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[PMID]:29341561
[Au] Autor:Dobrosavljevic A; Martic J; Rakic S; Pazin V; Jankovic-Raznatovic S; Sreckovic S; Dobrosavljevic B
[Ti] Título:Massive fetomaternal hemorrhage as a cause of severe fetal anemia.
[So] Source:Vojnosanit Pregl;73(11):1068-71, 2016 Nov.
[Is] ISSN:0042-8450
[Cp] País de publicação:Serbia
[La] Idioma:eng
[Ab] Resumo:Introduction: Fetomaternal hemorrhage (FMH) is a transfu-sion of fetal blood into the maternal circulation. A volume of transfused fetal blood required to cause severe, life-threatening fetal anemia, is not clearly defined. Some authors suggest vol-umes of 80 mL and 150 mL as a threshold which defines mas-sive FMH. Therefore, a rate of massive FMH is 1 : 1,000 and 1 : 5,000 births, respectively. Fetal and neonatal anemia is one of the most serious complications of the FMH. Clinical manifesta-tions of FMH are nonspecific, and mostly it presented as re-duced fetal movements and changes in cardiotocography (CTG). The standard for diagnosing FMH is Kleihaurer-Betke test. Case report: A 34-year-old gravida (G) 1, para (P) 1 was hospitalized due to uterine contractions at 39 weeks of gesta-tion. CTG monitoring revealed sinusoidal fetal heart rate and clinical examination showed complete cervical dilatation. Im-mediately after admission, the women delivered vaginally. Ap-gar scores were 1 and 2 at the first and fifth minute, respec-tively. Immediately baby was intubated and mechanical ventila-tion started. Initial analysis revealed pronounced acidosis and severe anemia. The patient received intravenous fluid therapy with sodium-bicarbonate as well as red cell transfusion. With all measures, the condition of the baby improved with normaliza-tion of hemoglobin level and blood pH. Kleihaurer-Betke test revealed the presence of fetal red cells in maternal circulation, equivalent to 531 mL blood loss. The level of maternal fetal hemoglobin (HbF) and elevated alpha fetoprotein also con-firmed the diagnosis of massive FMH. Conclusion: For the successful diagnosis and management of FMH direct commu-nication between the obstetrician and the pediatrician is neces-sary as presented in this report.
[Mh] Termos MeSH primário: Anemia Neonatal/etiologia
Transfusão Feto-Materna/complicações
Circulação Placentária
[Mh] Termos MeSH secundário: Adulto
Anemia Neonatal/sangue
Anemia Neonatal/diagnóstico
Anemia Neonatal/terapia
Asfixia Neonatal/etiologia
Biomarcadores/sangue
Cardiotocografia
Transfusão de Eritrócitos
Feminino
Hemoglobina Fetal/metabolismo
Transfusão Feto-Materna/sangue
Transfusão Feto-Materna/diagnóstico
Transfusão Feto-Materna/terapia
Hidratação
Seres Humanos
Nascimento Vivo
Gravidez
Resultado do Tratamento
alfa-Fetoproteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AFP protein, human); 0 (Biomarkers); 0 (alpha-Fetoproteins); 9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.2298/VSP150605130D


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[PMID]:28450766
[Au] Autor:Vincent O; Oluwaseyi B; James B; Saidat L
[Ad] Endereço:Haematology and Blood Transfusion Science Department, University of Lagos, Nigeria.
[Ti] Título:Coinheritance of B-Thalassemia and Sickle Cell Anaemia in Southwestern Nigeria.
[So] Source:Ethiop J Health Sci;26(6):517-522, 2016 Nov.
[Is] ISSN:2413-7170
[Cp] País de publicação:Ethiopia
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Genes for haemoglobin S are found in high frequencies in Nigeria. However, there is little information on beta thalassemia in sickle cell anaemia in this population. The clinical presentation of HbS- ß thalassemia is enormously variable, ranging from an asymptomatic state to a severe disorder similar to homozygous sickle cell disease. MATERIALS AND METHODS: Haemoglobin A and HbF were determined in sickle cell anaemia patients attending LAUTECH Teaching Hospital, Osogbo, by elution after electrophoresis and alkaline denaturation methods respectively. Haematological parameters were estimated using Sysmex KX-21N and percentage target cells using Leishman's staining technique. RESULTS: Exactly 6% f the SCA patients were found to have elevated HbA (>3.3%) and HbF (>1.3%). These patients also had normal erythrocyte indices, increased platelet count, a significantly higher HCT and an increased % target cell. CONCLUSION: These findings confirm that the frequency of beta thalassaemia in sickle cell patients in Nigeria is higher than previously thought. It is therefore important to consider the possibility of this variant in patients with sickle cell anaemia since their course may differ from that of patients with homozygous sickle cell anaemia.
[Mh] Termos MeSH primário: Anemia Falciforme/epidemiologia
Anemia Falciforme/genética
Talassemia beta/epidemiologia
Talassemia beta/genética
[Mh] Termos MeSH secundário: Estudos Transversais
Índices de Eritrócitos
Feminino
Hemoglobina Fetal/análise
Hematócrito
Hemoglobina A2/análise
Seres Humanos
Masculino
Nigéria/epidemiologia
Contagem de Plaquetas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9034-53-1 (Hemoglobin A2); 9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


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[PMID]:28880867
[Au] Autor:Molokie R; Lavelle D; Gowhari M; Pacini M; Krauz L; Hassan J; Ibanez V; Ruiz MA; Ng KP; Woost P; Radivoyevitch T; Pacelli D; Fada S; Rump M; Hsieh M; Tisdale JF; Jacobberger J; Phelps M; Engel JD; Saraf S; Hsu LL; Gordeuk V; DeSimone J; Saunthararajah Y
[Ad] Endereço:Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, Illinois, United States of America.
[Ti] Título:Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study.
[So] Source:PLoS Med;14(9):e1002382, 2017 Sep.
[Is] ISSN:1549-1676
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1). METHODS AND FINDINGS: To pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical trial (NCT01685515) combined 2 small molecules-decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates decitabine, severely limiting its half-life, tissue distribution, and oral bioavailability. Oral decitabine doses, administered after oral THU 10 mg/kg, were escalated from a very low starting level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in depleting DNMT1 without cytotoxicity. Patients were SCD adults at risk of early death despite standard-of-care, randomized 3:2 to THU-decitabine versus placebo in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of follow-up. The primary endpoint was ≥ grade 3 non-hematologic toxicity. This endpoint was not triggered, and adverse events (AEs) were not significantly different in THU-decitabine-versus placebo-treated patients. At the decitabine 0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (Cmax) and remained elevated for several hours. This dose decreased DNMT1 protein in peripheral blood mononuclear cells by >75% and repetitive element CpG methylation by approximately 10%, and increased HbF by 4%-9% (P < 0.001), doubling fetal hemoglobin-enriched red blood cells (F-cells) up to approximately 80% of total RBCs. Total hemoglobin increased by 1.2-1.9 g/dL (P = 0.01) as reticulocytes simultaneously decreased; that is, better quality and efficiency of HbF-enriched erythropoiesis elevated hemoglobin using fewer reticulocytes. Also indicating better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation (LDH, bilirubin, D-dimer, C-reactive protein [CRP]) improved. As expected with non-cytotoxic DNMT1-depletion, platelets increased and neutrophils concurrently decreased, but not to an extent requiring treatment holds. As an early phase study, limitations include small patient numbers at each dose level and narrow capacity to evaluate clinical benefits. CONCLUSION: Administration of oral THU-decitabine to patients with SCD was safe in this study and, by targeting DNMT1, upregulated HbF in RBCs. Further studies should investigate clinical benefits and potential harms not identified to date. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01685515.
[Mh] Termos MeSH primário: Anemia Falciforme/tratamento farmacológico
Azacitidina/análogos & derivados
Inibidores Enzimáticos/administração & dosagem
Epigênese Genética/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Tetra-Hidrouridina/administração & dosagem
[Mh] Termos MeSH secundário: Adulto
Anemia Falciforme/genética
Azacitidina/administração & dosagem
Azacitidina/farmacologia
Quimioterapia Combinada
Inibidores Enzimáticos/farmacologia
Feminino
Hemoglobina Fetal/efeitos dos fármacos
Inativação Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Meia-Idade
Tetra-Hidrouridina/farmacologia
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 18771-50-1 (Tetrahydrouridine); 776B62CQ27 (decitabine); 9034-63-3 (Fetal Hemoglobin); M801H13NRU (Azacitidine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170917
[Lr] Data última revisão:
170917
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pmed.1002382


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[PMID]:28851297
[Au] Autor:Breveglieri G; Bianchi N; Cosenza LC; Gamberini MR; Chiavilli F; Zuccato C; Montagner G; Borgatti M; Lampronti I; Finotti A; Gambari R
[Ad] Endereço:Department of Life Sciences and Biotechnology, Ferrara University, Via Fossato di Mortara 74, 44121, Ferrara, Italy.
[Ti] Título:An Aγ-globin G->A gene polymorphism associated with ß 39 thalassemia globin gene and high fetal hemoglobin production.
[So] Source:BMC Med Genet;18(1):93, 2017 Aug 29.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Increase of the expression of γ-globin gene and high production of fetal hemoglobin (HbF) in ß-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify ß-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea). METHODS: Aγ-globin gene sequencing was performed on genomic DNA isolated from a total of 75 ß-thalassemia patients, including 31 ß 39/ß 39, 33 ß 39/ß IVSI-110, 9 ß IVSI-110/ß IVSI-110, one ß IVSI-1/ß IVSI-6 and one ß 39/ß IVSI-6. RESULTS: The results show that the rs368698783 polymorphism is present in ß-thalassemia patients in the 5'UTR sequence (+25) of the Aγ-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This Aγ(+25 G->A) polymorphism is associated with the Gγ-globin-XmnI polymorphism and both are linked with the ß 39-globin gene, but not with the ß IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the Aγ(+25 G->A) and Gγ-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from ß 39/ß 39 thalassemia patients. CONCLUSIONS: As a potential explanation of our findings, we hypothesize that in ß-thalassemia the Gγ-globin-XmnI/Aγ-globin-(G->A) genotype is frequently under genetic linkage with ß -thalassemia mutations, but not with the ß -thalassemia mutation here studied (i.e. ß IVSI-110) and that this genetic combination has been selected within the population of ß -thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the Aγ-globin gene associated in ß 39 thalassemia patients with high HbF in erythroid precursor cells.
[Mh] Termos MeSH primário: Hemoglobina Fetal/biossíntese
Polimorfismo Genético
Talassemia beta/genética
gama-Globinas/genética
[Mh] Termos MeSH secundário: Sítios de Ligação/genética
Proteínas de Ligação a DNA/metabolismo
Feminino
Seres Humanos
Desequilíbrio de Ligação
Masculino
Proteínas Nucleares/metabolismo
Mutação Puntual
Análise de Sequência de DNA
gama-Globinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (LYAR protein, human); 0 (Nuclear Proteins); 0 (gamma-Globins); 9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0450-3


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[PMID]:28776729
[Au] Autor:Dai Y; Chen T; Ijaz H; Cho EH; Steinberg MH
[Ad] Endereço:Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, 02118.
[Ti] Título:SIRT1 activates the expression of fetal hemoglobin genes.
[So] Source:Am J Hematol;92(11):1177-1186, 2017 Nov.
[Is] ISSN:1096-8652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:High fetal hemoglobin (HbF, α γ ) levels ameliorate the clinical manifestations of sickle cell disease and ß thalassemia. The mechanisms that repress HbF expression and silence γ-globin genes in adults are incompletely characterized and only a single HbF inducer, hydroxyurea, is approved for treatment, and only in patients with sickle cell disease. We identified SIRT1, a protein deacetylase, as a new inducer of γ-globin. SIRT1 knockdown decreased, while SIRT1 ectopic expression upregulated γ-globin gene (HBG) expression in primary human erythroid cells and in K562 cells. The small molecule SIRT1 activators SRT2104 and SRT1720 enhanced HBG expression in cord blood human erythroblasts and reactivated silenced HBG in adult human erythroblasts. Furthermore, SIRT1 binds in the ß-globin gene cluster locus control region (LCR) and HBG promoters, promotes the looping of the LCR to HBG promoter, and increases the binding of RNA polymerase II and H4K16Ac in the HBG promoter. SIRT1 suppressed the expression of the HBG suppressors BCL11A, KLF1, HDAC1 and HDAC2. Lastly, SIRT1 did not change the proliferation of human erythroid progenitor cells or the expression of differentiation marker CD235a. These data suggest that SIRT1 activates HBG expression through facilitating LCR looping to the HBG promoter, inhibiting the expression of transcriptional suppressors of HBG, and indirectly increasing histone acetylation in the HBG promoter. SIRT1 is a potential therapeutic target for γ-globin gene induction, and small molecule SIRT1 activators might serve as a lead compound for the development of new HbF inducers.
[Mh] Termos MeSH primário: Hemoglobina Fetal/genética
Regulação da Expressão Gênica
Sirtuína 1/metabolismo
Ativação Transcricional
gama-Globinas/genética
[Mh] Termos MeSH secundário: Diferenciação Celular/genética
Proliferação Celular/genética
Expressão Ectópica do Gene
Eritroblastos/metabolismo
Células Precursoras Eritroides/metabolismo
Eritropoese/genética
Hemoglobina Fetal/metabolismo
Técnicas de Silenciamento de Genes
Inativação Gênica
Seres Humanos
Células K562
Região de Controle de Locus Gênico
Especificidade de Órgãos/genética
Regiões Promotoras Genéticas
Ligação Proteica
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Sirtuína 1/genética
gama-Globinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (gamma-Globins); 9034-63-3 (Fetal Hemoglobin); EC 3.5.1.- (Sirtuin 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24879


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[PMID]:28736939
[Au] Autor:Habara AH; Shaikho EM; Steinberg MH
[Ad] Endereço:Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, 02118.
[Ti] Título:Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents.
[So] Source:Am J Hematol;92(11):1233-1242, 2017 Nov.
[Is] ISSN:1096-8652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.
[Mh] Termos MeSH primário: Anemia Falciforme/sangue
Anemia Falciforme/genética
Hemoglobina Fetal/genética
[Mh] Termos MeSH secundário: Anemia Falciforme/tratamento farmacológico
Anemia Falciforme/metabolismo
Animais
Sítios de Ligação
Hemoglobina Fetal/metabolismo
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Haplótipos
Hemoglobina Falciforme/genética
Seres Humanos
MicroRNAs/genética
MicroRNAs/metabolismo
Terapia de Alvo Molecular
Família Multigênica
Motivos de Nucleotídeos
Fenótipo
Ligação Proteica
Sequências Reguladoras de Ácido Nucleico
Fatores de Transcrição/metabolismo
Globinas beta/genética
gama-Globinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Hemoglobin, Sickle); 0 (MicroRNAs); 0 (Transcription Factors); 0 (beta-Globins); 0 (gamma-Globins); 9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170725
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24872


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[PMID]:28669403
[Au] Autor:Chen D; Zuo Y; Zhang X; Ye Y; Bao X; Huang H; Tepakhan W; Wang L; Ju J; Chen G; Zheng M; Liu D; Huang S; Zong L; Li C; Chen Y; Zheng C; Shi L; Zhao Q; Wu Q; Fucharoen S; Zhao C; Xu X
[Ad] Endereço:Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, 510515, China.
[Ti] Título:A Genetic Variant Ameliorates ß-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression.
[So] Source:Am J Hum Genet;101(1):130-138, 2017 Jul 06.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of ß-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the ß-globin cluster using capture-based next-generation sequencing of 1142 Chinese ß-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for ß-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of ß-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from ß-thalassemia persons. The present study demonstrates that this common rSNP in the proximal γ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of ß-hemoglobinopathy.
[Mh] Termos MeSH primário: Epigênese Genética
Hemoglobina Fetal/genética
Variação Genética
Talassemia beta/genética
[Mh] Termos MeSH secundário: Sequência de Bases
Células Cultivadas
Pré-Escolar
Estudos de Coortes
Feminino
Hemoglobina Fetal/metabolismo
Seres Humanos
Lactente
Células K562
Masculino
Polimorfismo de Nucleotídeo Único/genética
Regiões Promotoras Genéticas
Modelos de Riscos Proporcionais
Transcrição Genética
Ativação Transcricional/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE


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[PMID]:28659276
[Au] Autor:Wienert B; Martyn GE; Kurita R; Nakamura Y; Quinlan KGR; Crossley M
[Ad] Endereço:School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW Sydney), Sydney, NSW, Australia.
[Ti] Título:KLF1 drives the expression of fetal hemoglobin in British HPFH.
[So] Source:Blood;130(6):803-807, 2017 Aug 10.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ß-Hemoglobinopathies are among the most common single-locus inherited diseases. In this condition, high fetal hemoglobin (HbF) levels have been found to be beneficial, and boosting HbF expression is seen as an attractive therapy. Naturally occurring mutations in the fetal promoter can result in high HbF persisting into adulthood in a benign condition known as hereditary persistence of fetal hemoglobin (HPFH). Individuals with one form of HPFH, British HPFH, carry a T to C substitution at position -198 of the fetal gene promoter. These individuals exhibit HbF levels of up to 20%, enough to ameliorate the symptoms of ß-hemoglobinopathies. Here, we use clustered regularly interspaced short palindromic repeat-mediated genome editing to introduce the -198 substitution into human erythroid HUDEP-2 cells and show that this mutation is sufficient to substantially elevate expression of HbF. We also examined the molecular mechanism underlying the increase in fetal expression. Through a combination of in vitro and in vivo studies, we demonstrate that the mutation creates a de novo binding site for the important erythroid gene activator Krüppel-like factor 1 (KLF1/erythroid KLF). Our results indicate that introducing this single naturally occurring mutation leads to significantly boosted HbF levels.
[Mh] Termos MeSH primário: Células Eritroides/metabolismo
Hemoglobina Fetal/genética
Fatores de Transcrição Kruppel-Like/metabolismo
Mutação Puntual
Regulação para Cima
gama-Globinas/genética
[Mh] Termos MeSH secundário: Linhagem Celular
Seres Humanos
Regiões Promotoras Genéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kruppel-Like Transcription Factors); 0 (erythroid Kruppel-like factor); 0 (gamma-Globins); 9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170815
[Lr] Data última revisão:
170815
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-02-767400


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[PMID]:28643377
[Au] Autor:Green NS; Manwani D; Matos S; Hicks A; Soto L; Castillo Y; Ireland K; Stennett Y; Findley S; Jia H; Smaldone A
[Ad] Endereço:Department of Pediatrics, Columbia University Medical Center, New York, New York.
[Ti] Título:Randomized feasibility trial to improve hydroxyurea adherence in youth ages 10-18 years through community health workers: The HABIT study.
[So] Source:Pediatr Blood Cancer;64(12), 2017 Dec.
[Is] ISSN:1545-5017
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The main therapeutic intervention for sickle cell disease (SCD) is hydroxyurea (HU). The effect of HU is largely through dose-dependent induction of fetal hemoglobin (HbF). Poor HU adherence is common among adolescents. METHODS: Our 6-month, two-site pilot intervention trial, "HABIT," was led by culturally aligned community health workers (CHWs). CHWs performed support primarily through home visits, augmented by tailored text message reminders. Dyads of youth with SCD ages 10-18 years and a parent were enrolled. A customized HbF biomarker, the percentage decrease from each patients' highest historical HU-induced HbF, "Personal best," was used to qualify for enrollment and assess HU adherence. Two primary outcomes were as follows: (1) intervention feasibility and acceptability and (2) HU adherence measured in three ways: monthly percentage improvement toward HbF Personal best, proportion of days covered (PDC) by HU, and self-report. RESULTS: Twenty-eight dyads were enrolled, of which 89% were retained. Feasibility and acceptability were excellent. Controlling for group assignment and month of intervention, the intervention group improved percentage decrease from Personal best by 2.3% per month during months 0-4 (P = 0.30), with similar improvement in adherence demonstrated using pharmacy records. Self-reported adherence did not correlate. Dyads viewed CHWs as supportive for learning about SCD and HU, living with SCD and making progress in coordinated self-management responsibility to support a daily HU habit. Most parents and youth appreciated text message HU reminders. CONCLUSIONS: The HABIT pilot intervention demonstrated feasibility and acceptability with promising effect toward improved medication adherence. Testing in a larger multisite intervention trial is warranted.
[Mh] Termos MeSH primário: Anemia Falciforme/tratamento farmacológico
Agentes Comunitários de Saúde
Hidroxiureia/uso terapêutico
Adesão à Medicação
[Mh] Termos MeSH secundário: Adolescente
Anemia Falciforme/sangue
Criança
Estudos de Viabilidade
Feminino
Hemoglobina Fetal/análise
Seres Humanos
Masculino
Projetos Piloto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
9034-63-3 (Fetal Hemoglobin); X6Q56QN5QC (Hydroxyurea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1002/pbc.26689


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[PMID]:28423290
[Au] Autor:Piel FB; Steinberg MH; Rees DC
[Ad] Endereço:From the Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England (MRC-PHE) Centre for Environment and Health, School of Public Health, Imperial College London (F.B.P.), and the Department of Haematological Medicine, King's College Hospital, King's College London (D.C.R.), London; and the Department of Medicine, Boston University School of Medicine, Boston (M.H.S.).
[Ti] Título:Sickle Cell Disease.
[So] Source:N Engl J Med;376(16):1561-1573, 2017 04 20.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Anemia Falciforme
[Mh] Termos MeSH secundário: Poluição do Ar/efeitos adversos
Anemia Falciforme/complicações
Anemia Falciforme/epidemiologia
Anemia Falciforme/genética
Anemia Falciforme/terapia
Hemoglobina Fetal/fisiologia
Seres Humanos
Recém-Nascido
Infecção/complicações
Fenótipo
Talassemia alfa/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
9034-63-3 (Fetal Hemoglobin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMra1510865



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