1 5564 90 ROLE OF HYPERMETHYLATION OF DAP-KINASE CPG ISLAND IN THE DEVELOPMENT OF THYROID LYMPHOMA. DEATH-ASSOCIATED PROTEIN-KINASE (DAP-KINASE) IS A SERINE/THREONINE KINASE WITH A DEATH DOMAIN THAT IS INVOLVED IN APOPTOSIS INDUCED BY INTERFERON-GAMMA, TNF-ALPHA, AND FAS LIGAND. EPIGENETIC DOWN-REGULATION OF DAP-KINASE GENE EXPRESSION BY HYPERMETHYLATION OF ITS PROMOTER REGION WAS REPORTED IN B-CELL MALIGNANCIES. PREVIOUS PATHOEPIDEMIOLOGIC STUDIES INDICATED THAT THYROID LYMPHOMA (TL) EVOLVES AMONG ACTIVE LYMPHOID CELLS IN CHRONIC LYMPHOCYTIC THYROIDITIS (CLTH). WITH USE OF METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION, THE METHYLATION STATUS OF DAP-KINASE CPG ISLAND WAS EXAMINED IN THYROID LESIONS OF 19 CASES WITH TL AND 9 WITH CLTH. THE FREQUENCY OF METHYLATION WAS HIGHER IN TL CASES (16 OF 19, 84.2%) THAN IN CLTH CASES (2 OF 9, 22.2%) (P < 0.01). DNA EXTRACTED FROM PERIPHERAL BLOOD LEUKOCYTES FROM TL AND CLTH CASES NEVER SHOWED METHYLATION, INDICATING THAT THE METHYLATION OCCURRED SOMATICALLY IN THE LESIONAL LYMPHOCYTES IN THYROID. THESE FINDINGS SUGGESTED THAT METHYLATION OF THE DAP-KINASE PROMOTER REGION MIGHT BE INVOLVED IN THE DEVELOPMENT OF TL FROM CLTH. 2000 2 6831 84 [HYPERMETHYLATION OF DAP-KINASE GENE CPG ISLAND IN MALIGNANT LYMPHOMA WITH B-CELL PHENOTYPE]. DEATH-ASSOCIATED PROTEIN-KINASE(DAP-KINASE) IS A PRO-APOPTOTIC SERINE/THREONINE KINASE WITH A DEATH DOMAIN, WHICH IS INVOLVED IN APOPTOSIS INDUCED BY INTERFERON-GAMMA, TUMOR NECROSIS FACTOR-ALPHA, AND FAS LIGAND. EPIGENETIC DOWN-REGULATION OF DAP-KINASE GENE EXPRESSION BY HYPERMETHYLATION OF ITS PROMOTER REGION WAS REPORTED IN CERTAIN KINDS OF MALIGNANCIES. PREVIOUS PATHO-EPIDEMIOLOGICAL STUDIES INDICATED THAT THYROID LYMPHOMA(TL) EVOLVES AMONG ACTIVE LYMPHOID CELLS IN CHRONIC LYMPHOCYTIC THYROIDITIS(CLTH). WITH THE USE OF METHYLATION SPECIFIC POLYMERASE CHAIN REACTION, METHYLATION STATUS OF DAP-KINASE CPG ISLAND WAS EXAMINED IN THYROID LESIONS OF 19 CASES WITH TL AND 9 WITH CLTH. FREQUENCY OF METHYLATION WAS HIGHER IN TL CASES(16 OF 19, 84.2%) THAN IN CLTH CASES(2 OF 9, 22.2%) (P < 0.01). DNA EXTRACTED FROM PERIPHERAL BLOOD LEUKOCYTES FROM TL AND CLTH CASES NEVER SHOWED METHYLATION, INDICATING THAT THE METHYLATION OCCURRED SOMATICALLY IN LESIONAL LYMPHOCYTES IN THE THYROID. WE ALSO EXAMINED THE METHYLATION STATUS OF DAP-KINASE GENE IN 16 CASES OF T-CELL MALIGNANCIES INCLUDING EIGHT ADULT T-CELL LEUKEMIA/LYMPHOMA AND 24 NK/T-CELL, 34 B-CELL, AND TWO IMMUNOPHENOTYPICALLY UNDETERMINED LYMPHOMAS. FREQUENCY OF METHYLATION WAS HIGHER IN B-CELL(27 OF 34, 79.4%) THAN IN T-CELL MALIGNANCIES(EIGHT OF 16, 50%) (P < 0.05). FIFTEEN OF 24(62.5%) NK/T-CELL LYMPHOMAS SHOWED DNA METHYLATION. HEMATOPOIETIC CELL LINES WITH A METHYLATED GENE WERE RESISTANT TO APOPTOSIS. TREATMENT OF THE CELLS WITH A DEMETHYLATING AGENT RESTORED APOPTOTIC CELL DEATH IN ONE B-CELL LYMPHOMA CELL LINE WITH DNA METHYLATION. OUR RESULTS SUGGESTED THAT SUPPRESSION OF DAP-KINASE EXPRESSION BY DNA METHYLATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF B-CELL MALIGNANCIES. 2001 3 80 19 A NEW ROLE FOR THE P2Y-LIKE GPR17 RECEPTOR IN THE MODULATION OF MULTIPOTENCY OF OLIGODENDROCYTE PRECURSOR CELLS IN VITRO. OLIGODENDROCYTE PRECURSOR CELLS (OPCS, ALSO CALLED NG2 CELLS) ARE SCATTERED THROUGHOUT BRAIN PARENCHYMA, WHERE THEY FUNCTION AS A RESERVOIR TO REPLACE LOST OR DAMAGED OLIGODENDROCYTES, THE MYELIN-FORMING CELLS. THE HYPOTHESIS THAT, UNDER SOME CIRCUMSTANCES, OPCS CAN ACTUALLY BEHAVE AS MULTIPOTENT CELLS, THUS GENERATING ASTROCYTES AND NEURONS AS WELL, HAS ARISEN FROM SOME IN VITRO AND IN VIVO EVIDENCE, BUT THE MOLECULAR PATHWAYS CONTROLLING THIS ALTERNATIVE FATE OF OPCS ARE NOT FULLY UNDERSTOOD. THEIR IDENTIFICATION WOULD OPEN NEW OPPORTUNITIES FOR NEURONAL REPLACE STRATEGIES, BY FOSTERING THE INTRINSIC ABILITY OF THE BRAIN TO REGENERATE. HERE, WE SHOW THAT THE ANTI-EPILEPTIC EPIGENETIC MODULATOR VALPROIC ACID (VPA) CAN PROMOTE THE GENERATION OF NEW NEURONS FROM NG2(+) OPCS UNDER NEUROGENIC PROTOCOLS IN VITRO, THROUGH THEIR INITIAL DE-DIFFERENTIATION TO A STEM CELL-LIKE PHENOTYPE THAT THEN EVOLVES TO "HYBRID" CELL POPULATION, SHOWING OPC MORPHOLOGY BUT EXPRESSING THE NEURONAL MARKER BETAIII-TUBULIN AND THE GPR17 RECEPTOR, A KEY DETERMINANT IN DRIVING OPC TRANSITION TOWARDS MYELINATING OLIGODENDROCYTES. UNDER THESE CONDITIONS, THE PHARMACOLOGICAL BLOCKADE OF THE P2Y-LIKE RECEPTOR GPR17 BY CANGRELOR, A DRUG RECENTLY APPROVED FOR HUMAN USE, PARTIALLY MIMICS THE EFFECTS MEDIATED BY VPA THUS ACCELERATING CELLS' NEUROGENIC CONVERSION. THESE DATA SHOW A CO-LOCALIZATION BETWEEN NEURONAL MARKERS AND GPR17 IN VITRO, AND SUGGEST THAT, BESIDES ITS INVOLVEMENT IN OLIGODENDROGENESIS, GPR17 CAN DRIVE THE FATE OF NEURAL PRECURSOR CELLS BY INSTRUCTING PRECURSORS TOWARDS THE NEURONAL LINEAGE. BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL "DRUGGABLE" TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC BRAIN DISEASES. 2016 4 3025 19 GENETICS AND PATHOPHYSIOLOGY OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND ITS MAIN AUTOANTIGEN PROTEINASE 3. GRANULOMATOSIS WITH POLYANGIITIS (GPA) IS A SEVERE AUTOIMMUNE DISEASE AND ONE OF THE SMALL VESSEL ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIDES. ALTHOUGH ITS ETIOLOGY AND PATHOPHYSIOLOGY ARE STILL WIDELY UNKNOWN, IT IS ACCEPTED THAT INFECTIONS, ENVIRONMENTAL FACTORS, EPIGENETIC MODIFICATIONS, AND A GENETIC PREDISPOSITION PROVIDE THE BASIS FOR THIS SYSTEMIC DISORDER. GPA TYPICALLY EVOLVES INTO TWO PHASES: AN INITIAL PHASE CHARACTERIZED BY EAR, NOSE AND THROAT (ENT) MANIFESTATIONS, SUCH AS CHRONIC SINUSITIS AND OTITIS, ULCERATION OF THE ORAL CAVITY AND PHARYNX, AS WELL AS PULMONARY NODULES AND A SEVERE GENERALIZED PHASE, DEFINED BY THE OCCURRENCE OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS, PULMONARY HEMORRHAGE, AND ARTHRITIS. ANCAS, DIRECTED AGAINST THE NEUTROPHILIC ENZYMES PROTEINASE 3 AND MYELOPEROXIDASE, ARE PRESENT IN UP TO 90% OF THE AFFECTED PATIENTS IN THE SYSTEMIC PHASE. AS THE HUMORAL IMMUNITY IS PREDOMINANTLY DIRECTED AGAINST NEUTROPHILIC ANTIGENS, IT IS APPARENT THAT NEUTROPHILS PLAY A CRITICAL ROLE IN GPA BOTH AS TARGET AND EFFECTOR CELLS. ALTHOUGH GPA PATHOGENESIS IS NOT WELL KNOWN, SOME SUSCEPTIBILITY GENES AND LOCI HAVE BEEN IDENTIFIED BY CANDIDATE GENE APPROACHES, GENOME-WIDE ASSOCIATION STUDIES, AND META-ANALYSES, AS WELL AS FAMILIAL ASSOCIATION STUDIES. SUCH GENES ARE CTLA4, PTPN22, COL11A2, SERPINA1, AND THE MHC CLASS II GENE CLUSTER. THIS REVIEW HIGHLIGHTS THE CLINICAL, PATHOPHYSIOLOGICAL, AND GENETIC BACKGROUND OF GPA AND AIMS TO GIVE AN OVERVIEW OF RECENT EFFORTS TO IDENTIFY GPA SUSCEPTIBILITY GENES. WE POINT OUT THE GENETIC BASIS OF THE MAIN AUTOANTIGEN PR3 AND WHY IT IS SO DIFFICULT TO ESTABLISH A MURINE GPA MODEL. 2016 5 4567 20 MYELOID-DERIVED SUPPRESSOR CELL FUNCTION AND EPIGENETIC EXPRESSION EVOLVES OVER TIME AFTER SURGICAL SEPSIS. BACKGROUND: SEPSIS IS AN INCREASINGLY SIGNIFICANT CHALLENGE THROUGHOUT THE WORLD AS ONE OF THE MAJOR CAUSES OF PATIENT MORBIDITY AND MORTALITY. CENTRAL TO THE HOST IMMUNOLOGIC RESPONSE TO SEPSIS IS THE INCREASE IN CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), WHICH HAVE BEEN DEMONSTRATED TO BE PRESENT AND INDEPENDENTLY ASSOCIATED WITH POOR LONG-TERM CLINICAL OUTCOMES. MDSCS ARE PLASTIC CELLS AND POTENTIALLY MODIFIABLE, PARTICULARLY THROUGH EPIGENETIC INTERVENTIONS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE HOW THE SUPPRESSIVE PHENOTYPE OF MDSCS EVOLVES AFTER SEPSIS IN SURGICAL ICU PATIENTS, AS WELL AS TO IDENTIFY EPIGENETIC DIFFERENCES IN MDSCS THAT MAY EXPLAIN THESE CHANGES. METHODS: CIRCULATING MDSCS FROM 267 SURVIVORS OF SURGICAL SEPSIS WERE PHENOTYPED AT VARIOUS INTERVALS OVER 6 WEEKS, AND HIGHLY ENRICHED MDSCS FROM 23 OF THESE SAMPLES WERE CO-CULTURED WITH CD3/CD28-STIMULATED AUTOLOGOUS T CELLS. MICRORNA EXPRESSION FROM ENRICHED MDSCS WAS ALSO IDENTIFIED. RESULTS: WE OBSERVED THAT MDSC NUMBERS REMAIN SIGNIFICANTLY ELEVATED IN HOSPITALIZED SEPSIS SURVIVORS FOR AT LEAST 6 WEEKS AFTER THEIR INFECTION. HOWEVER, ONLY MDSCS OBTAINED AT AND BEYOND 14 DAYS POST-SEPSIS SIGNIFICANTLY SUPPRESSED T LYMPHOCYTE PROLIFERATION AND IL-2 PRODUCTION. THESE SAME MDSCS DISPLAYED UNIQUE EPIGENETIC (MIRNA) EXPRESSION PATTERNS COMPARED TO EARLIER TIME POINTS. CONCLUSIONS: WE CONCLUDE THAT IN SEPSIS SURVIVORS, IMMATURE MYELOID CELL NUMBERS ARE INCREASED BUT THE IMMUNE SUPPRESSIVE FUNCTION SPECIFIC TO MDSCS DEVELOPS OVER TIME, AND THIS IS ASSOCIATED WITH A SPECIFIC EPIGENOME. THESE FINDINGS MAY EXPLAIN THE CHRONIC AND PERSISTENT IMMUNE SUPPRESSION SEEN IN THESE SUBJECTS. 2019 6 4404 21 MODULATION OF THE RESPONSE TO MYCOBACTERIUM LEPRAE AND PATHOGENESIS OF LEPROSY. THE INITIAL INFECTION BY THE OBLIGATE INTRACELLULAR BACILLUS MYCOBACTERIUM LEPRAE EVOLVES TO LEPROSY IN A SMALL SUBSET OF THE INFECTED INDIVIDUALS. TRANSMISSION IS BELIEVED TO OCCUR MAINLY BY EXPOSURE TO BACILLI PRESENT IN AEROSOLS EXPELLED BY INFECTED INDIVIDUALS WITH HIGH BACILLARY LOAD. MYCOBACTERIUM LEPRAE-SPECIFIC DNA HAS BEEN DETECTED IN THE BLOOD OF ASYMPTOMATIC HOUSEHOLD CONTACTS OF LEPROSY PATIENTS YEARS BEFORE ACTIVE DISEASE ONSET, SUGGESTING THAT, FOLLOWING INFECTION, THE BACTERIUM REACHES THE LYMPHATIC DRAINAGE AND THE BLOOD OF AT LEAST SOME INDIVIDUALS. THE LOWER TEMPERATURE AND AVAILABILITY OF PROTECTED MICROENVIRONMENTS MAY PROVIDE THE INITIAL CONDITIONS FOR THE SURVIVAL OF THE BACILLUS IN THE AIRWAYS AND SKIN. A SUBSET OF SKIN-RESIDENT MACROPHAGES AND THE SCHWANN CELLS OF PERIPHERAL NERVES, TWO M. LEPRAE PERMISSIVE CELLS, MAY PROTECT M. LEPRAE FROM EFFECTOR CELLS IN THE INITIAL PHASE OF THE INFECTION. THE INTERACTION OF M. LEPRAE WITH THESE CELLS INDUCES METABOLIC CHANGES, INCLUDING THE FORMATION OF LIPID DROPLETS, THAT ARE ASSOCIATED WITH MACROPHAGE M2 PHENOTYPE AND THE PRODUCTION OF MEDIATORS THAT FACILITATE THE DIFFERENTIATION OF SPECIFIC T CELLS FOR M. LEPRAE-EXPRESSED ANTIGENS TO A MEMORY REGULATORY PHENOTYPE. HERE, WE DISCUSS THE POSSIBLE INITIALS STEPS OF M. LEPRAE INFECTION THAT MAY LEAD TO ACTIVE DISEASE ONSET, MAINLY FOCUSING ON EVENTS PRIOR TO THE MANIFESTATION OF THE ESTABLISHED CLINICAL FORMS OF LEPROSY. WE HYPOTHESIZE THAT THE PROGRESSIVE DIFFERENTIATION OF T CELLS TO THE TREGS PHENOTYPE INHIBITS EFFECTOR FUNCTION AGAINST THE BACILLUS, ALLOWING AN INCREASE IN THE BACILLARY LOAD AND EVOLUTION OF THE INFECTION TO ACTIVE DISEASE. EPIGENETIC AND METABOLIC MECHANISMS DESCRIBED IN OTHER CHRONIC INFLAMMATORY DISEASES ARE EVALUATED FOR POTENTIAL APPLICATION TO THE UNDERSTANDING OF LEPROSY PATHOGENESIS. A POTENTIAL ROLE FOR POST-EXPOSURE PROPHYLAXIS OF LEPROSY IN REDUCING M. LEPRAE-INDUCED ANTI-INFLAMMATORY MEDIATORS AND, IN CONSEQUENCE, TREG/T EFFECTOR RATIOS IS PROPOSED. 2022 7 6824 24 [GENETIC ALTERATIONS IN PRENEOPLASTIC AND NEOPLASTIC INJURIES OF THE GALLBLADDER]. THIS ARTICLE AIMS TO REVIEW THE MOST RELEVANT MORPHOLOGICAL AND MOLECULAR ASPECTS INVOLVED IN GALLBLADDER (GB) CANCER. IN CHILE, GALLBLADDER CANCER IS THE MAIN CAUSE OF DEATH DUE TO CANCER, AMONG WOMEN OLDER THAN 40 YEARS. HOWEVER, THERE IS ALMOST NONE INFORMATION ABOUT THE MORPHOLOGICAL CHANGES AND THE GENETIC ALTERATIONS INVOLVED IN THE BEGINNING AND DEVELOPMENT OF THIS NEOPLASIA. TWO CARCINOGENIC WAYS HAVE BEEN DESCRIBED. THE SEQUENCE ADENOMA-CARCINOMA IS ACCEPTED TO BE LESS FREQUENT AND IMPORTANT. THE MOST IMPORTANT IS THE SEQUENCE WHERE A METAPLASIA EVOLVES TO DISPLASIA THAT PROGRESSES TO CARCINOMA IN SITU AND FINALLY IT BECOMES INVASIVE. THIS PROGRESS REQUIRES 10 TO 15 YEARS APPROXIMATELY. DURING THIS TIME, A CONTINUE PROGRESSION OF INJURIES HAVE BEEN DESCRIBED. MOLECULAR RESEARCH STUDIES SHOW GENETIC ANOMALIES IN SOME GENES WHICH ARE TEMPORARY EVENTS IN PRENEOPLASTIC INJURIES OF THE GALLBLADDER. SOME OF THEM EVEN EXIST BEFORE THE FIRST MORPHOLOGICAL CHANGES, WHILE THE EXPRESSION OF TUMOR SUPPRESSOR GENES LIKE P53, ADHESION MOLECULES AND ONCOGENES, AMONG OTHERS, CAN BE RELATED TO LATE GB CARCINOGENESIS. THE K-RAS GENE SEEMS TO PLAY A ROLE IN THIS NEOPLASIA, MAINLY IN THOSE THAT PRESENT AN ABNORMAL BILIOPANCREATIC UNION. THE MICROSATELITAL INSTABILITY HAS BEEN FOUND IN A SMALL SUBSET OF PRENEOPLASTIC AND NEOPLASTIC LESIONS. THE EXISTENCE OF METHYLATION IN THE PROMOTOR GENE AREAS HAS BEEN RELATED TO THE CELLULAR PROLIFERATION, INVASION AND METASTASIS AND ALSO IN CASES OF CHRONIC CHOLECYSTITIS, SUGGESTING THAT THIS EPIGENETIC PHENOMENON REPRESENTS A CRUCIAL EARLY EVENT IN GB CARCINOGENESIS. 2010 8 5408 15 REGULATION AND SIGNALING OF THE GPR17 RECEPTOR IN OLIGODENDROGLIAL CELLS. REMYELINATION, NAMELY, THE FORMATION OF NEW MYELIN SHEATHS AROUND DENUDED AXONS, COUNTERACTS AXONAL DEGENERATION AND RESTORES NEURONAL FUNCTION. CONSIDERABLE ADVANCES HAVE BEEN MADE IN UNDERSTANDING THIS REGENERATIVE PROCESS THAT OFTEN FAILS IN DISEASES LIKE MULTIPLE SCLEROSIS, LEAVING AXONS DEMYELINATED AND VULNERABLE TO DAMAGE, THUS CONTRIBUTING TO DISEASE PROGRESSION. THE IDENTIFICATION OF THE MEMBRANE RECEPTOR GPR17 ON A SUBSET OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS), WHICH MEDIATE REMYELINATION IN THE ADULT CENTRAL NERVOUS SYSTEM (CNS), HAS LED TO A HUGE AMOUNT OF EVIDENCE THAT VALIDATED THIS RECEPTOR AS A NEW ATTRACTIVE TARGET FOR REMYELINATING THERAPIES. HERE, WE SUMMARIZE THE ROLE OF GPR17 IN OPC FUNCTION, MYELINATION AND REMYELINATION, DESCRIBING ITS ATYPICAL PHARMACOLOGY, ITS DOWNSTREAM SIGNALING, AND THE GENETIC AND EPIGENETIC FACTORS MODULATING ITS ACTIVITY. WE ALSO HIGHLIGHT CRUCIAL INSIGHTS INTO GPR17 PATHOPHYSIOLOGY COMING FROM THE DEMONSTRATION THAT OLIGODENDROCYTE INJURY, ASSOCIATED WITH INFLAMMATION IN CHRONIC NEURODEGENERATIVE CONDITIONS, IS INVARIABLY CHARACTERIZED BY ABNORMAL AND PERSISTENT GPR17 UPREGULATION, WHICH, IN TURN, IS ACCOMPANIED BY A BLOCK OF OPCS AT IMMATURE PREMYELINATING STAGES. FINALLY, WE DISCUSS THE CURRENT LITERATURE IN LIGHT OF THE POTENTIAL EXPLOITMENT OF GPR17 AS A THERAPEUTIC TARGET TO PROMOTE REMYELINATION. 2020 9 367 15 AMPLIFIED PAIN SYNDROMES IN CHILDREN: TREATMENT AND NEW INSIGHTS INTO DISEASE PATHOGENESIS. PURPOSE OF REVIEW: ALTHOUGH MANY DIAGNOSTIC TERMS ARE USED FOR PEDIATRIC CHRONIC PAIN, EVIDENCE SUGGESTS A COMMON THREAD OF SIGNAL AMPLIFICATION, LEADING TO THE UNIFYING TERM 'AMPLIFIED PAIN SYNDROMES'. ONGOING RESEARCH PROVIDES NEW INSIGHTS INTO BIOPSYCHOSOCIAL CONTRIBUTORS AND TREATMENTS FOR PEDIATRIC AMPLIFIED PAIN SYNDROMES. RECENT FINDINGS: BASIC SCIENCE INDICATES A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, NEUROCHEMICAL, ENDOCRINE, AND INFLAMMATORY CONTRIBUTORS, ALONG WITH ENVIRONMENTAL AND PSYCHOLOGICAL FACTORS. ALTHOUGH MEDICATIONS AND INTERVENTIONS REMAIN COMMON APPROACHES TO CHILDREN WITH CHRONIC PAIN, THEIR EVIDENCE IS LIMITED. PRELIMINARY EVIDENCE EXISTS FOR MINDFULNESS-BASED THERAPIES, YOGA, AND OTHER COMPLEMENTARY/ALTERNATIVE MEDICINE APPROACHES. THE STRONGEST EVIDENCE IS FOR EXERCISE-BASED AND COGNITIVE-BEHAVIORAL TREATMENTS, IN PARTICULAR, WHEN COMBINED IN A MULTIDISCIPLINARY FORMAT. INTENSIVE APPROACHES (PAIN REHABILITATION) HAVE THE POTENTIAL TO EFFECTIVELY AND EFFICIENTLY TREAT THOSE MOST DISABLED BY AMPLIFIED PAIN SYNDROMES, AND LEAD TO SUSTAINED IMPROVEMENT IN PAIN, FUNCTIONING, AND MEDICAL UTILIZATION. SUMMARY: ALTHOUGH UNDERSTANDING OF THE MECHANISMS UNDERLYING PEDIATRIC AMPLIFIED PAIN SYNDROMES EVOLVES, STANDARD OF CARE IS MULTIDISCIPLINARY EMPHASIZING EXERCISE THERAPY, COGNITIVE-BEHAVIORAL TREATMENT, AND SELF-REGULATION. TREATMENT SHOULD TARGET FULL RETURN TO PHYSICAL FUNCTION, WHICH LEADS TO SUBSEQUENT IMPROVEMENT OR RESOLUTION OF PAIN. MULTIDISCIPLINARY CARE CAN BE COORDINATED BY A RHEUMATOLOGIST OR OTHER PHYSICIAN WITH APPROPRIATE REFERRALS, OR THROUGH A MULTIDISCIPLINARY TEAM. 2014 10 4964 23 PATHOGENETIC AND CLINICAL ASPECTS OF ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIDES. ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODIES (ANCA) TARGETING PROTEINASE 3 (PR3) AND MYELOPEROXIDASE EXPRESSED BY INNATE IMMUNE CELLS (NEUTROPHILS AND MONOCYTES) ARE SALIENT DIAGNOSTIC AND PATHOGENIC FEATURES OF SMALL VESSEL VASCULITIS, COMPRISING GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS, AND EOSINOPHILIC GPA. GENETIC STUDIES SUGGEST THAT ANCA-ASSOCIATED VASCULITIDES (AAV) CONSTITUTE SEPARATE DISEASES, WHICH SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES, BUT ARE OTHERWISE HETEROGENEOUS. THE SUCCESSFUL THERAPEUTIC USE OF ANTI-CD20 ANTIBODIES EMPHASIZES THE PROMINENT ROLE OF ANCA AND POSSIBLY OTHER AUTOANTIBODIES IN THE PATHOGENESIS OF AAV. HOWEVER, TO ELUCIDATE CAUSAL EFFECTS IN AAV, A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY LEADING TO THE EMERGENCE OF B LYMPHOCYTES THAT PRODUCE PATHOGENIC ANCA REMAINS A CHALLENGE. DIFFERENT SCENARIOS SEEM POSSIBLE; E.G., THE BREAK OF TOLERANCE INDUCED BY A SHIFT FROM NON-PATHOGENIC TOWARD PATHOGENIC AUTOANTIGEN EPITOPES IN INFLAMED TISSUE. THIS REVIEW GIVES A BRIEF OVERVIEW ON CURRENT KNOWLEDGE ABOUT GENETIC AND EPIGENETIC FACTORS, BARRIER DYSFUNCTION AND CHRONIC NON-RESOLVING INFLAMMATION, NECRO-INFLAMMATORY AUTO-AMPLIFICATION OF CELLULAR DEATH AND INFLAMMATION, ALTERED AUTOANTIGEN PRESENTATION, ALTERNATIVE COMPLEMENT PATHWAY ACTIVATION, ALTERATIONS WITHIN PERIPHERAL AND INFLAMED TISSUE-RESIDING T- AND B-CELL POPULATIONS, ECTOPIC LYMPHOID TISSUE NEOFORMATION, THE CHARACTERIZATION OF PR3-SPECIFIC T-CELLS, PROPERTIES OF ANCA, LINKS BETWEEN AUTOIMMUNE DISEASE AND INFECTION-TRIGGERED PATHOLOGY, AND ANIMAL MODELS IN AAV. 2018 11 2882 20 G-PROTEIN-COUPLED RECEPTOR GPR17 REGULATES OLIGODENDROCYTE DIFFERENTIATION IN RESPONSE TO LYSOLECITHIN-INDUCED DEMYELINATION. OLIGODENDROCYTES ARE THE MYELIN-PRODUCING CELLS OF THE CENTRAL NERVOUS SYSTEM (CNS). A VARIETY OF BRAIN DISORDERS FROM "CLASSICAL" DEMYELINATING DISEASES, SUCH AS MULTIPLE SCLEROSIS, STROKE, SCHIZOPHRENIA, DEPRESSION, DOWN SYNDROME AND AUTISM, ARE SHOWN MYELINATION DEFECTS. OLIGODENDROCYTE MYELINATION IS REGULATED BY A COMPLEX INTERPLAY OF INTRINSIC, EPIGENETIC AND EXTRINSIC FACTORS. GPR17 (G PROTEIN-COUPLED RECEPTOR 17) IS A G PROTEIN-COUPLED RECEPTOR, AND HAS BEEN IDENTIFIED TO BE A REGULATOR FOR OLIGODENDROCYTE DEVELOPMENT. HERE, WE DEMONSTRATE THAT THE ABSENCE OF GPR17 ENHANCES REMYELINATION IN VIVO WITH A TOXIN-INDUCED MODEL WHEREBY FOCAL DEMYELINATED LESIONS ARE GENERATED IN SPINAL CORD WHITE MATTER OF ADULT MICE BY LOCALIZED INJECTION OF LPC(L-A-LYSOPHOSPHATIDYLCHOLINE). THE INCREASED EXPRESSION OF THE ACTIVATED FORM OF ERK1/2 (PHOSPHO-ERK1/2) IN LESION AREAS SUGGESTED THE POTENTIAL ROLE OF ERK1/2 ACTIVITY ON THE GPR17-DEPENDENT MODULATION OF MYELINATION. THE ABSENCE OF GPR17 ENHANCES REMYELINATION IS CORRELATE WITH THE ACTIVATED ERK1/2 (PHOSPHO-ERK1/2).BEING A MEMBRANE RECEPTOR, GPR17 REPRESENTS AN IDEAL DRUGGABLE TARGET TO BE EXPLOITED FOR INNOVATIVE REGENERATIVE APPROACHES TO ACUTE AND CHRONIC CNS DISEASES. 2018 12 5798 15 STEM CELLS AND LUNG REGENERATION. THE ABILITY TO REPLACE DEFECTIVE CELLS IN AN AIRWAY WITH CELLS THAT CAN ENGRAFT, INTEGRATE, AND RESTORE A FUNCTIONAL EPITHELIUM COULD POTENTIALLY CURE A NUMBER OF LUNG DISEASES. PROGRESS TOWARD THE DEVELOPMENT OF STRATEGIES TO REGENERATE THE ADULT LUNG BY EITHER IN VIVO OR EX VIVO TARGETING OF ENDOGENOUS STEM CELLS OR PLURIPOTENT STEM CELL DERIVATIVES IS LIMITED BY OUR FUNDAMENTAL LACK OF UNDERSTANDING OF THE MECHANISMS CONTROLLING HUMAN LUNG DEVELOPMENT, THE PRECISE IDENTITY AND FUNCTION OF HUMAN LUNG STEM AND PROGENITOR CELL TYPES, AND THE GENETIC AND EPIGENETIC CONTROL OF HUMAN LUNG FATE. IN THIS REVIEW, WE INTEND TO DISCUSS THE KNOWN STEM/PROGENITOR CELL POPULATIONS, THEIR RELATIVE DIFFERENCES BETWEEN RODENTS AND HUMANS, THEIR ROLES IN CHRONIC LUNG DISEASE, AND THEIR THERAPEUTIC PROSPECTS. ADDITIONALLY, WE HIGHLIGHT THE RECENT BREAKTHROUGHS THAT HAVE INCREASED OUR UNDERSTANDING OF THESE CELL TYPES. THESE ADVANCEMENTS INCLUDE NOVEL LINEAGE-TRACED ANIMAL MODELS AND SINGLE-CELL RNA SEQUENCING OF HUMAN AIRWAY CELLS, WHICH HAVE PROVIDED CRITICAL INFORMATION ON THE STEM CELL SUBTYPES, TRANSITION STATES, IDENTIFYING CELL MARKERS, AND INTRICATE PATHWAYS THAT COMMIT A STEM CELL TO DIFFERENTIATE OR TO MAINTAIN PLASTICITY. AS OUR CAPACITY TO MODEL THE HUMAN LUNG EVOLVES, SO WILL OUR UNDERSTANDING OF LUNG REGENERATION AND OUR ABILITY TO TARGET ENDOGENOUS STEM CELLS AS A THERAPEUTIC APPROACH FOR LUNG DISEASE. 2020 13 4568 16 MYELOID-DERIVED SUPPRESSOR CELLS (MDSC): WHEN GOOD INTENTIONS GO AWRY. MDSC ARE A HETEROGENEOUS POPULATION OF IMMATURE MYELOID CELLS THAT ARE RELEASED BY BIOLOGICAL STRESS SUCH AS TISSUE DAMAGE AND INFLAMMATION. CONVENTIONALLY, MDSC ARE KNOWN FOR THEIR DETRIMENTAL ROLE IN CHRONIC INFLAMMATION AND NEOPLASTIC CONDITIONS. HOWEVER, THEIR INTRINSIC FUNCTIONS IN IMMUNOREGULATION, WOUND HEALING, AND ANGIOGENESIS ARE INTENDED TO PROTECT FROM OVER-REACTIVE IMMUNE RESPONSES, MAINTENANCE OF IMMUNOTOLERANCE, TISSUE REPAIR, AND HOMEOSTASIS. PARADOXICALLY, UNDER CERTAIN CONDITIONS, MDSC CAN IMPAIR PROTECTIVE IMMUNE RESPONSES AND EXACERBATE THE DISEASE. THE TRANSITION FROM PROTECTIVE TO HARMFUL MDSC IS MOST LIKELY DRIVEN BY ENVIRONMENTAL AND EPIGENETIC MECHANISMS INDUCED BY PROLONGED EXPOSURE TO UNRESOLVED INFLAMMATORY TRIGGERS. HERE, WE REVIEW SEVERAL EXAMPLES OF THE DUAL IMPACT OF MDSC IN CONDITIONS SUCH AS MATERNAL-FETAL TOLERANCE, SELF-ANTIGENS IMMUNOTOLERANCE, OBESITY-ASSOCIATED CANCER, SEPSIS AND TRAUMA. MOREOVER, WE ALSO HIGHLIGHTED THE EVIDENCE INDICATING THAT MDSC HAVE A ROLE IN COVID-19 PATHOPHYSIOLOGY. FINALLY, WE HAVE SUMMARIZED THE EVIDENCE INDICATING EPIGENETIC MECHANISMS ASSOCIATED WITH MDSC FUNCTION. 2021 14 2856 28 FROM METHYLATION TO MYELINATION: EPIGENOMIC AND TRANSCRIPTOMIC PROFILING OF CHRONIC INACTIVE DEMYELINATED MULTIPLE SCLEROSIS LESIONS. IN THE PROGRESSIVE PHASE OF MULTIPLE SCLEROSIS (MS), THE HAMPERED DIFFERENTIATION CAPACITY OF OLIGODENDROCYTE PRECURSOR CELLS (OPCS) EVENTUALLY RESULTS IN REMYELINATION FAILURE. WE HAVE PREVIOUSLY SHOWN THAT DNA METHYLATION OF ID2/ID4 IS HIGHLY INVOLVED IN OPC DIFFERENTIATION AND REMYELINATION. IN THIS STUDY, WE TOOK AN UNBIASED APPROACH BY DETERMINING GENOME-WIDE DNA METHYLATION PATTERNS WITHIN CHRONICALLY DEMYELINATED MS LESIONS AND INVESTIGATED HOW CERTAIN EPIGENETIC SIGNATURES RELATE TO OPC DIFFERENTIATION CAPACITY. WE COMPARED GENOME-WIDE DNA METHYLATION AND TRANSCRIPTIONAL PROFILES BETWEEN CHRONICALLY DEMYELINATED MS LESIONS AND MATCHED NORMAL-APPEARING WHITE MATTER (NAWM), MAKING USE OF POST-MORTEM BRAIN TISSUE (N = 9/GROUP). DNA METHYLATION DIFFERENCES THAT INVERSELY CORRELATED WITH MRNA EXPRESSION OF THEIR CORRESPONDING GENES WERE VALIDATED FOR THEIR CELL-TYPE SPECIFICITY IN LASER-CAPTURED OPCS USING PYROSEQUENCING. THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM WAS USED TO EPIGENETICALLY EDIT HUMAN-IPSC-DERIVED OLIGODENDROCYTES TO ASSESS THE EFFECT ON CELLULAR DIFFERENTIATION. OUR DATA SHOW HYPERMETHYLATION OF CPGS WITHIN GENES THAT CLUSTER IN GENE ONTOLOGIES RELATED TO MYELINATION AND AXON ENSHEATHMENT. CELL TYPE-SPECIFIC VALIDATION INDICATES A REGION-DEPENDENT HYPERMETHYLATION OF MBP, ENCODING FOR MYELIN BASIC PROTEIN, IN OPCS OBTAINED FROM WHITE MATTER LESIONS COMPARED TO NAWM-DERIVED OPCS. BY ALTERING THE DNA METHYLATION STATE OF SPECIFIC CPGS WITHIN THE PROMOTOR REGION OF MBP, USING EPIGENETIC EDITING, WE SHOW THAT CELLULAR DIFFERENTIATION AND MYELINATION CAN BE BIDIRECTIONALLY MANIPULATED USING THE CRISPR-DCAS9-DNMT3A/TET1 SYSTEM IN VITRO. OUR DATA INDICATE THAT OPCS WITHIN CHRONICALLY DEMYELINATED MS LESIONS ACQUIRE AN INHIBITORY PHENOTYPE, WHICH TRANSLATES INTO HYPERMETHYLATION OF CRUCIAL MYELINATION-RELATED GENES. ALTERING THE EPIGENETIC STATUS OF MBP CAN RESTORE THE DIFFERENTIATION CAPACITY OF OPCS AND POSSIBLY BOOST (RE)MYELINATION. 2023 15 3904 20 LEPROSY PIRNOME: EXPLORING NEW POSSIBILITIES FOR AN OLD DISEASE. LEPROSY, WHICH IS CAUSED BY THE HUMAN PATHOGEN MYCOBACTERIUM LEPRAE, CAUSES NERVE DAMAGE, DEFORMITY AND DISABILITY IN OVER 200,000 PEOPLE EVERY YEAR. BECAUSE OF THE LONG DOUBLING TIME OF M. LEPRAE (13 DAYS) AND THE DELAYED ONSET OF DETECTABLE SYMPTOMS, WHICH IS ESTIMATED TO BE APPROXIMATELY 3-7 YEARS AFTER INFECTION, THERE IS ALWAYS A LARGE PERCENTAGE OF SUBCLINICALLY INFECTED INDIVIDUALS IN THE POPULATION WHO WILL EVENTUALLY DEVELOP THE DISEASE, MAINLY IN ENDEMIC COUNTRIES. PIRNAS COMPRISE THE LARGEST GROUP OF SMALL NONCODING RNAS FOUND IN HUMANS, AND THEY ARE DISTINCT FROM MICRORNAS (MIRNAS) AND SMALL INTERFERING RNAS (SIRNAS). PIRNAS FUNCTION IN TRANSPOSON SILENCING, EPIGENETIC REGULATION, AND GERMLINE DEVELOPMENT. THE FUNCTIONAL ROLE OF PIRNAS AND THEIR ASSOCIATED PIWI PROTEINS HAVE STARTED TO EMERGE IN THE DEVELOPMENT OF HUMAN CANCERS AND VIRAL INFECTIONS, BUT THEIR RELEVANCE TO BACTERIAL DISEASES HAS NOT BEEN INVESTIGATED. THE PRESENT STUDY REPORTS THE PIRNOME OF HUMAN SKIN, REVEALING THAT ALL BUT ONE OF THE PIRNAS EXAMINED ARE DOWNREGULATED IN LEPROSY SKIN LESIONS. CONSIDERING THAT ONE OF THE BEST CHARACTERIZED FUNCTIONS OF PIRNAS IN HUMANS IS POSTTRANSCRIPTIONAL MRNA SILENCING, THEIR FUNCTIONS ARE SIMILAR TO WHAT WE HAVE DESCRIBED FOR MIRNAS, INCLUDING ACTING ON APOPTOSIS, M. LEPRAE RECOGNITION AND ENGULFMENT, SCHWANN CELL (SC) DEMYELINATION, EPITHELIAL-MESENCHYMAL TRANSITION (EMT), LOSS OF SENSATION AND NEUROPATHIC PAIN. IN ADDITION TO NEW FINDINGS ON LEPROSY PHYSIOPATHOLOGY, THE DISCOVERY OF RELEVANT PIRNAS INVOLVED IN DISEASE PROCESSES IN HUMAN SKIN MAY PROVIDE NEW CLUES FOR THERAPEUTIC TARGETS, SPECIFICALLY TO CONTROL NERVE DAMAGE, A PROMINENT FEATURE OF LEPROSY THAT HAS NO CURRENTLY AVAILABLE PHARMACEUTICAL TREATMENT. 2020 16 6427 21 THE TRANSITION FROM ACUTE TO CHRONIC PAIN: DYNAMIC EPIGENETIC REPROGRAMMING OF THE MOUSE PREFRONTAL CORTEX UP TO 1 YEAR AFTER NERVE INJURY. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT STRUCTURAL AND FUNCTIONAL CHANGES THROUGHOUT THE NEUROAXIS, INCLUDING IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPORTANT IN THE INTEGRATION OF SENSORY, COGNITIVE, AND EMOTIONAL INFORMATION AND IN CONDITIONED PAIN MODULATION. WE PREVIOUSLY REPORTED WIDESPREAD EPIGENETIC REPROGRAMMING IN THE PFC MANY MONTHS AFTER NERVE INJURY IN RODENTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, CAN DRIVE CHANGES IN GENE EXPRESSION WITHOUT MODIFYING DNA SEQUENCES. TO DATE, LITTLE IS KNOWN ABOUT EPIGENETIC DYSREGULATION AT THE ONSET OF ACUTE PAIN OR HOW IT PROGRESSES AS PAIN TRANSITIONS FROM ACUTE TO CHRONIC. WE HYPOTHESIZE THAT ACUTE PAIN AFTER INJURY RESULTS IN RAPID AND PERSISTENT EPIGENETIC REMODELLING IN THE PFC THAT EVOLVES AS PAIN BECOMES CHRONIC. WE FURTHER PROPOSE THAT UNDERSTANDING EPIGENETIC REMODELLING WILL PROVIDE INSIGHTS INTO THE MECHANISMS DRIVING PAIN-RELATED CHANGES IN THE BRAIN. EPIGENOME-WIDE ANALYSIS WAS PERFORMED IN THE MOUSE PFC 1 DAY, 2 WEEKS, 6 MONTHS, AND 1 YEAR AFTER PERIPHERAL INJURY USING THE SPARED NERVE INJURY IN MICE. SPARED NERVE INJURY RESULTED IN RAPID AND PERSISTENT CHANGES IN DNA METHYLATION, WITH ROBUST DIFFERENTIAL METHYLATION OBSERVED BETWEEN SPARED NERVE INJURY AND SHAM-OPERATED CONTROL MICE AT ALL TIME POINTS. HUNDREDS OF DIFFERENTIALLY METHYLATED GENES WERE IDENTIFIED, INCLUDING MANY WITH KNOWN FUNCTION IN PAIN. PATHWAY ANALYSIS REVEALED ENRICHMENT IN GENES RELATED TO STIMULUS RESPONSE AT EARLY TIME POINTS, IMMUNE FUNCTION AT LATER TIME POINTS, AND ACTIN AND CYTOSKELETAL REGULATION THROUGHOUT THE TIME COURSE. THESE RESULTS EMPHASIZE THE IMPORTANCE OF CONSIDERING PAIN CHRONICITY IN BOTH PAIN RESEARCH AND IN TREATMENT OPTIMIZATION. 2020 17 1053 18 CLINICAL IMPLICATIONS OF INTERFERON-GAMMA GENETIC AND EPIGENETIC VARIANTS. INTERFERON-GAMMA (IFN-GAMMA) IS AN INTEGRAL AND CRITICAL MOLECULE OF THE IMMUNE SYSTEM, WITH MULTIPLE FUNCTIONS, MOSTLY RELATED TO THE T HELPER TYPE 1 (TH1) RESPONSE TO INFECTION. IT IS CRITICAL FOR DEFENCE AGAINST MYCOBACTERIAL INFECTION AND IS OF INCREASING INTEREST IN DEFENCE AGAINST FUNGI. IN THIS ARTICLE, WE REVIEW THE GENETIC AND EPIGENETIC VARIANTS AFFECTING IFN-GAMMA EXPRESSION AND INVESTIGATE ITS ROLE IN DISEASE, WITH AN EMPHASIS ON FUNGAL DISEASES SUCH AS INVASIVE AND CHRONIC PULMONARY ASPERGILLOSIS. OVER 347 IFN-GAMMA GENE VARIANTS HAVE BEEN DESCRIBED, IN MULTIPLE ETHNIC POPULATIONS. MANY APPEAR TO CONFER A SUSCEPTIBILITY TO DISEASE, ESPECIALLY TUBERCULOSIS (TB) AND HEPATITIS, BUT ALSO SOME NON-INFECTIOUS CONDITIONS SUCH AS APLASTIC ANAEMIA, CERVICAL CANCER AND PSORIASIS. SEVERAL EPIGENETIC MODIFICATIONS ARE ALSO DESCRIBED, INCREASING IFN-GAMMA EXPRESSION IN TH1 LYMPHOCYTES AND REDUCING IFN-GAMMA EXPRESSION IN TH2 LYMPHOCYTES. RECOMBINANT IFN-GAMMA ADMINISTRATION IS LICENSED FOR THE PROPHYLAXIS OF INFECTION (BACTERIAL AND FUNGAL) IN PATIENTS WITH THE PHAGOCYTE FUNCTIONAL DEFICIENCY SYNDROME CHRONIC GRANULOMATOUS DISEASE, ALTHOUGH THE BENEFITS APPEAR LIMITED. INTERFERON-GAMMA THERAPY IS GIVEN TO PATIENTS WITH PROFOUND DEFECTS IN IFN-GAMMA AND INTERLEUKIN-12 PRODUCTION AND APPEARS TO BE BENEFICIAL FOR PATIENTS WITH INVASIVE ASPERGILLOSIS AND CRYPTOCOCCAL MENINGITIS, BUT THE STUDIES ARE NOT DEFINITIVE. A HIGH PROPORTION OF PATIENTS WITH CHRONIC PULMONARY ASPERGILLOSIS ARE POOR PRODUCERS OF IFN-GAMMA IN RESPONSE TO MULTIPLE STIMULI AND COULD ALSO BENEFIT FROM IFN-GAMMA ADMINISTRATION. THE INVESTIGATION AND MANAGEMENT OF PATIENTS WITH POSSIBLE OR DEMONSTRATED IFN-GAMMA DEFICIENCY IN ADULTHOOD IS POORLY STUDIED AND COULD BE GREATLY ENHANCED WITH THE INTEGRATION OF GENETIC DATA. 2014 18 2329 18 EPIGENETIC REGULATION OF IMMUNE CELL FUNCTIONS DURING POST-SEPTIC IMMUNOSUPPRESSION. STUDIES IN HUMANS AND ANIMAL MODELS INDICATE THAT PROFOUND IMMUNOSUPPRESSION IS ONE OF THE CHRONIC CONSEQUENCES OF SEVERE SEPSIS. THIS IMMUNE DYSFUNCTION ENCOMPASSES DEFICIENCIES IN ACTIVATION OF CELLS IN BOTH THE MYELOID AND LYMPHOID CELL LINEAGES. AS A RESULT, SURVIVORS OF SEVERE SEPSIS ARE AT RISK OF SUCCUMBING TO INFECTIONS PERPETRATED BY OPPORTUNISTIC PATHOGENS THAT ARE NORMALLY CONTROLLED BY A FULLY FUNCTIONING IMMUNE SYSTEM. RECENT STUDIES HAVE INDICATED THAT EPIGENETIC MECHANISMS MAY BE ONE DRIVING FORCE BEHIND THIS IMMUNOSUPPRESSION, THROUGH SUPPRESSION OF PROINFLAMMATORY GENE PRODUCTION AND SUBSEQUENT IMMUNE CELL ACTIVATION, PROLIFERATION AND EFFECTOR FUNCTION. A BETTER UNDERSTANDING OF EPIGENETICS AND POST-SEPTIC IMMUNOSUPPRESSION CAN IMPROVE OUR DIAGNOSTIC TOOLS AND MAY BE AN IMPORTANT POTENTIAL SOURCE OF NOVEL MOLECULAR TARGETS FOR NEW THERAPIES. THIS REVIEW WILL DISCUSS IMPORTANT PATHWAYS OF IMMUNE CELL ACTIVATION AFFECTED BY SEVERE SEPSIS, AND HIGHLIGHT PATHWAYS OF EPIGENETIC REGULATION THAT MAY BE INVOLVED IN POST-SEPTIC IMMUNOSUPPRESSION. 2011 19 1674 15 DRIVER MUTATIONS IN LEUKEMIA PROMOTE DISEASE PATHOGENESIS THROUGH A COMBINATION OF CELL-AUTONOMOUS AND NICHE MODULATION. STUDIES OF PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) HAVE LED TO THE IDENTIFICATION OF MUTATIONS THAT AFFECT DIFFERENT CELLULAR PATHWAYS. SOME OF THESE HAVE BEEN CLASSIFIED AS PRELEUKEMIC, AND A STEPWISE EVOLUTION PROGRAM WHEREBY CELLS ACQUIRE ADDITIONAL MUTATIONS HAS BEEN PROPOSED IN THE DEVELOPMENT OF AML. HOW THE TIMING OF ACQUISITION OF THESE MUTATIONS AND THEIR IMPACT ON TRANSFORMATION AND THE BONE MARROW (BM) MICROENVIRONMENT OCCURS HAS ONLY RECENTLY BEGUN TO BE INVESTIGATED. WE SHOW THAT CONSTITUTIVE AND EARLY LOSS OF THE EPIGENETIC REGULATOR, TET2, WHEN COMBINED WITH CONSTITUTIVE ACTIVATION OF FLT3, RESULTS IN TRANSFORMATION OF CHRONIC MYELOMONOCYTIC LEUKEMIA-LIKE OR MYELOPROLIFERATIVE NEOPLASM-LIKE PHENOTYPE TO AML, WHICH IS MORE PRONOUNCED IN DOUBLE-MUTANT MICE RELATIVE TO MICE CARRYING MUTATIONS IN SINGLE GENES. FURTHERMORE, WE SHOW THAT IN PRELEUKEMIC AND LEUKEMIC MICE THERE ARE ALTERATIONS IN THE BM NICHE AND SECRETED CYTOKINES, WHICH CREATES A PERMISSIVE ENVIRONMENT FOR THE GROWTH OF MUTATION-BEARING CELLS RELATIVE TO NORMAL CELLS. 2020 20 3380 17 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