• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.187-194
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• 2011

Atherosclerosis and post-angiography restenosis are associated with intimal thickening and concomitant vascular smooth muscle cell (VSMC) proliferation. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have anti-inflammatory and anti-tumor activities. The goal of the present study was to enhance the inhibitory effects of obovatol to improve its potential as a preventive or therapeutic agent in atherosclerosis and restenosis. Platelet-derived growth factor (PDGF)-BB-induced proliferation of rat aortic smooth muscle cells (RASMCs) was examined in the presence or absence of a newly synthesized obovatol derivative, OD78. The observed anti-proliferative effect of OD78 was further investigated by cell counting and [$^3H$]-thymidine incorporation assays. Treatment with 1-4 ${\mu}M$ OD78 dose-dependently inhibited the proliferation and DNA synthesis of 25 ng/ml PDGF-BB-stimulated RASMCs. Accordingly, OD78 blocked PDGF-BB-induced progression from the $G_0/G_1$ to S phase of the cell cycle in synchronized cells. OD78 decreased the expression levels of CDK4, cyclin E, and cyclin D1 proteins, as well as the phosphorylation of retinoblastoma protein and proliferating cell nuclear antigen; however, it did not change the CDK2 expression level. In addition, OD78 inhibited downregulation of the cyclin-dependent kinase inhibitor (CKI) $p27^{kip1}$. However, OD78 did not affect the CKI $p21^{cip1}$ or phosphorylation of early PDGF signaling pathway. These results suggest that OD78 may inhibit PDGF-BB-induced RASMC proliferation by perturbing cell cycle progression, potentially through $p27^{kip1}$ pathway activation. Consequently, OD78 may be developed as a potential anti-proliferative agent for the treatment of atherosclerosis and angioplasty restenosis.

• Radiation Oncology Journal
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• v.29 no.4
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• pp.260-268
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• 2011

Purpose: To evaluate the treatment outcome and prognostic factor after postoperative radiotherapy in retroperitoneal sarcoma. Materials and Methods: Forty patients were treated with surgical resection and postoperative radiotherapy for retroperitoneal sarcoma from August 1990 to August 2008. Treatment volume was judged by the location of initial tumor and surgical field, and 45-50 Gy of radiation was basically delivered and additional dose was considered to the high-risk area. Results: The median follow-up period was 41.4 months (range, 3.9 to 140.6 months). The 5-year overall survival (OS) was 51.8% and disease free survival was 31.5%. The 5-year locoregional recurrence free survival was 61.9% and distant metastasis free survival was 50.6%. In univariate analysis, histologic type (p = 0.006) was the strongest prognostic factor for the OS and histologic grade (p = 0.044) or resection margin (p = 0.032) had also effect on the OS. Histologic type (p = 0.004) was unique significant prognostic factor for the actuarial local control. Conclusion: Retroperitoneal sarcoma still remains as a poor prognostic disease despite the combined modality treatment including surgery and postoperative radiotherapy. Selective dose-escalation of radiotherapy or combination of effective chemotherapeutic agent must be considered to improve the treatment result especially for the histopathologic type showing poor prognosls.

• Radiation Oncology Journal
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• v.34 no.3
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• pp.193-201
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• 2016

Purpose: To assess the clinical outcomes of radiotherapy (RT) using two-dimensional (2D) and three-dimensional conformal RT (3D-CRT) for patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma to evaluate the effectiveness of involved field RT with moderate-dose and to evaluate the benefit of 3D-CRT comparing with 2D-RT. Materials and Methods: Between July 2003 and March 2015, 33 patients with stage IE and IIE gastric MALT lymphoma received RT were analyzed. Of 33 patients, 17 patients (51.5%) were Helicobacter pylori (HP) negative and 16 patients (48.5%) were HP positive but refractory to HP eradication (HPE). The 2D-RT (n = 14) and 3D-CRT (n = 19) were performed and total dose was 30.6 Gy/17 fractions. Of 11 patients who RT planning data were available, dose-volumetric parameters between 2D-RT and 3D-CRT plans was compared. Results: All patients reached complete remission (CR) eventually and median time to CR was 3 months (range, 1 to 15 months). No local relapse occurred and one patient died with second primary malignancy. Tumor response, survival, and toxicity were not significantly different between 2D-RT and 3D-CRT (p > 0.05, each). In analysis for dose-volumetric parameters, $D_{max}$ and CI for PTV were significantly lower in 3D-CRT plans than 2D-RT plans (p < 0.05, each) and $D_{mean}$ and V15 for right kidney and $D_{mean}$ for left kidney were significantly lower in 3D-CRT than 2D-RT (p < 0.05, each). Conclusion: Our data suggested that involved field RT with moderate-dose for gastric MALT lymphoma could be promising and 3D-CRT could be considered to improve the target coverage and reduce radiation dose to the both kidneys.

• Asian-Australasian Journal of Animal Sciences
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• v.23 no.2
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• pp.205-212
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• 2010

The effects of chromium (Cr), dietary crude protein (CP) level, and potential interactions of these two factors were investigated in term of energy metabolism in lambs. Forty-eight 9-week-old weaned lambs (Dorper${\times}$Small-tail Han sheep, male, mean initial body weight = 22.96 kg${\pm}$2.60 kg) were used in a 2${\times}$3 factorial arrangement of supplemental Cr (0 ${\mu}g$/kg, 400 $\mu{g}$/kg or 800 ${\mu}g$/kg from chromium yeast) and protein levels (low protein: 157 g/d to 171 g/d for each animal, or high protein: 189 g/d to 209 g/d for each animal). Blood samples were collected at the beginning and end of the feeding trial. The lambs were then sacrificed and tissue samples were frozen for further analysis. Chromium at 400 ${\mu}g$/kg decreased fasting insulin level and the ratio of plasma insulin to glucagon, but these differences were not statistically significant; in contrast, chromium at 800 ${\mu}g$/kg increased the ratio significantly (p<0.05). Protein at the high level increased plasma tumor necrosis factor $\alpha$ (TNF-$\alpha$) level (p = 0.060). Liver glycogen content was increased significantly by Cr (p<0.05), which also increased liver glucose-6-phosphatase (G-6-Pase) and adipose hormone-sensitive lipase (HSL) activity. At 400 ${\mu}g$/kg, Cr increased muscle hexokinase (HK) activity. High protein significantly increased G-6-Pase activities in both the liver (p<0.05) and the kidney (p<0.05), but significantly decreased fatty acid synthase (FAS) activity in subcutaneous adipose tissue (p<0.05). For HSL activity in adipose tissue, a Cr${\times}$CP interaction (p<0.05) was observed. Overall, Cr improved energy metabolism, primarily by promoting the glycolytic rate and lipolytic processes, and these regulations were implemented mainly through the modulation by Cr of the insulin signal transduction system. High protein improved gluconeogenesis in both liver and kidney. The interaction of Cr${\times}$CP indicated that 400 $\mu{g}$/kg Cr could reduce energy consumption in situations where energy was being conserved, but could improve energy utilization when metabolic rate was increased.

• Asian-Australasian Journal of Animal Sciences
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• v.31 no.9
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• pp.1420-1430
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• 2018

Objective: Epigallocatechin-3-gallate (EGCG) is a major ingredient of catechin polyphenols and is considered one of the most promising bioactive compounds in green tea because of its strong antioxidant properties. However, the protective role of EGCG in bovine oocyte in vitro maturation (IVM) has not been investigated. Therefore, we aimed to study the effects of EGCG on IVM of bovine oocytes. Methods: Bovine oocytes were treated with different concentrations of EGCG (0, 25, 50, 100, and $200{\mu}M$), and the nuclear and cytoplasmic maturation, cumulus cell expansion, intracellular reactive oxygen species (ROS) levels, total antioxidant capacity, the early apoptosis and the developmental competence of in vitro fertilized embryos were measured. The mRNA abundances of antioxidant genes (nuclear factor erythriod-2 related factor 2 [NRF2], superoxide dismutase 1 [SOD1], catalase [CAT], and glutathione peroxidase 4 [GPX4]) in matured bovine oocytes were also quantified. Results: Nuclear maturation which is characterized by first polar body extrusion, and cytoplasmic maturation characterized by peripheral and cortical distribution of cortical granules and homogeneous mitochondrial distribution were significantly improved in the $50{\mu}M$ EGCG-treated group compared with the control group. Adding $50{\mu}M$ EGCG to the maturation medium significantly increased the cumulus cell expansion index and upregulated the mRNA levels of cumulus cell expansion-related genes (hyaluronan synthase 2, tumor necrosis factor alpha induced protein 6, pentraxin 3, and prostaglandin 2). Both the intracellular ROS level and the early apoptotic rate of matured oocytes were significantly decreased in the $50{\mu}M$ EGCG group, and the total antioxidant ability was markedly enhanced. Additionally, both the cleavage and blastocyst rates were significantly higher in the $50{\mu}M$ EGCG-treated oocytes after in vitro fertilization than in the control oocytes. The mRNA abundance of NRF2, SOD1, CAT, and GPX4 were significantly increased in the $50{\mu}M$ EGCG-treated oocytes. Conclusion: In conclusion, $50{\mu}M$ EGCG can improve the bovine oocyte maturation, and the protective role of EGCG may be correlated with its antioxidative property.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.6073-6080
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• 2015

Background: Melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24), a unique tumor suppressor gene, has killing activity in a broad spectrum of cancer cells. Herein, plasmids producing mda-7 proteins fused to different RGD peptides (full RGD4C and shortened RGD, tRGD) were evaluated for apoptosis induction with a hepatocellular carcinoma cell line, Hep-G2. The study aim was to improve the apoptosis potency of mda-7 by tethering to RGD peptides. Materials and Methods: Three plasmids including mda-7, mda-7-RGD and mda-7-tRGD genes beside a control vector were transfected into Hep-G2 cells. After 72 hours incubation, cell viability was evaluated by MTT assay. In addition, the rate of apoptosis was analyzed by flow cytometry using PI/annexin staining. To detect early events in apoptosis, 18 hours after transfection, expression of the BAX gene was quantified by real time PCR. Modeling of proteins was also performed to extrapolate possible consequences of RGD modification on their structures and subsequent attachment to receptors. Results and Conclusions: In MTT assays, while all mda-7 forms showed measurable inhibition of proliferation, unmodified mda-7 protein exhibited most significant effect compared to control plasmid (P<0.001). Again, flow cytometry analysis showed a significant apoptosis induction by simple mda-7 gene but not for those RGD-fused mda-7 proteins. These findings were also supported by expression analysis of BAX gene (P<0.001). Protein modelling analysis revealed that tethering RGD at the end of IL-24/Mda7 disrupt attachment to cognate receptor, IL-20R1/IL-20R2. In conclusion, fusion of RGD4C and shortened RGD peptides to carboxyl terminal of mda7, not only reduce apoptosis property in vitro but also disrupt receptor attachment as demonstrated by protein modelling.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.8661-8666
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• 2014

Background: Docetaxel and cisplatin in combination with fluorouracil (DCF) regimen is accepted to be one of the standard regimens in the treatment of advanced gastric cancer. However, substantial toxicity has limited its use in daily clinical practice. Therefore, modification of DCF regimens, including introduction of capecitabine has been investigated to improve the safety profiles. In the present study, the efficacy and toxicity of a regimen with a modified dose of docetaxel and cisplatin in combination with oral capecitabine (DCX) was evaluated in untreated patients with HER2-negative advanced gastric cancer. Materials and Methods: Fifty-four patients with HER2-negative locally advanced or metastatic gastric cancer were included in this cohort. Patients received docetaxel $60mg/m^2$ plus cisplatin $60mg/m^2$ (day 1) combined with capecitabine $1650mg/m^2$ (days 1-14) every 3 weeks. Treatment response, survival, and toxicity were retrospectively analyzed. Results: The median age was 54 years (range: 24-76). The majority of patients (70%) had metastatic disease, while 11 patients (21%) had recurrent disease and underwent curative gastrectomy, and 5 patients (9%) had locally advanced disease (LAD). The median number of DCX cycles was 4. There were 28 partial responses and 11 complete responses, with an overall response rate of 72%. Curative surgery could be performed in four patients among five with LAD. At the median follow-up of 10 months, the median progression-free survival (PFS) and overall survival (OS) of the entire cohort of patients were 7.4 and 12.1 months, respectively. Dose modification was done in 12 patients due to toxicity in 8 and noncompliance in 4 patients. The most common hematological toxicity was neutropenia, which occurred at grade 3-4 intensity in 10 of 54 patients (27.7%). Febrile neutropenia was diagnosed only in two cases. Conclusions: DCX regimen offers prominent anti-tumor activity and considered to be effective first-line treatment with manageable toxicity for patients with HER2-negative advanced gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.8
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• pp.3435-3441
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• 2014

Background: Axillary lymph node status at diagnosis remains the strongest predictor of long-term survival in breast cancer. Patients with more than ten axillary lymph nodes at diagnosis have a poor long-term survival. In this single institutional study, we set out to evaluate the prognosis of this high-risk group in the era of multimodality therapy. Materials and Methods: In this retrospective study, we looked at all breast cancer patients with greater than ten axillary lymph nodes diagnosed at Mount Sinai Medical Center (MSMC) from January 1st 1990 to December 31st 2007 (n=161). In the univariate analysis, descriptive frequencies, median survival, and 5- and 10-year survival rates were estimated for common prognostic factors. A multivariate prognostic analysis for time-to-event data, using the extended Cox regression model was carried out. Results: With a median and mean follow-up of 70 and 89.9 months, respectively, the overall median survival was estimated to be 99 months. The five-year disease-free survival (DFS) was 59.3% and the ten-year DFS was 37.9%, whereas the five- and ten-year overall survival (OS) was 66.6% and 43.9%, respectively. Multivariate analysis revealed a significant improvement in DFS among black patients compared to whites (p=0.05), improved DFS and OS among young patients (ages 21-45) compared to elderly patients (age greater than 70) (p=0.00176, p=0.0034, respectively), and improved DFS and OS among patients whose tumors were ER positive (p=0.049, p=0.0034). Conclusions: In this single institution study of patients with greater than 10 positive axillary nodes, black patients had a significantly improved DFS compared with white patients. Young age and ER tumor positivity was associated with improved outcomes. Using multivariate analysis, there were no other variables associated with statistically significant improvements in DFS or OS including date of diagnosis. Further work is needed to improve breast cancer survival in this subgroup of patients.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.8
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• pp.4583-4589
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• 2013

Objective: This study aimed to investigate the effect of multimodality treatment of advanced paediatric hepatoblastoma (HB) and the factors affecting prognosis. Methods: A total of 35 children underwent multimodality treatments consisting of chemotherapy, surgery, interventional therapy, and autologous peripheral blood stem cell transplantation. The patients were followed up every month. Results: Serum AFP levels in 33 out of 35 patients in this study were significantly increased (P = 0.0002). According to the statistical scatter plot, the values of serum AFP on the 25th, 50th, and 75th percentages were 1,210, 1,210 and 28,318 ng/dl, respectively. Of the 35 cases, 21 were stage IV. 18 cases were treated with systemic chemotherapy before surgery, and 3 cases with locally interventional chemotherapy before surgery. Statistical analysis showed that the preferred interventional treatment affected prognosis, and that there was a statistically significant difference (P = 0.024). Some 33 patients completed the follow-up, of which 17 were in complete remission (CR), 5 were in partial remission (PR), 1 became disease progressive (DP), and 10 died. The remission and overall survival rates were 66.7% (22/33) and 69.7% (23/33), respectively. Patients with the mixed HB phenotypes had worse prognoses than the epithelial phenotype (P < 0.001), and patients in stage IV had a lower survival rate than those in stage III (P < 0.001). Conclusion: Multimodality treatment can effectively improve remission rate and prolong the survival of children with advanced HB. In addition, alpha-fetoprotein (AFP), a tumor marker of liver malignant tumors, HB pathological classification, and staging are highly useful in predicting prognosis.

• Progress in Medical Physics
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• v.9 no.4
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• pp.201-206
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• 1998

IMRT optimization method on multiple slice has been developed by using gradient based algorithm. On about 10-30 CT slices including treatment region of a patient, dose optimization has been performed slice by slice to meet the condition that each organ should be exposed below maximum tolerable doses and that the tumor dose within the range of 100$\pm$5 %. Field size was limited to 8$\times$8 cm$^2$ and in this condition, beam divergence was not taken into account to calculate dose distribution. Total dose distribution was calculated by superposing each beamlet whose dose distribution had been precalculated. In order to investigate beam number dependency, dose optimization was performed for one, three, five, seven, and nine coplanar beams and then each optimization index was evaluated. It is found that optimization time was proportional to number of slices to be optimized, and the most efficient plan was obtained from the case of three-to-seven incident beams with respect to calculation time and optimization index. In conclusion, dose optimization of multiple slice was able to be obtained by repeating dose optimization of single slice under condition that the beam size is not too large to ignore beam divergence. And it turns out that result of dose optimization was so sensitive to the position of isocenter that some method to optimize isocenter position is needed to improve it.