1   255 115 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  1841  20 EFFECTS OF SHORT CHAIN FATTY ACID PRODUCING BACTERIA ON EPIGENETIC REGULATION OF FFAR3 IN TYPE 2 DIABETES AND OBESITY. THE HUMAN GUT MICROBIOTA AND MICROBIAL INFLUENCES ON LIPID AND GLUCOSE METABOLISM, SATIETY, AND CHRONIC LOW-GRADE INFLAMMATION ARE KNOWN TO BE INVOLVED IN METABOLIC SYNDROME. FERMENTATION END PRODUCTS, ESPECIALLY SHORT CHAIN FATTY ACIDS, ARE BELIEVED TO ENGAGE THE EPIGENETIC REGULATION OF INFLAMMATORY REACTIONS VIA FFARS (FREE FATTY ACID RECEPTOR) AND OTHER SHORT CHAIN FATTY ACID RECEPTORS. WE STUDIED A POTENTIAL INTERACTION OF THE MICROBIOTA WITH EPIGENETIC REGULATION IN OBESE AND TYPE 2 DIABETES PATIENTS COMPARED TO A LEAN CONTROL GROUP OVER A FOUR MONTH INTERVENTION PERIOD. INTERVENTION COMPRISED A GLP-1 AGONIST (GLUCAGON-LIKE PEPTIDE 1) FOR TYPE 2 DIABETICS AND NUTRITIONAL COUNSELING FOR BOTH INTERVENTION GROUPS. MICROBIOTA WAS ANALYZED FOR ABUNDANCE, BUTYRYL-COA:ACETATE COA-TRANSFERASE GENE AND FOR DIVERSITY BY POLYMERASE CHAIN REACTION AND 454 HIGH-THROUGHPUT SEQUENCING. EPIGENETIC METHYLATION OF THE PROMOTER REGION OF FFAR3 AND LINE1 (LONG INTERSPERSED NUCLEAR ELEMENT 1) WAS ANALYZED USING BISULFITE CONVERSION AND PYROSEQUENCING. THE DIVERSITY OF THE MICROBIOTA AS WELL AS THE ABUNDANCE OF FAECALIBACTERIUM PRAUSNITZII WERE SIGNIFICANTLY LOWER IN OBESE AND TYPE 2 DIABETIC PATIENTS COMPARED TO LEAN INDIVIDUALS. RESULTS FROM CLOSTRIDIUM CLUSTER IV AND CLOSTRIDIUM CLUSTER XIVA SHOWED A DECREASING TREND IN TYPE 2 DIABETICS IN COMPARISON TO THE BUTYRYL-COA:ACETATE COA-TRANSFERASE GENE AND ACCORDING TO MELT CURVE ANALYSIS. DURING INTERVENTION NO SIGNIFICANT CHANGES WERE OBSERVED IN EITHER INTERVENTION GROUP. THE ANALYSIS OF FIVE CPGS IN THE PROMOTER REGION OF FFAR3 SHOWED A SIGNIFICANT LOWER METHYLATION IN OBESE AND TYPE 2 DIABETICS WITH AN INCREASE IN OBESE PATIENTS OVER THE INTERVENTION PERIOD. THESE RESULTS DISCLOSED A SIGNIFICANT CORRELATION BETWEEN A HIGHER BODY MASS INDEX AND LOWER METHYLATION OF FFAR3. LINE-1, A MARKER OF GLOBAL METHYLATION, INDICATED NO SIGNIFICANT DIFFERENCES BETWEEN THE THREE GROUPS OR THE TIME POINTS, ALTHOUGH METHYLATION OF TYPE 2 DIABETICS TENDED TO INCREASE OVER TIME. OUR RESULTS PROVIDE EVIDENCE THAT A DIFFERENT COMPOSITION OF GUT MICROBIOTA IN OBESITY AND TYPE 2 DIABETES AFFECT THE EPIGENETIC REGULATION OF GENES. INTERACTIONS BETWEEN THE MICROBIOTA AND EPIGENETIC REGULATION MAY INVOLVE NOT ONLY SHORT CHAIN FATTY ACIDS BINDING TO FFARS. THEREFORE DIETARY INTERVENTIONS INFLUENCING MICROBIAL COMPOSITION MAY BE CONSIDERED AS AN OPTION IN THE ENGAGEMENT AGAINST METABOLIC SYNDROME.	2014	

3  4748  38 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  6856  36 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  6442  46 THERAPEUTIC APPROACHES IN MYELOFIBROSIS AND MYELODYSPLASTIC/MYELOPROLIFERATIVE OVERLAP SYNDROMES. THE DISCOVERY OF JAK2 (V617F) A DECADE AGO LED TO OPTIMISM FOR A RAPIDLY DEVELOPING TREATMENT REVOLUTION IN PH(-) MYELOPROLIFERATIVE NEOPLASMS. UNLIKE BCR-ABL, HOWEVER, JAK2 WAS FOUND TO HAVE A MORE HETEROGENEOUS ROLE IN CARCINOGENESIS. THEREFORE, FOR YEARS, DEVELOPMENT OF NEW THERAPIES WAS SLOW, DESPITE STANDARD TREATMENT OPTIONS THAT DID NOT ADDRESS THE OVERWHELMING SYMPTOM BURDEN IN PATIENTS WITH PRIMARY MYELOFIBROSIS (MF), POST-ESSENTIAL THROMBOCYTHEMIA MF, POST-POLYCYTHEMIA VERA MF, AND MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) SYNDROMES. JAK-STAT INHIBITORS HAVE CHANGED THIS, DRASTICALLY AMELIORATING SYMPTOMS AND ULTIMATELY BEGINNING TO SHOW EVIDENCE OF IMPACT ON SURVIVAL. NOW, THE GENETIC FOUNDATIONS OF MYELOFIBROSIS AND MDS/MPN ARE RAPIDLY BEING ELUCIDATED AND CONTRIBUTING TO TARGETED THERAPY DEVELOPMENT. THIS HAS BEEN EMPOWERED THROUGH UPDATED RESPONSE CRITERIA FOR MDS/MPN AND REFINED PROGNOSTIC SCORING SYSTEMS IN THESE DISEASES. THE AIM OF THIS ARTICLE IS TO SUMMARIZE CONCISELY THE CURRENT AND RATIONALLY DESIGNED INVESTIGATIONAL THERAPEUTICS DIRECTED AT JAK-STAT, HEDGEHOG, PI3K-AKT, BONE MARROW FIBROSIS, TELOMERASE, AND ROGUE EPIGENETIC SIGNALING. THE REVOLUTION IN IMMUNOTHERAPY AND NOVEL TREATMENTS AIMED AT PREVIOUSLY UNTARGETED SIGNALING PATHWAYS PROVIDES HOPE FOR CONSIDERABLE ADVANCEMENT IN THERAPY OPTIONS FOR THOSE WITH CHRONIC MYELOID DISEASE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  5953  35 TARGETS IN MPNS AND POTENTIAL THERAPEUTICS. PHILADELPHIA-NEGATIVE CLASSICAL MYELOPROLIFERATIVE NEOPLASMS (MPNS), INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL HEMOPATHIES THAT EMERGE IN THE HEMATOPOIETIC STEM CELL (HSC) COMPARTMENT. MPN DRIVER MUTATIONS ARE RESTRICTED TO SPECIFIC EXONS (14 AND 12) OF JANUS KINASE 2 (JAK2), THROMBOPOIETIN RECEPTOR (MPL/TPOR) AND CALRETICULIN (CALR) GENES, ARE INVOLVED DIRECTLY IN CLONAL MYELOPROLIFERATION AND GENERATE THE MPN PHENOTYPE. AS A RESULT, AN INCREASED NUMBER OF FULLY FUNCTIONAL ERYTHROCYTES, PLATELETS AND LEUKOCYTES IS OBSERVED IN THE PERIPHERAL BLOOD. NEVERTHELESS, THE COMPLEXITY AND HETEROGENEITY OF MPN CLINICAL PHENOTYPES CANNOT BE SOLELY EXPLAINED BY THE TYPE OF DRIVER MUTATION. OTHER FACTORS, SUCH AS ADDITIONAL SOMATIC MUTATIONS AFFECTING EPIGENETIC REGULATORS OR SPLICEOSOMES COMPONENTS, MUTANT ALLELE BURDENS AND MODIFIERS OF SIGNALING BY DRIVER MUTANTS, CLONAL ARCHITECTURE AND THE ORDER OF MUTATION ACQUISITION, SIGNALING EVENTS THAT OCCUR DOWNSTREAM OF A DRIVER MUTATION, THE PRESENCE OF SPECIFIC GERM-LINE VARIANTS, THE INTERACTION OF THE NEOPLASTIC CLONE WITH BONE MARROW MICROENVIRONMENT AND CHRONIC INFLAMMATION, ALL CAN MODULATE THE DISEASE PHENOTYPE, INFLUENCE THE MPN CLINICAL COURSE AND THEREFORE, MIGHT BE USEFUL THERAPEUTIC TARGETS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
7  4562  32 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  3747  34 INSIGHTS INTO THE MOLECULAR GENETICS OF MYELOPROLIFERATIVE NEOPLASMS. THE MOLECULAR BIOLOGY OF THE BCR-ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) HAS WITNESSED UNPRECEDENTED ADVANCES SINCE THE DISCOVERY OF THE ACQUIRED JAK2 V617F MUTATION IN 2005. DESPITE THE HIGH PREVALENCE OF JAK2 V617F IN POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), AND PRIMARY MYELOFIBROSIS (PMF), AND THE COMMON FINDING OF DYSREGULATED JAK-STAT SIGNALING IN THESE DISORDERS, IT IS NOW APPRECIATED THAT MPN PATHOGENESIS CAN REFLECT THE ACQUISITION OF MULTIPLE GENETIC MUTATIONS THAT ALTER SEVERAL BIOLOGIC PATHWAYS, INCLUDING EPIGENETIC CONTROL OF GENE EXPRESSION. ALTHOUGH CERTAIN GENE MUTATIONS ARE IDENTIFIED AT HIGHER FREQUENCIES WITH DISEASE EVOLUTION TO THE BLAST PHASE, MPN INITIATION AND PROGRESSION ARE NOT EXPLAINED BY A SINGLE, TEMPORAL PATTERN OF CLONAL CHANGES. A COMPLEX INTERPLAY BETWEEN ACQUIRED MOLECULAR ABNORMALITIES AND HOST GENETIC BACKGROUND, IN ADDITION TO THE TYPE AND ALLELIC BURDEN OF MUTATIONS, CONTRIBUTES TO THE PHENOTYPIC HETEROGENEITY OF MPNS. AT THE POPULATION LEVEL, AN INHERITED PREDISPOSITION TO DEVELOPING MPNS IS LINKED TO A RELATIVELY COMMON JAK2-ASSOCIATED HAPLOTYPE (REFERRED TO AS '46/1'), BUT IT EXHIBITS A RELATIVELY LOW PENETRANCE. THIS REVIEW DETAILS THE CURRENT STATE OF KNOWLEDGE OF THE MOLECULAR GENETICS OF THE CLASSIC MPNS PV, ET, AND PMF AND DISCUSSES THE CLINICAL IMPLICATIONS OF THESE FINDINGS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  2149  23 EPIGENETIC MARKERS TO PREDICT CONVERSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES. CONTEXT: LIFESTYLE FACTORS MEDIATE EPIGENETIC CHANGES THAT CAN CAUSE CHRONIC DISEASES. ALTHOUGH ANIMAL AND LABORATORY STUDIES LINK EPIGENETIC CHANGES TO DIABETES, EPIGENETIC INFORMATION IN WOMEN WITH GESTATIONAL DIABETES (GDM) AND TYPE 2 DIABETES IS LACKING. OBJECTIVE: THIS STUDY SOUGHT TO MEASURE EPIGENETIC MARKERS ACROSS PREGNANCY AND EARLY POSTPARTUM AND IDENTIFY MARKERS THAT COULD BE USED AS PREDICTORS FOR CONVERSION FROM GDM TO TYPE 2 DIABETES. DESIGN: GLOBAL HISTONE H3 DIMETHYLATION WAS MEASURED IN WHITE BLOOD CELLS AT THREE TIME POINTS: 30 WK GESTATION, 8-10 WK POSTPARTUM, AND 20 WK POSTPARTUM, FROM FOUR GROUPS OF WOMEN WITH AND WITHOUT DIABETES. SETTING AND PARTICIPANTS: A TOTAL OF 39 PARTICIPANTS (SIX TO NINE IN EACH GROUP) WERE RECRUITED INCLUDING: NONDIABETIC WOMEN; WOMEN WITH GDM WHO DEVELOPED POSTPARTUM TYPE 2 DIABETES; WOMEN WITH GDM WITHOUT POSTPARTUM TYPE 2 DIABETES; AND WOMEN WITH TYPE 2 DIABETES. MAIN OUTCOME MEASURE: PERCENTAGES OF DIMETHYLATION OF H3 HISTONES RELATIVE TO TOTAL H3 HISTONE METHYLATION WERE COMPARED BETWEEN DIABETIC/NONDIABETIC GROUPS USING APPROPRIATE COMPARATIVE STATISTICS. RESULTS: H3K27 DIMETHYLATION WAS 50-60% LOWER AT 8-10 AND 20 WK POSTPARTUM IN WOMEN WITH GDM WHO DEVELOPED TYPE 2 DIABETES, COMPARED WITH NONDIABETIC WOMEN. H3K4 DIMETHYLATION WAS 75% LOWER AT 8-10 WK POSTPARTUM IN WOMEN WITH GDM WHO SUBSEQUENTLY DEVELOPED TYPE 2 DIABETES COMPARED WITH WOMEN WHO HAD GDM WHO DID NOT. CONCLUSIONS: THE PERCENTAGE OF DIMETHYLATION OF HISTONES H3K27 AND H3K4 VARIED WITH DIABETIC STATE AND HAS THE POTENTIAL AS A PREDICTIVE TOOL TO IDENTIFY WOMEN WHO WILL CONVERT FROM GDM TO TYPE 2 DIABETES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  1947  37 EPIGENETIC ABNORMALITIES IN MYELOPROLIFERATIVE NEOPLASMS: A TARGET FOR NOVEL THERAPEUTIC STRATEGIES. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF CLONAL HEMATOLOGICAL MALIGNANCIES CHARACTERIZED BY A HYPERCELLULAR BONE MARROW AND A TENDENCY TO DEVELOP THROMBOTIC COMPLICATIONS AND TO EVOLVE TO MYELOFIBROSIS AND ACUTE LEUKEMIA. UNLIKE CHRONIC MYELOGENOUS LEUKEMIA, WHERE A SINGLE DISEASE-INITIATING GENETIC EVENT HAS BEEN IDENTIFIED, A MORE COMPLICATED SERIES OF GENETIC MUTATIONS APPEAR TO BE RESPONSIBLE FOR THE BCR-ABL1-NEGATIVE MPNS WHICH INCLUDE POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND PRIMARY MYELOFIBROSIS. RECENT STUDIES HAVE REVEALED A NUMBER OF EPIGENETIC ALTERATIONS THAT ALSO LIKELY CONTRIBUTE TO DISEASE PATHOGENESIS AND DETERMINE CLINICAL OUTCOME. INCREASING EVIDENCE INDICATES THAT ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA EXPRESSION PATTERNS CAN COLLECTIVELY INFLUENCE GENE EXPRESSION AND POTENTIALLY CONTRIBUTE TO MPN PATHOGENESIS. EXAMPLES INCLUDE MUTATIONS IN GENES ENCODING PROTEINS THAT MODIFY CHROMATIN STRUCTURE (EZH2, ASXL1, IDH1/2, JAK2V617F, AND IKZF1) AS WELL AS EPIGENETIC MODIFICATION OF GENES CRITICAL FOR CELL PROLIFERATION AND SURVIVAL (SUPPRESSORS OF CYTOKINE SIGNALING, POLYCYTHEMIA RUBRA VERA-1, CXC CHEMOKINE RECEPTOR 4, AND HISTONE DEACETYLASE (HDAC)). THESE EPIGENETIC LESIONS SERVE AS NOVEL TARGETS FOR EXPERIMENTAL THERAPEUTIC INTERVENTIONS. CLINICAL TRIALS ARE CURRENTLY UNDERWAY EVALUATING HDAC INHIBITORS AND DNA METHYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF PATIENTS WITH MPNS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  4491  30 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS.	1992	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  5799  31 STEPPING OUT OF ANTIQUITY: AN UPDATE ON EMERGING DRUGS FOR THE TREATMENT OF POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA IS A CHRONIC HEMATOLOGIC MALIGNANCY FREQUENTLY PRESENTED WITH CONSTITUTIONAL SYMPTOMS AND ASSOCIATED WITH AN INCREASED RISK OF THROMBOSIS, HEMORRHAGE, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE MYELOID LEUKEMIA. CURRENT TREATMENT STRATEGIES REDUCE THROMBOHEMORRHAGIC RISK BY CONTROLLING BLOOD COUNTS AND INHIBITING PLATELETS, BUT OFTEN FAIL TO ADDRESS DISEASE-RELATED SYMPTOMS OR BIOLOGICALLY MODIFY THE DISEASE.AREAS COVERED: WE REVIEW THE CURRENT PARADIGM FOR TREATING POLYCYTHEMIA VERA, HIGHLIGHT AREAS OF UNMET NEED, REVIEW THERAPEUTIC AGENTS IN LATE STAGE CLINICAL DEVELOPMENT, AND PROVIDE AN OVERARCHING VIEW OF HOW THESE EMERGING AGENT MAY FIT INTO THE FUTURE ARMAMENTARIUM OF POLYCYTHEMIA VERA TREATMENTS.EXPERT OPINION: THE SHIFT FROM FOCUSING SOLELY ON SECONDARY PREVENTION OF THROMBOHEMORRHAGIC EVENTS TO A COMPREHENSIVE TREATMENT STRATEGY THAT ADDITIONALLY AIMS TO IMPROVE QUALITY OF LIFE AND PREVENT DISEASE PROGRESSION HAS RESULTED IN A RAPIDLY EVOLVING THERAPEUTIC LANDSCAPE THAT PROMISES TO MOVE THE TREATMENT OF POLYCYTHEMIA VERA OUT OF ANTIQUITY INTO THE MODERN AGE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  1100  27 COMBINATION OF MYELOPROLIFERATIVE NEOPLASM DRIVER GENE ACTIVATION WITH MUTATIONS OF SPLICE FACTOR OR EPIGENETIC MODIFIER GENES INCREASES RISK OF RAPID BLASTIC PROGRESSION. OBJECTIVES: MYELOPROLIFERATIVE NEOPLASMS (MPN) COMPRISING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF) FOLLOW A BI-PHASIC COURSE OF DISEASE WITH FIBROTIC AND/OR BLASTIC PROGRESSION. AT PRESENTATION IN THE CHRONIC PHASE, CURRENTLY THERE ARE ONLY INSUFFICIENT TOOLS TO PREDICT THE RISK OF PROGRESSION IN INDIVIDUAL CASES. METHODS: IN THIS STUDY, CHRONIC PHASE MPN (16 PMF, 11 PV, AND 11 MPN UNCLASSIFIED) WITH BLASTIC TRANSFORMATION DURING COURSE OF DISEASE (N = 38, MEDIAN FOLLOW-UP 5.3 YEARS) WERE ANALYZED BY HIGH-THROUGHPUT SEQUENCING. MPN CASES WITH A COMPARABLE FOLLOW-UP PERIOD AND WITHOUT EVIDENCE OF BLAST INCREASE SERVED AS CONTROL (N = 63, MEDIAN FOLLOW-UP 5.8 YEARS). RESULTS: FREQUENT ARCH/CHIP-ASSOCIATED MUTATIONS (TET2, ASXL1, DNMT3A) FOUND AT PRESENTATION WERE NOT SIGNIFICANTLY ASSOCIATED WITH BLASTIC TRANSFORMATION. BY CONTRAST, MUTATIONS OF SRSF2, U2AF1, AND IDH1/2 AT FIRST PRESENTATION WERE FREQUENTLY OBSERVED IN THE PROGRESSION COHORT (13/38, 34.2%) AND WERE COMPLETELY MISSING IN THE CONTROL GROUP WITHOUT BLAST TRANSFORMATION DURING FOLLOW-UP (P = .0007 FOR SRSF2; P = .0063 FOR U2AF1 AND IDH1/2). CONCLUSION: UNLIKE FREQUENT ARCH/CHIP ALTERATIONS (TET2, ASXL1, DNMT3A), MUTATIONS IN SRSF2, IDH1/2, AND U2AF1 WHEN MANIFEST ALREADY AT FIRST PRESENTATION PROVIDE AN INDEPENDENT RISK FACTOR FOR RAPID BLAST TRANSFORMATION OF MPN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  4554  34 MUTATIONAL PROFILING IN MYELOFIBROSIS: IMPLICATIONS FOR MANAGEMENT. MUTATIONAL PROFILING, USUALLY BY TARGETED NEXT-GENERATION SEQUENCING, IS INCREASINGLY PERFORMED ON PATIENTS WITH MYELOPROLIFERATIVE NEOPLASM-ASSOCIATED MYELOFIBROSIS (MF), WHETHER PRIMARY (PMF) OR POST-POLYCYTHEMIA VERA/ESSENTIAL THROMBOCYTHEMIA (POST-PV/ET MF). "DRIVER" MUTATIONS IN JAK2, MPL AND INDELS IN CALR UNDERLIE THE VAST MAJORITY OF CASES OF PMF AND POST-ET MF; THE REMAINDER ( APPROXIMATELY 10%) LACK IDENTIFIABLE DRIVER MUTATIONS, BUT OTHER CLONAL MARKERS ARE USUALLY DETECTABLE. NEARLY ALL PATIENTS WITH POST-PV MF CARRY ACTIVATING JAK2 MUTATIONS. IN BOTH PMF AND POST-ET MF, TYPE 1/-LIKE CALR MUTATIONS CONFER A FAVORABLE PROGNOSIS. SINCE BOTH TYPE 1/-LIKE AND TYPE 2/-LIKE CALR MUTATIONS HAVE ESSENTIALLY THE SAME FUNCTIONAL CONSEQUENCE, THIS IS A SUBJECT OF INTENSE RESEARCH. ADDITIONAL, "NON-DRIVER" MUTATIONS, MOSTLY AFFECTING GENES ENCODING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, E.G., ASXL1, EZH2, TET2, DNMT3A, SRSF2 AND U2AF1, ARE FREQUENTLY FOUND; SOME OF THESE ARE ASSOCIATED WITH INFERIOR SURVIVAL AND HAVE BEEN INCORPORATED INTO PROGNOSTIC MODELS. SOME MUTATIONS, E.G., IDH1/2, ARE RELATIVELY INFREQUENT IN CHRONIC PHASE BUT ARE SUBSTANTIALLY MORE COMMON IN BLAST PHASE, AND ARE NOW THERAPEUTICALLY TARGETABLE. WHILE MUTATIONAL INFORMATION DOES NOT CURRENTLY INFLUENCE CHOICE OF DRUG THERAPY IN CHRONIC-PHASE MF, THE PRESENCE OF A "HIGH MOLECULAR RISK" GENOTYPE IS NOW ROUTINELY TAKEN INTO ACCOUNT FOR TRANSPLANT DECISION-MAKING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15  3111  24 GENOTYPE-PHENOTYPE INTERACTIONS IN THE MYELOPROLIFERATIVE NEOPLASMS. THE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL DISORDERS CHARACTERIZED BY OVERPRODUCTION OF MATURE MYELOID CELLS. THEY SHARE ASSOCIATIONS WITH MOLECULAR ABNORMALITIES SUCH AS THE JAK2V617F MUTATION BUT ARE DISTINGUISHED BY IMPORTANT PHENOTYPIC DIFFERENCES. THIS REVIEW FIRST CONSIDERS THE FACTORS THAT MAY INFLUENCE PHENOTYPE IN JAK2-MUTATED MPNS, ESPECIALLY POLYCYTHEMIA VERA (PV) AND ESSENTIAL THROMBOCYTHEMIA (ET), AND THEN DISCUSSES THE MUTATIONS IMPLICATED IN JAK2-NEGATIVE MPNS SUCH AS IN MPL AND EPIGENETIC REGULATORS. CURRENT EVIDENCE SUPPORTS A MODEL WHERE ET AND PV ARE DISORDERS OF RELATIVELY LOW GENETIC COMPLEXITY, WHEREAS EVOLUTION TO MYELOFIBROSIS OR BLAST-PHASE DISEASE REFLECTS ACCUMULATION OF A HIGHER MUTATION BURDEN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16   144  34 ABERRANT DNA METHYLATION PROFILE OF CHRONIC AND TRANSFORMED CLASSIC PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS. MOST DNA METHYLATION STUDIES IN CLASSIC PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS HAVE BEEN PERFORMED ON A GENE-BY-GENE BASIS. THEREFORE, A MORE COMPREHENSIVE METHYLATION PROFILING IS NEEDED TO STUDY THE IMPLICATIONS OF THIS EPIGENETIC MARKER IN MYELOPROLIFERATIVE NEOPLASMS. HERE, WE HAVE ANALYZED 71 CHRONIC (24 POLYCYTHEMIA VERA, 23 ESSENTIAL THROMBOCYTHEMIA AND 24 PRIMARY MYELOFIBROSIS) AND 13 TRANSFORMED MYELOPROLIFERATIVE NEOPLASMS USING GENOME-WIDE DNA METHYLATION ARRAYS. THE THREE TYPES OF CHRONIC PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS SHOWED A SIMILAR ABERRANT DNA METHYLATION PATTERN WHEN COMPARED TO CONTROL SAMPLES. DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN A GENE NETWORK CENTERED ON THE NF-KAPPAB PATHWAY, INDICATING THAT THEY MAY BE INVOLVED IN THE PATHOGENESIS OF THESE DISEASES. IN THE CASE OF TRANSFORMED MYELOPROLIFERATIVE NEOPLASMS, WE DETECTED AN INCREASED NUMBER OF DIFFERENTIALLY METHYLATED REGIONS WITH RESPECT TO CHRONIC MYELOPROLIFERATIVE NEOPLASMS. INTERESTINGLY, THESE GENES WERE ENRICHED IN A LIST OF DIFFERENTIALLY METHYLATED REGIONS IN PRIMARY ACUTE MYELOID LEUKEMIA AND IN A GENE NETWORK CENTERED AROUND THE IFN PATHWAY. OUR RESULTS SUGGEST THAT ALTERATIONS IN THE DNA METHYLATION LANDSCAPE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS AND LEUKEMIC TRANSFORMATION OF MYELOPROLIFERATIVE NEOPLASMS. THE THERAPEUTIC MODULATION OF EPIGENETICALLY-DEREGULATED PATHWAYS MAY ALLOW US TO DESIGN TARGETED THERAPIES FOR THESE PATIENTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  4555  26 MUTATIONAL SPECTRUM ANALYSIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA INCLUDES GENES ASSOCIATED WITH EPIGENETIC REGULATION: UTX, EZH2, AND DNMT3A. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY MONOCYTIC PROLIFERATION, DYSPLASIA, AND PROGRESSION TO ACUTE MYELOID LEUKEMIA. CMML HAS BEEN ASSOCIATED WITH SOMATIC MUTATIONS IN DIVERSE RECENTLY IDENTIFIED GENES. WE ANALYZED 72 WELL-CHARACTERIZED PATIENTS WITH CMML (N = 52) AND CMML-DERIVED ACUTE MYELOID LEUKEMIA (N = 20) FOR RECURRENT CHROMOSOMAL ABNORMALITIES WITH THE USE OF ROUTINE CYTOGENETICS AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS ALONG WITH COMPREHENSIVE MUTATIONAL SCREENING. CYTOGENETIC ABERRATIONS WERE PRESENT IN 46% OF CASES, WHEREAS SINGLE NUCLEOTIDE POLYMORPHISM ARRAY INCREASED THE DIAGNOSTIC YIELD TO 60%. AT LEAST 1 MUTATION WAS FOUND IN 86% OF ALL CASES; NOVEL UTX, DNMT3A, AND EZH2 MUTATIONS WERE FOUND IN 8%, 10%, AND 5.5% OF PATIENTS, RESPECTIVELY. TET2 MUTATIONS WERE PRESENT IN 49%, ASXL1 IN 43%, CBL IN 14%, IDH1/2 IN 4%, KRAS IN 7%, NRAS IN 4%, AND JAK2 V617F IN 1% OF PATIENTS. VARIOUS MUTANT GENOTYPE COMBINATIONS WERE OBSERVED, INDICATING MOLECULAR HETEROGENEITY IN CMML. OUR RESULTS SUGGEST THAT MOLECULAR DEFECTS AFFECTING DISTINCT PATHWAYS CAN LEAD TO SIMILAR CLINICAL PHENOTYPES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18   960  35 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  6040  37 THE CHRONIC MYELOPROLIFERATIVE DISORDERS: CLONALITY AND CLINICAL HETEROGENEITY. THE CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD), POLYCYTHEMIA VERA (PV), CHRONIC IDIOPATHIC MYELOFIBROSIS (IMF), ESSENTIAL THROMBOCYTOSIS (ET), AND CHRONIC MYELOGENOUS LEUKEMIA (CML), ARE THOUGHT TO BE CLONAL DISORDERS ARISING IN A MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL. HOWEVER, ESTABLISHING THE DIAGNOSIS OF AN MPD OTHER THAN CML IS PROBLEMATIC DUE TO A LACK OF CLINICALLY APPLICABLE CLONAL MARKERS. FURTHERMORE, IN SOME PATIENTS, IN WHOM A CLASSICAL MPD PHENOTYPE IS PRESENT, THE HEMATOPOIETIC STEM CELLS APPEAR TO BE POLYCLONAL, SUGGESTING THAT THE CHRONIC MPD OTHER THAN CML MAY ACTUALLY BE A GENETICALLY HETEROGENEOUS GROUP OF DISORDERS. FURTHERMORE, SINCE THE ABERRANT CLONE IS BELIEVED TO ARISE FROM A MULTIPOTENT HEMATOPOIETIC STEM CELL, THE NON-CML CHRONIC MPD-ET, PV, AND IMF-COULD BE RELATED. ADDITIONAL UNRESOLVED ISSUES REGARDING THE MPD INCLUDE: IDENTIFICATION OF THE MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL INVOLVED, THE MOLECULAR BASIS FOR THE CLINICAL HETEROGENEITY AMONGST THE INDIVIDUAL MPD, THE CLINICAL SIGNIFICANCE OF CLONALITY IN NON-CML MPD, AND RECONCILIATION OF THERAPY WITH THE CLONAL AND CLINICAL HETEROGENEITY OF THESE DISORDERS. DETERMINATION OF CLONALITY HAS LARGELY BEEN CARRIED OUT USING X CHROMOSOME-LINKED POLYMORPHISMS, BUT SUCH STUDIES ARE LIMITED TO WOMEN AND WITH INCREASING PATIENT AGE ARE COMPROMISED BY SKEWING OF ALLELIC EXPRESSION IN BOTH NEUTROPHILS AND T LYMPHOCYTES, MAKING THE RESULTS DIFFICULT TO INTERPRET. X CHROMOSOME-LINKED POLYMORPHISM STUDIES HAVE INDICATED THAT IN PV THE TARGET STEM CELL IS ONE THAT GIVES RISE TO BOTH LYMPHOID AND MYELOID PROGENITORS. RECENTLY, TWO EPIGENETIC MARKERS HAVE BEEN IDENTIFIED IN THE MPD: IMPAIRED EXPRESSION OF THE THROMBOPOIETIN RECEPTOR, MPL, IN PLATELETS AND MEGAKARYOCYTES, AND OVEREXPRESSION IN NEUTROPHILS OF THE MRNA OF A GENE DESIGNATED POLYCYTHEMIA RUBRA VERA-1 (PRV-1). THE ROLE OF THESE EPIGENETIC ABNORMALITIES IN THE DIAGNOSIS OF THE MPD REMAINS TO BE ESTABLISHED. CURRENTLY, GIVEN THE UNRESOLVED ISSUES WITH RESPECT TO THE CLINICAL AND CLONAL HETEROGENEITY OF THE MPD, TREATMENT NEEDS TO BE TAILORED INDIVIDUALLY IN PATIENTS WITH AN MPD.	2004	
                                                                                                                                                                                                                                                                                                                                                       
20  4010  23 LOW MATERNAL ADHERENCE TO A MEDITERRANEAN DIET IS ASSOCIATED WITH INCREASE IN METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION IN FEMALE INFANTS. DIET IS DICTATED BY THE SURROUNDING ENVIRONMENT, AS FOOD ACCESS AND AVAILABILITY MAY CHANGE DEPENDING ON WHERE ONE LIVES. MATERNAL DIET DURING PREGNANCY IS AN IMPORTANT PART OF THE IN UTERO ENVIRONMENT, AND MAY AFFECT THE EPIGENOME. STUDIES LOOKING AT OVERALL DIET PATTERN IN RELATION TO DNA METHYLATION HAVE BEEN LACKING. THE MEDITERRANEAN DIET IS KNOWN FOR ITS HEALTH BENEFITS, INCLUDING DECREASED INFLAMMATION, WEIGHT LOSS, AND MANAGEMENT OF CHRONIC DISEASES. THIS STUDY ASSESSES THE ASSOCIATION BETWEEN MATERNAL ADHERENCE TO A MEDITERRANEAN DIET PATTERN DURING PREGNANCY AND INFANT DNA METHYLATION AT BIRTH. MEDITERRANEAN DIET ADHERENCE IN EARLY PREGNANCY WAS MEASURED IN 390 WOMEN ENROLLED IN THE NEWBORN EPIGENETIC STUDY, AND DNA METHYLATION WAS ASSESSED IN THEIR INFANTS AT BIRTH. MULTINOMIAL LOGISTIC REGRESSION WAS USED TO ASSESS THE ASSOCIATION BETWEEN ADHERENCE TO A MEDITERRANEAN DIET AND INFANT METHYLATION AT THE MEG3, MEG3-IG, PLEIOMORPHIC ADENOMA GENE-LIKE 1, INSULIN-LIKE GROWTH FACTOR 2 GENE, H19, MESODERM-SPECIFIC TRANSCRIPT, NEURONATIN, PATERNALLY EXPRESSED GENE 3, SARCOGLYCAN AND PATERNALLY EXPRESSED GENE 10 REGIONS, MEASURED BY PYROSEQUENCING. INFANTS OF MOTHERS WITH A LOW ADHERENCE TO A MEDITERRANEAN DIET HAD A GREATER ODDS OF HYPO-METHYLATION AT THE MEG3-IG DIFFERENTIALLY METHYLATED REGION (DMR). SEX-STRATIFIED MODELS SHOWED THAT THIS ASSOCIATION WAS PRESENT IN GIRLS ONLY. THIS STUDY PROVIDES EARLY EVIDENCE ON THE ASSOCIATION BETWEEN OVERALL DIET PATTERN AND METHYLATION AT THE 9 DMRS INCLUDED IN THIS STUDY, AND SUGGESTS THAT MATERNAL DIET CAN HAVE A SEX-SPECIFIC IMPACT ON INFANT DNA METHYLATION AT SPECIFIC IMPRINTED DMRS.	2017