1 5913 100 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 2 4429 28 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 3 6675 28 USING EPIGENETIC THERAPY TO OVERCOME CHEMOTHERAPY RESISTANCE. IT HAS BEEN KNOWN FOR DECADES THAT AS CANCER PROGRESSES, TUMORS DEVELOP GENETIC ALTERATIONS, MAKING THEM HIGHLY PRONE TO DEVELOPING RESISTANCE TO THERAPIES. CLASSICALLY, IT HAS BEEN THOUGHT THAT THESE ACQUIRED GENETIC CHANGES ARE FIXED. THIS HAS LED TO THE PARADIGM OF MOVING FROM ONE CANCER THERAPY TO THE NEXT WHILE AVOIDING PAST THERAPIES. HOWEVER, EMERGING DATA ON EPIGENETIC CHANGES DURING TUMOR PROGRESSION AND USE OF EPIGENETIC THERAPIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS LEADING TO CHEMOTHERAPY RESISTANCE HAVE THE POTENTIAL TO BE REVERSIBLE WITH EPIGENETIC THERAPY. IN FACT, PROMISING CLINICAL DATA EXIST THAT TREATMENT WITH EPIGENETIC AGENTS CAN DIMINISH CHEMOTHERAPY RESISTANCE IN A NUMBER OF TUMOR TYPES INCLUDING CHRONIC MYELOGENOUS LEUKEMIA, COLORECTAL, OVARIAN, LUNG AND BREAST CANCER. THE POTENTIAL FOR EPIGENETIC-MODIFYING DRUGS TO ALLOW FOR TREATMENT OF RESISTANT DISEASE IS EXCITING AND CLINICAL TRIALS HAVE JUST BEGUN TO EVALUATE THIS AREA. 2016 4 944 28 CHRONIC LYMPHOCYTIC LEUKEMIA: FROM MOLECULAR PATHOGENESIS TO NOVEL THERAPEUTIC STRATEGIES. CHRONIC LYMPHOCYTIC LEUKEMIA IS A WELL-DEFINED LYMPHOID NEOPLASM WITH VERY HETEROGENEOUS BIOLOGICAL AND CLINICAL BEHAVIOR. THE LAST DECADE HAS BEEN REMARKABLY FRUITFUL IN NOVEL FINDINGS ELUCIDATING MULTIPLE ASPECTS OF THE PATHOGENESIS OF THE DISEASE INCLUDING MECHANISMS OF GENETIC SUSCEPTIBILITY, INSIGHTS INTO THE RELEVANCE OF IMMUNOGENETIC FACTORS DRIVING THE DISEASE, PROFILING OF GENOMIC ALTERATIONS, EPIGENETIC SUBTYPES, GLOBAL EPIGENOMIC TUMOR CELL REPROGRAMMING, MODULATION OF TUMOR CELL AND MICROENVIRONMENT INTERACTIONS, AND DYNAMICS OF CLONAL EVOLUTION FROM EARLY STEPS IN MONOCLONAL B CELL LYMPHOCYTOSIS TO PROGRESSION AND TRANSFORMATION INTO DIFFUSE LARGE B-CELL LYMPHOMA. ALL THIS KNOWLEDGE HAS OFFERED NEW PERSPECTIVES THAT ARE BEING EXPLOITED THERAPEUTICALLY WITH NOVEL TARGET AGENTS AND MANAGEMENT STRATEGIES. IN THIS REVIEW WE PROVIDE AN OVERVIEW OF THESE NOVEL ADVANCES AND HIGHLIGHT QUESTIONS AND PERSPECTIVES THAT NEED FURTHER PROGRESS TO TRANSLATE INTO THE CLINICS THE BIOLOGICAL KNOWLEDGE AND IMPROVE THE OUTCOME OF THE PATIENTS. 2020 5 4481 26 MOLECULAR PROFILING OF CHRONIC LYMPHOCYTIC LEUKAEMIA: GENETICS MEETS EPIGENETICS TO IDENTIFY PREDISPOSING GENES. MOLECULAR PROFILING MAY LEAD TO A BETTER UNDERSTANDING OF A DISEASE. THIS KNOWLEDGE IS ESPECIALLY IMPORTANT IN MALIGNANCIES, WHERE MULTIPLE ALTERATIONS ARE REQUIRED DURING THE PROGRESSION FROM PREMALIGNANT TO MALIGNANT STAGES. SUCH INFORMATION CAN BE USEFUL FOR THE DEVELOPMENT OF NOVEL BIOMARKERS THAT ALLOW THE PREDICTION OF A CLINICAL COURSE, RESPONSE TO TREATMENT OR EARLY DETECTION. MOLECULAR DATA IS ALSO UTILIZED TO DEVELOP TARGETED THERAPIES. MOREOVER, GENE DEFECTS IDENTIFIED IN PROFILING STUDIES WILL HELP TO UNDERSTAND THE MOLECULAR PATHWAYS DISRUPTED IN THE DISEASE. THIS REVIEW PROVIDES AN OVERVIEW OF MOLECULAR PROFILING APPROACHES IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). WE WILL DESCRIBE OUR CURRENT UNDERSTANDING OF GENETIC ALTERATIONS IN CLL, THE USE OF FAMILIAL CLL FOR THE IDENTIFICATION OF PREDISPOSING MUTATIONS, AND THE SEARCH FOR EPIGENETIC ALTERATIONS IN CLL. 2007 6 2535 26 EPIGENETICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ENORMOUS EVIDENCE HAS ACCUMULATED IN THE PAST DECADES THAT ESTABLISHES THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CANCER AND HAS RESULTED IN SHIFTING THE FOCUS FROM ENTIRELY GENETIC-BASED STUDIES TO INTEGRATED STUDIES INVOLVING BOTH GENETIC AND EPIGENETIC ALTERATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS ONE SUCH EXAMPLE WHERE STUDIES INVOLVING EPIGENETIC ABERRATIONS HAVE ACCELERATED THE SEARCH FOR AFFECTED GENES, WHICH WAS INITIALLY RESTRICTED TO COMMONLY DELETED CHROMOSOMAL REGIONS. MANY NOVEL GENES THAT ARE EPIGENETICALLY SILENCED IN CLL HAVE BEEN IDENTIFIED. ADVANCES IN THE UNDERSTANDING OF POST-TRANSLATIONAL HISTONE MODIFICATIONS AND DNA METHYLATION IN NORMAL AND IN CLL CELLS HAVE PROVEN TO BE EXTREMELY BENEFICIAL IN FINDING POWERFUL DIAGNOSTIC MARKERS, AS WELL AS IN EXPLORING NOVEL THERAPIES. AT PRESENT, THE FIELD OF EPIGENETICS IS AT AN EVOLVING STAGE, BUT THERE IS NO DOUBT THAT FURTHER UNRAVELING OF ITS CAUSE AND EFFECTS IN TRANSFORMED CELLS WILL BRING A NEW REVOLUTION IN CANCER THERAPEUTICS. 2006 7 3089 22 GENOMIC AND EPIGENOMIC ALTERATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA IS A COMMON DISEASE IN WESTERN COUNTRIES AND HAS HETEROGENEOUS CLINICAL BEHAVIOR. THE RELEVANCE OF THE GENETIC BASIS OF THE DISEASE HAS COME TO THE FOREFRONT RECENTLY, WITH GENOME-WIDE STUDIES THAT HAVE PROVIDED A COMPREHENSIVE VIEW OF STRUCTURAL VARIANTS, SOMATIC MUTATIONS, AND DIFFERENT LAYERS OF EPIGENETIC CHANGES. THE MUTATIONAL LANDSCAPE IS CHARACTERIZED BY RELATIVELY COMMON COPY NUMBER ALTERATIONS, A FEW MUTATED GENES OCCURRING IN 10-15% OF CASES, AND A LARGE NUMBER OF GENES MUTATED IN A SMALL NUMBER OF CASES. THE EPIGENOMIC PROFILE HAS REVEALED A MARKED REPROGRAMMING OF REGULATORY REGIONS IN TUMOR CELLS COMPARED WITH NORMAL B CELLS. ALL OF THESE ALTERATIONS ARE DIFFERENTIALLY DISTRIBUTED IN CLINICAL AND BIOLOGICAL SUBSETS OF THE DISEASE, INDICATING THAT THEY MAY UNDERLIE THE HETEROGENEOUS EVOLUTION OF THE DISEASE. THESE GLOBAL STUDIES ARE REVEALING THE MOLECULAR COMPLEXITY OF CHRONIC LYMPHOCYTIC LEUKEMIA AND PROVIDE NEW PERSPECTIVES THAT HAVE HELPED TO UNDERSTAND ITS PATHOGENIC MECHANISMS AND IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS. 2020 8 6573 41 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES. 2020 9 3958 32 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 10 3110 36 GENOTYPE- OR PHENOTYPE-TARGETING ANTICANCER THERAPIES? LESSONS FROM TUMOR EVOLUTIONARY BIOLOGY. DESPITE THE EFFICACY OF MOST CANCER THERAPIES, DRUG RESISTANCE REMAINS A MAJOR PROBLEM IN THE CLINIC. THE ERADICATION OF THE ENTIRE TUMOR AND THE CURE OF THE PATIENT BY CHEMOTHERAPY ALONE ARE RARE, IN PARTICULAR FOR ADVANCED DISEASE. FROM AN EVOLUTIONARY PERSPECTIVE, THE SELECTIVE PRESSURE EXERTED BY CHEMOTHERAPY LEADS TO THE EMERGENCE OF RESISTANT CLONES WHERE RESISTANCE CAN BE ASSOCIATED WITH MANY DIFFERENT FUNCTIONAL MECHANISMS AT THE SINGLE CELL LEVEL OR CAN INVOLVE CHANGES IN THE TUMOR MICRO-ENVIRONMENT. IN THE LAST DECADE, TUMOR GENOMICS HAS CONTRIBUTED TO THE IMPROVEMENT OF OUR UNDERSTANDING OF TUMORIGENESIS AND HAS LED TO THE IDENTIFICATION OF NUMEROUS CELLULAR TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPIES. HOWEVER, SINCE TUMORS ARE BY NATURE EXTREMELY HETEROGENEOUS, THE DRUG EFFICACY AND ECONOMICAL SUSTAINABILITY OF THIS APPROACH IS NOW DEBATABLE. IMPORTANTLY, TUMOR CELL HETEROGENEITY DEPENDS NOT ONLY ON GENETIC MODIFICATIONS BUT ALSO ON NON-GENETIC PROCESSES INVOLVING EITHER STOCHASTIC EVENTS OR EPIGENETIC MODIFICATIONS MAKING GENETIC BIOMARKERS OF UNCERTAIN UTILITY. IN THIS REVIEW, WE WISH TO HIGHLIGHT HOW EVOLUTIONARY BIOLOGY CAN IMPACT OUR UNDERSTANDING OF CARCINOGENESIS AND RESISTANCE TO THERAPIES. WE WILL DISCUSS NEW APPROACHES BASED ON APPLIED ECOLOGY AND EVOLUTION DYNAMICS THAT CAN BE USED TO CONVERT THE CANCER INTO A CHRONIC DISEASE WHERE THE DRUGS WOULD CONTROL TUMOR GROWTH. FINALLY, WE WILL DISCUSS THE WAY METABOLIC DYSFUNCTION OR PHENOTYPIC CHANGES CAN HELP DEVELOPING NEW DELIVERY SYSTEMS OR PHENOTYPETARGETED DRUGS AND HOW EXPLORING NEW SOURCES OF ACTIVE COMPOUNDS CAN CONDUCT TO THE DEVELOPMENT OF DRUGS WITH ORIGINAL MECHANISMS OF ACTION. 2016 11 2695 25 EVOLVING UNDERSTANDING OF THE CLL GENOME. OVER THE PAST FEW YEARS, MASSIVELY PARALLEL SEQUENCING TECHNOLOGIES HAVE REVEALED WITH HIGH RESOLUTION THE TREMENDOUS GENETIC AND EPIGENETIC HETEROGENEITY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). WE HAVE LEARNED HOW THE MOLECULAR ARCHITECTURE DIFFERS NOT ONLY BETWEEN AFFECTED INDIVIDUALS BUT ALSO WITHIN SAMPLES AND OVER TIME. THESE INSIGHTS HAVE CATALYZED OUR UNDERSTANDING OF THE PATHOBIOLOGY OF CLL AND POINT TO CRITICAL SIGNALING PATHWAYS IN THE DEVELOPMENT AND PROGRESSION OF THE DISEASE. SEVERAL KEY DRIVER ALTERATIONS HAVE BEEN IDENTIFIED, WHICH SERVE TO REFINE PROGNOSTIC SCHEMATA BUT ALSO TO INSPIRE THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES. ONGOING ADVANCES IN TECHNOLOGY PROMISE TO FURTHER ELUCIDATE THE MOLECULAR BASIS OF CLL, AND THIS KNOWLEDGE IS ANTICIPATED TO AID US IN UNDERSTANDING AND ADDRESSING THE CLINICAL CHALLENGE PRESENTED BY THE VAST VARIABILITY IN THE CLINICAL COURSE OF PATIENTS WITH CLL. 2014 12 3038 30 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 13 3651 35 INCREASING COMPLEXITY OF MOLECULAR LANDSCAPES IN HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS DURING DEVELOPMENT AND AGING. THE PAST FIVE DECADES HAVE SEEN SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF HUMAN HEMATOPOIESIS. THIS HAS IN PART BEEN DUE TO THE UNPRECEDENTED DEVELOPMENT OF ADVANCED TECHNOLOGIES, WHICH HAVE ALLOWED THE IDENTIFICATION AND CHARACTERIZATION OF RARE SUBSETS OF HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS AND THEIR LINEAGE TRAJECTORIES FROM EMBRYONIC THROUGH TO ADULT LIFE. ADDITIONALLY, SURROGATE IN VITRO AND IN VIVO MODELS, ALTHOUGH NOT FULLY RECAPITULATING HUMAN HEMATOPOIESIS, HAVE SPURRED ON THESE SCIENTIFIC ADVANCES. THESE APPROACHES HAVE HEIGHTENED OUR KNOWLEDGE OF HEMATOLOGICAL DISORDERS AND DISEASES AND HAVE LED TO THEIR IMPROVED DIAGNOSIS AND THERAPIES. HERE, WE REVIEW HUMAN HEMATOPOIESIS AT EACH END OF THE AGE SPECTRUM, DURING EMBRYONIC AND FETAL DEVELOPMENT AND ON AGING, PROVIDING EXEMPLARS OF RECENT PROGRESS IN DECIPHERING THE INCREASINGLY COMPLEX CELLULAR AND MOLECULAR HEMATOPOIETIC LANDSCAPES IN HEALTH AND DISEASE. THIS REVIEW CONCLUDES BY HIGHLIGHTING LINKS BETWEEN CHRONIC INFLAMMATION AND METABOLIC AND EPIGENETIC CHANGES ASSOCIATED WITH AGING AND IN THE DEVELOPMENT OF CLONAL HEMATOPOIESIS. 2022 14 1522 36 DNA METHYLATION CHANGE PROFILING OF COLORECTAL DISEASE: SCREENING TOWARDS CLINICAL USE. COLON CANCER REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. TRANSFORMATION OF COLON EPITHELIAL CELLS INTO INVASIVE ADENOCARCINOMAS HAS BEEN WELL KNOWN TO BE DUE TO THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC CHANGES. IN THE PAST DECADE, THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) WHICH IS CHARACTERIZED BY CHRONIC INFLAMMATION OF THE INTESTINAL MUCOSA, WAS ONLY PARTIALLY EXPLAINED BY GENETIC STUDIES PROVIDING SUSCEPTIBILITY LOCI, BUT RECENTLY EPIGENETIC STUDIES HAVE PROVIDED CRITICAL EVIDENCES AFFECTING IBD PATHOGENESIS. OVER THE PAST DECADE, A DEEP UNDERSTANDING OF EPIGENETICS ALONG WITH TECHNOLOGICAL ADVANCES HAVE LED TO IDENTIFYING NUMEROUS GENES THAT ARE REGULATED BY PROMOTER DNA HYPERMETHYLATION IN COLORECTAL DISEASES. RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN COLORECTAL DISEASES COULD IMPROVE A MULTITUDE OF POWERFUL DNA METHYLATION-BASED BIOMARKERS, PARTICULARLY FOR USE AS DIAGNOSIS, PROGNOSIS, AND PREDICTION FOR THERAPEUTIC APPROACHES. THIS REVIEW FOCUSES ON THE EMERGING POTENTIAL FOR TRANSLATIONAL RESEARCH OF EPIGENETIC ALTERATIONS INTO CLINICAL UTILITY AS MOLECULAR BIOMARKERS. MOREOVER, THIS REVIEW DISCUSSES RECENT PROGRESS REGARDING THE IDENTIFICATION OF UNKNOWN HYPERMETHYLATED GENES IN COLON CANCERS AND IBD, AS WELL AS THEIR POSSIBLE ROLE IN CLINICAL PRACTICE, WHICH WILL HAVE IMPORTANT CLINICAL SIGNIFICANCE, PARTICULARLY IN THE ERA OF THE PERSONALIZED MEDICINE. 2021 15 6588 30 TUMOR HETEROGENEITY IN LYMPHOMAS: A DIFFERENT BREED. THE FACTS THAT CANCER REPRESENTS TISSUES CONSISTING OF HETEROGENEOUS NEOPLASTIC, AS WELL AS REACTIVE, CELL POPULATIONS AND THAT CANCERS OF THE SAME HISTOTYPE MAY SHOW PROFOUND DIFFERENCES IN CLINICAL BEHAVIOR HAVE LONG BEEN RECOGNIZED. WITH THE ADVENT OF NEW TECHNOLOGIES AND THE DEMANDS OF PRECISION MEDICINE, THE INVESTIGATION OF TUMOR HETEROGENEITY HAS GAINED MUCH INTEREST. AN UNDERSTANDING OF INTERTUMORAL HETEROGENEITY IN PATIENTS WITH THE SAME DISEASE ENTITY IS NECESSARY TO OPTIMALLY GUIDE PERSONALIZED TREATMENT. IN ADDITION, INCREASING EVIDENCE INDICATES THAT DIFFERENT TUMOR AREAS OR PRIMARY TUMORS AND METASTASES IN AN INDIVIDUAL PATIENT CAN SHOW SIGNIFICANT INTRATUMORAL HETEROGENEITY ON DIFFERENT LEVELS. THIS PHENOMENON CAN BE DRIVEN BY GENOMIC INSTABILITY, EPIGENETIC EVENTS, THE TUMOR MICROENVIRONMENT, AND STOCHASTIC VARIATIONS IN CELLULAR FUNCTION AND ANTITUMORAL THERAPIES. THESE MECHANISMS MAY LEAD TO BRANCHED SUBCLONAL EVOLUTION FROM A COMMON PROGENITOR CLONE, RESULTING IN SPATIAL VARIATION BETWEEN DIFFERENT TUMOR SITES, DISEASE PROGRESSION, AND TREATMENT RESISTANCE. THIS REVIEW ADDRESSES TUMOR HETEROGENEITY IN LYMPHOMAS FROM A PATHOLOGIST'S VIEWPOINT. THE RELATIONSHIP BETWEEN MORPHOLOGIC, IMMUNOPHENOTYPIC, AND GENETIC HETEROGENEITY IS EXEMPLIFIED IN DIFFERENT LYMPHOMA ENTITIES AND REVIEWED IN THE CONTEXT OF HIGH-GRADE TRANSFORMATION AND TRANSDIFFERENTIATION. IN ADDITION, FACTORS DRIVING HETEROGENEITY, AS WELL AS CLINICAL AND THERAPEUTIC IMPLICATIONS OF LYMPHOMA HETEROGENEITY, WILL BE DISCUSSED. 2018 16 6854 26 [NEW ADVANCES OF EPIGENETIC STUDY IN TUMORS OF LYMPHATIC SYSTEM---REVIEW]. EPIGENETICS IS AIMED TO STUDY THE HERITABLE CHANGES IN GENE EXPRESSION PATTERNS INDEPENDENT OF ALTERATIONS IN GENOMIC DNA SEQUENCE STRUCTURE, AND THE MECHANISMS OF TRANSLATION FROM GENOTYPE TO PHENOTYPE. IN RECENT YEARS, COMPELLING EVIDENCE GATHERED SUPPORTS A ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF LYMPHATIC SYSTEM TUMORS. FOR EXAMPLE, RECENT DATA FROM MULTIPLE LABORATORIES INDICATE THAT SEVERAL HUNDRED GENES, INVOLVING DOZENS OF CRITICAL MOLECULAR PATHWAYS, ARE EPIGENETICALLY SUPPRESSED IN ACUTE LYMPHOCYTIC LEUKEMIA; A PANEL OF METHYLATION MARKERS CAN BE USED FOR ADDITIONAL RISK STRATIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS; BASED ON THE EPIGENETIC PROFILES, THE CLASS PREDICTION MODELS IN GRAY ZONE LYMPHOMA CAN BE ESTABLISHED; THE EPIGENETIC SILENCING OF MICRORNAS IN MULTIPLE MYELOMA GENERALLY APPEARS TO HAVE INTACT P53 FUNCTION; EPIGENETIC THERAPIES HAVE BROADER IMPLICATION AND HIGH POTENTIAL FOR THE DEVELOPMENT OF IMMUNOTHERAPEUTIC STRATEGIES AND SO ON. IN THIS REVIEW, THE LATEST ADVANCES OF EPIGENETIC STUDY AND THE PROSPECT OF EPIGENETIC THERAPY FOR TUMORS IN LYMPHATIC SYSTEM ARE SUMMARIZED. 2012 17 2652 33 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS. 2011 18 963 31 CHRONIC MYELOMONOCYTIC LEUKEMIA: INSIGHTS INTO BIOLOGY, PROGNOSTIC FACTORS, AND TREATMENT. PURPOSE OF REVIEW: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGICAL MALIGNANCY CHARACTERIZED BY BOTH DYSPLASTIC AND PROLIFERATIVE FEATURES, WITH AN INHERENT RISK FOR LEUKEMIC TRANSFORMATION. WITH THE HELP OF THIS REVIEW, WE AIM TO SUMMARIZE KEY CONCEPTS WITH REGARDS TO CMML BIOLOGY, DIAGNOSIS, RISK STRATIFICATION, AND THERAPEUTICS. RECENT FINDINGS: BASED ON RECENT STUDIES, CMML IS HALLMARKED BY A RELATIVELY LOW GENETIC COMPLEXITY, WHICH CONTRASTS WITH A COMPELLING PHENOTYPICAL HETEROGENEITY, LARGELY DRIVEN BY EPIGENETIC MECHANISMS. RECENT ADVANCES IN THE CHARACTERIZATION OF CMML BIOLOGY HAS LED TO AN IMPROVEMENT IN RISK-STRATIFICATION, BY MEANS OF INCORPORATING PROGNOSTICALLY RELEVANT GENE MUTATIONS. THIS, HOWEVER, HAS NOT SIGNIFICANTLY IMPACTED AVAILABLE THERAPIES AND OUTCOMES CONTINUE TO REMAIN POOR. ADVANCES IN CMML BIOLOGY HAVE BETTER EXPLAINED THE PHENOTYPIC HETEROGENEITY, WHILE CONTINUING TO DEFINE THE GENETIC AND EPIGENETIC LANDSCAPE. IN SPITE OF RECENT ADVANCES, LIMITED EFFECTIVE THERAPIES EXIST AND DEVELOPING RATIONALLY DERIVED THERAPEUTIC APPROACHES IS MUCH NEEDED. 2019 19 3015 21 GENETICS AND EPIGENETICS OF CLL. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS A HETEROGENEOUS BIOLOGICAL BEHAVIOR, WHICH IS HIGHLY INFLUENCED BY ITS IMMUNOGENETIC, EPIGENETIC, AND GENOMIC PROPERTIES. THE REMARKABLY VARIABLE CLINICAL COURSE OF THE DISEASE HAS BEEN ASSOCIATED WITH GENETIC FEATURES SUCH AS CHROMOSOMAL ABNORMALITIES, THE PRESENCE OF EITHER HIGH OR LOW NUMBERS OF SOMATIC HYPERMUTATIONS (SHM) IN THE VARIABLE REGION OF THE IMMUNOGLOBULIN HEAVY CHAIN LOCUS (IGHV), AND SOMATIC MUTATIONS OF SEVERAL SPECIFIC DRIVER GENES. NEXT-GENERATION SEQUENCING (NGS) TECHNOLOGIES HAVE PROVIDED A COMPREHENSIVE CHARACTERIZATION OF THE GENOMIC AND EPIGENOMIC LANDSCAPE IN CLL, ELUCIDATING IMPORTANT UNDERLYING MECHANISMS OF THE DISEASE'S BIOLOGY. THE SCOPE OF THIS REVIEW IS TO SUMMARIZE THE MOST RECENT DISCOVERIES ABOUT NOVEL GENETIC AND EPIGENETIC ALTERATIONS, DISCUSSING THEIR IMPACT ON CLINICAL OUTCOMES AND RESPONSE TO CURRENTLY AVAILABLE THERAPY. 2023 20 733 27 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011