1 6371 148 THE ROLE OF MICRORNAS IN THE PATHOGENESIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES. MICRORNAS (MIRNAS) COMPRISE A RECENTLY DISCOVERED CLASS OF NON-CODING RNAS WITH REGULATORY FUNCTIONS IN POST-TRANSCRIPTIONAL GENE EXPRESSION CONTROL. MANY MIRNAS ARE LOCATED IN GENOMIC REGIONS THAT ARE FREQUENTLY DELETED IN CANCER, OR ARE SUBJECT TO EPIGENETIC AND TRANSCRIPTIONAL DEREGULATION IN CANCER CELLS. THE MIRNA TRANSCRIPTOME OF CANCER CELLS IS VERY DIFFERENT FROM THAT OF THEIR NORMAL CELL COUNTERPARTS. MIRNAS CAN EXHIBIT ONCOGENIC OR TUMOR SUPPRESSIVE OR EVEN BOTH PROPERTIES DEPENDING ON THE SPECIFIC TARGETS AND CELLULAR CONTEXT. IT IS BECOMING INCREASINGLY CLEAR THAT MIRNAS NOT ONLY SERVE AS USEFUL TUMOR BIOMARKERS WITH IMPLICATIONS FOR DIAGNOSIS, PROGNOSIS AND THE PREDICTION OF TREATMENT RESPONSES, BUT MAY ALSO BE USED FOR TARGETED CANCER TREATMENT AND EVEN AS THERAPEUTICS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE TUMOR SUPPRESSOR MIRNAS AND ONCOMIRS INVOLVED IN THE PATHOGENESIS OF LEUKEMIAS AND LYMPHOMAS, AND THEIR TARGET TRANSCRIPTS IN CANCER SIGNALING NETWORKS. IN PARTICULAR, WE FOCUS ON THE ROLE OF MIRNAS IN CHRONIC LYMPHOCYTIC AND ACUTE LYMPHOBLASTIC LEUKEMIA AND IN B-CELL LYMPHOMAS. IN THE SECOND PART, WE REVIEW THE VARIOUS ALTERNATIVE STRATEGIES OF TARGETING MIRNAS IN CANCER THERAPY. METHODS OF ONCOMIR ANTAGONIZATION BY ANTAGOMIRS OR LOCKED NUCLEID ACIDS ARE CONTRASTED WITH STRATEGIES THAT HARNESS THE TUMOR SUPPRESSIVE PROPERTIES OF CERTAIN MIRNAS FOR CANCER TREATMENT. PRECLINICAL PROGRESS, ALSO WITH REGARD TO DELIVERY STRATEGIES, POSSIBLE SIDE EFFECTS AND OTHER PHARMACOLOGICAL ASPECTS, IS PRESENTED ALONG WITH RESULTS FROM THE FIRST HUMAN TRIALS ASSESSING THE SAFETY AND EFFICACY OF MIRNA-TARGETING THERAPEUTICS. 2013 2 6326 29 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010 3 4285 51 MICRORNA EPIGENETIC SIGNATURES IN HUMAN DISEASE. MICRORNAS (MIRNAS) ARE SHORT NON-CODING RNAS THAT ACT AS IMPORTANT REGULATORS OF GENE EXPRESSION AS PART OF THE EPIGENETIC MACHINERY. IN ADDITION TO POSTTRANSCRIPTIONAL GENE SILENCING BY MIRNAS, THE EPIGENETIC MECHANISMS ALSO INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND THEIR CROSSTALK. EPIGENETIC MODIFICATIONS WERE REPORTED TO PLAY AN IMPORTANT ROLE IN MANY DISEASE ONSETS AND PROGRESSIONS AND CAN BE USED TO EXPLAIN SEVERAL FEATURES OF COMPLEX DISEASES, SUCH AS LATE ONSET AND FLUCTUATION OF SYMPTOMS. HOWEVER, MIRNAS NOT ONLY FUNCTION AS A PART OF EPIGENETIC MACHINERY, BUT ARE ALSO EPIGENETICALLY MODIFIED BY DNA METHYLATION AND HISTONE MODIFICATION LIKE ANY OTHER PROTEIN-CODING GENE. THERE IS A STRONG CONNECTION BETWEEN EPIGENOME AND MIRNOME, AND ANY DYSREGULATION OF THIS COMPLEX SYSTEM CAN RESULT IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS. IN ADDITION, MIRNAS PLAY AN IMPORTANT ROLE IN TOXICOGENOMICS AND MAY EXPLAIN THE RELATIONSHIP BETWEEN TOXICANT EXPOSURE AND TUMORIGENESIS. THE PRESENT REVIEW PROVIDES INFORMATION ON 63 MIRNA GENES SHOWN TO BE EPIGENETICALLY REGULATED IN ASSOCIATION WITH 21 DISEASES, INCLUDING 11 CANCER TYPES: CARDIAC FIBROSIS, CARDIOVASCULAR DISEASE, PREECLAMPSIA, HIRSCHSPRUNG'S DISEASE, RHEUMATOID ARTHRITIS, SYSTEMIC SCLEROSIS, SYSTEMIC LUPUS ERYTHEMATOSUS, TEMPORAL LOBE EPILEPSY, AUTISM, PULMONARY FIBROSIS, MELANOMA, ACUTE MYELOID LEUKEMIA, CHRONIC LYMPHOCYTIC LEUKEMIA, COLORECTAL, GASTRIC, CERVICAL, OVARIAN, PROSTATE, LUNG, BREAST, AND BLADDER CANCER. THE REVIEW REVEALED THAT HSA-MIR-34A, HSA-MIR-34B, AND HSA-MIR-34C ARE THE MOST FREQUENTLY REPORTED EPIGENETICALLY DYSREGULATED MIRNAS. THERE IS A NEED TO FURTHER STUDY MOLECULAR MECHANISMS OF VARIOUS DISEASES TO BETTER UNDERSTAND THE CROSSTALK BETWEEN EPIGENETICS AND GENE EXPRESSION AND TO DEVELOP NEW THERAPEUTIC OPTIONS AND BIOMARKERS. 2016 4 2535 33 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 5 3958 49 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 6 6896 40 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 7 4228 32 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 8 6854 39 [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 9 4335 57 MICRORNAS: SMALL MOLECULES WITH SIGNIFICANT FUNCTIONS, PARTICULARLY IN THE CONTEXT OF VIRAL HEPATITIS B AND C INFECTION. A MICRORNA (MIRNA) IS DEFINED AS A SMALL MOLECULE OF NON-CODING RNA (NCRNA). ITS MOLECULAR SIZE IS ABOUT 20 NUCLEOTIDES (NT), AND IT ACTS ON GENE EXPRESSION'S REGULATION AT THE POST-TRANSCRIPTION LEVEL THROUGH BINDING TO THE 3'UNTRANSLATED REGIONS (UTR), CODING SEQUENCES, OR 5'UTR OF THE TARGET MESSENGER RNAS (MRNAS), WHICH LEADS TO THE SUPPRESSION OR DEGRADATION OF THE MRNA. IN RECENT YEARS, A HUGE EVOLUTION HAS IDENTIFIED THE ORIGIN AND FUNCTION OF MIRNAS, FOCUSING ON THEIR IMPORTANT EFFECTS IN RESEARCH AND CLINICAL APPLICATIONS. FOR EXAMPLE, MICRORNAS ARE KEY PLAYERS IN HCV INFECTION AND HAVE IMPORTANT HOST CELLULAR FACTORS REQUIRED FOR HCV REPLICATION AND CELL GROWTH. ALTERED EXPRESSION OF MIRNAS AFFECTS THE PATHOGENICITY ASSOCIATED WITH HCV INFECTION THROUGH REGULATING DIFFERENT SIGNALING PATHWAYS THAT CONTROL HCV/IMMUNITY INTERACTIONS, PROLIFERATION, AND CELL DEATH. ON THE OTHER HAND, CIRCULATING MIRNAS CAN BE USED AS NOVEL BIOMARKERS AND DIAGNOSTIC TOOLS FOR HCV PATHOGENESIS AND EARLY THERAPEUTIC RESPONSE. MOREOVER, MICRORNAS (MIRNA) HAVE BEEN INVOLVED IN HEPATITIS B VIRUS (HBV) GENE EXPRESSION AND ADVANCED ANTIVIRAL DISCOVERY. THEY REGULATE HBV/HCV REPLICATION AND PATHOGENESIS WITH DIFFERENT PATHWAYS INVOLVING FACILITATION, INHIBITION, ACTIVATION OF THE IMMUNE SYSTEM (INNATE AND ADAPTIVE), AND EPIGENETIC MODIFICATIONS. IN THIS SHORT REVIEW, WE WILL DISCUSS HOW MICRORNAS CAN BE USED AS PROGNOSTIC, DIAGNOSTIC, AND THERAPEUTIC TOOLS, ESPECIALLY FOR CHRONIC HEPATITIS VIRUSES (HBV AND HCV), AS WELL AS HOW THEY COULD BE USED AS NEW BIOMARKERS DURING INFECTION AND ADVANCED TREATMENT. 2023 10 4429 42 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 11 4320 32 MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA: AN OLD DISEASE WITH NEW GENETIC INSIGHTS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON LEUKEMIA AMONG ADULT POPULATION IN WESTERN COUNTRY. IN THE LAST DECADE, SEVERAL FINDINGS HAVE SUBSTANTIALLY REVOLUTIONIZED THE OLD CONCEPT THAT CLL IS A DISEASE ORIGINATING FROM MATURE, NOT-DIVIDING CELL WITH INDOLENT CLINICAL COURSE. NOTABLY, NEXT GENERATION SEQUENCING (NGS) HAS CONTRIBUTED TO DEEPEN THE KNOWLEDGE OF THE CELLULAR NETWORKS THAT IMPLY THE ONSET AND THE PROGRESSION OF CLL. AMONG GENETIC ABERRATIONS THAT ARE RECURRENTLY OBSERVED IN B-CELLS FROM PATIENTS WITH CLL, MICRORNA DEREGULATION REPRESENTED THE FIRST EPIGENETIC MECHANISM THAT HAS BEEN IDENTIFIED. THROUGH EPIGENETIC MECHANISM THEY CAN MODULATE GENE EXPRESSION AND INTERFERE WITH CELLULAR PATHWAYS THAT ARE INVOLVED IN CELL CYCLE, APOPTOSIS AND B-CELL RECEPTOR (BCR) ACTIVATION. ALTHOUGH FEW STUDIES HAVE SHOWN THE PROGNOSTIC AND PREDICTIVE VALUE OF MICRORNA EXPRESSION LEVELS, THEIR VALIDATION WITHIN PROSPECTIVE CLINICAL TRIALS IS WARRANTED. 2016 12 209 34 ACTIVATION-INDUCED CYTIDINE DEAMINASE: IN SICKNESS AND IN HEALTH. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) IS AN ESSENTIAL ENZYME OF THE ADAPTIVE IMMUNE SYSTEM. ITS CANONICAL ACTIVITY IS RESTRICTED TO B LYMPHOCYTES, PLAYING AN ESSENTIAL ROLE IN THE DIVERSIFICATION OF ANTIBODIES BY ENHANCING SPECIFICITY AND CHANGING AFFINITY. THIS IS POSSIBLE THROUGH ITS DNA DEAMINASE FUNCTION, LEADING TO MUTATIONS IN DNA. IN THE LAST DECADE, AID HAS BEEN ASSIGNED AN ADDITIONAL FUNCTION: THAT OF A POWERFUL DNA DEMETHYLATOR. ADVERSE CELLULAR CONDITIONS SUCH AS CHRONIC INFLAMMATION CAN LEAD TO ITS DEREGULATION AND OVEREXPRESSION. IT IS AN IMPORTANT DRIVER OF B-CELL LYMPHOMA DUE TO ITS NATURAL ABILITY TO MODIFY DNA THROUGH DEAMINATION, LEADING TO MUTATIONS AND EPIGENETIC CHANGES. HOWEVER, THE DEREGULATION OF AID IS NOT RESTRICTED TO LYMPHOID CELLS. RECENT FINDINGS HAVE PROVIDED NEW INSIGHTS INTO THE ROLE THAT THIS PROTEIN PLAYS IN THE DEVELOPMENT OF NON-LYMPHOID CANCERS, WITH SOME RESEARCH SHEDDING LIGHT ON NOVEL AID-DRIVEN MECHANISMS OF CELLULAR TRANSFORMATION. IN THIS REVIEW, WE PROVIDE AN UPDATED NARRATIVE OF THE NORMAL PHYSIOLOGICAL FUNCTIONS OF AID. ADDITIONALLY, WE REVIEW AND DISCUSS THE RECENT RESEARCH STUDIES THAT HAVE IMPLICATED AID IN CARCINOGENESIS IN VARYING TISSUE TYPES INCLUDING LYMPHOID AND NON-LYMPHOID CANCERS. WE REVIEW THE MECHANISMS, WHEREBY AID PROMOTES CARCINOGENESIS AND HIGHLIGHT IMPORTANT AREAS OF FUTURE RESEARCH. 2020 13 3964 48 LONG NONCODING RNAS IN LUNG CANCER. DESPITE GREAT PROGRESS IN RESEARCH AND TREATMENT OPTIONS, LUNG CANCER REMAINS THE LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE. ONCOGENIC DRIVER MUTATIONS IN PROTEIN-ENCODING GENES WERE DEFINED AND ALLOW FOR PERSONALIZED THERAPIES BASED ON GENETIC DIAGNOSES. NONETHELESS, DIAGNOSIS OF LUNG CANCER MOSTLY OCCURS AT LATE STAGES, AND CHRONIC TREATMENT IS FOLLOWED BY A FAST ONSET OF CHEMORESISTANCE. HENCE, THERE IS AN URGENT NEED FOR RELIABLE BIOMARKERS AND ALTERNATIVE TREATMENT OPTIONS. WITH THE ERA OF WHOLE GENOME AND TRANSCRIPTOME SEQUENCING TECHNOLOGIES, LONG NONCODING RNAS EMERGED AS A NOVEL CLASS OF VERSATILE, FUNCTIONAL RNA MOLECULES. ALTHOUGH FOR MOST OF THEM THE MECHANISM OF ACTION REMAINS TO BE DEFINED, ACCUMULATING EVIDENCE CONFIRMS THEIR INVOLVEMENT IN VARIOUS ASPECTS OF LUNG TUMORIGENESIS. THEY ARE FUNCTIONAL ON THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVEL AND ARE REGULATORS OF PATHOPHYSIOLOGICAL KEY PATHWAYS INCLUDING CELL GROWTH, APOPTOSIS, AND METASTASIS. LONG NONCODING RNAS ARE GAINING INCREASING ATTENTION AS POTENTIAL BIOMARKERS AND A NOVEL CLASS OF DRUGGABLE MOLECULES. IT HAS BECOME CLEAR THAT WE ARE ONLY BEGINNING TO UNDERSTAND THE COMPLEXITY OF TUMORIGENIC PROCESSES. THE CLINICAL INTEGRATION OF LONG NONCODING RNAS IN TERMS OF PROGNOSTIC AND PREDICTIVE BIOMARKER SIGNATURES AND ADDITIONAL CANCER TARGETS COULD PROVIDE A CHANCE TO INCREASE THE THERAPEUTIC BENEFIT. HERE, WE REVIEW THE CURRENT KNOWLEDGE ABOUT THE EXPRESSION, REGULATION, BIOLOGICAL FUNCTION, AND CLINICAL RELEVANCE OF LONG NONCODING RNAS IN LUNG CANCER. 2016 14 1232 42 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 15 4289 38 MICRORNA IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT DEGENERATIVE JOINT DISEASE AND IS ACCOMPANIED BY PAIN AND JOINT DYSFUNCTION. ITS CLINICAL TREATMENT TENDS TO BE UNSATISFACTORY. NOVEL TARGETS IN OA INCLUDE GENES THAT ARE INVOLVED IN OA PATHOPHYSIOLOGY AND HAVE BEEN DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA (MIRNA) APPROACHES. MIRNA HAS BEEN IMPLICATED IN IMPORTANT CELLULAR PROCESSES SUCH AS LIPID METABOLISM, APOPTOSIS, DIFFERENTIATION AND ORGAN DEVELOPMENT. THE IMPORTANCE OF MIRNA REGULATION IN CELLULAR FUNCTION IS BECOMING INCREASINGLY CLEAR AS NEW MIRNA TARGETS ARE REVEALED. THE PRESENT REVIEW SUMMARIZES THE CURRENT EVIDENCE OF THE IMPORTANT ROLE PLAYED BY MIRNA IN DETERMINING THE COMPLEX GENE EXPRESSION PATTERNS OF OA CHONDROCYTES AND THEIR ROLE IN THE REGULATION OF TRANSCRIPTION, AND POSSIBLE DEMETHYLATION MECHANISMS THAT MIGHT BE APPLICABLE IN OA. IN SUMMARY, MIRNA MAY HAVE IMPORTANT DIAGNOSTIC AND THERAPEUTIC POTENTIAL, AND MIGHT PROVIDE A NOVEL MEANS OF TREATING OA. 2011 16 1568 43 DNA METHYLATION OF TUMOR-SUPPRESSOR MIRNA GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA. DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS OF THE GENOME INVOLVED IN THE REGULATION OF NUMEROUS CELLULAR PROCESSES THROUGH GENE SILENCING WITHOUT ALTERING DNA SEQUENCES. MIRNAS, A CLASS OF SINGLE-STRANDED NONCODING RNAS OF 19-25 NUCLEOTIDES IN LENGTH, FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS OF GENE EXPRESSION LEADING TO MRNA CLEAVAGE OR TRANSLATIONAL REPRESSION OF THEIR CORRESPONDING TARGET PROTEIN-CODING GENES. RECENTLY, DYSREGULATION OF TUMOR SUPPRESSOR MIRNAS MEDIATED BY PROMOTER DNA HYPERMETHYLATION IS IMPLICATED IN HUMAN CANCERS, INCLUDING B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). MOREOVER, IT APPEARS THAT METHYLATED MIRNA GENES COULD BE POTENTIAL BIOMARKERS FOR CLL DIAGNOSIS OR THERAPY. THIS REVIEW WILL HIGHLIGHT THE ROLE OF ABERRANT METHYLATION OF MIRNA GENES IN THE PATHOGENESIS OF CLL. 2015 17 3350 45 HISTONE DEACETYLATION MEETS MIRNA: EPIGENETICS AND POST-TRANSCRIPTIONAL REGULATION IN CANCER AND CHRONIC DISEASES. INTRODUCTION: EPIGENETIC REGULATION VIA DNA METHYLATION, HISTONE ACETYLATION, AS WELL AS BY MICRORNAS (MIRNAS) IS CURRENTLY IN THE SCIENTIFIC FOCUS DUE TO ITS ROLE IN CARCINOGENESIS AND ITS INVOLVEMENT IN INITIATION, PROGRESSION AND METASTASIS. WHILE MANY TARGET GENES OF DNA METHYLATION, HISTONE ACETYLATION AND MIRNAS ARE KNOWN, EVEN LESS INFORMATION EXISTS AS TO HOW THESE MECHANISMS COOPERATE AND HOW THEY MAY REGULATE EACH OTHER IN A SPECIFIC PATHOLOGICAL CONTEXT. FOR FURTHER DEVELOPMENT OF THERAPEUTIC APPROACHES, THIS REVIEW PRESENTS THE CURRENT STATUS OF THE CROSSTALK OF HISTONE ACETYLATION AND MIRNAS IN HUMAN CARCINOGENESIS AND CHRONIC DISEASES. AREAS COVERED: THIS ARTICLE REVIEWS INFORMATION FROM COMPREHENSIVE PUBMED SEARCHES TO EVALUATE RELEVANT LITERATURE WITH A FOCUS ON POSSIBLE ASSOCIATION BETWEEN HISTONE ACETYLATION, MIRNAS AND THEIR TARGETS. OUR ANALYSIS IDENTIFIED SPECIFIC MIRNAS WHICH COLLABORATE WITH HISTONE DEACETYLASES (HDACS) AND COOPERATIVELY REGULATE SEVERAL RELEVANT TARGET GENES. EXPERT OPINION: FOURTEEN MIRNAS COULD BE LINKED TO THE EXPRESSION OF EIGHT HDACS INFLUENCING THE ALPHA-(1,6)-FUCOSYLTRANSFERASE, POLYCYSTIN-2 AND THE FIBROBLAST-GROWTH-FACTOR 2 PATHWAYS. FOCUSING ON THE COMPLEX LINKAGE OF MIRNA AND HDAC EXPRESSION COULD GIVE DEEPER INSIGHTS IN NEW 'DRUGGABLE' TARGETS AND MIGHT PROVIDE POSSIBLE NOVEL THERAPEUTIC APPROACHES IN FUTURE. 2015 18 4693 29 NEXT GENERATION OF TARGETED MOLECULES FOR NON-HODGKIN LYMPHOMAS: SMALL-MOLECULE INHIBITORS OF INTRACELLULAR TARGETS AND SIGNALING PATHWAYS. ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF B-CELL LYMPHOMA HAVE GUIDED THE DEVELOPMENT OF TARGETED THERAPIES THAT DISRUPT ABERRANT SIGNALING PATHWAYS IMPORTANT FOR COMMUNICATION WITHIN LYMPHOMA CELLS AND FOR THEIR INTERACTIONS WITH THE TUMOR MICROENVIRONMENT. THIS HAS LED TO UNPRECEDENTED THERAPEUTIC PROGRESS, WITH BIOLOGIC AGENTS THAT HAVE BEGUN TO TRANSFORM THE CARE OF PATIENTS WITH LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA. THIS REVIEW DISCUSSES THE MECHANISMS OF ACTION, CLINICAL DEVELOPMENT, AND EMERGING APPLICATIONS OF SMALL-MOLECULE INHIBITORS THAT TARGET B-CELL RECEPTOR SIGNALING PATHWAYS, B-CELL LYMPHOMA-2 INHIBITORS, SELECTIVE INHIBITORS OF NUCLEAR EXPORT, AND EPIGENETIC MODIFIERS. 2016 19 5291 30 PROSTATE CARCINOGENESIS: INSIGHTS IN RELATION TO EPIGENETICS AND INFLAMMATION. PROSTATE CANCER IS A MULTIFACTORIAL DISEASE THAT MAINLY OCCURS DUE TO THE ACCUMULATION OF SOMATIC, GENETIC, AND EPIGENETIC CHANGES, RESULTING IN THE INACTIVATION OF TUMOR-SUPPRESSOR GENES AND ACTIVATION OF ONCOGENES. MUTATIONS IN GENES, SPECIFICALLY THOSE THAT CONTROL CELL GROWTH AND DIVISION OR THE REPAIR OF DAMAGED DNA, MAKE THE CELLS GROW AND DIVIDE UNCONTROLLABLY TO FORM A TUMOR. THE RISK OF DEVELOPING PROSTATE CANCER DEPENDS UPON THE GENE THAT HAS UNDERGONE THE MUTATION. IDENTIFYING SUCH GENETIC RISK FACTORS FOR PROSTATE CANCER POSES A CHALLENGE FOR THE RESEARCHERS. BESIDES GENETIC MUTATIONS, MANY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS (METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION) NUCLEOSOMAL REMODELING, AND CHROMOSOMAL LOOPING, HAVE SIGNIFICANTLY CONTRIBUTED TO THE ONSET OF PROSTATE CANCER AS WELL AS THE PROGNOSIS, DIAGNOSIS, AND TREATMENT OF PROSTATE CANCER. CHRONIC INFLAMMATION ALSO PLAYS A MAJOR ROLE IN THE ONSET AND PROGRESSION OF HUMAN CANCER, VIA MODIFICATIONS IN THE TUMOR MICROENVIRONMENT BY INITIATING EPITHELIALMESENCHYMAL TRANSITION AND REMODELING THE EXTRACELLULAR MATRIX. IN THIS ARTICLE, THE AUTHORS PRESENT A BRIEF HISTORY OF THE MECHANISMS AND POTENTIAL LINKS BETWEEN THE GENETIC ABERRATIONS, EPIGENETIC CHANGES, INFLAMMATION, AND INFLAMMASOMES THAT ARE KNOWN TO CONTRIBUTE TO THE PROGNOSIS OF PROSTATE CANCER. FURTHERMORE, THE AUTHORS EXAMINE AND DISCUSS THE CLINICAL POTENTIAL OF PROSTATE CARCINOGENESIS IN RELATION TO EPIGENETICS AND INFLAMMATION FOR ITS DIAGNOSIS AND TREATMENT.. 2021 20 2014 34 EPIGENETIC BIOMARKERS FOR THE DIAGNOSIS AND TREATMENT OF LIVER DISEASE. RESEARCH IN THE LAST DECADES HAS DEMONSTRATED THE RELEVANCE OF EPIGENETICS IN CONTROLLING GENE EXPRESSION TO MAINTAIN CELL HOMEOSTASIS, AND THE IMPORTANT ROLE PLAYED BY EPIGENOME ALTERATIONS IN DISEASE DEVELOPMENT. MOREOVER, THE REVERSIBILITY OF EPIGENETIC MARKS CAN BE HARNESSED AS A THERAPEUTIC STRATEGY, AND EPIGENETIC MARKS CAN BE USED AS DIAGNOSIS BIOMARKERS. EPIGENETIC ALTERATIONS IN DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS), AND NON-CODING RNA (NCRNA) EXPRESSION HAVE BEEN ASSOCIATED WITH THE PROCESS OF HEPATOCARCINOGENESIS. HERE, WE SUMMARIZE EPIGENETIC ALTERATIONS INVOLVED IN THE PATHOGENESIS OF CHRONIC LIVER DISEASE (CLD), PARTICULARLY FOCUSING ON DNA METHYLATION. WE ALSO DISCUSS THEIR UTILITY AS EPIGENETIC BIOMARKERS IN LIQUID BIOPSY FOR THE DIAGNOSIS AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA (HCC). FINALLY, WE DISCUSS THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES FOR HCC TREATMENT. 2021