1 3900 129 LATEST INSIGHTS INTO PATHOGENESIS OF MYCOSIS FUNGOIDES AND CUTANEOUS T-CELL LYMPHOMA. CUTANEOUS T-CELL LYMPHOMA (CTCL) IS A RARE BUT INCREASING MALIGNANCY WHOSE PROTEAN MANIFESTATIONS NECESSARILY PRESENT IN THE INTEGUMENT, BUT CAN ALSO SPREAD TO INVOLVE BLOOD, LYMPH NODES AND INTERNAL ORGANS. WE HAVE DEVELOPED EFFICACIOUS AND VARIED THERAPIES TO TREAT EARLY AND ADVANCED STAGE DISEASE, BUT THERE ARE STILL MANY WHO SUFFER TREMENDOUSLY FROM THIS ILLNESS. ALTHOUGH THE PATHOGENESIS OF THIS CANCER REMAINS FRUSTRATINGLY ELUSIVE, OVER THE LAST 200 YEARS WE HAVE GENERATED A ROBUST BODY OF EVIDENCE THAT POINTS TOWARD POSSIBLE SINGULAR AS WELL AS MULTIFACTORIAL ETIOLOGIES. COMBINING THE HISTORICAL HYPOTHESES WHICH HAVE FOCUSED UPON THE CONCEPT OF INFECTIOUS CAUSES, INCLUDING CARCINOGENIC GENOMIC VIRAL INTEGRATION AND BACTERIAL SUPERANTIGENIC CHRONIC STIMULATION AS WELL AS INDUSTRIAL/OCCUPATIONAL EXPOSURE, ALONG WITH THE MORE RECENT REVELATIONS OF BOTH GENETIC AND EPIGENETIC ALTERATION AND IMMUNE DYSREGULATION, WE ARE CLOSER THAN EVER TO UNDERSTANDING THE ETIOLOGY OF CTCL. IT IS THROUGH THIS KNOWLEDGE AND CONTINUED RESEARCH EFFORTS THAT WE WILL BE ABLE TO BETTER DIAGNOSE, TREAT, AND POTENTIALLY PREVENT OR CURE CTCL. 2017 2 705 25 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 3 6655 31 UPDATE ON THE MOLECULAR PATHOLOGY OF CUTANEOUS SQUAMOUS CELL CARCINOMA. CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) IS THE SECOND MOST COMMON SKIN CANCER, ORIGINATING FROM KERATINOCYTES OF THE SPINOUS LAYER. NUMEROUS RISK FACTORS HAVE BEEN DISCOVERED FOR THE INITIATION AND GROWTH OF THIS TYPE OF CANCER, SUCH AS EXPOSURE TO UV AND IONIZING RADIATION, CHEMICAL CARCINOGENS, THE PRESENCE OF IMMUNOSUPPRESSION STATES, CHRONIC INFLAMMATION, INFECTIONS WITH HIGH-RISK VIRAL STRAINS, AND, LAST BUT NOT LEAST, THE PRESENCE OF DISEASES ASSOCIATED WITH GENETIC ALTERATIONS. THE IMPORTANT SOCIO-ECONOMIC IMPACT, AS WELL AS THE DIFFICULTY ASSOCIATED WITH THERAPY FOR ADVANCED FORMS, HAS MADE THE MOLECULAR MECHANISMS UNDERLYING THIS NEOPLASIA MORE AND MORE INTENSIVELY STUDIED, WITH THE INTENTION OF ACHIEVING A BETTER UNDERSTANDING AND ADVANCING THE TREATMENT OF THIS PATHOLOGY. THIS REVIEW AIMS TO PROVIDE A BRIEF FORAY INTO THE MOLECULAR, GENETIC, AND EPIGENETIC ASPECTS OF THIS CANCER, AS WELL AS THE TREATMENT METHODS, RANGING FROM THE FIRST USED TO THE LATEST TARGETED THERAPIES. 2023 4 5899 30 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 5 461 35 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 6 2461 26 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 7 49 22 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 8 3418 23 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 9 4399 31 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 10 2049 22 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014 11 6334 23 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 12 2586 33 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 13 5905 28 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 14 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 15 3020 33 GENETICS AND EPIGENETICS OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGE-RELATED DISEASE THAT AFFECTS THE TISSUES OF THE SYNOVIAL JOINT, LEADING TO LOSS OF FUNCTION AND PAIN. IT IMPACTS ON BOTH PATIENT MORBIDITY AND MORTALITY. IT IS A COMPLEX, POLYGENIC DISEASE THAT LACKS ANY LARGE-EFFECT SUSCEPTIBILITY LOCI. INSTEAD, OA SUSCEPTIBILITY ALLELES INDIVIDUALLY CONTRIBUTE ONLY MODESTLY TO THE OVERALL DISEASE RISK, MAKING THEIR IDENTIFICATION CHALLENGING. DESPITE THIS, BREAKTHROUGHS HAVE OCCURRED WITH COMPELLING ASSOCIATIONS SO FAR REPORTED TO POLYMORPHISMS WITHIN THE GENES GDF5 AND MCF2L AND TO THE GENOMIC REGION 7Q22. THE LATTER TWO HAVE EMERGED FROM GENOME-WIDE ASSOCIATION SCANS, WHICH ARE LIKELY TO YIELD MORE HITS IN THE NEAR FUTURE. AS FOR MANY COMPLEX DISEASES, IT IS NOW APPARENT THAT EPIGENETIC EFFECTS ARE ALSO IMPORTANT MEDIATORS OF DISEASE BIOLOGY, WITH DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS ALL HAVING A ROLE. AT PRESENT, MUCH OF THE EPIGENETIC FOCUS HAS BEEN ON CARTILAGE, THE TISSUE AT THE CENTER OF THE OA DISEASE PROCESS. IF WE ARE TO GET CLOSE TO A QUALITATIVE AND QUANTITATIVE UNDERSTANDING OF THE IMPACT OF EPIGENETICS ON OA, THEN IN FUTURE THE OTHER TISSUES OF THE JOINT WILL ALSO NEED TO BE INVESTIGATED. ONE OF THE MORE EXCITING INSIGHTS TO HAVE EMERGED RECENTLY IS THE FACT THAT EPIGENETIC EFFECTS CAN IMPACT ON OA GENETIC EFFECTS AND THIS MAY BE A PARTICULARLY FRUITFUL AVENUE FOR INTEGRATING BOTH AS WE MOVE TOWARD A CLEARER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF THIS INTRIGUING DISEASE. 2012 16 5447 27 REPOSITIONING LIDOCAINE AS AN ANTICANCER DRUG: THE ROLE BEYOND ANESTHESIA. WHILE CANCER TREATMENT HAS IMPROVED DRAMATICALLY, IT HAS ALSO ENCOUNTERED MANY CRITICAL CHALLENGES, SUCH AS DISEASE RECURRENCE, METASTASIS, AND DRUG RESISTANCE, MAKING NEW DRUGS WITH NOVEL MECHANISMS AN URGENT CLINICAL NEED. THE TERM "DRUG REPOSITIONING," ALSO KNOWN AS OLD DRUGS FOR NEW USES, HAS EMERGED AS ONE PRACTICAL STRATEGY TO DEVELOP NEW ANTICANCER DRUGS. ANESTHETICS HAVE BEEN WIDELY USED IN SURGICAL PROCEDURES TO REDUCE THE EXCRUCIATING PAIN. LIDOCAINE, ONE OF THE MOST-USED LOCAL ANESTHETICS IN CLINICAL SETTINGS, HAS BEEN FOUND TO SHOW MULTI-ACTIVITIES, INCLUDING POTENTIAL IN CANCER TREATMENT. GROWING EVIDENCE SHOWS THAT LIDOCAINE MAY NOT ONLY WORK AS A CHEMOSENSITIZER THAT SENSITIZES OTHER CONVENTIONAL CHEMOTHERAPEUTICS TO CERTAIN RESISTANT CANCER CELLS, BUT ALSO COULD SUPPRESS CANCER CELLS GROWTH BY SINGLE USE AT DIFFERENT DOSES OR CONCENTRATIONS. LIDOCAINE COULD SUPPRESS CANCER CELL GROWTH IN VITRO AND IN VIVO VIA MULTIPLE MECHANISMS, SUCH AS REGULATING EPIGENETIC CHANGES AND PROMOTING PRO-APOPTOSIS PATHWAYS, AS WELL AS REGULATING ABC TRANSPORTERS, METASTASIS, AND ANGIOGENESIS, ETC., PROVIDING VALUABLE INFORMATION FOR ITS FURTHER APPLICATION IN CANCER TREATMENT AND FOR NEW DRUG DISCOVERY. IN ADDITION, LIDOCAINE IS NOW UNDER CLINICAL TRIALS TO TREAT CERTAIN TYPES OF CANCER. IN THE CURRENT REVIEW, WE SUMMARIZE THE RESEARCH AND ANALYZE THE UNDERLYING MECHANISMS, AND ADDRESS KEY ISSUES IN THIS AREA. 2020 17 2136 31 EPIGENETIC INFLUENCES IN THE OBESITY/COLORECTAL CANCER AXIS: A NOVEL THERAGNOSTIC AVENUE. THE WORLD HEALTH ORGANIZATION (WHO) CONSIDERS THAT OBESITY HAS REACHED PROPORTIONS OF PANDEMIC. EXPERTS ALSO INSIST ON THE IMPORTANCE OF CONSIDERING OBESITY AS A CHRONIC DISEASE AND ONE OF THE MAIN CONTRIBUTORS TO THE WORLDWIDE BURDEN OF OTHER NONTRANSMISSIBLE CHRONIC DISEASES, WHICH HAVE A GREAT IMPACT ON HEALTH, LIFESTYLE, AND ECONOMIC COST. ONE OF THE MOST CURRENT CHALLENGES OF BIOMEDICAL SCIENCE FACES IS TO UNDERSTAND THE ORIGIN OF THE CHRONIC NONTRANSMISSIBLE DISEASES, SUCH AS OBESITY AND CANCER. THERE IS A LARGE EVIDENCE, BOTH IN EPIDEMIOLOGICAL STUDIES IN HUMANS AND IN ANIMAL MODELS, OF THE ASSOCIATION BETWEEN OBESITY AND AN INCREASED RISK OF CANCER INCIDENCE. IN THE LAST YEARS, THE INITIAL DISCOVERY OF EPIGENETIC MECHANISMS REPRESENTS THE MOST RELEVANT FINDING TO EXPLAIN HOW THE GENOME INTERACTS WITH ENVIRONMENTAL FACTORS AND THE RIPPLE EFFECTS ON DISEASE PATHOGENESES. SINCE THEN, ALL EPIGENETIC PROCESS HAS BEEN INVESTIGATED BY THE SCIENTIFIC COMMUNITIES FOR NEARLY TWO DECADES TO DETERMINE WHICH COMPONENTS ARE INVOLVED IN THIS PROCESS. DNA/RNA METHYLATION AND MIRNA ARE CLASSIFIED AS TWO OF THE MOST IMPORTANT REPRESENTATIVE CLASSES OF SUCH EPIGENETIC MECHANISMS AND DYSREGULATED ACTIVITY OF SUCH MECHANISM CAN CERTAINLY CONTRIBUTE TO DISEASE PATHOGENESIS AND/OR PROGRESSION ESPECIALLY IN TUMORS. THIS REVIEW ARTICLE SERVES TO HIGHLIGHT THE IMPACT OF DNA/RNA METHYLATION AND MIRNA-BASED EPIGENETIC MECHANISM ACTIVITIES IN THE INTERPLAY BETWEEN OBESITY AND THE DEVELOPMENT AND CLINICAL SIGNIFICANCE OF COLORECTAL CANCER. 2019 18 5359 27 REBOOTING REGULATORY T CELL AND DENDRITIC CELL FUNCTION IN IMMUNE-MEDIATED INFLAMMATORY DISEASES: BIOMARKER AND THERAPY DISCOVERY UNDER A MULTI-OMICS LENS. IMMUNE-MEDIATED INFLAMMATORY DISEASES (IMIDS) ARE A GROUP OF AUTOIMMUNE AND CHRONIC INFLAMMATORY DISORDERS WITH CONSTANTLY INCREASING PREVALENCE IN THE MODERN WORLD. THE VAST MAJORITY OF IMIDS DEVELOP AS A CONSEQUENCE OF COMPLEX MECHANISMS DEPENDENT ON GENETIC, EPIGENETIC, MOLECULAR, CELLULAR, AND ENVIRONMENTAL ELEMENTS, THAT LEAD TO DEFECTS IN IMMUNE REGULATORY GUARDIANS OF TOLERANCE, SUCH AS DENDRITIC (DCS) AND REGULATORY T (TREGS) CELLS. AS A RESULT OF THIS DYSFUNCTION, IMMUNE TOLERANCE COLLAPSES AND PATHOGENESIS EMERGES. DEEPER UNDERSTANDING OF SUCH DISEASE DRIVING MECHANISMS REMAINS A MAJOR CHALLENGE FOR THE PREVENTION OF INFLAMMATORY DISORDERS. THE RECENT RENAISSANCE IN HIGH THROUGHPUT TECHNOLOGIES HAS ENABLED THE INCREASE IN THE AMOUNT OF DATA COLLECTED THROUGH MULTIPLE OMICS LAYERS, WHILE ADDITIONALLY NARROWING THE RESOLUTION DOWN TO THE SINGLE CELL LEVEL. IN LIGHT OF THE AFOREMENTIONED, THIS REVIEW FOCUSES ON DCS AND TREGS AND DISCUSSES HOW MULTI-OMICS APPROACHES CAN BE HARNESSED TO CREATE ROBUST CELL-BASED IMID BIOMARKERS IN HOPE OF LEADING TO MORE EFFICIENT AND PATIENT-TAILORED THERAPEUTIC INTERVENTIONS. 2022 19 3902 34 LEARNING FROM THE FAILURES OF DRUG DISCOVERY IN B-CELL NON-HODGKIN LYMPHOMAS AND PERSPECTIVES FOR THE FUTURE: CHRONIC LYMPHOCYTIC LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA AS TWO ENDS OF A SPECTRUM IN DRUG DEVELOPMENT. DESPITE SUBSTANTIAL RECENT ADVANCES, THERE IS STILL AN UNMET NEED FOR BETTER THERAPIES IN B-CELL NON HODGKIN LYMPHOMAS (B-NHL), ESPECIALLY IN RELAPSED OR REFRACTORY DISEASE. MANY NOVEL TARGETED DRUGS HAVE BEEN DEVELOPED BASED ON A BETTER MOLECULAR UNDERSTANDING OF B-NHL. AREAS COVERED: THIS ARTICLE FOCUSES ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS A REPRESENTATIVE FOR INDOLENT LYMPHOMAS AND PARADIGMATIC FOR THE TREMENDOUS PROGRESS IN TREATING B-NHL ON THE ONE HAND AND DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) AS A REPRESENTATIVE FOR AGGRESSIVE LYMPHOMAS AND PARADIGMATIC FOR MANY UNSOLVED PROBLEMS IN LYMPHOMA TREATMENT OR THE OTHER HAND. WE HIGHLIGHT SALIENT POINTS IN CURRENT THERAPIES TARGETING GENETIC, EPIGENETIC, IMMUNOLOGICAL AND MICROENVIRONMENTAL ALTERATIONS. POSSIBLE REASONS FOR DRUG FAILURE IN CLINICAL TRIALS LIKE TUMOR HETEROGENEITY, CLONAL EVOLUTION AND DRUG RESISTANCE MECHANISMS ARE DISCUSSED. BASED THEREON, SOME PERSPECTIVES FOR FURTHER DRUG DISCOVERY ARE GIVEN. EXPERT OPINION: IN VIEW OF THE PATHOGENETIC COMPLEXITY OF LYMPHOMAS, THERAPIES TARGETING EXCLUSIVELY A SINGLE ALTERATION MAY FAIL BECAUSE RESISTANCE MECHANISMS ARE PRESENT EITHER INITIALLY OR EVOLVE DURING TREATMENT. THEREFORE, FUTURE THERAPIES IN B-NHL MAY HAVE TO TARGET THE GREATEST POSSIBLE NUMBER OF GENETIC, IMMUNOLOGICAL OR EPIGENETIC ALTERATIONS STILL ALLOWING TOLERABILITY AND TO MONITOR THESE ALTERATIONS DURING THERAPY. 2017 20 2000 19 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021