1 3996 131 LOOKING FORWARD: NOVEL THERAPEUTIC APPROACHES IN CHRONIC AND ADVANCED PHASES OF MYELOFIBROSIS. MYELOFIBROSIS (MF) IS COMPLEX AT THE PATHOBIOLOGIC LEVEL AND HETEROGENEOUS AT THE CLINICAL LEVEL. THE ADVANCES IN MOLECULAR CHARACTERIZATION OF MF PROVIDE IMPORTANT INSIGHT INTO THE MECHANISMS DRIVING THIS CHRONIC MYELOID MALIGNANCY, REFINE RISK STRATIFICATION, OFFER NOVEL THERAPEUTIC TARGETS, AND SERVE TO MEASURE THERAPEUTIC RESPONSE. ALTHOUGH JAK2 INHIBITION HAS BEEN THE FOCUS OF LABORATORY AND CLINICAL EFFORTS OVER THE LAST DECADE, CURRENT EXPERIMENTAL THERAPEUTIC APPROACHES HAVE BROADENED TO INCLUDE INHIBITORS OF KEY ALTERNATIVE SIGNALING PATHWAYS, EPIGENETIC MODULATORS, ANTI-FIBROTICS, AND IMMUNOTHERAPIES. BASED ON COMPELLING PRECLINICAL RATIONALE, A NUMBER OF JAK2 INHIBITOR BASED COMBINATION THERAPIES ARE NOW ACTIVELY BEING EVALUATED IN THE CLINIC WITH THE GOAL OF DISEASE COURSE MODIFICATION. THE ROLE AND TIMING OF HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) FOR MF HAS BEEN CHALLENGED WITH THE AVAILABILITY OF COMMERCIAL RUXOLITINIB AND THE PLETHORA OF EXPERIMENTAL TREATMENT OPTIONS THAT EXIST. INTEGRATION OF PRECONDITIONING JAK2 INHIBITION, REDUCED INTENSITY CONDITIONING REGIMENS, AND ALTERNATIVE DONOR SOURCES ARE ALL BEING EXPLORED IN AN ATTEMPT TO OPTIMIZE THIS POTENTIALLY CURATIVE MODALITY. THIS REVIEW WILL SUMMARIZE MODERN MF RISK STRATIFICATION, CURRENT CLINICAL RESEARCH APPROACHES TO CHRONIC AND ADVANCE PHASE MF FOCUSING ON NOVEL AGENTS ALONE AND IN COMBINATION, AND UPDATE THE READER ON NEW DIRECTIONS IN HSCT. 2015 2 5913 30 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 3 6573 43 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 4 3575 39 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 5 6675 27 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 6 963 35 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 7 944 36 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 8 4325 32 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 9 4429 33 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 10 3110 41 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 11 467 37 ARE WE FINALLY GETTING PERSONAL? MOVING TOWARDS A PERSONALIZED APPROACH IN CHRONIC LYMPHOCYTIC LEUKEMIA. WITH ITS HETEROGENEOUS BIOLOGICAL FEATURES AND CLINICAL COURSE, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST FREQUENT ADULT LEUKEMIA IN THE WESTERN WORLD, IS A PARADIGMATIC CONDITION REQUIRING A TAILORED APPROACH AND A PRECISE KNOWLEDGE OF THE BIOLOGY BEHIND EACH INDIVIDUAL PATIENT. THIS PERSONALIZED MANAGEMENT IS BECOMING EVEN MORE CRUCIAL, SINCE, AFTER DECADES OF PRECLINICAL WORK UNRAVELLING THE KEY ROLE OF THE B-CELL RECEPTOR (BCR) SIGNALLING PATHWAYS AND THE ANTI-APOPTOTIC MECHANISMS IN CLL CELL SURVIVAL AND PROLIFERATION, WE HAVE NOW BCR AND BCL2 INHIBITORS AVAILABLE IN CLINICAL PRACTICE. THANKS TO THIS, WE ARE NOW ABLE TO EXPLOIT SPECIFIC BIOMARKERS TO TAILOR OUR TREATMENT STRATEGIES AND IMPROVE LONG-TERM DISEASE CONTROL, PATIENT OUTCOME AND QUALITY OF LIFE. THAT NOTWITHSTANDING, AS THE DISEASE ITSELF REMAINS INCURABLE, NOVEL CHALLENGES AND UNMET CLINICAL NEEDS HAVE RISEN FROM THE INTRODUCTION OF NOVEL TARGETED AGENTS, INCLUDING MECHANISMS OF RESISTANCE AT BOTH GENETIC AND EPIGENETIC LEVELS. IN THIS REVIEW, WE SUMMARIZE THE CURRENTLY ESTABLISHED PREDICTIVE BIOMARKERS (I.E. IGHV MUTATION STATUS AND TP53 GENE DISRUPTION) THAT SHOULD BE APPLIED IN CLINICAL PRACTICE TO INFORM TREATMENT DECISION IN 2021 BUT ALSO DISCUSS THE MOST PROMISING PROGNOSTIC BIOMARKERS (B-CELL RECEPTOR STEREOTYPY, COMPLEX KARYOTYPE, SOMATIC GENE MUTATIONS, MEASURABLE RESIDUAL DISEASE - MRD) THAT MIGHT BECOME KEY TO DEFINE THE MANAGEMENT OF OUR PATIENTS IN A NEAR FUTURE. 2022 12 3958 34 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 13 1673 42 DRIVER GENE MUTATIONS AND EPIGENETICS IN COLORECTAL CANCER. OBJECTIVE: THE MAJORITY OF PATIENTS WITH COLORECTAL CANCER ARE DIAGNOSED WITH LOCALLY ADVANCED AND/OR DISSEMINATED DISEASE, AND TREATMENT OPTIONS INCLUDE SURGERY IN COMBINATION WITH CYTOTOXIC CHEMOTHERAPY REGIMENS, BIOLOGICS, AND/OR RADIOTHERAPY. THUS, COLORECTAL CANCER REMAINS A HEAVY BURDEN ON SOCIETY AND HEALTH CARE SYSTEMS.MOUNTING EVIDENCE SHOW THAT DRIVER GENE MUTATIONS PLAY ONLY PART OF THE ROLE IN CARCINOGENESIS. EPIGENETICS ARE STRONGLY IMPLICATED IN INITIATION AND PROGRESSION OF COLORECTAL CANCER ALONG WITH MAJOR PLAYERS SUCH AS INTESTINAL MICROBIOTIC DYSBIOSIS AND CHRONIC MUCOSAL INFLAMMATION.TO ASSESS PHENOTYPIC CHANGES IN PROTEINS AND GENE EXPRESSION, MULTIGENE EXPRESSION SIGNATURES BASED ON SEQUENCING TECHNIQUES HAVE BEEN DEVELOPED TO HOPEFULLY IMPROVE PREDICTORS OF THE TUMOR PROFILE, IMMUNE RESPONSE, AND THERAPEUTIC OUTCOMES. OUR OBJECTIVE WAS TO REVIEW CURRENT ADVANCES IN THE FIELD AND TO UPDATE SURGEONS AND ACADEMICS ON DRIVER GENE MUTATIONS AND EPIGENETICS IN COLORECTAL CANCER. BACKGROUND AND METHODS: THIS IS A NARRATIVE REVIEW STUDYING RELEVANT RESEARCH PUBLISHED IN THE PUBMED DATABASE FROM 2012-2018. RESULTS AND CONCLUSION: INCREASED UNDERSTANDING OF THE MOLECULAR BIOLOGY WILL IMPROVE OPTIONS TO CHARACTERIZE COLORECTAL CANCER WITH REGARD TO MUTATIONS AND MOLECULAR PATHWAYS, INCLUDING MICROSATELLITE INSTABILITY, EPIGENETICS, MICROBIOTA, AND MICROENVIRONMENT. RESEARCH WILL INEVITABLY IMPROVE RISK GROUP STRATIFICATION AND TARGETED TREATMENT APPROACHES.EPIGENETIC PROFILING AND EPIGENETIC MODULATING DRUGS WILL INCREASE RISK STRATIFICATION, INCREASE ACCESSIBILITY FOR DNA TARGETING CHEMOTHERAPEUTICS AND REDUCE CYTOTOXIC DRUG RESISTANCE.NEW GENERATION ANTIBIOTICS SUCH AS BIOFILM INHIBITORS AND QUORUM SENSING INHIBITORS ARE BEING DEVELOPED TO TARGET THE CARCINOGENETIC IMPACT OF COLONIC DYSBIOSIS AND INFLAMMATION. 2020 14 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 15 5026 38 PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS: FACTS AND PROMISES. PURPOSE OF REVIEW: IN THIS ARTICLE, WE SUMMARIZE AND DISCUSS THE MOST RECENT LITERATURE ON PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS (IPF), A CHRONIC PROGRESSIVE AND ALMOST INVARIABLY LETHAL DISEASE OF UNKNOWN CAUSE. THIS REVIEW IS TIMELY AS MAJOR ADVANCES IN OUR UNDERSTANDING OF DISEASE PATHOBIOLOGY AND IMPROVEMENTS IN MOLECULAR TECHNIQUES HAVE RECENTLY LED TO THE IDENTIFICATION OF POTENTIAL SURROGATES OF DIAGNOSIS, PROGNOSIS AND RESPONSE TO TREATMENT. RECENT FINDINGS: THE MOST PROMISING AND ADVANCED CANDIDATE BIOMARKERS ARE PRESENTED BASED ON THEIR PROPOSED MECHANISTIC PATHWAYS (E.G. ALVEOLAR EPITHELIAL CELL DYSFUNCTION, IMMUNE DYSREGULATION, MICROBIOME, EXTRACELLULAR MATRIX REMODELING AND FIBROPROLIFERATION, EPIGENETIC MARKERS AND METABOLOMICS). RECENT DATA SUGGEST THAT COMPONENTS OF THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE DEVELOPMENT OF IPF. A POTENTIAL ROLE FOR INFECTIONS AS A COFACTOR IN DISEASE DEVELOPMENT AND PROGRESSION OR AS A TRIGGER IN DISEASE EXACERBATION HAS ALSO RECENTLY BEEN PROPOSED. SUMMARY: CLINICAL MANAGEMENT OF IPF IS UNSATISFACTORY BECAUSE OF LIMITED AVAILABILITY OF TRULY EFFECTIVE THERAPIES, LACK OF ACCURATE PREDICTORS OF DISEASE BEHAVIOR AND ABSENCE OF SIMPLE SHORT-TERM MEASURES OF THERAPEUTIC RESPONSE. A NUMBER OF PUTATIVE BIOMARKERS HAVE BEEN IDENTIFIED IN PATIENTS WITH IPF, ALTHOUGH NONE HAS BEEN VALIDATED TO THE STANDARD NECESSARY FOR THEIR USE IN EITHER THERAPEUTIC TRIALS OR CLINICAL PRACTICE. CURRENTLY, ONGOING PROSPECTIVE LONGITUDINAL STUDIES WILL HOPEFULLY PERMIT SUCH VALIDATION. 2015 16 3682 22 INFLAMMATION, FIBROSIS AND CANCER: MECHANISMS, THERAPEUTIC OPTIONS AND CHALLENGES. UNCONTROLLED INFLAMMATION IS A SALIENT FACTOR IN MULTIPLE CHRONIC INFLAMMATORY DISEASES AND CANCERS. IN THIS REVIEW, WE PROVIDED AN IN-DEPTH ANALYSIS OF THE RELATIONSHIPS AND DISTINCTIONS BETWEEN UNCONTROLLED INFLAMMATION, FIBROSIS AND CANCERS, WHILE EMPHASIZING THE CHALLENGES AND OPPORTUNITIES OF DEVELOPING NOVEL THERAPIES FOR THE TREATMENT AND/OR MANAGEMENT OF THESE DISEASES. WE DESCRIBED HOW DRUG DELIVERY SYSTEMS, COMBINATION THERAPY AND THE INTEGRATION OF TISSUE-TARGETED AND/OR PATHWAYS SELECTIVE STRATEGIES COULD OVERCOME THE CHALLENGES OF CURRENT AGENTS FOR MANAGING AND/OR TREATING CHRONIC INFLAMMATORY DISEASES AND CANCERS. WE ALSO RECOGNIZED THE VALUE OF THE RE-EVALUATION OF THE DISEASE-SPECIFIC ROLES OF MULTIPLE PATHWAYS IMPLICATED IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCERS-AS WELL AS THE APPLICATION OF DATA FROM SINGLE-CELL RNA SEQUENCING IN THE SUCCESS OF FUTURE DRUG DISCOVERY ENDEAVORS. 2022 17 2548 30 EPIGENETICS IN MYELOPROLIFERATIVE NEOPLASMS. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF ACQUIRED CLONAL DISORDERS WHERE MUTATIONS DRIVE PROLIFERATIVE DISEASE RESULTING IN INCREASED BLOOD COUNTS AND IN SOME CASES END-STAGE MYELOFIBROSIS. EPIGENETIC CHANGES ARE THE REVERSIBLE MODIFICATIONS TO DNA- AND RNA-ASSOCIATED PROTEINS THAT IMPACT GENE ACTIVITY WITHOUT CHANGING THE DNA SEQUENCE. THIS REVIEW SUMMARIZES MECHANISMS OF EPIGENETIC CHANGES AND THE NUCLEOSOME. THE DRIVERS AND EPIGENETIC REGULATORS IN MPNS ARE OUTLINED. IN MPNS, DISTINCT PATTERNS OF EPIGENETIC DYSREGULATION HAVE BEEN SEEN IN CHRONIC AND IN ADVANCED PHASES. METHYLATION AGE AND HISTONE MODIFICATION ARE ALTERED IN MPNS AND BY FURTHER TREATMENT. THE ALTERATIONS FOUND IN METHYLATION AGE IN MPNS AND WITH TREATMENT ARE DISCUSSED, AND THE CHANGES IN HISTONE MODIFICATION WITH JANUS KINASE (JAK) INHIBITION ARE EVALUATED. CURRENTLY AVAILABLE THERAPEUTIC AREAS WHERE THE EPIGENOME CAN BE ALTERED ARE OUTLINED. THUS, WE REVIEW THE CURRENT KNOWLEDGE AND UNDERSTANDING OF EPIGENETICS IN MPN AND CONSIDER FURTHER MANAGEMENT OPTIONS. UNDERSTANDING THE EPIGENOME AND ITS ALTERATION IN MPNS AND EPIGENETIC CHANGES ASSOCIATED WITH THE PROGRESSION OF DISEASE WILL LEAD TO ADVANCES IN THERAPEUTIC OPTIONS. 2023 18 5162 36 PRECISION MEDICINE DRIVEN BY CANCER SYSTEMS BIOLOGY. MOLECULAR INSIGHTS FROM GENOME AND SYSTEMS BIOLOGY ARE INFLUENCING HOW CANCER IS DIAGNOSED AND TREATED. WE CRITICALLY EVALUATE BIG DATA CHALLENGES IN PRECISION MEDICINE. THE MELANOMA RESEARCH COMMUNITY HAS IDENTIFIED DISTINCT SUBTYPES INVOLVING CHRONIC SUN-INDUCED DAMAGE AND THE MITOGEN-ACTIVATED PROTEIN KINASE DRIVER PATHWAY. IN ADDITION, DESPITE LOW MUTATION BURDEN, NON-GENOMIC MITOGEN-ACTIVATED PROTEIN KINASE MELANOMA DRIVERS ARE FOUND IN MEMBRANE RECEPTORS, METABOLISM, OR EPIGENETIC SIGNALING WITH THE ABILITY TO BYPASS CENTRAL MITOGEN-ACTIVATED PROTEIN KINASE MOLECULES AND ACTIVATING A SIMILAR PROGRAM OF MITOGENIC EFFECTORS. MUTATION HOTSPOTS, STRUCTURAL MODELING, UV SIGNATURE, AND GENOMIC AS WELL AS NON-GENOMIC MECHANISMS OF DISEASE INITIATION AND PROGRESSION ARE TAKEN INTO CONSIDERATION TO IDENTIFY RESISTANCE MUTATIONS AND NOVEL DRUG TARGETS. A COMPREHENSIVE PRECISION MEDICINE PROFILE OF A MALIGNANT MELANOMA PATIENT ILLUSTRATES FUTURE RATIONAL DRUG TARGETING STRATEGIES. NETWORK ANALYSIS EMPHASIZES AN IMPORTANT ROLE OF EPIGENETIC AND METABOLIC MASTER REGULATORS IN ONCOGENESIS. CO-OCCURRENCE OF DRIVER MUTATIONS IN SIGNALING, METABOLIC, AND EPIGENETIC FACTORS HIGHLIGHTS HOW CUMULATIVE ALTERATIONS OF OUR GENOMES AND EPIGENOMES PROGRESSIVELY LEAD TO UNCONTROLLED CELL PROLIFERATION. PRECISION INSIGHTS HAVE THE ABILITY TO IDENTIFY INDEPENDENT MOLECULAR PATHWAYS SUITABLE FOR DRUG TARGETING. SYNERGISTIC TREATMENT COMBINATIONS OF ORTHOGONAL MODALITIES INCLUDING IMMUNOTHERAPY, MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS, EPIGENETIC INHIBITORS, AND METABOLIC INHIBITORS HAVE THE POTENTIAL TO OVERCOME IMMUNE EVASION, SIDE EFFECTS, AND DRUG RESISTANCE. 2017 19 5290 20 PROSTATE CANCER PREVENTION: AGENT DEVELOPMENT STRATEGIES. DESPITE ADVANCES IN SURGERY, RADIATION, AND MEDICAL THERAPY OVER THE PAST DECADE AND THE WIDESPREAD ADOPTION OF PSA SCREENING, PROSTATE CANCER CONTINUES TO BE THE SECOND LEADING CAUSE OF CANCER DEATH IN MEN IN THE UNITED STATES. INVASIVE CANCER IS THE END RESULT OF CARCINOGENESIS, A CHRONIC PROCESS OCCURRING OVER MANY YEARS DRIVEN BY GENETIC AND EPIGENETIC ALTERATIONS. THE PROTRACTED NATURE OF THIS TRANSFORMATION TO THE MALIGNANT PHENOTYPE PROVIDES AN OPPORTUNITY TO INTERVENE PHARMACOLOGICALLY TO PREVENT, REVERSE, OR DELAY CARCINOGENESIS, I.E. CHEMOPREVENTION. HEREIN, WE DESCRIBE THE UNIQUE FEATURES OF CANCER PREVENTION, AS OPPOSED TO CANCER TREATMENT, AGENT DEVELOPMENT CLINICAL TRIALS, AND PROVIDE A SUMMARY OF THE ONGOING RESEARCH IN THIS FIELD BEING SUPPORTED BY THE NATIONAL CANCER INSTITUTE. 2014 20 6447 32 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