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1.
Cancer Cell ; 33(3): 435-449.e6, 2018 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-29533784

RESUMO

Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas do Olho/genética , Proteínas de Homeodomínio/genética , Meduloblastoma/genética , Transativadores/genética , Animais , Diferenciação Celular/genética , Neoplasias Cerebelares/genética , Humanos , Camundongos Nus , Retina/patologia , Transcrição Gênica/genética
2.
Magn Reson Med ; 70(3): 823-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23023865

RESUMO

The purpose of this study was to provide proof of concept for a new three-dimensional (3D) radial dynamic contrast enhanced MRI acquisition technique, called "Radial Entire Tumor with Individual Arterial input function dynamic contrast-enhanced MRI" (RETIA dynamic contrast-enhanced MRI), which allows for the simultaneous measurement of an arterial input function in the mouse heart at 2 s temporal resolution and coverage of the whole tumor. Alternating 2D and 3D projections contribute to the 2D heart image or 3D tumor data with a 3-cm field of view. Sixty-four 2D images of the heart are obtained during acquisition of each 3D tumor dataset. In a pilot study, global K(trans) and ve values were measured in four mice, in a respiratory motion-animated subcutaneously implanted breast tumor model. This technique is expected to be most useful for the characterization of microvasculature in motion-animated orthotopic tumors.


Assuntos
Imagem Cinética por Ressonância Magnética/métodos , Neoplasias Experimentais/irrigação sanguínea , Animais , Artérias , Feminino , Neoplasias Cardíacas/irrigação sanguínea , Neoplasias Mamárias Experimentais/irrigação sanguínea , Camundongos , Projetos Piloto
3.
Neurobiol Aging ; 33(9): 1995-2005, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22079157

RESUMO

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of ß-amyloid peptide. This event occurs early in the disease process. In humans, [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emission tomography (PET) is largely used to follow-up in vivo cerebral glucose utilization (CGU) and brain metabolism modifications associated with the Alzheimer's disease pathology. Here, [18F]-FDG positron emission tomography was used to study age-related changes of cerebral glucose utilization under resting conditions in 3-, 6-, and 12-month-old APP(SweLon)/PS1(M146L), a mouse model of amyloidosis. We showed an age-dependent increase of glucose uptake in several brain regions of APP/PS1 mice but not in control animals and a higher [18F]-FDG uptake in the cortex and the hippocampus of 12-month-old APP/PS1 mice as compared with age-matched control mice. We then developed a method of 3-D microscopic autoradiography to evaluate glucose uptake at the level of amyloid plaques and showed an increased glucose uptake close to the plaques rather than in amyloid-free cerebral tissues. These data suggest a macroscopic and microscopic reorganization of glucose uptake in relation to cerebral amyloidosis.


Assuntos
Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Circulação Cerebrovascular/fisiologia , Glucose/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Córtex Cerebral/diagnóstico por imagem , Circulação Cerebrovascular/genética , Modelos Animais de Doenças , Fluordesoxiglucose F18 , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Tomografia por Emissão de Pósitrons , Presenilina-1/genética
4.
MAGMA ; 23(1): 53-64, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20066469

RESUMO

OBJECT: The brain of patients with Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles. Vascular alterations such as amyloid angiopathy are also commonly reported in patients with AD and participate in mechanisms involved in disease onset and progression. Transgenic mouse models of AD have been engineered to evaluate the pathophysiology and new treatments of the disease. Our study evaluated vascular alterations in APP(SweLon)/PS1(M146L) mouse model of AD. MATERIALS AND METHODS: Histological analysis and in vivo magnetic resonance angiography protocols based on time of flight (TOF) and contrast-enhanced (CE) angiography were applied to evaluate cerebrovascular alterations. Results Histological analysis showed that cerebrovascular amyloid deposition starts by the same time as extracellular amyloid plaques. However, unlike plaques deposition, severity of cerebrovascular alterations is stabilized in older animals. Alteration of the middle cerebral artery was detected in old APP(SweLon)/PS1(M146L) mice with respect to adult ones by evaluating the severity of vessel voids and the reduction of vessel length on TOF- and CE-angiograms. Age-related alterations in control PS1 mice were only detected as a reduced vessel length on CE-angiograms. CONCLUSION: These results show that macroscopic vascular abnormalities are part of the pathological alterations developed by APP(SweLon)/PS1(M146L) mouse models of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Angiografia por Ressonância Magnética , Fatores Etários , Doença de Alzheimer/metabolismo , Animais , Angiopatia Amiloide Cerebral/diagnóstico , Angiopatia Amiloide Cerebral/metabolismo , Angiopatia Amiloide Cerebral/patologia , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Camundongos , Camundongos Transgênicos , Artéria Cerebral Média/metabolismo , Artéria Cerebral Média/patologia
5.
Neurobiol Aging ; 30(1): 41-53, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17588710

RESUMO

Amyloid deposits are one of the hallmarks of Alzheimer's disease. Recent studies, in transgenic mice modeling Alzheimer's disease showed that, using in vivo, contrast agent-free, MRI, thalamic amyloid plaques are more easily detected than other plaques of the brain. Our study evaluated the characteristics of these thalamic plaques in a large population of APP/PS1, PS1 and C57BL/6 mice. Thalamic spots were detected in all mice but with different frequency and magnitude. Hence, the prevalence and size of the lesions were higher in APP/PS1 mice. However, even in APP/PS1 mice, thalamic spots did not occur in all the old animals. In APP/PS1 mice, spots detection was related to high iron and calcium load within amyloid plaques and thus reflects the ability of such plaque to capture large amounts of minerals. Interestingly, calcium and iron was also detected in extra-thalamic plaques but with a lower intensity. Hypointense lesions in the thalamus were not associated with the iron load in the tissue surrounding the plaques, nor with micro-hemorrhages, inflammation, or a neurodegenerative context.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Modelos Animais de Doenças , Imageamento por Ressonância Magnética/métodos , Placa Amiloide/patologia , Presenilina-1/genética , Tálamo/patologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
6.
Magn Reson Med ; 58(1): 179-184, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17659609

RESUMO

Amyloid deposits are one of the hallmarks of Alzheimer's disease (AD), one of the most devastating neurodegenerative disorders. In transgenic mice modeling Alzheimer's pathology, the MR transverse relaxation time (T(2)) has been described to be modulated by amyloidosis. This modification has been attributed to the age-related iron deposition that occurs within the amyloid plaques of old animals. In the present study, young APP/PS1 transgenic mice without histochemically detectable iron in the brain were specifically studied. In vivo measurements of T(2) in the hippocampus, at the level of the subiculum, were shown to reflect the density of amyloid plaques. This suggests that T(2) variations can be induced solely by aggregated amyloid deposits in the absence of associated histologically-detectable iron. Thus T(2) from regions with high amyloid load, such as the subiculum, is particularly well suited for following plaque deposition in young animals, i.e., at the earliest stages of the pathological process.


Assuntos
Doença de Alzheimer/diagnóstico , Amiloide/análise , Amiloidose/diagnóstico , Encefalopatias/diagnóstico , Hipocampo/química , Imageamento por Ressonância Magnética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos
7.
Neurobiol Dis ; 22(1): 199-208, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16337798

RESUMO

T1 and T2 magnetic resonance relaxation times have the potential to provide biomarkers of amyloid-beta deposition that could be helpful to the development of new therapies for Alzheimer's disease. Here, we measured T1 and T2 times as well as plaques and iron loads in APP/PS1 mice, which model brain amyloidosis, and control PS1 mice. Iron was mostly associated with amyloid deposits in APP/PS1 animals, while it was diffuse in the PS1 mice. T1 was negatively correlated with age in most structures in APP/PS1 animals. This may be related to the age-associated myelin loss described in APP/PS1 mice rather than to amyloid deposition. T2 in the subiculum of adult APP/PS1 animals was lower than in PS1 mice, which may be related to the very high amyloid and iron loads in this region. T2 in the subiculum could thus serve as an early marker of the amyloid pathology.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ferro/metabolismo , Placa Amiloide/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/patologia , Estudos Transversais , Doenças Desmielinizantes/etiologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Placa Amiloide/genética , Placa Amiloide/patologia , Presenilina-1
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