• Maxillofacial Plastic and Reconstructive Surgery
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• v.30 no.6
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• pp.529-539
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• 2008

Background and Purpose : Oral squamous cell carcinoma (OSCC) is one of the most aggressive tumors of the head and neck area. OSCC is known to preferentially metastasize via lymphatic system, and resulting cervical lymph node metastasis is the most reliable of treatment failure. But the biological mechanism of the regional nodal metastasis is not clear. So, we determined metastasis-related factors in orthotopic nude mouse models of OSCC. Experimental Design : Two cell lines-KB and YD-10B cells, established from human oral mucosal squamous cell carcinoma, were xenografted into the tissue space of athymic murine mouth floor. The mice were followed for tumor development and growth, the murine tumors were examined histopathologically for local invasion or regional or distant metastasis. Finally, we performed immunohistochemical assays with antiepithelial growth factor (EGF), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), and anti-vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-2, phosphorylated VEGFR-2/3 (pVEGFR-2/3) antibodies. We also determined the microvessel density. Results : Transplantation of human OSCC tumor cells into the mouth floor successfully resulted in the formation of orthotopic tumors. KB cell line showed significantly higher tumor proliferation and higher nodal metastatic potential than YD-10B cell line. Furthermore, immunohistochemical staining demonstrated higher expression of EGFR/pEGFR, VEGF, and pVEGFR-2/3 as well as higher microvessel density in KB murine tumors than in YD-10B murine tumors. Conclusion : An orthotopic model of OSCC in athymic mice was established which copies the cervical lymph nodal metastasis of human OSCC. Our mouth floor model should facillitate the understanding of the molecular pathogenesis of cervical nodal metastasis of OSCC.

• BMB Reports
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• v.53 no.10
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• pp.533-538
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• 2020

Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4545-4548
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• 2014

Objective: To investigate the changes of serum vascular endothelial growth factor (VEGF), soluble interleukin-2 receptor (SIL-2R) and hepatocyte growth factor (HGF) contents in patients with primary hepatocellular carcinoma (HCC) before and after percutaneous microwave coagulation therapy (PMCT) and determine their clinical significance. Materials and Methods: Fasting venous blood (3 mL) from 81 patients with primary HCC diagnosed by pathology was collected in the mornings 1 day before PMCT, and 1 day, 7 days and 1 month after PMCT, and then the serum was separated and stored in $-70^{\circ}C$. The contents of VEGF, SIL-2R and HGF were detected by enzyme linked immunosorbent assay (ELISA). Results: The serum VEGF, SIL-2R and HGF contents in 81 patients with primary HCC had obviously dynamic changes before and after PMCT. By comparison to 1 day after PMCT with pre-operation, there was no statistical significance regarding VEGF and SIL-2R contents (P>0.05), but HGF content showed significant difference (P<0.01). Compared with pre-operation, VEGF, SIL-2R and HGF contents 7 days and 1 month after PMCT all manifested significant differences (P<0.01). By comparison to 7 days with 1 month after PMCT, there was no statistical significance regarding the VEGF content (P>0.05), whereas SIL-2R and HGF contents showed significant change (P<0.01). Conclusions: The contents of serum VEGF, SIL-2R and HGF have obviously dynamic changes in primary HCC before and after PMCT, and their joint detection is expected to be an effective hematologic evaluation index of PMCT for primary HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6681-6686
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• 2013

Background: Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Methods: Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. Results: 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). Conclusions: It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.

• Journal of Korean Neurosurgical Society
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• v.63 no.4
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• pp.444-454
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• 2020

Objective : Glioblastoma multiforme (GBM) is the most aggressive for of brain tumor and treatment often fails due to the invasion of tumor cells into neighboring healthy brain tissues. Activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway is essential for normal cellular function including angiogenesis, and has been proposed to have a pivotal role in glioma invasion. This study aimed to determine the dose-dependent effects of ruxolitinib, an inhibitor of JAK, on the interferon (IFN)-I/IFN-α/IFN-β receptor/STAT and IFN-γ/IFN-γ receptor/STAT1 axes of the IFN-receptor-dependent JAK/STAT signaling pathway in glioblastoma invasion and tumorigenesis in U87 glioblastoma tumor spheroids. Methods : We administered three different doses of ruxolitinib (50, 100, and 200 nM) to human U87 glioblastoma spheroids and analyzed the gene expression profiles of IFNs receptors from the JAK/STAT pathway. To evaluate activation of this pathway, we quantified the phosphorylation of JAK and STAT proteins using Western blotting. Results : Quantitative real-time polymerase chain reaction analysis demonstrated that ruxolitinib led to upregulated of the IFN-α and IFN-γ while no change on the hypoxia-inducible factor-1α and vascular endothelial growth factor expression levels. Additionally, we showed that ruxolitinib inhibited phosphorylation of JAK/STAT proteins. The inhibition of IFNs dependent JAK/STAT signaling by ruxolitinib leads to decreases of the U87 cells invasiveness and tumorigenesis. We demonstrate that ruxolitinib may inhibit glioma invasion and tumorigenesis through inhibition of the IFN-induced JAK/STAT signaling pathway. Conclusion : Collectively, our results revealed that ruxolitinib may have therapeutic potential in glioblastomas, possibly by JAK/STAT signaling triggered by IFN-α and IFN-γ.

• 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 Ginseng Research
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• v.47 no.2
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• pp.246-254
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• 2023

Background: Here, we aimed to assess the inhibitory effect of a new compound from Panax ginseng on the migration of human ovarian cancer cells and tube formation of human umbilical vein endothelial cells (HUVECs). Methods: A new compound, ginsenglactone A (1), was isolated from ginseng roots, together with seven known compounds (2-8). Spectroscopic data were used to elucidate the chemical structure of 1. The tubular structure formation in HUVECs was assessed by Mayer's hematoxylin staining. The migration of A2780 cells was evaluated using the scratch wound healing assay. Results: HUVECs treated with 1 had the statistically significant decrease in tubular structure formation compared to the HUVECs treated with compounds 2-8. This effect was enhanced by co-treatment with inhibitors for phosphatidylinositol 3-kinase (PI3K) (LY294002) and extracellular signal-regulated kinase (ERK) (U0126). Treatment with 1 decreased the expression of phosphorylation of ERK, PI3K, vascular endothelial growth factor receptor2 (VEGFR2), Akt, and mammalian target of rapamycin (mTOR). In addition, the ability of A2780 cells to cover the scratched area were also decreased. This effect was enhanced by co-treatment with U0126. Lastly, treatment with 1 decreased the phosphorylation of ERK, matrix metalloproteinase-9 (MMP-9), and MMP-2. Conclusion: These results suggest that ginsenglactone A is a potential inhibitor of HUVEC tubular structure formation and A2780 cellular migration, which may be helpful for understanding its anticancer mechanism.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.168-177
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• 2020

Background: Ginseng has been widely used as a health-promoting tonic. Gintonin present in ginseng acts as a lysophosphatidic acid (LPA) receptor ligand that activates six LPA receptor subtypes. The LPA6 subtype plays a key role in normal hair growth, and mutations in the LPA6 receptor impair normal human hair growth. Currently, human hair loss and alopecia are concerning issues that affect peoples' social and day-to-day lives. Objective: We investigated the in vitro and in vivo effects of a gintonin-enriched fraction (GEF) on mouse hair growth. Methods: Human hair follicle dermal papilla cells (HFDPCs) and six-week-old male C57BL/6 mice were used. The mice were divided into the four groups: control, 1% minoxidil, 0.75% GEF, and 1.5% GEF. The dorsal hair was removed to synchronize the telogen phase. Each group was treated topically, once a day, for 15 days. We analyzed hair growth activity and histological changes. Results: GEF induced transient [Ca²⁺]_i, which stimulated HFDPC proliferation and caused 5-bromo-2'-deoxyuridine (BrdU) incorporation in a concentration-dependent manner. GEF-mediated HFDPC proliferation was blocked by the LPA receptor antagonist and Ca²⁺ chelator. HFDPC treatment with GEF stimulated vascular endothelial growth factor release. Topical application of GEF and minoxidil promoted hair growth in a dose-dependent manner. Histological analysis showed that GEF and minoxidil increased the number of hair follicles and hair weight. Conclusion: Topical application of GEF promotes mouse hair growth through HFDPC proliferation. GEF could be one of the main components of ginseng that promote hair growth and could be used to treat human alopecia.

• Korean Journal of Biological Psychiatry
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• v.14 no.4
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• pp.232-240
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• 2007

Objectives : Vascular endothelial growth factor(VEGF), one of potent cytokines, and its receptors were related with various biological functions and pathological conditions. The purpose of this study was to investigate the changes of serum level of free VEGF, soluble VEGFR-1, and soluble VEGFR-2 after treatment with atypical antipsychotic drug in schizophrenia. Method : The schizophrenic patients were diagnosed with DSM-IV and were prospectively followed up for 4 and 8 weeks. Thirteen schizophrenic patients were evaluated their clinical assessment with serum levels of free VEGF, sVEGFR-1, sVEGFR-2, and positive and negative symptom scale(PANSS) at baseline, 4 weeks, and 8 weeks after treatment with atypical antipsychotic drug. Thirteen normal control subjects were recruited and matched with the patient group by age and sex. Result : The serum level of free VEGF($295.2{\pm}43.7$pg/ml)and sVEGFR-2($8259{\pm}336.7$) at baseline(before treatment) in schizophrenic patients were not significantly different, compared with the control group($199.0{\pm}28.8$ and $8481{\pm}371.9$) respectively. However, the serum level of sVEGFR-1($86.2{\pm}10.3$, p<0.05) was significantly increased in the schizophrenic patients compared with the control group($59.0{\pm}6.4$). After treatment with antipsychotic drug, the serum levels of free VEGF at 4 weeks($338.9{\pm}56.5$) and 8 weeks($309.5{\pm}58.7$) were not significantly, different compared with baseline. But the serum levels of sVEGFR-1 was significantly decreased at 8 weeks ($57.3{\pm}6.3$, p<0.05) after antipsychotic drug treatment. The serum levels of sVEGFR-2 were decreased at 4 weeks ($7761{\pm}403.0$, p<0.05) and 8 weeks($7435{\pm}333.5$, p<0.05) compared with baseline. Conclusion : The decreased serum level of sVEGFR-1 and sVEGFR-2 might be affected by dopaminergic system which was influenced by antipsychotic drug.

• Journal of Ginseng Research
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• v.40 no.2
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• pp.151-159
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• 2016

Background: Ginsenoside-Rg3, the pharmacologically active component of red ginseng, has been found to inhibit tumor growth, invasion, metastasis, and angiogenesis in various cancer models. Previously, we found that 20(R)-ginsenoside-Rg3 (Rg3) could inhibit angiogenesis. Since microRNAs (miRNAs) have been shown to affect many biological processes, they might play an important role in ginsenoside-mediated angiomodulation. Methods: In this study, we examined the underlying mechanisms of Rg3-induced angiosuppression through modulating the miRNA expression. In the miRNA-expression profiling analysis, six miRNAs and three miRNAs were found to be up- or down-regulated in vascular-endothelial-growth-factor-induced human-umbilical-vein endothelial cells (HUVECs) after Rg3 treatment, respectively. Results: A computational prediction suggested that mature hsa-miR-520h (miR-520h) targets ephrin receptor (Eph) B2 and EphB4, and hence, affecting angiogenesis. The up-regulation of miR-520h after Rg3 treatment was validated by quantitative real-time polymerase chain reaction, while the protein expressions of EphB2 and EphB4 were found to decrease, respectively. The mimics and inhibitors of miR- 520h were transfected into HUVECs and injected into zebra-fish embryos. The results showed that overexpression of miR-520h could significantly suppress the EphB2 and EphB4 protein expression, proliferation, and tubulogenesis of HUVECs, and the subintestinal-vessel formation of the zebra fish. Conclusion: These results might provide further information on the mechanism of Rg3-induced angiosuppression and the involvement of miRNAs in angiogenesis.