Constitutive hedgehog （Hh） signaling is associated with the genesis of medulloblastomas （MB）. The objective of this study is to identify special microRNAs （miRNAs） regulated by the Hh pathway, and to clarify the...Constitutive hedgehog （Hh） signaling is associated with the genesis of medulloblastomas （MB）. The objective of this study is to identify special microRNAs （miRNAs） regulated by the Hh pathway, and to clarify the role of miRNAs during the genesis of MB induced by sustained Hh activation. In the primary screening, we used stemloop RT-PCR to test the expression of 90 different miRNAs in the wildtype （WT） and Ptc-/- MEF cell lines. In the secondary screening, the miRNAs screened from the first screening were validated in the Sufu-/- MEF cell lines. We then verified the expression of miRNAs both in the normal cerebellar tissues and the MB induced by activated Hh pathway, and examined the expression of the other 21 miRNA members of the miR-154 cluster in the MB and normal cerebellum. In the first screening, 13 miRNAs showed significant differential expression in WT and Ptc-/- MEF cell lines, while 10 of them had significant difference in the Sufu-/- MEF cell line. Compared to the normal mouse cerebellum, only 2 miRNAs in 15 miRNAs were differentially expressed between the MB and normal cerebellar tissues. Among 21 members of the miR-154 cluster, 6 miRNAs were downregulated in the MB. Our study demonstrated that miR-154 may be regulated by the Hh pathway, and the activation of the Hh pathway led to the downregulation of the miR-154 cluster, resulting in the genesis of MB.展开更多
Microvesicles (MVs) or shedding membrane vesicles have recently been described as a novel model of intercellular communication. Previously, MVs were considered as unnecessary or secreted cellular debris, but MVs have ...Microvesicles (MVs) or shedding membrane vesicles have recently been described as a novel model of intercellular communication. Previously, MVs were considered as unnecessary or secreted cellular debris, but MVs have lately been described as having roles in a variety of biological functions, such as cell homeostasis and the cellular processes involved in the oncogenesis of many types of tumors. Carrying several key molecules that contribute to tumor development and progression, similar to mRNAs, microRNAs and other non-coding RNAs, DNA and even small proteins, MVs can be considered as a ubiquitous form of novel cell communication that is present in most somatic cells. Although tumor-derived MVs have been demonstrated in different types of cancers, the literature data on MVs in primary central nervous system (CNS) tumors are relatively scarce. In this review, we address the involvement of MVs in diffuse astrocytomas, particularly glioblastomas, as well as oligodendrogliomas and medulloblastomas. We placed particular focus on the cellular crosstalk between tumor and “normal” cells, the putative mechanisms how the tumor microenvironment is modulated and the spread of aggressive phenotypes. Additionally, a better understanding of the participation of tumor-derived MVs in the regulation of key cancer pathways will offer new insights into tumor pathogenesis and the mechanisms of multidrug resistance, and may help to develop new strategies for novel therapies against these infiltrative CNS tumors.展开更多
Signaling pathways known to have components with mutations in human medulloblastoma include sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor. Microarray analysis was applied to examine the gene expressi...Signaling pathways known to have components with mutations in human medulloblastoma include sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor. Microarray analysis was applied to examine the gene expression changes in medulloblastomas of pTet-on/pTRE-SV40Tag transgenic mice. Altogether, 14 112 genes were detectable, including 152 genes with significantly different expression levels. These genes were associated with immunity, the cell cycle, signal transduction, cytoskeleton and metabolism. To further confirm the microarray data, real-time polymerase chain reactions were used to examine the expression changes of genes related to sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor signal pathways. Immunohistochemistry detected insulin receptor substrate-1 in the nuclei of brain tumor tissue cells from pTet-on/pTRE-SV40Tag transgenic mice, suggesting that SV40 large T antigen may activate the insulin-like growth factor signal pathway to promote tumorigenesis.展开更多
Background MicroRNAs （miRNAs） are small noncoding regulatory RNAs whose aberrant expression may be observed in many malignancies. However, few data are yet available on human primary medulloblastomas. This work aime...Background MicroRNAs （miRNAs） are small noncoding regulatory RNAs whose aberrant expression may be observed in many malignancies. However, few data are yet available on human primary medulloblastomas. This work aimed to identify that whether miRNAs would be aberrantly expressed in tumor tissues compared with non-tumorous cerebellum tissues from same patients, and to explore a possible role during carcinogenesis. Methods A high throughput microRNA microarray was performed in human primary medulloblastoma specimens to investigate differentially expressed miRNAs, and some miRNAs were validated using real-time quantitative RT-PCR method. In addition, the predicted target genes for the most significantly downor up-regulated miRNAs were analyzed by using a newly modified ensemble algorithm. Results Nine miRNA species were differentially expressed in medulloblastoma specimens versus normal non-tumorous cerebellum tissues. Of these, 4 were over expressed and 5 were under expressed. The changes ranged from 0.02-fold to 6.61-fold. These findings were confirmed using real-time quantitative RT-PCR for most significant deregulated miRNAs （miR-17, miR-100, miR-106b, and miR-218） which are novel and have not been previously published. Interestingly, most of the predicted target genes for these miRNAs were involved in medulloblastoma carcinogenesis. Conclusions MJRNAs are differentially expressed between human medulloblastoma and non-tumorous cerebellum tissue. MiRNAs may play a role in the tumorigenesis of medulloblastoma and maybe serve as potential targets for novel therapeutic strategies in future.展开更多
Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According ...Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.展开更多
Medulloblastoma(MB)is considered the commonest malignant brain tumor in children.Multimodal treatments consisting of surgery,radiation,and chemotherapy have improved patients’survival.Nevertheless,the recurrence occu...Medulloblastoma(MB)is considered the commonest malignant brain tumor in children.Multimodal treatments consisting of surgery,radiation,and chemotherapy have improved patients’survival.Nevertheless,the recurrence occurs in 30%of cases.The persistent mortality rates,the failure of current therapies to extend life expectancy,and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic approaches.Most MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent connections.Recently,MBs have been segregated into four molecular subgroups:Wingless-activated(WNT-MB)(Group 1);Sonichedgehog-activated(SHH-MB)(Group 2);Group 3 and 4 MBs.These molecular alterations follow specific gene mutations and disease-risk stratifications.The current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall survival.However,the need to explore new therapies targeting specific receptors in MB microenvironment became essential.The immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune cells.Tumour associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment,and their role are still under investigation.In this review,we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment,with an overview of the recent investigations and clinical trials.展开更多
This research work develops new and better prognostic markers for predicting Childhood MedulloBlastoma(CMB)using a well-defined deep learning architecture.A deep learning architecture could be designed using ideas fro...This research work develops new and better prognostic markers for predicting Childhood MedulloBlastoma(CMB)using a well-defined deep learning architecture.A deep learning architecture could be designed using ideas from image processing and neural networks to predict CMB using histopathological images.First,a convolution process transforms the histopathological image into deep features that uniquely describe it using different two-dimensional filters of various sizes.A 10-layer deep learning architecture is designed to extract deep features.The introduction of pooling layers in the architecture reduces the feature dimension.The extracted and dimension-reduced deep features from the arrangement of convolution layers and pooling layers are used to classify histopathological images using a neural network classifier.The performance of the CMB classification system is evaluated using 1414(10×magnification)and 1071(100×magnification)augmented histopathological images with five classes of CMB such as desmoplastic,nodular,large cell,classic,and normal.Experimental results show that the average classification accuracy of 99.38%(10×)and 99.07%(100×)is attained by the proposed CNB classification system.展开更多
Medulloblastoma(MB)is the most common childhood embryonal malignant tumour in the central nervous system.The diagnosis,prognosis and therapeutic targets of MB depend on the molecular characteristics of the tumor,and i...Medulloblastoma(MB)is the most common childhood embryonal malignant tumour in the central nervous system.The diagnosis,prognosis and therapeutic targets of MB depend on the molecular characteristics of the tumor,and it is a great challenge to obtain the tissue samples from the patients with brain tumor.Genomic changes found in cell-free DNA(cfDNA)of cerebrospinal fluid(CSF)can predict genomic changes present in tumor tissue,fluid biopsy of CSF can detect the genomic profile of tumor-associated cfDNA and evaluate cfDNA as a marker of measurable residual disease(MRD)in a relatively noninvasive manner,which provides the evidence of"individualized precision therapy"for MB patients.In this paper,we reviewed the recent studies in medulloblastoma based on cfDNA Liquid Biopsy of CSF.展开更多
Medulloblastoma(MB)is a form of malignant brain tumor that predominantly arises in infants and children,of which approximately 25%is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1.Therefo...Medulloblastoma(MB)is a form of malignant brain tumor that predominantly arises in infants and children,of which approximately 25%is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1.Therefore,Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer.In our present study,we undertook a screening for antagonists of Wnt signaling from 600 natural compounds,and identified Ginkgetin,a biflavone isolated from Cephalotaxus fortunei var.alpina.Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 lM and structure–activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group.Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells.Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells.Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes,including Axin2,cyclinD1 and survivin in MB cells.The phosphorylation level of b-catenin also decreased in a time-and concentration-dependent manner.Collectively,our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling,and as such warrants further exploration as a promising antimedulloblastoma candidate.展开更多
Objective： To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application. Methods： Immunohistochemical stainin...Objective： To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of GSK-3beta, Beta-catenin and PPAR-gamma in 48 cases of medulloblastoma and 10 normal cerebellar tissues. Results： The rate of abnormal expressions of beta-catenin and PPAR-gamma in MB was higher than that in normal. Conversely, GSK-3beta in MB was lower than that in the normal （P〈0.05）. Furthermore, in medulloblastoma, beta-catenin and GSK-3beta showed a negative correlation, PPAR-gamma and beta-catenin had a positive correlation. Conclusion： Abnormal expression of beta-catenin plays a crucial role in the development of medulloblastoma. Meanwhile, PPAR-gamma and GSK-3beta which are tightly related with beta-catenin are both involved in the genesis and development of medulloblastoma.展开更多
Purpose: Craniospinal axis irradiation (CSI) is a method of treating various central nervous system malignancies. The large target volume typically includes entire spinal cord and whole brain. Dosimetric comparison wa...Purpose: Craniospinal axis irradiation (CSI) is a method of treating various central nervous system malignancies. The large target volume typically includes entire spinal cord and whole brain. Dosimetric comparison was performed between tomotherapy, volumetric modulated arc therapy (VMAT), and 3D conformal radiation therapy (3D-CRT) for CSI. Methods and Materials: Five (n = 5) CSI patients were planned using 3D-CRT, VMAT, and tomotherapy (normalized such that 95% of PTV received at least 23.4 Gy in 13 fractions). Plans were compared using PTV conformity number (CN) and homogeneity index (HI), normal tissue (NT) dose statistics, integral dose, and treatment time. Results: On average, tomotherapy plans showed higher CN (0.932 vs. 0.860 and 0.672 for SmartArc and 3D-CRT). In terms of HI, VMAT plans consistently showed better dose homogeneity (1.07 vs. 1.15 and 1.13 for tomotherapy and 3D-CRT). SmartArc delivered lower maximum dose for majority of NT, but higher mean dose. 3D-CRT plans delivered higher maximum dose but lower mean dose to NT. Conclusions: SmartArc treatments achieved better PTV homogeneity and reduced maximum dose to NT. Tomotherapy showed better target conformity, but 3D-CRT was shown to reduce mean dose to NT. Integral doses were similar between treatment modalities, but tomotherapy treatment times were much longer.展开更多
Medulloblastoma is the most common malignant pediatric brain tumor. Some are thought to originate from cerebellar granule neuron progenitors （CGNPs） that fail to undergo normal cell cycle exit and differentiation. T...Medulloblastoma is the most common malignant pediatric brain tumor. Some are thought to originate from cerebellar granule neuron progenitors （CGNPs） that fail to undergo normal cell cycle exit and differentiation. The contribution of microRNAs to the initiation and progression of medulloblastoma remains poorly understood. Increased expression of the miR-183-96-182 cluster of microRNAs has been noted in several aggressive sub- groups. We identified that expression of miR-183-96-182 was higher in medulloblastomas with Pten gene loss in the background of the activated sonic hedgehog （Shh） signaling pathway. Ectopic miR-183-96-182 expression in CGNPs synergized with exogenous Shh to increase proliferation and its role depended on hedgehog signaling ac- tivation. Our findings suggest a new microRNA cluster, the miR-183-96-182, functionally collaborates with the Shh signaling pathway in the development of medulloblastomas in mice.展开更多
During the last years increasing evidence implies that human cytomegalovirus(CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential me...During the last years increasing evidence implies that human cytomegalovirus(CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.展开更多
Objective： to investigate the expressions of beta-catenin, SUFU and VEGFR-2 proteins in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of beta-cateni...Objective： to investigate the expressions of beta-catenin, SUFU and VEGFR-2 proteins in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of beta-catenin, SUFU and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： the abnormal expression rates of beta-catenin and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. While the positive expression of SUFU gene in medulloblastoma was significantly lower than that in 10 normal cerebellar tissues, A significant negative correlation was found between beta-catenin and SUFU proteins and a positive correlation between beta-catenin and VEGFR-2 was found in medulloblastoma. Conclusion： Beta-catenin, VEGFR-2 and SUFU have important effects on the pathogenesis and development of medulloblastoma.展开更多
1H magnetic resonance spectroscopy and diffusion weighted imaging features of the cerebellar vermis in 17 medulloblastoma patients were retrospectively analyzed, and 17 healthy volunteers were selected as controls. 1H...1H magnetic resonance spectroscopy and diffusion weighted imaging features of the cerebellar vermis in 17 medulloblastoma patients were retrospectively analyzed, and 17 healthy volunteers were selected as controls. 1H magnetic resonance spectroscopy showed that in all 17 medulloblastoma patients, N-acetyl aspartate and creatine peaks were significantly decreased, the choline peak was significantly increased, and there was evidence of a myo-inositol peak. Further, 11 patients showed a low taurine peak at 3.4 ppm, five patients showed a lipid peak at 0.9-1.3 ppm, and three patients showed a negative lactic acid peak at 1.33 ppm. Compared with the control group, the ratios of N-acetyl aspartate/choline and N-acetyl aspartate/creatine were significantly decreased, and the ratio of choline/creatine was increased, in medulloblastoma patients. Diffusion weighted imaging displayed hyperintensity and decreased apparent diffusion coefficient in medulloblastoma patients. These findings indicate that 1H magnetic resonance spectroscopy and diffusion weighted imaging are useful for qualitative diagnosis of medulloblastoma.展开更多
The association between cerebellar medulloblastoma and syringomyelia is uncommon and only found in pediatric patients.To date,adult medulloblastoma associated with syringomyelia has not been reported in the literature...The association between cerebellar medulloblastoma and syringomyelia is uncommon and only found in pediatric patients.To date,adult medulloblastoma associated with syringomyelia has not been reported in the literature.Paroxysmal bradycardia is an uncommon clinical manifestation in posterior fossa tumors and likely to be vagally mediated via brainstem preganglionic cardiac motor neurons.This report introduces the diagnosis and treatment of a case of adult medulloblastoma associated with syringomyelia, which presented with paroxysmal bradycardia.展开更多
Objective： To investigate the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGF receptor-2 （VEGFR-2） protein in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to...Objective： To investigate the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGF receptor-2 （VEGFR-2） protein in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： The expression rate of beta-catenin, and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. A significant positive correlation was found between beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 protein in medulloblastoma. Conclusion： There was a correlation between beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in medulloblastoma, which may play a role in the pathogenesis and development of medulloblastoma.展开更多
Medulloblastoma (MB) is a malignant brain tumor with a usual potential for leptomeningeal spread. Intramedullary metastases of MB are rare and there are very few cases reported in the literature. Here, we report the c...Medulloblastoma (MB) is a malignant brain tumor with a usual potential for leptomeningeal spread. Intramedullary metastases of MB are rare and there are very few cases reported in the literature. Here, we report the case of an 18-year-old man with intramedullary spinal cord metastasis of MB occurring 9 years after the first diagnosis. The patient presented a 2-month history of progressive weakness in both lower limbs associated with urinary incontinence. Magnetic resonance imaging (MRI) demonstrated a large intramedullary spinal cord tumor extending from T10 to L1. The patient underwent surgical decompression and adjuvant therapy. Histological examination confirmed the diagnosis of classic MB metastasis. Postoperatively, the neurological status was stationary. Intramedullary metastasis of medulloblastoma is rare and difficult to manage with a poor prognosis. Comprehensive studies on the medulloblastoma dissemination mechanisms and clinical trials are needed to assess combined therapeutic approaches on metastases of MB.展开更多
PURPOSE:To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated withconcurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost.METH-ODS ...PURPOSE:To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated withconcurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost.METH-ODS AND MATERIALS:Thirty-three patients with average risk(defined as<==1.5 cm(2)of residual tumorafter resection,age>3 years,and no involvement of the cerebrospinal fluid or spine)medulloblastoma werediagnosed at our institution between January 1994 and December 2001.They were enrolled in an institutional展开更多
Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptcl haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kipl, Ink4d, or Inkd.c inactivat...Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptcl haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kipl, Ink4d, or Inkd.c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma. To identify genes important for this tumor, we evaluated gene expression profiles in medulloblastomas from these mice. Unexpectedly, medulloblastoma展开更多
文摘Constitutive hedgehog （Hh） signaling is associated with the genesis of medulloblastomas （MB）. The objective of this study is to identify special microRNAs （miRNAs） regulated by the Hh pathway, and to clarify the role of miRNAs during the genesis of MB induced by sustained Hh activation. In the primary screening, we used stemloop RT-PCR to test the expression of 90 different miRNAs in the wildtype （WT） and Ptc-/- MEF cell lines. In the secondary screening, the miRNAs screened from the first screening were validated in the Sufu-/- MEF cell lines. We then verified the expression of miRNAs both in the normal cerebellar tissues and the MB induced by activated Hh pathway, and examined the expression of the other 21 miRNA members of the miR-154 cluster in the MB and normal cerebellum. In the first screening, 13 miRNAs showed significant differential expression in WT and Ptc-/- MEF cell lines, while 10 of them had significant difference in the Sufu-/- MEF cell line. Compared to the normal mouse cerebellum, only 2 miRNAs in 15 miRNAs were differentially expressed between the MB and normal cerebellar tissues. Among 21 members of the miR-154 cluster, 6 miRNAs were downregulated in the MB. Our study demonstrated that miR-154 may be regulated by the Hh pathway, and the activation of the Hh pathway led to the downregulation of the miR-154 cluster, resulting in the genesis of MB.
文摘Microvesicles (MVs) or shedding membrane vesicles have recently been described as a novel model of intercellular communication. Previously, MVs were considered as unnecessary or secreted cellular debris, but MVs have lately been described as having roles in a variety of biological functions, such as cell homeostasis and the cellular processes involved in the oncogenesis of many types of tumors. Carrying several key molecules that contribute to tumor development and progression, similar to mRNAs, microRNAs and other non-coding RNAs, DNA and even small proteins, MVs can be considered as a ubiquitous form of novel cell communication that is present in most somatic cells. Although tumor-derived MVs have been demonstrated in different types of cancers, the literature data on MVs in primary central nervous system (CNS) tumors are relatively scarce. In this review, we address the involvement of MVs in diffuse astrocytomas, particularly glioblastomas, as well as oligodendrogliomas and medulloblastomas. We placed particular focus on the cellular crosstalk between tumor and “normal” cells, the putative mechanisms how the tumor microenvironment is modulated and the spread of aggressive phenotypes. Additionally, a better understanding of the participation of tumor-derived MVs in the regulation of key cancer pathways will offer new insights into tumor pathogenesis and the mechanisms of multidrug resistance, and may help to develop new strategies for novel therapies against these infiltrative CNS tumors.
基金supported by the National Natural Science Foundation of China,No.31000574the Fundamental Research Fund for the Central Universities,No.78210042the Development Program of China during the 10~(th) Five-Year Plan Period,No.2001BA70113
文摘Signaling pathways known to have components with mutations in human medulloblastoma include sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor. Microarray analysis was applied to examine the gene expression changes in medulloblastomas of pTet-on/pTRE-SV40Tag transgenic mice. Altogether, 14 112 genes were detectable, including 152 genes with significantly different expression levels. These genes were associated with immunity, the cell cycle, signal transduction, cytoskeleton and metabolism. To further confirm the microarray data, real-time polymerase chain reactions were used to examine the expression changes of genes related to sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor signal pathways. Immunohistochemistry detected insulin receptor substrate-1 in the nuclei of brain tumor tissue cells from pTet-on/pTRE-SV40Tag transgenic mice, suggesting that SV40 large T antigen may activate the insulin-like growth factor signal pathway to promote tumorigenesis.
文摘Background MicroRNAs （miRNAs） are small noncoding regulatory RNAs whose aberrant expression may be observed in many malignancies. However, few data are yet available on human primary medulloblastomas. This work aimed to identify that whether miRNAs would be aberrantly expressed in tumor tissues compared with non-tumorous cerebellum tissues from same patients, and to explore a possible role during carcinogenesis. Methods A high throughput microRNA microarray was performed in human primary medulloblastoma specimens to investigate differentially expressed miRNAs, and some miRNAs were validated using real-time quantitative RT-PCR method. In addition, the predicted target genes for the most significantly downor up-regulated miRNAs were analyzed by using a newly modified ensemble algorithm. Results Nine miRNA species were differentially expressed in medulloblastoma specimens versus normal non-tumorous cerebellum tissues. Of these, 4 were over expressed and 5 were under expressed. The changes ranged from 0.02-fold to 6.61-fold. These findings were confirmed using real-time quantitative RT-PCR for most significant deregulated miRNAs （miR-17, miR-100, miR-106b, and miR-218） which are novel and have not been previously published. Interestingly, most of the predicted target genes for these miRNAs were involved in medulloblastoma carcinogenesis. Conclusions MJRNAs are differentially expressed between human medulloblastoma and non-tumorous cerebellum tissue. MiRNAs may play a role in the tumorigenesis of medulloblastoma and maybe serve as potential targets for novel therapeutic strategies in future.
基金funded by the Key Research and Development Project of the Science and Technology Department of Sichuan Province(No.2021YFS0010).
文摘Purpose:The present study summarized cases of children(n=32)with medulloblastoma(MB)who were treated using stratified therapy based on risk grading and also discussed the factors affecting prognosis.Methods:According to the risk stratification criteria,the cases were divided into the following four risk groups:low,standard,high,and very high.The 5-year overall survival(OS)and progression-free survival(PFS)rates were summarized.Further,the effects on the prognosis of tumor size,tumor stage,degree of resection,treatment mode,metastatic recurrence,molecular typing,and risk stratification were analyzed.Results:In the present study,following surgery,3 cases abandoned radiotherapy(RT)and chemotherapy(CHT),7 cases(<3 years of age)received only CHT,and 22 cases received combined RT and CHT.Total and near-total tumor resections were performed in 29 cases(90.6%).Subtotal resections were performed in 3 cases,and there were no surgery-related deaths.The average follow-up duration was 47 months.The average 5-year PFS and OS rates were 57.3%±7.2%and 68.7%±8.6%,respectively.The OS and PFS rates were significantly correlated with tumor-risk stratification,molecular staging,tumor stage,treatment mode,and recurrence after surgery(p<0.01).The degree of tumor resection,pathological type,and the presence of preoperative implantation were secondary factors affecting the prognosis(p<0.05).Age was correlated with the PFS rate.There was no correlation between age/tumor location/tumor size and prognosis(p>0.05).Favorable prognostic factors in the low-and standard-risk groups were stage M0,wingless-type MB,postoperative RT combined with CHT,no postoperative recurrence,age≥3 years,and total tumor resection.Conclusions:Personalized treatment strategies based on the risk stratification of MB and postoperative stratified comprehensive treatment could help improve the prognosis for MB.
文摘Medulloblastoma(MB)is considered the commonest malignant brain tumor in children.Multimodal treatments consisting of surgery,radiation,and chemotherapy have improved patients’survival.Nevertheless,the recurrence occurs in 30%of cases.The persistent mortality rates,the failure of current therapies to extend life expectancy,and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic approaches.Most MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent connections.Recently,MBs have been segregated into four molecular subgroups:Wingless-activated(WNT-MB)(Group 1);Sonichedgehog-activated(SHH-MB)(Group 2);Group 3 and 4 MBs.These molecular alterations follow specific gene mutations and disease-risk stratifications.The current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall survival.However,the need to explore new therapies targeting specific receptors in MB microenvironment became essential.The immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune cells.Tumour associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment,and their role are still under investigation.In this review,we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment,with an overview of the recent investigations and clinical trials.
文摘This research work develops new and better prognostic markers for predicting Childhood MedulloBlastoma(CMB)using a well-defined deep learning architecture.A deep learning architecture could be designed using ideas from image processing and neural networks to predict CMB using histopathological images.First,a convolution process transforms the histopathological image into deep features that uniquely describe it using different two-dimensional filters of various sizes.A 10-layer deep learning architecture is designed to extract deep features.The introduction of pooling layers in the architecture reduces the feature dimension.The extracted and dimension-reduced deep features from the arrangement of convolution layers and pooling layers are used to classify histopathological images using a neural network classifier.The performance of the CMB classification system is evaluated using 1414(10×magnification)and 1071(100×magnification)augmented histopathological images with five classes of CMB such as desmoplastic,nodular,large cell,classic,and normal.Experimental results show that the average classification accuracy of 99.38%(10×)and 99.07%(100×)is attained by the proposed CNB classification system.
基金Key Social Development Project in Hainan Province(No.ZDYF2019173)。
文摘Medulloblastoma(MB)is the most common childhood embryonal malignant tumour in the central nervous system.The diagnosis,prognosis and therapeutic targets of MB depend on the molecular characteristics of the tumor,and it is a great challenge to obtain the tissue samples from the patients with brain tumor.Genomic changes found in cell-free DNA(cfDNA)of cerebrospinal fluid(CSF)can predict genomic changes present in tumor tissue,fluid biopsy of CSF can detect the genomic profile of tumor-associated cfDNA and evaluate cfDNA as a marker of measurable residual disease(MRD)in a relatively noninvasive manner,which provides the evidence of"individualized precision therapy"for MB patients.In this paper,we reviewed the recent studies in medulloblastoma based on cfDNA Liquid Biopsy of CSF.
基金the hundreds top talents program from Chinese Academy of Sciences,the NSFC(Nos.81173076,81403050)the projects of science and technology of Yunnan Province(2009C1120,2013FA047).
文摘Medulloblastoma(MB)is a form of malignant brain tumor that predominantly arises in infants and children,of which approximately 25%is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1.Therefore,Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer.In our present study,we undertook a screening for antagonists of Wnt signaling from 600 natural compounds,and identified Ginkgetin,a biflavone isolated from Cephalotaxus fortunei var.alpina.Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 lM and structure–activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group.Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells.Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells.Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes,including Axin2,cyclinD1 and survivin in MB cells.The phosphorylation level of b-catenin also decreased in a time-and concentration-dependent manner.Collectively,our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling,and as such warrants further exploration as a promising antimedulloblastoma candidate.
文摘Objective： To investigate the expressions of GSK-3beta, Beta-catenin and PPAR-gamma, and their relationship in medulloblastoma, and to explore their value in clinic application. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of GSK-3beta, Beta-catenin and PPAR-gamma in 48 cases of medulloblastoma and 10 normal cerebellar tissues. Results： The rate of abnormal expressions of beta-catenin and PPAR-gamma in MB was higher than that in normal. Conversely, GSK-3beta in MB was lower than that in the normal （P〈0.05）. Furthermore, in medulloblastoma, beta-catenin and GSK-3beta showed a negative correlation, PPAR-gamma and beta-catenin had a positive correlation. Conclusion： Abnormal expression of beta-catenin plays a crucial role in the development of medulloblastoma. Meanwhile, PPAR-gamma and GSK-3beta which are tightly related with beta-catenin are both involved in the genesis and development of medulloblastoma.
文摘Purpose: Craniospinal axis irradiation (CSI) is a method of treating various central nervous system malignancies. The large target volume typically includes entire spinal cord and whole brain. Dosimetric comparison was performed between tomotherapy, volumetric modulated arc therapy (VMAT), and 3D conformal radiation therapy (3D-CRT) for CSI. Methods and Materials: Five (n = 5) CSI patients were planned using 3D-CRT, VMAT, and tomotherapy (normalized such that 95% of PTV received at least 23.4 Gy in 13 fractions). Plans were compared using PTV conformity number (CN) and homogeneity index (HI), normal tissue (NT) dose statistics, integral dose, and treatment time. Results: On average, tomotherapy plans showed higher CN (0.932 vs. 0.860 and 0.672 for SmartArc and 3D-CRT). In terms of HI, VMAT plans consistently showed better dose homogeneity (1.07 vs. 1.15 and 1.13 for tomotherapy and 3D-CRT). SmartArc delivered lower maximum dose for majority of NT, but higher mean dose. 3D-CRT plans delivered higher maximum dose but lower mean dose to NT. Conclusions: SmartArc treatments achieved better PTV homogeneity and reduced maximum dose to NT. Tomotherapy showed better target conformity, but 3D-CRT was shown to reduce mean dose to NT. Integral doses were similar between treatment modalities, but tomotherapy treatment times were much longer.
文摘Medulloblastoma is the most common malignant pediatric brain tumor. Some are thought to originate from cerebellar granule neuron progenitors （CGNPs） that fail to undergo normal cell cycle exit and differentiation. The contribution of microRNAs to the initiation and progression of medulloblastoma remains poorly understood. Increased expression of the miR-183-96-182 cluster of microRNAs has been noted in several aggressive sub- groups. We identified that expression of miR-183-96-182 was higher in medulloblastomas with Pten gene loss in the background of the activated sonic hedgehog （Shh） signaling pathway. Ectopic miR-183-96-182 expression in CGNPs synergized with exogenous Shh to increase proliferation and its role depended on hedgehog signaling ac- tivation. Our findings suggest a new microRNA cluster, the miR-183-96-182, functionally collaborates with the Shh signaling pathway in the development of medulloblastomas in mice.
基金Supported by Grants from Ragnar Soderbergs FoundationThe Swedish Children’s Cancer Foundation+9 种基金BILTEMA FoundationFamily Ehring Perssons FoundationSten A Olssons FoundationStichting af Jochnicks FoundationThe Swedish Cancer Society,The Swedish Research Council,the Marta and Gunnar V Philipson FoundationThe Hans and Marit Rausing Charitable FundThe Damman FoundationSwedish Society for Medical Research(SLS),Goljes Memory FoundationMagnus Bergvalls FoundationSwedish Society for Medical Research(SSMF)and Tore Nilsons Foundation
文摘During the last years increasing evidence implies that human cytomegalovirus(CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.
文摘Objective： to investigate the expressions of beta-catenin, SUFU and VEGFR-2 proteins in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of beta-catenin, SUFU and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： the abnormal expression rates of beta-catenin and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. While the positive expression of SUFU gene in medulloblastoma was significantly lower than that in 10 normal cerebellar tissues, A significant negative correlation was found between beta-catenin and SUFU proteins and a positive correlation between beta-catenin and VEGFR-2 was found in medulloblastoma. Conclusion： Beta-catenin, VEGFR-2 and SUFU have important effects on the pathogenesis and development of medulloblastoma.
基金supported by the National Natural Science Foundation of China, No. 81171315the Fundamental Research Funds of the Central Universities, No. 303275894the Natural Science Foundation of Hubei Province, No.2009CDA071
文摘1H magnetic resonance spectroscopy and diffusion weighted imaging features of the cerebellar vermis in 17 medulloblastoma patients were retrospectively analyzed, and 17 healthy volunteers were selected as controls. 1H magnetic resonance spectroscopy showed that in all 17 medulloblastoma patients, N-acetyl aspartate and creatine peaks were significantly decreased, the choline peak was significantly increased, and there was evidence of a myo-inositol peak. Further, 11 patients showed a low taurine peak at 3.4 ppm, five patients showed a lipid peak at 0.9-1.3 ppm, and three patients showed a negative lactic acid peak at 1.33 ppm. Compared with the control group, the ratios of N-acetyl aspartate/choline and N-acetyl aspartate/creatine were significantly decreased, and the ratio of choline/creatine was increased, in medulloblastoma patients. Diffusion weighted imaging displayed hyperintensity and decreased apparent diffusion coefficient in medulloblastoma patients. These findings indicate that 1H magnetic resonance spectroscopy and diffusion weighted imaging are useful for qualitative diagnosis of medulloblastoma.
文摘The association between cerebellar medulloblastoma and syringomyelia is uncommon and only found in pediatric patients.To date,adult medulloblastoma associated with syringomyelia has not been reported in the literature.Paroxysmal bradycardia is an uncommon clinical manifestation in posterior fossa tumors and likely to be vagally mediated via brainstem preganglionic cardiac motor neurons.This report introduces the diagnosis and treatment of a case of adult medulloblastoma associated with syringomyelia, which presented with paroxysmal bradycardia.
文摘Objective： To investigate the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGF receptor-2 （VEGFR-2） protein in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expression of beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： The expression rate of beta-catenin, and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. A significant positive correlation was found between beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 protein in medulloblastoma. Conclusion： There was a correlation between beta-catenin and VEGFs （VEGF-A, VEGF-C） and VEGFR-2 in medulloblastoma, which may play a role in the pathogenesis and development of medulloblastoma.
文摘Medulloblastoma (MB) is a malignant brain tumor with a usual potential for leptomeningeal spread. Intramedullary metastases of MB are rare and there are very few cases reported in the literature. Here, we report the case of an 18-year-old man with intramedullary spinal cord metastasis of MB occurring 9 years after the first diagnosis. The patient presented a 2-month history of progressive weakness in both lower limbs associated with urinary incontinence. Magnetic resonance imaging (MRI) demonstrated a large intramedullary spinal cord tumor extending from T10 to L1. The patient underwent surgical decompression and adjuvant therapy. Histological examination confirmed the diagnosis of classic MB metastasis. Postoperatively, the neurological status was stationary. Intramedullary metastasis of medulloblastoma is rare and difficult to manage with a poor prognosis. Comprehensive studies on the medulloblastoma dissemination mechanisms and clinical trials are needed to assess combined therapeutic approaches on metastases of MB.
文摘PURPOSE:To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated withconcurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost.METH-ODS AND MATERIALS:Thirty-three patients with average risk(defined as<==1.5 cm(2)of residual tumorafter resection,age>3 years,and no involvement of the cerebrospinal fluid or spine)medulloblastoma werediagnosed at our institution between January 1994 and December 2001.They were enrolled in an institutional
文摘Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptcl haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kipl, Ink4d, or Inkd.c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma. To identify genes important for this tumor, we evaluated gene expression profiles in medulloblastomas from these mice. Unexpectedly, medulloblastoma
