO ACUTE AND CHRONIC RENAL EPITHELIAL INJURY, WE PERFORMED UNBIASED WHOLE TRANSCRIPTOME PROFILING OF HUMAN PROXIMAL TUBULAR EPITHELIAL CELLS (PTECS) IN HYPOXIC AND INFLAMMATORY CONDITIONS. RNA SEQUENCING REVEALED THAT THE PROTEIN-CODING AND NONCODING TRANSCRIPTOMIC LANDSCAPE DIFFERED BETWEEN HYPOXIA-STIMULATED AND CYTOKINE-STIMULATED HUMAN PTECS. HYPOXIA- AND INFLAMMATION-MODULATED LNCRNAS WERE PRIORITIZED FOR FOCUSED FOLLOWUP ACCORDING TO THEIR DEGREE OF INDUCTION BY THESE STRESS STIMULI, THEIR EXPRESSION IN HUMAN KIDNEY TISSUE, AND WHETHER EXPOSURE OF HUMAN PTECS TO PLASMA OF CRITICALLY ILL SEPSIS PATIENTS WITH ACUTE KIDNEY INJURY MODULATED THEIR EXPRESSION. FOR THREE LNCRNAS (MIR210HG, LINC-ATP13A4-8, AND LINC-KIAA1737-2) THAT FULFILLED OUR CRITERIA, WE VALIDATED THEIR EXPRESSION PATTERNS, EXAMINED THEIR LOCI FOR CONSERVATION AND SYNTENY, AND DEFINED THEIR ASSOCIATED EPIGENETIC MARKS. THE LNCRNA LANDSCAPE CHARACTERIZED HERE PROVIDES INSIGHTS INTO NOVEL TRANSCRIPTOMIC VARIATIONS IN THE RENAL EPITHELIAL CELL RESPONSE TO HYPOXIC AND INFLAMMATORY STRESS. 2015 9 6209 29 THE INTERFERON-STIMULATED GENE TRIM22: A DOUBLE-EDGED SWORD IN HIV-1 INFECTION. INFECTION OF TARGET CELLS BY THE HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 (HIV-1) IS HAMPERED BY CONSTITUTIVELY EXPRESSED HOST CELL PROTEINS PREVENTING OR CURTAILING VIRUS REPLICATION AND THEREFORE DEFINED AS "RESTRICTION FACTORS". AMONG THEM, MEMBERS OF THE TRIPARTITE MOTIF (TRIM) FAMILY HAVE EMERGED AS IMPORTANT PLAYERS ENDOWED WITH BOTH ANTIVIRAL EFFECTS AND MODULATORY CAPACITY OF THE INNATE IMMUNE RESPONSE. TRIM5ALPHA AND TRIM19 (I.E. PROMYELOCYTIC LEUKEMIA, PML) ARE AMONG THE BEST-CHARACTERIZED FAMILY MEMBERS; HOWEVER, IN THIS REVIEW WE WILL FOCUS ON THE POTENTIAL ROLE OF ANOTHER FAMILY MEMBER, I.E. TRIM22, A FACTOR STRONGLY INDUCED BY INTERFERON STIMULATION, IN HIV INFECTION IN VIVO AND IN VITRO IN THE CONTEXT OF ITS BROADER ANTIVIRAL EFFECTS. WE WILL ALSO FOCUS ON THE POTENTIAL ROLE OF TRIM22 IN HIV-1-INFECTED INDIVIDUALS SPECULATING ON ITS DUAL ROLE IN CONTROLLING VIRUS REPLICATION AND MORE COMPLEX ROLE IN CHRONIC INFECTION. AT THE MOLECULAR LEVELS, WE WILL REVIEW THE EVIDENCE IN FAVOR OF A RELEVANT ROLE OF TRIM22 AS EPIGENETIC INHIBITOR OF HIV-1 TRANSCRIPTION ACTING BY PREVENTING THE BINDING OF THE HOST CELL TRANSCRIPTION FACTOR SP1 TO THE VIRAL PROMOTER. THESE EVIDENCES SUGGEST THAT TRIM22 SHOULD BE CONSIDERED A POTENTIAL NEW PLAYER IN EITHER THE ESTABLISHMENT OR MAINTENANCE OF HIV-1 RESERVOIRS OF LATENTLY INFECTED CELLS UNAFFECTED BY COMBINATION ANTIRETROVIRAL THERAPY. 2018 10 5688 25 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 11 6421 30 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 12 4866 26 ORTHOGONAL CRISPR SCREENS TO IDENTIFY TRANSCRIPTIONAL AND EPIGENETIC REGULATORS OF HUMAN CD8 T CELL FUNCTION. THE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPIES IS STRONGLY ASSOCIATED WITH TRANSCRIPTIONAL AND EPIGENETIC STATE. THUS, TECHNOLOGIES TO DISCOVER REGULATORS OF T CELL GENE NETWORKS AND THEIR CORRESPONDING PHENOTYPES HAVE GREAT POTENTIAL TO IMPROVE THE EFFICACY OF T CELL THERAPIES. WE DEVELOPED POOLED CRISPR SCREENING APPROACHES WITH COMPACT EPIGENOME EDITORS TO SYSTEMATICALLY PROFILE THE EFFECTS OF ACTIVATION AND REPRESSION OF 120 TRANSCRIPTION FACTORS AND EPIGENETIC MODIFIERS ON HUMAN CD8+ T CELL STATE. THESE SCREENS NOMINATED KNOWN AND NOVEL REGULATORS OF T CELL PHENOTYPES WITH BATF3 EMERGING AS A HIGH CONFIDENCE GENE IN BOTH SCREENS. WE FOUND THAT BATF3 OVEREXPRESSION PROMOTED SPECIFIC FEATURES OF MEMORY T CELLS SUCH AS INCREASED IL7R EXPRESSION AND GLYCOLYTIC CAPACITY, WHILE ATTENUATING GENE PROGRAMS ASSOCIATED WITH CYTOTOXICITY, REGULATORY T CELL FUNCTION, AND T CELL EXHAUSTION. IN THE CONTEXT OF CHRONIC ANTIGEN STIMULATION, BATF3 OVEREXPRESSION COUNTERED PHENOTYPIC AND EPIGENETIC SIGNATURES OF T CELL EXHAUSTION. CAR T CELLS OVEREXPRESSING BATF3 SIGNIFICANTLY OUTPERFORMED CONTROL CAR T CELLS IN BOTH IN VITRO AND IN VIVO TUMOR MODELS. MOREOVER, WE FOUND THAT BATF3 PROGRAMMED A TRANSCRIPTIONAL PROFILE THAT CORRELATED WITH POSITIVE CLINICAL RESPONSE TO ADOPTIVE T CELL THERAPY. FINALLY, WE PERFORMED CRISPR KNOCKOUT SCREENS WITH AND WITHOUT BATF3 OVEREXPRESSION TO DEFINE CO-FACTORS AND DOWNSTREAM FACTORS OF BATF3, AS WELL AS OTHER THERAPEUTIC TARGETS. THESE SCREENS POINTED TO A MODEL WHERE BATF3 INTERACTS WITH JUNB AND IRF4 TO REGULATE GENE EXPRESSION AND ILLUMINATED SEVERAL OTHER NOVEL TARGETS FOR FURTHER INVESTIGATION. 2023 13 1309 34 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 14 6059 30 THE DEVELOPMENT OF A SENSITIVE FLUORESCENT PROTEIN-BASED TRANSCRIPT REPORTER FOR HIGH THROUGHPUT SCREENING OF NEGATIVE MODULATORS OF LNCRNAS. WHILE THE HUMAN GENOME IS PERVASIVELY TRANSCRIBED, <2% OF THE HUMAN GENOME IS TRANSCRIBED INTO PROTEIN-CODING MRNAS, LEAVING MOST OF THE TRANSCRIPTS AS NONCODING RNAS, SUCH AS MICRORNAS AND LONG-NONCODING RNAS (LNCRNAS), WHICH ARE CRITICAL COMPONENTS OF EPIGENETIC REGULATION. LNCRNAS ARE EMERGING AS CRITICAL REGULATORS OF GENE EXPRESSION AND GENOMIC STABILITY. HOWEVER, IT REMAINS LARGELY UNKNOWN ABOUT HOW LNCRNAS ARE REGULATED. HERE, WE DEVELOP A HIGHLY SENSITIVE AND DYNAMIC REPORTER THAT ALLOWS US TO IDENTIFY AND/OR MONITOR NEGATIVE MODULATORS OF LNCRNA TRANSCRIPT LEVELS IN A HIGH THROUGHPUT FASHION. SPECIFICALLY, WE ENGINEER A FLUORESCENT FUSION PROTEIN BY FUSING THREE COPIES OF THE PEST DESTRUCTION DOMAIN OF MOUSE ORNITHINE DECARBOXYLASE (MODC) TO THE C-TERMINAL END OF THE CODON-OPTIMIZED BILIRUBIN-INDUCIBLE FLUORESCENT PROTEIN, DESIGNATED AS DBIFP, AND SHOW THAT THE DBIFP PROTEIN IS HIGHLY DESTABILIZED, COMPARED WITH THE COMMONLY-USED EGFP PROTEIN. WE FURTHER DEMONSTRATE THAT THE DBIFP SIGNAL IS EFFECTIVELY DOWN-REGULATED WHEN THE DBIFP AND MOUSE LNCRNA H19 CHIMERIC TRANSCRIPT IS SILENCED BY MOUSE H19-SPECIFIC SIRNAS. THEREFORE, OUR RESULTS STRONGLY SUGGEST THAT THE DBIFP FUSION PROTEIN MAY SERVE AS A SENSITIVE AND DYNAMIC TRANSCRIPT REPORTER TO MONITOR THE INHIBITION OF LNCRNAS BY MICRORNAS, SYNTHETIC REGULATORY RNA MOLECULES, RNA BINDING PROTEINS, AND/OR SMALL MOLECULE INHIBITORS SO THAT NOVEL AND EFFICACIOUS INHIBITORS TARGETING THE EPIGENETIC CIRCUIT CAN BE DISCOVERED TO TREAT HUMAN DISEASES SUCH AS CANCER AND OTHER CHRONIC DISORDERS. 2018 15 6766 26 ZINC METALLOPROTEINS IN EPIGENETICS AND THEIR CROSSTALK. MORE THAN HALF A CENTURY AGO, ZINC WAS ESTABLISHED AS AN ESSENTIAL MICRONUTRIENT FOR NORMAL HUMAN PHYSIOLOGY. IN SILICO DATA SUGGEST THAT ABOUT 10% OF THE HUMAN PROTEOME POTENTIALLY BINDS ZINC. MANY PROTEINS WITH ZINC-BINDING DOMAINS (ZBDS) ARE INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS, WHICH REGULATE TRANSCRIPTION IN PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. ZINC METALLOPROTEINS IN EPIGENETICS ARE MAINLY ZINC METALLOENZYMES AND ZINC FINGER PROTEINS (ZFPS), WHICH ARE CLASSIFIED INTO WRITERS, ERASERS, READERS, EDITORS, AND FEEDERS. ALTOGETHER, THESE CLASSES OF PROTEINS ENGAGE IN CROSSTALK THAT FUNDAMENTALLY MAINTAINS THE EPIGENOME'S MODUS OPERANDI. CHANGES IN THE EXPRESSION OR FUNCTION OF THESE PROTEINS INDUCED BY ZINC DEFICIENCY OR LOSS OF FUNCTION MUTATIONS IN THEIR ZBDS MAY LEAD TO ABERRANT EPIGENETIC REPROGRAMMING, WHICH MAY WORSEN THE RISK OF NON-COMMUNICABLE CHRONIC DISEASES. THIS REVIEW ATTEMPTS TO ADDRESS ZINC'S ROLE AND ITS PROTEINS IN NATURAL EPIGENETIC PROGRAMMING AND ARTIFICIAL REPROGRAMMING AND BRIEFLY DISCUSSES HOW THE ZBDS IN THESE PROTEINS INTERACT WITH THE CHROMATIN. 2021 16 4002 25 LOSS OF P120 CATENIN AND LINKS TO MITOTIC ALTERATIONS, INFLAMMATION, AND SKIN CANCER. TUMOR FORMATION INVOLVES EPIGENETIC MODIFICATIONS AND MICROENVIRONMENTAL CHANGES AS WELL AS CUMULATIVE GENETIC ALTERATIONS ENCOMPASSING SOMATIC MUTATIONS, LOSS OF HETEROZYGOSITY, AND ANEUPLOIDY. HERE, WE SHOW THAT CONDITIONAL TARGETING OF P120 CATENIN IN MICE LEADS TO PROGRESSIVE DEVELOPMENT OF SKIN NEOPLASIAS ASSOCIATED WITH INTRINSIC NF-KAPPAB ACTIVATION. WE FIND THAT, SIMILARLY, SQUAMOUS CELL CARCINOMAS IN HUMANS DISPLAY ALTERED P120 AND ACTIVATED NF-KAPPAB. WE SHOW THAT EPIDERMAL HYPERPROLIFERATION ARISING FROM P120 LOSS CAN BE ABROGATED BY IKAPPAB KINASE 2 INHIBITORS. ALTHOUGH THIS UNDERSCORES THE IMPORTANCE OF THIS PATHWAY, THE ROLE OF NF-KAPPAB IN HYPERPROLIFERATION APPEARS ROOTED IN ITS IMPACT ON EPIDERMAL MICROENVIRONMENT BECAUSE AS P120-NULL KERATINOCYTES DISPLAY A GROWTH-ARRESTED PHENOTYPE IN CULTURE. WE TRACE THIS TO A MITOTIC DEFECT, RESULTING IN UNSTABLE, BINUCLEATED CELLS IN VITRO AND IN VIVO. WE SHOW THAT THE ABNORMAL MITOSES CAN BE AMELIORATED BY INHIBITING RHOA, THE ACTIVITY OF WHICH IS ABNORMALLY HIGH. CONVERSELY, WE CAN ELICIT SUCH MITOTIC DEFECTS IN CONTROL KERATINOCYTES BY ELEVATING RHOA ACTIVITY. THE ABILITY OF P120 DEFICIENCY TO ELICIT MITOTIC ALTERATIONS AND CHRONIC INFLAMMATORY RESPONSES, THAT TOGETHER MAY FACILITATE THE DEVELOPMENT OF GENETIC INSTABILITY IN VIVO, PROVIDES INSIGHTS INTO WHY IT FIGURES SO PROMINENTLY IN SKIN CANCER PROGRESSION. 2008 17 4545 22 MUTANT P53 GAIN OF FUNCTION AND CHEMORESISTANCE: THE ROLE OF MUTANT P53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. PURPOSE: TO REVIEW MECHANISMS UNDERLYING MUTANT P53 (MUTP53) GAIN OF FUNCTION (GOF) AND MUTP53-INDUCED CHEMORESISTANCE, AND TO INVESTIGATE THE ROLE OF MUTP53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. METHODS: WE SEARCHED THE PUBMED DATABASE FOR CLINICAL STUDIES FROM THE PAST DECADE, INCLUDING DATA EVALUATING THE IMPACT OF MUTP53 IN CLINICAL CHEMOTHERAPY RESPONSE. RESULTS: INTERACTIONS BETWEEN MUTP53 AND TRANSCRIPTIONAL FACTORS, PROTEINS OR DNA STRUCTURES, AS WELL AS EPIGENETIC REGULATION, CONTRIBUTE TO MUTP53 GOF. MAJOR MECHANISMS OF MUTP53-INDUCED CHEMORESISTANCE INCLUDE ENHANCED DRUG EFFLUX AND METABOLISM, PROMOTING SURVIVAL, INHIBITING APOPTOSIS, UPREGULATING DNA REPAIR, SUPPRESSING AUTOPHAGY, ELEVATING MICROENVIRONMENTAL RESISTANCE AND INDUCING A STEM-LIKE PHENOTYPE. CLINICALLY, MUTP53 PREDICTED RESISTANCE TO CHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA, AND ESOPHAGEAL AND OROPHARYNGEAL CANCERS, BUT ITS IMPACT ON CHRONIC LYMPHOCYTIC LEUKEMIA WAS UNCLEAR. IN BLADDER CANCER, MUTP53 DID NOT PREDICT RESISTANCE, WHEREAS IN SOME BREAST AND OVARIAN CANCERS, IT WAS ASSOCIATED WITH SENSITIVITY TO CERTAIN CHEMOTHERAPEUTIC AGENTS. CONCLUSION: MUTP53 HAS AN INTRICATE ROLE IN THE RESPONSE TO CLINICAL CHEMOTHERAPY AND SHOULD NOT BE INTERPRETED IN ISOLATION. FURTHERMORE, WHEN PREDICTING TUMOR RESPONSE TO CHEMOTHERAPY BASED ON THE P53 STATUS, THE DRUGS USED SHOULD ALSO BE TAKEN INTO CONSIDERATION. THESE CONCEPTS REQUIRE FURTHER INVESTIGATION. 2017 18 3899 21 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 19 3465 32 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS. 2019 20 2446 25 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