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  1 / 1207 MEDLINE  
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[PMID]:28453575
[Au] Autor:Hodonsky CJ; Jain D; Schick UM; Morrison JV; Brown L; McHugh CP; Schurmann C; Chen DD; Liu YM; Auer PL; Laurie CA; Taylor KD; Browning BL; Li Y; Papanicolaou G; Rotter JI; Kurita R; Nakamura Y; Browning SR; Loos RJF; North KE; Laurie CC; Thornton TA; Pankratz N; Bauer DE; Sofer T; Reiner AP
[Ad] Endereço:Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC, United States of America.
[Ti] Título:Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.
[So] Source:PLoS Genet;13(4):e1006760, 2017 Apr.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prior GWAS have identified loci associated with red blood cell (RBC) traits in populations of European, African, and Asian ancestry. These studies have not included individuals with an Amerindian ancestral background, such as Hispanics/Latinos, nor evaluated the full spectrum of genomic variation beyond single nucleotide variants. Using a custom genotyping array enriched for Amerindian ancestral content and 1000 Genomes imputation, we performed GWAS in 12,502 participants of Hispanic Community Health Study and Study of Latinos (HCHS/SOL) for hematocrit, hemoglobin, RBC count, RBC distribution width (RDW), and RBC indices. Approximately 60% of previously reported RBC trait loci generalized to HCHS/SOL Hispanics/Latinos, including African ancestral alpha- and beta-globin gene variants. In addition to the known 3.8kb alpha-globin copy number variant, we identified an Amerindian ancestral association in an alpha-globin regulatory region on chromosome 16p13.3 for mean corpuscular volume and mean corpuscular hemoglobin. We also discovered and replicated three genome-wide significant variants in previously unreported loci for RDW (SLC12A2 rs17764730, PSMB5 rs941718), and hematocrit (PROX1 rs3754140). Among the proxy variants at the SLC12A2 locus we identified rs3812049, located in a bi-directional promoter between SLC12A2 (which encodes a red cell membrane ion-transport protein) and an upstream anti-sense long-noncoding RNA, LINC01184, as the likely causal variant. We further demonstrate that disruption of the regulatory element harboring rs3812049 affects transcription of SLC12A2 and LINC01184 in human erythroid progenitor cells. Together, these results reinforce the importance of genetic study of diverse ancestral populations, in particular Hispanics/Latinos.
[Mh] Termos MeSH primário: Proteínas de Homeodomínio/genética
Complexo de Endopeptidases do Proteassoma/genética
RNA Longo não Codificante/genética
Membro 2 da Família 12 de Carreador de Soluto/genética
Proteínas Supressoras de Tumor/genética
alfa-Globinas/genética
[Mh] Termos MeSH secundário: Contagem de Eritrócitos
Eritrócitos
Feminino
Estudo de Associação Genômica Ampla
Hemoglobinas/genética
Hispano-Americanos/genética
Seres Humanos
Masculino
Polimorfismo de Nucleotídeo Único
Globinas beta/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hemoglobins); 0 (Homeodomain Proteins); 0 (RNA, Long Noncoding); 0 (SLC12A2 protein, human); 0 (Solute Carrier Family 12, Member 2); 0 (Tumor Suppressor Proteins); 0 (alpha-Globins); 0 (beta-Globins); 0 (long noncoding RNA LINC01186, human); 0 (prospero-related homeobox 1 protein); EC 3.4.25.1 (PSMB5 protein, human); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171228
[Lr] Data última revisão:
171228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006760


  2 / 1207 MEDLINE  
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[PMID]:28916711
[Au] Autor:Huang P; Keller CA; Giardine B; Grevet JD; Davies JOJ; Hughes JR; Kurita R; Nakamura Y; Hardison RC; Blobel GA
[Ad] Endereço:Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
[Ti] Título:Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element.
[So] Source:Genes Dev;31(16):1704-1713, 2017 Aug 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled ß-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and ß) globin genes (encompassing the and noncoding genes) and two distal chromosomal sites (HS5 and 3'HS1) that flank the locus. In contrast, in adult cells, the - region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR-γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new control elements.
[Mh] Termos MeSH primário: Cromatina/química
Eritroblastos/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Elementos Reguladores de Transcrição
Globinas beta/genética
[Mh] Termos MeSH secundário: Adulto
Proteínas de Transporte/genética
Feto
Inativação Gênica
Seres Humanos
Região de Controle de Locus Gênico
Proteínas Nucleares/genética
Pseudogenes
Transcriptoma
gama-Globinas/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL11A protein, human); 0 (Carrier Proteins); 0 (Chromatin); 0 (Nuclear Proteins); 0 (beta-Globins); 0 (gamma-Globins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171029
[Lr] Data última revisão:
171029
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1101/gad.303461.117


  3 / 1207 MEDLINE  
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[PMID]:28910278
[Au] Autor:Park S; Han CR; Park JW; Zhao L; Zhu X; Willingham M; Bodine DM; Cheng SY
[Ad] Endereço:Laboratory of Molecular Biology, the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
[Ti] Título:Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene.
[So] Source:PLoS Genet;13(9):e1006991, 2017 Sep.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Patients with mutations of the THRA gene exhibit classical features of hypothyroidism, including erythroid disorders. We previously created a mutant mouse expressing a mutated TRα1 (denoted as PV; Thra1PV/+ mouse) that faithfully reproduces the classical hypothyroidism seen in patients. Using Thra1PV/+ mice, we explored how the TRα1PV mutant acted to cause abnormalities in erythropoiesis. Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, ß-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. These results provide new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders.
[Mh] Termos MeSH primário: Eritropoese/genética
Fator de Transcrição GATA1/genética
Hipotireoidismo/genética
Receptores alfa dos Hormônios Tireóideos/genética
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/genética
Eritrócitos
Seres Humanos
Hipotireoidismo/fisiopatologia
Fatores de Transcrição Kruppel-Like/genética
Camundongos
Camundongos Transgênicos
Mutação
Transcriptoma
Tri-Iodotironina/genética
Globinas beta/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GATA1 Transcription Factor); 0 (Gata1 protein, mouse); 0 (Kruppel-Like Transcription Factors); 0 (Thyroid Hormone Receptors alpha); 0 (beta-Globins); 0 (erythroid Kruppel-like factor); 06LU7C9H1V (Triiodothyronine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006991


  4 / 1207 MEDLINE  
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[PMID]:28841410
[Au] Autor:Liu X; Zhang Y; Chen Y; Li M; Zhou F; Li K; Cao H; Ni M; Liu Y; Gu Z; Dickerson KE; Xie S; Hon GC; Xuan Z; Zhang MQ; Shao Z; Xu J
[Ad] Endereço:Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
[Ti] Título:In Situ Capture of Chromatin Interactions by Biotinylated dCas9.
[So] Source:Cell;170(5):1028-1043.e19, 2017 Aug 24.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cis-regulatory elements (CREs) are commonly recognized by correlative chromatin features, yet the molecular composition of the vast majority of CREs in chromatin remains unknown. Here, we describe a CRISPR affinity purification in situ of regulatory elements (CAPTURE) approach to unbiasedly identify locus-specific chromatin-regulating protein complexes and long-range DNA interactions. Using an in vivo biotinylated nuclease-deficient Cas9 protein and sequence-specific guide RNAs, we show high-resolution and selective isolation of chromatin interactions at a single-copy genomic locus. Purification of human telomeres using CAPTURE identifies known and new telomeric factors. In situ capture of individual constituents of the enhancer cluster controlling human ß-globin genes establishes evidence for composition-based hierarchical organization. Furthermore, unbiased analysis of chromatin interactions at disease-associated cis-elements and developmentally regulated super-enhancers reveals spatial features that causally control gene transcription. Thus, comprehensive and unbiased analysis of locus-specific regulatory composition provides mechanistic insight into genome structure and function in development and disease.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas
Endonucleases/metabolismo
Técnicas Genéticas
Elementos Reguladores de Transcrição
[Mh] Termos MeSH secundário: Animais
Biotinilação
Células Cultivadas
Células-Tronco Embrionárias/metabolismo
Endonucleases/genética
Elementos Facilitadores Genéticos
Seres Humanos
Células K562
Camundongos
RNA Guia/metabolismo
Telômero/metabolismo
Globinas beta/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Guide); 0 (beta-Globins); EC 3.1.- (Endonucleases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170826
[St] Status:MEDLINE


  5 / 1207 MEDLINE  
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[PMID]:28772282
[Au] Autor:Ponzetti M; Capulli M; Angelucci A; Ventura L; Monache SD; Mercurio C; Calgani A; Sanità P; Teti A; Rucci N
[Ad] Endereço:Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
[Ti] Título:Non-conventional role of haemoglobin beta in breast malignancy.
[So] Source:Br J Cancer;117(7):994-1006, 2017 Sep 26.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Besides its role as oxygen transporter, recent findings suggest that haemoglobin beta (HBB) may have roles in other contexts. METHODS: We evaluated the impact of HBB expression in primary human breast cancers, and in breast cancer cell lines overexpressing HBB by in vitro and in vivo studies. Publicly available microarray databases were used to perform multivariate survival analyses. RESULTS: A significantly higher expression of HBB was observed in invasive carcinoma histotypes vs in situ counterparts, along with a positive correlation between HBB and the Ki67 proliferation marker. HBB-overexpressing breast cancer cells migrate and invade more, show HIF-1α upregulation and their conditioned media enhances angiogenesis. Blocking the oxygen-binding site of HBB reverts the increase of migration and HIF-1α upregulation observed in HBB-overexpressing breast cancer cells. Orthotopically implanted MDA-MB-231 overexpressing HBB (MDA-HBB) generated tumours with faster growth rate and increased neoangiogenesis. Moreover, local recurrence and visceral metastases were observed only in MDA-HBB-implanted mice. Similar results were observed with 4T1 mouse breast cancer cells. Finally, bioinformatics analyses of public data sets correlated high HBB expression with lower overall survival. CONCLUSIONS: HBB expression increases breast cancer cells aggressiveness and associates with poor prognosis, pointing to HBB as a novel biomarker for breast cancer progression.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Carcinoma Ductal de Mama/metabolismo
Carcinoma Intraductal não Infiltrante/metabolismo
Carcinoma Lobular/metabolismo
Recidiva Local de Neoplasia/metabolismo
Neovascularização Patológica/metabolismo
Globinas beta/metabolismo
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/química
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/química
Carcinoma Ductal de Mama/secundário
Carcinoma Intraductal não Infiltrante/química
Carcinoma Lobular/química
Carcinoma Lobular/secundário
Linhagem Celular Tumoral
Movimento Celular
Biologia Computacional
Feminino
Inativação Gênica
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Antígeno Ki-67/análise
Linfonodos/química
Metástase Linfática
Camundongos
Camundongos Endogâmicos BALB C
Invasividade Neoplásica
Transplante de Neoplasias
Estresse Oxidativo
Taxa de Sobrevida
Análise Serial de Tecidos
Globinas beta/análise
Globinas beta/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIF1A protein, human); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Ki-67 Antigen); 0 (beta-Globins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.247


  6 / 1207 MEDLINE  
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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


  7 / 1207 MEDLINE  
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[PMID]:28681914
[Au] Autor:Viganó C; Haas C; Rühli FJ; Bouwman A
[Ad] Endereço:Institute of Evolutionary Medicine, University of Zurich, Zurich, 8057, Switzerland.
[Ti] Título:2,000 Year old ß-thalassemia case in Sardinia suggests malaria was endemic by the Roman period.
[So] Source:Am J Phys Anthropol;164(2):362-370, 2017 Oct.
[Is] ISSN:1096-8644
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: The island of Sardinia has one of the highest incidence rates of ß-thalassemia in Europe due to its long history of endemic malaria, which, according to historical records, was introduced around 2,600 years ago by the Punics and only became endemic around the Middle Ages. In particular, the cod39 mutation is responsible for more than 95% of all ß-thalassemia cases observed on the island. Debates surround the origin of the mutation. Some argue that its presence in the Western Mediterranean reflects the migration of people away from Sardinia, others that it reflects the colonization of the island by the Punics who might have carried the disease allele. The aim of this study was to investigate ß-globin mutations, including cod39, using ancient DNA (aDNA) analysis, to better understand the history and origin of ß-thalassemia and malaria in Sardinia. MATERIALS AND METHODS: PCR analysis followed by sequencing were used to investigate the presence of ß-thalassemia mutations in 19 individuals from three different Roman and Punic necropolises in Sardinia. RESULTS: The cod39 mutation was identified in one male individual buried in a necropolis from the Punic/Roman period. Further analyses have shown that his mitochondrial DNA (mtDNA) and Y-chromosome haplogroups were U5a and I2a1a1, respectively, indicating the individual was probably of Sardinian origin. CONCLUSIONS: This is the earliest documented case of ß-thalassemia in Sardinia to date. The presence of such a pathogenic mutation and its persistence until present day indicates that malaria was likely endemic on the island by the Roman period, earlier than the historical sources suggest.
[Mh] Termos MeSH primário: Globinas beta/genética
Talassemia beta/genética
Talassemia beta/história
[Mh] Termos MeSH secundário: Antropologia Física
Cromossomos Humanos Y/genética
DNA Mitocondrial/análise
DNA Mitocondrial/genética
Doenças Endêmicas/história
Feminino
Haplótipos/genética
História Antiga
Seres Humanos
Itália
Malária/história
Masculino
Mutação/genética
[Pt] Tipo de publicação:HISTORICAL ARTICLE; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); 0 (beta-Globins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1002/ajpa.23278


  8 / 1207 MEDLINE  
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[PMID]:28654322
[Au] Autor:Fresco JR; Amosova O
[Ad] Endereço:Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544; email: jrfresco@princeton.edu , amosova@princeton.edu.
[Ti] Título:Site-Specific Self-Catalyzed DNA Depurination: A Biological Mechanism That Leads to Mutations and Creates Sequence Diversity.
[So] Source:Annu Rev Biochem;86:461-484, 2017 Jun 20.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Self-catalyzed DNA depurination is a sequence-specific physiological mechanism mediated by spontaneous extrusion of a stem-loop catalytic intermediate. Hydrolysis of the 5'G residue of the 5'GA/TGG loop and of the first 5'A residue of the 5'GAGA loop, together with particular first stem base pairs, specifies their hydrolysis without involving protein, cofactor, or cation. As such, this mechanism is the only known DNA catalytic activity exploited by nature. The consensus sequences for self-depurination of such G- and A-loop residues occur in all genomes examined across the phyla, averaging one site every 2,000-4,000 base pairs. Because apurinic sites are subject to error-prone repair, leading to substitution and short frameshift mutations, they are both a source of genome damage and a means for creating sequence diversity. Their marked overrepresentation in genomes, and largely unchanging density from the lowest to the highest organisms, indicate their selection over the course of evolution. The mutagenicity at such sites in many human genes is associated with loss of function of key proteins responsible for diverse diseases.
[Mh] Termos MeSH primário: Adenina/metabolismo
Síndrome de Bloom/genética
DNA Catalítico/genética
Guanina/metabolismo
Polimorfismo Genético
Síndrome de Werner/genética
[Mh] Termos MeSH secundário: Evolução Biológica
Síndrome de Bloom/metabolismo
Síndrome de Bloom/patologia
Catálise
Reparo do DNA
DNA Catalítico/metabolismo
DNA Cruciforme/genética
DNA Cruciforme/metabolismo
DNA de Cadeia Simples/genética
DNA de Cadeia Simples/metabolismo
Seres Humanos
Hidrólise
Sequências Repetidas Invertidas
Mutação
Síndrome de Werner/metabolismo
Síndrome de Werner/patologia
Globinas beta/genética
Globinas beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (DNA, Catalytic); 0 (DNA, Cruciform); 0 (DNA, Single-Stranded); 0 (beta-Globins); 5Z93L87A1R (Guanine); JAC85A2161 (Adenine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-070611-095951


  9 / 1207 MEDLINE  
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[PMID]:28646491
[Au] Autor:Sun CW; Wu LC; Knopick PL; Bradley DS; Townes T; Terman DS
[Ad] Endereço:Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama.
[Ti] Título:Sickle cells produce functional immune modulators and cytotoxics.
[So] Source:Am J Hematol;92(10):981-988, 2017 Oct.
[Is] ISSN:1096-8652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sickle erythrocytes' (SSRBCs) unique physical adaptation to hypoxic conditions renders them able to home to hypoxic tumor niches in vivo, shut down tumor blood flow and induce tumoricidal responses. SSRBCs are also useful vehicles for transport of encapsulated drugs and oncolytic virus into hypoxic tumors with enhanced anti-tumor effects. In search of additional modes for arming sickle cells with cytotoxics, we turned to a lentiviral ß-globin vector with optimized Locus Control Region/ß-globin coding region/promoter/enhancers. We partially replaced the ß-globin coding region of this vector with genes encoding T cell cytolytics, perforin and granzyme or immune modulating superantigens SEG and SEI. These modified vectors efficiently transduced Sca ckit Lin hematopoietic stem cells (HSCs) from humanized sickle cell knockin mice. Irradiated mice reconstituted with these HSCs displayed robust expression of transgenic RNAs and proteins in host sickle cells that was sustained for more than 10 months. SSRBCs from reconstituted mice harboring SEG/SEI transgenes induced robust proliferation and a prototypical superantigen-induced cytokine reaction when exposed to human CD4+/CD8+ cells. The ß-globin lentiviral vector therefore produces a high level of functional, erythroid-specific immune modulators and cytotoxics that circulate without toxicity. Coupled with their unique ability to target and occlude hypoxic tumor vessels these armed SSRBCs constitute a potentially useful tool for treatment of solid tumors.
[Mh] Termos MeSH primário: Anemia Falciforme
Citotoxicidade Imunológica
Eritrócitos Anormais/imunologia
Neoplasias Experimentais/imunologia
Neovascularização Patológica/imunologia
Globinas beta/genética
[Mh] Termos MeSH secundário: Anemia Falciforme/sangue
Animais
Citotoxicidade Imunológica/genética
Sistemas de Liberação de Medicamentos
Eritrócitos Anormais/metabolismo
Eritrócitos Anormais/transplante
Técnicas de Introdução de Genes
Vetores Genéticos
Transplante de Células-Tronco Hematopoéticas
Hipóxia
Lentivirus/genética
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neoplasias Experimentais/irrigação sanguínea
Neoplasias Experimentais/terapia
Neovascularização Patológica/patologia
Neovascularização Patológica/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (beta-Globins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.1002/ajh.24836


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[PMID]:28643346
[Au] Autor:Vasseur C; Domingues-Hamdi E; Ledudal K; Le Corvoisier P; Barau C; Ghaleh B; Rialland A; Pissard S; Galactéros F; Baudin-Creuza V
[Ad] Endereço:Institut National de la Santé et de la Recherche Médicale (Inserm)-U955, équipe 2 : Transfusion et Maladies du Globule Rouge, Institut Mondor de Recherche Biomédicale (IMRB), Université de Paris Est Créteil (UPEC), Créteil, France.
[Ti] Título:Red blood cells free α-haemoglobin pool: a biomarker to monitor the ß-thalassemia intermedia variability. The ALPHAPOOL study.
[So] Source:Br J Haematol;179(1):142-153, 2017 Oct.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The severity of ß-thalassaemia (ß-thal) intermedia is mainly correlated to the degree of imbalanced α/non α-globin chain synthesis. The phenotypic diversity of ß-thal depends on this imbalance and reflects all possible combinations of α- and ß-globin genotypes, levels of fetal haemoglobin (HbF) and co-inheritance of other modulating factors. This study aimed to demonstrate the validity of a new surrogate of α/non α-globin biosynthetic ratio by measuring the soluble α-Hb pool in lysed red blood cells. Our results confirm that the α-Hb pool measurement allows a good discrimination between ß-thal intermedia patients, controls and α-thal patients (P < 0·003). Receiver operator characteristic analyses revealed an area under the curve of 0·978 for the α-Hb pool measurement at a threshold of 120 ng free α-Hb/mg of total Hb/ml of haemolysate (ppm) with a sensitivity and specificity of 86% and 100%, respectively, to discriminate between ß-thal and not ß-thal subjects. Significant correlations were observed between the α-Hb pool and biological parameters of ß-thal, the most significant association being observed with red cell hexokinase activity. This study indicates that the α-Hb pool could be a new marker for assistance in diagnostic orientation of ß-thal intermedia patients and may be clinically useful for monitoring the evolution of the disequilibrium of globin synthesis in response to treatments.
[Mh] Termos MeSH primário: Eritrócitos/metabolismo
alfa-Globinas/metabolismo
Talassemia beta/sangue
Talassemia beta/diagnóstico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Biomarcadores
Estudos de Casos e Controles
Feminino
França
Genótipo
Testes Hematológicos
Seres Humanos
Masculino
Meia-Idade
Mutação
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
Adulto Jovem
alfa-Globinas/genética
Talassemia alfa/sangue
Talassemia alfa/genética
Globinas beta/genética
Talassemia beta/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (alpha-Globins); 0 (beta-Globins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14800



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