1 5023 155 PERSONAL MEDICINE AND BONE METASTASES: BIOMARKERS, MICRO-RNAS AND BONE METASTASES. BONE METASTASIS IS A MAJOR CAUSE OF MORBIDITY WITHIN SOLID TUMOURS OF THE BREAST, PROSTATE, LUNG AND KIDNEY. METASTASIS TO THE SKELETON IS ASSOCIATED WITH A WIDE RANGE OF COMPLICATIONS INCLUDING BONE FRACTURES, SPINAL CORD COMPRESSION, HYPERCALCAEMIA AND INCREASED BONE PAIN. IMPROVED TREATMENTS FOR BONE METASTASIS, SUCH AS THE USE OF ANTI-BONE RESORPTIVE BISPHOSPHONATE AGENTS, WITHIN POST-MENOPAUSAL WOMEN HAVE IMPROVED DISEASE-FREE SURVIVAL; HOWEVER, THESE TREATMENTS ARE NOT WITHOUT SIDE EFFECTS. THERE IS THUS A NEED FOR BIOMARKERS, WHICH WILL PREDICT THE RISK OF DEVELOPING THE SPREAD TO BONE WITHIN THESE CANCERS. THE APPLICATION OF MOLECULAR PROFILING TECHNIQUES, TOGETHER WITH ANIMAL MODEL SYSTEMS AND ENGINEERED CELL-LINES HAS ENABLED THE IDENTIFICATION OF A SERIES OF POTENTIAL BONE-METASTASIS BIOMARKER MOLECULES PREDICTIVE OF BONE METASTASIS RISK. SOME OF THESE BIOMARKER CANDIDATES HAVE BEEN VALIDATED WITHIN PATIENT-DERIVED SAMPLES PROVIDING A STEP TOWARDS CLINICAL UTILITY. RECENT DEVELOPMENTS IN MULTIPLEX BIOMARKER QUANTIFICATION NOW ENABLE THE SIMULTANEOUS MEASUREMENT OF UP TO 96 MICRO-RNA/PROTEIN MOLECULES IN A SPATIALLY DEFINED MANNER WITH SINGLE-CELL RESOLUTION, THUS ENABLING THE CHARACTERISATION OF THE KEY MOLECULES ACTIVE AT THE SITES OF PRE-METASTATIC NICHE FORMATION AS WELL AS TUMOUR-STROMA SIGNALLING. THESE TECHNOLOGIES HAVE CONSIDERABLE POTENTIAL TO INFORM BIOMARKER DISCOVERY. ADDITIONALLY, A POTENTIAL FUTURE EXTENSION OF THESE DISCOVERIES COULD ALSO BE THE IDENTIFICATION OF NOVEL DRUG TARGETS WITHIN CANCER SPREAD TO BONE. THIS CHAPTER SUMMARISES RECENT FINDINGS IN BIOMARKER DISCOVERY WITHIN THE KEY BONE METASTATIC CANCERS (BREAST, PROSTATE, LUNG AND RENAL CELL CARCINOMA). TISSUE-BASED AND CIRCULATING BLOOD-BASED BIOMARKERS ARE DISCUSSED FROM THE FIELDS OF GENOMICS, EPIGENETIC REGULATION (MICRO-RNAS) AND PROTEIN/CELL-SIGNALLING TOGETHER WITH A DISCUSSION OF THE POTENTIAL FUTURE DEVELOPMENT OF THESE MARKERS TOWARDS CLINICAL DEVELOPMENT. 2020 2 406 22 ANALYSIS OF FIVE CHRONIC INFLAMMATORY DISEASES IDENTIFIES 27 NEW ASSOCIATIONS AND HIGHLIGHTS DISEASE-SPECIFIC PATTERNS AT SHARED LOCI. WE SIMULTANEOUSLY INVESTIGATED THE GENETIC LANDSCAPE OF ANKYLOSING SPONDYLITIS, CROHN'S DISEASE, PSORIASIS, PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE COLITIS TO INVESTIGATE PLEIOTROPY AND THE RELATIONSHIP BETWEEN THESE CLINICALLY RELATED DISEASES. USING HIGH-DENSITY GENOTYPE DATA FROM MORE THAN 86,000 INDIVIDUALS OF EUROPEAN ANCESTRY, WE IDENTIFIED 244 INDEPENDENT MULTIDISEASE SIGNALS, INCLUDING 27 NEW GENOME-WIDE SIGNIFICANT SUSCEPTIBILITY LOCI AND 3 UNREPORTED SHARED RISK LOCI. COMPLEX PLEIOTROPY WAS SUPPORTED WHEN CONTRASTING MULTIDISEASE SIGNALS WITH EXPRESSION DATA SETS FROM HUMAN, RAT AND MOUSE TOGETHER WITH EPIGENETIC AND EXPRESSED ENHANCER PROFILES. THE COMORBIDITIES AMONG THE FIVE IMMUNE DISEASES WERE BEST EXPLAINED BY BIOLOGICAL PLEIOTROPY RATHER THAN HETEROGENEITY (A SUBGROUP OF CASES GENETICALLY IDENTICAL TO THOSE WITH ANOTHER DISEASE, POSSIBLY OWING TO DIAGNOSTIC MISCLASSIFICATION, MOLECULAR SUBTYPES OR EXCESSIVE COMORBIDITY). IN PARTICULAR, THE STRONG COMORBIDITY BETWEEN PRIMARY SCLEROSING CHOLANGITIS AND INFLAMMATORY BOWEL DISEASE IS LIKELY THE RESULT OF A UNIQUE DISEASE, WHICH IS GENETICALLY DISTINCT FROM CLASSICAL INFLAMMATORY BOWEL DISEASE PHENOTYPES. 2016 3 103 36 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 4 5702 28 SINGLE-CELL GENOMICS FOR INVESTIGATING PATHOGENESIS OF INFLAMMATORY DISEASES. RECENT TECHNICAL ADVANCES HAVE ENABLED UNBIASED TRANSCRIPTOMIC AND EPIGENETIC ANALYSIS OF EACH CELL, KNOWN AS "SINGLE-CELL ANALYSIS". SINGLE-CELL ANALYSIS HAS A VARIETY OF TECHNICAL APPROACHES TO INVESTIGATE THE STATE OF EACH CELL, INCLUDING MRNA LEVELS (TRANSCRIPTOME), THE IMMUNE REPERTOIRE (IMMUNE REPERTOIRE ANALYSIS), CELL SURFACE PROTEINS (SURFACE PROTEOME ANALYSIS), CHROMATIN ACCESSIBILITY (EPIGENOME), AND ACCORDANCE WITH GENOME VARIANTS (EQTLS; EXPRESSION QUANTITATIVE TRAIT LOCI). AS AN EFFECTIVE TOOL FOR INVESTIGATING ROBUST IMMUNE RESPONSES IN CORONAVIRUS DISEASE 2019 (COVID-19), MANY RESEARCHERS PERFORMED SINGLE-CELL ANALYSIS TO CAPTURE THE DIVERSE, UNBIASED IMMUNE CELL ACTIVATION AND DIFFERENTIATION. DESPITE CHALLENGES ELUCIDATING THE COMPLICATED IMMUNE MICROENVIRONMENTS OF CHRONIC INFLAMMATORY DISEASES USING EXISTING EXPERIMENTAL METHODS, IT IS NOW POSSIBLE TO CAPTURE THE SIMULTANEOUS IMMUNE FEATURES OF DIFFERENT CELL TYPES ACROSS INFLAMED TISSUES USING VARIOUS SINGLE-CELL TOOLS. IN THIS REVIEW, WE INTRODUCE PATIENT-BASED AND EXPERIMENTAL MOUSE MODEL RESEARCH UTILIZING SINGLE-CELL ANALYSES IN THE FIELD OF CHRONIC INFLAMMATORY DISEASES, AS WELL AS MULTI-ORGAN ATLAS TARGETING IMMUNE CELLS. 2023 5 1678 35 DRUG REPURPOSING AT THE INTERFACE OF MELANOMA IMMUNOTHERAPY AND AUTOIMMUNE DISEASE. CANCER CELLS HAVE A REMARKABLE ABILITY TO EVADE RECOGNITION AND DESTRUCTION BY THE IMMUNE SYSTEM. AT THE SAME TIME, CANCER HAS BEEN ASSOCIATED WITH CHRONIC INFLAMMATION, WHILE CERTAIN AUTOIMMUNE DISEASES PREDISPOSE TO THE DEVELOPMENT OF NEOPLASIA. ALTHOUGH CANCER IMMUNOTHERAPY HAS REVOLUTIONIZED ANTITUMOR TREATMENT, IMMUNE-RELATED TOXICITIES AND ADVERSE EVENTS DETRACT FROM THE CLINICAL UTILITY OF EVEN THE MOST ADVANCED DRUGS, ESPECIALLY IN PATIENTS WITH BOTH, METASTATIC CANCER AND PRE-EXISTING AUTOIMMUNE DISEASES. HERE, THE COMBINATION OF MULTI-OMICS, DATA-DRIVEN COMPUTATIONAL APPROACHES WITH THE APPLICATION OF NETWORK CONCEPTS ENABLES IN-DEPTH ANALYSES OF THE DYNAMIC LINKS BETWEEN CANCER, AUTOIMMUNE DISEASES, AND DRUGS. IN THIS REVIEW, WE FOCUS ON MOLECULAR AND EPIGENETIC METASTASIS-RELATED PROCESSES WITHIN CANCER CELLS AND THE IMMUNE MICROENVIRONMENT. WITH MELANOMA AS A MODEL, WE UNCOVER VULNERABILITIES FOR DRUG DEVELOPMENT TO CONTROL CANCER PROGRESSION AND IMMUNE RESPONSES. THEREBY, DRUG REPURPOSING ALLOWS TAKING ADVANTAGE OF EXISTING SAFETY PROFILES AND ESTABLISHED PHARMACOKINETIC PROPERTIES OF APPROVED AGENTS. THESE PROCEDURES PROMISE FASTER ACCESS AND OPTIMAL MANAGEMENT FOR CANCER TREATMENT. TOGETHER, THESE APPROACHES PROVIDE NEW DISEASE-BASED AND DATA-DRIVEN OPPORTUNITIES FOR THE PREDICTION AND APPLICATION OF TARGETED AND CLINICALLY USED DRUGS AT THE INTERFACE OF IMMUNE-MEDIATED DISEASES AND CANCER TOWARDS NEXT-GENERATION IMMUNOTHERAPIES. 2022 6 5912 28 TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM DISORDER CHARACTERISED BY LOSS OF TOLERANCE TO ENDOGENOUS NUCLEAR ANTIGENS AND AUTOANTIBODY FORMATION. RECENT INSIGHT INTO THE IMMUNOPATHOGENESIS OF LUPUS HAS PROVIDED THE FOUNDATION FOR A NOVEL CLASS OF AGENTS WHICH TARGET SPECIFIC, DYSREGULATED COMPONENTS OF THE IMMUNE SYSTEM. EFFORTS HAVE FOCUSED PREDOMINANTLY ON B-CELL DEPLETING THERAPIES, OF WHICH BELIMUMAB WAS THE FIRST TO DEMONSTRATE SUCCESS IN PHASE III STUDIES AND THUS RECEIVE MARKETING AUTHORISATION. OFF-LABEL PRESCRIBING OF RITUXIMAB IN REFRACTORY CASES IS COMMON AND SUPPORTED BY UNCONTROLLED STUDIES, WHICH SUGGEST A FAVOURABLE RISK:BENEFIT PROFILE. HOWEVER, TWO PLACEBO-CONTROLLED TRIALS FAILED TO SHOW BENEFIT, POSSIBLY BECAUSE OF INAPPROPRIATE PATIENT SELECTION AND OTHER ASPECTS OF TRIAL METHODOLOGY. INHIBITION OF DYSREGULATED CO-STIMULATORY SIGNALS AND CYTOKINES ARE OTHER THERAPEUTIC STRATEGIES CURRENTLY UNDER INVESTIGATION. SOME CANDIDATE DRUGS FAILED TO MEET PRIMARY ENDPOINTS IN EARLY-PHASE CLINICAL TRIALS, YET DEMONSTRATED CLINICAL BENEFIT WHEN ALTERNATIVE ASSESSMENT CRITERIA WERE APPLIED OR SPECIFIC PATIENT SUB-GROUPS ANALYSED. WELL-DESIGNED STUDIES OF GREATER SIZE AND DURATION ARE NEEDED TO CLARIFY THE THERAPEUTIC UTILITY OF THESE AGENTS. FUTURE IMMUNOMODULATORY STRATEGIES TARGETING INTERFERON-ALPHA, T CELLS, OXIDATIVE STRESS AND EPIGENETIC ABNORMALITIES MAY REDUCE MULTISYSTEM DISEASE ACTIVITY AND PROLONG SURVIVAL IN THIS COMPLEX AND HETEROGENEIC DISEASE. 2013 7 1442 27 DIFFERENTIAL RESPONSE OF HUMAN HEPATOCYTE CHROMATIN TO HDAC INHIBITORS AS A FUNCTION OF MICROENVIRONMENTAL GLUCOSE LEVEL. DIABETES IS A COMPLEX MULTIFACTORIAL DISORDER CHARACTERIZED BY CHRONIC HYPERGLYCEMIA DUE TO IMPAIRED INSULIN SECRETION. RECENT OBSERVATIONS SUGGEST THAT THE COMPLEXITY OF THE DISEASE CANNOT BE ENTIRELY ACCOUNTED FOR GENETIC PREDISPOSITION AND A COMPELLING ARGUMENT FOR AN EPIGENETIC COMPONENT IS RAPIDLY EMERGING. THE USE OF HISTONE DEACETYLASE INHIBITOR (HDACI) IN CLINICAL SETTING IS AN EMERGING AREA OF INVESTIGATION. IN THIS STUDY, WE HAVE AIMED TO UNDERSTAND AND COMPARE THE RESPONSE OF HEPATOCYTE CHROMATIN TO VALPROIC ACID (VPA) AND TRICHOSTATIN A (TSA) TREATMENTS UNDER NORMOGLYCEMIC OR HYPERGLYCEMIC CONDITIONS TO EXPAND OUR KNOWLEDGE ABOUT THE CONSEQUENCES OF HDACI TREATMENT IN A DIABETES CELL MODEL. UNDER NORMOGLYCEMIC CONDITIONS, THESE TREATMENTS PROMOTED CHROMATIN REMODELING, AS ASSESSED BY IMAGE ANALYSIS AND H3K9AC AND H3K9ME2 ABUNDANCE. SIMULTANEOUSLY, H3K9AC MARKS SHIFTED TO THE NUCLEAR PERIPHERY ACCOMPANIED BY HP1 DISSOCIATION FROM THE HETEROCHROMATIN AND A G1 CELL CYCLE ARREST. MORE STRIKING CHANGES IN THE CELL CYCLE PROGRESSION AND MITOTIC RATIOS REQUIRED DRASTIC TREATMENT. UNDER HYPERGLYCEMIC CONDITIONS, HIGH GLUCOSE PER SE PROMOTED CHROMATIN CHANGES SIMILAR TO THOSE PROMOTED BY VPA AND TSA. NONETHELESS, THESE RESULTS WERE NOT INTENSIFIED IN CELLS TREATED WITH HDACIS UNDER HYPERGLYCEMIC CONDITIONS. DESPITE THE ABSENCE OF MORPHOLOGICAL CHANGES BEING PROMOTED, HDACI TREATMENT SEEMS TO CONFER A PHYSIOLOGICAL MEANING, AMELIORATING THE CELLULAR HYPERGLYCEMIC STATE THROUGH REDUCTION OF GLUCOSE PRODUCTION. THESE OBSERVATIONS ALLOW US TO CONCLUDE THAT THE GLUCOSE LEVEL TO WHICH THE HEPATOCYTES ARE SUBJECTED AFFECTS HOW CHROMATIN RESPONDS TO HDACI AND THEIR ACTION UNDER HIGH-GLUCOSE ENVIRONMENT MIGHT NOT REFLECT ON CHROMATIN REMODELING. J. CELL. PHYSIOL. 231: 2257-2265, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 8 6449 49 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 9 593 31 BET PROTEIN INHIBITION REGULATES CYTOKINE PRODUCTION AND PROMOTES NEUROPROTECTION AFTER SPINAL CORD INJURY. BACKGROUND: SPINAL CORD INJURY (SCI) USUALLY CAUSES A DEVASTATING LIFELONG DISABILITY FOR PATIENTS. AFTER A TRAUMATIC LESION, DISRUPTION OF THE BLOOD-SPINAL CORD BARRIER INDUCES THE INFILTRATION OF MACROPHAGES INTO THE LESION SITE AND THE ACTIVATION OF RESIDENT GLIAL CELLS, WHICH RELEASE CYTOKINES AND CHEMOKINES. THESE EVENTS RESULT IN A PERSISTENT INFLAMMATION, WHICH HAS BOTH DETRIMENTAL AND BENEFICIAL EFFECTS, BUT EVENTUALLY LIMITS FUNCTIONAL RECOVERY AND CONTRIBUTES TO THE APPEARANCE OF NEUROPATHIC PAIN. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE THE EXPRESSION OF INFLAMMATORY GENES BY INTERACTING WITH ACETYLATED LYSINE RESIDUES. WHILE BET INHIBITORS ARE A PROMISING THERAPEUTIC STRATEGY FOR CANCER, LITTLE IS KNOWN ABOUT THEIR IMPLICATION AFTER SCI. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY ROLE OF BET INHIBITORS IN THIS PATHOLOGIC CONDITION. METHODS: WE EVALUATED THE EFFECTIVENESS OF THE BET INHIBITOR JQ1 TO MODIFY MACROPHAGE REACTIVITY IN VITRO AND TO MODULATE INFLAMMATION IN A SCI MICE MODEL. WE ANALYZED THE EFFECTS OF BET INHIBITION IN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PRODUCTION IN VITRO AND IN VIVO. WE DETERMINED THE EFFECTIVENESS OF BET INHIBITION IN TISSUE SPARING, INFLAMMATION, NEURONAL PROTECTION, AND BEHAVIORAL OUTCOME AFTER SCI. RESULTS: WE HAVE FOUND THAT THE BET INHIBITOR JQ1 REDUCED THE LEVELS OF PRO-INFLAMMATORY MEDIATORS AND INCREASED THE EXPRESSION OF ANTI-INFLAMMATORY CYTOKINES. A PROLONGED TREATMENT WITH JQ1 ALSO DECREASED REACTIVITY OF MICROGLIA/MACROPHAGES, ENHANCED NEUROPROTECTION AND FUNCTIONAL RECOVERY, AND ACUTELY REDUCED NEUROPATHIC PAIN AFTER SCI. CONCLUSIONS: BET PROTEIN INHIBITION IS AN EFFECTIVE TREATMENT TO REGULATE CYTOKINE PRODUCTION AND PROMOTE NEUROPROTECTION AFTER SCI. THESE NOVEL RESULTS DEMONSTRATE FOR THE FIRST TIME THAT TARGETING BET PROTEINS IS AN ENCOURAGING APPROACH FOR SCI REPAIR AND A POTENTIAL STRATEGY TO TREAT OTHER INFLAMMATORY PATHOLOGIES. 2019 10 3510 30 IDENTIFYING NOVEL B-CELL TARGETS FOR CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE BY SCREENING OF CHEMICAL PROBES IN A PATIENT-DERIVED CELL ASSAY. B-CELL SECRETION OF AUTOANTIBODIES DRIVES AUTOIMMUNE DISEASES, INCLUDING SYSTEMIC LUPUS ERYTHEMATOSUS AND IDIOPATHIC INFLAMMATORY MYOSITIS. FEW THERAPIES ARE PRESENTLY AVAILABLE FOR TREATMENT OF THESE PATIENTS, OFTEN RESULTING IN UNSATISFACTORY EFFECTS AND HELPING ONLY SOME OF THE PATIENTS. WE DEVELOPED A SCREENING ASSAY FOR EVALUATION OF NOVEL TARGETS SUSPENDING B-CELL MATURATION INTO ANTIBODY SECRETING CELLS, WHICH COULD CONTRIBUTE TO FUTURE DRUG DEVELOPMENT. THE ASSAY WAS EMPLOYED FOR TESTING 43 HIGH QUALITY CHEMICAL PROBES AND COMPOUNDS INHIBITING UNDER-EXPLORED PROTEIN TARGETS, USING PRIMARY CELLS FROM PATIENTS WITH AUTOIMMUNE DISEASE. PROBES INHIBITING BROMODOMAIN FAMILY PROTEINS AND HISTONE METHYL TRANSFERASES DEMONSTRATED ABROGATION OF B-CELL FUNCTIONS TO A DEGREE COMPARABLE TO A POSITIVE CONTROL, THE JAK INHIBITOR TOFACITINIB. INHIBITION OF EACH TARGET RENDERED A SPECIFIC FUNCTIONAL CELL AND POTENTIAL DISEASE MODIFYING EFFECT, INDICATING SPECIFIC EPIGENETIC PROTEIN TARGETS AS POTENTIAL NEW INTERVENTION POINTS FOR FUTURE DRUG DISCOVERY AND DEVELOPMENT EFFORTS. 2021 11 295 27 AGING INDUCES B CELL DEFECTS AND DECREASED ANTIBODY RESPONSES TO INFLUENZA INFECTION AND VACCINATION. BACKGROUND: AGING IS CHARACTERIZED BY A PROGRESSIVE DECLINE IN THE CAPACITY OF THE IMMUNE SYSTEM TO FIGHT INFLUENZA VIRUS INFECTION AND TO RESPOND TO VACCINATION. AMONG THE SEVERAL FACTORS INVOLVED, IN ADDITION TO INCREASED FRAILTY AND HIGH-RISK CONDITIONS, THE AGE-ASSOCIATED DECREASE IN CELLULAR AND HUMORAL IMMUNE RESPONSES PLAYS A RELEVANT ROLE. THIS IS IN LARGE PART DUE TO INFLAMMAGING, THE CHRONIC LOW-GRADE INFLAMMATORY STATUS OF THE ELDERLY, ASSOCIATED WITH INTRINSIC INFLAMMATION OF THE IMMUNE CELLS AND DECREASED IMMUNE FUNCTION. RESULTS: AGING IS USUALLY ASSOCIATED WITH REDUCED INFLUENZA VIRUS-SPECIFIC AND INFLUENZA VACCINE-SPECIFIC ANTIBODY RESPONSES BUT SOME ELDERLY INDIVIDUALS WITH HIGHER PRE-EXPOSURE ANTIBODY TITERS, DUE TO A PREVIOUS INFECTION OR VACCINATION, HAVE LESS PROBABILITY TO GET INFECTED. EXAMPLES OF THIS EXCEPTION ARE THE ELDERLY INDIVIDUALS INFECTED DURING THE 2009 PANDEMIC SEASON WHO MADE ANTIBODIES WITH BROADER EPITOPE RECOGNITION AND HIGHER AVIDITY THAN THOSE MADE BY YOUNGER INDIVIDUALS. SEVERAL STUDIES HAVE ALLOWED THE IDENTIFICATION OF B CELL INTRINSIC DEFECTS ACCOUNTING FOR SUB-OPTIMAL ANTIBODY RESPONSES OF ELDERLY INDIVIDUALS. THESE DEFECTS INCLUDE 1) REDUCED CLASS SWITCH RECOMBINATION, RESPONSIBLE FOR THE GENERATION OF A SECONDARY RESPONSE OF CLASS SWITCHED ANTIBODIES, 2) REDUCED DE NOVO SOMATIC HYPERMUTATION OF THE ANTIBODY VARIABLE REGION, 3) REDUCED BINDING AND NEUTRALIZATION CAPACITY, AS WELL AS BINDING SPECIFICITY, OF THE SECRETED ANTIBODIES, 4) INCREASED EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH LOWER ANTIBODY RESPONSES, 5) INCREASED FREQUENCIES OF INFLAMMATORY B CELL SUBSETS, AND 6) SHORTER TELOMERES. CONCLUSIONS: ALTHOUGH INFLUENZA VACCINATION REPRESENTS THE MOST EFFECTIVE WAY TO PREVENT INFLUENZA INFECTION, VACCINES WITH GREATER IMMUNOGENICITY ARE NEEDED TO IMPROVE THE RESPONSE OF ELDERLY INDIVIDUALS. RECENT ADVANCES IN TECHNOLOGY HAVE MADE POSSIBLE A BROAD APPROACH TO BETTER UNDERSTAND THE AGE-ASSOCIATED CHANGES IN IMMUNE CELLS, NEEDED TO DESIGN TAILORED VACCINES AND EFFECTIVE THERAPEUTIC STRATEGIES THAT WILL BE ABLE TO IMPROVE THE IMMUNE RESPONSE OF VULNERABLE INDIVIDUALS. 2020 12 1650 29 DOMAIN-SELECTIVE TARGETING OF BET PROTEINS IN CANCER AND IMMUNOLOGICAL DISEASES. CANCER AND INFLAMMATION ARE STRONGLY INTERCONNECTED PROCESSES. CHRONIC INFLAMMATORY PATHOLOGIES CAN BE AT THE HEART OF TUMOR DEVELOPMENT; SIMILARLY, TUMOR-ELICITED INFLAMMATION IS A CONSEQUENCE OF MANY CANCERS. THE MECHANISTIC INTERDEPENDENCE BETWEEN CANCER AND INFLAMMATORY PATHOLOGIES POINTS TOWARD COMMON PROTEIN EFFECTORS WHICH REPRESENT POTENTIAL SHARED TARGETS FOR PHARMACOLOGICAL INTERVENTION. EPIGENETIC MECHANISMS OFTEN DRIVE RESISTANCE TO CANCER THERAPY AND IMMUNOMODULATORY STRATEGIES. THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC ADAPTERS WHICH PLAY A MAJOR ROLE IN CONTROLLING CELL PROLIFERATION AND THE PRODUCTION OF INFLAMMATORY MEDIATORS. A PLETHORA OF SMALL MOLECULES AIMED AT INHIBITING BET PROTEIN FUNCTION TO TREAT CANCER AND INFLAMMATORY DISEASES HAVE POPULATED ACADEMIC AND INDUSTRY EFFORTS IN THE LAST 10 YEARS. IN THIS REVIEW, WE WILL DISCUSS RECENT PHARMACOLOGICAL APPROACHES AIMED AT TARGETING A SINGLE OR A SUBSET OF THE EIGHT BROMODOMAINS WITHIN THE BET FAMILY WHICH HAVE THE POTENTIAL TO TEASE APART CLINICAL EFFICACY AND SAFETY SIGNALS OF BET INHIBITORS. 2020 13 5039 30 PHARMACOGENETICS OF CHRONIC PAIN MANAGEMENT. OBJECTIVE: THE EXPERIENCE OF CHRONIC PAIN IS ONE OF THE COMMONEST REASONS INDIVIDUALS SEEK MEDICAL ATTENTION, MAKING THE MANAGEMENT OF CHRONIC PAIN A MAJOR ISSUE IN CLINICAL PRACTICE. DRUG METABOLISM AND RESPONSES ARE AFFECTED BY MANY FACTORS, WITH GENETIC VARIATIONS OFFERING ONLY A PARTIAL EXPLANATION OF AN INDIVIDUAL'S RESPONSE. THERE IS A PAUCITY OF EVIDENCE FOR THE BENEFITS OF PHARMACOGENETIC TESTING IN THE CONTEXT OF PAIN MANAGEMENT. DESIGN AND METHODS: WE REVIEWED THE LITERATURE BETWEEN 2000 AND 2013, AND REFERENCES CITED THEREIN, USING VARIOUS KEYWORDS RELATED TO PAIN MANAGEMENT, PHARMACOLOGY AND PHARMACOGENETICS. RESULTS: OPIOIDS CONTINUE TO BE THE MAINSTAY OF CHRONIC PAIN MANAGEMENT. SEVERAL NON-OPIOID BASED THERAPIES, SUCH AS TREATMENT WITH CANNABINOIDS, GENE THERAPY AND EPIGENETIC-BASED APPROACHES ARE NOW AVAILABLE FOR THESE PATIENTS. ADJUVANT THERAPIES WITH ANTIDEPRESSANTS, BENZODIAZEPINES OR ANTICONVULSANTS CAN ALSO BE USEFUL IN MANAGING PAIN. CURRENTLY, LABORATORY MONITORING OF PAIN MANAGEMENT PATIENTS, IF PERFORMED, IS LARGELY THROUGH URINE DRUG MEASUREMENTS. CONCLUSIONS: DRUG HALF-LIFE CALCULATIONS CAN BE USED AS FUNCTIONAL MARKERS OF THE CUMULATIVE EFFECT OF PHARMACOGENETICS AND DRUG-DRUG INTERACTIONS. ASSESSMENT OF HALF-LIFE AND THERAPEUTIC EFFECTS MAY BE MORE USEFUL THAN GENETIC TESTING IN PREVENTING ADVERSE DRUG REACTIONS TO PAIN MEDICATIONS, WHILE ENSURING EFFECTIVE ANALGESIA. DEFINITIVE, MASS SPECTROMETRY-BASED METHODS, CAPABLE OF MEASURING PARENT DRUG AND METABOLITE LEVELS, ARE THE MOST USEFUL ASSAYS FOR THIS PURPOSE. URINE DRUG MEASUREMENTS DO NOT NECESSARILY CORRELATE WITH SERUM DRUG CONCENTRATIONS OR THERAPEUTIC EFFECTS. THEREFORE, THEY ARE LIMITED IN THEIR USE IN MONITORING EFFICACY AND TOXICITY. 2014 14 1102 27 COMBINED CHEMOSENSITIVITY AND CHROMATIN PROFILING PRIORITIZES DRUG COMBINATIONS IN CLL. THE BRUTON TYROSINE KINASE (BTK) INHIBITOR IBRUTINIB HAS SUBSTANTIALLY IMPROVED THERAPEUTIC OPTIONS FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). ALTHOUGH IBRUTINIB IS NOT CURATIVE, IT HAS A PROFOUND EFFECT ON CLL CELLS AND MAY CREATE NEW PHARMACOLOGICALLY EXPLOITABLE VULNERABILITIES. TO IDENTIFY SUCH VULNERABILITIES, WE DEVELOPED A SYSTEMATIC APPROACH THAT COMBINES EPIGENOME PROFILING (CHARTING THE GENE-REGULATORY BASIS OF CELL STATE) WITH SINGLE-CELL CHEMOSENSITIVITY PROFILING (QUANTIFYING CELL-TYPE-SPECIFIC DRUG RESPONSE) AND BIOINFORMATIC DATA INTEGRATION. BY APPLYING OUR METHOD TO A COHORT OF MATCHED PATIENT SAMPLES COLLECTED BEFORE AND DURING IBRUTINIB THERAPY, WE IDENTIFIED CHARACTERISTIC IBRUTINIB-INDUCED CHANGES THAT PROVIDE A STARTING POINT FOR THE RATIONAL DESIGN OF IBRUTINIB COMBINATION THERAPIES. SPECIFICALLY, WE OBSERVED AND VALIDATED PREFERENTIAL SENSITIVITY TO PROTEASOME, PLK1, AND MTOR INHIBITORS DURING IBRUTINIB TREATMENT. MORE GENERALLY, OUR STUDY ESTABLISHES A BROADLY APPLICABLE METHOD FOR INVESTIGATING TREATMENT-SPECIFIC VULNERABILITIES BY INTEGRATING THE COMPLEMENTARY PERSPECTIVES OF EPIGENETIC CELL STATES AND PHENOTYPIC DRUG RESPONSES IN PRIMARY PATIENT SAMPLES. 2019 15 1688 33 DUAL BET/HDAC INHIBITION TO RELIEVE NEUROPATHIC PAIN: RECENT ADVANCES, PERSPECTIVES, AND FUTURE OPPORTUNITIES. DESPITE THE INTENSE RESEARCH ON DEVELOPING NEW THERAPIES FOR NEUROPATHIC PAIN STATES, AVAILABLE TREATMENTS HAVE LIMITED EFFICACY AND UNFAVORABLE SAFETY PROFILES. EPIGENETIC ALTERATIONS HAVE A GREAT INFLUENCE ON THE DEVELOPMENT OF CANCER AND NEUROLOGICAL DISEASES, AS WELL AS NEUROPATHIC PAIN. HISTONE ACETYLATION HAS PREVAILED AS ONE OF THE WELL INVESTIGATED EPIGENETIC MODIFICATIONS IN THESE DISEASES. ALTERED SPINAL ACTIVITY OF HISTONE DEACETYLASE (HDAC) AND BROMO AND EXTRA TERMINAL DOMAIN (BET) HAVE BEEN DESCRIBED IN NEUROPATHIC PAIN MODELS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS SHOWED PAIN-RELIEVING ACTIVITY. OVER THE LAST DECADES HDACS AND BETS HAVE BEEN THE FOCUS OF DRUG DISCOVERY STUDIES, LEADING TO THE DEVELOPMENT OF NUMEROUS SMALL-MOLECULE INHIBITORS. CLINICAL TRIALS TO EVALUATE THEIR ANTICANCER ACTIVITY SHOWED GOOD EFFICACY BUT RAISED TOXICITY CONCERNS THAT LIMITED TRANSLATION TO THE CLINIC. TO MAXIMIZE ACTIVITY AND MINIMIZE TOXICITY, THESE COMPOUNDS CAN BE APPLIED IN COMBINATION OF SUB-MAXIMAL DOSES TO PRODUCE ADDITIVE OR SYNERGISTIC INTERACTIONS (COMBINATION THERAPY). RECENTLY, OF PARTICULAR INTEREST, DUAL BET/HDAC INHIBITORS (MULTI-TARGET DRUGS) HAVE BEEN DEVELOPED TO ASSURE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE. THIS REVIEW WILL SUMMARIZE THE MOST RECENT ADVANCES WITH THESE STRATEGIES, DESCRIBING ADVANTAGES AND LIMITATIONS OF SINGLE DRUG TREATMENT VS COMBINATION REGIMENS. THIS REVIEW WILL ALSO PROVIDE A FOCUS ON DUAL BET/HDAC DRUG DISCOVERY INVESTIGATIONS AS FUTURE THERAPEUTIC OPPORTUNITY FOR HUMAN THERAPY OF NEUROPATHIC PAIN. 2021 16 5699 36 SIMULTANEOUS DETECTION OF DNA VARIATION AND METHYLATION AT HLA CLASS II LOCUS AND IMMUNE GENE PROMOTERS USING TARGETED SURESELECT METHYL-SEQUENCING. THE HUMAN LEUKOCYTE ANTIGEN (HLA) LOCUS ASSOCIATES WITH A VARIETY OF COMPLEX DISEASES, PARTICULARLY AUTOIMMUNE AND INFLAMMATORY CONDITIONS. THE HLA-DR15 HAPLOTYPE, FOR EXAMPLE, CONFERS THE MAJOR RISK FOR DEVELOPING MULTIPLE SCLEROSIS IN CAUCASIANS, PINPOINTING AN IMPORTANT ROLE IN THE ETIOLOGY OF THIS CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM. IN ADDITION TO THE PROTEIN-CODING VARIANTS THAT SHAPE THE FUNCTIONAL HLA-ANTIGEN-T CELL INTERACTION, RECENT STUDIES SUGGEST THAT THE LEVELS OF HLA MOLECULE EXPRESSION, THAT ARE EPIGENETICALLY CONTROLLED, ALSO PLAY A ROLE IN DISEASE DEVELOPMENT. HOWEVER, DECIPHERING THE EXACT MOLECULAR MECHANISMS OF THE HLA ASSOCIATION HAS BEEN HAMPERED BY THE TREMENDOUS GENETIC COMPLEXITY OF THE LOCUS AND A LACK OF ROBUST APPROACHES TO INVESTIGATE IT. HERE, WE DEVELOPED A METHOD TO SPECIFICALLY ENRICH THE GENOMIC DNA FROM THE HLA CLASS II LOCUS (CHR6:32,426,802-34,167,129) AND PROXIMAL PROMOTERS OF 2,157 IMMUNE-RELEVANT GENES, UTILIZING THE AGILENT RNA-BASED SURESELECT METHYL-SEQ CAPTURE RELATED METHOD, FOLLOWED BY SEQUENCING TO DETECT GENETIC AND EPIGENETIC VARIATION. WE DEMONSTRATED SUCCESSFUL SIMULTANEOUS DETECTION OF THE GENETIC VARIATION AND QUANTIFICATION OF DNA METHYLATION LEVELS IN HLA LOCUS. MOREOVER, BY THE DETECTION OF DIFFERENTIALLY METHYLATED POSITIONS IN PROMOTERS OF IMMUNE-RELATED GENES, WE IDENTIFIED RELEVANT PATHWAYS FOLLOWING STIMULATION OF CELLS. TAKEN TOGETHER, WE PRESENT A METHOD THAT CAN BE UTILIZED TO STUDY THE INTERPLAY BETWEEN GENETIC VARIANCE AND EPIGENETIC REGULATION IN THE HLA CLASS II REGION, POTENTIALLY, IN A WIDE DISEASE CONTEXT. 2023 17 250 34 ADVANCED GLYCATION END PRODUCTS (AGES): BIOCHEMISTRY, SIGNALING, ANALYTICAL METHODS, AND EPIGENETIC EFFECTS. THE ADVANCED GLYCATION END PRODUCTS (AGES) ARE ORGANIC MOLECULES FORMED IN ANY LIVING ORGANISMS WITH A GREAT VARIETY OF STRUCTURAL AND FUNCTIONAL PROPERTIES. THEY ARE CONSIDERED ORGANIC MARKERS OF THE GLYCATION PROCESS. DUE TO THEIR GREAT HETEROGENEITY, THERE IS NO SPECIFIC TEST FOR THEIR OPERATIONAL MEASUREMENT. IN THIS REVIEW, WE HAVE UPDATED THE MOST COMMON CHROMATOGRAPHIC, COLORIMETRIC, SPECTROSCOPIC, MASS SPECTROMETRIC, AND SEROLOGICAL METHODS, TYPICALLY USED FOR THE DETERMINATION OF AGES IN BIOLOGICAL SAMPLES. WE HAVE DESCRIBED THEIR SIGNALING AND SIGNAL TRANSDUCTION MECHANISMS AND CELL EPIGENETIC EFFECTS. ALTHOUGH MASS SPECTROMETRIC ANALYSIS IS NOT WIDESPREAD IN THE DETECTION OF AGES AT THE CLINICAL LEVEL, THIS TECHNIQUE IS HIGHLY PROMISING FOR THE EARLY DIAGNOSIS AND THERAPEUTICS OF DISEASES CAUSED BY AGES. PROTOCOLS ARE AVAILABLE FOR HIGH-RESOLUTION MASS SPECTROMETRY OF GLYCATED PROTEINS ALTHOUGH THEY ARE CHARACTERIZED BY COMPLEX MACHINE MANAGEMENT. SIMPLER PROCEDURES ARE AVAILABLE ALTHOUGH MUCH LESS PRECISE THAN MASS SPECTROMETRY. AMONG THEM, IMMUNOCHEMICAL TESTS ARE VERY COMMON SINCE THEY ARE ABLE TO DETECT AGES IN A SIMPLE AND IMMEDIATE WAY. IN THESE YEARS, NEW METHODOLOGIES HAVE BEEN DEVELOPED USING AN IN VIVO NOVEL AND NONINVASIVE SPECTROSCOPIC METHODS. THESE METHODS ARE BASED ON THE MEASUREMENT OF AUTOFLUORESCENCE OF AGES. ANOTHER METHOD CONSISTS OF DETECTING AGES IN THE HUMAN SKIN TO DETECT CHRONIC EXPOSURE, WITHOUT THE INCONVENIENCE OF INVASIVE METHODS. THE AIM OF THIS REVIEW IS TO COMPARE THE DIFFERENT APPROACHES OF MEASURING AGES AT A CLINICAL PERSPECTIVE DUE TO THEIR STRICT ASSOCIATION WITH OXIDATIVE STRESS AND INFLAMMATION. 2020 18 4363 41 MIRNA AS MARKERS FOR THE DIAGNOSTIC SCREENING OF COLON CANCER. EARLY SCREENING FOR COLON CANCER (CC) ALLOWS FOR EARLY STAGE DIAGNOSIS OF THE MALIGNANCY AND POTENTIALLY REDUCES DISEASE MORTALITY AS THE CANCER IS MOST LIKELY CURABLE AT ITS EARLIEST STAGES. EARLY DETECTION WOULD BE DESIRABLE IF ACCURATE, PRACTICAL AND COST-EFFECTIVE DIAGNOSTIC MEASURES FOR THIS CANCER WERE AVAILABLE. MORTALITY AND MORBIDITY FROM CC REPRESENT A MAJOR HEALTH PROBLEM INVOLVING A MALIGNANT DISEASE THAT IS THEORETICALLY PREVENTABLE THROUGH SCREENING. CURRENT SCREENING METHODS (E.G., THE CONVENIENT AND INEXPENSIVE IMMUNOLOGICAL FECAL OCCULT BLOOD TEST, FOBTI, OBTAINED FROM PATIENTS' MEDICAL RECORDS) EITHER LACK SENSITIVITY AND REQUIRE DIETARY RESTRICTION, WHICH IMPEDES COMPLIANCE AND USE; ARE COSTLY (E.G., COLONOSCOPY), WHICH DECREASES COMPLIANCE; OR COULD RESULT IN MORTALITY. IN COMPARISON WITH THE FOBT TEST, A NON-INVASIVE SENSITIVE SCREEN FOR WHICH THERE IS NO REQUIREMENT FOR DIETARY RESTRICTION WOULD BE A MORE CONVENIENT TEST. COLORECTAL CANCER IS THE ONLY CANCER FOR WHICH COLONOSCOPY IS RECOMMENDED AS A SCREENING METHOD. ALTHOUGH COLONOSCOPY IS A RELIABLE SCREENING TOOL, THE INVASIVE NATURE, ABDOMINAL PAIN, POTENTIAL COMPLICATIONS AND HIGH COST HAVE HAMPERED THE APPLICATION OF THIS PROCEDURE WORLDWIDE. A SCREENING APPROACH USING THE STABLE MIRNA MOLECULES, WHICH ARE RELATIVELY NON-DEGRADABLE WHEN EXTRACTED FROM NON-INVASIVE STOOL AND SEMI-INVASIVE BLOOD SAMPLES BY COMMERCIALLY AVAILABLE KITS AND MANIPULATED THEREAFTER, WOULD BE PREFERABLE TO A TRANSCRIPTOMIC MRNA-, A MUTATION DNA-, AN EPIGENETIC- OR A PROTEOMIC-BASED TEST. THE APPROACH USES REVERSE TRANSCRIPTASE, MODIFIED REAL-TIME QUANTITATIVE PCR. ALTHOUGH EXOSOMAL RNA WOULD BE MISSED, USING A RESTRICTED EXTRACTION OF TOTAL RNA FROM STOOL OR BLOOD, A PARALLEL TEST COULD ALSO BE CARRIED OUT ON RNA OBTAINED FROM STOOL OR PLASMA SAMPLES, AND APPROPRIATE CORRECTIONS FOR EXSOSOMAL LOSS CAN BE MADE FOR ACCURATE AND QUANTITATIVE TEST RESULT. EVENTUALLY, A CHIP CAN BE DEVELOPED TO FACILITATE DIAGNOSIS, AS HAS BEEN DONE FOR THE QUANTIFICATION OF GENETICALLY MODIFIED ORGANISMS IN FOODS. THE GOLD STANDARD TO WHICH THE MOLECULAR MIRNA TEST IS COMPARED IS COLONOSCOPY, WHICH CAN BE OBTAINED FROM PATIENTS' MEDICAL RECORDS. IF PERFORMANCE CRITERIA ARE MET, AS DETAILED HEREIN, A MIRNA TEST IN HUMAN STOOL OR BLOOD SAMPLES BASED ON HIGH-THROUGHPUT AUTOMATED TECHNOLOGIES AND QUANTITATIVE EXPRESSION MEASUREMENTS COMMONLY USED IN THE DIAGNOSTIC CLINICAL LABORATORY SHOULD BE ADVANCED TO THE CLINICAL SETTING, WHICH WILL MAKE A SIGNIFICANT IMPACT ON CC PREVENTION. 2014 19 2900 28 GENDER BIAS IN THERAPEUTIC EFFORT: FROM RESEARCH TO HEALTH CARE. THERE ARE RELEVANT DIMENSIONS FROM A GENDER PERSPECTIVE RELATED TO THERAPEUTIC EFFORT. TO ILLUSTRATE AND DISCUSS POSSIBLE GENDER BIAS RELATED TO MEDICINES, THROUGH THE CONSUMPTION ANALYSIS IN WOMEN, THE PRESCRIPTION OF BIOLOGICAL DRUGS ACCORDING TO SEX, THE POTENTIAL GENDER INEQUALITY IN ADVERSE DRUG REACTIONS, AND RESEARCH WITH CLINICAL TRIALS, AS WELL AS THE DECISIONS OF INTERNATIONAL INSTITUTIONS IN THE MARKETING OF MEDICINAL PRODUCTS. THERE IS GREATER TENDENCY TO PRESCRIBE PAIN RELIEVERS, REGARDLESS OF PAIN, AND DRUGS FOR LOW INTENSITY DEPRESSIVE SYMPTOMS IN WOMEN THAN IN MEN. THE OPPOSITE OCCURS IN THE PRESCRIPTION OF STATINS AND ADEQUATE DOSES, AND WITH THE GREATER PROBABILITY OF PRESCRIBING ANTI-TUMOR NECROSIS FACTOR IN MEN THAN IN WOMEN WITH ANKYLOSING SPONDYLITIS, DESPITE A SIMILAR DISEASE BURDEN. ADVERSE DRUG REACTIONS ARE OBSERVED MORE FREQUENTLY IN WOMEN THAN IN MEN, WHERE DETERMINANTS SUCH AS BODY WEIGHT ARE HAVING LITTLE INFLUENCE ON THE DOSAGE. IT IS CURRENTLY SCARCELY CONSIDERED IN THE PRESCRIPTION THAT WOMEN HAVE DIFFERENCES IN THE ACTIVITY OF CYTOCHROME CYPP450 ENZYMES, WHICH CAN AFFECT THE LIVER'S METABOLISM RATE. THERE ARE EVEN IMMUNOLOGICAL, GENETIC AND EPIGENETIC EFFECTS (DUE TO HEREDITY AND UNEVEN GENE DOSING LOCATED IN THE X AND Y CHROMOSOMES) THAT CAN INFLUENCE THESE DIFFERENCES BY SEX. FINALLY, THROUGH CASES OF HORMONAL THERAPY CLINICAL TRIALS, A DRUG FOR WOMEN'S INHIBITED SEXUAL DESIRE AND A CONTRACEPTIVE FOR MEN, GENDER BIAS AND STEREOTYPES ARE SHOWN TO INFLUENCE A POTENTIAL GENERATION OF INEQUALITIES, ESPECIALLY IN ADVERSE DRUG REACTIONS TO THE DETRIMENT OF WOMEN. IN CONCLUSION, HEALTH PROFESSIONALS FREQUENTLY ATTRIBUTE PHYSICAL SYMPTOMS TO WOMEN'S EMOTIONALITY, INFLUENCING THEIR GREATER PRESCRIPTION OF SYMPTOMATIC DRUGS. WHETHER THE SAME REASON INFLUENCES THE LOWER PRESCRIPTION OF THERAPEUTIC DRUGS IN WOMEN THAN IN MEN SHOULD BE ANALYZED. THERE ARE BIOLOGICAL DETERMINANTS TO CONSIDER DUE TO THEIR INFLUENCE ON A GREATER PHARMACOLOGICAL TOXICITY IN WOMEN. CLINICAL TRIALS SHOULD IMPROVE ACCORDING TO THE GENDER RECOMMENDATIONS BY THE FOOD AND DRUGS ADMINISTRATION. 2020 20 5947 25 TARGETING THE EPIGENOME: SCREENING BIOACTIVE COMPOUNDS THAT REGULATE HISTONE DEACETYLASE ACTIVITY. SCOPE: NUTRIGENOMICS IS A RAPIDLY EXPANDING FIELD THAT ELUCIDATES THE LINK BETWEEN DIET-GENOME INTERACTIONS. RECENT EVIDENCE DEMONSTRATES THAT REGULATION OF THE EPIGENOME, AND IN PARTICULAR INHIBITION OF HISTONE DEACETYLASES (HDACS), IMPACT PATHOGENETIC MECHANISMS INVOLVED IN CHRONIC DISEASE. FEW STUDIES, TO DATE, HAVE SCREENED LIBRARIES OF BIOACTIVE COMPOUNDS THAT ACT AS EPIGENETIC MODIFIERS. THIS STUDY SCREENED A LIBRARY OF 131 NATURAL COMPOUNDS TO DETERMINE BIOACTIVE COMPOUNDS THAT INHIBIT ZN-DEPENDENT HDAC ACTIVITY. METHODS AND RESULTS: USING CLASS-SPECIFIC HDAC SUBSTRATES, WE SCREENED 131 NATURAL COMPOUNDS FOR HDAC ACTIVITY IN BOVINE CARDIAC TISSUE. FROM THIS SCREEN, WE IDENTIFIED 18 BIOACTIVE COMPOUND HDAC INHIBITORS. USING OUR CLASS-SPECIFIC HDAC SUBSTRATES, WE NEXT SCREENED THESE 18 BIOACTIVE COMPOUNDS AGAINST RECOMBINANT HDAC PROTEINS. CONSISTENT WITH INHIBITION OF HDAC ACTIVITY, THESE COMPOUNDS WERE CAPABLE OF INHIBITING ACTIVITY OF INDIVIDUAL HDAC ISOFORMS. LASTLY, WE REPORT THAT TREATMENT OF H9C2 CARDIAC MYOBLASTS WITH BIOACTIVE HDAC INHIBITORS WAS SUFFICIENT TO INCREASE LYSINE ACETYLATION AS ASSESSED VIA IMMUNOBLOT. CONCLUSION: THIS STUDY PROVIDED THE FIRST STEP IN IDENTIFYING MULTIPLE BIOACTIVE COMPOUND HDAC INHIBITORS. TAKEN TOGETHER, THIS REPORT SETS THE STAGE FOR FUTURE EXPLORATION OF THESE BIOACTIVE COMPOUNDS AS EPIGENETIC REGULATORS TO POTENTIALLY AMELIORATE CHRONIC DISEASE. 2017