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1.
Cancer ; 127(20): 3772-3781, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34255353

RESUMO

BACKGROUND: TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Decitabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Sulfonamidas , Proteína Supressora de Tumor p53/genética
2.
BMC Cancer ; 20(1): 3, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898537

RESUMO

BACKGROUND: Ewing sarcoma is a malignancy of primitive cells, possibly of mesenchymal origin. It is probable that genetic perturbations other than EWS-FLI1 cooperate with it to produce the tumor. Sequencing studies identified STAG2 mutations in approximately 15% of cases in humans. In the present study, we hypothesize that loss of Stag2 cooperates with EWS-FLI1 in generating sarcomas derived from murine mesenchymal stem cells (MSCs). METHODS: Mice bearing an inducible EWS-FLI1 transgene were crossed to p53-/- mice in pure C57/Bl6 background. MSCs were derived from the bone marrow of the mice. EWS-FLI1 induction and Stag2 knockdown were achieved in vitro by adenovirus-Cre and shRNA-bearing pGIPZ lentiviral infection, respectively. The cells were then treated with ionizing radiation to 10 Gy. Anchorage independent growth in vitro was assessed by soft agar assays. Cellular migration and invasion were evaluated by transwell assays. Cells were injected with Matrigel intramuscularly into C57/Bl6 mice to test for tumor formation. RESULTS: Primary murine MSCs with the genotype EWS-FLI1 p53-/- were resistant to transformation and did not form tumors in syngeneic mice without irradiation. Stag2 inhibition increased the efficiency and speed of sarcoma formation significantly in irradiated EWS-FLI1 p53-/- MSCs. The efficiency of tumor formation was 91% for cells in mice injected with Stag2-repressed cells and 22% for mice receiving cells without Stag2 inhibition (p < .001). Stag2 knockdown reduced survival of mice in Kaplan-Meier analysis (p < .001). It also increased MSC migration and invasion in vitro but did not affect proliferation rate or aneuploidy. CONCLUSION: Loss of Stag2 has a synergistic effect with EWS-FLI1 in the production of sarcomas from murine MSCs, but the mechanism may not relate to increased proliferation or chromosomal instability. Primary murine MSCs are resistant to transformation, and the combination of p53 null mutation, EWS-FLI1, and Stag2 inhibition does not confer immediate conversion of MSCs to sarcomas. Irradiation is necessary in this model, suggesting that perturbations of other genes beside Stag2 and p53 are likely to be essential in the development of EWS-FLI1-driven sarcomas from MSCs.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Animais , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Aberrações Cromossômicas , Modelos Animais de Doenças , Expressão Gênica , Genes p53 , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Interferência de RNA , Sarcoma de Ewing/etiologia , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia
3.
Genes Dev ; 31(18): 1847-1857, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29021240

RESUMO

TP53 is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that contribute to metastasis, but the mechanisms mediating these functions remain poorly defined in vivo. To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic osteosarcoma mouse model that is initiated with either a single p53 mutation (p53R172H) or p53 loss in osteoblasts. Our study confirmed that p53 mutant mice developed osteosarcomas with increased metastasis as compared with p53-null mice. Comprehensive transcriptome RNA sequencing (RNA-seq) analysis of 16 tumors identified a cluster of small nucleolar RNAs (snoRNAs) that are highly up-regulated in p53 mutant tumors. Regulatory element analysis of these deregulated snoRNA genes identified strong enrichment of a common Ets2 transcription factor-binding site. Homozygous deletion of Ets2 in p53 mutant mice resulted in strong down-regulation of snoRNAs and reversed the prometastatic phenotype of mutant p53 but had no effect on osteosarcoma development, which remained 100% penetrant. In summary, our studies identify Ets2 inhibition as a potential therapeutic vulnerability in p53 mutant osteosarcomas.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/genética , Osteossarcoma/secundário , Proteína Proto-Oncogênica c-ets-2/genética , RNA Nucleolar Pequeno/genética , Proteína Supressora de Tumor p53/genética , Animais , Regulação para Baixo , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Knockout , Mutação , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/metabolismo , Osteoblastos/patologia , Regulação para Cima
4.
Stem Cell Reports ; 7(2): 139-48, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27396937

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by mutations in the gene encoding the WAS protein (WASp). Here, induced pluripotent stem cells (iPSCs) were derived from a WAS patient (WAS-iPSC) and the endogenous chromosomal WAS locus was targeted with a wtWAS-2A-eGFP transgene using zinc finger nucleases (ZFNs) to generate corrected WAS-iPSC (cWAS-iPSC). WASp and GFP were first expressed in the earliest CD34(+)CD43(+)CD45(-) hematopoietic precursor cells and later in all hematopoietic lineages examined. Whereas differentiation to non-lymphoid lineages was readily obtained from WAS-iPSCs, in vitro T lymphopoiesis from WAS-iPSC was deficient with few CD4(+)CD8(+) double-positive and mature CD3(+) T cells obtained. T cell differentiation was restored for cWAS-iPSCs. Similarly, defects in natural killer cell differentiation and function were restored on targeted correction of the WAS locus. These results demonstrate that the defects exhibited by WAS-iPSC-derived lymphoid cells were fully corrected and suggests the potential therapeutic use of gene-corrected WAS-iPSCs.


Assuntos
Terapia Genética , Células-Tronco Pluripotentes Induzidas/patologia , Linfopoese , Síndrome de Wiskott-Aldrich/patologia , Síndrome de Wiskott-Aldrich/terapia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Células Matadoras Naturais/metabolismo , Linfócitos T/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética
5.
J Biol Chem ; 286(43): 37732-40, 2011 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-21908606

RESUMO

The Zic transcription factors play critical roles during embryonic development. Mutations in the ZIC2 gene are associated with human holoprosencephaly, but the etiology is still unclear. Here, we report a novel function for ZIC2 as a regulator of ß-catenin·TCF4-mediated transcription. We show that ZIC2 can bind directly to the DNA-binding high mobility group box of TCF4 via its zinc finger domain and inhibit the transcriptional activity of the ß-catenin·TCF4 complex. However, the binding of TCF4 to DNA was not affected by ZIC2. Zic2 RNA injection completely inhibited ß-catenin-induced axis duplication in Xenopus embryos and strongly blocked the ability of ß-catenin to induce expression of known Wnt targets in animal caps. Moreover, Zic2 knockdown in transgenic Xenopus Wnt reporter embryos led to ectopic Wnt signaling activity mainly at the midbrain-hindbrain boundary. Together, our results demonstrate a previously unknown role for ZIC2 as a transcriptional regulator of the ß-catenin·TCF4 complex.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Transcrição Genética/fisiologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/microbiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Embrião não Mamífero/metabolismo , Células HEK293 , Humanos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/genética , Fator de Transcrição 4 , Fatores de Transcrição/genética , Proteínas Wnt/genética , Xenopus laevis , beta Catenina/genética
6.
FEBS Lett ; 581(26): 5122-6, 2007 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-17936758

RESUMO

RNA and protein analysis revealed the consistent upregulation of the neural transcription factors ZIC1 and ZIC4 in desmoid tumors and other fibroproliferative disorders. The 5' flanking region of the ZIC1 promoter was unmethylated in desmoid tumor fibroblasts, while a hypermethylated ZIC1 promoter was found in human and mouse cell lines not expressing the gene. In addition, expressing cells showed a H3K4me2 at the ZIC1 promoter, whereas non-expressing cells showed higher levels of H3K9me2 in the same region. To our knowledge, this is the first report describing ZIC1 expression in mesenchymal proliferations and a role for DNA methylation in the control of ZIC1 expression.


Assuntos
Metilação de DNA , Fibromatose Agressiva/genética , Regulação da Expressão Gênica , Histonas/metabolismo , Fatores de Transcrição/genética , Animais , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Sequência de Bases , Proliferação de Células , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Fibromatose Agressiva/patologia , Humanos , Mesoderma/química , Mesoderma/metabolismo , Mesoderma/patologia , Metilação , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Regiões Promotoras Genéticas , Fatores de Transcrição/análise
7.
Eur J Cardiovasc Prev Rehabil ; 13(2): 229-35, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16575277

RESUMO

BACKGROUND: A parental history of cardiovascular disease has a strong relationship with risk factor clusters in the offspring. This study was performed to identify major cardiovascular risk factors in middle school-aged children and their parents in both high and low-risk families. DESIGN: A school-based, cross-sectional study. METHODS: The middle schools of the 6th district of Tehran were divided randomly into two groups. A total of 169 high-risk children with their families were recruited from the first group and 105 low-risk children with their families were recruited from the second group of schools. Anthropometric and metabolic measurements were performed. RESULTS: The means of the waist circumference and waist-to-hip ratio were significantly higher in high-risk fathers. The means of total and low-density lipoprotein (LDL) cholesterol were significantly higher in both parents and children of the high-risk group. The means of the fasting plasma glucose were significantly higher in fathers and offspring of high-risk families. More fathers in high-risk families were smokers. The prevalence of increased total cholesterol, LDL-cholesterol and hyperglycemia (> or = 100 mg/dl) were higher in high-risk parents and children. The prevalence of increased body mass index (> or = 25 kg/m for parents and 85th percentile for children) was higher in fathers and children of high-risk families. CONCLUSIONS: Cardiovascular risk factors are more prevalent and clustered in high-risk families. The screening of high-risk families is essential to prevent the progression of atherosclerosis from childhood and reduce the burden of cardiovascular disease in adulthood.


Assuntos
Doenças Cardiovasculares/epidemiologia , Adolescente , Adulto , Tamanho Corporal , Doenças Cardiovasculares/prevenção & controle , Criança , Estudos Transversais , Gorduras na Dieta , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Fatores de Risco
8.
BMC Public Health ; 6: 29, 2006 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-16472406

RESUMO

BACKGROUND: Elevated plasma total homocysteine is an independent risk factor for cardiovascular disease and a sensitive marker of the inadequate vitamin B12 and folate insufficiency. Folate and vitamin B12 have a protective effect on cardiovascular disease. This population based study was conducted to evaluate the plasma total homocysteine, folate, and vitamin B12 in healthy Iranian individuals. METHODS: This study was a part of the Cardiovascular Risk Factors Survey in the Population Lab Region of Tehran University has been designed and conducted based on the methodology of MONICA/WHO Project. A total of 1214 people aged 25-64 years, were recruited and assessed regarding demographic characteristics, homocysteine, folate, and vitamin B12 levels with interview, questionnaires, examination and blood sampling. Blood samples were gathered and analyzed according to standard methods. RESULTS: The variables were assessed in 1214 participants including 428 men (35.3%) and 786 women (64.7%). Age-adjusted prevalence of hyperhomocysteinemia (Hcy > or = 15 micromol/L) was 73.1% in men and 41.07% in women (P < 0.0001). Geometric mean of plasma homocysteine was 19.02 +/- 1.46 micromol/l in men and 14.05 +/- 1.45 micromol/l in women (P < 0.004) which increased by ageing. Age-adjusted prevalence of low serum folate level was 98.67% in men and 97.92% in women. Age-adjusted prevalence of low serum vitamin B12 level was 26.32% in men and 27.2% in women. Correlation coefficients (Pearson's r) between log tHcy and serum folate, and vitamin B12 indicated an inverse correlation (r = -0.27, r = -0.19, P < 0.0001, respectively). CONCLUSION: These results revealed that the prevalence of hyperhomocysteinemia, low folate and vitamin B12 levels are considerably higher than other communities. Implementation of preventive interventions such as food fortification with folic acid is necessary.


Assuntos
Deficiência de Ácido Fólico/epidemiologia , Ácido Fólico/sangue , Homocisteína/sangue , Hiper-Homocisteinemia/epidemiologia , Inquéritos Nutricionais , Deficiência de Vitamina B 12/epidemiologia , Vitamina B 12/sangue , Adulto , Fatores Etários , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Hiper-Homocisteinemia/complicações , Incidência , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais
9.
Metab Syndr Relat Disord ; 4(3): 172-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-18370735

RESUMO

Insulin resistance syndrome is a cluster of metabolic abnormalities that is accompanied with an increased risk of diabetes and cardiovascular diseases. This has become an important problem in urban children due to their increasing levels of obesity. A total of 535 obese 7-11- year-old students of all the primary schools of the 6th district of Tehran were screened according to their waist circumference and then confirmed according to the International Obesity Task Force (IOTF) criteria. Waist circumference, fasting serum triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, fasting plasma glucose, and insulin levels were measured. Response rate of the study was 96.3%. The crude prevalence rate of metabolic syndrome in these children was 20.6%. There was no significant difference between genders. Only 8.2% of the studied children were without any of the criteria of the metabolic syndrome. The most common metabolic abnormality was hypertriglyceridemia, and the less common one was low HDL levels. Fasting blood sugar, triglyceride, HDL, blood pressure, and waist circumference were all related to the metabolic syndrome with odds ratio of 9.6, 18.71, 6.12, 17.64, and 13.68, respectively. Moreover, insulin levels were significantly higher in these children (12.25 +/- 5.25 vs. 10.75 +/- 4.25 AmicroIU/mL, p = 0.019). This difference was significant in girls with and without metabolic syndrome, but such a difference was not detected in boys. The prevalence of metabolic syndrome is high in Iranian obese children. Early intervention in this population who will become our future obese adults is needed, not only to increase their life quality, but also to decrease the future burden of diabetes and cardiovascular diseases on the society.

10.
Metab Syndr Relat Disord ; 4(1): 28-34, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-18370767

RESUMO

BACKGROUND: Metabolic syndrome includes obesity, hypertriglyceridemia, glucose intolerance, hypertension, and lipid profile abnormalities. The risk of cardiovascular diseases with this syndrome is higher than with each of its components alone. Currently, cardiovascular disorders have a great burden and a high mortality rate in Iran. This study was performed to determine prevalence of the metabolic syndrome and its underlying components in an urban population of Tehran. METHODS: The 25-64-year-old individuals in the Population Laboratory of Tehran University of Medical Sciences were studied through a single-stage cluster sampling; 1573 participants were studied. The response rate was 94.08%. The study was designed according to the World Health Organization (WHO) MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) project using the Adult Treatment Panel III (ATPIII) criteria. The parameters used for the risk analysis were waist circumference, fasting serum triglycerides, high density lipoprotein (HDL)-cholesterol, blood pressure, and fasting plasma glucose. RESULTS: The crude prevalence rate of the metabolic syndrome was 29.9% (age-adjusted: 27.5%). The prevalence was significantly higher in women than in men (35.9% vs. 20.3%). The prevalence increased with age in both genders. In the whole population, 88% met at least one of the metabolic syndrome criteria. The most prevalent metabolic abnormalities were hypertriglyceridemia and hypertension that were present in more than half of the population. Also, means of HDL was significantly higher in metabolic syndrome positive group. By further adjustment for age and sex in multivariate analysis, the difference disappeared and even HDL-C level was slightly lower in people with metabolic syndrome. CONCLUSIONS: RESULTS demonstrate high metabolic syndrome rate among target population especially in women. In view of correlation between metabolic syndrome and cardiovascular disease, it must be the priority for interventional preventive measures.

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