1 5036 164 PHARMACOGENETICS AND PHARMACOGENOMICS IN MODERATE-TO-SEVERE PSORIASIS. PHARMACOGENETICS IS THE STUDY OF VARIATIONS IN DNA SEQUENCE RELATED TO DRUG RESPONSE. MOREOVER, THE EVOLUTION OF BIOTECHNOLOGY AND THE SEQUENCING OF HUMAN DNA HAVE ALLOWED THE CREATION OF PHARMACOGENOMICS, A BRANCH OF GENETICS THAT ANALYZES HUMAN GENES, THE RNAS AND PROTEINS ENCODED BY THEM, AND THE INTER-AND INTRA-INDIVIDUAL VARIATIONS IN EXPRESSION AND FUNCTION IN RELATION TO DRUG RESPONSE. PHARMACOGENETICS AND PHARMACOGENOMICS ARE BEING USED TO SEARCH FOR BIOMARKERS THAT CAN PREDICT RESPONSE TO SYSTEMIC TREATMENTS, INCLUDING THOSE FOR MODERATE-TO-SEVERE PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY DISEASE WITH AN AUTOIMMUNE CONTRIBUTION. ALTHOUGH ITS ETIOLOGY REMAINS UNKNOWN, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN ITS DEVELOPMENT. DIVERSE SYSTEMIC AND BIOLOGIC THERAPIES ARE USED TO TREAT MODERATE-TO-SEVERE PSORIASIS. HOWEVER, THESE TREATMENTS ARE NOT CURATIVE, AND PATIENTS EXHIBIT A WIDE RANGE OF RESPONSES TO THEM. MODERATE-TO-SEVERE PSORIASIS IS USUALLY TREATED WITH SYSTEMIC IMMUNOMODULATORS SUCH AS ACITRETIN, CICLOSPORIN, AND METHOTREXATE. ANTI-TUMOR NECROSIS FACTOR (TNF) DRUGS (ADALIMUMAB, ETANERCEPT, OR INFLIXIMAB) ARE THE FIRST-LINE TREATMENT FOR PATIENTS RESISTANT TO CONVENTIONAL SYSTEMIC THERAPIES. ALTHOUGH THESE THERAPIES ARE VERY EFFICIENT, AROUND 30-50% OF PATIENTS HAVE INADEQUATE RESPONSE. USTEKINUMAB IS A MONOCLONAL ANTIBODY THAT TARGETS INTERLEUKIN (IL)-12 AND IL-23 AND IS USED FOR MODERATE-TO-SEVERE PSORIASIS. NEW DRUGS (APREMILAST, BRODALUMAB, GUSELKUMAB, IXEKIZUMAB, AND SECUKINUMAB) HAVE RECENTLY BEEN APPROVED FOR PSORIASIS. HOWEVER, RESPONSE RATES TO SYSTEMIC TREATMENTS FOR MODERATE-TO-SEVERE PSORIASIS RANGE FROM 35 TO 80%, SO IT IS NECESSARY TO IDENTIFY NON-INVASIVE BIOMARKERS THAT COULD HELP PREDICT TREATMENT OUTCOMES OF THESE THERAPIES AND INDIVIDUALIZE CARE FOR PATIENTS WITH PSORIASIS. THESE BIOMARKERS COULD IMPROVE PATIENT QUALITY OF LIFE AND REDUCE HEALTH COSTS AND POTENTIAL SIDE EFFECTS. PHARMACOGENETIC STUDIES HAVE IDENTIFIED POTENTIAL BIOMARKERS FOR RESPONSE TO BIOLOGIC TREATMENTS FOR MODERATE-TO-SEVERE PSORIASIS. THESE BIOMARKERS NEED TO BE VALIDATED IN CLINICAL TRIALS INVOLVING LARGE COHORTS OF PATIENTS BEFORE THEY CAN BE TRANSLATED TO THE CLINIC. WE REVIEW PHARMACOGENETICS AND PHARMACOGENOMICS STUDIES FOR THE TREATMENT OF MODERATE-TO-SEVERE PLAQUE PSORIASIS. 2018 2 6624 37 UNDERSTANDING PSORIASIS: ROLE OF MIRNAS. PSORIASIS IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY SKIN DISEASE, WITH A MULTIFACTORIAL ETIOLOGY AND IMPORTANT IMMUNOLOGIC, GENETIC AND ENVIRONMENTAL COMPONENTS. PSORIASIS VULGARIS REPRESENTS ITS MOST COMMON FORM, WITH A VARIABLE PREVALENCE ACROSS THE GLOBE. ALTHOUGH ITS PATHOGENESIS REMAINS TO BE FULLY ELUCIDATED, A LACK OF BALANCE IN THE EPIGENETIC NETWORK HAS BEEN SHOWN TO TRIGGER CERTAIN ELEMENTS OF THIS DISEASE, POSSIBLY ALTERING ITS OUTCOME. MICRORNAS ARE SMALL NON-CODING RNA MOLECULES INVOLVED IN RNA-SILENCING AND THE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, WHICH ALSO APPEAR TO MEDIATE THE IMMUNE DYSFUNCTION IN PSORIASIS. ALTHOUGH MICRORNA RESEARCH IS A NEW FIELD IN DERMATOLOGY AND PSORIASIS, THERE IS RAPIDLY ACCUMULATING EVIDENCE FOR ITS MAJOR CONTRIBUTION IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PSORIASIS AND OTHER DERMATOLOGICAL DISORDERS. FURTHERMORE, CIRCULATING MIRNAS IDENTIFIED IN PATIENTS' BLOOD SAMPLES HAVE BEEN IDENTIFIED AS PROMISING BIOMARKERS OF DIAGNOSIS, PROGNOSIS OR TREATMENT RESPONSE. EXTENDED INVESTIGATIONS IN THIS FIELD ARE REQUIRED, AS UNTIL NOW, THE EXACT INVOLVEMENT OF MIRNAS IN PSORIASIS HAVE REMAINED TO BE ENTIRELY ELUCIDATED. THIS SHORT REVIEW HIGHLIGHTS A NUMBER OF THE ROLES OF MIRNAS FOUND IN DIFFERENT STAGES OF PSORIASIS. 2018 3 4961 37 PATHOGENESIS OF PSORIASIS IN THE "OMIC" ERA. PART II. GENETIC, GENOMIC AND EPIGENETIC CHANGES IN PSORIASIS. PSORIASIS IS A MULTIFACTORIAL DISEASE IN WHICH GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS REGULATING GENE EXPRESSION PLAY A KEY ROLE. IN THE "GENOMIC ERA", GENOME-WIDE ASSOCIATION STUDIES TOGETHER WITH TARGET GENOTYPING PLATFORMS PERFORMED IN DIFFERENT ETHNIC POPULATIONS HAVE FOUND MORE THAN 50 GENETIC SUSCEPTIBLE MARKERS ASSOCIATED WITH THE RISK OF PSORIASIS WHICH HAVE BEEN IDENTIFIED SO FAR. UP TILL NOW, THE STRONGEST ASSOCIATION WITH THE RISK OF THE DISEASE HAS BEEN PROVED FOR HLA-C*06 GENE. THE MAJORITY OF OTHER PSORIASIS RISK SNPS ARE SITUATED NEAR THE GENES ENCODING MOLECULES INVOLVED IN ADAPTIVE AND INNATE IMMUNITY, AND SKIN BARRIER FUNCTION. MANY CONTEMPORARY STUDIES INDICATE THAT THE EPIGENETIC CHANGES: HISTONE MODIFICATION, PROMOTER METHYLATIONS, LONG NON-CODING AND MICRO-RNA HYPEREXPRESSION ARE CONSIDERED AS FACTORS CONTRIBUTING TO PSORIASIS PATHOGENESIS AS THEY REGULATE ABNORMAL KERATINOCYTE DIFFERENTIATION AND PROLIFERATION, ABERRANT KERATINOCYTES - INFLAMMATORY CELLS COMMUNICATION, NEOANGIOGENESIS AND CHRONIC INFLAMMATION. THE CIRCULATING MIRNAS DETECTED IN THE BLOOD MAY BECOME SPECIFIC MARKERS IN THE DIAGNOSIS, PROGNOSIS AND RESPONSE TO THE TREATMENT OF THE DISEASE. THE INHIBITION OF EXPRESSION IN SELECTED MIRNAS MAY BE A NEW PROMISING THERAPY OPTION FOR PATIENTS WITH PSORIASIS. 2020 4 2591 45 EPIGENETICS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE, INVOLVING THE RAPID PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES AND ACTIVATION OF T CELLS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS A T CELL-DOMINANT IMMUNE DISORDER AFFECTED BY MULTIPLE FACTORS INCLUDING GENETIC SUSCEPTIBILITY, ENVIRONMENTAL FACTORS, INNATE AND ADAPTIVE IMMUNE RESPONSES, ETC. HOWEVER, THE EXACT ETIOLOGY IS LARGELY UNKNOWN. IN RECENT YEARS, EPIGENETIC INVOLVEMENTS, SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS, AND NONCODING RNA REGULATION ARE REPORTED TO BE CRITICAL FOR THE PATHOGENESIS OF PSORIASIS. HOWEVER, THE INTERPLAY BETWEEN THESE FACTORS HAS ONLY RECENTLY BEEN STARTED TO BE UNRAVELED. NOTABLY, INHIBITORS OF ENZYMES THAT WORK IN EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES, ARE BEGINNING TO APPEAR IN THE CLINICAL SETTING TO RESTORE NORMAL EPIGENETIC PATTERNS (GENERALI ET AL. IN J AUTOIMMUN 83:51-61, 2017), PROVIDING NOVEL THERAPEUTIC POTENTIAL AS NOVEL TREATMENT TARGETS FOR PSORIASIS. INDEED, MEDICATIONS PREVIOUSLY USED TO TREAT AUTOIMMUNE DISEASES HAVE LATER BEEN DISCOVERED TO EXERT THEIR ACTION VIA EPIGENETIC MECHANISMS. HEREIN, WE REVIEW THE FINDINGS ON EPIGENETICS ASSOCIATED WITH PSORIASIS, AND DISCUSS FUTURE PERSPECTIVES IN THIS FIELD. 2020 5 3038 40 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 6 5041 42 PHARMACOGENETICS: CAN GENES DETERMINE TREATMENT EFFICACY AND SAFETY IN JIA? JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATIC CONDITION IN CHILDHOOD, WITH MANY CHILDREN REQUIRING IMMUNOMODULATORY THERAPIES FOR MANY YEARS FOLLOWING DIAGNOSIS. A CONSIDERABLE PROPORTION OF CHILDREN EXPERIENCE THERAPEUTIC INEFFICACY OR SUBSTANTIAL ADVERSE EFFECTS, OR BOTH, BUT A LACK OF RELIABLE CLINICAL INDICATORS AND BIOMARKERS TO PREDICT TREATMENT RESPONSE PREVENTS OPTIMIZATION OF EXISTING THERAPIES. THE IDENTIFICATION OF VALID CANDIDATE GENE VARIANTS INVOLVED IN THE PATHWAYS OF METHOTREXATE AND ETANERCEPT, THE MOST COMMONLY USED MEDICATIONS IN JIA, HAS SEEN LITTLE SUCCESS TO DATE. THE LIMITED SUCCESS OF THESE STUDIES IS POSSIBLY DUE TO THE PRESENCE OF CONFOUNDING VARIABLES IN THE STUDY POPULATIONS, THE HETEROGENEITY OF OUTCOME PARAMETERS USED TO DETERMINE TREATMENT RESPONSE AND THE SMALL NUMBER OF CANDIDATE GENE VARIANTS ANALYSED. THE FIRST GENOME-WIDE PHARMACOGENETIC STUDY IN JIA HAS IDENTIFIED GENE REGIONS OF PARTICULAR BIOLOGICAL INTEREST, BUT THESE FINDINGS REQUIRE VALIDATION. MOREOVER, EPIGENETIC MECHANISMS AS WELL AS ONTOGENY PROCESSES MIGHT BE ADDITIONAL FACTORS INFLUENCING DRUG RESPONSES. ACCESS TO LARGE, WELL-DOCUMENTED JIA COHORTS AND THE RAPID DEVELOPMENT OF ADVANCED GENOME ANALYTICS IS USHERING IN A PERSONALIZED APPROACH TO TREATMENT. THE DISCOVERY OF NEW PHARMACOGENOMIC BIOMARKERS AND SYSTEMS PATHWAYS CAN PROVIDE NEW DRUG TARGETS AND PREDICTIVE TOOLS FOR IMPROVED DRUG RESPONSE AND FEWER ADVERSE DRUG REACTIONS IN JIA. 2014 7 2238 37 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 8 1935 40 ENVIRONMENTAL RISK FACTORS AND EPIGENETIC ALTERNATIONS IN PSORIASIS. INTRODUCTION AND OBJECTIVE: PSORIASIS ISA QUITE COMMON, CHRONIC AND IMMUNE-MEDIATED SKIN DISORDER. THE PREVALENCE OF PSORIASIS DIFFERS IN VARIOUS COUNTRIES, BUT IT IS SAID TO AFFECT 2% OF THE WORLD'S POPULATION IN GENERAL. PSORIASIS HAS MANY DIFFERENT CLINICAL FEATURES BUT ALL LESIONS HAVE THE SAME CHARACTERISTIC: ERYTHEMA, THICKENING AND SCALE, ALTHOUGH OTHER CLINICAL FEATURES ARE ALSO CONNECTED, SUCH AS PSORIATIC ARTHRITIS, OBESITY AND METABOLIC SYNDROME. ALL OF THESE MAY LEAD TO CONDITIONS IMPAIRING THE QUALITY OF LIFE. THIS REVIEW IS AN ATTEMPT TO SUMMARIZE RECENT DATA REGARDING ENVIRONMENTAL FACTORS, TOGETHER WITH EPIGENETIC MARKERS AND PROCESSES PLAYING AN IMPORTANT ROLE IN PSORIASIS. STATE OF KNOWLEDGE: MANY DIFFERENT ENVIRONMENTAL FACTORS PLAY A ROLE IN GENETICALLY PREDISPOSED PATIENTS. THIS IS CAUSES EPIGENETIC ALTERNATIONS WHICH MAY BE A LINKING PART IN THE WHOLE PROCESS. MANY STUDIES HAVE INDICATED A CONNECTION BETWEEN PSORIASIS AND VARIOUS GENES AND ANTIGENS. THE PRESENCE OF HLA-CW6 IS COMMON AS WELL A STRONG LINK BETWEEN ITS PRESENCE AND THE ONSET OF PSORIASIS BEING OBSERVED. THE MAIN ALTERNATIONS ARE DNA METHYLATION, HISTONE'S MODIFICATIONS AND THE ROLE OF MICRORNA. EXCESSIVE REACTION IS USUALLY NOT PRESENT WITHOUT A TRIGGERING FACTOR. ENVIRONMENTAL FACTORS ARE MOSTLY RATED, SUCH AS DRUGS, LIFE STYLE AND HABITS (SMOKING, ALCOHOL), DIET, PHYSICAL TRAUMA (SKIN INJURY PROVOKING KOEBNER PHENOMENON), STRESS, MICROORGANISM AND INFECTIONS. CONCLUSIONS: THE CORRELATION BETWEEN PATHOGENESIS OF PSORIASIS AND ENVIRONMENTAL RISK FACTORS, TOGETHER WITH EPIGENETIC ALTERNATIONS STILL REQUIRE MORE INVESTIGATION. EDUCATION ABOUT DIET HABITS, NUTRITION, WEIGHT LOSS AND HEALTHY LIFESTYLE SEEMS TO BE IMPORTANT DURING THE TREATMENT OF PSORIASIS. 2020 9 6343 39 THE ROLE OF EPIGENETICS AND IMMUNOLOGICAL IMBALANCE IN THE ETIOPATHOGENESIS OF PSORIASIS AND PSORIATIC ARTHRITIS. PSORIASIS (PS) AND PSORIATIC ARTHRITIS (PSA) REPRESENT A CLINICAL AND IMMUNOPATHOGENIC CONTINUUM, CALLED PSORIATIC DISEASE, CUMULATIVELY AFFECTING APPROXIMATELY 3% OF THE GENERAL POPULATION. PSORIATIC DISEASE IS A CHRONIC INFLAMMATORY DISORDER AFFECTING THE SKIN AND MUSCULOSKELETAL SYSTEM. THE IMMUNO-PATHOGENESIS IS CHARACTERIZED BY AN ACTIVATION OF THE TNF/IL-23/IL-17 CYTOKINE AXIS, LEADING TO AN IMMUNOLOGIC IMBALANCE OF T-CELLS RESIDENT IN ALL AFFECTED TISSUES, MAINLY ENTHESES. IN THE MAJORITY OF CASES, SKIN PS PREDATES RHEUMATOLOGICAL MANIFESTATIONS. SECONDARY TO THE HIGHER INCIDENCE AND THE AVAILABILITY OF MOUSE MODELS, THERE IS STRONGER DATA AVAILABLE ON SKIN PS, AND DATA ARE, IN MOST CASES, RELEVANT ALSO TO PSA. IN A WIDELY ACCEPTED MODEL, ENVIRONMENTAL TRIGGER FACTORS LIKE INFECTIONS OR TRAUMA ARE CAPABLE OF INITIATING AN INFLAMMATORY CASCADE, ULTIMATELY CREATING A SUSTAINED STATE OF CHRONIC INFLAMMATION IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. BESIDES WELL-KNOWN GENETIC SUSCEPTIBILITY LOCI, EPIGENETIC DNA MODIFICATIONS, WHICH ARE ASSOCIATED WITH PS DEVELOPMENT HAVE BEEN CHARACTERIZED RECENTLY AND WILL BE DISCUSSED IN THIS ARTICLE. THE CURRENT EVIDENCE IS PROMISING IN THE POSSIBILITY TO PROVIDE NEW THERAPEUTIC AVENUES AND FILL THE UNMET NEED OF PATIENTS, FOR WHOM CURRENT TREATMENTS EITHER DO NOT ALLOW THE DISEASE TO BE CONTROLLED OR MUST BE CONTINUED FOR LIFE. 2019 10 5038 27 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 11 2984 38 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 12 6791 29 [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 13 2945 30 GENETIC AND EPIGENETIC BASIS OF PSORIASIS PATHOGENESIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WHOSE PREVALENCE VARIES AMONG DIFFERENT POPULATIONS WORLDWIDE. IT IS A COMPLEX MULTI-FACTORIAL DISEASE AND THE EXACT ETIOLOGY IS LARGELY UNKNOWN. FAMILY BASED STUDIES HAVE INDICATED A GENETIC PREDISPOSITION; HOWEVER THEY CANNOT FULLY EXPLAIN THE DISEASE PATHOGENESIS. IN ADDITION TO GENETIC SUSCEPTIBILITY, ENVIRONMENTAL AS WELL AS GENDER AND AGE RELATED FACTORS WERE ALSO BEEN FOUND TO BE ASSOCIATED. RECENTLY, IMBALANCES IN EPIGENETIC NETWORKS ARE INDICATED TO BE CAUSATIVE ELEMENTS IN PSORIASIS. THE PRESENT KNOWLEDGE OF EPIGENETIC INVOLVEMENT, MAINLY THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND MIRNA DEREGULATION IS SURVEYED HERE. AN INTEGRATED APPROACH CONSIDERING GENETIC AND EPIGENETIC ANOMALIES IN THE LIGHT OF IMMUNOLOGICAL NETWORK MAY EXPLORE THE PATHOGENESIS OF PSORIASIS. 2015 14 3016 38 GENETICS AND EPIGENETICS OF IBD. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC INTERMITTENT INFLAMMATORY DISORDERS OF THE GASTROINTESTINAL TRACT OF UNKNOWN ETIOLOGY BUT A CLEAR GENETIC PREDISPOSITION. PROMPTED BY THE FIRST INVESTIGATIONS ON IBD FAMILIES AND TWINS, THE GENETIC AND EPIGENETIC STUDIES HAVE PRODUCED AN UNPRECEDENTED AMOUNT OF INFORMATION IN COMPARISON WITH OTHER IMMUNE-MEDIATED OR COMPLEX DISEASES. NEW INFLAMMATORY PATHWAYS AND POSSIBLE MECHANISMS OF ACTION HAVE BEEN DISCLOSED, POTENTIALLY LEADING TO NEW-TARGETED THERAPY. HOWEVER, THE IDENTIFICATION OF GENETIC MARKERS DUE TO THE GREAT DISEASE HETEROGENEITY AND THE OVERWHELMING CONTRIBUTION OF ENVIRONMENTAL RISK FACTORS HAS NOT MODIFIED YET THE DISEASE MANAGEMENT. THE POSSIBILITY FOR THE FUTURE OF A BETTER PREDICTION OF DISEASE COURSE, RESPONSE TO THERAPY AND THERAPY-RELATED ADVERSE EVENTS MAY ALLOW A MORE EFFICIENT AND PERSONALIZED STRATEGY. THIS REVIEW WILL FOCUS ON MORE RECENT DISCOVERIES THAT MAY POTENTIALLY BE OF RELEVANCE IN DAILY CLINICAL PRACTICE. 2020 15 6142 44 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 16 6807 25 [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 17 6447 40 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 18 4852 35 OPPORTUNITIES AND CHALLENGES IN DRUG DEVELOPMENT FOR PEDIATRIC CANCERS. THE USE OF TARGETED SMALL-MOLECULE THERAPEUTICS AND IMMUNOTHERAPEUTICS HAS BEEN LIMITED TO DATE IN PEDIATRIC ONCOLOGY. RECENTLY, THE NUMBER OF PEDIATRIC APPROVALS HAS RISEN, AND REGULATORY INITIATIVES IN THE UNITED STATES AND EUROPE HAVE AIMED TO INCREASE THE STUDY OF NOVEL ANTICANCER THERAPIES IN CHILDREN. CHALLENGES OF DRUG DEVELOPMENT IN CHILDREN INCLUDE THE RARITY OF INDIVIDUAL CANCER DIAGNOSES AND THE HIGH PREVALENCE OF DIFFICULT-TO-DRUG TARGETS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC REGULATORS. ONGOING PEDIATRIC ADAPTATION OF BIOMARKER-DRIVEN TRIAL DESIGNS AND FURTHER EXPLORATION OF AGENTS TARGETING NON-KINASE DRIVERS CONSTITUTE HIGH-PRIORITY OBJECTIVES FOR FUTURE PEDIATRIC ONCOLOGY DRUG DEVELOPMENT. SIGNIFICANCE: INCREASING ATTENTION TO DRUG DEVELOPMENT FOR CHILDREN WITH CANCER BY REGULATORS AND PHARMACEUTICAL COMPANIES HOLDS THE PROMISE OF ACCELERATING THE AVAILABILITY OF NEW THERAPIES FOR CHILDREN WITH CANCER, POTENTIALLY IMPROVING SURVIVAL AND DECREASING THE ACUTE AND CHRONIC TOXICITIES OF THERAPY. HOWEVER, UNIQUE APPROACHES ARE NECESSARY TO STUDY NOVEL THERAPIES IN CHILDREN THAT TAKE INTO ACCOUNT LOW PATIENT NUMBERS, THE PEDIATRIC CANCER GENOMIC LANDSCAPE AND TUMOR MICROENVIRONMENT, AND THE NEED FOR PEDIATRIC FORMULATIONS. IT IS ALSO CRITICAL TO EVALUATE THE POTENTIAL FOR UNIQUE TOXICITIES IN GROWING HOSTS WITHOUT AFFECTING THE PACE OF DISCOVERY FOR CHILDREN WITH THESE LIFE-THREATENING DISEASES. 2021 19 6676 44 USING EPIGENETIC TOOLS TO INVESTIGATE ANTIDEPRESSANT RESPONSE. MAJOR DEPRESSIVE DISORDER IS A CHRONIC AND DEBILITATING ILLNESS. IT IS MOST COMMONLY TREATED WITH ANTIDEPRESSANT DRUGS, HOWEVER, AS THE MAJORITY OF PATIENTS DO NOT RESPOND ON THEIR FIRST TRIAL OR FOLLOWING SEVERAL ADEQUATE TRIALS, THERE IS GREAT INTEREST IN IDENTIFYING BIOLOGICAL FACTORS THAT MAY HELP SELECT THE MOST APPROPRIATE TREATMENT FOR EACH PATIENT AND IN UNDERSTANDING BIOLOGICAL PROCESSES THAT MEDIATE TREATMENT RESPONSE. EPIGENETIC FACTORS, SUCH AS NON-CODING RNAS (NCRNAS), HOLD POTENTIAL AS BIOMARKERS OF ANTIDEPRESSANT RESPONSE. IN THIS CHAPTER, WE REVIEW KEY METHODOLOGICAL CONSIDERATIONS WHEN INVESTIGATING NCRNA BIOMARKERS, INCLUDING BIOLOGICAL SAMPLES AND TECHNOLOGIES WHICH HAVE BEEN USED IN THESE STUDIES. SECONDLY, WE SUMMARIZE FINDINGS FROM STUDIES INVESTIGATING NCRNAS IN ANTIDEPRESSANT TREATMENT RESPONSE. FINALLY, WE DISCUSS SOME OF THE FUTURE DIRECTIONS WHICH WILL BE NECESSARY FOR THE DEVELOPMENT OF CLINICALLY RELEVANT EPIGENETIC TOOLS. 2018 20 3958 39 LONG NON-CODING RNAS IN BONE METASTASIS: PROGRESSES AND PERSPECTIVES AS POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN A PRECISION MEDICINE PERSPECTIVE, AMONG THE BIOMARKERS POTENTIALLY USEFUL FOR EARLY DIAGNOSIS OF CANCERS, AS WELL AS TO DEFINE THEIR PROGNOSIS AND EVENTUALLY TO IDENTIFY NOVEL AND MORE EFFECTIVE THERAPEUTIC TARGETS, THERE ARE THE LONG NON-CODING RNAS (LNCRNAS). THE TERM LNCRNA IDENTIFIES A CLASS OF NON-CODING RNA MOLECULES INVOLVED IN THE REGULATION OF GENE EXPRESSION THAT INTERVENE AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVEL. METASTASIS IS A NATURAL EVOLUTION OF SOME MALIGNANT TUMOURS, FREQUENTLY ENCOUNTERED IN PATIENTS WITH ADVANCED CANCERS. ONSET AND DEVELOPMENT OF METASTASIS REPRESENTS A DETRIMENTAL EVENT THAT WORSEN THE PATIENT'S PROGNOSIS BY PROFOUNDLY INFLUENCING THE QUALITY OF LIFE AND IS RESPONSIBLE FOR THE OMINOUS PROGRESSION OF THE DISEASE. DUE TO THE PECULIAR ENVIRONMENT AND THE BIOMECHANICAL PROPERTIES, BONE IS A PREFERENTIAL SITE FOR THE SECONDARY GROWTH OF BREAST, PROSTATE AND LUNG CANCERS. UNFORTUNATELY, ONLY PALLIATIVE AND PAIN THERAPIES ARE CURRENTLY AVAILABLE FOR PATIENTS WITH BONE METASTASES, WHILE NO EFFECTIVE AND DEFINITIVE TREATMENTS ARE AVAILABLE. THE UNDERSTANDING OF PATHOPHYSIOLOGICAL BASIS OF BONE METASTASIS FORMATION AND PROGRESSION, AS WELL AS THE IMPROVEMENT IN THE CLINICAL MANAGEMENT OF THE PATIENT, ARE CENTRAL BUT CHALLENGING TOPICS IN BASIC RESEARCH AND CLINICAL PRACTICE. THE IDENTIFICATION OF NEW MOLECULAR SPECIES THAT MAY HAVE A ROLE AS EARLY HALLMARKS OF THE METASTATIC PROCESS COULD OPEN THE DOOR TO THE DEFINITION OF NEW, AND MORE EFFECTIVE, THERAPEUTIC AND DIAGNOSTIC APPROACHES. NON-CODING RNAS SPECIES AND, PARTICULARLY, LNCRNAS ARE PROMISING COMPOUNDS IN THIS SETTING, AND THEIR STUDY MAY BRING TO THE IDENTIFICATION OF RELEVANT PROCESSES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF LNCRNAS AS EMERGING MOLECULES IN MEDIATING THE FORMATION AND DEVELOPMENT OF BONE METASTASES, AS POSSIBLE BIOMARKERS FOR CANCER DIAGNOSIS AND PROGNOSIS, AND AS THERAPEUTIC TARGETS TO COUNTERACT CANCER SPREAD. 2023