1  4686 167 NEW THERAPEUTIC TARGETS IN TRANSFUSION-DEPENDENT AND -INDEPENDENT THALASSEMIA. BETA-THALASSEMIAS ARE CHARACTERIZED BY REDUCED PRODUCTION OF BETA-GLOBIN CHAIN, RESULTING IN ALPHA/BETA-CHAIN UNBALANCE AND PRECIPITATION OF ALPHA-GLOBIN-HEME COMPLEXES AND DETERMINING INEFFECTIVE ERYTHROPOIESIS. INEFFECTIVE ERYTHROPOIESIS, CHRONIC HEMOLYTIC ANEMIA, AND COMPENSATORY HEMATOPOIETIC EXPANSION ARE THE DISEASE HALLMARKS, AND THEY ARE RELATED TO THE SEVERITY OF THE CHAIN UNBALANCE. SEVERAL CLINICAL FORMS OF BETA-THALASSEMIA, INCLUDING THE COINHERITANCE OF BETA-THALASSEMIA WITH HEMOGLOBIN E RESULTING IN HEMOGLOBIN E/BETA-THALASSEMIA, HAVE BEEN DESCRIBED. CLINICALLY, BETA-THALASSEMIAS CAN BE CLASSIFIED AS TRANSFUSION-DEPENDENT THALASSEMIA (TDT) AND NON-TRANSFUSION-DEPENDENT THALASSEMIA (NTDT) ACCORDING TO THE SEVERITY OF THE PHENOTYPE, WHICH IS CAUSED BY A WIDE SPECTRUM OF MUTATIONS IN A HOMOZYGOUS OR COMPOUND HETEROZYGOUS STATE. CURRENT TREATMENT OF TDT CONSISTS OF REGULAR TRANSFUSIONS THAT LEAD TO IRON OVERLOAD, REQUIRING IRON CHELATION TO PREVENT IRON-RELATED ORGAN TOXICITY. NTDT PATIENTS DO NOT REQUIRE TRANSFUSIONS OR ONLY OCCASIONALLY REQUIRE THEM; HOWEVER, THEY DEVELOP IRON OVERLOAD AS WELL BECAUSE OF INCREASED INTESTINAL IRON ABSORPTION CAUSED BY CHRONIC ANEMIA. HEMATOPOIETIC STEM CELL ALLOGENIC TRANSPLANT IS THE ONLY APPROVED CURE FOR BETA-THALASSEMIA; HOWEVER, IT IS STILL LIMITED BY CLINICAL CONDITIONS AND THE AVAILABILITY OF MATCHED DONORS AS WELL AS BY POTENTIAL GRAFT-VERSUS-HOST DISEASE (GVHD). GENE THERAPY COULD AVOID THE GVHD RISK, ALTHOUGH HEMATOPOIETIC STEM CELLS MUST BE GENETICALLY MODIFIED EX VIVO. EPIGENETIC MANIPULATION AND GENOMIC EDITING ARE NOVEL EXPERIMENTAL APPROACHES. AN INCREASED UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT CONTROLS THE DISEASE PROCESS PROMPTED US TO EXPLORE ALTERNATIVE THERAPEUTIC APPROACHES THAT ADDRESS THE UNDERLYING CHAIN UNBALANCE, INEFFECTIVE ERYTHROPOIESIS, AND IRON DYSREGULATION. MOLECULES, SUCH AS JAK2 INHIBITORS AND THE ACTIVIN-RECEPTOR LIGAND TRAP THAT TARGET INEFFECTIVE ERYTHROPOIESIS, ARE ALREADY IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS AIMED TO GENERATE IRON-RESTRICTED ERYTHROPOIESIS ARE ALSO UNDER EXPERIMENTAL EVALUATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2    12  68 2017 CLINICAL TRIALS UPDATE IN NEW TREATMENTS OF BETA-THALASSEMIA. THE UNDERLYING BASIS OF BETA-THALASSEMIA PATHOLOGY IS THE DIMINISHED BETA-GLOBIN SYNTHESIS LEADING TO ALPHA-GLOBIN ACCUMULATION AND PREMATURE APOPTOTIC DESTRUCTION OF ERYTHROBLASTS, CAUSING OXIDATIVE STRESS-INDUCED INEFFECTIVE ERYTHROPOIESIS, BONE MARROW HYPERPLASIA, SPLENOMEGALY, AND INCREASED INTESTINAL IRON ABSORPTION WITH PROGRESSIVE IRON OVERLOAD. BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE LED TO THE RECOGNITION OF NEW TARGETS WITH POTENTIAL THERAPEUTIC UTILITY. AGENTS SUCH AS JAK2 INHIBITORS AND TGF-BETA LIGAND TRAPS THAT REDUCE THE INEFFECTIVE ERYTHROPOIESIS PROCESS ARE ALREADY BEING TESTED IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS THAT AIM TO REDUCE OXIDATIVE STRESS (ACTIVATORS OF FOXO3, HRI-EIF2AP, PRX2, HSP70, AND PK ANTI-OXIDANT SYSTEMS AND INHIBITORS OF HO-1) AND TO DECREASE IRON OVERLOAD (HEPCIDIN AGONISTS, ERYTHROFERRONE INHIBITORS AND EXOGENOUS TRANSFERRIN) ARE ALSO UNDER EXPERIMENTAL INVESTIGATION. SIGNIFICANT PROGRESS HAS ALSO BEEN MADE IN THE AREA OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH SEVERAL ONGOING CLINICAL TRIALS EXAMINING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONOR SELECTION AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS REACHED A CRITICAL POINT AND PHASE 1 CLINICAL TRIALS HAVE RECENTLY BEEN LAUNCHED TO EXAMINE THE EFFECTIVENESS AND ESPECIALLY LONG TERM SAFETY. EPIGENETIC MANIPULATION AND GENOMIC EDITING OF THE GAMMA- OR BETA-GLOBIN GENE ARE NOVEL AND PROMISING EXPERIMENTAL GENE THERAPY APPROACHES FOR BETA-THALASSEMIA GIVING HOPE FOR CURE FOR THIS CHRONIC DISEASE. THIS REVIEW OUTLINES THE KEY POINTS OF THE MOLECULAR MECHANISMS UNDERLYING BETA-THALASSEMIA IN RELATION TO THE DEVELOPMENT OF NEW THERAPIES AND AN UPDATE IS GIVEN BOTH AT THE PRE-CLINICAL AND CLINICAL LEVEL. AM. J. HEMATOL. 91:1135-1145, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  4753  70 NOVEL THERAPEUTIC ADVANCES IN BETA-THALASSEMIA. THE MAIN CHARACTERISTIC OF THE PATHOPHYSIOLOGY OF BETA-THALASSEMIA IS REDUCED BETA-GLOBIN CHAIN PRODUCTION. THE INEVITABLE IMBALANCE IN THE ALPHA/BETA-GLOBIN RATIO AND ALPHA-GLOBIN ACCUMULATION LEAD TO OXIDATIVE STRESS IN THE ERYTHROID LINEAGE, APOPTOSIS, AND INEFFECTIVE ERYTHROPOIESIS. THE RESULT IS COMPENSATORY HEMATOPOIETIC EXPANSION AND IMPAIRED HEPCIDIN PRODUCTION THAT CAUSES INCREASED INTESTINAL IRON ABSORPTION AND PROGRESSIVE IRON OVERLOAD. CHRONIC HEMOLYSIS AND RED BLOOD CELL TRANSFUSIONS ALSO CONTRIBUTE TO IRON TISSUE DEPOSITION. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS LED TO THE DETECTION OF NEW CURATIVE OR "DISEASE-MODIFYING" THERAPEUTIC OPTIONS. SUBSTANTIAL EVOLVEMENT HAS BEEN MADE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH CURRENT CLINICAL TRIALS INVESTIGATING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONORS AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS ALSO MOVED FORWARD, AND PHASE 2 CLINICAL TRIALS WITH THE USE OF BETA-GLOBIN INSERTION TECHNIQUES HAVE RECENTLY BEEN SUCCESSFULLY COMPLETED LEADING TO APPROVAL FOR USE IN TRANSFUSION-DEPENDENT PATIENTS. GENETIC AND EPIGENETIC MANIPULATION OF THE GAMMA- OR BETA-GLOBIN GENE HAVE ENTERED THE CLINICAL TRIAL SETTING. AGENTS SUCH AS TGF-BETA LIGAND TRAPS AND PYRUVATE KINASE ACTIVATORS, WHICH REDUCE THE INEFFECTIVE ERYTHROPOIESIS, HAVE BEEN TESTED IN CLINICAL TRIALS WITH FAVORABLE RESULTS. ONE TGF-BETA LIGAND TRAP, LUSPATERCEPT, HAS BEEN APPROVED FOR USE IN ADULTS WITH TRANSFUSION-DEPENDENT BETA-THALASSEMIA. THE INDUCTION OF HBF WITH THE PHOSPHODIESTERASE 9 INHIBITOR IMR-687, WHICH INCREASE CYCLIC GUANOSINE MONOPHOSPHATE, IS CURRENTLY BEING TESTED. ANOTHER THERAPEUTIC APPROACH IS TO TARGET THE DYSREGULATION OF IRON HOMEOSTASIS, USING, FOR EXAMPLE, HEPCIDIN AGONISTS (INHIBITORS OF TMPRSS6 AND MINIHEPCIDINS) OR FERROPORTIN INHIBITORS (VIT-2763). THIS REVIEW PROVIDES AN UPDATE ON THE NOVEL THERAPEUTIC OPTIONS THAT ARE PRESENTLY IN DEVELOPMENT AT THE CLINICAL LEVEL IN BETA-THALASSEMIA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  4660  48 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW.	2002	

5  1242  50 CURRENT AND NOVEL THERAPEUTIC APPROACHES IN MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC NEOPLASMS WITH AN ANNUAL INCIDENCE OF 4.1 CASES PER 100,000 AMERICANS. PATIENTS WITH MDS SUFFER FROM CHRONIC CYTOPENIAS THAT MAY LEAD TO RECURRENT TRANSFUSIONS, INFECTIONS, AND INCREASED RISK FOR BLEEDING. THEY ARE ALSO AT RISK FOR PROGRESSION TO ACUTE MYELOID LEUKEMIA. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IS THE ONLY POTENTIALLY CURATIVE TREATMENT FOR MDS, ALTHOUGH 3 DRUGS HAVE BEEN APPROVED BY THE US FOOD AND DRUG ADMINISTRATION FOR ITS TREATMENT: LENALIDOMIDE, 5-AZACITIDINE, AND DECITABINE. THESE THERAPIES CAN BE EFFECTIVE IN THE RELIEF OF CYTOPENIAS, ACHIEVEMENT OF CYTOGENETIC REMISSIONS, AND REDUCTION IN BONE MARROW BLASTS. 5-AZACITIDINE HAS ALSO BEEN SHOWN TO IMPROVE OVERALL SURVIVAL. HOWEVER, THERE REMAIN MANY UNMET NEEDS IN THE TREATMENT OF MDS. BREAKTHROUGHS IN OUR UNDERSTANDING OF THE COMPLEX PATHOGENESIS OF MDS THROUGH EPIGENETIC, GENETIC, IMMUNOLOGIC, AND OTHER BIOLOGICAL MECHANISMS HAVE ALLOWED US TO DEVELOP NEW THERAPEUTIC STRATEGIES THAT CAN LEAD TO IMPROVEMENTS IN OUTCOMES IN MDS. IN THIS REVIEW, WE AIM TO PROVIDE AN OVERVIEW OF THE EVOLUTION IN CLASSIFCATION AND RISK STRATIFCATION IN MDS AND TO ILLUSTRATE HOW WE CAN USE THIS TO GUIDE US IN TAILORING THERAPEUTIC CHOICES IN THIS DISEASE. RESPONSES AND OUTCOMES RELATED TO COM MONLY USED MDS THERAPIES WILL BE DISCUSSED TOGETHER WITH NOVEL THERAPIES THAT HAVE EVOLVED WITH THE IMPROVED UNDERSTANDING OF MDS PATHOPHYSIOLOGY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6  2259  31 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  3878  35 KDM6B OVEREXPRESSION ACTIVATES INNATE IMMUNE SIGNALING AND IMPAIRS HEMATOPOIESIS IN MICE. KDM6B IS AN EPIGENETIC REGULATOR THAT MEDIATES TRANSCRIPTIONAL ACTIVATION DURING DIFFERENTIATION, INCLUDING IN BONE MARROW (BM) HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS). OVEREXPRESSION OF KDM6B HAS BEEN REPORTED IN BM HSPCS OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). WHETHER THE OVEREXPRESSION OF KDM6B CONTRIBUTES TO THE PATHOGENESIS OF THESE DISEASES REMAINS TO BE ELUCIDATED. TO STUDY THIS, WE GENERATED A VAV-KDM6B MOUSE MODEL, WHICH OVEREXPRESSES KDM6B IN THE HEMATOPOIETIC COMPARTMENT. KDM6B OVEREXPRESSION ALONE LED TO MILD HEMATOPOIETIC PHENOTYPE, AND CHRONIC INNATE IMMUNE STIMULATION OF VAV-KDM6B MICE WITH THE TOLL-LIKE RECEPTOR (TLR) LIGAND LIPOPOLYSACCHARIDE (LPS) RESULTED IN SIGNIFICANT HEMATOPOIETIC DEFECTS. THESE DEFECTS RECAPITULATED FEATURES OF MDS AND CMML, INCLUDING LEUKOPENIA, DYSPLASIA, AND COMPROMISED REPOPULATING FUNCTION OF BM HSPCS. TRANSCRIPTOME STUDIES INDICATED THAT KDM6B OVEREXPRESSION ALONE COULD LEAD TO ACTIVATION OF DISEASE-RELEVANT GENES SUCH AS S100A9 IN BM HSPCS, AND WHEN COMBINED WITH INNATE IMMUNE STIMULATION, KDM6B OVEREXPRESSION RESULTED IN MORE PROFOUND OVEREXPRESSION OF INNATE IMMUNE AND DISEASE-RELEVANT GENES, INDICATING THAT KDM6B WAS INVOLVED IN THE ACTIVATION OF INNATE IMMUNE SIGNALING IN BM HSPCS. FINALLY, PHARMACOLOGIC INHIBITION OF KDM6B WITH THE SMALL MOLECULE INHIBITOR GSK-J4 AMELIORATED THE INEFFECTIVE HEMATOPOIESIS OBSERVED IN VAV-KDM6B MICE. THIS EFFECT WAS ALSO OBSERVED WHEN GSK-J4 WAS APPLIED TO THE PRIMARY BM HSPCS OF PATIENTS WITH MDS BY IMPROVING THEIR REPOPULATING FUNCTION. THESE RESULTS INDICATE THAT OVEREXPRESSION OF KDM6B MEDIATES ACTIVATION OF INNATE IMMUNE SIGNALS AND HAS A ROLE IN MDS AND CMML PATHOGENESIS, AND THAT KDM6B TARGETING HAS THERAPEUTIC POTENTIAL IN THESE MYELOID DISORDERS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  4681  31 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY).	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  5326  33 PULP INNATE IMMUNE DEFENSE: TRANSLATIONAL OPPORTUNITIES. INTRODUCTION: THE IMPROVEMENT OF REGENERATIVE ENDODONTIC PROCEDURES REQUIRES AN UNDERSTANDING OF THE KEY CLINICAL QUESTIONS COMBINED WITH A FUNDAMENTAL BIOLOGICAL KNOWLEDGE OF HOW THE DENTAL TISSUES BEHAVE DURING HEALTH, DISEASE, AND REPAIR. THEREFORE, PARTNERSHIPS BETWEEN CLINICIANS AND BASIC SCIENTISTS ARE ESSENTIAL TO DRIVE THE FIELD FORWARD AND IMPROVE PATIENT OUTCOMES. METHODS: THIS REVIEW AIMED TO PROVIDE A BACKGROUND TO DENTIN-PULP BIOLOGY AND THE INTERACTION BETWEEN INFECTION, INFLAMMATION, AND REGENERATION. RESULTS: WE HAVE HIGHLIGHTED HOW THE RELEASE OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) WITHIN THE PULP ARE DOUBLE-EDGED; WHILE THEY AIM TO LIMIT THE BACTERIAL INFECTION, THEY MAY ACTUALLY EXACERBATE CELL DEATH AND CHRONIC INFLAMMATION. ABERRANT LEVELS OF THESE STRUCTURES MAY OCCUR BECAUSE OF INEFFECTIVE HOST IMMUNOLOGIC PROCESSES, VIRAL INFECTIONS, OR IMPAIRED CLEARANCE CAUSED BY BACTERIAL VIRULENCE FACTORS. WE ALSO POSTULATE A PROINFLAMMATORY LINK IN THE PULP BETWEEN NETS AND THE INFLAMMASOME ACTIVATED BY PATHOGEN-ASSOCIATED MOLECULAR PATTERNS AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS. SUBSEQUENTLY, WE DISCUSS AREAS POTENTIALLY FRUITFUL FOR FUTURE CLINICAL EXPLOITATION INVOLVING NET INHIBITORS, INFLAMMASOME MODULATORS, PHOTOTHERAPIES, AND NOVEL EPIGENETIC APPROACHES. CONCLUSIONS: SUSTAINED SCIENTIST-CLINICIAN RESEARCH PARTNERSHIPS ALONG WITH AN INCREASED UNDERSTANDING OF THE ASSOCIATION BETWEEN INFLAMMATION AND REGENERATION WITHIN THE DENTIN-PULP COMPLEX WILL LEAD TO FUTURE PATIENT BENEFIT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  4533  38 MULTIPLE GENE KNOCKDOWN STRATEGIES FOR INVESTIGATING THE PROPERTIES OF HUMAN LEUKEMIA STEM CELLS AND EXPLORING NEW THERAPIES. THE PAST TWO DECADES HAVE WITNESSED SIGNIFICANT STRIDES IN LEUKEMIA THERAPIES THROUGH APPROVAL OF THERAPEUTIC INHIBITORS TARGETING ONCOGENE-DRIVING DYSREGULATED TYROSINE KINASE ACTIVITIES AND KEY EPIGENETIC AND APOPTOSIS REGULATORS. ALTHOUGH THESE DRUGS HAVE BROUGHT ABOUT COMPLETE REMISSION IN THE MAJORITY OF PATIENTS, MANY PATIENTS FACE RELAPSE OR HAVE REFRACTORY DISEASE. THE MAIN FACTOR CONTRIBUTING TO RELAPSE IS THE PRESENCE OF A SMALL SUBPOPULATION OF DORMANT DRUG-RESISTANT LEUKEMIA CELLS THAT POSSESS STEM CELL FEATURES (TERMED AS LEUKEMIA STEM CELLS OR LSCS). THUS, OVERCOMING DRUG RESISTANCE AND TARGETING LSCS REMAIN MAJOR CHALLENGES FOR CURATIVE TREATMENT OF HUMAN LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A GOOD EXAMPLE, WITH RARE, PROPAGATING LSCS AND DRUG-RESISTANT CELLS THAT CANNOT BE ERADICATED BY BCR-ABL-DIRECTED TYROSINE KINASE INHIBITOR (TKI) MONOTHERAPY AND THAT ARE RESPONSIBLE FOR DISEASE RELAPSE/PROGRESSION. THEREFORE, IT IS IMPERATIVE TO IDENTIFY KEY PLAYERS IN REGULATING BCR-ABL1-DEPENDENT AND INDEPENDENT DRUG-RESISTANCE MECHANISMS, AND THEIR KEY PATHWAYS, SO THAT CML LSCS CAN BE SELECTIVELY TARGETED OR SENSITIZED TO TKIS. HERE, WE DESCRIBE SEVERAL EASILY ADAPTABLE GENE KNOCKDOWN APPROACHES IN CD34(+) CML STEM/PROGENITOR CELLS THAT CAN BE USED TO INVESTIGATE THE BIOLOGICAL PROPERTIES OF LSCS AND MOLECULAR EFFECTS OF GENES OF INTEREST (GOI), WHICH CAN BE FURTHER EXPLORED AS THERAPEUTIC MODALITIES AGAINST LSCS IN THE CONTEXT OF HUMAN LEUKEMIA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  4149  25 MECHANISTIC INSIGHT INTO THE EFFECTS OF CURCUMIN ON NEUROINFLAMMATION-DRIVEN CHRONIC PAIN. CHRONIC PAIN IS A PERSISTENT AND UNREMITTING CONDITION THAT HAS IMMENSE EFFECTS ON PATIENTS' QUALITY OF LIFE. STUDIES HAVE SHOWN THAT NEUROINFLAMMATION IS ASSOCIATED WITH THE INDUCTION AND PROGRESSION OF CHRONIC PAIN. THE ACTIVATION OF MICROGLIA AND ASTROCYTES IS THE MAJOR HALLMARK OF SPINAL NEUROINFLAMMATION LEADING TO NEURONAL EXCITABILITY IN THE PROJECTION NEURONS. EXCESSIVE ACTIVATION OF MICROGLIA AND ASTROCYTES IS ONE OF THE MAJOR CONTRIBUTING FACTORS TO THE EXACERBATION OF PAIN. HOWEVER, THE CURRENT CHRONIC PAIN TREATMENTS, MAINLY BY TARGETING THE NEURONAL CELLS, REMAIN INEFFECTIVE AND UNABLE TO MEET THE PATIENTS' NEEDS. CURCUMIN, A NATURAL PLANT PRODUCT FOUND IN THE CURCUMA GENUS, IMPROVES CHRONIC PAIN BY DIMINISHING THE RELEASE OF INFLAMMATORY MEDIATORS FROM THE SPINAL GLIA. THIS REVIEW DETAILS THE ROLE OF CURCUMIN IN MICROGLIA AND ASTROCYTES BOTH IN VITRO AND IN VIVO AND HOW IT IMPROVES PAIN. WE ALSO DESCRIBE THE MECHANISM OF CURCUMIN BY HIGHLIGHTING THE MAJOR GLIA-MEDIATED CASCADES IN PAIN. MOREOVER, THE ROLE OF CURCUMIN ON INFLAMMASOME AND EPIGENETIC REGULATION IS DISCUSSED. FURTHERMORE, WE DISCUSS THE STRATEGIES USED TO IMPROVE THE EFFICACY OF CURCUMIN. THIS REVIEW ILLUSTRATES THAT CURCUMIN MODULATING MICROGLIA AND ASTROCYTES COULD ASSURE THE TREATMENT OF CHRONIC PAIN BY SUPPRESSING SPINAL NEUROINFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12  6857  44 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13   958  40 CHRONIC MYELOMONOCYTIC LEUKEMIA - A REVIEW. INTRODUCTION: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL MYELOID NEOPLASM, DENOTED BY OVERLAPPING MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES, WITH POOR OVERALL SURVIVAL AND HIGH TRANSFORMATION RATE TO ACUTE MYELOID LEUKEMIA. AREAS COVERED: THIS REVIEW, FOLLOWING A THOROUGH MEDLINE SEARCH OF PERTINENT PUBLISHED LITERATURE, DISCUSSES THE DIAGNOSTIC CRITERIA, THE PATHOGENESIS, AND THE COMPLEX GENETIC LANDSCAPE OF THE DISEASE. PROGNOSTICATION, RESPONSE CRITERIA, THERAPEUTIC MANAGEMENT OF PATIENTS, EFFICACY OF ESTABLISHED AND NOVEL TREATMENT MODALITIES ARE THOROUGHLY REVIEWED. EXPERT OPINION: CYTOGENETIC ABNORMALITIES AND MUTATIONS IN GENES INVOLVED IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION, AND CELL-SIGNALING ARE ABUNDANT IN CMML AND IMPLICATED IN ITS COMPLEX PATHOGENESIS. AS PRESENCE OF THESE MUTATIONS CARRY A PROGNOSTIC IMPACT, THEY ARE INCREASINGLY INCORPORATED IN RISK-STRATIFICATION SCHEMES. NOVEL RESPONSE CRITERIA HAVE BEEN PROPOSED, CONSIDERING THE UNIQUE FEATURES OF THE DISEASE. ALTHOUGH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION REMAINS THE ONLY TREATMENT WITH CURATIVE INTENT, IT IS RESERVED FOR A MINORITY OF PATIENTS; THEREFORE, THERE IS AN UNMET NEED FOR OPTIMIZING TREATMENT MODALITIES, SUCH AS HYPOMETHYLATING AGENTS, AND INTRODUCING NOVEL AGENTS, WHICH COULD SUBSTANTIALLY IMPROVE SURVIVAL AND QUALITY OF LIFE OF CMML PATIENTS. CLINICAL TRIALS DEDICATED SPECIFICALLY TO CMML ARE NEEDED TO EXPLORE THE EFFICACY AND SAFETY OF NOVEL TREATMENT MODALITIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  1685  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  4181  28 MESENCHYMAL STEM CELLS IN IMMUNE-MEDIATED BONE MARROW FAILURE SYNDROMES. IMMUNE-MEDIATED BONE MARROW FAILURE SYNDROMES (BMFS) ARE CHARACTERIZED BY INEFFECTIVE MARROW HAEMOPOIESIS AND SUBSEQUENT PERIPHERAL CYTOPENIAS. INEFFECTIVE HAEMOPOIESIS IS THE RESULT OF A COMPLEX MARROW DEREGULATION INCLUDING GENETIC, EPIGENETIC, AND IMMUNE-MEDIATED ALTERATIONS IN HAEMOPOIETIC STEM/PROGENITOR CELLS, AS WELL AS ABNORMAL HAEMOPOIETIC-TO-STROMAL CELL INTERACTIONS, WITH ABNORMAL RELEASE OF HAEMOPOIETIC GROWTH FACTORS, CHEMOKINES, AND INHIBITORS. MESENCHYMAL STEM/STROMAL CELLS (MSCS) AND THEIR PROGENY (I.E., OSTEOBLASTS, ADIPOCYTES, AND RETICULAR CELLS) ARE CONSIDERED AS KEY CELLULAR COMPONENTS OF THE BONE MARROW HAEMOPOIETIC NICHE. MSCS MAY INTERFERE WITH HAEMOPOIETIC AS WELL AS IMMUNE REGULATION. EVIDENCE SUGGESTS THAT BONE MARROW MSCS MAY BE INVOLVED IN IMMUNE-MEDIATED BMFS UNDERLYING PATHOPHYSIOLOGY, HARBORING EITHER NATIVE ABNORMALITIES AND/OR SECONDARY DEFECTS, CAUSED BY EXPOSURE TO ACTIVATED MARROW COMPONENTS. THIS REVIEW SUMMARIZES PREVIOUS AS WELL AS MORE RECENT INFORMATION RELATED TO THE BIOLOGIC/FUNCTIONAL CHARACTERISTICS OF BONE MARROW MSCS IN MYELODYSPLASTIC SYNDROMES, ACQUIRED APLASTIC ANEMIA, AND CHRONIC IDIOPATHIC NEUTROPENIA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  6376  27 THE ROLE OF NEUTROPHILS IN TRAINED IMMUNITY. THE PRINCIPLE OF TRAINED IMMUNITY REPRESENTS INNATE IMMUNE MEMORY DUE TO SUSTAINED, MAINLY EPIGENETIC, CHANGES TRIGGERED BY ENDOGENOUS OR EXOGENOUS STIMULI IN BONE MARROW (BM) PROGENITORS (CENTRAL TRAINED IMMUNITY) AND THEIR INNATE IMMUNE CELL PROGENY, THEREBY TRIGGERING ELEVATED RESPONSIVENESS AGAINST SECONDARY STIMULI. BM PROGENITORS CAN RESPOND TO MICROBIAL AND STERILE SIGNALS, THEREBY POSSIBLY ACQUIRING TRAINED IMMUNITY-MEDIATED LONG-LASTING ALTERATIONS THAT MAY SHAPE THE FATE AND FUNCTION OF THEIR PROGENY, FOR EXAMPLE, NEUTROPHILS. NEUTROPHILS, THE MOST ABUNDANT INNATE IMMUNE CELL POPULATION, ARE PRODUCED IN THE BM FROM COMMITTED PROGENITOR CELLS IN A PROCESS DESIGNATED GRANULOPOIESIS. NEUTROPHILS ARE THE FIRST RESPONDERS AGAINST INFECTIOUS OR INFLAMMATORY CHALLENGES AND HAVE VERSATILE FUNCTIONS IN IMMUNITY. TOGETHER WITH OTHER INNATE IMMUNE CELLS, NEUTROPHILS ARE EFFECTORS OF PERIPHERAL TRAINED IMMUNITY. HOWEVER, GIVEN THE SHORT LIFETIME OF NEUTROPHILS, THEIR ABILITY TO ACQUIRE IMMUNOLOGICAL MEMORY MAY LIE IN THE CENTRAL TRAINING OF THEIR BM PROGENITORS RESULTING IN GENERATION OF REPROGRAMMED, THAT IS, "TRAINED", NEUTROPHILS. ALTHOUGH TRAINED IMMUNITY MAY HAVE BENEFICIAL EFFECTS IN INFECTION OR CANCER, IT MAY ALSO MEDIATE DETRIMENTAL OUTCOMES IN CHRONIC INFLAMMATION. HERE, WE REVIEW THE EMERGING RESEARCH AREA OF TRAINED IMMUNITY WITH A PARTICULAR EMPHASIS ON THE ROLE OF NEUTROPHILS AND GRANULOPOIESIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  1882  39 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  5333  39 PYRUVATE KINASE DEFICIENCY: THE GENOTYPE-PHENOTYPE ASSOCIATION. RED CELL PYRUVATE KINASE (PK) DEFICIENCY IS THE MOST FREQUENT ENZYME ABNORMALITY OF GLYCOLYSIS CAUSING CHRONIC NON-SPHEROCYTIC HAEMOLYTIC ANAEMIA. THE DISEASE IS TRANSMITTED AS AN AUTOSOMAL RECESSIVE TRAIT, CLINICAL SYMPTOMS USUALLY OCCURRING IN COMPOUND HETEROZYGOTES FOR TWO MUTANT ALLELES AND IN HOMOZYGOTES. THE SEVERITY OF HAEMOLYSIS IS HIGHLY VARIABLE, RANGING FROM VERY MILD OR FULLY COMPENSATED FORMS TO LIFE-THREATENING NEONATAL ANAEMIA NECESSITATING EXCHANGE TRANSFUSIONS. ERYTHROCYTE PK IS SYNTHESISED UNDER THE CONTROL OF THE PK-LR GENE LOCATED ON CHROMOSOME 1. ONE HUNDRED EIGHTY DIFFERENT MUTATIONS IN PK-LR GENE, MOSTLY MISSENSE, HAVE BEEN SO FAR REPORTED ASSOCIATED TO PK DEFICIENCY. FIRST ATTEMPTS TO DELINEATE THE GENOTYPE-PHENOTYPE ASSOCIATION WERE MAINLY BASED ON THE ANALYSIS OF THE ENZYME'S THREE-DIMENSIONAL STRUCTURE AND THE OBSERVATION OF THE FEW HOMOZYGOUS PATIENTS. MORE RECENTLY, THE COMPARISON OF THE RECOMBINANT MUTANTS OF HUMAN RED CELL PK WITH THE WILD-TYPE ENZYME HAS ENABLED THE EFFECTS OF AMINO ACID REPLACEMENTS ON THE ENZYME MOLECULAR PROPERTIES TO BE DETERMINED. HOWEVER, THE CLINICAL MANIFESTATIONS OF RED CELL ENZYME DEFECTS ARE NOT MERELY DEPENDENT ON THE MOLECULAR PROPERTIES OF THE MUTANT PROTEIN BUT RATHER REFLECT THE COMPLEX INTERACTIONS OF ADDITIONAL FACTORS, INCLUDING GENETIC BACKGROUND, CONCOMITANT FUNCTIONAL POLYMORPHISMS OF OTHER ENZYMES, POSTTRANSLATIONAL OR EPIGENETIC MODIFICATIONS, INEFFECTIVE ERYTHROPOIESIS AND DIFFERENCES IN SPLENIC FUNCTION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  5212  33 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20   953  33 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