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Ultraviolet A (UVA) is a risk factor for photoaging and wrinkle formation. Zizania latifolia is an herbaceous perennial plant. It contains many bioactive compounds such as tricin that show antioxidative and anti-inflammatory effects. The aim of this study was to investigate the antiwrinkle effect of a mixture of hydrolytic enzyme (cellulase, hemicellulase and pectinase)-treated Z. latifolia extract (ZLE) and tricin on UVA-irradiated human dermal fibroblasts (HDFs) and SKH-1 hairless mice. Treatment of UVA-irradiated HDF cells with ZLE and tricin significantly decreased UVA induced-plasma membrane rupture, generation of ROS, expression levels of total and secreted lysosomal associated membrane protein (LAMP-1), cathepsin B and metalloproteinases (MMPs) and inhibited NF-&kappa, B activation. In the animal study, UVA-damaged epidermal and dermal tissues were repaired by the ZLE and tricin treatments. Administration of ZLE or tricin to UVA-irradiated animals recovered skin surface moisture and collagen fiber in dermal tissue. Treatment of ZLE or tricin decreased wrinkle formation, secretion of MMPs and expression levels of vascular endothelial growth factor (VEGF) and cathepsin B, and increased the expression level of collagen-1 in UVA-irradiated animals. Overall, the ZLE and tricin treatments decreased the skin damage induced by UVA irradiation via inhibition of lysosomal exocytosis and ROS generation. Therefore, ZLE and tricin are promising as antiwrinkle and antiphotoaging agents.

Patients with oral squamous cell carcinoma (OSCC) bone invasion are surgically treated with bone resection, which results in severe physical and psychological damage. Here, we investigated the potential of fractalkine (CX3CL1), which is regulated by transforming growth factor (TGF-β), as a novel biomarker for correct prediction and early detection of OSCC-associated bone invasion. TGF-β knockdown and treatment with a TGF-β-neutralizing antibody decreased the level of fractalkine in the culture media of HSC-2 and YD10B OSCC cells. Treatment with a fractalkine-neutralizing antibody reduced TGF-β-stimulated invasion by HSC-2 and YD10B cells. Fractalkine treatment increased the viability, invasion, and uPA secretion of both OSCC cell lines. Furthermore, OSCC cell bone invasion was assessed following subcutaneous inoculation of wild-type or TGF-β knockdown OSCC cells in mouse calvaria. TGF-β knockdown prevented erosive bone invasion, reduced the number of osteoclasts at the tumor-bone interface, and downregulated fractalkine expression in mouse tumor tissues. Our results indicate that the production of fractalkine is stimulated by TGF-β and mediates TGF-β-induced cell invasion in several OSCC cell lines showing an erosive pattern of bone invasion. Fractalkine may be a useful predictive marker and therapeutic target for OSCC-induced bone destruction.

Purpose/Objective(s) There is a paucity of data studying the significance of neutrophil-to-lymphocyte ratio (NLR) in peripheral blood of patients with locally advanced rectal cancer (LARC) planning to undergo preoperative RT. We aimed to investigate the prognostic impact of NLR in patients with LARC and whether there are modifiable factors in RT which influencing the level of NLR. Materials/Methods We studied 1366 patients treated with neoadjuvant RT with concurrent or sequential chemotherapy for LARC from 2006 to 2019. Most (97.8%) were treated with long-course RT (50-50.4 Gy in 25-28 fractions) with 3DCRT (n = 851) or helical tomotherapy (n = 504). Short-course RT (25 Gy in 5 fractions, followed by 6-week XELOX) was used in 30 cases (NCT03676517). The absolute neutrophil and lymphocyte counts were obtained from the sample collected at the time of initial diagnosis, before and during the course of preoperative RT and before surgery. The primary endpoint was distant metastasis-free survival (DMFS). Results With the median follow-up time of 61.3 months (4.1-173.7 months), the 5-year DMFS was 80.1%. 5-year DMFS was significantly associated with the level of NLR after RT, but not with the level of NLR before RT. In Cox multivariate model, post-RT NLR greater than 4 was independently correlated with worse DMFS (HR 1.37, 95% CI, 1.08-1.73), along with higher icT stage, ypT stage and ypN stage. The 5-year OS of patients with post-RT NLR > 4.0 was 83.2%, compared to 94.4% in post-RT NLR ≤ 4 patients (P 4.0) was more frequently developed after long-course RT (OR, 2.77, P = 0.032) or helical tomotherapy (OR, 1.29, P .05). Conclusion Elevation of NLR after neoadjuvant RT is associated with increased risk of DM development and poor OS in LARC. Development of high NLR following RT is directly related to RT fractionation and delivery modality, and tumor characteristics. Incorporation of SCRT with 3D-CRT or active bone marrow sparing-IMRT may be a modifiable factor that can indirectly affect DMFS by means of attenuating NLR in LARC patients, which needs further investigations.

Background Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination therapy in patients with refractory bone and soft tissue sarcoma (STS). Patients and Methods Patients were included in this multicenter, phase II study (ClinicalTrials.gov identifier NCT03809637) if they progressed after receiving one or more chemotherapy regimens containing an anthracycline and/or ifosfamide. Pemetrexed was first administered intravenously, followed by cisplatin, over a cycle of 21 days, for a maximum of six cycles. The primary endpoint was a progression-free rate (PFR) at 3 months (3-month PFR). Results From January 2017 to September 2019, we enrolled 37 patients; of these, 73% had previously undergone three or more rounds of chemotherapy. Five patients (13.5%) exhibited objective responses, including two patients (2/6, 33.3%) with malignant peripheral nerve sheath tumors, one patient (1/4, 25%) with synovial sarcoma, one patient (1/4, 25%) with undifferentiated pleomorphic sarcoma, and one patient (1/4, 25%) with angiosarcoma. The median progression-free survival was 2.6 months, and the 3-month PFR was 45.9% (n = 17). None of the four patients with osteosarcoma exhibited objective responses or were progression free at 3 months. The most frequent treatment-related grade 3-4 toxicities included neutropenia (16.2%), anemia (13.5%), thrombocytopenia (13.5%), and fatigue (8.1%). Among 26 patients (70.3%) available for immunohistochemical assessments, patients in the low-excision repair cross-complementation group 1 (ERCC1) and low-thymidylate synthase expression groups showed a tendency for longer overall survival. Conclusions Combination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint., Highlights • Pemetrexed and cisplatin show promising efficacy for advanced sarcoma treatment, particularly as a salvage therapy option. • The combination therapy met its predefined primary endpoint, with a 3-month PFR of 45.9%. • Pemetrexed and cisplatin showed acceptable toxicity in heavily treated sarcoma patients.

Background Inflammatory bowel disease (IBD) has a risk of venous thromboembolism (VTE) compared with healthy controls, which justify prophylaxis in practice. There are few data on VTE in Asian IBD patients including Koreans. We aimed to investigate the incidence of VTE and the potential risk factors in Korean IBD patients. Methods A nationwide population-based cohort study was performed using claims data from the National Health Insurance service in Korea for 10 years, from 2006 to 2015. VTE, Crohn’s disease (CD) and ulcerative colitis (UC) were operationally defined by using ICD-10 codes, codes for Rare and Intractable Diseases registration, and pharmaceutical prescriptions for IBD-specific drugs. Control group was defined as age- and sex-matched health insurance subscribers without IBD for the same period. The hazard ratio (HR) for the risk of VTE was calculated after adjusting for covariates such as age, sex, rural area, comorbidities, Charlson Comorbidity Index (CCI), admission, and therapeutic drugs use for IBD using multivariate Cox proportional hazard regression. Results A total of 45,037 patients were diagnosed with IBD (13,850 CD and 31,187 UC), and 133,019 were defined as controls. VTE occurred in 411 (0.91%) in IBD, 106 (0.76%) in CD, and 305 (0.98%) in UC, whereas 641 (0.48%) in controls. In univariate analysis among IBD patients, old age (>59 years: HR = 6.256), female sex (HR = 1.537), low income (HR = 1.3090), high CCI (>3 score: HR = 4.053), steroid use (HR = 1.872), emergency care (HR = 1.513) and hospitalisation (HR = 1.352) significantly increased a risk of VTE. However, anti-TNF agent use (HR = 0.611) significantly decreased a risk of VTE. In multivariate analysis with adjustment among all subjects, CD (HR = 15.833) and UC (HR = 8.125) significantly increased a risk of VTE compared with controls. Conclusion Our study demonstrates that VTE is significantly high in Korean IBD patients compared with controls. In addition, old age, female sex, low income, high CCI, steroid use, emergency care, and hospitalisation are suggested as risk factors of VTE in IBD. Interestingly, use of anti-TNF agents may reduce risk of VTE, which should be considered for prophylaxis strategy suitable for Korean IBD patients.

// Junhee Park 1, 2 , Hyun-Jeong Kim 2 , Ki Rim Kim 3 , Sun Kyoung Lee 2 , Hyungkeun Kim 2, 4 , Kwang-Kyun Park 1, 2, 4 , Won-Yoon Chung 1, 2, 4 1 Department of Dentistry, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea 2 Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea 3 Department of Dental Hygiene, Kyungpook National University, Sangju 742-711, Korea 4 Department of Applied Life Sciences, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea Correspondence to: Won-Yoon Chung, email: wychung@yuhs.ac Kwang-Kyun Park, email: biochelab@yuhs.ac Keywords: oral squamous cell carcinoma, bone invasion, runt-related transcription factor 3, transforming growth factor-β Received: October 08, 2015 Accepted: December 15, 2016 Published: December 21, 2016 ABSTRACT High recurrence and lower survival rates in patients with oral squamous cell carcinoma (OSCC) are associated with its bone invasion. We identified the oncogenic role of RUNX3 during bone invasion by OSCC. Tumor growth and the generation of osteolytic lesions were significantly inhibited in mice that were subcutaneously inoculated with RUNX3-knockdown human OSCC cells. RUNX3 knockdown enhanced TGF-β-induced growth arrest and inhibited OSCC cell migration and invasion in the absence or presence of transforming growth factor-β (TGF-β), a major growth factor abundant in the bone microenvironment. RUNX3 knockdown induced cell cycle arrest at the G1 and G2 phases and promoted G2 arrest by TGF-β in Ca9.22 OSCC cells. RUNX3 knockdown also inhibited both the basal and TGF-β-induced epithelial-to-mesenchymal transition by increasing E-cadherin expression and suppressing the nuclear translocation of β-catenin. In addition, the expression and TGF-β-mediated induction of parathyroid hormone-related protein (PTHrP), one of key osteolytic factors, was blocked in RUNX3-knockdown OSCC cells. Furthermore, treating human osteoblastic cells with conditioned medium derived from RUNX3-knockdown OSCC cells reduced the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin ratio compared with treatment with conditioned medium from RUNX3-expressing cells. These findings indicate that RUNX3 expression in OSCC cells contributes to their bone invasion and the resulting osteolysis by inducing their malignant behaviors and production of osteolytic factors. RUNX3 alone or in combination with TGF-β and PTHrP may be a useful predictive biomarker and therapeutic target for bone invasion by oral cancer.

Chemerin is secreted as prochemerin from various cell types and then cleaved into the bioactive isoform by specific proteases. In various cancer types, chemerin exhibits pro- or antitumor effects. In the present study, chemerin treatment significantly inhibited the viability and invasion of breast cancer cells in the absence or presence of transforming growth factor (TGF)-&beta, and insulin-like growth factor (IGF)-1. The expression levels of E-cadherin and vimentin were reduced in chemerin-treated breast cancer cells. However, chemerin treatment recovered the reduced E-cadherin expression level in breast cancer cells treated with TGF-&beta, or IGF-1. Chemerin treatment inhibited nuclear &beta, catenin levels in breast cancer cells stimulated with or without TGF-&beta, or IGF-1. In addition, chemerin treatment blocked the increase in the receptor activator of nuclear factor kappa-&Beta, ligand (RANKL)/osteoprotegerin (OPG) ratio in osteoblastic cells exposed to metastatic breast cancer cell-derived conditioned medium. Chemerin treatment inhibited RANKL-induced osteoclast formation and bone resorption by reducing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K. Intraperitoneal administration of chemerin inhibited tumor growth in MCF-7 breast cancer cell-injected mice and reduced the development of osteolytic lesions resulting from intratibial inoculation of MDA-MB-231 cells. Taken together, chemerin inhibits the growth and invasion of breast cancer cells and prevents bone loss resulting from breast cancer cells by inhibiting finally osteoclast formation and activity.

Objective Remodeling of alveolar bone is controlled by osteoclast-mediated bone resorption and osteoblast-induced bone formation. LPS of Porphyromonas gingivalis, a major causative agent of periodontitis, produces proinflammatory cytokines in host immune cells, which thereby triggers osteoclastogenesis and leads to alveolar bone resorption. We investigated the anti-periodontitis potential of Platycarya strobilacea leaf extract (PLE), which is used as a traditional medicine in Asian countries. Design TNF-α levels in cell culture media were measured using a commercially available enzyme-linked immunosorbent assay kit. Osteoclast differentiation was observed by tartrate-resistant acid phosphatase staining, and the expression levels of osteoclastogenic genes were measured by quantitative real-time PCR. Bone-resorbing activity was confirmed by the resorption pit formation, gelatin zymographic, and the cathepsin K activity assays. Osteogenic differentiation was confirmed with an ALP activity assay and alizarin red S staining. Results PLE treatment inhibited the production of TNF-α in P. gingivalis LPS-stimulated RAW264.7 macrophages. In bone marrow-derived macrophages serving as osteoclast precursors, PLE treatment blocked RANKL-induced osteoclastogenesis and gene expression levels of the osteoclastogenic transcription factor NFATc1, DC-STAMP for osteoclast fusion, and cathepsin K for osteoclast activity. In addition, PLE treatment reduced the formation of resorption pits and the secretion of MMP 9 and cathepsin K from the differentiated osteoclasts. Furthermore, PLE treatment induced osteogenesis by increasing ALP activity and calcium content in preosteoblastic cells. Conclusion PLE inhibits P. gingivalis LPS-induced TNF-α production and bone resorption and induces bone formation. PLE may be a beneficial agent to promote oral health by inhibiting periodontitis-induced alveolar bone loss.

Background Although the current standard preoperative chemoradiotherapy (PCRT) for stage II/III rectal cancer decreases the risk of local recurrence, it does not improve overall survival and increase the likelihood of preoperative overtreatment, especially in patients without the circumferential resection margin (CRM) involvement. Methods Stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis was radiologically defined by preoperative magnetic resonance imaging (MRI). Patients who received either PCRT followed by TME (PCRT group) or upfront surgery with TME (US group) between 2011 and 2016 were analyzed. We derived cohorts of PCRT group versus US group using propensity-score matching using staging, age, and distance from anal verge). Three-year relapse-free survival rate, disease-free survival (DFS), and overall survival (OS) were compared between two groups. Results A total of 221 patients were analyzed after propensity score matching. There were no differences in baseline characteristics. The median follow-up was 75 months (range, 28-101). No difference in 3-year relapse-free survival rate was noted between PCRT and US groups (89% vs 92% with US; P=0.657). Likewise, there was no statistically significant difference in DFS (7.7 years vs 8.0 years with US; P=0.162) and OS (8.1 years vs 8.3 years with US; P=0.431), respectively. The rates of locoregional recurrence (2.9% vs 0% with US, P=0.301) and distant metastasis (7.4% vs 7.1%, P=1.0) at 3-years were not significantly different between two groups. Interestingly, approximately half of patients had pathologic stage I cancer in both groups (56% with PCRT vs 45% with US; P=0.167) and 69% of patients in US group had not received adjuvant treatment, suggesting that upfront surgery without neoadjuvant therapy can be considered in early stage patients with good prognosis. Conclusions PCRT may not be required for all stage II/III rectal cancer patients, especially for the MRI-based intermediate-risk group (cT1-2/N1, cT3N0) without CRM involvement and lateral lymph node metastasis. Further prospective studies are warranted. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Summary Background Because inflammatory cytokines are known to be potent inducers of matrix metalloproteinases (MMPs), and MMPs themselves can promote inflammation, we speculated that MMP activation might be involved in the pathogenesis of Henoch–Schonlein purpura (HSP) vasculitis. Objectives To investigate the gene expression profile of all known MMPs and tissue inhibitors of metalloproteinases (TIMPs) in children with HSP and to examine the role, if any, of MMPs in the pathogenesis of HSP. Methods Peripheral blood samples were obtained from 10 patients with HSP (nine were in the acute stage, one had HSP nephritis) and four healthy controls. Peripheral blood samples were also taken from the nine patients with HSP when they reached the convalescent stage of the disease. From these samples, total RNA was purified and gene expressions were measured using real-time polymerase chain reaction. Results MMP-8 expression was decreased in patients with arthralgia (P = 0·038), and MMP-3 (P = 0·03) and TIMP-4 expressions (P = 0·016) were elevated in HSP patients with nephritis. Soft tissue oedema was associated with decreased expressions of MMP-26 (P = 0·038) and MMP-28 (P = 0·038). MMP-1, MMP-8, MMP-9, MMP-10, MMP-13, MMP-16 and MMP-26 levels were significantly higher in patients in the acute stage of HSP than in normal controls (P

Unilateral condylar overgrowth induces severe facial asymmetry. Therefore, treatment focuses on both elimination of the condyle lesion and correction of the facial asymmetry. The aim of this report is to present three patient cases, introducing a simpler surgical method, the indications for this surgical method, and a treatment planning flow that is consistently applicable regardless of the origin of the condylar lesion. Condylectomy was performed simultaneously with orthognathic surgery, with the vertical ramus osteotomy selected as the method of ramus surgery; ipsilateral ramus surgery was not performed on the condylectomy side. This method is applicable in cases in which facial asymmetry originates solely from unilateral condylar overgrowth, and the maxilla and mandible are presumed to have been in the normal class I anteroposterior position before the onset of condylar lesion growth. After surgery, temporomandibular joint pain and/or mouth limitations were resolved, the new condyle showed satisfactory bone remodelling, and favourable facial symmetry was attained. The postoperative results were maintained long-term and there was no recurrence on the condylectomy side. This simply modified surgical strategy for facial asymmetry due to unilateral condylar overgrowth may be used in selected patients, regardless of the origin of the condylar lesion.

Many osteopenic disorders, including a postmenopausal osteoporosis and lytic bone metastasis in breast and prostate cancers, are linked with a hyperosteoclast activity due to increased receptor activator of nuclear factor kappa-B ligand (RANKL) expression in osteoblastic/stromal cells. Therefore, inhibition of RANKL-induced osteoclastogenesis and osteoclast-induced bone resorption is an important approach in controlling pathophysiology of these skeletal diseases. We found that, of seven type I, II, and III saikosaponins isolated fromBupleurum falcatum, saikosaponins A and D, type I saikosaponins with an allyl oxide linkage between position 13 and 28 and two carbohydrate chains that are directly attached to the hydroxyl groups in position 3, exhibited the most potent inhibition on RANKL-induced osteoclast formation at noncytotoxic concentrations. The stereochemistry of the hydroxyl group at C16 did not affect their activity. Saikosaponins A and D inhibited the formation of resorptive pits by reducing the secreted levels of matrix metalloproteinase- (MMP-) 2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Additionally, saikosaponins A and D inhibited mRNA expression of parathyroid hormone-related protein as well as cell viability and invasion in metastatic human breast cancer cells. Thus, saikosaponins A and D can serve as a beneficial agent for the prevention and treatment of osteoporosis and cancer-induced bone loss.

SummaryDespite the increasing use of dendritic cell (DC) vaccination in clinical trials, optimal conditions for the generation of functionally mature DCs remain to be established. The current standard DC maturation protocol for clinical trials has been used as an inflammatory cytokine cocktail [tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and prostaglandin E2], but this cocktail induced insufficient maturation of DCs derived from elutriated monocytes when cultured in X-VIVO 15. The aim of this study was to define effective combinations of stimulators for generating functionally mature DCs from elutriated monocytes under current good manufacturing practice conditions. We compared the functional capacity of DCs in response to all possible pairwise combinations of four different classes of stimuli: TNF-α, peptidoglycan, polyinosinic : polycytidylic acid [poly(I:C)] and soluble CD40 ligand (CD40L). Maturation status of DCs stimulated with combination of four stimuli was similar to that of the cytokine cocktail as assessed by the cell surface phenotype. However, only the combination of poly(I:C) + CD40L induced complete functional activation of the whole DC population, assessing IL-12p70 production, allostimulatory activity, migratory response to CCL19 and T helper 1-polarizing capacity. Thus, the protocol based on the combination of poly(I:C) and CD40L is more effective for the induction of clinical-grade DCs from elutriated monocytes than the standard cytokine cocktail.

Breast cancer is the most frequent cancer in women and the main cause of its mortality is induced by metastasizing to distant organs. Breast cancer primarily metastasizes to the bone, lung, liver and brain, and the bone is the most susceptible to metastasis. When breast cancer metastasizes to the bone, the dominant lesion is osteolytic. This osteolytic bone metastasis is highly associated with the complex interaction between cancer cells and the bone microenvironment. Interleukin-1 beta (IL-1β) and IL-17 act as osteolytic factors and promote osteolytic lesions in breast cancer pateints by increasing osteoclastogenesis and decreasing osteoblastogenesis. Especially, both of IL-1β and IL-17 increase in patients with breast cancer and decrease disease-free survival in cancer patients. Wogonin, one of the major flavonoids in the roots of Scutellaria baicalensis Georgi, has been recognized as a potent anti-cancer agent through increased apoptosis and decreased proliferation. We investigated whether wogonin could reduce the cancer cell-induced osteolysis by controlling interaction between cancer cells and bone-related cells. Wogonin suppressed cell viability, DNA synthesis and migration in MDA-MB 231 cells. Wogonin reduced the secretion of IL-1β and IL-17 in MDA-MB 231 cells. Wogonin at non-cytotoxic concentrations inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, wogonin blocked an increase in RANKL/osteoprotegerin mRNA ratio in the osteoblastic hFOB1.19 cells exposed to MDA-MB 231 cells-derived conditioned medium. Finally, oral administration of wogonin significantly inhibited osteolytic lesions in MDA-MB 231 cells-injected mice. Taken together, these results indicate that wogonin is a promising agent for preventing and treating cancer-cell mediated bone loss. Citation Format: Hyungkeun Kim, Kwang-Kyun Park, Won-Yoon Chung. Wogonin suppresses the production of breast cancer-derived osteolytic factors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1543. doi:10.1158/1538-7445.AM2015-1543

P368 Serological response to the 23-valent pneumococcal polysaccharide vaccine in patients with Crohn’s disease: preliminary results of a prospective, multicentre study C.K. Lee1 *, H.-S. Kim2, H.-J. Kim1, W. Moon3, K.M. Lee4, J.-S. Koo5, G.S. Seo6, S.J. Park7, B.D. Ye8, C.H. Choi9, S.-A. Jung10, Y.S. Kim11, J.P. Im12, E.S. Kim13, S.N. Hong14. 1Kyung Hee University, South Korea, 2Yonsei University Wonju College of Medicine, South Korea, 3Kosin University, South Korea, 4The Catholic University of Korea, South Korea, 5Korea University, South Korea, 6Wonkwang University, South Korea, 7Yonsei University, South Korea, 8University of Ulsan, South Korea, 9Chung-Ang University, South Korea, 10Ewha Womans University, South Korea, 11Inje University, South Korea, 12Seoul National University, South Korea, 13Keimyung University, South Korea, 14Konkuk University, South Korea