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1.
Int J Biomed Imaging ; 2018: 9780349, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29805438

RESUMO

We created and evaluated a preclinical, multimodality imaging, and software platform to assess molecular imaging of small metastases. This included experimental methods (e.g., GFP-labeled tumor and high resolution multispectral cryo-imaging), nonrigid image registration, and interactive visualization of imaging agent targeting. We describe technological details earlier applied to GFP-labeled metastatic tumor targeting by molecular MR (CREKA-Gd) and red fluorescent (CREKA-Cy5) imaging agents. Optimized nonrigid cryo-MRI registration enabled nonambiguous association of MR signals to GFP tumors. Interactive visualization of out-of-RAM volumetric image data allowed one to zoom to a GFP-labeled micrometastasis, determine its anatomical location from color cryo-images, and establish the presence/absence of targeted CREKA-Gd and CREKA-Cy5. In a mouse with >160 GFP-labeled tumors, we determined that in the MR images every tumor in the lung >0.3 mm2 had visible signal and that some metastases as small as 0.1 mm2 were also visible. More tumors were visible in CREKA-Cy5 than in CREKA-Gd MRI. Tape transfer method and nonrigid registration allowed accurate (<11 µm error) registration of whole mouse histology to corresponding cryo-images. Histology showed inflammation and necrotic regions not labeled by imaging agents. This mouse-to-cells multiscale and multimodality platform should uniquely enable more informative and accurate studies of metastatic cancer imaging and therapy.

2.
Neuroimage ; 102 Pt 2: 809-16, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25213753

RESUMO

Dystrophin, the main component of the dystrophin-glycoprotein complex, plays an important role in maintaining the structural integrity of cells. It is also involved in the formation of the blood-brain barrier (BBB). To elucidate the impact of dystrophin disruption in vivo, we characterized changes in cerebral perfusion and diffusion in dystrophin-deficient mice (mdx) by magnetic resonance imaging (MRI). Arterial spin labeling (ASL) and diffusion-weighted MRI (DWI) studies were performed on 2-month-old and 10-month-old mdx mice and their age-matched wild-type controls (WT). The imaging results were correlated with Evan's blue extravasation and vascular density studies. The results show that dystrophin disruption significantly decreased the mean cerebral diffusivity in both 2-month-old (7.38 ± 0.30 × 10(-4)mm(2)/s) and 10-month-old (6.93 ± 0.53 × 10(-4)mm(2)/s) mdx mice as compared to WT (8.49 ± 0.24 × 10(-4), 8.24 ± 0.25 × 10(-4)mm(2)/s, respectively). There was also an 18% decrease in cerebral perfusion in 10-month-old mdx mice as compared to WT, which was associated with enhanced arteriogenesis. The reduction in water diffusivity in mdx mice is likely due to an increase in cerebral edema or the existence of large molecules in the extracellular space from a leaky BBB. The observation of decreased perfusion in the setting of enhanced arteriogenesis may be caused by an increase of intracranial pressure from cerebral edema. This study demonstrates the defects in water handling at the BBB and consequently, abnormal perfusion associated with the absence of dystrophin.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Circulação Cerebrovascular/fisiologia , Distrofina/deficiência , Animais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Int J Cancer ; 132(7): 1624-32, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22987116

RESUMO

Detection of an extracellular cleaved fragment of a cell-cell adhesion molecule represents a new paradigm in molecular recognition and imaging of tumors. We previously demonstrated that probes that recognize the cleaved extracellular domain of receptor protein tyrosine phosphatase mu (PTPmu) label human glioblastoma brain tumor sections and the main tumor mass of intracranial xenograft gliomas. In this article, we examine whether one of these probes, SBK2, can label dispersed glioma cells that are no longer connected to the main tumor mass. Live mice with highly dispersive glioma tumors were injected intravenously with the fluorescent PTPmu probe to test the ability of the probe to label the dispersive glioma cells in vivo. Analysis was performed using a unique three-dimensional (3D) cryo-imaging technique to reveal highly migratory and invasive glioma cell dispersal within the brain and the extent of colabeling by the PTPmu probe. The PTPmu probe labeled the main tumor site and dispersed cells up to 3.5 mm away. The cryo-images of tumors labeled with the PTPmu probe provide a novel, high-resolution view of molecular tumor recognition, with excellent 3D detail regarding the pathways of tumor cell migration. Our data demonstrate that the PTPmu probe recognizes distant tumor cells even in parts of the brain where the blood-brain barrier is likely intact. The PTPmu probe has potential translational significance for recognizing tumor cells to facilitate molecular imaging, a more complete tumor resection and to serve as a molecular targeting agent to deliver chemotherapeutics to the main tumor mass and distant dispersive tumor cells.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular , Glioblastoma/patologia , Técnicas de Diagnóstico Molecular , Sondas Moleculares , Fragmentos de Peptídeos/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Animais , Barreira Hematoencefálica , Neoplasias Encefálicas/enzimologia , Espaço Extracelular/metabolismo , Citometria de Fluxo , Corantes Fluorescentes , Glioblastoma/enzimologia , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Mol Imaging Biol ; 14(5): 572-83, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22125093

RESUMO

PURPOSE: The goals of this study were to create cryo-imaging methods to quantify characteristics (size, dispersal, and blood vessel density) of mouse orthotopic models of glioblastoma multiforme (GBM) and to enable studies of tumor biology, targeted imaging agents, and theranostic nanoparticles. PROCEDURES: Green fluorescent protein-labeled, human glioma LN-229 cells were implanted into mouse brain. At 20-38 days, cryo-imaging gave whole brain, 4-GB, 3D microscopic images of bright field anatomy, including vasculature, and fluorescent tumor. Image analysis/visualization methods were developed. RESULTS: Vessel visualization and segmentation methods successfully enabled analyses. The main tumor mass volume, the number of dispersed clusters, the number of cells/cluster, and the percent dispersed volume all increase with age of the tumor. Histograms of dispersal distance give a mean and median of 63 and 56 µm, respectively, averaged over all brains. Dispersal distance tends to increase with age of the tumors. Dispersal tends to occur along blood vessels. Blood vessel density did not appear to increase in and around the tumor with this cell line. CONCLUSION: Cryo-imaging and software allow, for the first time, 3D, whole brain, microscopic characterization of a tumor from a particular cell line. LN-229 exhibits considerable dispersal along blood vessels, a characteristic of human tumors that limits treatment success.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Movimento Celular , Glioblastoma/diagnóstico , Glioblastoma/patologia , Processamento de Imagem Assistida por Computador/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Algoritmos , Animais , Neoplasias Encefálicas/irrigação sanguínea , Linhagem Celular Tumoral , Criopreservação , Congelamento , Glioblastoma/irrigação sanguínea , Humanos , Camundongos , Invasividade Neoplásica , Neovascularização Patológica/patologia , Carga Tumoral
5.
Cancer Res ; 71(17): 5932-40, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21862632

RESUMO

Traditional methods of imaging cell migration in the tumor microenvironment include serial sections of xenografts and standard histologic stains. Current molecular imaging techniques suffer from low resolution and difficulty in imaging through the skull. Here we show how computer algorithms can be used to reconstruct images from tissue sections obtained from mouse xenograft models of human glioma and can be rendered into three-dimensional images offering exquisite anatomic detail of tumor cell dispersal. Our findings identify human LN-229 and rodent CNS-1 glioma cells as valid systems to study the highly dispersive nature of glioma tumor cells along blood vessels and white matter tracts in vivo. This novel cryo-imaging technique provides a valuable tool to evaluate therapeutic interventions targeted at limiting tumor cell invasion and dispersal.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular , Glioma/patologia , Interpretação de Imagem Assistida por Computador/métodos , Neovascularização Patológica/diagnóstico , Microambiente Tumoral , Algoritmos , Animais , Neoplasias Encefálicas/irrigação sanguínea , Criopreservação , Glioma/irrigação sanguínea , Humanos , Imageamento Tridimensional , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Comput Med Imaging Graph ; 35(3): 195-205, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21041065

RESUMO

We developed multi-scale, live-time interactive visualization of color image data, including microscopic whole-mouse cryo-images serving many biomedical applications. Using true-color volume rendering, we interactively, selectively enhanced anatomy using feature detection. For example, to enhance red organs (vessels, liver, etc.) and internal surfaces, we computed a red feature from R/(R+G+B) and surface features from color/gray-scale gradients, respectively. For >70GB cryo-image volumes, we developed multi-resolution visualization, which provided low-resolution rendering of an entire mouse and zooming to organs, tissues, and cells. Fusions of fluorescence and color cryo-volumes uniquely showed biodistribution of metastatic and stem cells within an anatomical context.


Assuntos
Colorimetria/métodos , Colorimetria/veterinária , Criopreservação/veterinária , Interpretação de Imagem Assistida por Computador/métodos , Microscopia de Fluorescência/métodos , Microscopia de Fluorescência/veterinária , Imagem Corporal Total/métodos , Imagem Corporal Total/veterinária , Animais , Aumento da Imagem/métodos , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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