1 257 161 ADVANCES IN ONCOANAESTHESIA AND CANCER PAIN. INTRODUCTION: THE GROWING INTEREST ON HOW PERI-?OPERATIVE INTERVENTIONS, ESPECIALLY REGIONAL ANESTHESIA, DURING CANCER SURGERY CAN ALTER ONCOLOGICAL OUTCOME INCREASING DISEASE FREE SURVIVAL IS PROBABLY RESPONSIBLE FOR THE BIRTH OF THE NEW SUBSPECIALTY CALLED ONCO-ANESTHESIA. A PARADIGM SHIFT IN THE CONCEPT OF ANESTHETIC MANAGEMENT HAS OCCURRED RECENTLY OWING TO THE INNUMERABLE DIVERSE REVELATIONS FROM THE ONGOING RESEARCH IN THIS FIELD. DISCUSSION: LONG LASTING BUT REVERSIBLE EPIGENETIC CHANGES CAN OCCUR DUE TO SURGICAL STRESS AND PERIOPERATIVE ANESTHETIC MEDICATIONS. THE EXACT RELATIONSHIP BETWEEN THESE FACTORS AND TUMOR BIOLOGY IS BEING STUDIED FURTHER. A POPULAR TOPIC UNDER RESEARCH NOW IS THE INFLUENCE OF REGIONAL ANESTHESIA ON CANCER RECURRENCE. COMBINING NERVE BLOCKS WITH TOTAL INTRAVENOUS ANESTHESIA (TIVA) BRINGS DOWN THE REQUIREMENT OF OPIOIDS AND VOLATILE ANESTHETIC AGENTS IMPLICATED IN CANCER RECURRENCE. THE STUDY OF MECHANISM OF PAIN AT THE MOLECULAR LEVEL HAS LED TO THE DISCOVERY OF NOVEL MODES OF PREVENTION OF CHRONIC POST-SURGICAL PAIN. NEWER COMBINATION AGGRESSIVE TREATMENT THERAPIES -INTRAOPERATIVE CHEMOTHERAPY AND RADIOTHERAPY, ISOLATED LIMB PERFUSION, PHOTODYNAMIC THERAPY AND ROBOTIC SURGERY REQUIRE SPECIALIZED ANESTHETIC MANAGEMENT. THE COVID PANDEMIC INTRODUCED NEW GUIDELINES FOR SAFE MANAGEMENT OF ONCOSURGICAL PATIENTS .USE OF GENOMIC MAPPING TO PERSONALIZE PAIN MANAGEMENT WILL BE THE BREAKTHROUGH OF THE DECADE. CONCLUSION: THE DISCOVERY THAT ANESTHETIC STRATEGY COULD HAVE SIGNIFICANT ONCOLOGICAL SEQUEL IS A QUANTUM LEAP FORWARD. AVOIDING SOME ANESTHETIC MEDICATIONS MAY DECREASE CANCER RECURRENCE. COMPREHENSIVE CANCER CARE AND TRANSLATIONAL RESEARCH WILL PAVE THE WAY TO UNCOVER SAFE ANESTHETIC PRACTICES. 2021 2 5447 39 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 3 3899 25 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 4 2000 24 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 5 6398 27 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 6 705 27 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 7 2568 27 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 4399 32 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 9 68 35 A MECHANISTIC MODEL FOR YOGA AS A PREVENTIVE AND THERAPEUTIC MODALITY. YOGA IS AN ANCIENT INDIAN TECHNIQUE OF HEALTHY LIVING. NUMEROUS STUDIES HAVE CORROBORATED YOGA'S BENEFICIAL EFFECTS, INCLUDING A FAVORABLE INFLUENCE ON AUTONOMIC FUNCTION AND NEGATIVE EMOTIONS. EXTENSIVE RESEARCH IN THE LAST FEW DECADES HAS REVEALED THE CRITICAL ROLE THAT YOGA CAN PLAY IN ERADICATING STRESS. THIS HAS LAID TO THE FOUNDATION FOR A SCIENTIFIC UNDERSTANDING OF PATHOPHYSIOLOGICAL CHANGES ATTRIBUTED TO STRESS, PARTICULARLY AT THE MOLECULAR AND GENETIC LEVELS. THIS PRIMARILY HAS HELPED UNDERSTAND THE EPIGENETIC AND GENETIC MECHANISM AT PLAY TO INDUCE AND ALLEVIATE STRESS, PARTICULARLY THOSE RELATED TO EMOTIONAL ABERRATIONS. AS RESEARCH HAS INDICATED, NEGATIVE EMOTIONS ARE TRANSLATED INTO VASCULAR INFLAMMATION APPROPRIATELY ACCENTUATED BY A SYMPATHETIC PREDOMINANT AUTONOMIC FUNCTION. THIS CASCADE IS BOLSTERED BY MULTIPLE FACTORS, INCLUDING ACTIVATION OF "STRESSOR" GENES AND ELABORATING HORMONES, INCLUDING STEROIDS WITH SOMETIMES NOCUOUS CONSEQUENCES, PARTICULARLY WHEN CHRONIC. YOGA HAS BEEN CATEGORICALLY FOUND TO HAVE INHIBITED EACH AND EVERY ONE OF THESE BANEFUL EFFECTS OF STRESS. IN FACT, IT ALSO CHANGES THE NEURONAL CIRCUITS THAT POTENTIATE SUCH A PLETHORA OF PATHOLOGICAL CHANGES. THIS, IN TURN, HAS ACCENTUATED YOGA'S RELEVANCE AS A POWERFUL PREVENTIVE INTERVENTION IN NONCOMMUNICABLE DISEASES (NCD). NCDS, INCLUDING HEART DISEASE, STROKE, AND RHEUMATOLOGICAL DISORDERS, ARE ESSENTIALLY INFLAMMATORY DISEASES THAT PERPETUATE INFLAMMATION IN DIFFERENT BEDS LIKE VASCULAR OR JOINT SPACES. THE PRECISE MECHANISM BY WHICH YOGA INDUCES SUCH BENEFICIAL CHANGES IS YET TO BE DELINEATED. HOWEVER, A CORNUCOPIA OF POINTERS INDICATES THAT NEURAL, ENDOCRINE, IMMUNOLOGICAL, CELLULAR, GENETIC, AND EPIGENETIC MECHANISMS ARE AT PLAY. THIS ARTICLE ATTEMPTS TO COBBLE TOGETHER NEWFANGLED RESEARCH TO DELINEATE A MEDICAL MODEL FOR THIS 5000-YEAR-OLD PRACTICE FROM INDIA. THIS IS IMPERATIVE, AS A MECHANISTIC MODEL OF THIS ANCIENT-BUT-COMPLEX SYSTEM WOULD ENABLE A MORE COMPREHENSIVE UNDERSTANDING OF ITS MECHANISM AND REVEAL ITS YET-UNDISCOVERED POSITIVE HEALTH EFFECTS. 2021 10 6480 30 TOWARDS PRECISION MEDICINE IN GENERALIZED ANXIETY DISORDER: REVIEW OF GENETICS AND PHARMACO(EPI)GENETICS. GENERALIZED ANXIETY DISORDER (GAD) IS A PREVALENT AND CHRONIC MENTAL DISORDER THAT ELICITS WIDESPREAD FUNCTIONAL IMPAIRMENT. GIVEN THE HIGH DEGREE OF NON-RESPONSE/PARTIAL RESPONSE AMONG PATIENTS WITH GAD TO AVAILABLE PHARMACOLOGICAL TREATMENTS, THERE IS A STRONG NEED FOR NOVEL APPROACHES THAT CAN OPTIMIZE OUTCOMES, AND LEAD TO MEDICATIONS THAT ARE SAFER AND MORE EFFECTIVE. ALTHOUGH INVESTIGATIONS HAVE IDENTIFIED INTERESTING TARGETS PREDICTING TREATMENT RESPONSE THROUGH PHARMACOGENETICS (PGX), PHARMACO-EPIGENETICS, AND NEUROIMAGING METHODS, THESE STUDIES ARE OFTEN SOLITARY, NOT REPLICATED, AND CARRY SEVERAL LIMITATIONS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT STATUS OF GAD GENETICS AND PGX AND PRESENTS POTENTIAL STRATEGIES TO IMPROVE TREATMENT RESPONSE BY COMBINING BETTER PHENOTYPING WITH PGX AND IMPROVED ANALYTICAL METHODS. THESE STRATEGIES CARRY THE DUAL BENEFIT OF DELIVERING DATA ON BIOMARKERS OF TREATMENT RESPONSE AS WELL AS POINTING TO DISEASE MECHANISMS THROUGH THE BIOLOGY OF THE MARKERS ASSOCIATED WITH RESPONSE. OVERALL, THESE EFFORTS CAN SERVE TO IDENTIFY CLINICAL, GENETIC, AND EPIGENETIC FACTORS THAT CAN BE INCORPORATED INTO A PHARMACO(EPI)GENETIC TEST THAT MAY ULTIMATELY IMPROVE TREATMENT RESPONSE AND REDUCE THE SOCIOECONOMIC BURDEN OF GAD. 2019 11 4599 24 NATURE AND NURTURE OF HUMAN PAIN. HUMANS ARE VERY DIFFERENT WHEN IT COMES TO PAIN. SOME GET PAINFUL PIERCINGS AND TATTOOS; OTHERS CAN NOT STAND EVEN A FLU SHOT. INTERINDIVIDUAL VARIABILITY IS ONE OF THE MAIN CHARACTERISTICS OF HUMAN PAIN ON EVERY LEVEL INCLUDING THE PROCESSING OF NOCICEPTIVE IMPULSES AT THE PERIPHERY, MODIFICATION OF PAIN SIGNAL IN THE CENTRAL NERVOUS SYSTEM, PERCEPTION OF PAIN, AND RESPONSE TO ANALGESIC STRATEGIES. AS FOR MANY OTHER COMPLEX BEHAVIORS, THE SOURCES OF THIS VARIABILITY COME FROM BOTH NURTURE (ENVIRONMENT) AND NATURE (GENES). HERE, I WILL DISCUSS HOW THESE FACTORS CONTRIBUTE TO HUMAN PAIN SEPARATELY AND VIA INTERPLAY AND HOW EPIGENETIC MECHANISMS ADD TO THE COMPLEXITY OF THEIR EFFECTS. 2013 12 461 32 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 13 6292 29 THE PRIMACY OF PSYCHOANALYTIC INTERVENTION IN RECOVERY FROM THE PSYCHOSES AND SCHIZOPHRENIAS. FUNCTIONAL CAPACITIES, SUCH AS ATTACHMENT AND AFFECT REGULATION, OBJECT RELATIONS CAPACITY, SYMBOLIC FUNCTION AND LANGUAGE DEVELOPMENT, NOW DOCUMENTED BY NEUROSCIENTIFIC RESEARCH AND EPIGENETICS, ARE REVIEWED. RESULTS FROM THIS RESEARCH, TOGETHER WITH OTHER FACTORS, ARE POSITED TO HAVE CONTRIBUTED TO EFFECTIVE CONTEMPORARY PSYCHOANALYTIC AND PSYCHOTHERAPEUTIC TREATMENTS FOR THE PSYCHOSES AND SCHIZOPHRENIAS. ETIOLOGICAL FACTORS INVOLVING THE SCHIZOPHRENIAS AND OTHER PSYCHOSES ARE CONSIDERED BOTH IN TERMS OF AN EPIGENETIC MODEL, AND IN TERMS OF HOW ETIOLOGY MAY, OR MAY NOT, AFFECT CLINICAL TREATMENT. THE LACANIAN 388 PROGRAM IS REVIEWED IN SOME DETAIL, AS ARE SEVERAL PSYCHOANALYTIC AND PSYCHOTHERAPEUTIC CLINICAL APPROACHES USED WITH THIS POPULATION OVER THE LAST SIX DECADES. ALL TREATMENTS FOCUS ON THE PRIMACY OF PSYCHOTHERAPEUTIC INTERVENTION, AND USE MEDICATIONS MINIMALLY, NOT AT ALL, OR ONLY AS INFORMED BY AN OVER-ARCHING PSYCHODYNAMIC MODEL OF TREATMENT. THE AUTHOR ARGUES THAT THERE IS NOW SUBSTANTIAL RESEARCH AND OUTCOME DATA SUGGESTING THAT THE PSYCHOSES AND SCHIZOPHRENIAS ARE NOT CHRONIC DETERIORATING CONDITIONS. RECOVERY IS OBSERVED IN MANY PSYCHOTIC AND SCHIZOPHRENIC PATIENTS TREATED WITH APPROACHES THAT FOCUS ON THE PRIMACY OF PSYCHOTHERAPEUTIC INTERVENTION. 2007 14 2461 30 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 15 4808 36 OBESITY MANAGEMENT: AT THE FOREFRONT AGAINST DISEASE STIGMA AND THERAPEUTIC INERTIA. OBESITY IS A COMPLEX CHRONIC RELAPSING DISEASE, RESULTING FROM THE INTERACTION BETWEEN MULTIPLE ENVIRONMENTAL, GENETIC AND EPIGENETIC CAUSES, AND SUPPORTED BY CHANGES IN THE NEUROENDOCRINE MECHANISMS REGULATING ENERGY BALANCE AND BODY WEIGHT. ADIPOSE TISSUE DYSFUNCTION CONTRIBUTES TO OBESITY-RELATED COMPLICATIONS. HOWEVER, THE PREVALENT NARRATIVE ABOUT THE CAUSES AND MECHANISMS OF OBESITY REMAINS A MUCH MORE SIMPLISTIC ONE, BASED ON THE FALSE ASSUMPTION THAT INDIVIDUALS CAN FULLY CONTROL THEIR BODY WEIGHT THROUGH APPROPRIATE BEHAVIOURAL CHOICES. ACCORDING TO THIS NARRATIVE, OBESITY IS SIMPLY REVERSIBLE "PERSUADING" THE PATIENT TO FOLLOW HEALTHIER AND MORE VIRTUOUS INDIVIDUAL BEHAVIOURS (MORAL JUDGEMENT). THIS PERSISTENT NARRATIVE FORMS THE DEEP ROOT OF THE STIGMATISATION OF PEOPLE WITH OBESITY AT THE INDIVIDUAL LEVEL AND CREATES A CLEAR DISCREPANCY ON HOW OBESITY PREVENTION AND CURE ARE DESIGNED IN COMPARISON WITH THE CASE OF OTHER NON-COMMUNICABLE CHRONIC DISEASES (CLINICAL STIGMA). THE PROMOTION OF SYSTEMIC PREVENTIVE MEASURES AGAINST OBESITY IS NOT SUPPORTED AT A POLITICAL AND SOCIAL LEVEL BY THE PERSISTENCE OF A NARRATIVE OF OBESITY AS THE SIMPLE CONSEQUENCE OF INDIVIDUAL FAILURES AND LACK OF WILLPOWER. THE SIMPLISTIC NARRATIVE OF OBESITY AS A SELF-IMPOSED CONDITION WITH AN EASY WAY-OUT ("EAT LESS AND MOVE MORE") CREATES A CLEAR DISCREPANCY ON HOW OBESITY IS MANAGED BY HEALTH CARE SYSTEMS IN COMPARISON WITH OTHER NCDS. THE OVER-ESTIMATION OF THE EFFICACY OF THERAPEUTIC INTERVENTION SOLELY BASED ON PATIENTS EDUCATION AND LIFESTYLE MODIFICATION IS RESPONSIBLE OF THERAPEUTIC INERTIA IN HEALTH CARE PROFESSIONALS AND IN CLINICAL GUIDELINES, LIMITING OR DELAYING THE ADOPTION OF MORE EFFECTIVE THERAPEUTIC STRATEGIES, LIKE ANTI-OBESITY MEDICATIONS AND BARIATRIC SURGERY. IN CONCLUSION, THE PERSISTENCE OF A NARRATIVE DESCRIBING OBESITY AS A SELF-INDUCED EASILY REVERSIBLE CONDITION HAS PROFOUND CONSEQUENCES ON HOW OBESITY PREVENTION AND MANAGEMENT ARE BUILD, INCLUDING THE DESIGN AND IMPLEMENTATION OF OBESITY MANAGEMENT GUIDELINES AND A TENDENCY TO THERAPEUTIC INERTIA.LEVEL OF EVIDENCE: NO LEVEL OF EVIDENCE. 2022 16 1676 26 DRUG ADDICTION: FROM BENCH TO BEDSIDE. DRUG ADDICTION IS RESPONSIBLE FOR MILLIONS OF DEATHS PER YEAR AROUND THE WORLD. STILL, ITS MANAGEMENT AS A CHRONIC DISEASE IS SHADOWED BY MISCONCEPTIONS FROM THE GENERAL PUBLIC. INDEED, DRUG CONSUMERS ARE OFTEN LABELLED AS "WEAK", "IMMORAL" OR "DEPRAVED". CONSEQUENTLY, DRUG ADDICTION IS OFTEN PERCEIVED AS AN INDIVIDUAL PROBLEM AND NOT SOCIETAL. IN TECHNICAL TERMS, DRUG ADDICTION IS DEFINED AS A CHRONIC, RELAPSING DISEASE RESULTING FROM SUSTAINED EFFECTS OF DRUGS ON THE BRAIN. THROUGH A BETTER CHARACTERISATION OF THE CEREBRAL CIRCUITS INVOLVED, AND THE LONG-TERM MODIFICATIONS OF THE BRAIN INDUCED BY ADDICTIVE DRUGS ADMINISTRATIONS, FIRST, WE MIGHT BE ABLE TO CHANGE THE WAY THE GENERAL PUBLIC SEE THE PATIENT WHO IS SUFFERING FROM DRUG ADDICTION, AND SECOND, WE MIGHT BE ABLE TO FIND NEW TREATMENTS TO NORMALISE THE ALTERED BRAIN HOMEOSTASIS. IN THIS REVIEW, WE SYNTHETISE THE CONTRIBUTION OF FUNDAMENTAL RESEARCH TO THE UNDERSTANDING DRUG ADDICTION AND ITS CONTRIBUTION TO POTENTIAL NOVEL THERAPEUTICS. MOSTLY BASED ON DRUG-INDUCED MODIFICATIONS OF SYNAPTIC PLASTICITY AND EPIGENETIC MECHANISMS (AND THEIR BEHAVIOURAL CORRELATES) AND AFTER DEMONSTRATION OF THEIR REVERSIBILITY, WE TRIED TO HIGHLIGHT PROMISING THERAPEUTICS. WE ALSO UNDERLINE THE SPECIFIC TEMPORAL DYNAMICS AND PSYCHOSOCIAL ASPECTS OF THIS COMPLEX PSYCHIATRIC DISEASE ADDING PARAMETERS TO BE CONSIDERED IN CLINICAL TRIALS AND PAVING THE WAY TO TEST NEW THERAPEUTIC VENUES. 2021 17 6141 29 THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. INTRODUCTION: PEYRONIE'S DISEASE (PD) IS A CHRONIC FIBROSING CONDITION THAT CONTRIBUTES TO PENILE DEFORMITY, CURVATURE, AND PAIN. INITIAL FAMILIAL STUDIES DEMONSTRATED POTENTIAL GENETIC LINKS TO PD. SINCE THAT TIME, VERY FEW INVESTIGATIONS HAVE SIGNIFICANTLY ADVANCED THE SCIENCE IN THIS AREA. HENCE, THERE IS A LARGE OPPORTUNITY AND SIGNIFICANT NEED TO BETTER STUDY THE UNDERLYING GENOMICS AND PATHOGENESIS OF PD. AIM: TO SUMMARIZE THE CURRENT GENOMIC LITERATURE RELEVANT TO PD. METHODS: A REVIEW WAS PERFORMED OF ALL PUBMED-INDEXED LITERATURE FROM 1970-2018 RELATING TO THE PATHOPHYSIOLOGY AND GENETICS OF PD. KEY FINDINGS WERE CATEGORICALLY SUMMARIZED TO INCLUDE EPIDEMIOLOGY, RISK FACTORS, INHERITANCE PATTERNS, CHROMOSOMAL INSTABILITY, GENETIC ASSOCIATIONS, EPIGENETICS, DIFFERENTIAL GENE EXPRESSION, AND PRECLINICAL MODELS OF PD. MAIN OUTCOME MEASURES: SUMMARY OF THE CURRENT LITERATURE ON THE GENETICS OF PD. RESULTS: PD IS A COMMON CONDITION AND HAS SEVERAL KNOWN RISK FACTORS AND COMORBID DISEASE ASSOCIATIONS. ALTHOUGH MEN WITH PD ARE BELIEVED TO BE GENETICALLY PREDISPOSED, THERE ARE LIKELY SEVERAL SUBTYPES OF THE CONDITION, EACH WITH VARIED PATHOPHYSIOLOGICAL DISORDERS AND CONTRIBUTING FACTORS. AVAILABLE DATA SUGGEST THAT PD IS ASSOCIATED WITH UNDERLYING GENETIC INSTABILITY, INCLUDING DYSREGULATION OF GENES RELATING TO FIBROSIS AND CELLULAR DEGRADATION, THUS, RESULTING IN ABNORMAL PLAQUE DEVELOPMENT AND PENILE DEFORMITY. PRECLINICAL MODELS, INCLUDING CELL CULTURES AND RAT MODELS, DEMONSTRATE SEVERAL CONSISTENCIES WITH PD CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS; HOWEVER, AN IDEAL MODEL WITH SPONTANEOUS DEVELOPMENT OF PD IS LACKING. CONCLUSION: BASED ON LIMITED DATA, PD LIKELY REPRESENTS A HETEROGENEOUS CONDITION, WITH BOTH HERITABLE AND ENVIRONMENTALLY-DRIVEN EPIGENETIC FACTORS CONTRIBUTING TO ITS DEVELOPMENT AND PROGRESSION. HOWEVER, THERE REMAINS A SIGNIFICANT GAP IN THE LITERATURE ON THE UNDERLYING CAUSE AND PATHOPHYSIOLOGY OF THE CONDITION, SUGGESTING A SUBSTANTIAL NEED FOR FURTHER INVESTIGATION AND STUDY. SHARMA KL, ALOM M, TROST L. THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. SEX MED REV 2020;8:314-323. 2020 18 6130 23 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 19 6334 21 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 20 2616 21 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022