1 791 128 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017 2 4436 30 MOLECULAR EVOLUTION OF CHRONIC MYELOID LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL DISORDER OF THE PLURIPOTENT HAEMATOPOIETIC STEM CELL. THE TYPICAL TRIPHASIC COURSE OF CML STARTS WITH THE PREMALIGNANT CHRONIC PHASE INITIATED BY BCR-ABL HYBRID ONCOGENE FORMATION. SECONDARY GENETIC AND EPIGENETIC ABERRATIONS ACCOMPANY THE PROGRESSION TO THE ACCELERATED PHASE AND FATAL BLASTIC CRISIS. PROPERLY TIMED BONE MARROW TRANSPLANTATION IN ELIGIBLE PATIENTS CAN RESULT IN DURABLE REMISSIONS OR CURE. BOTH OF THESE STATES ARE OFTEN ACCOMPANIED BY A LONG-TERM PERSISTENCE OF QUIESCENT LEUKAEMIC CELLS. ACCORDINGLY, A "FUNCTIONAL CURE" (I.E. TUMOUR DORMANCY INDUCTION), RATHER THAN COMPLETE ERADICATION OF THE MALIGNANT CELLS, IS AN ADEQUATE THERAPEUTICAL GOAL. THE LEVEL OF THE RESIDUAL BCR-ABL-POSITIVE CLONES SHOULD BE MONITORED AND SALVAGE TREATMENT INITIATED WHENEVER THESE QUIESCENT LEUKAEMIC CELLS EXIT THEIR DORMANT STATE. 2001 3 6573 30 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 4 955 36 CHRONIC MYELOID LEUKEMIA: MECHANISMS OF BLASTIC TRANSFORMATION. THE BCR-ABL1 ONCOPROTEIN TRANSFORMS PLURIPOTENT HSCS AND INITIATES CHRONIC MYELOID LEUKEMIA (CML). PATIENTS WITH EARLY PHASE (ALSO KNOWN AS CHRONIC PHASE [CP]) DISEASE USUALLY RESPOND TO TREATMENT WITH ABL TYROSINE KINASE INHIBITORS (TKIS), ALTHOUGH SOME PATIENTS WHO RESPOND INITIALLY LATER BECOME RESISTANT. IN MOST PATIENTS, TKIS REDUCE THE LEUKEMIA CELL LOAD SUBSTANTIALLY, BUT THE CELLS FROM WHICH THE LEUKEMIA CELLS ARE DERIVED DURING CP (SO-CALLED LEUKEMIA STEM CELLS [LSCS]) ARE INTRINSICALLY INSENSITIVE TO TKIS AND SURVIVE LONG TERM. LSCS OR THEIR PROGENY CAN ACQUIRE ADDITIONAL GENETIC AND/OR EPIGENETIC CHANGES THAT CAUSE THE LEUKEMIA TO TRANSFORM FROM CP TO A MORE ADVANCED PHASE, WHICH HAS BEEN SUBCLASSIFIED AS EITHER ACCELERATED PHASE OR BLASTIC PHASE DISEASE. THE LATTER RESPONDS POORLY TO TREATMENT AND IS USUALLY FATAL. HERE, WE DISCUSS WHAT IS KNOWN ABOUT THE MOLECULAR MECHANISMS LEADING TO BLASTIC TRANSFORMATION OF CML AND PROPOSE SOME NOVEL THERAPEUTIC APPROACHES. 2010 5 6320 29 THE ROCKY ROAD TO PERSONALIZED MEDICINE IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS A MALIGNANT DISORDER OF THE MYELOID BLOOD LINEAGE CHARACTERIZED BY IMPAIRED DIFFERENTIATION AND INCREASED PROLIFERATION OF HEMATOPOIETIC PRECURSOR CELLS. RECENT TECHNOLOGICAL ADVANCES HAVE LED TO AN IMPROVED UNDERSTANDING OF AML BIOLOGY BUT ALSO UNCOVERED THE ENORMOUS CYTOGENETIC AND MOLECULAR HETEROGENEITY OF THE DISEASE. DESPITE THIS HETEROGENEITY, AML IS MOSTLY MANAGED BY A 'ONE-SIZE-FITS-ALL' APPROACH CONSISTING OF INTENSIVE, HIGHLY TOXIC INDUCTION AND CONSOLIDATION CHEMOTHERAPY. THESE TREATMENT PROTOCOLS HAVE REMAINED LARGELY UNCHANGED FOR THE PAST SEVERAL DECADES AND ONLY LEAD TO A CURE IN APPROXIMATELY 30-35% OF CASES. THE ADVENT OF TARGETED THERAPIES IN CHRONIC MYELOID LEUKAEMIA AND OTHER MALIGNANCIES HAS SPARKED HOPE TO IMPROVE PATIENT OUTCOME IN AML. HOWEVER, THE IMPLEMENTATION OF TARGETED AGENTS IN AML THERAPY HAS BEEN UNEXPECTEDLY CUMBERSOME AND REMAINS A DIFFICULT TASK DUE TO A VARIETY OF DISEASE- AND PATIENT-SPECIFIC FACTORS. IN THIS REVIEW, WE DESCRIBE CURRENT STANDARD AND INVESTIGATIONAL THERAPEUTIC STRATEGIES WITH A FOCUS ON TARGETED AGENTS AND HIGHLIGHT POTENTIAL TOOLS THAT MIGHT FACILITATE THE DEVELOPMENT OF TARGETED THERAPIES FOR THIS FATAL DISEASE. THE CLASSES OF AGENTS DESCRIBED IN THIS REVIEW INCLUDE CONSTITUTIVELY ACTIVATED SIGNALLING PATHWAY INHIBITORS, SURFACE RECEPTOR TARGETS, EPIGENETIC MODIFIERS, DRUGS TARGETING THE INTERACTION OF THE HEMATOPOIETIC PROGENITOR CELL WITH THE STROMA AND DRUGS THAT TARGET THE APOPTOTIC MACHINERY. THE CLINICAL CONTEXT AND OUTCOME WITH THESE AGENTS WILL BE EXAMINED TO GAIN INSIGHT ABOUT THEIR OPTIMAL UTILIZATION. 2018 6 4480 27 MOLECULAR PATHWAYS AND ROLE OF EPIGENETICS IN THE IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A FATAL LUNG DISEASE WITH UNKNOWN ETIOLOGICAL FACTORS THAT CAN PROGRESS TO OTHER DANGEROUS DISEASES LIKE LUNG CANCER. ENVIRONMENTAL AND GENETIC PREDISPOSITION ARE THE TWO MAJOR ETIOLOGICAL OR RISK FACTORS INVOLVED IN THE PATHOLOGY OF THE IPF. AMONG THE ENVIRONMENTAL RISK FACTORS, SMOKING IS ONE OF THE MAJOR CAUSES FOR THE DEVELOPMENT OF IPF. EPIGENETIC PATHWAYS LIKE NUCLEOSOMES REMODELING, DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA MEDIATED GENES PLAY A CRUCIAL ROLE IN DEVELOPMENT OF IPF. MUTATIONS IN THE GENES MAKE THE EPIGENETIC FACTORS AS IMPORTANT DRUG TARGETS IN IPF. TRANSCRIPTIONAL CHANGES DUE TO ENVIRONMENTAL FACTORS ARE ALSO INVOLVED IN THE PROGRESSION OF IPF. THE MUTATIONS IN HUMAN TELOMERASE REVERSE TRANSCRIPTASE (HTERT) HAVE SHOWN DECREASED LIFE EXPECTANCY IN IPF PATIENTS. THE TERT-GENE IS HIGHLY EXPRESSED IN CHRONIC SMOKERS AND MAKES THE ROLE OF EPIGENETICS EVIDENT. DRUG LIKE NINTEDANIB ACTS THROUGH VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS (VEGFR), WHILE DRUG PIRFENIDONE ACTS THROUGH TRANSFORMING GROWTH FACTOR (TGF), WHICH IS USEFUL IN IPF. GEFITINIB, A TYROSINE KINASE INHIBITOR OF EGFR, IS USEFUL AS AN ANTI-FIBROSIS AGENT IN PRECLINICAL MODELS. NEWER DRUGS SUCH AS CELGENE-CC90001 AND FIBROGEN-FG-3019 ARE CURRENTLY UNDER INVESTIGATIONS ACTS THROUGH THE MODULATING EPIGENETIC MECHANISMS. THUS, THE STUDY ON EPIGENETICS OPENS A WIDE WINDOW FOR THE DISCOVERY OF NEWER DRUGS. THIS STUDY PROVIDES AN ELEMENTARY ANALYSIS OF MULTIPLE REGULATORS OF EPIGENETICS AND THEIR ROLES ASSOCIATED WITH THE PATHOLOGY OF IPF. FURTHER, THIS REVIEW ALSO INCLUDES EPIGENETIC DRUGS UNDER DEVELOPMENT IN PRECLINICAL AND CLINICAL STAGES. 2022 7 6609 35 TYROSINE KINASE INHIBITORS IN PH+ CHRONIC MYELOID LEUKEMIA THERAPY: A REVIEW. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL MYELOPROLIFERATIVE HEMATOPOIETIC STEM CELL DISORDER. DEREGULATED BCRABL FUSION TYROSINE KINASE ACTIVITY IS THE MAIN CAUSE OF CML DISEASE PATHOGENESIS, MAKING BCRABL AN IDEAL TARGET FOR INHIBITION. CURRENT TYROSINE KINASE INHIBITORS (TKIS) DESIGNED TO INHIBIT BCRABL ONCOPROTEIN ACTIVITY, HAVE COMPLETELY TRANSFORMED THE PROGNOSIS OF CML. INTERRUPTION OF TKI TREATMENT LEADS TO MINIMAL RESIDUAL DISEASE RESIDE (MRD), THOUGHT TO RESIDE IN TKIINSENSITIVE LEUKAEMIA STEM CELLS WHICH REMAIN A POTENTIAL RESERVOIR FOR DISEASE RELAPSE. THIS HIGHLIGHTS THE NEED TO DEVELOP NEW THERAPEUTIC STRATEGIES FOR CML EITHER AS SMALL MOLECULE MASTER TKIS OR PHYTOPHARMACEUTICALS DERIVED FROM NATURE TO ACHIEVE CHRONIC MOLECULAR REMISSION. THIS REVIEW OUTLINES THE PAST, PRESENT AND FUTURE THERAPEUTIC APPROACHES FOR CML INCLUDING COVERAGE OF RELEVANT MECHANISMS, WHETHER ABL DEPENDENT OR INDEPENDENT, AND EPIGENETIC FACTORS RESPONSIBLE FOR DEVELOPING RESISTANCE AGAINST TKIS. APPEARANCE OF MUTANT CLONES ALONG THE COURSE OF THERAPY EITHER PREEXISTING OR INDUCED DUE TO THERAPY IS STILL A CHALLENGE FOR THE CLINICIAN. A PROPOSED INVITRO MODEL OF GENERATING COLONY FORMING UNITS FROM CML STEM CELLS DERIVED FROM DIAGNOSTIC SAMPLES SEEMS TO BE ACHIEVABLE IN THE ERA OF HIGH THROUGHPUT TECHNOLOGY WHICH CAN TAKE CARE OF SINGLE CELL GENOMIC PROFILING. 2016 8 261 36 ADVANCES IN TARGET THERAPY FOR LUNG CANCER. RECENT PROGRESS IN MOLECULAR BIOLOGY HAS SHOWN THAT CANCER CELLS ACQUIRE COMMON PHENOTYPES SUCH AS SELF-SUFFICIENCY OF GROWTH SIGNALS, RESISTANCE TO ANTI-PROLIFERATIVE AND APOPTOTIC SIGNALS THROUGH THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES. RECENTLY DEVELOPED ANTICANCER DRUGS TARGET THESE MOLECULAR MECHANISMS AND GOOD RESULTS HAVE BEEN REPORTED FOR VARIOUS CANCER TYPES. IN LUNG CANCER, TYROSINE KINASE INHIBITORS SPECIFIC FOR THE EPIDERMAL GROWTH FACTOR RECEPTOR SUCH AS GEFITINIB AND ERLOTINIB HAVE CHANGED CLINICAL PRACTICE DRAMATICALLY. ABOUT HALF OF THE JAPANESE PATIENTS WITH LUNG CANCERS HARBOR AN ACTIVATING MUTATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR GENE AND THEY ARE VERY SENSITIVE TO EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS. PROGRESSION-FREE SURVIVAL OF SUCH PATIENTS IS APPROXIMATELY 10 MONTHS WHEN TREATED WITH GEFITINIB, WHEREAS THE SURVIVAL FOR THOSE TREATED WITH PLATINUM DOUBLET THERAPY IS APPROXIMATELY 6 MONTHS. TARGET THERAPIES AGAINST ECHINODERM MICROTUBULE-ASSOCIATED PROTEIN-LIKE 4-ANAPLASTIC LYMPHOMA KINASE FUSION PROTEIN OR A MUTATED ERBB2 (V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOGUE 2) PRESENT IN APPROXIMATELY 5% AND APPROXIMATELY 3% OF THE JAPANESE PATIENTS WITH ADENOCARCINOMAS, RESPECTIVELY, ARE CURRENTLY UNDER DEVELOPMENT. ADDITION OF AN ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY, CETUXIMAB, OR ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ANTIBODY, BEVACIZUMAB, TO PLATINUM DOUBLET THERAPY SIGNIFICANTLY BUT MODESTLY PROLONGED THE SURVIVAL IN RECENT CLINICAL TRIALS. HOWEVER, CLINICAL DEVELOPMENT OF SMALL MOLECULE MULTI-KINASE INHIBITORS INCLUDING THOSE TARGETING VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS, SUCH AS VANDETANIB, SUNITINIB AND SORAFENIB, HAS NOT BEEN VERY SUCCESSFUL. THROUGH THESE COLLABORATIONS AMONG CLINICIANS, BASIC RESEARCHERS AND PHARMACEUTICAL COMPANIES, IT SHOULD BE POSSIBLE TO INDIVIDUALIZE LUNG CANCER TREATMENT TO TURN THIS FATAL DISEASE INTO A CHRONIC DISORDER AND, EVENTUALLY, TO CURE IT. 2010 9 5769 23 SPECIFIC EPIGENETIC REGULATORS SERVE AS POTENTIAL THERAPEUTIC TARGETS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DISORDER OBSERVED MOSTLY IN OLDER HUMAN BEINGS, IS CHARACTERISED BY CHRONIC AND PROGRESSIVE LUNG SCARRING LEADING TO AN IRREVERSIBLE DECLINE IN LUNG FUNCTION. THIS HEALTH CONDITION HAS A DISMAL PROGNOSIS AND THE CURRENTLY AVAILABLE DRUGS ONLY DELAY BUT FAIL TO REVERSE THE PROGRESSION OF LUNG DAMAGE. CONSEQUENTLY, IT BECOMES IMPERATIVE TO DISCOVER IMPROVED THERAPEUTIC COMPOUNDS AND THEIR CELLULAR TARGETS TO CURE IPF. IN THIS REGARD, A NUMBER OF RECENT STUDIES HAVE TARGETED THE EPIGENETIC REGULATION BY HISTONE DEACETYLASES (HDACS) TO DEVELOP AND CATEGORISE ANTIFIBROTIC DRUGS FOR LUNGS. THEREFORE, THIS REVIEW FOCUSES ON HOW ABERRANT EXPRESSION OR ACTIVITY OF CLASSES I, II AND III HDACS ALTER TGF-BETA SIGNALLING TO PROMOTE EVENTS SUCH AS EPITHELIAL-MESENCHYMAL TRANSITION, DIFFERENTIATION OF ACTIVATED FIBROBLASTS INTO MYOFIBROBLASTS, AND EXCESS DEPOSITION OF THE EXTRACELLULAR MATRIX TO PROPEL LUNG FIBROSIS. FURTHER, THIS STUDY DESCRIBES HOW CERTAIN CHEMICAL COMPOUNDS OR DIETARY CHANGES MODULATE DYSREGULATED HDACS TO ATTENUATE FIVE FAULTY TGF-BETA-DEPENDENT PROFIBROTIC PROCESSES, BOTH IN ANIMAL MODELS AND CELL LINES REPLICATING IPF, THEREBY IDENTIFYING PROMISING MEANS TO TREAT THIS LUNG DISORDER. 2022 10 1082 34 CML - NOT ONLY BCR-ABL1 MATTERS. BCR-ABL1 IS IN THE CENTER OF CHRONIC MYELOID LEUKEMIA (CML) PATHOLOGY, DIAGNOSIS AND TREATMENT, AS CONFIRMED BY THE SUCCESS OF TYROSINE KINASE INHIBITOR (TKI) THERAPY. HOWEVER, ADDITIONAL MECHANISMS AND EVENTS, MANY OF WHICH FUNCTION INDEPENDENTLY OF BCR-ABL1, PLAY IMPORTANT ROLES, PARTICULARLY IN TERMS OF LEUKEMIC STEM CELL (LSC) PERSISTENCE, PRIMARY AND SECONDARY RESISTANCE, AND DISEASE PROGRESSION. PROMISING THERAPEUTIC APPROACHES AIM TO DISRUPT PATHWAYS WHICH MEDIATE LSC SURVIVAL DURING SUCCESSFUL TKI TREATMENT, IN THE HOPE OF IMPROVING LONG-TERM TREATMENT-FREE-REMISSION AND PERHAPS PROVIDE A FUNCTIONAL CURE FOR SOME PATIENTS. OVER THE YEARS THROUGH ADVANCES IN SEQUENCING TECHNOLOGY FREQUENT MOLECULAR ABERRATIONS IN ADDITION TO BCR-ABL1 HAVE BEEN IDENTIFIED NOT ONLY IN ADVANCED DISEASE BUT ALSO IN CHRONIC PHASE CML, OFTEN AFFECTING EPIGENETIC REGULATORS SUCH AS ASXL1, DNMT3A AND TET2. ANALYSES OF SERIAL SAMPLES HAVE REVEALED VARIOUS PATTERNS OF CLONAL EVOLUTION WITH SOME MUTATIONS PRECEDING THE BCR-ABL1 ACQUISITION. SUCH MUTATIONS CAN BE CONSIDERED TO BE IMPORTANT CO-FACTORS IN THE PATHOGENESIS OF CML AND COULD POTENTIALLY INFLUENCE THERAPEUTIC STRATEGIES IN THE FUTURE. 2020 11 6857 31 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS. 2011 12 2393 33 EPIGENETIC REPROGRAMMING AND EMERGING EPIGENETIC THERAPIES IN CML. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY BCR-ABL1, AN ONCOGENIC FUSION GENE ARISING FROM THE PHILADELPHIA CHROMOSOME. THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKIS) TO OVERCOME THE CONSTITUTIVE TYROSINE KINASE ACTIVITY OF THE BCR-ABL PROTEIN HAS DRAMATICALLY IMPROVED DISEASE MANAGEMENT AND PATIENT OUTCOMES OVER THE PAST 20 YEARS. HOWEVER, THE MAJORITY OF PATIENTS ARE NOT CURED AND DEVELOPING NOVEL THERAPEUTIC STRATEGIES THAT TARGET EPIGENETIC PROCESSES ARE A PROMISING AVENUE TO IMPROVE CURE RATES. A NUMBER OF EPIGENETIC MECHANISMS ARE ALTERED OR REPROGRAMMED DURING THE DEVELOPMENT AND PROGRESSION OF CML, RESULTING IN ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION AND DYSREGULATION OF THE TRANSCRIPTIONAL MACHINERY. IN THIS REVIEW THESE EPIGENETIC ALTERATIONS ARE EXAMINED AND THE POTENTIAL OF EPIGENETIC THERAPIES ARE DISCUSSED AS A MEANS OF ERADICATING RESIDUAL DISEASE AND OFFERING A POTENTIAL CURE FOR CML IN COMBINATION WITH CURRENT THERAPIES. 2019 13 953 36 CHRONIC MYELOID LEUKEMIA STEM CELLS. ALTHOUGH RARE, CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE MOLECULAR EVENTS LEADING TO MALIGNANT TRANSFORMATION OF PRIMITIVE HEMATOPOIETIC PROGENITORS. CML WAS THE FIRST CANCER TO BE ASSOCIATED WITH A DEFINED GENETIC ABNORMALITY, BCR-ABL, THAT IS NECESSARY AND SUFFICIENT FOR INITIATING CHRONIC PHASE DISEASE AS WELL AS THE FIRST CANCER TO BE TREATED WITH MOLECULAR TARGETED THERAPY. MALIGNANT PROGENITORS OR LEUKEMIA STEM CELLS (LSCS) EVOLVE AS A RESULT OF BOTH EPIGENETIC AND GENETIC EVENTS THAT ALTER HEMATOPOIETIC PROGENITOR DIFFERENTIATION, PROLIFERATION, SURVIVAL, AND SELF-RENEWAL. LSCS ARE RARE AND DIVIDE LESS FREQUENTLY, AND THUS, REPRESENT A RESERVOIR FOR RELAPSE AND RESISTANCE TO A MOLECULARLY TARGETED SINGLE AGENT. ON SUBVERTING DEVELOPMENTAL PROCESSES NORMALLY RESPONSIBLE FOR MAINTAINING ROBUST LIFE-LONG HEMATOPOIESIS, THE LSCS ARE ABLE TO EVADE THE MAJORITY OF CURRENT CANCER TREATMENTS THAT TARGET RAPIDLY DIVIDING CELLS. ENTHUSIASM FOR THE ENORMOUS SUCCESS OF TYROSINE KINASE INHIBITORS AT CONTROLLING THE CHRONIC PHASE DISEASE IS TEMPERED SOMEWHAT BY THE PERSISTENCE OF THE LSC POOL IN THE MAJORITY OF THE PATIENTS. COMBINED THERAPIES TARGETING ABERRANT PROPERTIES OF LSC MAY OBVIATE THERAPEUTIC RESISTANCE AND RELAPSE IN ADVANCED PHASE AND THERAPEUTICALLY RECALCITRANT CML. 2008 14 4552 31 MUTATIONAL LANDSCAPE OF CHRONIC MYELOID LEUKEMIA: MORE THAN A SINGLE ONCOGENE LEUKEMIA. THE BCR-ABL1 FUSION GENE, WHICH CAUSES ABERRANT KINASE ACTIVITY AND UNCONTROLLED CELL PROLIFERATION, IS THE HALLMARK OF CHRONIC MYELOID LEUKEMIA (CML). THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKI) THAT TARGET THE BCR-ABL ONCOPROTEIN HAS LED TO DRAMATIC IMPROVEMENT IN CML MANAGEMENT. HOWEVER, SOME CHALLENGES REMAIN TO BE ADDRESSED IN THE TKI ERA, INCLUDING PATIENT STRATIFICATION AND THE SELECTION OF FRONTLINE TKIS AND CML PROGRESSION. ADDITIONALLY, WITH THE EMERGING GOAL OF TREATMENT-FREE REMISSION (TFR) IN CML MANAGEMENT, BIOMARKERS THAT PREDICT THE OUTCOMES OF STOPPING TKI REMAIN TO BE IDENTIFIED. NOTABLY, RECENT REPORTS HAVE REVEALED THE POWER OF GENOME SCREENING IN UNDERSTANDING THE ROLE OF GENOME ABERRATIONS OTHER THAN BCR-ABL1 IN CML PATHOGENESIS. THESE STUDIES HAVE DISCOVERED THE PRESENCE OF DISEASE-PHASE SPECIFIC MUTATIONS AND LINKED CERTAIN MUTATIONS TO INFERIOR RESPONSES TO TKI TREATMENT AND CML PROGRESSION. A PERSONALIZED APPROACH THAT INCORPORATES GENETIC DATA IN TAILORING TREATMENT STRATEGIES HAS BEEN SUCCESSFULLY IMPLEMENTED IN ACUTE LEUKEMIA, AND IT REPRESENTS A PROMISING APPROACH FOR THE MANAGEMENT OF HIGH-RISK CML PATIENTS. IN THIS ARTICLE, WE WILL REVIEW CURRENT KNOWLEDGE ABOUT THE MUTATIONAL PROFILE IN DIFFERENT PHASES OF CML AS WELL AS PATTERNS OF MUTATIONAL DYNAMICS IN PATIENTS HAVING DIFFERENT OUTCOMES. WE HIGHLIGHT THE EFFECTS OF SOMATIC MUTATIONS INVOLVING CERTAIN GENES (E.G. EPIGENETIC MODIFIERS) ON THE OUTCOMES OF TKI TREATMENT. WE ALSO DISCUSS THE POTENTIAL VALUE OF INCORPORATING GENETIC DATA IN TREATMENT DECISIONS AND THE ROUTINE CARE OF CML PATIENTS AS A FUTURE DIRECTION FOR OPTIMIZING CML MANAGEMENT. 2021 15 3513 24 IDIOPATHIC PULMONARY FIBROSIS: PATHOGENESIS AND MANAGEMENT. BACKGROUND: IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE DISEASE CHARACTERIZED BY THE ABERRANT ACCUMULATION OF FIBROTIC TISSUE IN THE LUNGS PARENCHYMA, ASSOCIATED WITH SIGNIFICANT MORBIDITY AND POOR PROGNOSIS. THIS REVIEW WILL PRESENT THE SUBSTANTIAL ADVANCES ACHIEVED IN THE UNDERSTANDING OF IPF PATHOGENESIS AND IN THE THERAPEUTIC OPTIONS THAT CAN BE OFFERED TO PATIENTS, AND WILL ADDRESS THE ISSUES REGARDING DIAGNOSIS AND MANAGEMENT THAT ARE STILL OPEN. MAIN BODY: OVER THE LAST TWO DECADES MUCH HAS BEEN CLARIFIED ABOUT THE PATHOGENIC PATHWAYS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF THE LUNG SCARRING IN IPF. SUSTAINED ALVEOLAR EPITHELIAL MICRO-INJURY AND ACTIVATION HAS BEEN RECOGNISED AS THE TRIGGER OF SEVERAL BIOLOGICAL EVENTS OF DISORDERED REPAIR OCCURRING IN GENETICALLY SUSCEPTIBLE AGEING INDIVIDUALS. DESPITE MULTIDISCIPLINARY TEAM DISCUSSION HAS DEMONSTRATED TO INCREASE DIAGNOSTIC ACCURACY, PATIENTS CAN STILL REMAIN UNCLASSIFIED WHEN THE CURRENT DIAGNOSTIC CRITERIA ARE STRICTLY APPLIED, REQUIRING THE IDENTIFICATION OF A USUAL INTERSTITIAL PATTERN EITHER ON HIGH-RESOLUTION COMPUTED TOMOGRAPHY SCAN OR LUNG BIOPSY. OUTSTANDING ACHIEVEMENTS HAVE BEEN MADE IN THE MANAGEMENT OF THESE PATIENTS, AS NINTEDANIB AND PIRFENIDONE CONSISTENTLY PROVED TO REDUCE THE RATE OF PROGRESSION OF THE FIBROTIC PROCESS. HOWEVER, MANY UNCERTAINTIES STILL LIE IN THE CORRECT USE OF THESE DRUGS, RANGING FROM THE INITIAL CHOICE OF THE DRUG, THE APPROPRIATE TIMING FOR TREATMENT AND THE BENEFIT-RISK RATIO OF A COMBINED TREATMENT REGIMEN. SEVERAL NOVEL COMPOUNDS ARE BEING DEVELOPED IN THE PERSPECTIVE OF A MORE TARGETED THERAPEUTIC APPROACH; IN THE MEANTIME, THE SUPPORTIVE CARE OF THESE PATIENTS AND THEIR CARERS SHOULD BE APPROPRIATELY PRIORITIZED, AND GREATER EFFORTS SHOULD BE MADE TOWARD THE PROMPT IDENTIFICATION AND MANAGEMENT OF RELEVANT COMORBIDITIES. CONCLUSIONS: BUILDING ON THE ADVANCES IN THE UNDERSTANDING OF IPF PATHOBIOLOGY, THE FURTHER INVESTIGATION OF THE ROLE OF GENE VARIANTS, EPIGENETIC ALTERATIONS AND OTHER MOLECULAR BIOMARKERS REFLECTING DISEASE ACTIVITY AND BEHAVIOUR WILL HOPEFULLY ENABLE EARLIER AND MORE CONFIDENT DIAGNOSIS, IMPROVE DISEASE PHENOTYPING AND SUPPORT THE DEVELOPMENT OF NOVEL AGENTS FOR PERSONALIZED TREATMENT OF IPF. 2018 16 952 36 CHRONIC MYELOID LEUKEMIA STEM CELL BIOLOGY. LEUKEMIA PROGRESSION AND RELAPSE IS FUELED BY LEUKEMIA STEM CELLS (LSC) THAT ARE RESISTANT TO CURRENT TREATMENTS. IN THE PROGRESSION OF CHRONIC MYELOID LEUKEMIA (CML), BLAST CRISIS PROGENITORS ARE CAPABLE OF ADOPTING MORE PRIMITIVE BUT DEREGULATED STEM CELL FEATURES WITH ACQUIRED RESISTANCE TO TARGETED THERAPIES. THIS IN TURN PROMOTES LSC BEHAVIOR CHARACTERIZED BY ABERRANT SELF-RENEWAL, DIFFERENTIATION, AND SURVIVAL CAPACITY. MULTIPLE REPORTS SUGGEST THAT CELL CYCLE ALTERATIONS, ACTIVATION OF CRITICAL SIGNALING PATHWAYS, ABERRANT MICROENVIRONMENTAL CUES FROM THE HEMATOPOIETIC NICHE, AND ABERRANT EPIGENETIC EVENTS AND DEREGULATION OF RNA PROCESSING MAY FACILITATE THE ENHANCED SURVIVAL AND MALIGNANT TRANSFORMATION OF CML PROGENITORS. HERE WE REVIEW THE MOLECULAR EVOLUTION OF CML LSC THAT PROMOTES CML PROGRESSION AND RELAPSE. RECENT ADVANCES IN THESE AREAS HAVE IDENTIFIED NOVEL TARGETS THAT REPRESENT IMPORTANT AVENUES FOR FUTURE THERAPEUTIC APPROACHES AIMED AT SELECTIVELY ERADICATING THE LSC POPULATION WHILE SPARING NORMAL HEMATOPOIETIC PROGENITORS IN PATIENTS SUFFERING FROM CHRONIC MYELOID MALIGNANCIES. 2012 17 4450 25 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION. 2021 18 1685 38 DRUGGABLE BIOCHEMICAL PATHWAYS AND POTENTIAL THERAPEUTIC ALTERNATIVES TO TARGET LEUKEMIC STEM CELLS AND ELIMINATE THE RESIDUAL DISEASE IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A DISEASE ARISING IN STEM CELLS EXPRESSING THE BCR-ABL ONCOGENIC TYROSINE KINASE THAT TRANSFORMS ONE HEMATOPOIETIC STEM/PROGENITOR CELL INTO A LEUKEMIC STEM CELL (LSC) AT THE ORIGIN OF DIFFERENTIATED AND PROLIFERATING LEUKEMIC CELLS IN THE BONE MARROW (BM). CML-LSCS ARE RECOGNIZED AS BEING RESPONSIBLE FOR RESISTANCES AND RELAPSES THAT OCCUR DESPITE THE ADVENT OF BCR-ABL-TARGETING THERAPIES WITH TYROSINE KINASE INHIBITORS (TKIS). LSCS SHARE A LOT OF FUNCTIONAL PROPERTIES WITH HEMATOPOIETIC STEM CELLS (HSCS) ALTHOUGH SOME PHENOTYPICAL AND FUNCTIONAL DIFFERENCES HAVE BEEN DESCRIBED DURING THE LAST TWO DECADES. SUBVERTED MECHANISMS AFFECTING EPIGENETIC PROCESSES, APOPTOSIS, AUTOPHAGY AND MORE RECENTLY METABOLISM AND IMMUNOLOGY IN THE BONE MARROW MICROENVIRONMENT (BMM) HAVE BEEN REPORTED. THE AIM OF THIS REVIEW IS TO BRING TOGETHER THE MODIFICATIONS AND MOLECULAR MECHANISMS THAT ARE KNOWN TO ACCOUNT FOR TKI RESISTANCE IN PRIMARY CML-LSCS AND TO FOCUS ON THE POTENTIAL SOLUTIONS THAT CAN CIRCUMVENT THESE RESISTANCES, IN PARTICULAR THOSE THAT HAVE BEEN, OR WILL BE TESTED IN CLINICAL TRIALS. 2019 19 6198 31 THE IMPLICATION OF CANCER PROGENITOR CELLS AND THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR CHRONIC MYELOID LEUKEMIA. SIGNIFICANCE: CHRONIC MYELOID LEUKEMIA (CML) INVOLVES THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS, DEFINED LARGELY BY THE PHILADELPHIA CHROMOSOME AND EXPRESSION OF THE BREAKPOINT CLUSTER REGION-ABELSON (BCR-ABL) ONCOPROTEIN. PHARMACOLOGICAL TYROSINE KINASE INHIBITORS (TKIS), INCLUDING IMATINIB MESYLATE, HAVE OVERCOME LIMITATIONS IN CONVENTIONAL TREATMENT FOR THE IMPROVED CLINICAL MANAGEMENT OF CML. RECENT ADVANCES: ACCUMULATED EVIDENCE HAS LED TO THE IDENTIFICATION OF A SUBPOPULATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS WITH STEM-LIKE SELF RENEWAL PROPERTIES THAT MAY INITIATE LEUKEMOGENESIS, WHICH ARE ALSO SHOWN TO BE PRESENT IN RESIDUAL DISEASE DUE TO THEIR INSENSITIVITY TO TYROSINE KINASE INHIBITION. CRITICAL ISSUES: THE CHARACTERIZATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS AS A UNIQUE CELL POPULATION IN CML PATHOGENESIS HAS BECOME CRITICAL WITH THE COMPLETE ELUCIDATION OF MECHANISMS INVOLVED IN THEIR SURVIVAL INDEPENDENT OF BCR-ABL THAT IS IMPORTANT IN THE DEVELOPMENT OF NOVEL ANTICANCER STRATEGIES. UNDERSTANDING OF THESE FUNCTIONAL PATHWAYS IN CML PROGENITOR CELLS WILL ALLOW FOR THEIR SELECTIVE THERAPEUTIC TARGETING. IN ADDITION, DISEASE PATHOGENESIS AND DRUG RESPONSIVENESS IS ALSO THOUGHT TO BE MODULATED BY EPIGENETIC REGULATORY MECHANISMS SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION, WITH A CAPACITY TO CONTROL CML-ASSOCIATED GENE TRANSCRIPTION. FUTURE DIRECTIONS: A NUMBER OF COMPOUNDS IN COMBINATION WITH TKIS ARE UNDER PRECLINICAL AND CLINICAL INVESTIGATION TO ASSESS THEIR SYNERGISTIC POTENTIAL IN TARGETING LEUKEMIC PROGENITOR CELLS AND/OR THE EPIGENOME IN CML. DESPITE THE COLLECTIVE PROMISE, FURTHER RESEARCH IS REQUIRED IN ORDER TO REFINE UNDERSTANDING, AND, ULTIMATELY, ADVANCE ANTILEUKEMIC THERAPEUTIC STRATEGIES. 2015 20 2720 30 EXOSOMAL MIRNAS IN HEPATITIS B VIRUS RELATED LIVER DISEASE: A NEW HOPE FOR BIOMARKER. THE WORLD HEALTH ORGANISATION, IN ITS 2019 PROGRESS REPORT ON HIV, VIRAL HEPATITIS AND STDS INDICATES THAT 257 MILLION PEOPLE ARE AFFLICTED WITH CHRONIC HBV INFECTIONS, OF WHICH, 1 MILLION PATIENTS LOSE THEIR LIVES EVERY YEAR DUE TO HBV RELATED CHRONIC LIVER DISEASES INCLUDING SERIOUS COMPLICATIONS SUCH AS LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. THE COURSE OF HBV INFECTION AND ASSOCIATED LIVER INJURY DEPEND ON SEVERAL HOST FACTORS, GENETIC VARIABILITY OF THE VIRUS, AND THE HOST VIRAL INTERPLAY. THE CHALLENGE OF MEDICAL SCIENCE IS THE EARLY DIAGNOSIS/IDENTIFICATION OF THE POTENTIAL FOR DEVELOPMENT OF FATAL COMPLICATIONS LIKE LIVER CIRRHOSIS AND HCC SO THAT TIMELY MEDICAL INTERVENTION CAN IMPROVE THE CHANCES OF SURVIVAL. CURRENTLY, NEITHER THE VACCINATION REGIME NOR THE DIAGNOSTIC METHODS ARE COMPLETELY EFFECTIVE AS REFLECTED IN THE HIGH NUMBER OF ANNUAL DEATHS. IT IS EVIDENT FROM NUMEROUS PUBLICATIONS THAT MICRORNAS (MIRNAS) ARE THE CRITICAL REGULATORS OF GENE EXPRESSION AND VARIOUS CELLULAR PROCESSES LIKE PROLIFERATION, DEVELOPMENT, DIFFERENTIATION, APOPTOSIS AND TUMORIGENESIS. EXPRESSIONS OF THESE DIMINUTIVE RNAS ARE SIGNIFICANTLY AFFECTED IN CANCEROUS TISSUES AS A RESULT OF NUMEROUS GENOMIC AND EPIGENETIC MODIFICATIONS. EXOSOMES ARE MEMBRANE-DERIVED VESICLES (30-100 NM) SECRETED BY NORMAL AS WELL AS MALIGNANT CELLS, AND ARE PRESENT IN ALL BODY FLUIDS. THEY ARE RECOGNIZED AS CRITICAL MOLECULES IN INTERCELLULAR COMMUNICATION BETWEEN CELLS THROUGH HORIZONTAL TRANSFER OF INFORMATION VIA THEIR CARGO, WHICH INCLUDES SELECTIVE PROTEINS, MRNAS AND MIRNAS. EXOSOMAL MIRNAS ARE TRANSFERRED TO RECIPIENT CELLS WHERE THEY CAN REGULATE TARGET GENE EXPRESSION. THIS PROVIDES AN INSIGHT INTO THE ELEMENTARY BIOLOGY OF CANCER PROGRESSION AND THEREFORE THE DEVELOPMENT OF THERAPEUTIC APPROACHES. THIS CONCISE REVIEW OUTLINES VARIOUS ON-GOING RESEARCH ON MIRNA MEDIATED REGULATION OF HBV PATHOGENESIS WITH SPECIAL EMPHASIS ON ASSOCIATION OF EXOSOMAL MIRNA IN ADVANCED STAGE LIVER DISEASE LIKE HEPATOCELLULAR CARCINOMA. THIS REVIEW ALSO DISCUSSES THE POSSIBLE USE OF EXOSOMAL MIRNAS AS BIOMARKERS IN THE EARLY DETECTION OF HCC AND LIVER CIRRHOSIS. 2020