• Molecules and Cells
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• 제42권2호
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• pp.135-142
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• 2019

OCT4, also known as POU5F1 (POU domain class 5 transcription factor 1), is a transcription factor that acts as a master regulator of pluripotency in embryonic stem cells and is one of the reprogramming factors required for generating induced pluripotent stem cells. The human OCT4 encodes three isoforms, OCT4A, OCT4B, and OCT4B1, which are generated by alternative splicing. Currently, the functions and expression patterns of OCT4B remain largely unknown in malignancies, especially in human glioblastomas. Here, we demonstrated the function of OCT4B in human glioblastomas. Among the isoform of OCT4B, OCT4B-190 ($OCT4B^{19kDa}$) was highly expressed in human glioblastoma stem cells and glioblastoma cells and was mainly detected in the cytoplasm rather than the nucleus. Overexpression of $OCT4B^{19kDa}$ promoted colony formation of glioblastoma cells when grown in soft agar culture conditions. Clinical data analysis revealed that patients with gliomas that expressed OCT4B at high levels had a poorer prognosis than patients with gliomas that expressed OCT4B at low levels. Thus, $OCT4B^{19kDa}$ may play a crucial role in regulating cancer cell survival and adaption in a rigid environment.

• Journal of Korean Neurosurgical Society
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• 제30권4호
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• pp.443-450
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• 2001

Objective : The cyclin-dependent kinase inhibitor $p27^{kip1}$ protein is a negative regulator of the cell cycle, and its degradation is required for entry into the S phase. Loss of $p27^{kip1}$ expression has been reported to be associated with aggressive behavior in a variety of tumors of epithelial and lymphoid origin. However, its association with various astrocytic tumors has not been clearly demonstrated. We studied to investigate the relationship of $p27^{kip1}$ expression with the biological behavior of astrocytic tumors in addition to study on the role of $p27^{kip1}$ in the tumorigenesis of these tumors. Patients and Methods : From 1990 to 1998, a total of 29 astrocytic tumor of all grades obtained by operative resection were included for evaluation. We studied the expression of $p27^{kip1}$ protein immunohistochemical assay in astrocytic tumors and compared the findings with the clinicopathologic parameters. Immunohistochemical staining was performed on formalin-fixed paraffin-embedded sections by the avidin-biotin-peroxidase complex method. According to WHO classification, all cases were divided into astrocytomas(4 cases), anaplastic astrocytomas(9 cases), and glioblastomas(16 cases) by 3 pathologists. Clinical information was obtained from medical records, and others such as location and size of tumors from imaging studies. Results : Mean $p27^{kip1}$ protein labeling indexes(LI, mean${\pm}$standard deviation) of astrocytomas, anaplastic astrocytomas, and glioblastomas were $80.6{\pm}9.1$, $63.6{\pm}21.0$, and $28.9{\pm}18.7$, respectively, and were inversely correlated with grade of glial tumors(p<0.0001). Mean $p27^{kip1}$ protein LI in the recurrent group was lower than that in the nonrecurrent group, but there was no significant difference statistically(p=0.464). Additionally, $p27^{kip1}$ protein expression did not show any significant relationship to other prognostic factors such as age(p=0.1643), tumor size(p=0.8), or location(p=0.8). Conclusion : These results suggested that reduced expression of $p27^{kip1}$ protein may play a important role in the malignant transformation process of astrocytic tumor cells.

• Journal of Korean Neurosurgical Society
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• 제48권1호
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• pp.20-30
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• 2010

Objective : We determined whether the expression of GRIM-19 is correlated with pathologic types and malignant grades in gliomas, and determined the function of GRIM-19 in human gliomas. Methods : Tumor tissues were isolated and frozen at $-80^{\circ}C$ just after surgery. The tissues consisted of normal brain tissue (4), astrocytomas (2), anaplastic astrocytomas (2), oligodendrogliomas (13), anaplastic oligodendrogliomas (11), and glioblastomas (16). To profile tumor-related genes, we applied RNA differential display using a $Genefishing^{TM}$ DEG kit, and validated the tumor-related genes by reverse transcription polymerase chain reaction (RT-PCR). A human glioblastoma cell line (U343MG-A) was used for the GRIM-19 functional studies. The morphologic and cytoskeletal changes were examined via light and confocal microscopy. The migratory and invasive abilities were investigated by the simple scratch technique and Matrigel assay. The antiproliferative activity was determined by thiazolyl blue Tetrazolium bromide (MTT) assay and FACS analysis. Results : Based on RT-PCR analysis, the expression of GRIM-19 was higher in astrocytic tumors than oligodendroglial tumors. The expression of GRIM-19 was higher in high-grade tumors than low-grade tumors or normal brain tissue; glioblastomas showed the highest expression. After transfection of GRIM-19 into U343MG-A, the morphology of the sense-transfection cells became larger and more spindly. The antisensetransfection cells became smaller and rounder compared with wild type U343MG-A. The MTT assay showed that the sense-transfection cells were more sensitive to the combination of interferon-$\beta$ and retinoic acid than U343MG-A cells or antisense-transfection cells; the antiproliferative activity was related to apoptosis. Conclusion : GRIM-19 may be one of the gene profiles which regulate cell death via apoptosis in human gliomas.

• Investigative Magnetic Resonance Imaging
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• 제5권2호
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• pp.130-137
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• 2001

목적: 대뇌 교종(glioma)에서 상대적 뇌혈액용적(relative cerebral blood volume, rCBV)과 종양의 조직학적 등급(grade)을 비교하고자 하였다. 대상 및 방법 대뇌 교종으로 진단된 총 16명의 환자에서 수술 전에 고식적 T1 및 T2 강조 자기 공명영상 및 조영제를 이용한 관류 자기공명영상을 시행하였다. 교종은 교아세포종(glioblas tora)이 7예, 역형성 성상세포종(anaplastic astrocytoma)이 2예, 역형성 핍지교세포종(anaplastic oligodendroglioma)이 1예, 저등급 성상세포종(low-grade astrocytoma)이 5예, 저등급 핍지교종(low-grade oligodendroglioma)이 1예 있었다. 관류 자기공명영상으로 얻은 교종의 최대 rCBV을 종양의 조직학적 진단 및 등급과 비교 하였다. 결과: 교아세포종의 최대 rCBV은 반대편 정상 백질과 비교하여 433%-1330% (펑균 790%)로 현저히 증가되어 있었다. 강한 조영증강을 보인 역형성 핍지교종 1예의 최대 rCBV은 502%로 증가되어 있었으나 조영증강되지 않는 역형성 성상세포종 2예의 최대 rCBV은 각각66%, 284%로 비교적 낮았다. 저등급 성상세포종의 최대 rCBV은 80%-369% (굉균 202 %)였다. 저등급 핍지교종 1예는 최대 rCBV이 1450%로 교아세포종 보다 높았다. 결론: 관류 자기공명영상을 이용한 rCBV수치는 교아세포종과 저등급 성상세포종은 분명히 구분되었으나 조영증강되지 않는 역형성 성상세포종파 저등급 성상세포종 간에는 차이가 없었다.

• Investigative Magnetic Resonance Imaging
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• 제22권3호
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• pp.158-167
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• 2018

Purpose: To investigate the surgical, perfusion, and molecular characteristics of glioblastomas which influence long-term survival after treatment, and to explore the association between MR perfusion parameters and the presence of MGMT methylation and 1p/19q deletions. Materials and Methods: This retrospective study was approved by our institutional review board. A total 43 patients were included, all with pathologic diagnosis of glioblastoma with known MGMT methylation and 1p/19q deletion statuses. We divided these patients into long-term (${\geq}60\;months$, n = 7) and short-term (< 60 months, n = 36) survivors, then compared surgical extent, molecular status, and rCBV parameters between the two groups using Fisher's exact test or Mann-Whitney test. The rCBV parameters were analyzed according to the presence of MGMT methylation and 1p/19q deletions. We investigated the relationship between the mean rCBV and overall survival using linear correlation. Multivariable linear regression was performed in order to find the variables related to overall survival. Results: Long-term survivors (100% [7 of 7]) demonstrated a greater percentage of gross total or near total resection than short-term survivors (54.5% [18 of 33]). A higher prevalence of 1p/19q deletions was also noted among the long-term survivors (42.9% [3 of 7]) than the short-term survivors (0.0% [0 of 36]). The rCBV parameters did not differ between the long-term and short-term survivors. The rCBV values were marginally lower in patients with MGMT methylation and 1p/19q deletions. Despite no correlation found between overall survival and rCBV in the whole group, the short-term survivor group showed negative correlation ($R^2=0.181$, P = 0.025). Multivariable linear regression revealed that surgical extent and 1p/19q deletions, but not rCBV values, were associated with prolonged overall survival. Conclusion: While preoperative rCBV and 1p/19q deletion status are related to each other, only surgical extent and the presence of 1p/19q deletion in GBM patients may predict long-term survival.

• Investigative Magnetic Resonance Imaging
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• 제19권4호
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• pp.218-223
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• 2015

Purpose: To investigate whether volumetric analysis based on T2WI and contrast-enhanced (CE) T1WI can distinguish between isocitrate dehydrogenase-1 mutation-positive ($IDH1^P$) and -negative ($IDH1^N$) glioblastomas (GBMs). Materials and Methods: We retrospectively enrolled 109 patients with histopathologically proven GBMs after surgery or stereotactic biopsy and preoperative MR imaging. We measured the whole-tumor volume in each patient using a semiautomatic segmentation method based on both T2WI and CE T1WI. We compared the tumor volumes between $IDH1^P$ (n = 12) and $IDH1^N$ (n = 97) GBMs using an unpaired t-test. In addition, we performed receiver operating characteristic (ROC) analysis for the differentiation of $IDH1^P$ and $IDH1^N$ GBMs using the tumor volumes based on T2WI and CE T1WI. Results: The mean tumor volume based on T2WI was larger for $IDH1^P$ GBMs than $IDH1^N$ GBMs ($108.8{\pm}68.1$ and $59.3{\pm}37.3mm^3$, respectively, P = 0.0002). In addition, $IDH1^P$ GBMs had a larger tumor volume on CE T1WI than did $IDH1^N$ tumors ($49.00{\pm}40.14$ and $22.53{\pm}17.51mm^3$, respectively, P < 0.0001). ROC analysis revealed that the tumor volume based on T2WI could distinguish $IDH1^P$ from $IDH1^N$ with a cutoff value of 90.25 (P < 0.05): 7 of 12 $IDH1^P$ (58.3%) and 79 of 97 $IDH1^N$ (81.4%). Conclusion: Volumetric analysis of T2WI and CE T1WI could enable $IDH1^P$ GBMs to be distinguished from $IDH1^N$ GBMs. We assumed that secondary GBMs with $IDH1^P$ underwent stepwise progression and were more infiltrative than those with $IDH1^N$, which might have resulted in the differences in tumor volume.

• Asian Pacific Journal of Cancer Prevention
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• 제17권11호
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• pp.4907-4911
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• 2016

Glioblastoma multiforme (GBM) is the most aggressive of the gliomas, a collection of tumors arising from glia in the central nervous system. Possible associations between the human cytomegalovirus (HCMV) and the JC virus with GBM are now attracting interest. Our present aim was to investigate the prevalence of the two viruses in Iranian patients from Kerman's cities in the south of Iran. In addition, the expression rates of pp65, large T antigen and p53 proteins were assessed and their relation with GBM evaluated using reverse transcription real time PCR (rReal Time PCR). A total of 199 patients with GBM cancer were enrolled, with $mean{\pm}SD$ ages of $50.0{\pm}19.5$ and $50.7{\pm}19.6$ years for males and females, respectively. The P53 rate was dramatically low suggesting an aetiological role,. Large T antigen expression was found in JC positive samples, while the PP65 antigen was observed in patients positive for CMV and JC. HCMV products and JC virus with oncogenic potential may induce the development of various tumors including glioblastomas. The JC virus produces an early gene product, T-antigen, which has the ability to associate with and functionally inactivate well-studied tumor suppressor proteins including p53 and pRB.

• Asian Pacific Journal of Cancer Prevention
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• 제16권2호
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• pp.591-594
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• 2015

Background: Aberrations in gene methylation patterns play important roles in gliomagenesis. However, whether the ALDH1A3 promoter methylation is related to prognoses of primary glioblastomas (GBMs) in Western China remains unclear. Materials and Methods: Methylation levels of ALDH1A3 CpG island in 36 GBMs were identified by pyrophosphate sequencing, while ALDH1A3 expression was assessed with matched paraffin section immunohistochemistry. Survival curves were analysed by Kaplan-Meier. Results: The hypermethylation status of ALDH1A3 promoter predicted a better prognosis accompanied with low expression of ALDH1A3 protein. Conclusions: Our results indicate ALDH1A3 promoter methylation correlates with prognosis in primary GBMs.

• Journal of Korean Neurosurgical Society
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• 제66권4호
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• pp.356-381
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• 2023

Although immunotherapy has been broadly successful in the treatment of hematologic malignancies and a subset of solid tumors, its clinical outcomes for glioblastoma are still inadequate. The results could be due to neuroanatomical structures such as the blood-brain-barrier, antigenic heterogeneity, and the highly immunosuppressive microenvironment of glioblastomas. The antitumor efficacy of endogenously activated effector cells induced by peptide or dendritic cell vaccines in particular has been insufficient to control tumors. Effector cells, such as T cells and natural killer (NK) cells can be expanded rapidly ex vivo and transferred to patients. The identification of neoantigens derived from tumor-specific mutations is expanding the list of tumor-specific antigens for glioblastoma. Moreover, recent advances in gene-editing technologies enable the effector cells to not only have multiple biological functionalities, such as cytokine production, multiple antigen recognition, and increased cell trafficking, but also relieve the immunosuppressive nature of the glioblastoma microenvironment by blocking immune inhibitory molecules, which together improve their cytotoxicity, persistence, and safety. Allogeneic chimeric antigen receptor (CAR) T cells edited to reduce graft-versus-host disease and allorejection, or induced pluripotent stem cell-derived NK cells expressing CARs that use NK-specific signaling domain can be a good candidate for off-the-shelf products of glioblastoma immunotherapy. We here discuss current progress and future directions for T cell and NK cell therapy in glioblastoma.

• Asian Pacific Journal of Cancer Prevention
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• 제17권5호
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• pp.2649-2653
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• 2016

Background: Genetic alterations in gliomas have increasing importance for classification purposes. Thus, we are especially interested in studying IDH mutations which may feature potential roles in diagnosis, prognosis and response to treatment. Our aim was to investigate IDH mutations in diffuse glioma patients diagnosed in university hospital centre of Fez in Morocco. Materials and Methods: IDH1 codon 132 and IDH2 codon 172 were direct-sequenced in 117 diffuse glioma samples diagnosed and treated in University Hospital Hassan II between 2010 and 2014. Results: The R132H IDH1 mutation was identified in 43/117 tumor samples and R172K IDH2 mutation was detected in only one anaplastic oligodendroglioma. IDH mutations were observed in 63.2% of astrocytomas, 73.3% of diffuse oligodendrogliomas and 12.90% of glioblastomas. Conclusions: Our results confirmed other studies published earlier for other populations with some small discrepancies.