1 3839 149 IPSC-DERIVED NEURAL PRECURSOR CELLS: POTENTIAL FOR CELL TRANSPLANTATION THERAPY IN SPINAL CORD INJURY. A NUMBER OF STUDIES HAVE DEMONSTRATED THAT TRANSPLANTATION OF NEURAL PRECURSOR CELLS (NPCS) PROMOTES FUNCTIONAL RECOVERY AFTER SPINAL CORD INJURY (SCI). HOWEVER, THE NPCS HAD BEEN MOSTLY HARVESTED FROM EMBRYONIC STEM CELLS OR FETAL TISSUE, RAISING THE ETHICAL CONCERN. YAMANAKA AND HIS COLLEAGUES ESTABLISHED INDUCED PLURIPOTENT STEM CELLS (IPSCS) WHICH COULD BE GENERATED FROM SOMATIC CELLS, AND THIS INNOVATIVE DEVELOPMENT HAS MADE RAPID PROGRESSION IN THE FIELD OF SCI REGENERATION. WE AND OTHER GROUPS SUCCEEDED IN PRODUCING NPCS FROM IPSCS, AND DEMONSTRATED BENEFICIAL EFFECTS AFTER TRANSPLANTATION FOR ANIMAL MODELS OF SCI. IN PARTICULAR, EFFICACY OF HUMAN IPSC-NPCS IN NON-HUMAN PRIMATE SCI MODELS FOSTERED MOMENTUM OF CLINICAL APPLICATION FOR SCI PATIENTS. AT THE SAME TIME, HOWEVER, ARTIFICIAL INDUCTION METHODS IN IPSC TECHNOLOGY CREATED ALTERNATIVE ISSUES INCLUDING GENETIC AND EPIGENETIC ABNORMALITIES, AND TUMORIGENICITY AFTER TRANSPLANTATION. TO OVERCOME THESE PROBLEMS, IT IS CRITICALLY IMPORTANT TO SELECT ORIGINS OF SOMATIC CELLS, USE INTEGRATION-FREE SYSTEM DURING TRANSFECTION OF REPROGRAMMING FACTORS, AND THOROUGHLY INVESTIGATE THE CHARACTERISTICS OF IPSC-NPCS WITH RESPECT TO QUALITY MANAGEMENT. MOREOVER, SINCE MOST OF THE PREVIOUS STUDIES HAVE FOCUSED ON SUBACUTE PHASE OF SCI, ESTABLISHMENT OF EFFECTIVE NPC TRANSPLANTATION SHOULD BE EVALUATED FOR CHRONIC PHASE HEREAFTER. OUR GROUP IS CURRENTLY PREPARING CLINICAL-GRADE HUMAN IPSC-NPCS, AND WILL MOVE FORWARD TOWARD CLINICAL STUDY FOR SUBACUTE SCI PATIENTS SOON IN THE NEAR FUTURE. 2018 2 454 83 APPLICATIONS OF INDUCED PLURIPOTENT STEM CELL TECHNOLOGIES IN SPINAL CORD INJURY. NUMEROUS BASIC RESEARCH STUDIES HAVE SUGGESTED THE POTENTIAL EFFICACY OF NEURAL PRECURSOR CELL (NPC) TRANSPLANTATION IN SPINAL CORD INJURY (SCI). HOWEVER, IN MOST SUCH STUDIES, THE ORIGIN OF THE CELLS USED WAS MAINLY FETAL TISSUE OR EMBRYONIC STEM CELLS, BOTH OF WHICH CARRY POTENTIAL ETHICAL CONCERNS WITH RESPECT TO CLINICAL USE. THE DEVELOPMENT OF INDUCED PLURIPOTENT STEM CELLS (IPSCS) OPENED A NEW PATH TOWARD REGENERATIVE MEDICINE FOR SCI. IPSCS CAN BE GENERATED FROM SOMATIC CELLS BY INDUCTION OF TRANSCRIPTION FACTORS, AND INDUCED TO DIFFERENTIATE INTO NPCS WITH CHARACTERISTICS OF CELLS OF THE CENTRAL NERVOUS SYSTEM. THE BENEFICIAL EFFECT OF IPSC-DERIVED NPC TRANSPLANTATION HAS BEEN REPORTED FROM OUR GROUP AND OTHERS WORKING IN RODENT AND NON-HUMAN PRIMATE MODELS. THESE PROMISING RESULTS FACILITATE THE APPLICATION OF IPSCS FOR CLINICAL APPLICATIONS IN SCI PATIENTS. HOWEVER, IPSCS ALSO HAVE ISSUES, SUCH AS GENETIC/EPIGENETIC ABNORMALITIES AND TUMORIGENESIS BECAUSE OF THE ARTIFICIAL INDUCTION METHOD, THAT MUST BE ADDRESSED PRIOR TO CLINICAL USE. THE SELECTION OF SOMATIC CELLS, GENERATION OF INTEGRATION-FREE IPSCS, AND CHARACTERIZATION OF DIFFERENTIATED NPCS WITH THOROUGH QUALITY MANAGEMENT ARE ALL NEEDED TO ADDRESS THESE POTENTIAL RISKS. TO ENHANCE THE EFFICACY OF THE TRANSPLANTED IPSC-NPCS, ESPECIALLY AT CHRONIC PHASE OF SCI, ADMINISTRATION OF A CHONDROITINASE OR SEMAPHORIN3A INHIBITOR REPRESENTS A POTENTIALLY IMPORTANT MEANS OF PROMOTING AXONAL REGENERATION THROUGH THE LESION SITE. THE COMBINED USE OF REHABILITATION WITH SUCH CELL THERAPY APPROACHES IS ALSO IMPORTANT, AS REPETITIVE TRAINING ENHANCES NEURITE OUTGROWTH OF TRANSPLANTED CELLS AND STRENGTHENS NEURAL CIRCUITS AT CENTRAL PATTERN GENERATORS. OUR GROUP HAS ALREADY EVALUATED CLINICAL GRADE IPSC-DERIVED NPCS, AND WE LOOK FORWARD TO INITIATING CLINICAL TESTING AS THE NEXT STEP TOWARD DETERMINING WHETHER THIS APPROACH IS SAFE AND EFFECTIVE FOR CLINICAL USE. THIS ARTICLE IS PART OF THE MINI REVIEW SERIES "60TH ANNIVERSARY OF THE JAPANESE SOCIETY FOR NEUROCHEMISTRY". 2017 3 2697 33 EX VIVO MODELS OF CHRONIC GRANULOMATOUS DISEASE. INDUCED PLURIPOTENT STEM CELLS (IPSCS) ARE PLURIPOTENT STEM CELLS THAT CAN BE ESTABLISHED FROM DEDIFFERENTIATION OF ALL SOMATIC CELL TYPES BY EPIGENETIC PHENOMENA. IPSCS CAN BE DIFFERENTIATED INTO ANY MATURE CELLS LIKE NEURONS, HEPATOCYTES, OR PANCREATIC CELLS THAT HAVE NOT BEEN EASILY AVAILABLE TO DATE. THUS, IPSCS ARE WIDELY USED FOR DISEASE MODELING, DRUG DISCOVERY, AND CELL THERAPY DEVELOPMENT. HERE, WE DESCRIBE A PROTOCOL TO OBTAIN HUMAN MATURE AND FUNCTIONAL NEUTROPHILS AND MACROPHAGES AS EX VIVO MODELS OF X-LINKED CHRONIC GRANULOMATOUS DISEASE (X-CGD). THIS METHOD CAN BE APPLIED TO MODEL THE OTHER GENETIC FORMS OF CGD. WE ALSO DESCRIBE METHODS FOR TESTING THE CHARACTERISTICS AND FUNCTIONS OF NEUTROPHILS AND MACROPHAGES BY MORPHOLOGY, PHAGOCYTOSIS ASSAY, RELEASE OF GRANULE MARKERS OR CYTOKINES, CELL SURFACE MARKERS, AND NADPH OXIDASE ACTIVITY. 2019 4 5839 36 STROKE RECOVERY ENHANCING THERAPIES: LESSONS FROM RECENT CLINICAL TRIALS. POSTSTROKE RECOVERY PROCESSES INCLUDE RESTORATION OR COMPENSATION OF FUNCTION, RESPECTIVELY FUNCTIONS INITIALLY LOST OR NEW FUNCTIONS ACQUIRED AFTER AN INJURY. THERAPEUTIC INTERVENTIONS CAN ENHANCE THESE PROCESSES AND/OR REDUCE PROCESSES IMPEDING REGENERATION. NUMEROUS EXPERIMENTAL STUDIES SUGGEST GREAT OPPORTUNITIES FOR SUCH TREATMENTS, BUT THE RESULTS FROM RECENT LARGE CLINICAL TRIALS USING NEUROMODULATORS SUCH AS DOPAMINE AND FLUOXETINE ARE DISAPPOINTING. THE REASONS FOR THIS ARE MANIFOLD AFFECTING FORWARD TRANSLATION OF RESULTS FROM ANIMALS MODELS INTO THE HUMAN SITUATION. THIS "TRANSLATIONAL ROAD BLOCK" IS DEFINED BY DIFFERENCES BETWEEN ANIMALS AND HUMANS WITH REGARD TO THE GENETIC AND EPIGENETIC BACKGROUND, SIZE AND ANATOMY OF THE BRAIN, CEREBRAL VASCULAR ANATOMY, IMMUNE SYSTEM, AS WELL AS CLINICAL FUNCTION AND BEHAVIOR. BACKWARD BLOCKADE INCLUDES THE INCOMPATIBLE ADAPTION OF TARGETS AND OUTCOMES IN CLINICAL TRIALS WITH REGARD TO PRIOR PRECLINICAL FINDINGS. FOR EXAMPLE, THE DESIGN OF CLINICAL RECOVERY TRIALS VARIES WIDELY AND WAS CHARACTERIZED BY THE SELECTION OF DIFFERENT CLINICAL ENDPOINTS, THE INCLUSION A BROAD SPECTRUM OF STROKE SUBTYPES AND CLINICAL SYNDROMES AS WELL AS DIFFERENT TIME WINDOWS FOR TREATMENT INITIATION AFTER INFARCT ONSET. THIS REVIEW WILL DISCUSS THESE ASPECTS BASED ON THE RESULTS OF THE RECENT STROKE RECOVERY TRIALS WITH THE GOAL TO CONTRIBUTE TO THE CURRENTLY BIGGEST UNMET NEED IN STROKE RESEARCH - THE DEVELOPMENT OF A RECOVERY ENHANCING THERAPY THAT IMPROVES THE FUNCTIONAL OUTCOME OF A CHRONIC STROKE PATIENT. 2022 5 6284 37 THE POTENTIAL OF HUMAN INDUCED PLURIPOTENT STEM CELLS FOR MODELLING DIABETIC WOUND HEALING IN VITRO. IMPAIRED WOUND HEALING AND ULCERATION CAUSED BY DIABETES MELLITUS, IS A SIGNIFICANT HEALTHCARE BURDEN, MARKEDLY IMPAIRS QUALITY OF LIFE FOR PATIENTS, AND IS THE MAJOR CAUSE OF AMPUTATION WORLDWIDE. CURRENT EXPERIMENTAL APPROACHES USED TO INVESTIGATE THE COMPLEX WOUND HEALING PROCESS OFTEN INVOLVE CULTURES OF FIBROBLASTS AND/OR KERATINOCYTES IN VITRO, WHICH CAN BE LIMITED IN TERMS OF COMPLEXITY AND CAPACITY, OR UTILISATION OF RODENT MODELS IN WHICH THE MECHANISMS OF WOUND REPAIR DIFFER SUBSTANTIVELY FROM THAT IN HUMANS. HOWEVER, ADVANCES IN TISSUE ENGINEERING, AND THE DISCOVERY OF STRATEGIES TO REPROGRAMME ADULT SOMATIC CELLS TO PLURIPOTENCY, HAS LED TO THE POSSIBILITY OF DEVELOPING MODELS OF HUMAN SKIN ON A LARGE SCALE. GENERATION OF INDUCED PLURIPOTENT STEM CELLS (IPSCS) FROM TISSUES DONATED BY DIABETIC PATIENTS ALLOWS THE (EPI)GENETIC BACKGROUND OF THIS DISEASE TO BE STUDIED, AND THE ABILITY TO DIFFERENTIATE IPSCS TO MULTIPLE CELL TYPES FOUND WITHIN SKIN MAY FACILITATE THE DEVELOPMENT OF MORE COMPLEX SKIN MODELS; THESE ADVANCES OFFER KEY OPPORTUNITIES FOR IMPROVING MODELLING OF WOUND HEALING IN DIABETES, AND THE DEVELOPMENT OF EFFECTIVE THERAPEUTICS FOR TREATMENT OF CHRONIC WOUNDS. 2018 6 103 34 A REHABILOMICS FRAMEWORK FOR PERSONALIZED AND TRANSLATIONAL REHABILITATION RESEARCH AND CARE FOR INDIVIDUALS WITH DISABILITIES: PERSPECTIVES AND CONSIDERATIONS FOR SPINAL CORD INJURY. DESPITE MANY PEOPLE HAVING SIMILAR CLINICAL PRESENTATION, DEMOGRAPHIC FACTORS, AND CLINICAL CARE, OUTCOME CAN DIFFER FOR THOSE SUSTAINING SIGNIFICANT INJURY SUCH AS SPINAL CORD INJURY (SCI) AND TRAUMATIC BRAIN INJURY (TBI). IN ADDITION TO TRADITIONAL DEMOGRAPHIC, SOCIAL, AND CLINICAL FACTORS, VARIABILITY ALSO MAY BE ATTRIBUTABLE TO INNATE (INCLUDING GENETIC, TRANSCRIPTOMIC PROTEOMIC, EPIGENETIC) BIOLOGICAL VARIATION THAT INDIVIDUALS BRING TO RECOVERY AND THEIR UNIQUE RESPONSE TO THEIR CARE AND ENVIRONMENT. TECHNOLOGIES COLLECTIVELY CALLED "-OMICS" ENABLE SIMULTANEOUS MEASUREMENT OF AN ENORMOUS NUMBER OF BIOMOLECULES THAT CAN CAPTURE MANY POTENTIAL BIOLOGICAL CONTRIBUTORS TO HETEROGENEITY OF INJURY/DISEASE COURSE AND OUTCOME. DUE TO THE NATURE OF INJURY AND COMPLEX DISEASE, AND ITS ASSOCIATIONS WITH IMPAIRMENT, DISABILITY, AND RECOVERY, REHABILITATION DOES NOT LEND ITSELF TO A SINGULAR "PROTOCOLIZED" PLAN OF THERAPY. YET, BY NATURE AND BY NECESSITY, REHABILITATION MEDICINE OPERATES AS A FUNCTIONAL MODEL OF "PERSONALIZED CARE". THUS, THE CHALLENGE FOR SUCCESSFUL PROGRAMS OF TRANSLATIONAL REHABILITATION CARE AND RESEARCH IS TO IDENTIFY VIABLE APPROACHES TO EXAMINE BROAD POPULATIONS, WITH VARIED IMPAIRMENTS AND FUNCTIONAL LIMITATIONS, AND TO IDENTIFY EFFECTIVE TREATMENT RESPONSES THAT INCORPORATE PERSONALIZED PROTOCOLS TO OPTIMIZE FUNCTIONAL RECOVERY. THE REHABILOMICS FRAMEWORK IS A TRANSLATIONAL MODEL THAT PROVIDES AN "-OMICS" OVERLAY TO THE SCIENTIFIC STUDY OF REHABILITATION PROCESSES AND MULTIDIMENSIONAL OUTCOMES. REHABILOMICS RESEARCH PROVIDES NOVEL OPPORTUNITIES TO EVALUATE THE NEUROBIOLOGY OF COMPLEX INJURY OR CHRONIC DISEASE AND CAN BE USED TO EXAMINE METHODS AND TREATMENTS FOR PERSON-CENTERED CARE AMONG POPULATIONS WITH DISABILITIES. EXEMPLARS FOR APPLICATION IN SCI AND OTHER NEUROREHABILITATION POPULATIONS ARE DISCUSSED. 2014 7 5523 34 RISKS AND MECHANISMS OF ONCOLOGICAL DISEASE FOLLOWING STEM CELL TRANSPLANTATION. UNIQUE BIOLOGICAL PROPERTIES OF STEM CELLS MAKE THEM A PRECIOUS SOURCE OF CELL MATERIAL FOR TREATMENT OF A NUMBER OF PATHOLOGICAL CONDITIONS. AMONG ISSUES INHIBITING TRANSITION OF STEM CELL TECHNOLOGIES TO THE CLINICS, THE RISK OF ONCOLOGICAL COMPLICATIONS OF STEM CELL-BASED THERAPIES IS THE MOST CRITICAL. A MASSIVE AMOUNT OF CLINICAL AND EXPERIMENTAL DATA DEMONSTRATES THAT BOTH HEMATOLOGICAL (INCLUDING ACUTE AND CHRONIC MYELOID LEUKEMIA) AND NON-HEMATOLOGICAL (INCLUDING TERATOMA AND NON-TERATOMA TUMORS) MALIGNANCIES COULD ARISE FROM DONOR STEM CELLS OF DIFFERENT TYPES. A WIDE SPECTRUM OF MECHANISMS COULD UNDERLIE THE DEVELOPMENT OF ONCOLOGICAL DISEASE IN RECIPIENTS, INCLUDING: I) BLAST TRANSFORMATION OF PROLIFERATING DONOR STEM CELLS UNDER PERSISTENT ACTION OF CERTAIN FACTORS IN THE RECIPIENT, THUS CAUSING DE NOVO MALIGNANCIES; II) CONTAMINATION OF DONOR CELL MATERIAL WITH MALIGNANT CELLS; III) TRANSMISSION OF PARTICULAR VIRAL SUBTYPES WITH DONOR STEM CELLS, COMBINED WITH IMMUNOSUPPRESSION THERAPY EFFECTS; IV) UNCONTROLLABLE PROLIFERATION OF RESIDUAL UNDIFFERENTIATED STEM CELLS OF VARIOUS PLASTICITY; AND V) KARYOTYPIC INSTABILITY IN STEM CELLS FOLLOWING PROLONGED CULTURING/EXPANSION IN VITRO. POTENTIAL PREVENTIVE STRATEGIES ARE DIVERSE AND INCLUDE I) HIGH-THROUGHPUT CELL SORTING-BASED STRATEGIES; II) INTRODUCTION OF SUICIDE GENES INTO THE DONOR STEM CELL GENOME; III) APPLICATION OF APOPTOSIS-INDUCING EPIGENETIC FACTORS; AND SOME OTHER OPTIONS. 2010 8 1923 30 ENVIRONMENTAL EPIGENETIC MODIFICATIONS AND REPROGRAMMING-RECALCITRANT GENES. THE TERM "ENVIRONMENTAL EPIGENETIC MODIFICATIONS" REFERS TO ALTERATIONS IN PHENOTYPE TRIGGERED BY ENVIRONMENTAL STIMULI VIA EPIGENETIC MECHANISMS. EPIDEMIOLOGIC AND ANIMAL MODEL STUDIES SHOW THAT A SUBSET OF SUCH ENVIRONMENTAL EPIGENETIC MARKS MAY AFFECT SUSCEPTIBILITY TO CHRONIC DISEASES. A GROWING BODY OF EVIDENCE REGARDING INCOMPLETENESS OF REPROGRAMMING INDICATES THAT THE POTENTIAL RETENTION OF PATHOGENIC ENVIRONMENTAL EPIGENETICS IN HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS) SHOULD BE SERIOUSLY CONSIDERED. GIVEN THIS POSSIBILITY, THE OPTIMIZATION OF METHODS FOR THE GENERATION OF HUMAN INDUC PLURIPOTENT STEM CELLS MAY REQUIRE THE IDENTIFICATION OF EPIGENETICALLY APPROPRIATE SOMATIC CELL SOURCES. SIMILARLY, TECHNIQUES FOR CONTROLLING EPIGENETIC MODIFICATION BY ENVIRONMENTAL FACTORS MAY ALSO PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF EPIGENETICALLY STABLE SOURCES OF PLURIPOTENT STEM CELLS. 2010 9 5313 26 PSYCHOLOGICAL STRESS AS A MODULATOR OF FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY. THERE IS STRONG EVIDENCE INDICATING THAT THE SOCIAL ENVIRONMENT TRIGGERS CHANGES TO THE PSYCHOLOGICAL STRESS RESPONSE AND GLUCOCORTICOID RECEPTOR FUNCTION. CONSIDERABLE LITERATURE LINKS THE SUBSEQUENT CHANGES IN STRESS RESILIENCY TO PHYSICAL HEALTH. HERE, CONVERGING EVIDENCE FOR THE MODULATORY ROLE OF CHRONIC PSYCHOLOGICAL STRESS IN THE RECOVERY PROCESS FOLLOWING SPINAL CORD INJURY (SCI) IS PRESENTED. DESPITE THE CONSIDERABLE ADVANCES IN SCI RESEARCH, WE ARE STILL UNABLE TO IDENTIFY THE CAUSES OF VARIABILITY IN PATIENTS' RECOVERY FOLLOWING INJURY. WE PROPOSE THAT INDIVIDUALS' PAST AND PRESENT LIFE EXPERIENCES (IN THE FORM OF STRESS EXPOSURE) MAY SIGNIFICANTLY MODULATE PATIENTS' OUTCOME POST-SCI. WE PROPOSE A THEORETICAL MODEL TO EXPLAIN THE NEGATIVE IMPACT OF CHRONIC PSYCHOLOGICAL STRESS ON PHYSICAL AND PSYCHOLOGICAL RECOVERY. THE STRESS EXPERIENCED IN LIFE PRIOR TO SCI AND ALSO AS A RESULT OF THE TRAUMATIC INJURY, COULD COMPROMISE GLUCOCORTICOID RECEPTOR SENSITIVITY AND FUNCTION, AND CONTRIBUTE TO HIGH LEVELS OF INFLAMMATION AND APOPTOSIS POST-SCI, DECREASING THE TISSUE REMAINING AT THE INJURY SITE AND UNDERMINING RECOVERY OF FUNCTION. BOTH STRESS-INDUCED GLUCOCORTICOID RESISTANCE AND STRESS-INDUCED EPIGENETIC CHANGES TO THE GLUCOCORTICOID RECEPTOR CAN MODULATE THE NUCLEAR FACTOR-KAPPA B REGULATED INFLAMMATORY PATHWAYS AND THE BCL-2 REGULATED APOPTOSIS PATHWAYS. THIS MODEL NOT ONLY CONTRIBUTES TO THE THEORETICAL UNDERSTANDING OF THE RECOVERY PROCESS FOLLOWING INJURY, BUT ALSO PROVIDES CONCRETE TESTABLE HYPOTHESES FOR FUTURE STUDIES. 2014 10 4277 41 MICROGLIA SEQUELAE: BRAIN SIGNATURE OF INNATE IMMUNITY IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A PSYCHIATRIC DISORDER WITH SIGNIFICANT IMPACT ON INDIVIDUALS AND SOCIETY. THE CURRENT PHARMACOLOGIC TREATMENT, WHICH PRINCIPALLY ALLEVIATES PSYCHOSIS, IS FOCUSED ON NEUROTRANSMITTERS MODULATION, RELYING ON DRUGS WITH SEVERE SIDE EFFECTS AND INEFFECTIVENESS IN A SIGNIFICANT PERCENTAGE OF CASES. THEREFORE, AND DUE TO DIFFICULTIES INHERENT TO DIAGNOSIS AND TREATMENT, IT IS VITAL TO REASSESS ALTERNATIVE CELLULAR AND MOLECULAR DRUG TARGETS. DISTINCT RISK FACTORS - GENETIC, DEVELOPMENTAL, EPIGENETIC, AND ENVIRONMENTAL - HAVE BEEN ASSOCIATED WITH DISEASE ONSET AND PROGRESSION, GIVING RISE TO THE PROPOSAL OF DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS AND PUTATIVE PHARMACOLOGICAL TARGETS. IMMUNITY IS INVOLVED AND, PARTICULARLY MICROGLIA - INNATE IMMUNE CELLS OF THE CENTRAL NERVOUS SYSTEM, CRITICALLY INVOLVED IN BRAIN DEVELOPMENT - HAVE CAPTURED ATTENTION AS CELLULAR PLAYERS. MICROGLIA UNDERGO MARKED MORPHOLOGIC AND FUNCTIONAL ALTERATIONS IN THE HUMAN DISEASE, AS WELL AS IN ANIMAL MODELS OF SCHIZOPHRENIA, AS REPORTED IN SEVERAL ORIGINAL PAPERS. WE CLUSTER THE MAIN FINDINGS OF CLINICAL STUDIES BY GROUPS OF PATIENTS: (1) AT ULTRA-HIGH RISK OF PSYCHOSIS, (2) WITH A FIRST EPISODE OF PSYCHOSIS OR RECENT-ONSET SCHIZOPHRENIA, AND (3) WITH CHRONIC SCHIZOPHRENIA; IN TRANSLATIONAL STUDIES, WE HIGHLIGHT THE TIME WINDOW OF APPEARANCE OF PARTICULAR MICROGLIA ALTERATIONS IN THE MOST WELL STUDIED ANIMAL MODEL IN THE FIELD (MATERNAL IMMUNE ACTIVATION). THE ORGANIZATION OF CLINICAL AND TRANSLATIONAL FINDINGS BASED ON SCHIZOPHRENIA-ASSOCIATED MICROGLIA CHANGES IN DIFFERENT PHASES OF THE DISEASE COURSE MAY HELP DEFINING A TEMPORAL PATTERN OF MICROGLIA CHANGES AND MAY DRIVE THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES. 2022 11 2770 33 EXTENDING INJURY- AND DISEASE-RESISTANT CNS PHENOTYPES BY REPETITIVE EPIGENETIC CONDITIONING. SIGNIFICANT REDUCTIONS IN THE EXTENT OF ACUTE INJURY IN THE CNS CAN BE ACHIEVED BY EXPOSURE TO DIFFERENT PRECONDITIONING STIMULI, BUT THE DURATION OF THE INDUCED PROTECTIVE PHENOTYPE IS TYPICALLY SHORT-LASTING, AND THUS IS DEEMED AS LIMITING ITS CLINICAL APPLICABILITY. EXTENDING THE PERIOD OVER WHICH SUCH ADAPTIVE EPIGENETIC CHANGES PERSIST - IN EFFECT, EXPANDING CONDITIONING'S "THERAPEUTIC WINDOW" - WOULD SIGNIFICANTLY BROADEN THE POTENTIAL APPLICATIONS OF SUCH A TREATMENT APPROACH IN PATIENTS. THE FREQUENCY OF THE CONDITIONING STIMULUS MAY HOLD THE KEY. WHILE TRANSIENT (1-3 DAYS) PROTECTION AGAINST CNS ISCHEMIC INJURY IS WELL ESTABLISHED PRECLINICALLY FOLLOWING A SINGLE PRECONDITIONING STIMULUS, REPETITIVELY PRESENTING PRECONDITIONING STIMULI EXTENDS THE DURATION OF ISCHEMIC TOLERANCE BY MANY WEEKS. MOREOVER, REPETITIVE INTERMITTENT POSTCONDITIONING ENHANCES POST-ISCHEMIC RECOVERY METRICS AND IMPROVES LONG-TERM SURVIVAL. INTERMITTENT CONDITIONING IS ALSO EFFICACIOUS FOR PREVENTING OR DELAYING INJURY IN PRECLINICAL MODELS OF CHRONIC NEURODEGENERATIVE DISEASE, AND FOR PROMOTING LONG-LASTING FUNCTIONAL IMPROVEMENTS IN A NUMBER OF OTHER PATHOLOGIES AS WELL. ALTHOUGH THE DETAILED MECHANISMS UNDERLYING THESE PROTRACTED KINDS OF NEUROPLASTICITY REMAIN LARGELY UNSTUDIED, ACCUMULATING EMPIRICAL EVIDENCE SUPPORTS THE CONTENTION THAT ALL OF THESE ADAPTIVE PHENOTYPES ARE EPIGENETICALLY MEDIATED. GOING FORWARD, ADDITIONAL PRECLINICAL DEMONSTRATIONS OF THE ABILITY TO INDUCE SUSTAINED BENEFICIAL PHENOTYPES THAT REDUCE THE BURDEN OF ACUTE AND CHRONIC NEURODEGENERATION, AND EXPERIMENTAL INTERROGATIONS OF THE REGULATORY CONSTRUCTS RESPONSIBLE FOR THESE EPIGENETIC RESPONSES, WILL ACCELERATE THE IDENTIFICATION OF NOT ONLY EFFICACIOUS BUT ALSO PRACTICAL, ADAPTIVE EPIGENETICS-BASED TREATMENTS FOR INDIVIDUALS WITH NEUROLOGICAL DISEASE. 2015 12 3380 39 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY. 2023 13 3472 31 IDENTIFICATION AND MANAGEMENT OF PAIN MEDICATION ABUSE AND MISUSE: CURRENT STATE AND FUTURE DIRECTIONS. LONG-TERM OPIOID THERAPY POSES A RISK FOR ABUSE AND MISUSE IN SOME PATIENTS. IDENTIFYING WHICH PATIENTS MAY POTENTIALLY BE AT RISK PRIOR TO INITIATION OF THERAPY, AND IDENTIFYING PATIENTS IN WHOM THESE PROBLEMS DEVELOP DURING THERAPY, ARE SIGNIFICANT CHALLENGES. OUTCOME PREDICTION IS IMPEDED BY THE COMPLEXITY OF THE PROBLEM, WHERE CONSIDERABLE HETEROGENEITY RESULTS FROM PSYCHOLOGICAL AND SOCIOECONOMIC FACTORS, AS WELL AS INTERINDIVIDUAL VARIATION IN BIOLOGICAL PATHWAYS DUE TO GENETIC AND EPIGENETIC FACTORS. SCREENING TOOLS DESIGNED TO DETECT OPIOID MISUSE AND URINE DRUG TESTING ARE BOTH USED CLINICALLY; SCANT EVIDENCE CURRENTLY EXISTS TO ALLOW THE FORMULATION OF AN ALGORITHM FOR JUDICIOUS USE OF THESE TOOLS. MOREOVER, THESE TOOLS MAY NOT BE ADDRESSING THE UNDERLYING ALTERATIONS IN BIOLOGICAL PATHWAYS THAT OCCUR OWING TO THE DEVELOPMENT OF CHRONIC PAIN OR IN RESPONSE TO CHRONIC OPIOID ADMINISTRATION. AN EVIDENCE-BASED ALGORITHMIC APPROACH TO RISK MITIGATION THAT CAN BE APPLIED IN A COST-EFFECTIVE MANNER TO GUIDE THERAPY IS URGENTLY NEEDED. 2012 14 6449 48 THERAPEUTIC TARGETING OF TELOMERASE. TELOMERE LENGTH AND CELL FUNCTION CAN BE PRESERVED BY THE HUMAN REVERSE TRANSCRIPTASE TELOMERASE (HTERT), WHICH SYNTHESIZES THE NEW TELOMERIC DNA FROM A RNA TEMPLATE, BUT IS NORMALLY RESTRICTED TO CELLS NEEDING A HIGH PROLIFERATIVE CAPACITY, SUCH AS STEM CELLS. CONSEQUENTLY, TELOMERASE-BASED THERAPIES TO ELONGATE SHORT TELOMERES ARE DEVELOPED, SOME OF WHICH HAVE SUCCESSFULLY REACHED THE STAGE I IN CLINICAL TRIALS. TELOMERASE IS ALSO PERMISSIVE FOR TUMORIGENESIS AND 90% OF ALL MALIGNANT TUMORS USE TELOMERASE TO OBTAIN IMMORTALITY. THUS, REVERSAL OF TELOMERASE UPREGULATION IN TUMOR CELLS IS A POTENTIAL STRATEGY TO TREAT CANCER. NATURAL AND SMALL-MOLECULE TELOMERASE INHIBITORS, IMMUNOTHERAPEUTIC APPROACHES, OLIGONUCLEOTIDE INHIBITORS, AND TELOMERASE-DIRECTED GENE THERAPY ARE USEFUL TREATMENT STRATEGIES. TELOMERASE IS MORE WIDELY EXPRESSED THAN ANY OTHER TUMOR MARKER. THE LOW EXPRESSION IN NORMAL TISSUES, TOGETHER WITH THE LONGER TELOMERES IN NORMAL STEM CELLS VERSUS CANCER CELLS, PROVIDES SOME DEGREE OF SPECIFICITY WITH LOW RISK OF TOXICITY. HOWEVER, LONG TERM TELOMERASE INHIBITION MAY ELICIT NEGATIVE EFFECTS IN HIGHLY-PROLIFERATIVE CELLS WHICH NEED TELOMERASE FOR SURVIVAL, AND IT MAY INTERFERE WITH TELOMERE-INDEPENDENT PHYSIOLOGICAL FUNCTIONS. MOREOVER, ONLY A FEW HTERT MOLECULES ARE REQUIRED TO OVERCOME SENESCENCE IN CANCER CELLS, AND TELOMERASE INHIBITION REQUIRES PROLIFERATING CELLS OVER A SUFFICIENT NUMBER OF POPULATION DOUBLINGS TO INDUCE TUMOR SUPPRESSIVE SENESCENCE. THESE LIMITATIONS MAY EXPLAIN THE MODERATE SUCCESS RATES IN MANY CLINICAL STUDIES. DESPITE EXTENSIVE STUDIES, ONLY ONE VACCINE AND ONE TELOMERASE ANTAGONIST ARE ROUTINELY USED IN CLINICAL WORK. FOR COMPLETE ERADICATION OF ALL SUBPOPULATIONS OF CANCER CELLS A SIMULTANEOUS TARGETING OF SEVERAL MECHANISMS WILL LIKELY BE NEEDED. POSSIBLE TECHNICAL IMPROVEMENTS HAVE BEEN PROPOSED INCLUDING THE DEVELOPMENT OF MORE SPECIFIC INHIBITORS, METHODS TO INCREASE THE EFFICACY OF VACCINATION METHODS, AND PERSONALIZED APPROACHES. TELOMERASE ACTIVATION AND CELL REJUVENATION IS SUCCESSFULLY USED IN REGENERATIVE MEDICINE FOR TISSUE ENGINEERING AND RECONSTRUCTIVE SURGERY. HOWEVER, THERE ARE ALSO A NUMBER OF PITFALLS IN THE TREATMENT WITH TELOMERASE ACTIVATING PROCEDURES FOR THE WHOLE ORGANISM AND FOR LONGER PERIODS OF TIME. EXTENDED CELL LIFESPAN MAY ACCUMULATE RARE GENETIC AND EPIGENETIC ABERRATIONS THAT CAN CONTRIBUTE TO MALIGNANT TRANSFORMATION. THEREFORE, NOVEL VECTOR SYSTEMS HAVE BEEN DEVELOPED FOR A 'MILD' INTEGRATION OF TELOMERASE INTO THE HOST GENOME AND LOSS OF THE VECTOR IN RAPIDLY-PROLIFERATING CELLS. IT IS CURRENTLY UNCLEAR IF THIS TECHNIQUE CAN ALSO BE USED IN HUMAN BEINGS TO TREAT CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS. 2016 15 2790 44 FACTORS TO CONSIDER IN THE USE OF STEM CELLS FOR PHARMACEUTIC DRUG DEVELOPMENT AND FOR CHEMICAL SAFETY ASSESSMENT. GIVEN THE REALITY OF THE INADEQUACIES OF CURRENT CONCEPTS OF THE MECHANISMS OF CHEMICAL TOXICITIES, OF THE VARIOUS ASSAYS TO PREDICT TOXICITIES FROM CURRENT MOLECULAR, BIOCHEMICAL, IN VITRO AND ANIMAL BIOASSAYS, AND OF THE FAILURE TO GENERATE EFFICACIOUS AND SAFE CHEMICALS FOR MEDICINES, FOOD SUPPLEMENTS, INDUSTRIAL, CONSUMER AND AGRICULTURAL CHEMICALS, THE RECENT NAS REPORT, "TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY", HAS DRAWN ATTENTION TO A RENEWED EXAMINATION OF WHAT NEEDS TO BE DONE TO IMPROVE OUR CURRENT APPROACH FOR BETTER ASSESSMENT OF POTENTIAL RISK TO HUMAN HEALTH. THIS "COMMENTARY" PROVIDES A MAJOR PARADIGM CHALLENGE TO THE CURRENT CONCEPTS OF HOW CHEMICALS INDUCE TOXICITIES AND HOW THESE VARIOUS MECHANISMS OF TOXICITIES CAN CONTRIBUTE TO THE PATHOGENESIS OF SOME HUMAN DISEASES, SUCH AS BIRTH DEFECTS AND CANCER. IN CONCORDANCE WITH THE NAS REPORT TO TAKE "... ADVANTAGE OF THE ON-GOING REVOLUTION IN BIOLOGY AND BIOTECHNOLOGY", THIS "COMMENTARY" SUPPORTS THE USE OF HUMAN EMBRYONIC AND ADULT STEM CELLS, GROWN IN VITRO UNDER SIMULATED "IN VIVO NICHE CONDITIONS". THE HUMAN BEING SHOULD BE VIEWED "AS GREATER THAN THE SUM OF ITS PARTS". HOMEOSTATIC CONTROL OF THE "EMERGENT PROPERTIES" OF THE HUMAN HIERARCHY, NEEDED TO MAINTAIN HUMAN HEALTH, REQUIRES COMPLEX INTEGRATION OF ENDOGENOUS AND EXOGENOUS SIGNALING MOLECULES THAT CONTROL CELL PROLIFERATION, DIFFERENTIATION, APOPTOSIS AND SENESCENCE OF STEM, PROGENITOR AND DIFFERENTIATED CELLS. CURRENTLY, IN VITRO TOXICITY ASSAYS (MUTAGENESIS, CYTOTOXICITY, EPIGENETIC MODULATION), DONE ON 2-DIMENSIONAL PRIMARY RODENT OR HUMAN CELLS (WHICH ARE ALWAYS MIXTURES OF CELLS), ON IMMORTALIZED OR TUMORIGENIC RODENT OR HUMAN CELL LINES DO NOT REPRESENT NORMAL HUMAN CELLS IN VIVO [WHICH DO NOT GROW ON PLASTIC AND WHICH ARE IN MICRO-ENVIRONMENTS REPRESENTING 3 DIMENSIONS AND CONSTANTLY INTERACTING FACTORS]. IN ADDITION, WITH THE KNOWN GENETIC, GENDER, AND DEVELOPMENTAL STATE OF CELLS IN VIVO, ANY IN VITRO TOXICITY ASSAY WILL NEED TO MIMIC THESE CONDITIONS IN VITRO. MORE SPECIFICALLY, WHILE TISSUES CONTAIN A FEW STEM CELLS, MANY PROGENITOR/TRANSIT CELLS AND TERMINALLY DIFFERENTIATED CELLS, IT SHOULD BE OBVIOUS THAT BOTH EMBRYONIC AND ADULT STEM CELLS WOULD BE CRITICAL "TARGET" CELLS FOR TOXICITY TESTING. THE ULTIMATE POTENTIAL FOR IN VITRO TESTING OF HUMAN STEM CELLS WILL TO TRY TO MIMIC A 3-D IN VITRO MICRO-ENVIRONMENT ON MULTIPLE "ORGAN-SPECIFIC AND MULTIPLE GENOTYPIC/GENDER "ADULT STEM CELLS. THE ROLE OF STEM CELLS IN MANY CHRONIC DISEASES, SUCH AS CANCER, BIRTH DEFECTS, AND POSSIBLY ADULT DISEASES AFTER PRE-NATAL AND EARLY POST-NATAL EXPOSURES (BARKER HYPOTHESIS), DEMANDS TOXICITY STUDIES OF STEM CELLS. WHILE ALTERATION OF GENE EXPRESSION ("TOXICO-EPIGENOMICS") IS A LEGITIMATE ENDPOINT OF THESE TOXICITY STUDIES, ALTERATION OF THE QUANTITY OF STEM CELLS DURING DEVELOPMENT MUST BE SERIOUS CONSIDERED. IF THE FUTURE UTILITY OF HUMAN STEM CELLS PROVES TO BE VALID, THE ELIMINATION OF LESS RELEVANT, EXPENSIVE AND TIME-CONSUMING RODENT AND 2-D HUMAN IN VITRO ASSAYS WILL BE ELIMINATED. 2010 16 5913 28 TARGETED THERAPY IN LEUKEMIA. RESEARCH CONDUCTED OVER THE LAST TWO DECADES HAS YIELDED A DETAILED UNDERSTANDING OF THE MOLECULAR LESIONS THAT CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITORS INTO THE VARIOUS FORMS OF ACUTE AND CHRONIC LEUKEMIA. ALTHOUGH OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LEUKEMIA REMAINS INCOMPLETE, THE INFORMATION GAINED TO DATE HAS HAD A PROFOUND IMPACT ON THE WAY THESE MALIGNANCIES ARE BOTH DIAGNOSED AND MONITORED DURING THERAPY. MORE RECENTLY, TARGETED THERAPIES HAVE BEEN DEVELOPED AGAINST SOME OF THE IDENTIFIED GENETIC LESIONS. THESE THERAPIES HAVE LED TO SIGNIFICANT IMPROVEMENTS IN PATIENT OUTCOMES WHILE SIMULTANEOUSLY DECREASING THERAPY-RELATED TOXICITY. WITH THE ADVENT OF GENOME-WIDE METHODS TO DEFINE THE TOTAL COMPLEMENT OF GENETIC AND EPIGENETIC LESIONS INVOLVED IN LEUKEMOGENESIS, NEW TARGETED THERAPIES CAN BE ANTICIPATED. THIS REVIEW HIGHLIGHTS SOME OF THE TARGETED THERAPIES THAT ARE PRESENTLY BEING USED TO TREAT HEMATOPOIETIC MALIGNANCIES AND DESCRIBES SOME OF THE RECENT ADVANCES THAT SHOULD HAVE A SIGNIFICANT IMPACT ON THE DEVELOPMENT OF FUTURE TARGET THERAPIES. 2008 17 5038 21 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 18 806 29 CHALLENGES FOR MODELING AND INTERPRETING THE COMPLEX BIOLOGY OF SEVERE INJURY AND INFLAMMATION. HUMAN INJURY IS ASSOCIATED WITH INFLAMMATORY RESPONSES THAT ARE MODULATED BY THE ACUTE AND CHRONIC ACTIVITY OF ENDOGENOUS FACTORS AND EXOGENOUS INTERVENTIONS. A CHARACTERISTIC FEATURE OF CHRONIC, SEVERE INFLAMMATORY STATES IS THE DIMINISHED SIGNAL OUTPUT VARIABILITY OF MANY ORGAN SYSTEMS, INCLUDING INNATE IMMUNE RESPONSIVENESS AND ENDOGENOUS NEURAL AND ENDOCRINE-MEDIATED FUNCTIONS. THE ATTENUATION OF SIGNAL/RESPONSE VARIABILITY AND INTEGRATION OF FEEDBACK CAPACITY MAY CONTRIBUTE TO SYSTEMIC AND TISSUE-SPECIFIC DETERIORATION OF FUNCTION. SOME WELL-INTENTIONED THERAPIES DIRECTED TOWARD SUPPORT OF SYSTEMIC AND TISSUE FUNCTIONS MAY ACTUALLY PROMOTE THE LOSS OF SYSTEM(S) ADAPTABILITY AND CONTRIBUTE TO ADVERSE OUTCOMES IN SEVERELY STRESSED PATIENTS. IN VIVO AND IN SILICO MODELS OF STRESS, INJURY, AND INFECTION HAVE YET TO FULLY DEFINE THE INFLUENCES OF ONGOING STRESSFUL STIMULAE AS WELL AS GENETIC VARIATION AND EPIGENETIC FACTORS IN THE CONTEXT OF AN EVOLVING INFLAMMATORY STATE. EXPERIMENTAL AND HUMAN MODELS INCORPORATING VARIABLE, ANTECEDENT STRESS(ES) AND ALTERED NEUROENDOCRINE RHYTHMS MIGHT APPROXIMATE THE ALTERED ADAPTABILITY IN IMMUNE AND ORGAN FUNCTION RESPONSES. SUCH MODELS MAY ALSO PROVIDE INSIGHTS INTO THE SALIENT MECHANISMS OF RISK AND OUTCOME MORE PRECISELY THAN DO THE CONSTRAINED STUDY CONDITIONS OF CURRENT ANIMAL OR HUMAN MODELS OF SYSTEMIC INFLAMMATION. 2008 19 4911 23 PAIN IMAGING: FUTURE APPLICATIONS TO INTEGRATIVE CLINICAL AND BASIC NEUROBIOLOGY. WE HAVE ENTERED A NEW ERA IN UNDERSTANDING CNS CIRCUITRY INVOLVED IN ACUTE AND CHRONIC PAIN. THE ABILITY TO OBJECTIVELY MEASURE A PAIN OR ANALGESIC STATE OF THE BRAIN USING NON-INVASIVE METHODS THAT DEFINE NEURAL ACTIVATION PROVIDES THE POSSIBILITY FOR TOP-DOWN APPROACHES TO DRUG DISCOVERY. THESE BRAIN MAPS REPRESENT THE SPECIFIC BRAIN STATE. IN THE FUTURE, CORRELATIONS WITH SUCH STATES AND BEHAVIORAL, GENETIC, EPIGENETIC OR OTHER CHEMICAL MARKERS MAY HELP DEFINE SPECIFIC DIAGNOSTIC TOOLS AND NOVEL APPROACHES TO DRUG DISCOVERY. 2003 20 1204 36 COULD TARGETING EPIGENETIC PROCESSES RELIEVE CHRONIC PAIN STATES? PURPOSE OF REVIEW: ABERRATIONS IN THE EPIGENETIC LANDSCAPE HAVE PREVIOUSLY BEEN ASSOCIATED WITH HUMAN DISEASES SUCH AS CANCER AND SCHIZOPHRENIA, AND DRUGS THAT TARGET EPIGENETIC PROCESSES ARE CURRENTLY USED AS THERAPEUTIC AGENTS. THIS ARTICLE WILL REVIEW THE EVIDENCE OBTAINED FROM ANIMAL STUDIES INDICATING THAT EPIGENETIC PROCESSES MIGHT REGULATE LONG-TERM PAIN STATES AND THEN DISCUSS THE POSSIBILITY THAT TARGETING EPIGENETIC MECHANISMS MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. RECENT FINDINGS: RECENT ANIMAL STUDIES HAVE REPORTED INJURY-INDUCED CHANGES IN EPIGENETIC PROCESSES IN THE CENTRAL NERVOUS SYSTEM. THE PICTURE THAT HAS EMERGED IS THAT OF VERY COMPLEX EPIGENETIC PROGRAMS THAT DEPEND ON THE INJURY. HOWEVER, SOME STUDIES HAVE REPORTED THE SUCCESSFUL USE OF NONSPECIFIC EPIGENETIC TOOLS TO IMPROVE THE HYPERSENSITIVITY THAT DEVELOPS IN ANIMAL MODELS OF LONG-TERM PAIN STATES. SUMMARY: THE FIELD OF EPIGENETICS AND PAIN IS RAPIDLY EMERGING BUT FURTHER INVESTIGATION IS NEEDED TO FULLY COMPREHEND THE CONTRIBUTION OF EPIGENETIC PROCESSES TO CHRONIC PAIN STATES. ALTHOUGH THERAPEUTIC APPROACHES TARGETING THESE MECHANISMS MIGHT SEEM WORTHWHILE, WE CANNOT ASSERT THAT CURRENTLY AVAILABLE GLOBAL TOOLS SUCH AS HISTONE DEACETYLASE INHIBITORS CAN BE USED SUCCESSFULLY FOR THE LONG-TERM TREATMENT OF CHRONIC PAIN STATES. 2015