The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised t...The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9L^LUC glioma cells syngenic to Fischer 344 （F344） rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9L^LUC/F344 rats, and tumor regression was found in some 9L^LUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9L^LUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9L^LUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.展开更多
Hypoxia is a typical feature of the tumor microenvironment,one of the most critical factors affecting cell behavior and tumor progression.However,the lack of tumor models able to precisely emulate natural brain tumor ...Hypoxia is a typical feature of the tumor microenvironment,one of the most critical factors affecting cell behavior and tumor progression.However,the lack of tumor models able to precisely emulate natural brain tumor tissue has impeded the study of the effects of hypoxia on the progression and growth of tumor cells.This study reports a three-dimensional(3D)brain tumor model obtained by encapsulating U87MG(U87)cells in a hydrogel containing type I collagen.It also documents the effect of various oxygen concentrations(1%,7%,and 21%)in the culture environment on U87 cell morphology,proliferation,viability,cell cycle,apoptosis rate,and migration.Finally,it compares two-dimensional(2D)and 3D cultures.For comparison purposes,cells cultured in flat culture dishes were used as the control(2D model).Cells cultured in the 3D model proliferated more slowly but had a higher apoptosis rate and proportion of cells in the resting phase(G0 phase)/gap I phase(G1 phase)than those cultured in the 2D model.Besides,the two models yielded significantly different cell morphologies.Finally,hypoxia(e.g.,1%O2)affected cell morphology,slowed cell growth,reduced cell viability,and increased the apoptosis rate in the 3D model.These results indicate that the constructed 3D model is effective for investigating the effects of biological and chemical factors on cell morphology and function,and can be more representative of the tumor microenvironment than 2D culture systems.The developed 3D glioblastoma tumor model is equally applicable to other studies in pharmacology and pathology.展开更多
The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractiv...The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of oncogene cooperation in tumor development and progression.展开更多
Background Treating intramedullary spinal cord gliomas is a big challenge because of limited options, high recurrence rate and poor prognosis. An intramedullary glioma model is prerequisite for testing new treatments....Background Treating intramedullary spinal cord gliomas is a big challenge because of limited options, high recurrence rate and poor prognosis. An intramedullary glioma model is prerequisite for testing new treatments. This paper describes the establishment of a rodent intramedullary glioma model and presents functional progression, neuroimaging and histopathological characterization of the tumour model. Methods Fischer344 rats （n=24） were randomized into two groups. Group 1 （n=16） received a 5 pl intramedullary implantation of 9L gliosarcomal （105） cells. Group 2 （n=8） received a 5 pl intramedullary injection of Dulbecco＇s modified Eagle medium. The rats were anesthetized, the spinous process of the T10 vertebra and the ligamentum flavum were removed to expose the T10-11 intervertebral space and an intramedullary injection was conducted into the spinal cord. The rats were evaluated preoperatively and daily postoperatively for neurological deficits using the Basso, Beattie and Bresnahan scale. High resolution magnetic resonance images were acquired preoperatively and weekly postoperatively. When score equal to 0, rats were sacrificed for histopathological examination. Results Rats implanted with 9L gliosarcoma cells had a statistically significant median onset of hind limb paraplegia at （16.0±0.4） days, compared with rats in the control group in which neurological deficits were absent. Imaging and pathological cross sections confirmed intramedullary 9L gliosarcoma invading the spinal cord. Rats in the control group showed no significant functional, radiological or histopathological findings of tumour. Conclusions Rats implanted with 9L cells regularly develop paraplegia in a reliable and reproducible manner. The progression of neurological deficits, neuroimaging and histopathological characteristics of intramedullary spinal cord gliomas in rats is comparable with the behaviour of infiltrative intramedullary spinal cord gliomas in patients.展开更多
This work presents an efficient method for volume rendering of glioma tumors from segmented 2D MRI Datasets with user interactive control, by replacing manual segmentation required in the state of art methods. The mos...This work presents an efficient method for volume rendering of glioma tumors from segmented 2D MRI Datasets with user interactive control, by replacing manual segmentation required in the state of art methods. The most common primary brain tumors are gliomas, evolving from the cerebral supportive cells. For clinical follow-up, the evaluation of the preoperative tumor volume is essential. Tumor portions were automatically segmented from 2D MR images using morphological filtering techniques. These segmented tumor slices were propagated and modeled with the software package. The 3D modeled tumor consists of gray level values of the original image with exact tumor boundary. Axial slices of FLAIR and T2 weighted images were used for extracting tumors. Volumetric assessment of tumor volume with manual segmentation of its outlines is a time-consuming process and is prone to error. These defects are overcome in this method. Authors verified the performance of our method on several sets of MRI scans. The 3D modeling was also done using segmented 2D slices with the help of medical software package called 3D DOCTOR for verification purposes. The results were validated with the ground truth models by the Radiologist.展开更多
Gliomas, the most aggressive form of brain cancer, are known for their widespread invasion into the tissue near the tumor lesion. Exponential models, which have been widely used in other types of cancers, cannot be us...Gliomas, the most aggressive form of brain cancer, are known for their widespread invasion into the tissue near the tumor lesion. Exponential models, which have been widely used in other types of cancers, cannot be used for the simulation of tumor growth, due to the diffusive behavior of glioma. Diffusive models that have been proposed in the last two decades seem to better approximate the expansion of gliomas. This paper covers the history of glioma diffusive modelling, starting from the simplified initial model in 90s and describing how this have been enriched to take into account heterogenous brain tissue, anisotropic migration of glioma cells and adjustable proliferation rates. Especially, adjustable proliferation rates are very important for modelling therapy plans and personalising therapy to different patients.展开更多
目的初步探讨基于术前对比增强T1WI(contrast enhancement T1WI,CE-T1WI)影像组学联合病理参数的列线图预测脑胶质瘤患者术后复发的应用价值。材料与方法回顾性分析2020年4月至2023年4月于宁夏医科大学总医院经术后病理确诊为脑胶质瘤患...目的初步探讨基于术前对比增强T1WI(contrast enhancement T1WI,CE-T1WI)影像组学联合病理参数的列线图预测脑胶质瘤患者术后复发的应用价值。材料与方法回顾性分析2020年4月至2023年4月于宁夏医科大学总医院经术后病理确诊为脑胶质瘤患者115例,按照7∶3随机分为训练集(n=81)和验证集(n=34)。于术前CE-T1WI图像上进行容积感兴趣区(volume of interest,VOI)的勾画并提取影像组学特征。采用U检验及最小绝对收缩和选择算子(least absolute shrinkage and selection operator,LASSO)进行影像组学特征的筛选,将最终筛选出的特征纳入影像组学标签并建立影像组学模型。根据筛选所得组学特征的相应系数计算影像组学评分(radiomics score,Radscore)。通过logistic回归筛选与复发存在相关性的病理预测因子并建立病理参数模型。二者结合为联合模型,绘制列线图将联合模型可视化。采用受试者工作特征曲线下面积(area under the curve,AUC)评估各模型的预测性能,使用DeLong检验比较不同模型间AUC值差异,采用决策曲线(decision curve analysis,DCA)分析观察各模型的临床价值。结果基于术前CE-T1WI图像勾画的VOI中共提取出200个影像组学特征,筛选出与复发相关的组学特征6个。通过logistic回归分析纳入异柠檬酸脱氢酶-1(isocitric dehydrogenase-1,IDH-1)基因型(OR=2.070,P=0.041)、Ki-67表达水平(OR=1.065,P<0.001)为与胶质瘤复发相关的病理参数。相较于单独的病理参数模型和影像组学模型,联合模型在预测效能上表现最佳(训练组AUC:0.875 vs.0.835、0.769,Z=-1.585、-2.458,P=0.013、0.014)。DCA分析示风险阈值概率大于0.32时,应用联合模型的临床获益水平高于另外两种模型。结论基于术前CE-T1WI图像影像组学和病理参数构建的联合模型在预测脑胶质瘤复发中具有较好的临床应用价值,为脑胶质瘤患者治疗决策及预后提供重要预测信息。展开更多
文摘The availability of a well-characterized animal brain tumor model will play an important role in identifying treatments for human brain tumors. Wistar rats bearing 9L glioma cells can develop solid, well-circumcised tumors, and may be a useful animal model for the evaluation of various therapeutic approaches for gliosarcomas. In this study, the 9L/Wistar rat glioma model was produced by intracerebral implantation of 9L^LUC glioma cells syngenic to Fischer 344 （F344） rats. Bioluminescence imaging showed that tumors progressively grew from day 7 to day 21 in 9L^LUC/F344 rats, and tumor regression was found in some 9L^LUC/Wistar rats. Hematoxylin-eosin staining verified that intracranial tumors were gliomas. Immunohistochemistry results demonstrated that no CD4- and CD8-positive cells were found in the syngeneic 9L^LUC/F344 model. However, many infiltrating CD4- and CD8-positive cells were observed within the tumors of the 9L^LUC/Wistar model. Our data suggests that compared with 9L/F344 rats, 9L glioma Wistar rats may not be suitable for evaluating brain glioma immunotherapies, even though the model induced an immune response and exhibited tumor regression.
基金supported by the National Natural Science Foundation of China (No. 52275291)the Fundamental Research Funds for the Central Universitiesthe Program for Innovation Team of Shaanxi Province,China (No. 2023-CX-TD-17)
文摘Hypoxia is a typical feature of the tumor microenvironment,one of the most critical factors affecting cell behavior and tumor progression.However,the lack of tumor models able to precisely emulate natural brain tumor tissue has impeded the study of the effects of hypoxia on the progression and growth of tumor cells.This study reports a three-dimensional(3D)brain tumor model obtained by encapsulating U87MG(U87)cells in a hydrogel containing type I collagen.It also documents the effect of various oxygen concentrations(1%,7%,and 21%)in the culture environment on U87 cell morphology,proliferation,viability,cell cycle,apoptosis rate,and migration.Finally,it compares two-dimensional(2D)and 3D cultures.For comparison purposes,cells cultured in flat culture dishes were used as the control(2D model).Cells cultured in the 3D model proliferated more slowly but had a higher apoptosis rate and proportion of cells in the resting phase(G0 phase)/gap I phase(G1 phase)than those cultured in the 2D model.Besides,the two models yielded significantly different cell morphologies.Finally,hypoxia(e.g.,1%O2)affected cell morphology,slowed cell growth,reduced cell viability,and increased the apoptosis rate in the 3D model.These results indicate that the constructed 3D model is effective for investigating the effects of biological and chemical factors on cell morphology and function,and can be more representative of the tumor microenvironment than 2D culture systems.The developed 3D glioblastoma tumor model is equally applicable to other studies in pharmacology and pathology.
基金the National Institutes of Health(NIH),the Texas Higher Education Coordination Board,and the Goldhirsh Foundation for supporting our research using the RCAS mouse modelLynette Mooreis supported by an American Cancer Society Postdoctoral FellowshipKristen Holmes is supportedby the NIH Pharmacoinformatic Training Grantfellow ship
文摘The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of oncogene cooperation in tumor development and progression.
文摘Background Treating intramedullary spinal cord gliomas is a big challenge because of limited options, high recurrence rate and poor prognosis. An intramedullary glioma model is prerequisite for testing new treatments. This paper describes the establishment of a rodent intramedullary glioma model and presents functional progression, neuroimaging and histopathological characterization of the tumour model. Methods Fischer344 rats （n=24） were randomized into two groups. Group 1 （n=16） received a 5 pl intramedullary implantation of 9L gliosarcomal （105） cells. Group 2 （n=8） received a 5 pl intramedullary injection of Dulbecco＇s modified Eagle medium. The rats were anesthetized, the spinous process of the T10 vertebra and the ligamentum flavum were removed to expose the T10-11 intervertebral space and an intramedullary injection was conducted into the spinal cord. The rats were evaluated preoperatively and daily postoperatively for neurological deficits using the Basso, Beattie and Bresnahan scale. High resolution magnetic resonance images were acquired preoperatively and weekly postoperatively. When score equal to 0, rats were sacrificed for histopathological examination. Results Rats implanted with 9L gliosarcoma cells had a statistically significant median onset of hind limb paraplegia at （16.0±0.4） days, compared with rats in the control group in which neurological deficits were absent. Imaging and pathological cross sections confirmed intramedullary 9L gliosarcoma invading the spinal cord. Rats in the control group showed no significant functional, radiological or histopathological findings of tumour. Conclusions Rats implanted with 9L cells regularly develop paraplegia in a reliable and reproducible manner. The progression of neurological deficits, neuroimaging and histopathological characteristics of intramedullary spinal cord gliomas in rats is comparable with the behaviour of infiltrative intramedullary spinal cord gliomas in patients.
文摘This work presents an efficient method for volume rendering of glioma tumors from segmented 2D MRI Datasets with user interactive control, by replacing manual segmentation required in the state of art methods. The most common primary brain tumors are gliomas, evolving from the cerebral supportive cells. For clinical follow-up, the evaluation of the preoperative tumor volume is essential. Tumor portions were automatically segmented from 2D MR images using morphological filtering techniques. These segmented tumor slices were propagated and modeled with the software package. The 3D modeled tumor consists of gray level values of the original image with exact tumor boundary. Axial slices of FLAIR and T2 weighted images were used for extracting tumors. Volumetric assessment of tumor volume with manual segmentation of its outlines is a time-consuming process and is prone to error. These defects are overcome in this method. Authors verified the performance of our method on several sets of MRI scans. The 3D modeling was also done using segmented 2D slices with the help of medical software package called 3D DOCTOR for verification purposes. The results were validated with the ground truth models by the Radiologist.
文摘Gliomas, the most aggressive form of brain cancer, are known for their widespread invasion into the tissue near the tumor lesion. Exponential models, which have been widely used in other types of cancers, cannot be used for the simulation of tumor growth, due to the diffusive behavior of glioma. Diffusive models that have been proposed in the last two decades seem to better approximate the expansion of gliomas. This paper covers the history of glioma diffusive modelling, starting from the simplified initial model in 90s and describing how this have been enriched to take into account heterogenous brain tissue, anisotropic migration of glioma cells and adjustable proliferation rates. Especially, adjustable proliferation rates are very important for modelling therapy plans and personalising therapy to different patients.
文摘目的初步探讨基于术前对比增强T1WI(contrast enhancement T1WI,CE-T1WI)影像组学联合病理参数的列线图预测脑胶质瘤患者术后复发的应用价值。材料与方法回顾性分析2020年4月至2023年4月于宁夏医科大学总医院经术后病理确诊为脑胶质瘤患者115例,按照7∶3随机分为训练集(n=81)和验证集(n=34)。于术前CE-T1WI图像上进行容积感兴趣区(volume of interest,VOI)的勾画并提取影像组学特征。采用U检验及最小绝对收缩和选择算子(least absolute shrinkage and selection operator,LASSO)进行影像组学特征的筛选,将最终筛选出的特征纳入影像组学标签并建立影像组学模型。根据筛选所得组学特征的相应系数计算影像组学评分(radiomics score,Radscore)。通过logistic回归筛选与复发存在相关性的病理预测因子并建立病理参数模型。二者结合为联合模型,绘制列线图将联合模型可视化。采用受试者工作特征曲线下面积(area under the curve,AUC)评估各模型的预测性能,使用DeLong检验比较不同模型间AUC值差异,采用决策曲线(decision curve analysis,DCA)分析观察各模型的临床价值。结果基于术前CE-T1WI图像勾画的VOI中共提取出200个影像组学特征,筛选出与复发相关的组学特征6个。通过logistic回归分析纳入异柠檬酸脱氢酶-1(isocitric dehydrogenase-1,IDH-1)基因型(OR=2.070,P=0.041)、Ki-67表达水平(OR=1.065,P<0.001)为与胶质瘤复发相关的病理参数。相较于单独的病理参数模型和影像组学模型,联合模型在预测效能上表现最佳(训练组AUC:0.875 vs.0.835、0.769,Z=-1.585、-2.458,P=0.013、0.014)。DCA分析示风险阈值概率大于0.32时,应用联合模型的临床获益水平高于另外两种模型。结论基于术前CE-T1WI图像影像组学和病理参数构建的联合模型在预测脑胶质瘤复发中具有较好的临床应用价值,为脑胶质瘤患者治疗决策及预后提供重要预测信息。
