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1.
J Cereb Blood Flow Metab ; 37(2): 396-412, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26762506

RESUMO

Insulin-like growth factors control numerous processes, namely somatic growth, metabolism and stress resistance, connecting this pathway to aging and age-related diseases. Insulin-like growth factor signaling also impacts on neurogenesis, neuronal survival and structural plasticity. Recent reports demonstrated that diminished insulin-like growth factor signaling confers increased stress resistance in brain and other tissues. To better understand the role of neuronal insulin-like growth factor signaling in neuroprotection, we inactivated insulin-like growth factor type-1-receptor in forebrain neurons using conditional Cre-LoxP-mediated gene targeting. We found that brain structure and function, including memory performance, were preserved in insulin-like growth factor receptor mutants, and that certain characteristics improved, notably synaptic transmission in hippocampal neurons. To reveal stress-related roles of insulin-like growth factor signaling, we challenged the brain using a stroke-like insult. Importantly, when charged with hypoxia-ischemia, mutant brains were broadly protected from cell damage, neuroinflammation and cerebral edema. We also found that in mice with insulin-like growth factor receptor knockout specifically in forebrain neurons, a substantial systemic upregulation of growth hormone and insulin-like growth factor-I occurred, which was associated with significant somatic overgrowth. Collectively, we found strong evidence that blocking neuronal insulin-like growth factor signaling increases peripheral somatotropic tone and simultaneously protects the brain against hypoxic-ischemic injury, findings that may contribute to developing new therapeutic concepts preventing the disabling consequences of stroke.


Assuntos
Deleção de Genes , Hormônio do Crescimento/metabolismo , Neuroproteção , Prosencéfalo/patologia , Receptor IGF Tipo 1/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Prosencéfalo/metabolismo , Acidente Vascular Cerebral/metabolismo , Regulação para Cima
2.
J Clin Oncol ; 34(26): 3195-203, 2016 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-27432915

RESUMO

PURPOSE: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. MATERIALS AND METHODS: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. RESULTS: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. CONCLUSION: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Variações do Número de Cópias de DNA , Terapia Neoadjuvante , Nefrectomia , Tumor de Wilms/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Nefrectomia/efeitos adversos , Nefrectomia/mortalidade , Fenótipo , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Tumor de Wilms/genética , Tumor de Wilms/mortalidade , Tumor de Wilms/patologia
3.
J Med Genet ; 52(1): 53-60, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25395389

RESUMO

BACKGROUND: The structural organisation of the human IGF2/ICR1/H19 11p15 domain is very complex, and the mechanisms underlying its regulation are poorly understood. The Imprinted Center Region 1 (ICR1) contains seven binding sites for the zinc-finger protein CTCF (CBS: CTCF Binding Sites); three additional differentially methylated regions (DMR) are located at the H19 promoter (H19DMR) and two in the IGF2 gene (DMR0 and DMR2), respectively. Loss of imprinting at the IGF2/ICR1/H19 domain results in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome and Russell Silver syndrome (RSS). Despite the IGF2/ICR1/H19 locus being widely studied, the extent of hypomethylation across the domain remains not yet addressed in patients with RSS. METHODS: We assessed a detailed investigation of the methylation status of the 11p15 ICR1 CBS1-7, IGF2DMR0 and H19DMR (H19 promoter) in a population of controls (n=50) and RSS carrying (n=104) or not (n=65) carrying a hypomethylation at the 11p15 ICR1 region. RESULTS: The methylation indexes (MI) were balanced at all regions in the control population and patients with RSS without any as yet identified molecular anomaly. Interestingly, patients with RSS with ICR1 hypomethylation showed uneven profiles of methylation among the CBSs and DMRs. Furthermore, normal MIs at CBS1 and CBS7 were identified in 9% of patients. CONCLUSIONS: The hypomethylation does not spread equally throughout the IGF2/ICR1/H19 locus, and some loci could have normal MI, which may lead to underdiagnosis of patients with RSS with ICR1 hypomethylation. The uneven pattern of methylation suggests that some CBSs may play different roles in the tridimensional chromosomal looping regulation of this locus.


Assuntos
Cromossomos Humanos Par 11/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Fator de Crescimento Insulin-Like II/genética , RNA Longo não Codificante/genética , Síndrome de Silver-Russell/genética , Sequência de Bases , Humanos , Fator de Crescimento Insulin-Like II/metabolismo , Dados de Sequência Molecular , Paris , Análise de Componente Principal , RNA Longo não Codificante/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Sulfitos
4.
Hum Mutat ; 35(10): 1211-20, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25044976

RESUMO

Russell-Silver Syndrome (RSS) is a prenatal and postnatal growth retardation syndrome caused mainly by 11p15 ICR1 hypomethylation. Clinical presentation is heterogeneous in RSS patients with 11p15 ICR1 hypomethylation. We previously identified a subset of RSS patients with 11p15 ICR1 and multilocus hypomethylation. Here, we examine the relationships between IGF2 expression, 11p15 ICR1 methylation, and multilocus imprinting defects in various cell types from 39 RSS patients with 11p15 ICR1 hypomethylation in leukocyte DNA. 11p15 ICR1 hypomethylation was more pronounced in leukocytes than in buccal mucosa cells. Skin fibroblast IGF2 expression was correlated with the degree of ICR1 hypomethylation. Different tissue-specific multilocus methylation defects coexisted in 38% of cases, with some loci hypomethylated and others hypermethylated within the same cell type in some cases. Our new results suggest that tissue-specific epigenotypes may lead to clinical heterogeneity in RSS.


Assuntos
Cromossomos Humanos Par 11/genética , Metilação de DNA , Impressão Genômica , Fator de Crescimento Insulin-Like II/genética , Síndrome de Silver-Russell/genética , Adulto , Criança , Pré-Escolar , Epitélio/metabolismo , Fibroblastos/metabolismo , Expressão Gênica , Humanos , Recém-Nascido , Leucócitos/metabolismo , Mucosa Bucal/metabolismo , Especificidade de Órgãos , Pele/metabolismo
5.
PLoS Biol ; 6(10): e254, 2008 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-18959478

RESUMO

Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.


Assuntos
Encéfalo/metabolismo , Longevidade/fisiologia , Sistemas Neurossecretores/metabolismo , Receptor IGF Tipo 1/fisiologia , Animais , Animais Recém-Nascidos , Western Blotting , Temperatura Corporal , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Feminino , Fertilidade/genética , Fertilidade/fisiologia , Hormônio do Crescimento/metabolismo , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/metabolismo , Longevidade/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
J Clin Oncol ; 24(10): 1507-15, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16575000

RESUMO

PURPOSE: To determine whether minimal residual disease (MRD) measured by Wilms' tumor gene 1 (WT1) expression is a prognostic marker in pediatric acute myeloid leukemia (AML), we quantified WT1 transcript by real-time quantitative-polymerase chain reaction in 92 AML at diagnosis and during follow-up. PATIENTS AND METHODS: Patients (median age, 6 years; cytogenetics, favorable 27%, intermediate 59%, poor 13%) were treated between 1995 and 2002 and enrolled in Leucémie aiguë Myéloblastique Enfant (LAME) 89/91, LAME 99 pilot study and Acute Promyelocytic Leukemia French collaborative protocols. With a median follow-up of 26 months, event-free survival was 56% with a standard deviation (SD) of 5% and overall survival of 62.5% with an SD of 6%. WT1 copy number was normalized by TATA box binding protein gene transcripts and expressed as WT1/TBP x 1,000 ratio. Median WT1 ratio in normal patient controls was 12 (range, 0 to 57). A level over two SD than normal bone marrow controls (ie, WT1 ratio > 50), was considered as significant overexpression. RESULTS: At diagnosis, WT1 overexpression was detected in 78% of patients (72 of 92 patients; median copy ratio, 2231). The WT1 values were significantly higher (P = .01) in favorable cytogenetics and lower (P < .0001) in M5-FAB subtype, 11q23 rearrangements (P < .001), and infants (P = .003) and demonstrate a strong correlation with fusion transcript AML1-ETO, PML-RARalpha expression. After induction treatment, WT1 ratio was analyzed in 46 of 72 patients and found above 50 in nine of 36 patients and five of 25 patients at D35-50 and 3 to 5 months, respectively. WT1 ratio > 50 after induction is an independent prognostic risk factor of relapse (P = .002) and death (P = .02). CONCLUSION: WT1 quantification is an informative molecular marker for MRD in pediatric AML and is now performed as prospective analysis in ELAM02 protocol.


Assuntos
Genes do Tumor de Wilms , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Dosagem de Genes , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Análise Multivariada , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/análise , Proteína 1 Parceira de Translocação de RUNX1 , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
FASEB J ; 20(6): 773-5, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16484330

RESUMO

Recent evidence indicates that growth hormone (GH) is involved in liver regeneration. To test whether insulin-like growth factor I (IGF-I) mediates this effect, we studied liver regeneration induced by partial hepatectomy in liver-specific IGF type 1 receptor knockout (LIGFREKO) mice. The absence of IGF-1R caused a significant decrease in hepatocyte proliferation in males (-52%), but not in females, as assessed by Ki67 immunohistochemistry. Cyclin D1 and cyclin A protein levels in the livers of LIGFREKO males were only half those in controls, indicating that cyclin induction during liver regeneration is dependent on IGF-1R signaling. Analyzing the signaling cascade initiated by IGF-1R, we observed a lack of IRS-1 induction in LIGFREKO livers. In contrast, the induction of IRS-2 synthesis was similar in LIGFREKO and control groups, suggesting the existence of differential regulation of IRS synthesis during liver regeneration. Regenerating livers from LIGFREKO animals also showed significantly less activated ERKs than controls. Our findings demonstrate that IGF-1R makes a significant contribution to liver regeneration. Using the LIGFREKO model, we provide new evidence that IGF-1R/IRS-1/ERK signaling may be the intracellular pathway controlling the cell cycle via cyclin D1 and cyclin A in the regenerating liver.


Assuntos
Hepatócitos/citologia , Hepatócitos/metabolismo , Regeneração Hepática , Fígado/metabolismo , Receptor IGF Tipo 1/deficiência , Receptor IGF Tipo 1/metabolismo , Animais , Proliferação de Células , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação da Expressão Gênica , Genótipo , Proteínas Substratos do Receptor de Insulina , Fígado/citologia , Masculino , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Receptor IGF Tipo 1/genética , Caracteres Sexuais
8.
Blood ; 100(3): 991-7, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12130513

RESUMO

The most frequent oncogenic activation events characterized in childhood T acute lymphoblastic leukemia (T-ALL) result in the transcriptional activation of genes coding for transcription factors. The main genes are TAL1/SCL, a member of the basic region helix-loop-helix gene family, and HOX11L2, a member of the homeobox-containing protein family. To gain insight into the pathogenesis of this type of hematologic malignancy, we analyzed 28 T-ALL samples. SIL-TAL1/SCL fusion was detected in 6 patients; expression of HOX11L2 was observed in 6 patients and of HOX11 in 3 patients. With one exception, these activations did not occur simultaneously in the same patients, and they allowed the subclassification of 50% of the patients. SIL-TAL1 fusion was detected in association with HOX11 expression in one patient and with a t(8;14) (q24;q11) in another. High expression of LYL1, LMO2, or TAL1 was observed mainly in samples negative for HOX11L2 expression. HOX11L1 and HOX11 expression were observed in one instance each, in the absence of detectable chromosomal abnormality of their respective loci, on chromosomes 2 and 10, respectively. HOX11L2 expression was associated with a chromosome 5q abnormality, the location of the HOX11L2 locus in each case tested. Finally, our data show that HOX11L2 expression was a suitable marker for minimal residual disease follow-up and was significantly associated with relapse (P =.02).


Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia de Células T/diagnóstico , Proteínas Oncogênicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteínas Proto-Oncogênicas , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Criança , Pré-Escolar , Aberrações Cromossômicas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Análise Citogenética , Proteínas de Ligação a DNA/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Lactente , Proteínas com Domínio LIM , Leucemia de Células T/metabolismo , Leucemia de Células T/mortalidade , Masculino , Metaloproteínas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasia Residual/diagnóstico , Neoplasia Residual/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Análise de Sobrevida , Proteína 1 de Leucemia Linfocítica Aguda de Células T
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