1 6576 136 TREATMENT OF PRIMARY SJOGREN SYNDROME. PRIMARY SJOGREN SYNDROME (PSS) IS A PROGRESSIVE AUTOIMMUNE DISEASE CHARACTERIZED BY SICCA AND SYSTEMIC MANIFESTATIONS. IN THIS REVIEW, WE SUMMARIZE THE AVAILABLE DATA ON TOPICAL AND SYSTEMIC MEDICATIONS, ACCORDING TO CLINICAL SIGNS AND DISEASE ACTIVITY, AND WE DESCRIBE THE ONGOING STUDIES USING BIOLOGIC DRUGS IN THE TREATMENT OF PSS. EXPANDING KNOWLEDGE ABOUT THE EPIDEMIOLOGY, CLASSIFICATION CRITERIA, SYSTEMIC ACTIVITY SCORING (ESSDAI) AND PATIENT-REPORTED OUTCOMES (ESSPRI) IS DRIVING ACTIVE RESEARCH. TREATMENT DECISIONS ARE BASED ON THE EVALUATION OF SYMPTOMS AND EXTRAGLANDULAR MANIFESTATIONS. SYMPTOMATIC TREATMENT IS USUALLY APPROPRIATE, WHEREAS SYSTEMIC TREATMENT IS RESERVED FOR SYSTEMIC MANIFESTATIONS. SICCA IS MANAGED BY EDUCATION, ENVIRONMENT MODIFICATION, ELIMINATION OF CONTINGENT OFFENDING DRUGS, ARTIFICIAL TEARS, SECRETAGOGUES AND TREATMENTS FOR COMPLICATIONS. MILD SYSTEMIC SIGNS SUCH AS FATIGUE ARE TREATED BY EXERCISE. PAIN CAN REQUIRE SHORT-TERM MODERATE-DOSE GLUCOCORTICOID THERAPY AND, IN SOME CASES, DISEASE-MODIFYING DRUGS. SEVERE AND ACUTE SYSTEMIC MANIFESTATIONS INDICATE TREATMENT WITH GLUCOCORTICOIDS AND/OR IMMUNOSUPPRESSANT DRUGS. THE ROLE FOR BIOLOGIC AGENTS IS PROMISING, BUT NO DOUBLE-BLIND RANDOMIZED CONTROLLED TRIALS (RCTS) PROVING THE EFFICACY OF THESE DRUGS ARE AVAILABLE. TARGETS FOR NEW TREATMENTS DIRECTED AGAINST THE IMMUNOPATHOLOGICAL MECHANISMS OF PSS INCLUDE EPITHELIAL CELLS, T CELLS, B-CELL OVERACTIVITY, THE INTERFERON SIGNATURE, PROINFLAMMATORY CYTOKINES, ECTOPIC GERMINAL CENTRE FORMATION, CHEMOKINES INVOLVED IN LYMPHOID CELL HOMING, AND EPIGENETIC MODIFICATIONS. 2016 2 3021 33 GENETICS AND EPIGENETICS OF PRIMARY SJOGREN SYNDROME: IMPLICATIONS FOR FUTURE THERAPIES. IN PRIMARY SJOGREN SYNDROME (PSS), CHRONIC INFLAMMATION OF EXOCRINE GLANDS RESULTS IN TISSUE DESTRUCTION AND SICCA SYMPTOMS, PRIMARILY OF THE MOUTH AND EYES. FATIGUE, ARTHRALGIA AND MYALGIA ARE ALSO COMMON SYMPTOMS, WHEREAS EXTRAGLANDULAR MANIFESTATIONS THAT INVOLVE THE RESPIRATORY, NERVOUS AND VASCULAR SYSTEMS OCCUR IN A SUBSET OF PATIENTS. THE DISEASE PREDOMINANTLY AFFECTS WOMEN, WITH AN ESTIMATED FEMALE TO MALE RATIO OF 14 TO 1. THE AETIOLOGY OF PSS, HOWEVER, REMAINS INCOMPLETELY UNDERSTOOD, AND EFFECTIVE TREATMENT IS LACKING. LARGE-SCALE GENETIC AND EPIGENETIC INVESTIGATIONS HAVE REVEALED ASSOCIATIONS BETWEEN PSS AND GENES IN BOTH INNATE AND ADAPTIVE IMMUNE PATHWAYS. THE GENETIC VARIANTS MEDIATE CONTEXT-DEPENDENT EFFECTS, AND BOTH SEX AND ENVIRONMENTAL FACTORS CAN INFLUENCE THE OUTCOME. AS SUCH, GENETIC AND EPIGENETIC STUDIES CAN PROVIDE INSIGHT INTO THE DYSREGULATED MOLECULAR MECHANISMS, WHICH IN TURN MIGHT REVEAL NEW THERAPEUTIC POSSIBILITIES. THIS REVIEW DISCUSSES THE GENETIC AND EPIGENETIC FEATURES THAT HAVE BEEN ROBUSTLY CONNECTED WITH PSS, PUTTING THEM INTO THE CONTEXT OF CELLULAR FUNCTION, CARRIER SEX AND ENVIRONMENTAL CHALLENGES. IN ALL, THE OBSERVATIONS POINT TO SEVERAL NOVEL OPPORTUNITIES FOR EARLY DETECTION, TREATMENT DEVELOPMENT AND THE PATHWAY TOWARDS PERSONALIZED MEDICINE. 2023 3 6791 27 [DOES THE NUMBER OF PATIENTS WITH AUTOIMMUNE DISORDERS AND THE FREQUENCY OF AUTOIMMUNE DISEASES INCREASE?]. AUTOIMMUNE DISEASES GENERALLY BELONG TO THE RARE DISEASES, HOWEVER, SOME OF THEM ARE FREQUENT IN THE POPULATION. IN THE PRESENT WORK THE AUTHORS ANALYSE WHETHER CAN ANY INCREASE BE OBSERVED IN THE NUMBER OF PATIENTS SUFFERING FROM AUTOIMMUNE DISEASES AND WHETHER DO THE FREQUENCY OF CERTAIN AUTOIMMUNE DISORDERS INCREASE. DUE MAINLY TO EPIGENETIC FACTORS THE INCIDENCE OF AUTOIMMUNE DISEASES ARE INCREASING, THEREFORE THERE ARE MORE PATIENTS RECOGNISED WITH PARTICULAR DISORDERS. ON THE OTHER HAND THE INCIDENCE IS INCREASED BY IMPROVING DIAGNOSTIC POSSIBILITIES, BY THE USE OF MORE SPECIFIC AND SENSITIVE CLASSIFICATION CRITERIA AND MORE SOPHISTICATED LABORATORY TESTS, RESULTED IN THE RECOGNITION OF MILDER AND ATYPICAL DISEASE VARIANTS AS WELL. THE PREVALENCE IS ALSO INCREASING IN CONSEQUENCE OF NOVEL IMMUNE SUPPRESSIVE THERAPEUTIC POSSIBILITIES AND THE CONSEQUENT IMPROVEMENT OF SURVIVAL IN THE MOST OF THESE DISEASES. BESIDES, MORE AND MORE DISEASES HAVE BEEN REVEALED TO HAVE AUTOIMMUNE BACKGROUND, AND LOT OF NEW AUTOIMMUNE SYNDROMES, DISEASES HAVE BEEN CHARACTERISED RECENTLY. THIS INCREASES THE NUMBER OF THE KNOWN AUTOIMMUNE RHEUMATIC DISORDERS WITH A CONSEQUENT INCREASE IN THE NUMBER OF AUTOIMMUNE PATIENTS. ASSIGNED TO THE INCREASING NUMBER OF VARIABLE CHRONIC AUTOIMMUNE DISORDERS, AND THE INCREASING NUMBER OF DISABLED PATIENTS WITH SUCH DISEASES INCREASING MEDICAL AND SOCIAL ATTENTION HAS TO BE FOCUSED ON. 2007 4 6142 32 THE EVALUATION OF CYTOKINES TO HELP ESTABLISH DIAGNOSIS AND GUIDE TREATMENT OF AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES. OUR KNOWLEDGE OF THE ROLE OF CYTOKINES IN PATHOLOGIC CONDITIONS HAS INCREASED CONSIDERABLY WITH THE EMERGENCE OF MOLECULAR AND GENETIC STUDIES, PARTICULARLY IN THE CASE OF AUTOINFLAMMATORY MONOGENIC DISEASES. MANY RARE DISORDERS, CONSIDERED ORPHAN UNTIL RECENTLY, ARE DIRECTLY RELATED TO ABNORMAL GENE REGULATION, AND THE TREATMENT WITH BIOLOGIC AGENTS (BIOLOGICS) TARGETING CYTOKINE RECEPTORS, INTRACELLULAR SIGNALING OR SPECIFIC CYTOKINES IMPROVE THE SYMPTOMS OF AN INCREASING NUMBER OF CHRONIC INFLAMMATORY DISEASES. AS IT IS CURRENTLY IMPOSSIBLE TO SYSTEMATICALLY CONDUCT GENETIC STUDIES FOR ALL PATIENTS WITH AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, THE EVALUATION OF CYTOKINES CAN BE SEEN AS A SIMPLE, LESS TIME CONSUMING, AND LESS EXPENSIVE ALTERNATIVE. THIS APPROACH COULD BE ESPECIALLY USEFUL WHEN THE DIAGNOSIS OF SYNDROMES OF DISEASES OF UNKNOWN ETIOLOGY REMAINS PROBLEMATIC. THE EVALUATION OF CYTOKINES COULD ALSO HELP AVOID THE CURRENT TRIAL-AND-ERROR APPROACH, WHICH HAS THE DISADVANTAGES OF EXPOSING PATIENTS TO INEFFECTIVE DRUGS WITH POSSIBLE UNNECESSARY SIDE EFFECTS AND PERMANENT ORGAN DAMAGES. IN THIS REVIEW, WE DISCUSS THE VARIOUS POSSIBILITIES, AS WELL AS THE LIMITATIONS OF EVALUATING THE CYTOKINE PROFILES OF PATIENTS SUFFERING FROM AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, WITH METHODS SUCH AS DIRECT DETECTION OF CYTOKINES IN THE PLASMA/SERUM OR FOLLOWING EX VIVO STIMULATION OF PBMCS LEADING TO THE PRODUCTION OF THEIR CYTOKINE SECRETOME. THE PATIENTS' SECRETOME, COMBINED WITH BIOMARKERS RANGING FROM GENETIC AND EPIGENETIC ANALYSES TO IMMUNOLOGIC BIOMARKERS, MAY HELP NOT ONLY THE DIAGNOSIS BUT ALSO GUIDE THE CHOICE OF BIOLOGICS FOR MORE EFFICIENT AND RAPID TREATMENTS. 2020 5 2238 30 EPIGENETIC MODULATION AS A THERAPEUTIC PROSPECT FOR TREATMENT OF AUTOIMMUNE RHEUMATIC DISEASES. SYSTEMIC INFLAMMATORY RHEUMATIC DISEASES ARE CONSIDERED AS AUTOIMMUNE DISEASES, MEANING THAT THE BALANCE BETWEEN RECOGNITION OF PATHOGENS AND AVOIDANCE OF SELF-ATTACK IS IMPAIRED AND THE IMMUNE SYSTEM ATTACKS AND DESTROYS ITS OWN HEALTHY TISSUE. TREATMENT WITH CONVENTIONAL DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) AND/OR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IS OFTEN ASSOCIATED WITH VARIOUS ADVERSE REACTIONS DUE TO UNSPECIFIC AND TOXIC PROPERTIES OF THOSE DRUGS. ALTHOUGH BIOLOGIC DRUGS HAVE LARGELY IMPROVED THE OUTCOME IN MANY PATIENTS, SUCH DRUGS STILL POSE SIGNIFICANT PROBLEMS AND FAIL TO PROVIDE A SOLUTION TO ALL PATIENTS. THEREFORE, DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND IMPROVEMENTS IN EARLY DIAGNOSIS OF RHEUMATIC DISEASES ARE BADLY NEEDED IN ORDER TO INCREASE PATIENT'S FUNCTIONING AND QUALITY OF LIFE. THE REVERSIBLE NATURE OF EPIGENETIC MECHANISMS OFFERS A NEW CLASS OF DRUGS THAT MODULATE THE IMMUNE SYSTEM AND INFLAMMATION. IN FACT, EPIGENETIC DRUGS ARE ALREADY IN USE IN SOME TYPES OF CANCER OR CARDIOVASCULAR DISEASES. THEREFORE, EPIGENETIC-BASED THERAPEUTICS THAT CONTROL AUTOIMMUNITY AND CHRONIC INFLAMMATORY PROCESS HAVE BROAD IMPLICATIONS FOR THE PATHOGENESIS, DIAGNOSIS, AND MANAGEMENT OF RHEUMATIC DISEASES. THIS REVIEW SUMMARISES THE LATEST INFORMATION ABOUT POTENTIAL THERAPEUTIC APPLICATION OF EPIGENETIC MODIFICATION IN TARGETING IMMUNE ABNORMALITIES AND INFLAMMATION OF RHEUMATIC DISEASES. 2016 6 2294 39 EPIGENETIC REGULATION IN THE PATHOGENESIS OF SJOGREN SYNDROME AND RHEUMATOID ARTHRITIS. AUTOIMMUNE RHEUMATIC DISEASES, SUCH AS SJOGREN SYNDROME (SS) AND RHEUMATOID ARTHRITIS (RA), ARE CHARACTERIZED BY CHRONIC INFLAMMATION AND AUTOIMMUNITY, WHICH CAUSE JOINT TISSUE DAMAGE AND DESTRUCTION BY TRIGGERING REDUCED MOBILITY AND DEBILITATION IN PATIENTS WITH THESE DISEASES. INITIATION AND MAINTENANCE OF CHRONIC INFLAMMATORY STAGES ACCOUNT FOR SEVERAL MECHANISMS THAT INVOLVE IMMUNE CELLS AS KEY PLAYERS AND THE INTERACTION OF THE IMMUNE CELLS WITH OTHER TISSUES. INDEED, THE OVERLAPPING OF CERTAIN CLINICAL AND SEROLOGIC MANIFESTATIONS BETWEEN SS AND RA MAY INDICATE THAT NUMEROUS IMMUNOLOGIC-RELATED MECHANISMS ARE INVOLVED IN THE PHYSIOPATHOLOGY OF BOTH THESE DISEASES. IT IS WIDELY ACCEPTED THAT EPIGENETIC PATHWAYS PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. ALTHOUGH MANY PUBLISHED STUDIES HAVE ATTEMPTED TO ELUCIDATE THE RELATION BETWEEN EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, MIRNAS) AND AUTOIMMUNE DISORDERS, THE CONTRIBUTION OF EPIGENETIC REGULATION TO THE PATHOGENESIS OF SS AND RA IS AT PRESENT POORLY UNDERSTOOD. THIS REVIEW ATTEMPTS TO SHED LIGHT FROM A CRITICAL POINT OF VIEW ON THE IDENTIFICATION OF THE MOST RELEVANT EPIGENETIC MECHANISMS RELATED TO RA AND SS BY EXPLAINING INTRICATE REGULATORY PROCESSES AND PHENOTYPIC FEATURES OF BOTH AUTOIMMUNE DISEASES. MOREOVER, WE POINT OUT SOME EPIGENETIC MARKERS WHICH CAN BE USED TO MONITOR THE INFLAMMATION STATUS AND THE DYSREGULATED IMMUNITY IN SS AND RA. FINALLY, WE DISCUSS THE INCONVENIENCE OF USING EPIGENETIC DATA OBTAINED FROM BULK IMMUNE CELL POPULATIONS INSTEAD SPECIFIC IMMUNE CELL SUBPOPULATIONS. 2019 7 1047 33 CLINICAL EFFECT AND BIOLOGICAL MECHANISM OF EXERCISE FOR RHEUMATOID ARTHRITIS: A MINI REVIEW. RHEUMATOID ARTHRITIS (RA) IS A COMMON SYSTEMATIC, CHRONIC INFLAMMATORY, AUTOIMMUNE, AND POLYARTICULAR DISEASE, CAUSING A RANGE OF CLINICAL MANIFESTATIONS, INCLUDING JOINT SWELLING, REDNESS, PAIN, STIFFNESS, FATIGUE, DECREASED QUALITY OF LIFE, PROGRESSIVE DISABILITY, CARDIOVASCULAR PROBLEMS, AND OTHER COMORBIDITIES. STRONG EVIDENCE HAS SHOWN THAT EXERCISE IS EFFECTIVE FOR RA TREATMENT IN VARIOUS CLINICAL DOMAINS. EXERCISE TRAINING FOR RELATIVELY LONGER PERIODS (E.G., >/= 12 WEEKS) CAN DECREASE DISEASE ACTIVITY OF RA. HOWEVER, THE MECHANISM UNDERLYING THE EFFECTIVENESS OF EXERCISE IN REDUCING RA DISEASE ACTIVITY REMAINS UNCLEAR. THIS REVIEW FIRST SUMMARIZES AND HIGHLIGHTS THE EFFECTIVENESS OF EXERCISE IN RA TREATMENT. THEN, WE INTEGRATE CURRENT EVIDENCE AND PROPOSE BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE POTENTIAL EFFECTS OF EXERCISE ON IMMUNE CELLS AND IMMUNITY, INFLAMMATORY RESPONSE, MATRIX METALLOPROTEINASES, OXIDATIVE STRESS, AND EPIGENETIC REGULATION. HOWEVER, A LARGE BODY OF EVIDENCE WAS OBTAINED FROM THE NON-RA POPULATIONS. FUTURE STUDIES ARE NEEDED TO FURTHER EXAMINE THE PROPOSED BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE EFFECTIVENESS OF EXERCISE IN DECREASING DISEASE ACTIVITY IN RA POPULATIONS. SUCH KNOWLEDGE WILL CONTRIBUTE TO THE BASIC SCIENCE AND STRENGTHEN THE SCIENTIFIC BASIS OF THE PRESCRIPTION OF EXERCISE THERAPY FOR RA IN THE CLINICAL ROUTINE. 2022 8 3038 33 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 9 6807 23 [EPIGENETICS AND PAIN]. CHRONIC PAIN AFFECTS APPROXIMATELY 20 % OF ADULTS WORLDWIDE AND IS OFTEN ASSOCIATED WITH A DECREASE IN THE QUALITY OF LIFE AND VARIOUS COMORBIDITIES. CONVENTIONAL ANALGESIC THERAPIES ARE FREQUENTLY INSUFFICIENT AND SOMETIMES LEAD TO SEVERE SIDE EFFECTS. THEREFORE, GREAT EFFORTS ARE STILL BEING MADE TO ELUCIDATE THE SIGNALLING PATHWAYS IN PAIN AND TO DEVELOP NEW, SAFE AND EFFECTIVE THERAPIES. EPIGENETIC MECHANISMS WHICH INTERFERE WITH THE REGULATION OF GENE EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OF SEVERAL DISEASES AND ARE GAINING INCREASING IMPETUS IN MEDICAL RESEARCH. AS THEY ARE ALSO INVOLVED IN PAIN PROCESSING, A MODULATION OF THESE MECHANISMS MIGHT REPRESENT A NOVEL OPTION FOR THE THERAPY OF PAIN PATIENTS. 2014 10 2984 28 GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA. SEVERE ASTHMA IS A MULTIFACTORIAL DISORDER WITH MARKED PHENOTYPIC HETEROGENEITY AND COMPLEX INTERACTIONS BETWEEN GENETICS AND ENVIRONMENTAL RISK FACTORS, WHICH COULD, AT LEAST IN PART, EXPLAIN WHY DURING STANDARD PHARMACOLOGIC TREATMENT, MANY PATIENTS REMAIN POORLY CONTROLLED AND AT AN INCREASED RISK OF AIRWAY REMODELING AND DISEASE PROGRESSION. THE CONCEPT OF "PRECISION MEDICINE" TO BETTER SUIT INDIVIDUAL UNIQUE NEEDS IS AN EMERGING TREND IN THE MANAGEMENT OF CHRONIC RESPIRATORY DISEASES. OVER THE PAST FEW YEARS, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE REVEALED NOVEL PHARMACOGENETIC VARIANTS RELATED TO RESPONSES TO INHALED CORTICOSTEROIDS AND THE CLINICAL EFFICACY OF BRONCHODILATORS. OPTIMAL CLINICAL RESPONSE TO TREATMENT MAY VARY BETWEEN RACIAL/ETHNIC GROUPS OR INDIVIDUALS DUE TO GENETIC DIFFERENCES. IT IS ALSO PLAUSIBLE TO ASSUME THAT EPIGENETIC FACTORS PLAY A KEY ROLE IN THE MODULATION OF GENE EXPRESSION PATTERNS AND INFLAMMATORY CYTOKINES. REMARKABLY, SPECIFIC GENETIC VARIANTS RELATED TO TREATMENT EFFECTIVENESS MAY INDICATE PROMISING PATHWAYS FOR NOVEL THERAPIES IN SEVERE ASTHMA. IN THIS REVIEW, WE PROVIDE A CONCISE UPDATE OF GENETIC DETERMINANTS OF POOR RESPONSE TO TREATMENT IN SEVERE ASTHMA AND FUTURE DIRECTIONS IN THE FIELD. 2021 11 6447 34 THERAPEUTIC PROSPECTS FOR EPIGENETIC MODULATION. INTRODUCTION: EPIGENETICS DESCRIBES THE PHENOMENON OF HERITABLE CHANGES IN GENE REGULATION GOVERNED BY NON-MENDELIAN PROCESSES, PRIMARILY THROUGH BIOCHEMICAL MODIFICATIONS TO CHROMATIN THAT OCCUR DURING CELL DIFFERENTIATION AND DEVELOPMENT. ABNORMAL LEVELS OF DNA AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. DRUGS THAT TARGET THE PROTEINS CONTROLLING THESE CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS WITH SINGLE TARGET PHARMACOLOGIES THAT ARE SUSCEPTIBLE TO BIOCHEMICAL PATHWAY DEGENERACY. AREAS COVERED: THIS ARTICLE REVIEWS RESEARCH CHARACTERIZING DYSREGULATION OF EPIGENETIC PROCESSES IN CANCER, IMMUNO-INFLAMMATORY, PSYCHIATRIC, NEUROLOGICAL, METABOLIC AND VIROLOGY DISEASE AREAS, AND SUMMARIZES RECENT DEVELOPMENTS IN IDENTIFYING SMALL MOLECULE MODULATORS THAT ARE BEING USED TO INFORM TARGET DISCOVERY AND INITIATE DRUG DISCOVERY PROJECTS. EXPERT OPINION: THERE ARE NUMEROUS POTENTIAL OPPORTUNITIES FOR EPIGENETIC MODULATORS IN TREATING A WIDE RANGE OF CHRONIC DISEASES; HOWEVER, THE FIELD IS COMPLEX, INVOLVING > 300 PROTEINS, AND MUCH WORK IS STILL REQUIRED TO PROVIDE TOOLS TO UNRAVEL THE FUNCTIONS OF INDIVIDUAL PROTEINS, PARTICULARLY IN VIVO. THIS GROUNDWORK IS ESSENTIAL TO ALLOW THE DRUG DISCOVERY COMMUNITY TO FOCUS ON THOSE EPIGENETIC PROTEINS MOST LIKELY TO BE SUITABLE TARGETS FOR SAFE, EFFICACIOUS NEW THERAPIES. 2011 12 5913 24 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 13 5839 35 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 14 5038 20 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 15 2303 26 EPIGENETIC REGULATION OF CANNABINOID-MEDIATED ATTENUATION OF INFLAMMATION AND ITS IMPACT ON THE USE OF CANNABINOIDS TO TREAT AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION IS CONSIDERED TO BE A SILENT KILLER BECAUSE IT IS THE UNDERLYING CAUSE OF A WIDE RANGE OF CLINICAL DISORDERS, FROM CARDIOVASCULAR TO NEUROLOGICAL DISEASES, AND FROM CANCER TO OBESITY. IN ADDITION, THERE ARE OVER 80 DIFFERENT TYPES OF DEBILITATING AUTOIMMUNE DISEASES FOR WHICH THERE ARE NO CURE. CURRENTLY, THE DRUGS THAT ARE AVAILABLE TO SUPPRESS CHRONIC INFLAMMATION ARE EITHER INEFFECTIVE OR OVERTLY SUPPRESS THE INFLAMMATION, THEREBY CAUSING INCREASED SUSCEPTIBILITY TO INFECTIONS AND CANCER. THUS, THE DEVELOPMENT OF A NEW CLASS OF DRUGS THAT CAN SUPPRESS CHRONIC INFLAMMATION IS IMPERATIVE. CANNABINOIDS ARE A GROUP OF COMPOUNDS PRODUCED IN THE BODY (ENDOCANNABINOIDS) OR FOUND IN CANNABIS (PHYTOCANNABINOIDS) THAT ACT THROUGH CANNABINOID RECEPTORS AND VARIOUS OTHER RECEPTORS EXPRESSED WIDELY IN THE BRAIN AND IMMUNE SYSTEM. IN THE LAST DECADE, CANNABINOIDS HAVE BEEN WELL ESTABLISHED EXPERIMENTALLY TO MEDIATE ANTI-INFLAMMATORY PROPERTIES. RESEARCH HAS SHOWN THAT THEY SUPPRESS INFLAMMATION THROUGH MULTIPLE PATHWAYS, INCLUDING APOPTOSIS AND INDUCING IMMUNOSUPPRESSIVE T REGULATORY CELLS (TREGS) AND MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS). INTERESTINGLY, CANNABINOIDS ALSO MEDIATE EPIGENETIC ALTERATIONS IN GENES THAT REGULATE INFLAMMATION. IN THE CURRENT REVIEW, WE HIGHLIGHT HOW THE EPIGENETIC MODULATIONS CAUSED BY CANNABINOIDS LEAD TO THE SUPPRESSION OF INFLAMMATION AND HELP IDENTIFY NOVEL PATHWAYS THAT CAN BE USED TO TARGET AUTOIMMUNE DISEASES. 2021 16 2704 20 EXERCISE AND COLORECTAL CANCER: PREVENTION AND MOLECULAR MECHANISMS. EXERCISE AND PHYSICAL ACTIVITY HAVE BEEN SHOWN TO BE STRONGLY ASSOCIATED WITH A DECREASED INCIDENCE RATE OF VARIOUS CHRONIC DISEASES ESPECIALLY NUMEROUS HUMAN MALIGNANCIES. A HUGE NUMBER OF CLINICAL TRIALS AND META-ANALYSIS HAVE DEMONSTRATED THAT EXERCISE IS SIGNIFICANTLY EFFECTIVE IN LOWERING THE RISK OF COLORECTAL CANCER. IN ADDITION, IT IS SUGGESTED AS AN EFFECTIVE THERAPEUTIC MODALITY AGAINST THIS CANCER TYPE. THEREFORE, IN THIS REVIEW, WE WILL REVIEW COMPREHENSIBLY THE EFFECTS OF EXERCISE IN PREVENTING, TREATING, AND ALLEVIATING THE ADVERSE EFFECTS OF CONVENTIONAL THERAPEUTIC OPTIONS IN COLORECTAL CANCER. MOREOVER, THE POSSIBLE MECHANISMS UNDERLYING THE POSITIVE EFFECTS OF EXERCISE AND PHYSICAL ACTIVITY IN COLORECTAL CANCER, INCLUDING REGULATION OF INFLAMMATION, APOPTOSIS, GROWTH FACTOR AXIS, IMMUNITY, EPIGENETIC, ETC. WILL BE ALSO DISCUSSED. 2022 17 845 31 CHILDHOOD ATOPIC DERMATITIS: CURRENT DEVELOPMENTS, TREATMENT APPROACHES, AND FUTURE EXPECTATIONS. ATOPIC DERMATITIS (AD) IS THE MOST COMMON CHRONIC INFLAMMATORY SKIN DISORDER OF CHILDHOOD. UNDERLYING FACTORS THAT CONTRIBUTE TO AD ARE IMPAIRED EPITHELIAL BARRIER, ALTERATIONS IN THE LIPID COMPOSITION OF THE SKIN, IMMUNOLOGICAL IMBALANCE INCLUDING INCREASED TH2/TH1 RATIO, PROINFLAMMATORY CYTOKINES, DECREASED T REGULATORY CELLS, GENETIC MUTATIONS, AND EPIGENETIC ALTERATIONS. ATOPIC DERMATITIS IS A MULTIFACTORIAL DISEASE WITH A PARTICULARLY COMPLICATED PATHOPHYSIOLOGY. DISCOVERIES TO DATE MAY BE CONSIDERED THE TIP OF THE ICEBERG, AND THE INCREASING NUMBER OF STUDIES IN THIS FIELD INDICATE THAT THERE ARE MANY POINTS TO BE ELUCIDATED IN AD PATHOPHYSIOLOGY. IN THIS REVIEW, WE AIMED TO ILLUSTRATE THE CURRENT UNDERSTANDING OF THE UNDERLYING PATHOGENIC MECHANISMS IN AD, TO EVALUATE AVAILABLE TREATMENT OPTIONS WITH A FOCUS ON RECENTLY DISCOVERED THERAPEUTIC AGENTS, AND TO DETERMINE THE PERSONAL, FAMILIAL, AND ECONOMIC BURDENS OF THE DISEASE, WHICH ARE FREQUENTLY NEGLECTED ISSUES IN AD. CURRENTLY AVAILABLE THERAPIES ONLY PROVIDE TRANSIENT SOLUTIONS AND CANNOT FULLY CURE THE DISEASE. HOWEVER, ADVANCES IN THE UNDERSTANDING OF THE PATHOGENIC MECHANISMS OF THE DISEASE HAVE LED TO THE PRODUCTION OF NEW TREATMENT OPTIONS, WHILE ONGOING DRUG TRIALS ALSO HAVE HAD PROMISING RESULTS. 2019 18 806 25 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 5886 32 SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE THAT IS HIGHLY HETEROGENEOUS IN ITS PRESENTATION. THIS CAN POSE SIGNIFICANT CHALLENGES FOR PHYSICIANS RESPONSIBLE FOR THE DIAGNOSIS AND TREATMENT OF SUCH PATIENTS. SLE ARISES FROM A COMBINATION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. PATHOLOGICALLY, THE DISEASE IS PRIMARILY DRIVEN BY LOSS OF IMMUNE TOLERANCE AND ABNORMAL B- AND T-CELL FUNCTION. MAJOR ORGAN INVOLVEMENT MAY LEAD TO SIGNIFICANT MORBIDITY AND MORTALITY. CLASSIFICATION CRITERIA FOR SLE HAVE BEEN DEVELOPED LARGELY FOR RESEARCH PURPOSES; HOWEVER, THESE ARE ALSO WIDELY USED IN CLINICAL PRACTICE. ANTINUCLEAR ANTIBODIES ARE THE HALLMARK SEROLOGICAL FEATURE, OCCURRING IN OVER 95% OF PATIENTS WITH SLE AT SOME POINT DURING THEIR DISEASE. THE MAINSTAY OF TREATMENT IS ANTIMALARIAL DRUGS SUCH AS HYDROXYCHLOROQUINE, COMBINED WITH CORTICOSTEROIDS AND CONVENTIONAL IMMUNOSUPPRESSIVE DRUGS. AN INCREASING UNDERSTANDING OF PATHOGENESIS HAS FACILITATED A MOVE TOWARDS THE DEVELOPMENT OF TARGETED BIOLOGIC THERAPIES, WITH THE INTRODUCTION OF RITUXIMAB AND BELIMUMAB INTO CLINICAL PRACTICE. 2017 20 943 28 CHRONIC LYMPHOCYTIC LEUKEMIA. PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA CAN BE DIVIDED INTO THREE CATEGORIES: THOSE WHO ARE MINIMALLY AFFECTED BY THE PROBLEM, OFTEN NEVER REQUIRING THERAPY; THOSE THAT INITIALLY FOLLOW AN INDOLENT COURSE BUT SUBSEQUENTLY PROGRESS AND REQUIRE THERAPY; AND THOSE THAT FROM THE POINT OF DIAGNOSIS EXHIBIT AN AGGRESSIVE DISEASE NECESSITATING TREATMENT. LIKEWISE, SUCH PATIENTS PASS THROUGH THREE PHASES: DEVELOPMENT OF THE DISEASE, DIAGNOSIS, AND NEED FOR THERAPY. FINALLY, THE LEUKEMIC CLONES OF ALL PATIENTS APPEAR TO REQUIRE CONTINUOUS INPUT FROM THE EXTERIOR, MOST OFTEN THROUGH MEMBRANE RECEPTORS, TO ALLOW THEM TO SURVIVE AND GROW. THIS REVIEW IS PRESENTED ACCORDING TO THE TEMPORAL COURSE THAT THE DISEASE FOLLOWS, FOCUSING ON THOSE EXTERNAL INFLUENCES FROM THE TISSUE MICROENVIRONMENT (TME) THAT SUPPORT THE TIME LINES AS WELL AS THOSE INTERNAL INFLUENCES THAT ARE INHERITED OR DEVELOP AS GENETIC AND EPIGENETIC CHANGES OCCURRING OVER THE TIME LINE. REGARDING THE FORMER, SPECIAL EMPHASIS IS PLACED ON THE INPUT PROVIDED VIA THE B-CELL RECEPTOR FOR ANTIGEN AND THE C-X-C-MOTIF CHEMOKINE RECEPTOR-4 AND THE THERAPEUTIC AGENTS THAT BLOCK THESE INPUTS. REGARDING THE LATTER, PROMINENCE IS LAID UPON INHERITED SUSCEPTIBILITY GENES AND THE GENETIC AND EPIGENETIC ABNORMALITIES THAT LEAD TO THE DEVELOPMENTAL AND PROGRESSION OF THE DISEASE. 2021