Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 159
Filtrar
1.
Genes Dev ; 35(21-22): 1398-1400, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725127

RESUMO

Definitive long-term hematopoietic stem cells (LT-HSCs) arise during embryogenesis in a process termed endothelial-to-hematopoietic transition (EHT), in which specialized hemogenic endothelial cells (HECs) transform into hematopoietic cells. The transcription factor RUNX1 marks HECs and is essential for EHT. Ectopic RUNX1 expression in non-HECs is sufficient to convert them into HECs. However, the conversion efficiency depends on the developmental timing of expression. In this issue of Genes & Development, Howell and colleagues (pp. 1475-1489) leverage this observation to further understand how RUNX1 mediates EHT. They engineered mice that ectopically express RUNX1 in endothelial cells at different developmental time points and doses. They then performed chromatin accessibility and other analyses and correlate this with hemogenic potential. They found that RUNX1 collaborates with TGFß signaling transcription factors to drive chromatin accessibility changes that specify HECs. They also highlight interesting parallels between EHT and endothelial-to-mesenchymal transition (EndoMT), which occurs during cardiac development. The results of Howell and colleagues provide new mechanistic insights into EHT and take us one step closer to generating patient-specific LT-HSCs from induced pluripotent stem cells.


Assuntos
Hemangioblastos , Hematopoese , Animais , Adesão Celular , Diferenciação Celular/genética , Hemangioblastos/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos
2.
Cell ; 143(2): 313-24, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20946988

RESUMO

c-Myc (Myc) is an important transcriptional regulator in embryonic stem (ES) cells, somatic cell reprogramming, and cancer. Here, we identify a Myc-centered regulatory network in ES cells by combining protein-protein and protein-DNA interaction studies and show that Myc interacts with the NuA4 complex, a regulator of ES cell identity. In combination with regulatory network information, we define three ES cell modules (Core, Polycomb, and Myc) and show that the modules are functionally separable, illustrating that the overall ES cell transcription program is composed of distinct units. With these modules as an analytical tool, we have reassessed the hypothesis linking an ES cell signature with cancer or cancer stem cells. We find that the Myc module, independent of the Core module, is active in various cancers and predicts cancer outcome. The apparent similarity of cancer and ES cell signatures reflects, in large part, the pervasive nature of Myc regulatory networks.


Assuntos
Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/genética , Acetilação , Animais , Linhagem Celular , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Fatores de Transcrição/metabolismo , Transcrição Gênica
3.
Cell ; 142(1): 133-43, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20603019

RESUMO

Recent genome-wide studies have demonstrated that pausing of RNA polymerase II (Pol II) occurred on many vertebrate genes. By genetic studies in the zebrafish tif1gamma mutant moonshine we found that loss of function of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1gamma-deficient animals. Biochemical analysis established physical interactions among TIF1gamma, the blood-specific SCL transcription complex, and the positive elongation factors p-TEFb and FACT. Chromatin immunoprecipitation assays in human CD34(+) cells supported a TIF1gamma-dependent recruitment of positive elongation factors to erythroid genes to promote transcription elongation by counteracting Pol II pausing. Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation.


Assuntos
Eritropoese , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Células Eritroides/metabolismo , Humanos , RNA Polimerase II/metabolismo , Peixe-Zebra/metabolismo
4.
Blood ; 139(21): 3159-3165, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34758059

RESUMO

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.


Assuntos
Síndrome de Down , Fator de Transcrição GATA1 , Leucemia Megacarioblástica Aguda , Leucemia Mieloide , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Mutação em Linhagem Germinativa , Humanos , Leucemia Megacarioblástica Aguda/complicações , Leucemia Megacarioblástica Aguda/genética , Leucemia Mieloide/complicações , Masculino , Mutação , Fenótipo , Trissomia
5.
Pediatr Blood Cancer ; 70(1): e30067, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36250986

RESUMO

Unstable gamma globin variants can cause transient neonatal hemolytic anemia. We have identified a novel variant in a newborn who presented with jaundice and anemia requiring phototherapy and red blood cell transfusion. The patient was found to be heterozygous for the mutation HGB2:c.290T>C, p.Leu97Pro, which we have termed hemoglobin (Hb) Wareham. This substitution is expected to generate an unstable hemoglobin with increased oxygen affinity based on the homologous mutation previously described in the beta globin gene, which is termed as Hb Debrousse. The patient fully recovered by 9 months of age as expected with the transition from fetal to adult hemoglobin.


Assuntos
Anemia Hemolítica , Hemoglobinas Anormais , gama-Globinas , Humanos , Recém-Nascido , Anemia Hemolítica/genética , Globinas beta/genética , gama-Globinas/genética , Hemoglobinas Anormais/genética , Heterozigoto , Mutação , Lactente
6.
Proc Natl Acad Sci U S A ; 117(38): 23626-23635, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32883883

RESUMO

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Hematopoese , Animais , Diferenciação Celular , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/química , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Baço/citologia , Peixe-Zebra
7.
J Clin Immunol ; 40(4): 554-566, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32303876

RESUMO

Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.


Assuntos
Mutação/genética , Mielofibrose Primária/diagnóstico , Proteína cdc42 de Ligação ao GTP/genética , Ciclo Celular , Microambiente Celular , Células HEK293 , Hematopoese/genética , Humanos , Lactente , Recém-Nascido , Mielofibrose Primária/genética , Irmãos , Sequenciamento do Exoma
8.
Mol Cell ; 45(3): 330-43, 2012 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-22325351

RESUMO

Polycomb repressive complexes (PRCs) play key roles in developmental epigenetic regulation. Yet the mechanisms that target PRCs to specific loci in mammalian cells remain incompletely understood. In this study we show that Bmi1, a core component of Polycomb Repressive Complex 1 (PRC1), binds directly to the Runx1/CBFß transcription factor complex. Genome-wide studies in megakaryocytic cells demonstrate significant chromatin occupancy overlap between the PRC1 core component Ring1b and Runx1/CBFß and functional regulation of a considerable fraction of commonly bound genes. Bmi1/Ring1b and Runx1/CBFß deficiencies generate partial phenocopies of one another in vivo. We also show that Ring1b occupies key Runx1 binding sites in primary murine thymocytes and that this occurs via PRC2-independent mechanisms. Genetic depletion of Runx1 results in reduced Ring1b binding at these sites in vivo. These findings provide evidence for site-specific PRC1 chromatin recruitment by core binding transcription factors in mammalian cells.


Assuntos
Cromatina/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade beta de Fator de Ligação ao Core/metabolismo , Proteínas Repressoras/metabolismo , Animais , Linhagem Celular , Cromatografia de Afinidade , Análise por Conglomerados , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células-Tronco Hematopoéticas/fisiologia , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 1 , Proteínas do Grupo Polycomb , Ligação Proteica , Multimerização Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/isolamento & purificação , Linfócitos T/metabolismo , Timócitos/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética
9.
Genes Dev ; 26(14): 1587-601, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22759635

RESUMO

Hematopoietic development occurs in complex microenvironments and is influenced by key signaling events. Yet how these pathways communicate with master hematopoietic transcription factors to coordinate differentiation remains incompletely understood. The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. It is also the most frequent target of genetic alterations in human leukemia. Here, we report that RUNX1 is phosphorylated by Src family kinases (SFKs) and that this occurs on multiple tyrosine residues located within its negative regulatory DNA-binding and autoinhibitory domains. Retroviral transduction, chemical inhibitor, and genetic studies demonstrate a negative regulatory role of tyrosine phosphorylation on RUNX1 activity in Mk and CD8 T-cell differentiation. We also demonstrate that the nonreceptor tyrosine phosphatase Shp2 binds directly to RUNX1 and contributes to its dephosphorylation. Last, we show that RUNX1 tyrosine phosphorylation correlates with reduced GATA1 and enhanced SWI/SNF interactions. These findings link SFK and Shp2 signaling pathways to the regulation of RUNX1 activity in hematopoiesis via control of RUNX1 multiprotein complex assembly.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/fisiologia , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Megacariócitos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Transdução de Sinais/fisiologia , Quinases da Família src/metabolismo , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Hematopoese/fisiologia , Humanos , Megacariócitos/citologia , Camundongos , Camundongos Transgênicos , Fosforilação/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Quinases da Família src/genética
10.
Pediatr Dev Pathol ; 22(4): 315-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30600763

RESUMO

Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/genética , Plaquetas/patologia , Medula Óssea/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Estudos de Coortes , Progressão da Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Masculino , Megacariócitos/patologia , Isoformas de Proteínas , Adulto Jovem
11.
Cancer ; 124(16): 3427-3435, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29932460

RESUMO

BACKGROUND: The current study assessed the feasibility of a mentored home-based vegetable gardening intervention and examined changes in health-related outcomes among breast cancer survivors (BCS). METHODS: BCS were randomized to either a year-long vegetable gardening intervention to begin immediately or a wait-list control. Master Gardeners mentored participants in planning, planting, and maintaining 3 seasonal gardens over the course of 1 year. Participant accrual, retention, and satisfaction rates of ≥80% served as feasibility (primary outcome) benchmarks. Secondary outcomes (ie, vegetable consumption, physical activity, performance and function, anthropometrics, biomarkers, and health-related quality of life) were collected at baseline and post-intervention (1-year follow-up) using subjective and objective measures. RESULTS: The trial surpassed all feasibility benchmarks at 82% of targeted accrual, 95% retention, and 100% satisfaction (ie, experience ratings of "good to excellent" and willingness to "do it again"). Compared with the controls, intervention participants reported significantly greater improvements in moderate physical activity (+14 vs -17 minutes/week) and demonstrated improvements in the 2-Minute Step Test (+22 vs + 10 steps), and Arm Curl (+2.7 vs + 0.1 repetitions) (P values < .05). A trend toward improved vegetable consumption was observed (+0.9 vs + 0.2 servings/day; P = .06). Approximately 86% of participants were continuing to garden at the 2-year follow-up. CONCLUSIONS: The results of the current study suggest that a mentored, home-based vegetable gardening intervention is feasible and offers an integrative and durable approach with which to improve health behaviors and outcomes among BCS. Harvest for Health led to the establishment of a group of trained Master Gardeners and gave rise to local and global community-based programs. Larger studies are needed to confirm the results presented herein and to define applicability across broader populations of survivors.


Assuntos
Neoplasias da Mama/reabilitação , Sobreviventes de Câncer , Exercício Físico/fisiologia , Jardinagem , Serviços de Assistência Domiciliar , Tutoria , Desempenho Físico Funcional , Adulto , Idoso , Idoso de 80 Anos ou mais , Sobreviventes de Câncer/educação , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Jardinagem/métodos , Comportamentos Relacionados com a Saúde/fisiologia , Humanos , Tutoria/métodos , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Qualidade de Vida , Verduras
13.
J Biol Chem ; 291(2): 826-36, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26598521

RESUMO

Src phosphorylates Runx1 on one central and four C-terminal tyrosines. We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter. Mutation of the four Runx1 C-terminal tyrosines to aspartate or glutamate to mimic phosphorylation increases trans-activation of the reporter in 293T cells and allows induction of Cebpa or Pu.1 mRNAs in 32Dcl3 myeloid cells, whereas mutation of these residues to phenylalanine to prevent phosphorylation obviates these effects. Three mechanisms contribute to increased Runx1 activity upon tyrosine modification as follows: increased stability, reduced histone deacetylase (HDAC) interaction, and increased DNA binding. Mutation of the five modified Runx1 tyrosines to aspartate markedly reduced co-immunoprecipitation with HDAC1 and HDAC3, markedly increased stability in cycloheximide or in the presence of co-expressed Cdh1, an E3 ubiquitin ligase coactivator, with reduced ubiquitination, and allowed DNA-binding in gel shift assay similar to wild-type Runx1. In contrast, mutation of these residues to phenylalanine modestly increased HDAC interaction, modestly reduced stability, and markedly reduced DNA binding in gel shift assays and as assessed by chromatin immunoprecipitation with the -14-kb Pu.1 or +37-kb Cebpa enhancers after stable expression in 32Dcl3 cells. Affinity for CBFß, the Runx1 DNA-binding partner, was not affected by these tyrosine modifications, and in vitro translated CBFß markedly increased DNA affinity of both the translated phenylalanine and aspartate Runx1 variants. Finally, further supporting a positive role for Runx1 tyrosine phosphorylation during granulopoiesis, mutation of the five Src-modified residues to aspartate but not phenylalanine allows Runx1 to increase Cebpa and granulocyte colony formation by Runx1-deleted murine marrow.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , DNA/metabolismo , Granulócitos/citologia , Hematopoese , Histona Desacetilases/metabolismo , Ativação Transcricional , Quinases da Família src/metabolismo , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/química , Granulócitos/metabolismo , Humanos , Camundongos , Fosforilação , Fosfotirosina/metabolismo , Ligação Proteica , Estabilidade Proteica
14.
Mol Cell ; 36(4): 682-95, 2009 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-19941827

RESUMO

The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1-induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA-binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus nondifferentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1-bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that polycomb repressive complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1-repressed genes. These data provide insights into GATA-1-mediated gene regulation in vivo.


Assuntos
Cromatina/metabolismo , Fator de Transcrição GATA1/metabolismo , Genoma/genética , Proteínas Repressoras/metabolismo , Ativação Transcricional/genética , Animais , Sequência de Bases , Sítios de Ligação , Biotina/metabolismo , Biotinilação , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Inativação Gênica , Camundongos , Modelos Genéticos , Dados de Sequência Molecular , Proteínas do Grupo Polycomb , Ligação Proteica , Sequências Reguladoras de Ácido Nucleico/genética , Análise de Sequência de DNA , Estreptavidina/metabolismo
15.
Stem Cells ; 33(3): 925-38, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25385494

RESUMO

While Polycomb group protein Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We have identified Bmi1 as a novel regulator of erythroid development. Bmi1 is highly expressed in mouse erythroid progenitor cells and its deficiency impairs erythroid differentiation. BMI1 is also important for human erythroid development. Furthermore, we discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Bmi1 deficiency stabilizes p53 protein, leading to upregulation of p21 expression and subsequent G0/G1 cell cycle arrest. Genetic inhibition of p53 activity rescues the erythroid defects seen in the Bmi1 null mice, demonstrating that a p53-dependent mechanism underlies the pathophysiology of the anemia. Mechanistically, Bmi1 is associated with multiple ribosomal protein genes and may positively regulate their expression in erythroid progenitor cells. Thus, Bmi1 promotes erythroid development, at least in part through regulating ribosome biogenesis. Ribosomopathies are human disorders of ribosome dysfunction, including Diamond-Blackfan anemia (DBA) and 5q- syndrome, in which genetic abnormalities cause impaired ribosome biogenesis, resulting in specific clinical phenotypes. We observed that BMI1 expression in human hematopoietic stem and progenitor cells from patients with DBA is correlated with the expression of some ribosomal protein genes, suggesting that BMI1 deficiency may play a pathological role in DBA and other ribosomopathies.


Assuntos
Células Eritroides/citologia , Células Eritroides/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ribossomos/metabolismo , Animais , Diferenciação Celular/fisiologia , Eritropoese/fisiologia , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Ribossômicas/biossíntese , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/genética
17.
Ann Surg Oncol ; 22(1): 75-81, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25059792

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NCT) downstages advanced primary tumors, with magnetic resonance imaging (MRI) being the most sensitive imaging predictor of response. However, the impact of MRI evaluation on surgical treatment decisions in the neoadjuvant setting has not been well described. We report surgical patterns of care across 8 National Cancer Institute comprehensive cancer centers in women receiving both NCT and MRI to evaluate the impact of MRI findings on surgical planning. METHODS: Seven hundred seventy women from 8 institutions received NCT with MRI obtained both before and after systemic treatment. Univariate and multivariate analyses of imaging, patient-, and tumor-related covariates associated with choice of breast surgery were conducted. RESULTS: MRI and surgical data were available on 759 of 770 patients. A total of 345 of 759 (45 %) patients received breast-conserving surgery and 414 of 759 (55 %) received mastectomy. Mastectomy occurred more commonly in patients with incomplete MRI response versus complete (58 vs. 43 %) (p = 0.0003). On multivariate analysis, positive estrogen receptor status (p = 0.02), incomplete MRI response (p = 0.0003), higher baseline T classification (p < 0.0001), younger age (p < 0.0006), and institution (p = 0.003) were independent predictors of mastectomy. A statistically significant trend toward increasing use of mastectomy with increasing T stage at presentation (p < 0.0001) was observed in patients with incomplete response by MRI only. Among women with complete response on MRI, 43 % underwent mastectomy. CONCLUSIONS: Within a multi-institutional cohort of women undergoing neoadjuvant treatment for breast cancer, MRI findings were not clearly associated with extent of surgery. This study shows that receptor status, T stage at diagnosis, young age, and treating institution are more significant determinants of surgical treatment choice than MRI response data.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Imageamento por Ressonância Magnética , Mastectomia , Terapia Neoadjuvante , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Adulto Jovem
18.
J Am Acad Dermatol ; 72(1): 99-104, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25458018

RESUMO

BACKGROUND: Tanning accelerators are topical products used by indoor tanners to augment and hasten the tanning process. These products contain tyrosine, psoralens, and/or other chemicals. OBJECTIVE: We sought to better define the population using accelerators, identify predictors of their use, and describe any related adverse effects. METHODS: This cross-sectional study surveyed 200 indoor tanners about their tanning practices and accelerator use. Primary analysis compared accelerator users with nonusers with respect to questionnaire variables. Descriptive statistics and χ(2) contingency tables were applied to identify statistically significant variables. RESULTS: Of respondents, 53% used accelerators; 97% were female and 3% were male with a median age of 22 years (range: 19-67). Users were more likely to spray tan, tan frequently, and be addicted to tanning. Acne and rashes were more common in accelerator users. Adverse reactions to accelerators prevented their further use 31% of the time. LIMITATIONS: A limited adult population was evaluated; exact accelerator ingredients were not examined. CONCLUSIONS: Tanning accelerator users are high-risk indoor tanners who tan more frequently and who are more likely addicted to tanning. Acne and rashes are more common with these products and act as only mild deterrents to continued use. Additional research should investigate accelerators' longer-term health effects.


Assuntos
Cosméticos/efeitos adversos , Banho de Sol , Raios Ultravioleta , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Banho de Sol/estatística & dados numéricos , Adulto Jovem
19.
Mol Ther ; 22(5): 1048-55, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24572293

RESUMO

G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin and were then treated focally with 5 Gy radiation. Treatment was well tolerated, and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean: 23 months; range: 11-51 months). Six of the nine patients had stable disease or partial response for at least one time point. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% confidence interval: 3.0-12.7). In conclusion, this study showed the safety and the potential for clinical response of single-dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.


Assuntos
Terapia Genética , Glioma/genética , Glioma/radioterapia , Herpesvirus Humano 1/genética , Adulto , Feminino , Glioma/diagnóstico por imagem , Glioma/virologia , Herpesvirus Humano 1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/patogenicidade , Radiografia , Replicação Viral/genética
20.
Dermatol Surg ; 41(5): 572-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25915625

RESUMO

BACKGROUND: Margin evaluation of melanoma in situ (MIS) is difficult because of its ill-defined clinical borders. Wood's light examination is commonly used to help delineate MIS margin before excision. OBJECTIVE: To prospectively study the accuracy of preoperative Wood's light examination for margin assessment of MIS. MATERIALS AND METHODS: The authors evaluated 60 patients before excision of MIS under white light and Wood's light. Staged excision was performed using the square procedure technique. After achieving clear margins, they compared final wound size with expected wound size if surgical margins had been based on Wood's light examination. RESULTS: Seven patients (11.7%) had Wood's light enhancement beyond the visible margin of the biopsy site. In all 7, increased wounding would have occurred if the surgical margins had been based on Wood's light examination. In 1 of the 7, use of the Wood's light examination would have reduced the surgical stages needed by 1 stage but would have increased the wound size by 83.3%. CONCLUSION: Wood's light examination has limited utility if complete excisional biopsy of MIS is performed before treatment. In this study, surgical margin based on the Wood's light examination would have resulted in an increased average wound size and would not have reduced the number of stages needed when performing the square procedure.


Assuntos
Melanoma/patologia , Neoplasias Cutâneas/patologia , Raios Ultravioleta , Adulto , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Melanoma/etiologia , Melanoma/cirurgia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e Especificidade , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/cirurgia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA