• Journal of Korean Neurosurgical Society
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• v.64 no.6
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• pp.983-994
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• 2021

Objective : The effectiveness of gamma knife radiosurgery (GKR) in the treatment of brain metastases is well established. The aim of this study was to evaluate the efficacy and safety of maximizing the radiation dose in GKR and the factors influencing tumor control in cases of small and medium-sized brain metastases from non-small cell lung cancer (NSCLC). Methods : We analyzed 230 metastatic brain tumors less than 5 mL in volume in 146 patients with NSCLC who underwent GKR. The patients had no previous radiation therapy for brain metastases. The pathologies of the tumors were adenocarcinoma (n=207), squamous cell carcinoma (n=18), and others (n=5). The radiation doses were classified as 18, 20, 22, and 24 Gy, and based on the tumor volume, the tumors were categorized as follows : small-sized (less than 1 mL) and medium-sized (1-3 and 3-5 mL). The progression-free survival (PFS) of the individual 230 tumors and 146 brain metastases was evaluated after GKR depending on the pathology, Eastern Cooperative Oncology Group (ECOG) performance score (PS), tumor volume, radiation dose, and anti-cancer regimens. The radiotoxicity after GKR was also evaluated. Results : After GKR, the restricted mean PFS of individual 230 tumors at 24 months was 15.6 months (14.0-17.1). In small-sized tumors, as the dose of radiation increased, the tumor control rates tended to increase (p=0.072). In medium-sized tumors, there was no statistically difference in PFS with an increase of radiation dose (p=0.783). On univariate analyses, a statistically significant increase in PFS was associated with adenocarcinomas (p=0.001), tumors with ECOG PS 0 (p=0.005), small-sized tumors (p=0.003), radiation dose of 24 Gy (p=0.014), synchronous lesions (p=0.002), and targeted therapy (p=0.004). On multivariate analyses, an improved PFS was seen with targeted therapy (hazard ratio, 0.356; 95% confidence interval, 0.150-0.842; p=0.019). After GKR, the restricted mean PFS of brain at 24 months was 9.8 months (8.5-11.1) in 146 patients, and the pattern of recurrence was mostly distant within the brain (66.4%). The small and medium-sized tumors treated with GKR showed radiotoxicitiy in five out of 230 tumors (2.2%), which were controlled with medical treatment. Conclusion : The small-sized tumors were effectively controlled without symptomatic radiation necrosis as the radiation dose was increased up to 24 Gy. The medium-sized tumors showed potential for symptomatic radiation necrosis without signifcant tumor control rate, when greater than 18 Gy. GKR combined targeted therapy improved the tumor control of GKR-treated tumors.

• Journal of Life Science
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• v.26 no.5
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• pp.509-518
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• 2016

Asparagus cochinchinensis is a medical plant that has long been used to treat fever, cough, kidney disease, breast cancer, inflammatory disease and brain disease in northeast Asian countries. Although several studies have been conducted on the anti-neuroinflammatory effects of A. cochinchinensis, the correlation between these effects and nerve growth factor (NGF) has not yet been examined. In this study, we investigated the effects of an aqueous extract of A. cochinchinensis (AEAC) on the secretion and action mechanism of NGF in neuronal cells. The concentration of the NGF protein in the supernatant collected from cultured cells increased significantly in B35 cells treated with AEAC in comparison with the vehicle-treated group without any specific cytotoxicity. Furthermore, the mRNA expression of NGF showed a very similar pattern to its protein concentration. To examine the bioactivity of NGF secreted from B35 cells, undifferentiated PC12 cells were cultured in an AEAC-conditioned medium and neuritic outgrowth was observed. The dendrite length of PC12 cells in the AEAC-treated group was significantly higher than that in the vehicle-treated group. Moreover, the level of the downstream effectors p-TrkA and p-ERK of the high-affinity NGF receptor was significantly higher in the AEAC-treated group, while the expression of the downstream effectors of the low-affinity NGF receptor was significantly lower in the same group. These results suggest that AEAC may contribute to the regulation of NGF expression and secretion in neuronal cells; it is therefore an excellent candidate for further investigation as a therapeutic drug for neurodegenerative diseases.

• Korean Journal of Veterinary Service
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• v.29 no.3
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• pp.347-364
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• 2006

This study is concerned with assessment of diethylnitrosamine (DEN 0.01 %) induced liver cell carcinogenesis by measurement of changes preceding the development of neoplasms. Therefore, it was undertaken to investigate changes of liver-specific enzyme activities in Sprague-Dawley (SD) rats by ad libitum feeding of DEN. And also. the changes of hepatic morphology in SD rats were detected by haematoxylineosin stain and immunohistochemistry (PCNA). 5- Fluorouracil (5- FU) is one of the most widely used anticancer agents for digestive cancers including hepatocellular carcinoma, and is known to affect the cell cycle and induce apoptosis of cancer cells. In the present study, SD rats were given drinking water containing 0.01% diethylnitrosamine (DEN) for 8 weeks. Minor behavioral change, brittleness of hair and decreased amount of water and diet intake were observed in rats 4 weeks after DEN administration. The body and liver weights were significantly (p < 0.05) decreased in rats 11 weeks after DEN administration. The liver weight ratio to body weight was rather stable and not significantly decreased in the all treatment groups. The liver specific enzyme activities (AST, ALT, ${\gamma}$-GTP) were significantly increased in all treatment groups compared to control group (p < 0.05). Variable size of liver tumor and hepatomegaly were observed in rats treated with DEN after 10 weeks. Numerous vacuoles were seen on the midzonal and or peripheral areas of hepatic lobules. The large and polymorphological hepatocytes with eosinophilic cytoplasm or densely basophilic mitotic nucleoli were seen. Several proliferative small round cells were seen on vacuolated and necrotic areas in peripheral hepatic lobules or portal areas. PCNA-positive cells were seen on the vacuolated portal areas and peripheral areas of hepatic lobules in the areas of small round cells. We examined functional and morphological changes of livers by 5 - FU treatments on DEN -treated rat. The DEN -treated rats compared to 5 - FU -treated rats after DEN treatment for 8 weeks. The serum total protein and triglyceride were significantly (p < 0.05) decreased, and the liver enzyme activities of AST and ALT were significantly(p < 0.05) increased. After 8 weeks, in the non-5-FU -treated group, the size of liver tumor were varied and hepatomegaly were observed, hepatocellular vacuolization, necrosis and steatosis were observed on the midzonal and peripheral areas of hepatic lobules. The large and polymorphological hepatocytes were seen, the interlobular connective tissues were proliferated. PCNA positive cells were seen in the portal areas and peripheral areas of hepatic lobules in the non-5-FU-treated group. In hepatocytes, condensation of nuclear chromatin and vacuolization were observed, shape of the nuclei were irregular, the degraded nuclei and organelles were observed. The livers of rats in the 5 - FU treatment group were seen grossly brilliant, red-brown color, and the vacuolated and degenerated regions, hyperplastic nodules were not nearly observed. In the electron microscope, the cytoplasm of the hepatocytes contained a large number of mitochondria, rough endoplasmic reticulum, developed organelles surrounding nuclei. The above findings suggest that 5 - FU will be effective as anti -liver tumor drug.

• Analytical Science and Technology
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• v.13 no.4
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• pp.494-503
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• 2000

A 21-residue peptide corresponding to amino acids 84-104 of $p16^{INK4A}$, the tumor suppressor, has been synthesized and its structure was studied by Circular Dichroism, $^1H$ NMR spectroscopy and molecular modeling. A p16-derived peptide (84-104 amino acids) forming stable complex with CDK4 and CDK6 inhibits the ability of CDK4/6 to phosphorylate pRb in vitro, and blocks cell-cycle progression through G1/S phase as shown in the function of the full-length p16. Its NMR spectral data including NOEs, $^3J_{NH-H{\alpha}}$ coupling constants, $C_{\alpha}H$ chemical shift, the average amplitude of amide chemical shift oscillation and temperature coefficients indicate that the secondary structure of a p16-derived peptide is similar to that of the same region of full-length p16, which consists of helix-turn-helix structure. The 3-D distance geometry structure based on NOE-hased distance and torsion angle restraints is characterized by ${\gamma}$-turn conformation between residues $Gly^{89}-Leu^{91}$(${\varphi}_{i+1}=-79.8^{\circ}$, ${\varphi}_{i+1}=60.2^{\circ}$) as evidenced in a single crystal structure for the corresponding region of p18 or p19, but is undefined at both the N and C termini. This compact and rigid ${\gamma}$-turn region is considered to stabilize the structure of p16-derived peptide and serve as a site recognizing cyelin dependent kinase, and this well-defined ${\gamma}$-turn structure could be utilized for the design of anti-cancer drug candidates.

• The Korean Journal of Nuclear Medicine
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• v.37 no.6
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• pp.382-392
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• 2003

Purpose: Uptakes of Tc-99m MIBI (MIBI) and Tc-99m tetrofosmin (tetrofosmin) in human non-small cell lung cancer A549, multidrug-resistance associated protein (MRP) expressing cell, were investigated in vitro and in vivo. Materials and Methods: Western blot analysis and immunohistochemistry were used for detection of MRP in A549 cells with anti-MRPr1 antibody. Cellular uptakes of two tracers were evaluated at $100{\mu}M$ of verapamil (Vrp), $50{\mu}M$ of cyclosporin A (CsA) and $25{\mu}M$ of butoxysulfoximide (BSO) after incubation with MIBI and tetrofosmin for 30 and 50 min at $37^{\circ}C$, using single cell suspensions at $1{\times}10^6cells/ml$. Radioactivities in supernatants and pellets were measured with gamma well counter. A549 cells were inoculated in each flanks of 24 nude mice. Group 1 (Gr1) and Gr3 mice were treated with only MIBI or tetrofosmin, and Gr2 and Gr4 mice were treated with 70mg/kg of CsA i.p. for 1 hour before injection of 370KBq of MIBI or tetrofosmin. Mice were sacrificed at 10, 60 and 240 min. Radioactivities of organs and tumors were expressed as percentage injected dose per gram of tissue (%ID/gm). Results: Western blot analysis of the A549 cells detected expression of MRPr1 (190 kDa) and immunohistochemical staining of tumor tissue for MRPr1 revealed brownish staining in cell membrane but not P-gp. Upon incubating A549 cells for 60 min with MIBI and tetrofosmin, cellular uptake of MIBI was higher than that of tetrofosmin. Coincubation with modulators resulted in an increase in cellular uptakes of MIBI and tetrofosmin. Percentage increase of MIBI was higher than that of tetrofosmin with Vrp by 623% and 427%, CsA by 753% and 629% and BSO by 219% and 140%, respectively. There was no significant difference in tumoral uptakes of MIBI and tetrofosmin between Gr1 and Gr3. Percentage increases in MIBI (114% at 10 min, 257% at 60 min, 396% at 240 min) and tetrofosmin uptake (110% at 10 min, 205% at 60 min, 410% at 240 min) were progressively higher by the time up to 240 min with CsA. Conclusion: These results indicate that MIBI and tetrofosmin are suitable tracers for imaging MRP-mediated drug resistance in A549 tumors. MIBI may be a better tracer than tetrofosmin for evaluating MRP reversal effect of modulators.