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1.
Nature ; 509(7499): 235-9, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24739962

RESUMO

Reactive oxygen species (ROS) produced by phagocytes are essential for host defence against bacterial and fungal infections. Individuals with defective ROS production machinery develop chronic granulomatous disease. Conversely, excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. Here we describe a protein, we termed negative regulator of ROS (NRROS), which limits ROS generation by phagocytes during inflammatory responses. NRROS expression in phagocytes can be repressed by inflammatory signals. NRROS-deficient phagocytes produce increased ROS upon inflammatory challenges, and mice lacking NRROS in their phagocytes show enhanced bactericidal activity against Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis owing to oxidative tissue damage in the central nervous system. Mechanistically, NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway. Thus, NRROS provides a hitherto undefined mechanism for regulating ROS production--one that enables phagocytes to produce higher amounts of ROS, if required to control invading pathogens, while minimizing unwanted collateral tissue damage.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Escherichia coli/imunologia , Listeria monocytogenes/imunologia , Proteínas/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Autoimunidade/genética , Células da Medula Óssea/citologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/metabolismo , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Proteínas de Ligação a TGF-beta Latente , Macrófagos/citologia , Macrófagos/enzimologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana , Camundongos , NADPH Oxidases/metabolismo , Oxirredução , Estresse Oxidativo , Fagócitos/citologia , Fagócitos/imunologia , Fagócitos/metabolismo , Proteínas/genética , Espécies Reativas de Oxigênio/metabolismo
2.
Cancer Cell ; 9(3): 157-73, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16530701

RESUMO

Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Expressão Gênica , Glioma/classificação , Glioma/genética , Encéfalo/crescimento & desenvolvimento , Neoplasias Encefálicas/patologia , Progressão da Doença , Dosagem de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Hibridização In Situ , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Invasividade Neoplásica/genética , Análise de Sequência com Séries de Oligonucleotídeos , PTEN Fosfo-Hidrolase/biossíntese , PTEN Fosfo-Hidrolase/genética , Reação em Cadeia da Polimerase , Prognóstico
3.
Glia ; 59(4): 590-602, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21294158

RESUMO

Glioblastomas contain stem-like cells that can be maintained in vitro using specific serum-free conditions. We investigated whether glioblastoma stem-like (GS) cell lines preserve the expression phenotype of human glioblastomas more closely than conventional glioma cell lines. Expression profiling revealed that a distinct subset of GS lines, which displayed a full stem-like phenotype (GSf), mirrored the expression signature of glioblastomas more closely than either other GS lines or cell lines grown in serum. GSf lines are highly tumorigenic and invasive in vivo, express CD133, grow spherically in vitro, are multipotent and display a Proneural gene expression signature, thus recapitulating key functional and transcriptional aspects of human glioblastomas. In contrast, GS lines with a restricted stem-like phenotype exhibited expression signatures more similar to conventional cell lines than to original patient tumors, suggesting that the transcriptional resemblance between GS lines and tumors is associated with different degrees of "stemness". Among markers overexpressed in patient tumors and GSf lines, we identified CXCR4 as a potential therapeutic target. GSf lines contained a minor population of CXCR4(hi) cells, a subfraction of which coexpressed CD133 and was expandable by hypoxia, whereas conventional cell lines contained only CXCR4(lo) cells. Convection-enhanced local treatment with AMD3100, a specific CXCR4 antagonist, inhibited the highly invasive growth of GS xenografts in vivo and cell migration in vitro. We thus demonstrate the utility of GSf lines in testing therapeutic agents and validate CXCR4 as a target to block the growth of invasive tumor-initiating glioma stem cells in vivo.


Assuntos
Linhagem Celular Tumoral/metabolismo , Movimento Celular/fisiologia , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptores CXCR4/metabolismo , Western Blotting , Citometria de Fluxo , Perfilação da Expressão Gênica , Glioblastoma/genética , Humanos , Imuno-Histoquímica , Fenótipo , Receptores CXCR4/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Células Tumorais Cultivadas
4.
EBioMedicine ; 2(7): 730-43, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26288846

RESUMO

Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/ßKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/ßKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/ßKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/ßKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/ßKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin.


Assuntos
Tecido Adiposo Marrom/metabolismo , Anticorpos Biespecíficos/farmacologia , Insulina/farmacologia , Proteínas de Membrana/agonistas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/agonistas , Adiponectina/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Linhagem Celular , Metabolismo Energético/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Células HEK293 , Humanos , Proteínas Klotho , Macaca fascicularis , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Obesos , Ligação Proteica/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Termogênese/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos
5.
Neurosci Med ; 5(2): 109-118, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-30473908

RESUMO

Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer's disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 µg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 µg/ml compared to 27.60 µg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 µg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD.

6.
J Clin Oncol ; 29(34): 4482-90, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22025148

RESUMO

PURPOSE: Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1(R132MUT)) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1(R132MUT) differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1(R132) mutation status. PATIENTS AND METHODS: In all, 618 treatment-naive primary GBMs and 235 lower-grade diffuse gliomas were sequenced for IDH1(R132) and analyzed for demographic, radiographic, anatomic, histologic, genomic, epigenetic, and transcriptional characteristics. RESULTS: Investigation revealed a constellation of features that distinguishes IDH1(R132MUT) GBMs from other GBMs (including frontal location and lesser extent of contrast enhancement and necrosis), relates them to lower-grade IDH1(R132MUT) gliomas, and supports the concept that IDH1(R132MUT) gliomas arise from a neural precursor population that is spatially and temporally restricted in the brain. The observed patterns of DNA sequence, methylation, and copy number alterations support a model of ordered molecular evolution of IDH1(R132MUT) GBM in which the appearance of mutant IDH1 protein is an initial event, followed by production of p53 mutant protein, and finally by copy number alterations of PTEN and EGFR. CONCLUSION: Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.


Assuntos
Neoplasias Encefálicas/genética , Linhagem da Célula , Evolução Molecular , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Transformação Celular Neoplásica/genética , Feminino , Genes p53 , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
7.
Cancer Cell ; 17(4): 362-75, 2010 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-20385361

RESUMO

The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation; however, instances of CD133(-) cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133(+) and CD133(-) self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stemlike cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage.


Assuntos
Neoplasias Encefálicas/patologia , Estruturas Celulares/patologia , Glioblastoma/patologia , Antígeno AC133 , Antígenos CD/análise , Antígenos CD/genética , Neoplasias Encefálicas/genética , Diferenciação Celular , Divisão Celular , Citometria de Fluxo , Perfilação da Expressão Gênica , Ligação Genética , Glioblastoma/genética , Glicoproteínas/análise , Glicoproteínas/deficiência , Glicoproteínas/genética , Humanos , Imuno-Histoquímica , Cinética , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/transplante , Peptídeos/análise , Peptídeos/deficiência , Peptídeos/genética
8.
Proc Natl Acad Sci U S A ; 104(9): 3466-71, 2007 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-17360667

RESUMO

Amplification or overexpression of growth factor receptors is a frequent occurrence in malignant gliomas. Using both expression profiling and in situ hybridization, we identified insulin-like growth factor 2 (IGF2) as a marker for a subset of glioblastomas (GBMs) that lack amplification or overexpression of EGF receptor. Among 165 primary high-grade astrocytomas, 13% of grade IV tumors and 2% of grade III tumors expressed IGF2 mRNA levels >50-fold the sample population median. IGF2-overexpressing tumors frequently displayed PTEN loss, were highly proliferative, exhibited strong staining for phospho-Akt, and belonged to a subclass of GBMs characterized by poor survival. Using a serum-free culture system, we discovered that IGF2 can substitute for EGF to support the growth of GBM-derived neurospheres. The growth-promoting effects of IGF2 were mediated by the insulin-like growth factor receptor 1 and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of phosphoinositide 3-kinase that shows genomic gains in some highly proliferative GBM cases. PIK3R3 knockdown inhibited IGF2-induced growth of GBM-derived neurospheres. The current results provide evidence that the IGF2-PIK3R3 signaling axis is involved in promoting the growth of a subclass of highly aggressive human GBMs that lack EGF receptor amplification. Our data underscore the importance of the phosphoinositide 3-kinase/Akt pathway for growth of high-grade gliomas and suggest that multiple molecular alterations that activate this signaling cascade may promote tumorigenesis. Further, these findings highlight the parallels between growth factors or receptors that are overexpressed in GBMs and those that support in vitro growth of tumor-derived stem-like cells.


Assuntos
Glioblastoma/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Western Blotting , Proliferação de Células , Perfilação da Expressão Gênica , Glioblastoma/fisiopatologia , Humanos , Imunoprecipitação , Hibridização In Situ , Fator de Crescimento Insulin-Like II , Receptores de Somatomedina/metabolismo
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