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  6901  35 [THE EXPERIMENTAL MODEL OF AUTOIMMUNE PROCESS: THE ROLE OF EPIGENETIC VARIATION IN THE POPULATION OF MICE HYBRIDS]. BACKGROUND: AT THE DEVELOPMENT OF GRAFT VERSUS HOST DISEASE IN GENETICALLY HOMOGENEOUS POPULATION OF (C57BI/6 X DBA/2) FL MICE TWO CLINICAL PHENOTYPES OF SLE-LIKE DISEASE WERE REVEALED: LUPUS+ (IMMUNE COMPLEX GLOMERULONEPHRITIS AND HEMNOLYTIC ANEMIA) AND LUPUS - (HEMOLYTIC ANEMIA). THE GVHD PHENOTYPIC HETEROGENEITY IS DETERMINED BY THE TH2-POLARIZATION: TH2 LYMPHOCYTE PREDOMINANT ACTIVITY, LEADS TO THE LUPUS+DEVELOPMENT, OR PREVALENCE ACTIVITY OF TH1 CELLS, LEADS TO THE LUPUS- DEVELOPMENT. OBJECTIVE: OUR AIM WAS TO EVALUATE THE POSSIBILITY OF USING AN EXPERIMENTAL MODEL OF AUTOIMMNUNE DISEASE FOR STUDYING AND TESTING OF EPIGENETIC MODIFICATIONS, SHIFTING TH1/TH2 BALANCE IN VIVO. METHODS: CHRONIC GVHD WAS INDUCED IN B6D2F1 MICE BY THE TRANSPLANTATION OF 130X10(6) PARENTAL DBA/2 SPLENOCYTES. ANTI-DS-DNA, TOTAL IGG AND IGGI, IGG2A ABS WERE MEASURED BY ELISA. RESULTS: SIX- TO 8-WEEK-OLD FEMALE DBA/2 AND B6D2F1 MICE WERE OBTAINED FROM BIOLOGICAL RESEARCH LABORATORY (NOVOSIBIRSK). IT WAS ESTABLISHED THAT REGULAR MODERATE PHYSICAL ACTIVITY (UNLADED SWIMMING) SHIFTED TH1/TH2 BALANCE TOWARDS TH1. THIS LEADS TO A DECREASE IN A POPULATION OF RECIPIENTS THE LUPUS+ MICE FROM 57 TO 26% (P <0,001) WITH SIGNIFICANTLY REDUCED HYPERGAMMAGLOBULINEMIA (IGG FROM 2,8 TO 2,0 MG/ML; P <0,047) AND DNA ANTIBODIES TITER FROM 0,18 TO 0,12 OD (P =0,05). ADMINISTRATION OF EPIGENETIC MODIFICATOR BISPHENOL A AT LOW DOSES, WHICH MIMICKING ESTROGEN EFFECTS, ENHANCES THE PROPORTION OF LUPUS+ MICE IN EXPERIMENTAL GROUPS FROM 33 TO 64% (P <0,001) AND IMPAIRS THEIR CLINICAL STATUS BY THE INCREASING THE URINE PROTEIN LEVEL FROM 2.8 TO 4,2 MG/ML (P <0,001) IN ANIMALS. CONCLUSION: TH1/TH2 - BALANCE PRESUMABLY IS DETERMINED BY THE IMMUNE SYSTEM EPIGENETIC MODIFICATION IN EXPERIMENTAL MICE, FORMED ON THE PREVIOUS STAGES OF ONTOGENY AND DEFINES THE DIRECTION OF IMMUNE PROCESSES DEVELOPMENT IN INDIVIDUAL ANIMAL.	2015	
                                                                                                                                                                                                        
3  2463  25 EPIGENETIC THERAPY REPROGRAMS HEREDITARY DISEASE. IN THIS ISSUE OF BLOOD, MAKARONA ET AL DEMONSTRATE THAT HISTONE DEACETYLASE (HDAC) INHIBITORS (HDACIS) IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD)-DEFICIENT CELLS REINSTATES ENZYME ACTIVITY BY BOOSTING GENE TRANSCRIPTION. THIS THERAPEUTIC APPROACH OPENS NEW AVENUES FOR PRECLINICAL AND CLINICAL STUDIES TO TREAT NOT ONLY CHRONIC NONSPHEROCYTIC HEMOLYTIC ANEMIA CAUSED BY SEVERE G6PD VARIANTS, BUT ALSO OTHER GENETIC DISEASES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4  6515  28 TRANSCRIPTIONAL AND EPIGENETIC BASIS FOR RESTORATION OF G6PD ENZYMATIC ACTIVITY IN HUMAN G6PD-DEFICIENT CELLS. HDAC INHIBITORS (HDACI) INCREASE TRANSCRIPTION OF SOME GENES THROUGH HISTONE HYPERACETYLATION. TO TEST THE HYPOTHESIS THAT HDACI-MEDIATED ENHANCED TRANSCRIPTION MIGHT BE OF THERAPEUTIC VALUE FOR INHERITED ENZYME DEFICIENCY DISORDERS, WE FOCUSED ON THE GLYCOLYTIC AND PENTOSE PHOSPHATE PATHWAYS (GPPPS). WE SHOW THAT AMONG THE 16 GENES OF THE GPPPS, HDACI SELECTIVELY ENHANCE TRANSCRIPTION OF GLUCOSE 6-PHOSPHATE DEHYDROGENASE (G6PD). THIS REQUIRES ENHANCED RECRUITMENT OF THE GENERIC TRANSCRIPTION FACTOR SP1, WITH COMMENSURATE RECRUITMENT OF HISTONE ACETYLTRANSFERASES AND DEACETYLASES, INCREASED HISTONE ACETYLATION, AND POLYMERASE II RECRUITMENT TO G6PD. THESE G6PD-SELECTIVE TRANSCRIPTIONAL AND EPIGENETIC EVENTS RESULT IN INCREASED G6PD TRANSCRIPTION AND ULTIMATELY RESTORED ENZYMATIC ACTIVITY IN B CELLS AND ERYTHROID PRECURSOR CELLS FROM PATIENTS WITH G6PD DEFICIENCY, A DISORDER ASSOCIATED WITH ACUTE OR CHRONIC HEMOLYTIC ANEMIA. THEREFORE, RESTORATION OF ENZYMATIC ACTIVITY IN G6PD-DEFICIENT NUCLEATED CELLS IS FEASIBLE THROUGH MODULATION OF G6PD TRANSCRIPTION. OUR FINDINGS ALSO SUGGEST THAT CLINICAL CONSEQUENCES OF PATHOGENIC MISSENSE MUTATIONS IN PROTEINS WITH ENZYMATIC FUNCTION CAN BE OVERCOME IN SOME CASES BY ENHANCEMENT OF THE TRANSCRIPTIONAL OUTPUT OF THE AFFECTED GENE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  5384  37 REDIFFERENTIATION OF RADIOIODINE-REFRACTORY THYROID CANCERS. THE MANAGEMENT OF RADIOIODINE REFRACTORY THYROID CANCERS (RAIR TC) IS CHALLENGING FOR THE CLINICIAN. TYROSINE KINASE INHIBITORS CLASSICALLY PRESCRIBED IN THIS SETTING CAN FAIL DUE TO PRIMARY OR ACQUIRED RESISTANCE OR THE NECESSITY OF DRUG WITHDRAWAL BECAUSE OF SERIOUS OR MODERATE BUT CHRONIC AND DELETERIOUS ADVERSE EFFECTS. THUS, THE CONCEPT OF REDIFFERENTIATION STRATEGY, WHICH INVOLVES TREATING PATIENTS WITH ONE OR MORE DRUGS CAPABLE OF RESTORING RADIOIODINE SENSITIVITY FOR RAIR TC, HAS EMERGED. THE AREA OF REDIFFERENTIATION STRATEGY LEADS TO THE CREATION OF NEW DEFINITIONS OF RAIR TC INCLUDING PERSISTENT NON RADIOIODINE-AVID PATIENTS AND 'TRUE' RAIR TC PATIENTS. THE LATTER GROUP PRESENTS A RESTORED OR INCREASED RADIOIODINE UPTAKE IN METASTATIC LESIONS BUT WITH NO RADIOLOGICAL RESPONSE ON CONVENTIONAL IMAGING, THAT IS, PROGRESSION OF A METASTATIC DISEASE, THUS PROVING THAT THEY ARE 'TRULY' RESISTANT TO THE RADIATION DELIVERED BY RADIOIODINE. UNLIKE THESE PATIENTS, METASTATIC TC PATIENTS WITH RESTORED RADIOIODINE UPTAKE OFFER THE HOPE OF PROLONGED REMISSION OR EVEN CURE OF THE DISEASE AS FOR RADIOIODINE-AVID METASTATIC TC. HERE, WE REVIEW THE DIFFERENT REDIFFERENTIATION STRATEGIES BASED ON THE UNDERLYING MOLECULAR MECHANISM LEADING TO THE SODIUM IODIDE SYMPORTER (NIS) AND RADIOIODINE UPTAKE REINDUCTION, THAT IS, BY MODULATING SIGNALING PATHWAYS, NIS TRANSCRIPTION, NIS TRAFFICKING TO THE PLASMA MEMBRANE, NIS POST-TRANSCRIPTIONAL REGULATION, BY GENE THERAPY AND OTHER POTENTIAL STRATEGIES. WE DISCUSS CLINICAL TRIALS AND PROMISING PRECLINICAL DATA OF POTENTIAL FUTURE TARGETS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6  1253  32 CURRENT PROBLEMS AND FUTURE DIRECTIONS OF TRANSFUSION-INDUCED ALLOIMMUNIZATION: SUMMARY OF AN NHLBI WORKING GROUP. IN APRIL 2010, A WORKING GROUP SPONSORED BY THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WAS ASSEMBLED TO IDENTIFY RESEARCH STRATEGIES TO IMPROVE OUR UNDERSTANDING OF ALLOIMMUNIZATION CAUSED BY THE TRANSFUSION OF ALLOGENEIC BLOOD COMPONENTS AND TO EVALUATE POTENTIAL APPROACHES TO BOTH REDUCE ITS OCCURRENCE AND MANAGE ITS EFFECTS. SIGNIFICANT SEQUELAE OF ALLOIMMUNIZATION WERE DISCUSSED AND IDENTIFIED, INCLUDING DIFFICULTIES IN MAINTAINING CHRONIC TRANSFUSION OF RED BLOOD CELLS AND PLATELETS, HEMOLYTIC DISEASE OF THE NEWBORN, NEONATAL ALLOIMMUNE THROMBOCYTOPENIA, AND REJECTION OF TRANSPLANTED CELLS AND TISSUES. THE DISCUSSIONS RESULTED IN A CONSENSUS THAT IDENTIFIED KEY AREAS OF FUTURE RESEARCH AND DEVELOPMENTAL AREAS, INCLUDING GENETIC AND EPIGENETIC RECIPIENT FACTORS THAT REGULATE ALLOIMMUNIZATION, BIOCHEMICAL SPECIFICS OF TRANSFUSED PRODUCTS THAT AFFECT ALLOIMMUNIZATION, AND NOVEL TECHNOLOGIES FOR HIGH-THROUGHPUT GENOTYPING TO FACILITATE EXTENSIVE AND EFFICIENT ANTIGEN MATCHING BETWEEN DONOR AND RECIPIENT. ADDITIONAL AREAS OF IMPORTANCE INCLUDED ANALYSIS OF UNAPPRECIATED MEDICAL SEQUELAE OF ALLOIMMUNIZATION, SUCH AS CELLULAR IMMUNITY AND ITS EFFECT UPON TRANSPLANT AND AUTOIMMUNITY. IN ADDITION, SUPPORT FOR RESEARCH INFRASTRUCTURE WAS DISCUSSED, WITH AN EMPHASIS ON ENCOURAGING COLLABORATION AND SYNERGY OF ANIMAL MODELS BIOLOGY AND HUMAN CLINICAL RESEARCH. FINALLY, TRAINING FUTURE INVESTIGATORS WAS IDENTIFIED AS AN AREA OF IMPORTANCE. IN AGGREGATE, THIS COMMUNICATION PROVIDES A SYNOPSIS OF THE OPINIONS OF THE WORKING GROUP ON THE ABOVE ISSUES AND PRESENTS BOTH A LIST OF SUGGESTED PRIORITIES AND THE RATIONALE FOR THE TOPICS OF FOCUS. THE AREAS OF RESEARCH IDENTIFIED IN THIS REPORT REPRESENT POTENTIAL FERTILE GROUND FOR THE MEDICAL ADVANCEMENT OF PREVENTING AND MANAGING ALLOIMMUNIZATION IN ITS DIFFERENT FORMS AND MITIGATING THE CLINICAL PROBLEMS IT PRESENTS TO MULTIPLE PATIENT POPULATIONS.	2011	
                                                                                                                                                                                     
7  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	
                                                                                                                                                                        
8    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	
                                                                                                                                                                                                                                                                                                   
9  3160  51 GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: PATHOPHYSIOLOGY-BASED REVIEW ON CURRENT APPROACHES AND FUTURE DIRECTIONS. GRAFT-VERSUS-HOST DISEASE (GVHD) WAS FIRST DESCRIBED IN 1959, SINCE THEN MAJOR EFFORTS HAVE BEEN MADE IN ORDER TO UNDERSTAND ITS PHYSIOPATHOLOGY AND ANIMAL MODELS HAVE PLAYED A KEY ROLE. THREE STEPS, INVOLVING DIFFERENT PATHWAYS, HAVE BEEN RECOGNISED IN EITHER ACUTE AND CHRONIC GVHD, IDENTIFYING THEM AS TWO DISTINCT ENTITIES. IN ORDER TO REDUCE GVHD INCIDENCE AND SEVERITY, PROPHYLACTIC MEASURES WERE ADDED TO TRANSPLANT PROTOCOLS. THE COMBINATION OF A CALCINEURIN INHIBITOR (CNI) PLUS AN ANTIMETABOLITE REMAINS THE STANDARD OF CARE. BETTER KNOWLEDGE OF GVHD PATHOPHYSIOLOGY HAS MOVED THIS FIELD FORWARD AND NOWADAYS DIFFERENT DRUGS ARE BEING USED ON A DAILY BASIS. IMPROVING GVHD PROPHYLAXIS IS A MAJOR GOAL AS IT WOULD TRANSLATE INTO LESS NON-RELAPSE MORTALITY AND BETTER OVERALL SURVIVAL. AS COMPARED TO CNI PLUS METHOTREXATE THE COMBINATION OF CNI PLUS MYCOPHENOLATE MOPHETIL (MMF) ALLOWS US TO OBTAIN SIMILAR RESULTS IN TERMS OF GVHD INCIDENCE BUT A LOWER TOXICITY RATE IN TERMS OF NEUTROPENIA OR MUCOSITIS. THE USE OF ATG HAS BEEN RELATED TO A LOWER RISK OF ACUTE AND CHRONIC GVHD IN PROSPECTIVE RANDOMIZED TRIALS AS WELL AS THE USE OF POSTTRANSPLANT CYCLOPHOSPHAMIDE, WITH NO OR MARGINAL IMPACT ON OVERALL SURVIVAL BUT WITH AN IMPROVEMENT IN GVHD-RELAPSE FREE SURVIVAL (GRFS). THE USE OF SIROLIMUS HAS BEEN RELATED TO A LOWER RISK OF ACUTE GVHD AND SIGNIFICANTLY INFLUENCED OVERALL SURVIVAL IN ONE PROSPECTIVE RANDOMIZED TRIAL. OTHER PROSPECTIVE TRIALS HAVE EVALUATED THE USE OF RECEPTORS SUCH AS CCR5 OR ALPHA4BETA7 TO AVOID T-CELLS TRAFFICKING INTO GVHD TARGET ORGANS, CYTOKINE BLOCKERS OR IMMUNE CHECK POINT AGONISTS. ALSO, EPIGENETIC MODIFIERS HAVE SHOWN PROMISING RESULTS IN PHASE II TRIALS. ATTENTION SHOULD BE PAID TO GRAFT-VERSUS-LEUKEMIA, INFECTIONS AND IMMUNE RECOVERY BEFORE BRINGING NEW PROPHYLACTIC STRATEGIES TO CLINICAL PRACTICE. ALTHOUGH THE LIST OF NOVEL AGENTS FOR GVHD PROPHYLAXIS IS GROWING, RANDOMIZED TRIALS ARE STILL LACKING FOR MANY OF THEM.	2021	
                                                                                                                                 
10  3537  41 IMMUNE DYSREGULATION IN KABUKI SYNDROME: A CASE REPORT OF EVANS SYNDROME AND HYPOGAMMAGLOBULINEMIA. KABUKI SYNDROME (KS) IS A RARE MULTISYSTEMIC DISEASE DUE TO MUTATIONS IN THE KMT2D OR KDM6A GENES, WHICH ACT AS EPIGENETIC MODULATORS OF DIFFERENT PROCESSES, INCLUDING IMMUNE RESPONSE. THE SYNDROME IS CHARACTERIZED BY ANOMALIES IN MULTIPLE ORGAN SYSTEMS, AND IT IS ASSOCIATED WITH AUTOIMMUNE AND INFLAMMATORY DISORDERS, AND AN UNDERLYING IMMUNOLOGICAL PHENOTYPE CHARACTERIZED BY IMMUNODEFICIENCY AND IMMUNE DYSREGULATION. UP TO 17% OF KS PATIENTS PRESENT WITH IMMUNE THROMBOCYTOPENIA CHARACTERIZED BY A SEVERE, CHRONIC OR RELAPSING COURSE, AND OFTEN ASSOCIATED TO OTHER HEMATOLOGICAL AUTOIMMUNE DISEASES INCLUDING AUTOIMMUNE HEMOLYTIC ANEMIA, EVENTUALLY RESULTING IN EVANS SYNDROME (ES). A 23-YEAR-OLD WOMAN, CLINICALLY DIAGNOSED WITH KS AND PRESENTING FROM THE AGE OF 3 YEARS WITH ES WAS REFERRED TO THE RARE DISEASES CENTRE OF OUR PEDIATRIC DEPARTMENT FOR CORTICOSTEROID-INDUCED HYPERGLYCEMIA. SEVERAL ES RELAPSES AND RECURRENT RESPIRATORY INFECTIONS IN THE PREVIOUS YEARS WERE REPORTED. SEVERE HYPOGAMMAGLOBULINEMIA, SPLENOMEGALY AND SIGNS OF CHRONIC LUNG INFLAMMATION WERE DIAGNOSED ONLY AT THE TIME OF OUR OBSERVATION. SUPPORTIVE TREATMENT WITH AMOXICILLIN-CLAVULANATE PROPHYLAXIS AND RECOMBINANT HUMAN HYALURONIDASE-FACILITATED SUBCUTANEOUS IMMUNOGLOBULIN REPLACEMENT WERE IMMEDIATELY STARTED. IN KS PATIENTS, THE FAILURE OF B-CELL DEVELOPMENT AND THE LACK OF AUTOREACTIVE IMMUNE CELLS SUPPRESSION CAN LEAD TO IMMUNODEFICIENCY AND AUTOIMMUNITY THAT MAY BE UNDIAGNOSED FOR A LONG TIME. OUR PATIENT'S CASE IS PARADIGMATIC SINCE SHE PRESENTED WITH PREVENTABLE MORBIDITY AND SEVERE LUNG DISEASE YEARS AFTER DISEASE ONSET. THIS CASE EMPHASIZES THE IMPORTANCE OF SUSPECTING IMMUNE DYSREGULATION IN KS. PATHOGENESIS AND IMMUNOLOGICAL COMPLICATIONS OF KS ARE DISCUSSED. MOREOVER, THE NEED TO PERFORM IMMUNOLOGIC EVALUATIONS IS HIGHLIGHTED BOTH AT THE TIME OF KS DIAGNOSIS AND DURING DISEASE FOLLOW-UP, IN ORDER TO ALLOW PROPER TREATMENT WHILE INTERCEPTING AVOIDABLE MORBIDITY IN THESE PATIENTS.	2023	
                                                                                                                           
11  4761  31 NRF2 SENSITIZES FERROPTOSIS THROUGH L-2-HYDROXYGLUTARATE-MEDIATED CHROMATIN MODIFICATIONS IN SICKLE CELL DISEASE. SICKLE CELL DISEASE (SCD) IS A CHRONIC HEMOLYTIC AND SYSTEMIC HYPOXIA CONDITION WITH CONSTANT OXIDATIVE STRESS AND SIGNIFICANT METABOLIC ALTERATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE CORRELATION BETWEEN METABOLIC ALTERATIONS AND THE PATHOPHYSIOLOGICAL SYMPTOMS. HERE, WE REPORT THAT NRF2, A MASTER REGULATOR OF CELLULAR ANTIOXIDANT RESPONSES, REGULATES THE PRODUCTION OF THE METABOLITE L-2-HYDROXYGLUTARATE (L2HG) TO MEDIATE EPIGENETIC HISTONE HYPERMETHYLATION FOR GENE EXPRESSION INVOLVED IN METABOLIC, OXIDATIVE, AND FERROPTOTIC STRESS RESPONSES IN SCD. MECHANISTICALLY, NRF2 WAS FOUND TO REGULATE THE EXPRESSION OF L2HG DEHYDROGENASE (L2HGDH) TO MEDIATE L2HG PRODUCTION UNDER HYPOXIA. GENE EXPRESSION PROFILE ANALYSIS INDICATED THAT REACTIVE OXYGEN SPECIES (ROS) AND FERROPTOSIS RESPONSES WERE THE MOST SIGNIFICANTLY AFFECTED SIGNALING PATHWAYS AFTER NRF2 ABLATION IN SCD. NRF2 SILENCING AND L2HG SUPPLEMENTATION SENSITIZE HUMAN SICKLE ERYTHROID CELLS TO ROS AND FERROPTOSIS STRESS. THE ABSENCE OF NRF2 AND ACCUMULATION OF L2HG SIGNIFICANTLY AFFECT HISTONE METHYLATION FOR CHROMATIN STRUCTURE MODIFICATION AND REDUCE THE ASSEMBLY OF TRANSCRIPTION COMPLEXES ON DOWNSTREAM TARGET GENES TO REGULATE ROS AND FERROPTOSIS RESPONSES. FURTHERMORE, PHARMACOLOGICAL ACTIVATION OF NRF2 WAS FOUND TO HAVE PROTECTIVE EFFECTS AGAINST ROS AND FERROPTOSIS STRESS IN SCD MICE. OUR DATA SUGGEST A NOVEL MECHANISM BY WHICH NRF2 REGULATES L2HG LEVELS TO MEDIATE SCD SEVERITY THROUGH ROS AND FERROPTOSIS STRESS RESPONSES, SUGGESTING THAT TARGETING NRF2 IS A VIABLE THERAPEUTIC STRATEGY FOR AMELIORATING SCD SYMPTOMS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  4148  42 MECHANISTIC BASIS OF EX VIVO UMBILICAL CORD BLOOD STEM PROGENITOR CELL EXPANSION. UMBILICAL CORD BLOOD (CB) TRANSPLANTATION HAS BEEN USED SUCCESSFULLY IN HUMANS FOR THREE DECADES DUE TO ITS RAPID AVAILABILITY FOR PATIENTS LACKING A SUITABLE ALLOGENEIC DONOR, LESS STRINGENT HLA MATCHING REQUIREMENTS, AND LOW RATES OF RELAPSE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD). HOWEVER, CB TRANSPLANTATION IS ASSOCIATED WITH COMPLICATIONS, SUCH AS DELAYED HEMATOPOIETIC ENGRAFTMENT, GRAFT FAILURE, WHICH INCREASES INFECTION AND BLEEDING AND CAUSES LONGER HOSPITAL STAYS, AND TRANSPLANT-RELATED MORTALITY. THE MAJORITY OF THESE BIOLOGICAL LIMITATIONS ARE DUE TO THE UNFORESEEABLE FUNCTIONAL POTENCY OF MULTIPOTENT HEMATOPOIETIC STEM CELLS (HSCS), WHICH REDUCE THE PREDICTABILITY OF SUCCESSFUL TRANSPLANTATION; HOWEVER, SEVERAL STRATEGIES HAVE BEEN DEVELOPED TO INCREASE THE NUMBER OF HEMATOPOIETIC STEM PROGENITOR CELLS (HSPCS) INFUSED DURING CB TRANSPLANTATION. THIS REVIEW PRIMARILY ADDRESSES THE METHODS THAT PROMOTE EX VIVO CB EXPANSION WITHIN THE CONTEXT OF SYMMETRICAL AND ASYMMETRICAL HSC DIVISION AND THOSE THAT RELY ON EPIGENETIC MECHANISMS, ALONG WITH THE REPORTEDLY MOST SUCCESSFUL CYTOKINE COMBINATIONS. WE ALSO REVIEW RECENT CLINICAL RESEARCH ON SMALL MOLECULES (STEMREGENIN-1, UM171, AND NICOTINAMIDE) IN EX VIVO EXPANDED CB AND DISCUSS YET UNVALIDATED PRECLINICAL STRATEGIES. EXPANDING AND TRANSPLANTING CB GRAFT ENRICHED IN HSPCS IN A SINGLE CB UNIT IS A PARTICULARLY EXCITING PROSPECT WITH THE POTENTIAL TO IMPROVE THE USE AND AVAILABILITY OF CB GRAFTS. GREATER KNOWLEDGE OF OPTIMAL EX VIVO EXPANSION STRATEGIES, CELL LONGEVITY, AND GRAFT POTENCY WILL EXPAND THE SCOPE OF CELLULAR THERAPIES. ALSO THE DEVELOPMENT OF ADEQUATE EX VIVO HSPC EXPANSION STRATEGIES COULD BRING EXPANDED CORD BLOOD GRAFTS TO THE FOREFRONT OF TRANSPLANT THERAPY AND REGENERATIVE MEDICINE.	2020	
                                                                                                                                                                                                                                                                                                                                                      
13  3129  37 GIVINOSTAT: AN EMERGING TREATMENT FOR POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA (PV), A PHILADELPHIA CHROMOSOME-NEGATIVE MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY PANMYELOSIS, PANCYTOSIS, AND A JAK2 MUTATION. PATIENTS ARE AT INCREASED RISK OF THROMBOHEMORRHAGIC EVENTS, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE LEUKEMIA. CURRENT TREATMENTS INCLUDE ASPIRIN, PHLEBOTOMY, AND CYTOREDUCTIVE DRUGS (MOST COMMONLY HYDROXYUREA). GIVINOSTAT IS A POTENT, CLASS I/II HISTONE DEACETYLASE (HDAC) INHIBITOR THAT IS IN PHASE I/II CLINICAL TRIALS IN PV. GIVINOSTAT WAS WELL TOLERATED AND YIELDED PROMISING CLINICO-HEMATOLOGICAL RESPONSES. A PHASE III STUDY OF GIVINOSTAT VERSUS HYDROXYUREA IN HIGH-RISK PV PATIENTS IS PLANNED. AREAS COVERED: WE PRESENT AN OVERVIEW OF PV, CURRENT TREATMENT GUIDELINES, AND THE PUTATIVE MECHANISM(S) OF ACTION OF GIVINOSTAT. WE DISCUSS THE PRECLINICAL AND CLINICAL STUDIES OF GIVINOSTAT IN PV AND BRIEFLY REVIEW APPROVED AND INVESTIGATIONAL COMPETITOR COMPOUNDS. EXPERT OPINION: HDAC INHIBITORS HAVE LONG BEEN KNOWN TO BE ACTIVE IN PV, BUT CHRONIC TOXICITIES CAN BE CHALLENGING. GIVINOSTAT, HOWEVER, IS ACTIVE AND WELL TOLERATED, AND IS ENTERING A PIVOTAL PHASE III RANDOMIZED TRIAL. GIVINOSTAT OFFERS THE POSSIBILITY OF REPLACING HYDROXYUREA AS THE STANDARD FIRST-LINE CYTOREDUCTIVE CHOICE FOR PV PATIENTS. THIS WOULD COMPLETELY CHANGE THE CURRENT THERAPEUTIC PARADIGM AND GUIDELINES FOR PV MANAGEMENT. ALTHOUGH SURROGATE CLINICAL STUDY ENDPOINTS MAY SUFFICE FOR REGULATORY PURPOSES, THROMBOSIS REDUCTION AND PREVENTION OF DISEASE PROGRESSION REMAIN MOST IMPORTANT TO PATIENTS AND CLINICIANS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  5912  32 TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM DISORDER CHARACTERISED BY LOSS OF TOLERANCE TO ENDOGENOUS NUCLEAR ANTIGENS AND AUTOANTIBODY FORMATION. RECENT INSIGHT INTO THE IMMUNOPATHOGENESIS OF LUPUS HAS PROVIDED THE FOUNDATION FOR A NOVEL CLASS OF AGENTS WHICH TARGET SPECIFIC, DYSREGULATED COMPONENTS OF THE IMMUNE SYSTEM. EFFORTS HAVE FOCUSED PREDOMINANTLY ON B-CELL DEPLETING THERAPIES, OF WHICH BELIMUMAB WAS THE FIRST TO DEMONSTRATE SUCCESS IN PHASE III STUDIES AND THUS RECEIVE MARKETING AUTHORISATION. OFF-LABEL PRESCRIBING OF RITUXIMAB IN REFRACTORY CASES IS COMMON AND SUPPORTED BY UNCONTROLLED STUDIES, WHICH SUGGEST A FAVOURABLE RISK:BENEFIT PROFILE. HOWEVER, TWO PLACEBO-CONTROLLED TRIALS FAILED TO SHOW BENEFIT, POSSIBLY BECAUSE OF INAPPROPRIATE PATIENT SELECTION AND OTHER ASPECTS OF TRIAL METHODOLOGY. INHIBITION OF DYSREGULATED CO-STIMULATORY SIGNALS AND CYTOKINES ARE OTHER THERAPEUTIC STRATEGIES CURRENTLY UNDER INVESTIGATION. SOME CANDIDATE DRUGS FAILED TO MEET PRIMARY ENDPOINTS IN EARLY-PHASE CLINICAL TRIALS, YET DEMONSTRATED CLINICAL BENEFIT WHEN ALTERNATIVE ASSESSMENT CRITERIA WERE APPLIED OR SPECIFIC PATIENT SUB-GROUPS ANALYSED. WELL-DESIGNED STUDIES OF GREATER SIZE AND DURATION ARE NEEDED TO CLARIFY THE THERAPEUTIC UTILITY OF THESE AGENTS. FUTURE IMMUNOMODULATORY STRATEGIES TARGETING INTERFERON-ALPHA, T CELLS, OXIDATIVE STRESS AND EPIGENETIC ABNORMALITIES MAY REDUCE MULTISYSTEM DISEASE ACTIVITY AND PROLONG SURVIVAL IN THIS COMPLEX AND HETEROGENEIC DISEASE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  4979  29 PATHOPHYSIOLOGY AND TREATMENT OF SICKLE CELL DISEASE. CURRENT TREATMENT AND UNDERSTANDING OF SICKLE CELL DISEASE REQUIRE AN APPRECIATION FOR THE COMPLEXITY OF ITS BASIC PATHOPHYSIOLOGY. THE CLINICAL MANIFESTATIONS OF VASO-OCCLUSION RESULT FROM A DYNAMIC COMBINATION OF ABNORMALITIES IN HEMOGLOBIN STRUCTURE AND FUNCTION, RED BLOOD CELL MEMBRANE INTEGRITY, ERYTHROCYTE DENSITY, ENDOTHELIAL ACTIVATION, MICROVASCULAR TONE, INFLAMMATORY MEDIATORS, AND COAGULATION FACTORS. EXISTING AND EMERGING THERAPIES ADDRESS EACH OF THESE BIOLOGIC ALTERATIONS, INDIVIDUALLY AND COLLECTIVELY. EXAMPLES INCLUDE INDUCTION OF FETAL HEMOGLOBIN, MODULATION OF ERYTHROCYTE HYDRATION, AUGMENTATION OF NITRIC OXIDE, CHRONIC TRANSFUSION, STEM CELL TRANSPLANTATION, AND GENE THERAPY. UNDERSTANDING THE PLEIOTROPIC AND EPIGENETIC FACTORS INFLUENCING DISEASE PHENOTYPE MAY LEAD TO MORE TARGETED APPLICATION OF THESE THERAPIES.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17   255  32 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  5686  32 SICKLE CELL DISEASE: CLINICAL PRESENTATION AND MANAGEMENT OF A GLOBAL HEALTH CHALLENGE. SICKLE CELL DISEASE IS AN AUTOSOMAL RECESSIVE, MULTISYSTEM DISORDER, CHARACTERISED BY CHRONIC HAEMOLYTIC ANAEMIA, PAINFUL EPISODES OF VASO-OCCLUSION, PROGRESSIVE ORGAN FAILURE AND A REDUCED LIFE EXPECTANCY. SICKLE CELL DISEASE IS THE MOST COMMON MONOGENETIC DISEASE, WITH MILLIONS AFFECTED WORLDWIDE. IN WELL-RESOURCED COUNTRIES, COMPREHENSIVE CARE PROGRAMS HAVE INCREASED LIFE EXPECTANCY OF SICKLE CELL DISEASE PATIENTS, WITH ALMOST ALL INFANTS SURVIVING INTO ADULTHOOD. THERAPEUTIC OPTIONS FOR SICKLE CELL DISEASE PATIENTS ARE HOWEVER, STILL SCARCE. PREDICTORS OF SICKLE CELL DISEASE SEVERITY AND A BETTER UNDERSTANDING OF PATHOPHYSIOLOGY AND (EPI)GENETIC MODIFIERS ARE WARRANTED AND COULD LEAD TO MORE PRECISE MANAGEMENT AND TREATMENT. THIS REVIEW PROVIDES AN EXTENSIVE SUMMARY OF THE PATHOPHYSIOLOGY AND MANAGEMENT OF SICKLE CELL DISEASE AND ENCOMPASSES THE CHARACTERISTICS, COMPLICATIONS AND CURRENT AND FUTURE TREATMENT OPTIONS OF THE DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  1046  31 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  3335  29 HISTONE DEACETYLASE INHIBITORS FOR CARDIOVASCULAR CONDITIONS AND HEALTHY LONGEVITY. HISTONE DEACETYLASE INHIBITORS (HDACI) REGULATE GENE EXPRESSION VIA EPIGENETIC MECHANISMS. ACCUMULATING EVIDENCE SUGGESTS THAT HDACI EXERT ANTIPROLIFERATIVE, ANTIOXIDANT, ANTINEOPLASTIC, AND PROAPOPTOTIC EFFECTS THROUGH EPIGENETIC MECHANISMS. FURTHERMORE, HDACI ALSO EXERT ANTITHROMBOTIC AND ANTIFIBROTIC EFFECTS THROUGH REGULATION OF THROMBOTIC AND FIBROTIC TRANSDUCTION MECHANISMS. ONE OF THE OLDEST HDACI IS VALPROIC ACID, WHICH WAS FIRST SYNTHESISED IN 1882. AFTER THE DISCOVERY OF ITS ANTICONVULSANT PROPERTIES FOR THE TREATMENT OF EPILEPSY, THE USE OF VALPROIC ACID WAS EXTENDED TO OTHER CONDITIONS, SUCH AS BIPOLAR DISORDER AND MIGRAINE. GIVEN THE ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF HDACI IN THE TREATMENT OF MULTIPLE MEDICAL CONDITIONS BEYOND EPILEPSY, THE INTEREST IN NOVEL POTENTIAL INDICATIONS FOR HDACI HAS BEEN RENEWED. CONSIDERING THE PLEOTROPIC EPIGENETIC EFFECTS OF HDACI, FUTURE STUDIES COULD ASSESS THEIR EFFICACY AND SAFETY FOR CARDIOVASCULAR DISEASE PREVENTION AND TREATMENT; TREATMENT OF VENOUS THROMBOSIS, ALZHEIMER'S DISEASE, AUTOIMMUNE AND PROINFLAMMATORY CONDITIONS, CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION, AND PULMONARY ARTERIAL HYPERTENSION; AND AS A COADJUVANT THERAPY FOR CANCER. ADEQUATELY DESIGNED AND POWERED CLINICAL TRIALS ARE REQUIRED TO ASSESS THE EFFICACY AND SAFETY OF HDACI BEFORE THEIR CLINICAL REPURPOSING.	2021