1 453 153 APPLICATIONS OF CRISPR SYSTEMS IN RESPIRATORY HEALTH: ENTERING A NEW 'RED PEN' ERA IN GENOME EDITING. RESPIRATORY DISEASES, SUCH AS INFLUENZA INFECTION, ACUTE TRACHEAL BRONCHITIS, PNEUMONIA, TUBERCULOSIS, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ASTHMA, LUNG CANCER AND NASOPHARYNGEAL CARCINOMA, CONTINUE TO SIGNIFICANTLY IMPACT HUMAN HEALTH. DISEASES OF THE LUNG AND RESPIRATORY TRACT ARE INFLUENCED BY ENVIRONMENTAL CONDITIONS AND SOCIO-ECONOMIC FACTORS; HOWEVER, MANY OF THESE SERIOUS RESPIRATORY DISORDERS ARE ALSO ROOTED IN GENETIC OR EPIGENETIC CAUSES. CLUSTERED REGULARLY INTERSPACED PALINDROMIC REPEATS (CRISPR) AND CRISPR-ASSOCIATED (CAS) PROTEINS, ISOLATED FROM THE IMMUNE SYSTEM OF PROKARYOTES, PROVIDE A TOOL TO MANIPULATE GENE SEQUENCES AND GENE EXPRESSION WITH SIGNIFICANT IMPLICATIONS FOR RESPIRATORY RESEARCH. CRISPR/CAS SYSTEMS ALLOW PRECLINICAL MODELLING OF CAUSAL FACTORS INVOLVED IN MANY RESPIRATORY DISEASES, PROVIDING NEW INSIGHTS INTO THEIR UNDERLYING MECHANISMS. CRISPR CAN ALSO BE USED TO SCREEN FOR GENES INVOLVED IN RESPIRATORY PROCESSES, DEVELOPMENT AND PATHOLOGY, IDENTIFYING NOVEL DISEASE DRIVERS OR DRUG TARGETS. FINALLY, CRISPR/CAS SYSTEMS CAN POTENTIALLY CORRECT GENETIC MUTATIONS AND EDIT EPIGENETIC MARKS THAT CONTRIBUTE TO RESPIRATORY DISORDERS, PROVIDING A FORM OF PERSONALIZED MEDICINE THAT COULD BE USED IN CONJUNCTION WITH OTHER TECHNOLOGIES SUCH AS STEM CELL REPROGRAMMING AND TRANSPLANTATION. CRISPR GENE EDITING IS A YOUNG FIELD OF RESEARCH, AND CONCERNS REGARDING ITS SPECIFICITY, AS WELL AS THE NEED FOR EFFICIENT AND SAFE DELIVERY METHODS, NEED TO BE ADDRESSED FURTHER. HOWEVER, CRISPR/CAS SYSTEMS REPRESENT A SIGNIFICANT STEP FORWARD FOR RESEARCH AND THERAPY IN RESPIRATORY HEALTH, AND IT IS LIKELY WE WILL SEE THE BREAKTHROUGHS GENERATED FROM THIS TECHNOLOGY CONTINUE. 2019 2 485 35 ARTIFICIAL AIRWAYS FOR THE STUDY OF RESPIRATORY DISEASE. THIS REVIEW WILL FOCUS ON HUMAN CELL-BASED EXPERIMENTAL MODELS TO STUDY RESPIRATORY DISEASES, IN PARTICULAR MODELS OF THE LARGE AIRWAYS RELEVANT TO ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. SUCH MODELS HAVE THE ADVANTAGE OF INCORPORATING CELLS THAT CAN BE DERIVED FROM DISEASE-RELEVANT TISSUE AND SO HAVE RETAINED IMPORTANT GENETIC AND EPIGENETIC FEATURES THAT CONTRIBUTE TO THE HUMAN DISEASE. THESE MODELS CAN BE USED FOR MECHANISTIC STUDIES, TARGET IDENTIFICATION AND VALIDATION AND TOXICOLOGICAL TESTING. WHILE MANY MODELS HAVE BEEN DEVELOPED TO VARYING DEGREES OF SOPHISTICATION, THE CHALLENGE REMAINS TO DEVELOP AN INTEGRATED SYSTEM THAT RECAPITULATES THE COMPLEX CELL-CELL AND CELL-MATRIX INTERACTIONS THAT OCCUR IN VIVO AND TO PROVIDE THESE WITH A 'CIRCULATION' TO STUDY THE DYNAMICS OF IMMUNE AND INFLAMMATORY CELL INFLUX AND EFFLUX. 2011 3 3028 31 GENETICS OF COMPLEX AIRWAY DISEASE. THE PAST 3 YEARS HAVE SEEN HIGHLY SIGNIFICANT GENETIC EFFECTS IDENTIFIED FOR A WIDE VARIETY OF COMMON COMPLEX DISEASES, INCLUDING THE AIRWAY DISORDERS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT APPEARS THAT ONLY A PORTION OF THE GENETICALLY MEDIATED SUSCEPTIBILITY TO COMPLEX DISEASES HAS BEEN IDENTIFIED, AND THERE IS MUCH LEFT TO BE DISCOVERED. THIS REVIEW BRIEFLY DESCRIBES THE RESULTS OF THE GENOME-WIDE ASSOCIATION STUDIES OF ASTHMA AND GIVES AN OVERVIEW OF THE PARALLEL AND INCREASINGLY LARGE-SCALE STUDIES THAT ARE TAKING PLACE WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE FUTURE IMPACT IS DISCUSSED OF TECHNOLOGICAL ADVANCES THAT ALLOW INCREASINGLY LARGE-SCALE GENE EXPRESSION STUDIES, NEXT-GENERATION SEQUENCING, AND GENOME-WIDE TESTING FOR EPIGENETIC EFFECTS. THE USE OF GENETIC TECHNOLOGY TO EXAMINE THE AIRWAY MICROBIOTA THAT INTERACT WITH THE MUCOSA IN HEALTH AND DISEASE IS DESCRIBED. 2011 4 3038 43 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 5 2906 43 GENE EDITING FOR INFLAMMATORY DISORDERS. TECHNOLOGY FOR PRECISE AND EFFICIENT GENETIC EDITING IS CONSTANTLY EVOLVING AND IS NOW CAPABLE OF HUMAN CLINICAL APPLICATIONS. AUTOIMMUNE AND INFLAMMATORY DISEASES ARE CHRONIC, DISABLING, SOMETIMES LIFE-THREATENING, CONDITIONS THAT FEATURE HERITABLE COMPONENTS. BOTH PRIMARY GENETIC LESIONS AND THE INFLAMMATORY PATHOBIOLOGY UNDERLYING THESE DISEASES REPRESENT FERTILE SOIL FOR NEW THERAPIES BASED ON THE CAPABILITIES OF GENE EDITING. THE ABILITY TO ORCHESTRATE PRECISE TARGETED MODIFICATIONS TO THE GENOME WILL LIKELY ENABLE CELL-BASED THERAPIES FOR INFLAMMATORY DISEASES SUCH AS MONOGENIC AUTOINFLAMMATORY DISEASE, ACQUIRED AUTOIMMUNE DISEASE AND FOR REGENERATIVE MEDICINE IN THE SETTING OF AN INFLAMMATORY ENVIRONMENT. HERE, WE DISCUSS RECENT ADVANCES IN GENOME EDITING AND THEIR EVOLVING APPLICATIONS IN IMMUNOINFLAMMATORY DISEASES. STRENGTHS AND LIMITATIONS OF OLDER GENETIC MODIFICATION TOOLS ARE COMPARED WITH CRISPR/CAS9, BASE EDITING, RNA EDITING, TARGETED ACTIVATORS AND REPRESSORS OF TRANSCRIPTION AND TARGETED EPIGENETIC MODIFIERS. COMMONLY EMPLOYED DELIVERY VEHICLES TO TARGET CELLS OR TISSUES OF INTEREST WITH GENETIC MODIFICATION MACHINERY, INCLUDING VIRAL, NON-VIRAL AND CELLULAR VECTORS, ARE DESCRIBED. FINALLY, APPLICATIONS IN ANIMAL AND HUMAN MODELS OF INFLAMMATORY DISEASES ARE DISCUSSED. USE OF CHIMERIC AUTOANTIGEN RECEPTOR T CELLS, CORRECTION OF MONOGENIC DISEASES WITH GENETICALLY EDITED HAEMATOPOIETIC STEM AND PROGENITOR CELLS, ENGINEERING OF INDUCED PLURIPOTENT STEM CELLS AND EX VIVO EXPANSION AND MODIFICATION OF REGULATORY T CELLS FOR A RANGE OF CHRONIC INFLAMMATORY DISEASES ARE REVIEWED. 2019 6 3100 44 GENOMIC IMPACT OF CIGARETTE SMOKE, WITH APPLICATION TO THREE SMOKING-RELATED DISEASES. THERE IS CONSIDERABLE EVIDENCE THAT INHALED TOXICANTS SUCH AS CIGARETTE SMOKE CAN CAUSE BOTH IRREVERSIBLE CHANGES TO THE GENETIC MATERIAL (DNA MUTATIONS) AND PUTATIVELY REVERSIBLE CHANGES TO THE EPIGENETIC LANDSCAPE (CHANGES IN THE DNA METHYLATION AND CHROMATIN MODIFICATION STATE). THE DISEASES THAT ARE BELIEVED TO INVOLVE GENETIC AND EPIGENETIC PERTURBATIONS INCLUDE LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND CARDIOVASCULAR DISEASE (CVD), ALL OF WHICH ARE STRONGLY LINKED EPIDEMIOLOGICALLY TO CIGARETTE SMOKING. IN THIS REVIEW, WE HIGHLIGHT THE SIGNIFICANCE OF GENOMICS AND EPIGENOMICS IN THESE MAJOR SMOKING-RELATED DISEASES. WE ALSO SUMMARIZE THE IN VITRO AND IN VIVO FINDINGS ON THE SPECIFIC PERTURBATIONS THAT SMOKE AND ITS CONSTITUENT COMPOUNDS CAN INFLICT UPON THE GENOME, PARTICULARLY ON THE PULMONARY SYSTEM. FINALLY, WE REVIEW STATE-OF-THE-ART GENOMICS AND NEW TECHNIQUES SUCH AS HIGH-THROUGHPUT SEQUENCING AND GENOME-WIDE CHROMATIN ASSAYS, RAPIDLY EVOLVING TECHNIQUES WHICH HAVE ALLOWED EPIGENETIC CHANGES TO BE CHARACTERIZED AT THE GENOME LEVEL. THESE TECHNIQUES HAVE THE POTENTIAL TO SIGNIFICANTLY IMPROVE OUR UNDERSTANDING OF THE SPECIFIC MECHANISMS BY WHICH EXPOSURE TO ENVIRONMENTAL CHEMICALS CAUSES DISEASE. SUCH MECHANISTIC KNOWLEDGE PROVIDES A VARIETY OF OPPORTUNITIES FOR ENHANCED PRODUCT SAFETY ASSESSMENT AND THE DISCOVERY OF NOVEL THERAPEUTIC INTERVENTIONS. 2012 7 2984 32 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 8 2333 34 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 9 3404 44 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 10 2497 29 EPIGENETICS AND ENVIRONMENTAL LUNG DISEASE. GENE-ENVIRONMENT INTERACTIONS ARE THE INDISPUTABLE CAUSE OF MOST RESPIRATORY DISEASES. HOWEVER, WE STILL HAVE VERY LIMITED UNDERSTANDING OF THE MECHANISMS THAT GUIDE THESE INTERACTIONS. ALTHOUGH THE CONCEPTUAL APPROACHES TO ENVIRONMENTAL GENOMICS WERE ESTABLISHED SEVERAL DECADES AGO, THE TOOLS ARE ONLY NOW AVAILABLE TO BETTER DEFINE THE MECHANISMS THAT UNDERLIE THE INTERACTION BETWEEN THESE IMPORTANT ETIOLOGIC FEATURES OF LUNG DISEASE. EPIGENETIC MECHANISMS CAN MEDIATE THE EFFECT OF THE ENVIRONMENT ON THE HUMAN GENOME BY CONTROLLING THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT SPECIFIC POINTS IN TIME, IN SPECIFIC ORGANS. IN THIS ARTICLE, WE DEMONSTRATE THE POTENTIAL IMPORTANCE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND ASTHMA. 2010 11 4112 45 MECHANISMS CONTRIBUTING TO THE COMORBIDITY OF COPD AND LUNG CANCER. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OFTEN CO-OCCUR, AND INDIVIDUALS WITH COPD ARE AT A HIGHER RISK OF DEVELOPING LUNG CANCER. WHILE THE UNDERLYING MECHANISM FOR THIS RISK IS NOT WELL UNDERSTOOD, ITS MAJOR CONTRIBUTING FACTORS HAVE BEEN PROPOSED TO INCLUDE GENOMIC, IMMUNE, AND MICROENVIRONMENT DYSREGULATION. HERE, WE REVIEW THE EVIDENCE AND SIGNIFICANT STUDIES THAT EXPLORE THE MECHANISMS UNDERLYING THE HEIGHTENED LUNG CANCER RISK IN PEOPLE WITH COPD. GENETIC AND EPIGENETIC CHANGES, AS WELL AS THE ABERRANT EXPRESSION OF NON-CODING RNAS, PREDISPOSE THE LUNG EPITHELIUM TO CARCINOGENESIS BY ALTERING THE EXPRESSION OF CANCER- AND IMMUNE-RELATED GENES. OXIDATIVE STRESS GENERATED BY TOBACCO SMOKING PLAYS A ROLE IN REDUCING GENOMIC INTEGRITY, PROMOTING EPITHELIAL-MESENCHYMAL-TRANSITION, AND GENERATING A CHRONIC INFLAMMATORY ENVIRONMENT. THIS LEADS TO ABNORMAL IMMUNE RESPONSES THAT PROMOTE CANCER DEVELOPMENT, THOUGH NOT ALL SMOKERS DEVELOP LUNG CANCER. SEX DIFFERENCES IN THE METABOLISM OF TOBACCO SMOKE PREDISPOSE FEMALES TO DEVELOPING COPD AND ACCUMULATING DAMAGE FROM OXIDATIVE STRESS THAT POSES A RISK FOR THE DEVELOPMENT OF LUNG CANCER. DYSREGULATION OF THE LUNG MICROENVIRONMENT AND MICROBIOME CONTRIBUTES TO CHRONIC INFLAMMATION, WHICH IS OBSERVED IN COPD AND KNOWN TO FACILITATE CANCER INITIATION IN VARIOUS TUMOR TYPES. FURTHER, THERE IS A NEED TO BETTER CHARACTERIZE AND IDENTIFY THE PROPORTION OF INDIVIDUALS WITH COPD WHO ARE AT A HIGH RISK FOR DEVELOPING LUNG CANCER. WE EVALUATE POSSIBLE NOVEL AND INDIVIDUALIZED SCREENING STRATEGIES, INCLUDING BIOMARKERS IDENTIFIED IN GENETIC STUDIES AND EXHALED BREATH CONDENSATE ANALYSIS. WE ALSO DISCUSS THE USE OF CORTICOSTEROIDS AND STATINS AS CHEMOPREVENTIVE AGENTS TO PREVENT LUNG CANCER. IT IS CRUCIAL THAT WE OPTIMIZE THE CURRENT METHODS FOR THE EARLY DETECTION AND MANAGEMENT OF LUNG CANCER AND COPD IN ORDER TO IMPROVE THE HEALTH OUTCOMES FOR A LARGE AFFECTED POPULATION. 2023 12 2859 33 FROM SMOKING TO COPD--CURRENT APPROACHES. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) REMAINS A LEADING CAUSE OF DEATH ALL OVER THE WORLD. EVEN THOUGH IT IS THE MOST INTENSELY STUDIED DISEASE INDUCED BY CIGARETTE SMOKING THERE ARE STILL INCOMPLETE RESEARCHES CONCERNING ITS PATHOPHYSIOLOGY AND TREATMENT. SO FAR IT HAS BEEN DETERMINED THE DELETERIOUS EFFECTS OF THE SECRETED MOLECULES DIVERSITY AND SOME FEASIBLE THERAPIES FOR THEIR DIMINUTION. ACCORDING TO CURRENT STUDIES MORE RELEVANCE GAINS THE POSSIBLE AUTOIMMUNE ORIGIN OF COPD AND THE EPIGENETIC MODIFICATIONS. THE IDEA OF AUTOIMMUNITY IN SMOKING INDUCED COPD BEGAN TO BE SPECULATED WITH THE DISCOVERY OF AUTOANTIBODIES IN PATIENT'S SERUM, BUT THERE ARE SOME STUDIES WHO CONSIDER ANTIBODY COMPLEXES THAT RESIDE IN THE LUNG TISSUE AS MORE RELEVANT FOR FUTURE RESEARCH. BY DEVELOPING THE AUTOIMMUNE ASPECT OF COPD IT WILL BECOME POSSIBLE TO SELECT MORE PRECISE TREATMENT STRATEGIES. THE IMPORTANCE OF EPIGENETIC CHANGES IN THIS FIELD MIGHT BE APPRECIATED STARTING WITH THE FACT OF AN EXISTING CONNECTION BETWEEN EPIGENETIC MODIFICATIONS INDUCED BY MATERNAL SMOKING AND LATTER COPD DEVELOPMENT. THIS EXPLAINS THE TENDENCY TOWARD DIFFERENT DRUGS CAPABLE OF RESTORING THESE TRANSFORMATIONS SUCH AS DEACETYLATION AGENTS EXPECTED ALSO TO PREVENT STEROID RESISTANCE. NEVERTHELESS SMOKING CESSATION REMAINS AS THE INDISPENSABLE APPROACH FOR COPD TREATMENT AND PREVENTION. 2016 13 4389 37 MODELING EPIGENETIC MODIFICATIONS IN RENAL DEVELOPMENT AND DISEASE WITH ORGANOIDS AND GENOME EDITING. UNDERSTANDING EPIGENETIC MECHANISMS IS CRUCIAL TO OUR COMPREHENSION OF GENE REGULATION IN DEVELOPMENT AND DISEASE. IN THE PAST DECADES, DIFFERENT STUDIES HAVE SHOWN THE ROLE OF EPIGENETIC MODIFICATIONS AND MODIFIERS IN RENAL DISEASE, ESPECIALLY DURING ITS PROGRESSION TOWARDS CHRONIC AND END-STAGE RENAL DISEASE. THUS, THE IDENTIFICATION OF GENETIC VARIATION ASSOCIATED WITH CHRONIC KIDNEY DISEASE HAS RESULTED IN BETTER CLINICAL MANAGEMENT OF PATIENTS. DESPITE THE IMPORTANCE OF THESE FINDINGS, THE TRANSLATION OF GENOTYPE-PHENOTYPE DATA INTO GENE-BASED MEDICINE IN CHRONIC KIDNEY DISEASE POPULATIONS STILL LACKS FAITHFUL CELLULAR OR ANIMAL MODELS THAT RECAPITULATE THE KEY ASPECTS OF THE HUMAN KIDNEY. THE LATEST ADVANCES IN THE FIELD OF STEM CELLS HAVE SHOWN THAT IT IS POSSIBLE TO EMULATE KIDNEY DEVELOPMENT AND FUNCTION WITH ORGANOIDS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS. THESE HAVE SUCCESSFULLY RECAPITULATED NOT ONLY KIDNEY DIFFERENTIATION, BUT ALSO THE SPECIFIC PHENOTYPICAL TRAITS RELATED TO KIDNEY FUNCTION. THE COMBINATION OF THIS METHODOLOGY WITH CRISPR/CAS9 GENOME EDITING HAS ALREADY HELPED RESEARCHERS TO MODEL DIFFERENT GENETIC KIDNEY DISORDERS. NOWADAYS, CRISPR/CAS9-BASED APPROACHES ALSO ALLOW EPIGENETIC MODIFICATIONS, AND THUS REPRESENT AN UNPRECEDENTED TOOL FOR THE SCREENING OF GENETIC VARIANTS, EPIGENETIC MODIFICATIONS OR EVEN CHANGES IN CHROMATIN STRUCTURE THAT ARE ALTERED IN RENAL DISEASE. IN THIS REVIEW, WE DISCUSS THESE TECHNICAL ADVANCES IN KIDNEY MODELING, AND OFFER AN OVERVIEW OF THE ROLE OF EPIGENETIC REGULATION IN KIDNEY DEVELOPMENT AND DISEASE. 2018 14 2330 35 EPIGENETIC REGULATION OF IMMUNE FUNCTION IN ASTHMA. ASTHMA IS A COMMON COMPLEX RESPIRATORY DISEASE CHARACTERIZED BY CHRONIC AIRWAY INFLAMMATION AND PARTIALLY REVERSIBLE AIRFLOW OBSTRUCTION RESULTING FROM GENETIC AND ENVIRONMENTAL DETERMINANTS. BECAUSE EPIGENETIC MARKS INFLUENCE GENE EXPRESSION AND CAN BE MODIFIED BY BOTH ENVIRONMENTAL EXPOSURES AND GENETIC VARIATION, THEY ARE INCREASINGLY RECOGNIZED AS RELEVANT TO THE PATHOGENESIS OF ASTHMA AND MAY BE A KEY LINK BETWEEN ENVIRONMENTAL EXPOSURES AND ASTHMA SUSCEPTIBILITY. UNLIKE CHANGES TO DNA SEQUENCE, EPIGENETIC SIGNATURES ARE DYNAMIC AND REVERSIBLE, CREATING AN OPPORTUNITY FOR NOT ONLY THERAPEUTIC TARGETS BUT MAY SERVE AS BIOMARKERS TO FOLLOW DISEASE COURSE AND IDENTIFY MOLECULAR SUBTYPES IN HETEROGENEOUS DISEASES SUCH AS ASTHMA. IN THIS REVIEW, WE WILL EXAMINE THE RELATIONSHIP BETWEEN ASTHMA AND 3 KEY EPIGENETIC PROCESSES THAT MODIFY GENE EXPRESSION: DNA METHYLATION, MODIFICATION OF HISTONE TAILS, AND NONCODING RNAS. IN ADDITION TO PRESENTING A COMPREHENSIVE ASSESSMENT OF THE EXISTING EPIGENETIC STUDIES FOCUSING ON IMMUNE REGULATION IN ASTHMA, WE WILL DISCUSS FUTURE DIRECTIONS FOR EPIGENETIC INVESTIGATION IN ALLERGIC AIRWAY DISEASE. 2022 15 4445 36 MOLECULAR LINKS BETWEEN COPD AND LUNG CANCER: NEW TARGETS FOR DRUG DISCOVERY? COPD AND LUNG CANCER ARE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE, AND THEY SHARE A COMMON ENVIRONMENTAL RISK FACTOR IN CIGARETTE SMOKE EXPOSURE AND A GENETIC PREDISPOSITION REPRESENTED BY THEIR INCIDENCE IN ONLY A FRACTION OF SMOKERS. THIS REFLECTS THE ABILITY OF CIGARETTE SMOKE TO INDUCE AN INFLAMMATORY RESPONSE IN THE AIRWAYS OF SUSCEPTIBLE SMOKERS. MOREOVER, COPD COULD BE A DRIVING FACTOR IN LUNG CANCER, BY INCREASING OXIDATIVE STRESS AND THE RESULTING DNA DAMAGE AND REPRESSION OF THE DNA REPAIR MECHANISMS, CHRONIC EXPOSURE TO PRO-INFLAMMATORY CYTOKINES, REPRESSION OF INNATE IMMUNITY AND INCREASED CELLULAR PROLIFERATION. AREAS COVERED: WE HAVE FOCUSED OUR REVIEW ON THE POTENTIAL PATHOGENIC MOLECULAR LINKS BETWEEN TOBACCO SMOKING-RELATED COPD AND LUNG CANCER AND THE POTENTIAL MOLECULAR TARGETS FOR NEW DRUG DEVELOPMENT BY UNDERSTANDING THE COMMON SIGNALING PATHWAYS INVOLVED IN COPD AND LUNG CANCER. EXPERT COMMENTARY: RESEARCH IN THIS FIELD IS MOSTLY LIMITED TO ANIMAL MODELS OR SMALL CLINICAL TRIALS. LARGE CLINICAL TRIALS ARE NEEDED BUT MOSTLY COMBINED MODELS OF COPD AND LUNG CANCER ARE NECESSARY TO INVESTIGATE THE PROCESSES CAUSED BY CHRONIC INFLAMMATION, INCLUDING GENETIC AND EPIGENETIC ALTERATION, AND THE EXPRESSION OF INFLAMMATORY MEDIATORS THAT LINK COPD AND LUNG CANCER, TO IDENTIFY NEW MOLECULAR THERAPEUTIC TARGETS. 2019 16 4325 41 MICRORNAS IN THE EVALUATION AND POTENTIAL TREATMENT OF LIVER DISEASES. ACUTE AND CHRONIC LIVER DISEASE CONTINUE TO RESULT IN SIGNIFICANT MORBIDITY AND MORTALITY OF PATIENTS, ALONG WITH INCREASING BURDEN ON THEIR FAMILIES, SOCIETY AND THE HEALTH CARE SYSTEM. THIS IN PART IS DUE TO INCREASED INCIDENCE OF LIVER DISEASE ASSOCIATED FACTORS SUCH AS METABOLIC SYNDROME; IMPROVED SURVIVAL OF PATIENTS WITH CHRONIC PREDISPOSING CONDITIONS SUCH AS HIV; AS WELL AS ADVANCES IN THE FIELD OF TRANSPLANTATION AND ASSOCIATED CARE LEADING TO IMPROVED SURVIVAL. THE FACT THAT ONE DISEASE CAN RESULT IN DIFFERENT MANIFESTATIONS AND OUTCOMES HIGHLIGHTS THE NEED FOR IMPROVED UNDERSTANDING OF NOT JUST GENETIC PHENOMENON PREDISPOSING TO A CONDITION, BUT ADDITIONALLY THE ROLE OF EPIGENETIC AND ENVIRONMENTAL FACTORS LEADING TO THE PHENOTYPE OF THE DISEASE. IT IS NOT SURPRISING THAT PROVIDERS CONTINUE TO FACE DAILY CHALLENGES PERTAINING TO DIAGNOSTIC ACCURACY, PROGNOSTICATION OF DISEASE SEVERITY, PROGRESSION, AND RESPONSE TO THERAPIES. A NUMBER OF THESE CHALLENGES CAN BE ADDRESSED BY INCORPORATING A PERSONALIZED APPROACH OF MANAGEMENT TO THE CURRENT PARADIGM OF CARE. RECENT ADVANCES IN THE FIELDS OF MOLECULAR BIOLOGY AND GENETICS HAVE PAVED THE WAY TO MORE ACCURATE, INDIVIDUALIZED AND PRECISE APPROACH TO CARING FOR LIVER DISEASE. THE STUDY OF MICRORNAS AND THEIR ROLE IN BOTH HEALTHY AND DISEASED LIVERS IS ONE EXAMPLE OF SUCH ADVANCES. AS THESE SMALL, NON-CODING RNAS WORK ON FINE-TUNING OF CELLULAR ACTIVITIES AND ORGAN FUNCTION IN A DYNAMIC AND PRECISE FASHION, THEY PROVIDE US A GOLDEN OPPORTUNITY TO ADVANCE THE FIELD OF HEPATOLOGY. THE STUDY OF MICRORNAS IN LIVER DISEASE PROMISES TREMENDOUS IMPROVEMENT IN HEPATOLOGY AND IS LIKELY TO LAY THE FOUNDATION TOWARDS A PERSONALIZED APPROACH IN LIVER DISEASE. 2016 17 6199 46 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 18 970 36 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER: COMMON PATHWAYS FOR PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER COMPRISE THE LEADING CAUSES OF LUNG DISEASE-RELATED MORTALITY WORLDWIDE. EXPOSURE TO TOBACCO SMOKE IS A MUTUAL AETIOLOGY UNDERLYING THE TWO DISEASES, ACCOUNTING FOR ALMOST 90% OF CASES. THERE IS ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF IMMUNE DYSFUNCTION, THE LUNG MICROBIOME, EXTRACELLULAR VESICLES AND UNDERLYING GENETIC SUSCEPTIBILITY IN THE DEVELOPMENT OF COPD AND LUNG CANCER. FURTHER, EPIGENETIC FACTORS, INVOLVING DNA METHYLATION AND MICRORNA EXPRESSION, HAVE BEEN IMPLICATED IN BOTH DISEASES. CHRONIC INFLAMMATION IS A KEY FEATURE OF COPD AND COULD BE A POTENTIAL DRIVER OF LUNG CANCER DEVELOPMENT. USING NEXT GENERATION TECHNOLOGIES, FURTHER STUDIES INVESTIGATING THE GENOMICS, EPIGENETICS AND GENE-ENVIRONMENT INTERACTION IN KEY MOLECULAR PATHWAYS WILL CONTINUE TO ELUCIDATE THE PATHOGENIC MECHANISMS UNDERLYING THE DEVELOPMENT OF COPD AND LUNG CANCER, AND CONTRIBUTE TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PROGNOSTIC TOOLS FOR EARLY INTERVENTION AND PERSONALISED THERAPEUTIC STRATEGIES. 2019 19 2929 19 GENES AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. ALTHOUGH MUCH REMAINS TO BE DONE, RECENT ADVANCES AND THE ADVENT OF NEW METHODOLOGIES ARE PROMISING AND SHOULD YIELD INCREASED UNDERSTANDING OF THE GENETIC AND EPIGENETIC MECHANISMS INFLUENCING THE PATHOGENESIS OF COPD, BOTH RELATED AND UNRELATED TO SEVERE AAT DEFICIENCY. SUCH UNDERSTANDING SHOULD ULTIMATELY BE TRANSLATED INTO NOVEL APPROACHES TO PREVENT, DIAGNOSE, AND TREAT COPD. 2012 20 396 38 AN UPDATE ON EPIGENETICS AND CHILDHOOD RESPIRATORY DISEASES. EPIGENETIC MECHANISMS, DEFINED AS CHANGES IN PHENOTYPE OR GENE EXPRESSION CAUSED BY MECHANISMS OTHER THAN CHANGES IN THE UNDERLYING DNA SEQUENCE, HAVE BEEN PROPOSED TO CONSTITUTE A LINK BETWEEN GENETIC AND ENVIRONMENTAL FACTORS THAT AFFECT COMPLEX DISEASES. RECENT STUDIES SHOW THAT DNA METHYLATION, ONE OF THE KEY EPIGENETIC MECHANISMS, IS ALTERED IN CHILDREN EXPOSED TO AIR POLLUTANTS AND ENVIRONMENTAL TOBACCO SMOKE EARLY IN LIFE. SEVERAL CANDIDATE GENE STUDIES ON EPIGENETICS HAVE BEEN PUBLISHED TO DATE, BUT IT IS ONLY RECENTLY THAT GLOBAL METHYLATION ANALYSES HAVE BEEN PERFORMED FOR RESPIRATORY DISORDERS SUCH AS ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. HOWEVER, LARGE-SCALE STUDIES WITH ADEQUATE POWER ARE YET TO BE PRESENTED IN CHILDREN, AND IMPLICATIONS FOR CLINICAL USE REMAIN TO BE EVALUATED. IN THIS REVIEW, WE SUMMARIZE THE RECENT ADVANCES IN EPIGENETICS AND RESPIRATORY DISORDERS IN CHILDREN, WITH A MAIN FOCUS ON METHODOLOGICAL CHALLENGES AND ANALYSES RELATED TO PHENOTYPE AND EXPOSURE USING GLOBAL METHYLATION APPROACHES. 2014