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Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic one-compartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CLi = 9.23× (1 + 0.0005× (θCrCL-105.78)) × (1 + 0.0017× (θWT-16)) × eηcl,i (L/h), IF (θDEX) CLi = 1.19× CLi (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy.  相似文献   
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Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown. The objective of this study is to examine the role of PELP1 in the progression of MB. Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in the MB specimens compared to normal brain. Knockdown of PELP1 reduced cell proliferation, cell survival, and cell invasion of MB cell lines. The RNA-sequencing analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation and extracellular matrix. Gene set enrichment analysis confirmed that the PELP1-regulated genes were negatively correlated with nuclear factor-κB (NF-κB), extracellular matrix, and angiogenesis gene sets. Interestingly, PELP1 knockdown reduced the expression of NF-κB target genes, NF-κB reporter activity, and inhibited the nuclear translocation of p65. Importantly, the knockdown of PELP1 significantly reduced in vivo MB progression in orthotopic models and improved the overall mice survival. Collectively, these results suggest that PELP1 could be a novel target for therapeutic intervention in MB.  相似文献   
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目的探讨髓母细胞瘤临床病理学特征及其影响患者预后的主要危险因素。方法收集85例髓母细胞瘤患者的临床病理学资料,观察其组织病理学及免疫学表型特征,分析其临床特点及影响患者预后的相关危险因素。结果 85例髓母细胞瘤患者中男性49例,女性36例,平均发病年龄(9.35±1.18)岁。75例患者病变位于小脑(其中59例位于小脑半球,16例位于小脑蚓部),10例分别位于脊髓(5例)、第四脑室(1例)、大脑颞叶(1例)、大脑额叶(1例)、大脑枕叶(1例)、中脑(1例)。临床表现主要为颅内压增高、共济失调及患侧肢体运动障碍等,部分病人表现为言语不清、记忆力下降及肢体感觉麻木等。免疫组织化学检查:突触素(Syn)阳性表达率为64%,β连环蛋白(β-catenin)阳性表达率为45%,胶质纤维酸性蛋白(GFAP)阳性表达率为50%;NF、CD99肿瘤细胞散在或弱阳性表达;Vimentin、CK、Neu-N、EMA肿瘤细胞呈阴性表达;肿瘤细胞Ki-67增殖指数较高,约为60%。结论髓母细胞瘤儿童多发,预后不良,β-catenin和Ki-67免疫组化染色对其诊断与鉴别诊断有一定参考价值,可能成为髓母细胞瘤判断预后的重要指标。  相似文献   
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Introduction: One of the major challenges in cancer treatment is the lack of specific and accurate treatment incancer. Data analysis can help to understand the underlying molecular mechanism that leads to better treatment.Increasing availability and reliability of DNA microarray data leads to increase the use of these data in a variety ofcancers. This study aimed at applying and evaluating microarray data analyzing, identification of important pathwaysand gene network for medulloblastoma patients to improve treatment approaches especially target therapy. Methods:In the current study, Microarray gene expression data (GSE50161) were extracted from Geo datasets and then analyzedby the affylmGUI package to predict and investigate upregulated and downregulated genes in medulloblastoma. Then,the important pathways were determined by using software and gene enrichment analyses. Pathways visualizationand network analyses were performed by Cytoscape. Results: A total number of 249 differentially expressed genes(DEGs) were identified in medulloblastoma compared to normal samples. Cell cycle, p53, and FoxO signaling pathwayswere indicated in medulloblastoma, and CDK1, CCNB1, CDK2, and WEE1 were identified as some of the importantgenes in the medulloblastoma. Conclusion: Identification of critical and specific pathway in any disease, in our casemedulloblastoma, can lead us to better clinical management and accurate treatment and target therapy.  相似文献   
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Introduction:Radiation induced gliomas often occurs after radiation therapy for other brain tumors. Medulloblastoma often occurs in children and its associated radiation-induced glioblastoma multiforme''s (GBM) after radiotherapy often has a long latency period. Our case is very unique because the medulloblastoma was detected at an advance age and the latency period of radiation-induced GBM was relatively shorter.Patients Concerns:A 64-year-old male was first admitted at our hospital in March 2018 with dizziness, vomiting, and blurred vision.Diagnosis:Magnetic resonance imaging of brain revealed a lesion with local mixed density and mass enhancement in left cerebellar region. Histopathology established medulloblastoma (World Health Organization) grade 4 and a classic histological subtype after surgery.Intervention:Surgical resection followed by radiation therapy were the initial therapeutic modalities.Outcomes:In April 2019, the patient was readmitted with dizziness and blurred vision. Magnetic resonance imaging showed the left cerebellar hemisphere bulky enhancement lesion. Again, a multimodal therapy comprising surgical resection, radiation therapy as well as chemotherapy was adapted after histopathology established GBM.Lesion:Radiotherapy for medulloblastoma patients at advance ages is a critical predisposing factor for the development of radiation-induced GBM in a very short period of time. We suggest that, radiotherapy as adjuvant therapy for medulloblastoma patients at advance ages should be chosen with extreme caution.  相似文献   
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