• Journal of Korean Neurosurgical Society
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• v.40 no.3
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• pp.154-158
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• 2006

Objective : We treated 10 pediatric diffuse intrinsic brain stem glioma[BSG] patients with Novalis system [linac based radiotherapy unit, Germany] and examined the efficacy of the Fractionated Stereotactic Radiotherapy[FSRT]. Methods : A retrospective review was conducted on 10 pediatric diffuse intrinsic BSG patients who were treated with FSRT between May, 2001 and August, 2004. The mean age of the patient group was 7.7 years old. Male to female ratio was 4 to 1. The mean dose of FSRT was 38.7Gy, mean fractionated dose was 2.6Gy, mean fractionation size was 16.6, and target volume was $42.78cm^3$. The mean follow up period was 14 months. Results : Four weeks after completion of FSRT, improvements on neurological status and Karnofsky performance scale[KPS] score were recorded in 9/10 (90%] patients and magnetic resonance imaging[MRI] showed decrease in target tumor volume in 8 pediatric patients. The median survival period was 13.5 months after FSRT and treatment toxicity was mild. Conclusion : It is difficult for surgeons to choose surgical treatment for diffuse intrinsic BSG due to its dangerous anatomical structures. FSRT made it possible to control the tumor volume to improve neurological symptoms with minimal complications. We expect that FSRT is a feasible treatment modality for pediatric diffuse intrinsic BSG with tolerable toxicities.

• The Korean Journal of Pain
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• v.36 no.1
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• pp.72-83
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• 2023

Background: Globally, spinal cord injury (SCI) results in a big burden, including 90% suffering permanent disability, and 60%-69% experiencing neuropathic pain. The main causes are oxidative stress, inflammation, and degeneration. The efficacy of the stem cell secretome is promising, but the role of human neural stem cell (HNSC)-secretome in neuropathic pain is unclear. This study evaluated how the mechanism of HNSC-secretome improves neuropathic pain and locomotor function in SCI rat models through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities. Methods: A proper experimental study investigated 15 Rattus norvegicus divided into normal, control, and treatment groups (30 µL HNSC-secretome, intrathecal in the level of T10, three days post-traumatic SCI). Twenty-eight days post-injury, specimens were collected, and matrix metalloproteinase (MMP)-9, F2-Isoprostanes, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and brain derived neurotrophic factor (BDNF) were analyzed. Locomotor recovery was evaluated via Basso, Beattie, and Bresnahan scores. Neuropathic pain was evaluated using the Rat Grimace Scale. Results: The HNSC-secretome could improve locomotor recovery and neuropathic pain, decrease F2-Isoprostane (antioxidant), decrease MMP-9 and TNF-α (anti-inflammatory), as well as modulate TGF-β and BDNF (neurotrophic factor). Moreover, HNSC-secretomes maintain the extracellular matrix of SCI by reducing the matrix degradation effect of MMP-9 and increasing the collagen formation effect of TGF-β as a resistor of glial scar formation. Conclusions: The present study demonstrated the mechanism of HNSC-secretome in improving neuropathic pain and locomotor function in SCI through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

• Journal of Life Science
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• v.17 no.8 s.88
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• pp.1039-1045
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• 2007

Glioblastoma multiforme (GBM) is the most frequently occurring brain cancer. Although the existence of cancer stem cells (CSCs) in GBM has been established, there is little evidence to explain the link between CSCs and chemoresistance. In this study, we investigated that only a few cells of A172 and established GBM2 survived after 1,3-bis(2chloroethyl)-1-nitrosourea (BiCNU) exposures and these sur-vived cells resist the subsequent BiCNU treatment. In addition, these BiCNU-resistant small pop-ulations derived from GBM cells increased the phosphorylations of Erk and Akt and highly expressed CD133 stem cell surface marker. Furthermore, we observed that the BiCNU-resistant cancer cells de-rived from GBM have grown tumors when transplanted into severe combined immuno-deficient (SCID) mouse brain. These results demonstrate that BiCNU-resistant subpopulation cells derived from GBM have cancer stem-like cell properties. Therefore, it may provide provide further evidence that CSCs in GBM have chemotherapeutic drug resistance.

• International Journal of Stem Cells
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• v.16 no.3
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• pp.315-325
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• 2023

Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

• BMB Reports
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• v.55 no.8
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• pp.380-388
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• 2022

The B cell translocation gene 1 (BTG1) and BTG2 play a key role in a wide range of cellular activities including proliferation, apoptosis, and cell growth via modulating a variety of central biological steps such as transcription, post-transcriptional, and translation. BTG1 and BTG2 have been identified by genomic profiling of B-cell leukemia and diverse lymphoma types where both genes are commonly mutated, implying that they serve as tumor suppressors. Furthermore, a low expression level of BTG1 or BTG2 in solid tumors is frequently associated with malignant progression and poor treatment outcomes. As physiological aspects, BTG1 and BTG2 have been discovered to play a critical function in regulating quiescence in hematopoietic lineage such as Hematopoietic stem cells (HSCs) and naive and memory T cells, highlighting their novel role in maintaining the quiescent state. Taken together, emerging evidence from the recent studies suggests that BTG1 and BTG2 play a central anti-proliferative role in various tissues and cells, indicating their potential as targets for innovative therapeutics.

• Journal of Korean Neurosurgical Society
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• v.43 no.1
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• pp.57-60
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• 2008

The authors herein propose the staged excision as a novel strategy to preserve facial nerve and minimize complication during microsurgery of large vestibular schwannoma (VS). At the first stage, for reducing mass effect on the brain stem and cerebellum, subtotal tumor resection was performed via a retrosigmoid craniotomy without intervention of meatal portion of tumor. With total resection of the remaining tumor, the facial nerve was decompressed and delineated during the second stage translabyrinthine approach at a later date. A 38-year-old female who underwent the staging operation for resection of her huge VS is illustrated.

• Radiation Oncology Journal
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• v.7 no.2
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• pp.189-196
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• 1989

Twenty five patients with tumors of the brain stem were treated with radiotherapy between 1979 and 1987. Histological diagnosis could be obtained in 6 cases, and other 19 patients were diagnosed by neurologic findings and CT or MRI. Eighteen patients were treated by radical radiotherapy and 6 patients received both operation and radiotherapy, while 1 patient received chemotherapy after radiotherapy. Total dose ranged from 50 Gy to 55 Gy. By an clinical scoring scale at 2 months after radiotherapy, no complete response was obtained, but 16 cases achieved partial response, 2 cases were stable, and 4 cases were deteriorated. The overall survival rate at 3 years was $36\%$ Age, performance status at diagnosis, degree of cranial nerve involvement, CT pattern of post-contrast enhancement, and clinical responese by scoring scale were correlated with survival.

• Journal of Korean Neurosurgical Society
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• v.29 no.6
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• pp.778-785
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• 2000

Objectives : Intraoperative neurophysiologic monitoring(INM) is a well known useful method to reduce intraoperative neurological complications during neurosurgical procedures. Furthermore, INM is required in most cerebellopontine angle(CPA) surgery because cranial nerves or brain stem injuries can result in serious complications. Object of this study is to the correlation between the changes of intraoperative monitoring modalities during cerebellopontine angle tumor surgery and post-operative functional outcomes in auditory and facial functions. Material and Methods : Fifty-seven patients who underwent intraoperative neurophysiologic monitoring during CPA tumor surgery were retrospectively reviewed. Their lesions were as follows ; vestibular schwannomas in 42, other cranial nerve schwannomas in seven, meningiomas in five and cysts in three cases. Pre- and postoperative audiologic examinations and facial nerve function tests were performed in all patients. Intraoperative neurophysiologic monitoring modalities includes brainstem auditory evoked potentials(BAEP) and facial electromyographies(EMG). We compared the events of INM during CPA tumor surgeries with the outcomes of auditory and facial nerve functions. Results : The subjects who had abnormal changes during CPA tumor surgery were twenty cases with BAEP changes and facial EMG changes in twenty one cases. The changes of intraoperative neurophysiologic monitoring did not always result in poor functional outcomes. However, most predictable intraoperative monitoring changes were wave III-V complex losses in BAEP and continuous neurotonic activities in facial EMG. Conclusion : These results indicate that intraoperative neurophysiologic monitoring in CPA tumor surgery usually provide predictive value for postoperative functional outcomes.

• Molecules and Cells
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• v.45 no.7
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• pp.479-494
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• 2022

Human mesenchymal stem cells (MSCs) are multipotent stem cells that have been intensively studied as therapeutic tools for a variety of disorders. To enhance the efficacy of MSCs, therapeutic genes are introduced using retroviral and lentiviral vectors. However, serious adverse events (SAEs) such as tumorigenesis can be induced by insertional mutagenesis. We generated lentiviral vectors encoding the wild-type herpes simplex virus thymidine kinase (HSV-TK) gene and a gene containing a point mutation that results in an alanine to histidine substitution at residue 168 (TK(A168H)) and transduced expression in MSCs (MSC-TK and MSC-TK(A168H)). Transduction of lentiviral vectors encoding the TK(A168H) mutant did not alter the proliferation capacity, mesodermal differentiation potential, or surface antigenicity of MSCs. The MSC-TK(A168H) cells were genetically stable, as shown by karyotyping. MSC-TK(A168H) responded to ganciclovir (GCV) with an half maximal inhibitory concentration (IC₅₀) value 10-fold less than that of MSC-TK. Because MSC-TK(A168H) cells were found to be non-tumorigenic, a U87-TK(A168H) subcutaneous tumor was used as a SAE-like condition and we evaluated the effect of valganciclovir (vGCV), an oral prodrug for GCV. U87-TK(A168H) tumors were more efficiently ablated by 200 mg/kg vGCV than U87-TK tumors. These results indicate that MSC-TK(A168H) cells appear to be pre-clinically safe for therapeutic use. We propose that genetic modification with HSV-TK(A168H) makes allogeneic MSC-based ex vivo therapy safer by eliminating transplanted cells during SAEs such as uncontrolled cell proliferation.

• Biomolecules & Therapeutics
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• v.18 no.1
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• pp.48-55
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• 2010

Neural progenitor cells (NPCs) differentiate into astrocytes, neurons and oligodendrocytes, which is controlled by various factors in brain. Recent evidences suggest that small molecules modulating the proliferation and differentiation of NPCs may have therapeutic value as well as the potential use as chemical probes. Phylligenin is a lignan with anti-inflammatory activity that is isolated from the fruits of Forsythia koreana. We investigated effects of phylligenin on proliferation and differentiation of NPCs. Treatment of phylligenin decreased the number of proliferating NPCs in culture without effects on the differentiation and survival of neural cells such as neurons and astrocytes. To examine the mechanism of the decreased NPCs number, we performed cell cycle analysis. Proliferation of NPCs was decreased via G1-S transition block by phylligenin treatment, and it was mediated by the increase of p21 level. However, phylligenin did not induce apoptosis of NPCs as determined by TUNEL assay and PARP cleavage. We also found that viability of glioma cell lines such as C6 and U87MG glioma cells, but not that of primary neuron and astrocyte, was inhibited by phylligenin. These results suggest that phylligenin selectively inhibits proliferation of rapidly growing cells such as neural stem cells and glioma cells. Given that the possible role of brain tumor stem cells in the pathology of brain cancers, the inhibitory effects of phylligenin might be useful in the development of new therapeutic agents against brain cancers.