• Journal of Chest Surgery
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• v.34 no.5
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• pp.377-385
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• 2001

배경: Cisplain과 같은 세포돗성 약제에 대한 내성은 폐암 치료 실패의 중요한 원인이다. 이러한 항암제에 대한 내성의 발생기전은 복잡하고 아직 완전히 알려져 있지 않지만 불량한 예후의 원인으로 생각된다. 특히 약제 내성이 발생한 환자의 경우 기존의 종양의 급속한 성장뿐 아니라 새로운 전이 병소가 급속히 발생 및 진단됨은 약제 내성을 가진 종양이 전이에의 용이성을 획득하는게 아닌가 의심케한다. 이를 규명하기 위해 Cisplatin에 내성을 지닌 비소세포폐암 세포주 H460/CISm이 전이 능력을 Cisplatin에 민감한 비소세포폐암 세로주 H460과 비교하고자 한다. 대상 및 방법: 약제 내성 세포주를 확보하기 위하여 H460세포에 cisplatin을 점차적으로 증가시켜 처리한 후 배양하였다. H460 세포와 H460/CIS 세로에서의 혈관신생인자와 성장관련인 자의 발현양상, gelatin zymography 분석 그리고 in vivo 실험으로 nude 마우스에서의 자발적 전이 능력의 차이를 비교하였다. 결과: H460 세포를 이식한 마우스에 폐에서는 종양이 형성되지 않았으나 H460/CIS세포를 이식한 마우스 10마리중 8마리에서 종양이 형성되었다. 또한 H460/CIS 세포주에서 전이 관련 유전자로 알려진 angiopoietin-1, vascular endothelial growth factor, basic fibroblast growth factor, matrix metalloproteinase 2 등이 더 발현되었고, 전이의 침습성을 유발하는 gelatinase의 활성이 증가된 것을 확인할 수 있었다. 결론: 본 여구 결과를 통해 cisplatin에 내성을 가진 비소세포폐암세포에서 전이 능력이 증가될 수 있다고 여겨지며 이러한 사실을 토대로 초기 비소세포폐암 환자의 수술 전 항암약물요법의 타당성에 대해서 이야기 하기 위해서는 많은 임상적 연구가 필요하리라 생각된다.

• Journal of Gastric Cancer
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• v.17 no.1
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• pp.1-10
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• 2017

Gastric cancer (GC) has high mortality owing to its aggressive nature. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of GC. The aim of this work was to review the angiogenic biomarkers related to the behavior of GC, documented in the literature. A search of the PubMed database was conducted with the MeSH terms: "Stomach neoplasms/blood [MeSH] or stomach neoplasms/blood supply [MeSH] and angiogenic proteins/blood [Major]". A total of 30 articles were initially collected, and 4 were subsequently excluded. Among the 26 articles collected, 16 examined the role of vascular endothelial growth factor (VEGF), 4 studied endostatin, 3 investigated angiopoietin (Ang)-2, 2 studied the Ang-like protein 2 (ANGTPL2), and 1 each examined interleukin (IL)-12, IL-8, and hypoxia inducible factor. Regarding VEGF, 6 articles concluded that the protein was related to lymph node metastasis or distant metastases. Five articles concluded that VEGF levels were elevated in the presence of GC and decreased following tumor regression, suggesting that VEGF levels could be a predictor of recurrence. Four articles concluded that high VEGF levels were correlated with poor prognosis and lower survival rates. Ang-2 and ANGTPL2 were elevated in GC and associated with more aggressive disease. Endostatin was associated with intestinal GC. VEGF is the most extensively studied angiogenic factor. It is associated with the presence of neoplastic disease and lymph node metastasis. It appears to be a good biomarker for disease progression and remission, but not for diagnosis. The data regarding other biomarkers are inconclusive.

• Archives of Plastic Surgery
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• v.49 no.1
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• pp.115-120
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• 2022

Background In addition to vascular endothelial cells, vascular smooth muscle cells (VSMCs) are subject to continuous shear stress because of blood circulation. The angiogenic properties of VSMCs in extracranial arteriovenous malformations (AVMs) may exceed those of normal blood vessels if the body responds more sensitively to mechanical stimuli. This study was performed to investigate the hypothesis that rapid angiogenesis may be achieved by mechanical shear stress. Methods VSMCs were obtained from six patients who had AVMs and six normal controls. The target genes were set to angiopoietin-2 (AGP2), aquaporin-1 (AQP1), and transforming growth factor-beta receptor 1 (TGFBR1). Reverse-transcriptase polymerase chain reaction (RT-PCR) and real-time PCR were implemented to identify the expression levels for target genes. Immunofluorescence was also conducted. Results Under the shear stress condition, mean relative quantity values of AGP2, AQP1, and TGFBR1 in AVM tissues were 1.927±0.528, 1.291±0.031, and 2.284±1.461 when compared with neutral conditions. The expression levels of all three genes in AVMs were higher than those in normal tissue except for AQP1 under shear stress conditions. Immunofluorescence also revealed increased staining of shear stress-induced genes in the normal tissue and in AVM tissue. Conclusions Shear stress made the VSMCs of AVMs more sensitive. Although the pathogenesis of AVMs remains unclear, our study showed that biomechanical stimulation imposed by shear stress may aggravate angiogenesis in AVMs.

• Journal of Physiology & Pathology in Korean Medicine
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• v.36 no.5
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• pp.175-180
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• 2022

The seeds of Trichosanthes kirilowii (STK) used in traditional Oriental medicine for the treatment of dry cough and constipation have diverse pharmacological activities, including hypolipidemic, antioxidant, immunosuppressive, and anticancer effects. However, the effect of STK on angiogenesis has not been studied yet. In this study, we investigated whether the ethanolic extract of STK (ESTK) can regulate the migration and tube formation of human umbilical vein endothelial cells (HUVECs) and explored the underlying mechanism. Results of transwell assay showed that ESTK treatment dose-dependently suppressed the migration of HUVECs. The conditioned medium collected from H1299 human lung cancer cells was used as a chemoattractant. Our observation suggests that ESTK would inhibit the recruitment of endothelial cells into tumors. In addition, ESTK treatment significantly reduced the tube formation of HUVECs. As a molecular mechanism, we found that vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGF receptor 2 (VEGFR2) was completely blocked by ESTK treatment. The expression of angiogenic factors, including VEGFA, fibroblast growth factor 2 (FGF2), angiopoietin, placental growth factor (PGF), platelet derived growth factor (PDGF), angiogenin, and tumor necrosis factor (TNF)-α, was commonly decreased by ESTK treatment in H1299 cells, indicating that ESTK would reduce the production of angiogenic factors from cancer cells. Taken together, our results clearly demonstrated that ESTK exhibited anti-angiogenic effects in HUVECs, which provides another possible mechanism underlying the anticancer activities of STK.

• Molecules and Cells
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• v.37 no.6
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• pp.487-496
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• 2014

Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout ($AGT^{+/-}$) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of $AGT^{+/-}$ EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in $AGT^{+/-}$ EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-$1{\alpha}$and $-2{\alpha}$ were downregulated in $AGT^{+/-}$ early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-$1{\alpha}$ were suppressed in $AGT^{+/-}$ EPCs. In $AGT^{+/-}$ mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis.

• The Journal of Advanced Prosthodontics
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• v.5 no.4
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• pp.374-381
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• 2013

PURPOSE. The purpose of this study was to evaluate the effect of alendronates on bone remodeling around titanium implant in the maxilla of rats. MATERIALS AND METHODS. The maxillary first molars were extracted and customized-titanium implants were placed immediately in thirty male Sprague-Dawley rats. The rats were divided into experimental (bisphosphonate) group and control group. At 4 weeks after implantation, the rats in the bisphosphonate group were subcutaneously injected with alendronate three times a week for 6 weeks where as the rats in control group were injected with saline. The rats were sacrificed at 1, 2, 3, 4, or 6 weeks after starting of injection and maxillary bones were collected subsequently. Alveolar bone remodeling around the implants were evaluated by radiographic and histologic analysis. Microarray analysis and immunohistomorphologic analysis were also performed on one rat, sacrificed at 6 weeks after starting of injection, from each group. Statistical analysis was performed using repeated measures analysis of variance and independent t test at a significance level of 5%. RESULTS. There was no statistically significant difference in the bone area (%) around implant between the bisphosphonate group and the control group. However, the amount of empty lacuna was significantly increased in the bisphosphonate group, especially in the rats sacrificed at 4 weeks after starting of injection compared to that of the corresponding control group. The bisphosphonate group showed the same level of TRAP positive cell count, osteocalcin and angiopoietin 1 as the control group. CONCLUSION. Alendronate may not decrease the amount of osteoclast. However, the significantly increased amount of empty lacuna in the bisphosphonate group may explain the suppression of bone remodeling in the bisphosphonate group.

• IMMUNE NETWORK
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• v.15 no.2
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• pp.66-72
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• 2015

Currently, detecting biochemical differences before and after allogeneic stem cell transplantation (SCT) for improved prediction of acute graft-versus-host disease (aGVHD) is a major clinical challenge. In this pilot study, we analyzed the kinetics of circulating adipokine levels in patients with or without aGVHD before and after allogeneic SCT. Serum samples were obtained and stored at $-80^{\circ}C$ within 3 hours after collection, prior to conditioning and at engraftment after transplantation. A protein array system was used to measure the levels of 7 adipokines of patients with aGVHD (n=20) and without aGVHD (n=20). The resistin level at engraftment was significantly increased (p<0.001) after transplantation, regardless of aGVHD occurrence. In the non-aGVHD group, the concentrations of the hepatocyte growth factor (HGF) (mean values${\pm}$SD; $206.6{\pm}34.3$ vs. $432.3{\pm}108.9pg/ml$, p=0.040) and angiopoietin-2 (ANG-2) (mean values${\pm}$SD; $3,197.2{\pm}328.3$ vs. $4,471.8{\pm}568.4pg/ml$, p=0.037) at engraftment were significantly higher than those of the pre-transplant period, whereas in the aGVHD group, the levels of adipokines did not change after transplantation. Our study suggests that changes in serum HGF and ANG-2 levels could be considered helpful markers for the subsequent occurrence of aGVHD.

• Radiation Oncology Journal
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• v.21 no.1
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• pp.54-65
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• 2003

Purpose : To analyze the gene expression Profiles of uterine ceulcal cancer, and its variation after radiation therapy, with or without concurrent chemotherapy, using a CDNA microarray. Materials and Methods :Sixteen patients, 8 with squamous ceil carcinomas of the uterine cervix, who were treated with radiation alone, and the other 8 treated w14h concurrent chemo-radiation, were Included in the study. Before the starling of the treatment, tumor biopsies were carried out, and the second time biopsies were peformed after a radiation dose of 16.2$\~$27 Gy. Three normal cervix tissues were used as a control group. The microarray experiments were peformed with 5 groups of the total RNAs extracted individually and then admixed as control, pre-radiation therapy alone, during-radiation therapy alone, pre-chemoradiation therapy, and during-chemoradlation therapy. The 33P-iabeled CDNAS were synthesized from the total RNAs of each group, by reverse transcription, and then they were hybridized to the CDNA microarray membrane. The gene expression of each microarrays was captured by the intensity of each spot produced by the radioactive isotopes. The pixels per spot were counted with an Arrayguage, and were exported to Microsoft Excel The data were normalized by the Z transformation, and the comparisons were peformed on the Z-ratio values calculated. Results : The expressions of 15 genes, including integrin linked kinase (ILK), CDC28 protein kinase 2, Spry 2, and ERK 3, were increased with the Z-ratio values of over 2.0 for the cervix cancer tissues compared to those for the normal controls. Those genes were involved In cell growth and proliferation, cell cycle control, or signal transduction. The expressions of the other 6 genes, Including G protein coupled receptor kinase 5, were decreased with the Z-ratio values of below -2.0. After the radiation thorapy, most of the genes, with a previously Increase expressions, represented the decreased expression profiles, and the genes, with the Z-ratio values of over 2.0, were cyclic nucleotlde gated channel and 3 Expressed sequence tags (EST). In the concurrent chemo-radiation group, the genes involved in cell growth and proliferation, cell cycle control, and signal transduction were shown to have increased expressions compared to the radiation therapy alone group. The expressions of genes involved in anglogenesis (angiopoietln-2), immune reactions (formyl peptide receptor-iike 1), and DNA repair (CAMP phosphodiesterase) were increased, however, the expression of gene involved In apoptosls (death associated protein kinase) was decreased. Conclusion : The different kinds of genes involved in the development and progression of cervical cancer were identified with the CDNA microarray, and the proposed theory is that the proliferation signal stalls with ILK, and is amplified with Spry 2 and MAPK signaling, and the cellular mitoses are Increased with the increased expression oi Cdc 2 and cell division kinases. After the radiation therapy, the expression profiles demonstrated 4he evidence of the decreased cancer cell proliferation. There was no sigificant difference in the morphological findings of cell death between the radiation therapy aione and the chemo-radiation groups In the second time biopsy specimen, however, the gene expression profiles were markedly different, and the mechanism at the molecular level needs further study.