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Objective:To investigate the role of subventricular zone (SVZ) irradiation in the prognosis of patients with glioblastoma (GBM), and to analyze the factors affecting the prognosis of patients with GBM.Methods:Clinical data of 52 patients with GBM treated in the Affiliated Cancer Hospital of Nanjing Medical University from 2017 to 2020 were analyzed retrospectively. According to the median dose of ipsilateral or contralateral SVZ, the patients were divided into the high-dose group and low-dose group. The prognostic differences between two groups were compared and the prognostic factors were analyzed.Results:The median progression-free survival (PFS) was 17.1 months (95% CI:12.4-30.7)and the median overall survival (OS) was 38.3 months (95% CI:20.4-44.5). Univariate analysis showed that whether the tumor invading SVZ ( P = 0.039), the degree of resection ( P = 0.009) and MGMT promoter methylation status ( P = 0.039) were the influencing factors of PFS. Age ( P = 0.018), Kanofsky performance score ( P = 0.043), whether the tumor invading SVZ ( P = 0.038), degree of resection ( P = 0.020) and MGMT promoter methylation status ( P = 0.019) were the influencing factors of OS. The analysis of SVZ dose as a continuous variable showed that SVZ dose was the influencing factor of PFS ( P < 0.05) rather than OS ( P ≥ 0.05). Whether the tumor invading SVZ or not, there was no significant difference in survival between the high-dose and low-dose groups. Multivariate analysis showed that whether the tumor invading SVZ and MGMT promoter methylation were the independent prognostic factor for PFS (both P < 0.05), and OS (both P < 0.05). The SVZ dose related variables were not statistically significant in multivariate analysis. Conclusions:Patients with tumors directly invading SVZ achieve worse survival. Increasing the ipsilateral or contralateral SVZ dose does not improve patient survival. Whether SVZ irradiation affects the survival of patients still needs to be further confirmed by prospective randomized clinical studies.
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Glioma is the most common intracranial malignant tumor of the nervous system. It is highly invasive, resistant to conventional treatment, and easy to relapse. The main treatment strategy is surgery plus radiotherapy, but the prognosis is still poor. Glioma stem cells (GSCs) are a group of cells with neural stem cell-like properties in glioma. As the starting cells of glioma, they are considered to be the key factors for tumorigenesis and recurrence. CD133 is considered to be a biomarker for glioblastoma and is used as a marker for GSCs. Although its biological significance is currently controversial, more and more studies have shown that CD133 is involved in GSCs-mediated tumor formation and recurrence. This article mainly reviews the GSCs surface marker CD133 and its related targeted therapies.
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Seven new isoquinoline alkaloids, 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy dehydroaporphine (1), 9-(2'-formyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy oxoaporphine (2), 3-methoxy-2'-formyl oxohernandalin (3), (-)-9-(2'-methoxycarbonyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (4), (-)-2'-methoxycarbonyl thaliadin (5), (-)-9-(2'-methoxyethyl-5', 6'-dimethoxyphenoxy)-1, 2, 3, 10-tetramethoxy aporphine (6), (-)-3-methoxy hydroxyhernandalinol (7), together with six known isoquinoline alkaloids (8-13) were isolated from the roots of Thalictrum foetidum. Their structures were elucidated by extensive spectroscopic measurements. Compounds 1 and 2 showed significant selective cytotoxicity against glioma stem cells (GSC-3 and GSC-18) with IC values ranging from 2.36 to 5.37 μg·mL.
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Objective:To investigate the influence of isoliquiritigenin on the radiosensitivity of glioma stem cells and demonstrate the potential underlying mechanism. Methods:Glioma stem cells were isolated from SHG44 human glioma cells by serum-free medium. Cell proliferation abilities were detected after isoliquiritigenin treatment and radiotherapy by using Cell Counting Kit-8. The formation of glioma stem cell spheres was observed using an inverted microscope. The protein expression levels of Notch1 signal pathway, NF-κB, and caspase-3 were examined by Western blot analysis. Results:Isoliquiritigenin (10μM) inhibited the formation of tumorspheres at 8 Gy radiation (P<0.05). Isoliquiritigenin (20μM) exerted evident growth inhibitory effect on glioma stem cells. Isoliquiritigenin pre-treatment combined with 4 or 8 Gy radiation reduced the cell radioresistance significantly (P<0.05). The protein expression levels of Notch1 in the isoliquiritigenin and DAPT groups were lower than those of the control at 48 h after isoliquiritigenin treatment (P<0.05). The protein expression levels of P-NF-κB began to increase at 6 and 24 h after 4 Gy radiation with isoliquiritigenin pretreatment (P<0.05). Isoliquiritigenin pretreatment combined with 4 Gy radiation increased the protein expression level of cleaved caspase-3 at 24 h after radiation compared with that of the isoliquiritigenin treatment alone (P<0.05). Conclusion:Isoliquiritigenin may downregulate Notch1 signal pathway and affect different aspects of cell stress and death, including NF-κB- and caspase-3-associated processes, thereby promoting the radiosensitivity of glioma stem cells.
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Objective To investigate the expression of miR-29s in the glioma stem cells,and explore how the members of miR-29s affect the bio-logical behaviors of glioma stem cells. Methods Eight patient specimens were used to culture glioma stem cells. Real-time PCR was adopted to test the expression of miR-29s. CCK-8 analysis was performed to test the proliferation ,Transwell was used to test cell migration and invasion ,and flow-cytometry analysis was carried out to test apoptosis. Results miR-29a,miR-29b and miR-29c were decreased in glioma stem cells. Over-ex-pression of miR-29s could inhibit the proliferation,cell migration and invasion,but promote apoptosis of glioma stem cells. Conclusion miR-29s acts as a cancer suppressor gene in the glioma stem cells ,and miR-29a plays the dominant functional role in the family.
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Glioblastoma multiforme (GBM,WHO grade IV) contains some glioma stem cells which have unique self-renewal capacity and multilineage potency.There are numerous neural stem cells in the subventricular zone (SVZ) of adult human brain;it may also act as a storehouse of glioma stem cells that can promote the development and recurrence of a tumor.GBM involving SVZ is prone to early recurrence and intracranial metastasis after resection,so irradiation of the SVZ potentially influences the survival of GBM patients.This review provides a summary of related experimental and clinical studies,and discusses the value of irradiation of the SVZ in GBM patients and the direction of future research.
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Aim To establish ICR animal model with C6 glioma stem cells, to provide the ideal model for the further study of gli-oma stem cells in brain glioma model. Methods C6 glioma stem cell was cultured in vitro by suspension,and was identified with Nestin antibody. C6 stem cells of ICR mouse glioma model were used to investigate survival state and tumor volume in mice after the operation. HE staining and CD133 immunohistochemi-cal study were adopted to investigate the postoperative pathologi-cal changes in mice. Results The expression of Nestin was 96. 01% in C6 glioma stem cells, and Nestin was highly ex-pressed in the cultured C6 glioma stem cells. Mice were inocula-ted with tumor after loss of appetite, weight, behavior and slow, sluggish reaction. Tumor volume at day 21 after modeling was (9. 77 ± 6. 58) mm3 . After HE staining, the model showed the invasive growth, tumor cell shrinkage and derangement. Immu-nohistochemical CD133 staining revealed that tumor cytoplasm color was brown. Conclusion Glioma model can be established based on glioma stem cells into a high rate of tumor, the tumor cycle is short, which can be used as an ideal model for glioma.
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Aim To explore the effect of shikonin on stemness maintance of glioma stem cells ( GSCs ). Methods After the U87-MG cells were cultured and isolated, the sphere cells were identified by immuno-fluorescent staining. The alteration of stemness of GSCs by shikonin treatment(2 μmol·L - 1 ) for 12 h, 24 h and 48 h was valued by morphological detection using optical microscope and sub-sphere forming assay. Mo-reover, the related markers of stem cells, such as CD133, were detected in shikonin treated GSCs by western blot assay. Protein expression of PI3K, p-PI3K, Akt and p-Akt was detected by western blot af-ter shikonin treatment alone. Furthermore, by combi-nation with insulin-like growth factor-1 ( IGF-1), we observed the alteration of stemness maintance of shiko-nin-treated GSCs. Results The presence of neural stem cell related markers CD133 and nestin proved the characteristics of GSCs. Shikonin treatment significant-ly inhibited the morphology of GSCs and the sub-sphere forming. Besides, the reduced expression of CD133 was detected in shikonin treated GSCs. Though, the expression of PI3K and Akt did not change compared with the control group, the expression of p-PI3K and p-Akt was reduced. Furthermore, the combination of IGF-1 markedly attenuated the inhibitory effect of shikonin on stemness maintance of GSCs. Conclusion The stemness maintance of GSCs can be significantly inhibited by shikonin treatment, in which PI3K/ Akt pathway is involved.
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Objective To investigate whether the malignant transformation of macrophages ( Mφ) in glioma mesenchyme was induced by the fusion of glioma cells ( SU3 ) and Mφ.Methods SU3 cells transfected with red fluorescent protein genes were co-cultured in vitro with Mφexpressing enhanced green fluorescent protein.The cell lineages with RFP+/GFP+dual-color fluorescence were established by using monoclonal selection method.A series of tests for analyzing cancer-related phenotypes, tumorigenicity and specific markers for murine macrophage were performed.Results (1) A few of dual-color fluorescent cells were observed in the co-culture.Three monoclonal cell lineages (C3, C4 and C12) were obtained success-fully.(2) Three types of cells including RFP+, EGFP+and RFP+/EGFP+cells were formed during the cul-ture of monoclonal C12 cell lineage.The percentage of EGFP+cells was increased along the extended culture time and increased passages.Then, EGFP+cells gradually became the predominant cell population.Nota-bly, the percentage of RFP+/EGFP+cells were decreased and maintained at a low level, but the RFP+cells almost disappeared.(3) EGFP+cells from monoclonal C12 cell lineage showed the malignant characteristics such as loss of contact inhibition, rapid proliferation andchromosome aneuploidy, as well as high tumorigenic rate in nude mice (5/5).They also expressed macrophage specific marker CD68 and showed a large number of telocentric chromosomes.Conclusion The results of this study suggested that the malignant transforma-tion of host macrophages as previously observed in solid tumor might be induced by cell fusion occurred be-tween human glioma cells and macrophages.Along with the previous evidences showing the isolation of the malignantly transformed macrophages ( ihCTC) from solid tumor tissue of tumor-bearing mice, the results confirmed an objective existence of malignant transformation of host macrophages in tumor microenvironment. The malignant transformation of host cells induced by fusion with tumor cells revealed not only a new under-standing for the progression of tumor and cancer heterogeneity, but also new targets for cancer therapy.
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Objective To observe the regulation of sry-related high-mobility-group box-containing 2 (Sox2) on epidermal growth factor receptor(EGFR)and on the sphere formation rate of glioma stem cells .Methods Promoter reporter plasmids of epidermal growth factor homologous receptor ErbB2 ,ErbB3 ,ErbB4 were respectively constructed .Sox2 expression plasmid was co-transfected together with the reporter plasmid into U251 cells .Then the luciferase activity was analyzed by dual-luciferase reporter assay sys-tem to test the regulation of Sox2 on ErbB2 ,ErbB3 ,ErbB4 promoters .Sphere formation assay was used to observe selfrenew of the cancer stem cells after transfection of Sox 2 .The expression of EGFR and ErbB2 proteins in the spheres was examined by Western blot .Results Sox2 could dose-dependently increase the ErbB2 ,ErbB3 ,ErbB4 promoter drived luciferase activity .Sox2 promotes the sphere-forming rate of U251 cells and upregulates the expression of EGFR and ErbB2 in the spheres .Conclusion Sox2 could up-regulate the expression of EGFR and promote selfrenew of glioma stem cells .
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10.3969/j.issn.1008-9691.2013.03.005