Inhibition of VEGF ‐dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC 14a

Kim, Taek&#x2010,Keun,Park, Chang Sik,Jang, Jihye,Kim, Mi Ra,Na, Hee&#x2010,Jun,Lee, Kangseung,Kim, Hyun Jung,Heo, Kyun,Yoo, Byong Chul,Kim, Young&#x2010,Myeong,Lee, Je&#x2010,Wook,Kim, Su Jin,Kim, Eu John Wiley and Sons Inc. 2018 MOLECULAR ONCOLOGY Vol.12 No.3

<P>The C‐type lectin‐like domain of CLEC14a (CLEC14a‐C‐type lectin‐like domain [CTLD]) is a key domain that mediates endothelial cell–cell contacts in angiogenesis. However, the role of CLEC14a‐CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity‐determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti‐angiogenic human monoclonal antibody that specifically targets CLEC14a‐CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a‐CTLD‐mediated endothelial cell–cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various <I>in vitro</I> and <I>in vivo</I> functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)‐dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC‐1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab‐adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a‐CTLD has the potential to suppress VEGF‐dependent angiogenesis and tumor angiogenesis and that CLEC14a‐CTLD may be a novel anti‐angiogenic target for VEGF‐dependent angiogenesis and tumor angiogenesis.</P>

Trend analysis of diabetic prevalence and incidence in a rural area of South Korea between 2003–2008

Jeong, Ji Yun,Kim, Jung&#x2010,Guk,Kim, Bo&#x2010,Wan,Moon, Seong Su,Kim, Hye&#x2010,Soon,Park, Keun&#x2010,Gyu,Won, Kyu Chang,Lee, Hyoung Woo,Yoon, Ji Sung,Shon, Ho&#x2010,Sang,Lee, Ji Hyun,Jung, Eui Blackwell Publishing Ltd 2010 Journal of diabetes investigation Vol.1 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction: </B> This study determined the change in prevalence of diabetes and prediabetes over a period of 5 years in South Korea. The incidence of diabetes and prediabetes and risk factors associated with the development of diabetes were also investigated.</P><P><B>Materials and Methods: </B> The Dalseong population‐based cohort survey recruited 1806 subjects who were over 20‐years‐old in 2003. Five years later, 1287 of the original subjects were re‐evaluated and 187 new subjects were added to the study. All participants completed a questionnaire, were given a physical examination, and provided blood samples for analysis including 2 h oral glucose tolerances.</P><P><B>Results: </B> Age‐adjusted prevalence of diabetes rose from 6.7% in 2003 to 9.1% in 2008. The prevalence of prediabetes also increased from 18.5% in 2003 to 28.4% in 2008. The incidence rates of diabetes and prediabetes were 18.3 per 1000 person‐years and 55.4 per 1000 person‐years, respectively. The development of diabetes was associated with impaired fasting glucose (IFG) (odds ratio [OR] 5.661), impaired glucose tolerance (IGT) (OR: 6.013), age (OR 1.013), and waist‐to‐hip ratio (OR 1.513). After excluding the IFG and IGT, systolic blood pressure (OR 1.023), high‐sensitivity C‐reactive protein (hsCRP; OR 1.097), triglyceride (OR 1.002) and waist‐to‐hip ratio (OR 1.696) were statistically significant risk factors in a multivariate logistic regression analysis.</P><P><B>Conclusions: </B> A significant rise in the prevalence of diabetes and prediabetes was observed between 2003 and 2008. In addition, this study newly demonstrated that waist‐to‐hip ratio and hsCRP were associated with the development of diabetes after adjusting for several confounding factors. <B>(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00045.x, 2010)</B></P>

<i>N</i>‐Benzoyl‐<small>L</small>‐Threonine‐Isopropyl‐Ester‐Mediated Crystallization‐Induced Dynamic Resolution of α‐Bromo Arylacetates for the Asymmetric Synthesis of α‐Thio and α‐

Park, Kon Ji,Kim, Yelim,Lee, Myung&#x2010,su,Park, Yong Sun WILEY‐VCH Verlag 2014 EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Vol.2014 No.8

<P>N-Benzoyl-L-threonine-isopropyl-ester-mediated crystallization-induced dynamic resolution (CIDR) of configurationally labile -bromo arylacetates has been investigated. The CIDR was successfully used for the asymmetric preparation of these compounds with up to 98:2 dr, under solution and solvent-free conditions. Subsequent nucleophilic substitution reactions with sulfur and oxygen nulceophiles gave -thio and -oxy arylacetates with up to 98:2 dr. The method was further developed for the preparation of highly enantioenriched 2-phenylthio-2-arylethanols with up to 97:3 er, and 1,4-benzoxazin-3-ones with up to 94:6 er.</P>

Synergistic associations of depression and apolipoprotein E genotype with incidence of dementia

Kim, Jae&#x2010,Min,Stewart, Robert,Kim, Seon&#x2010,Young,Kim, Sung&#x2010,Wan,Bae, Kyung&#x2010,Yeol,Yang, Su‐,Jin,Shin, Il&#x2010,Seon,Yoon, Jin&#x2010,Sang John Wiley Sons, Ltd. 2011 INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Vol.26 No.9

<P><B>Abstract</B></P><P><B>Objectives</B></P><P>A cohort study of Japanese‐American men suggested interactive effects of depression and apolipoprotein E (APOE) e4 allele on risk of incident dementia. In another sample of East Asian origin, we sought to replicate the findings and to explore individual depressive symptoms where this interaction was most evident.</P><P><B>Methods</B></P><P>Of 625 Korean community elders without dementia at baseline, 518 (83%) were followed over a 2.4‐year period and were clinically assessed for incident dementia. Depression was identified by the Geriatric Mental State Schedule (GMS), and nine individual depressive symptoms relevant to DSM‐IV major depressive episode criteria were extracted. APOE genotype was ascertained. Covariates included age, gender, education, and disability.</P><P><B>Results</B></P><P>There were synergistic interactions between depression and APOE e4 on incident dementia independent of covariates. This interaction was particularly strong for four depressive symptoms: depressed mood, worthlessness, concentration difficulty, and suicidal ideation.</P><P><B>Conclusions</B></P><P>We were able to replicate the previous study, finding that, at least in East Asian origin populations, the APOE e4 allele is a stronger predictor of incident dementia in the presence of depressive syndrome, and particular depressive symptoms. Copyright © 2010 John Wiley & Sons, Ltd.</P>

In Situ Observation of Voltage‐Induced Multilevel Resistive Switching in Solid Electrolyte Memory

Choi, Sang&#x2010,Jun,Park, Gyeong&#x2010,Su,Kim, Ki&#x2010,Hong,Cho, Soohaeng,Yang, Woo&#x2010,Young,Li, Xiang&#x2010,Shu,Moon, Jung&#x2010,Hwan,Lee, Kyung&#x2010,Jin,Kim, Kinam WILEY‐VCH Verlag 2011 ADVANCED MATERIALS Vol.23 No.29

<P><B>Solid electrolyte memories</B> utilizing voltage‐induced resistance change display the capability of multilevel switching, but understanding of the microscopic switching mechanism has been left incomplete. Here, in situ TEM observation of voltage‐induced changes in the microstructure of a solid electrolyte memory is reported, revealing that the multilevel switching originates from the growth of multiple conducting filaments with nanometer‐sized diameter and spacing. </P>

Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

Shin, Su‐,Jin,Kim, Sang Yong,Choi, Yoon Young,Son, Taeil,Cheong, Jae&#x2010,Ho,Hyung, Woo Jin,Noh, Sung Hoon,Park, Chung&#x2010,Gyu,Kim, Hyoung&#x2010,Il AlphaMed Press 2019 The oncologist Vol.24 No.9

<P>This article reports on the relationship between microsatellite instability (MSI) status and the antitumor host immune response, focusing on the affect of these factors on prognosis in MSI‐high versus non MSI‐high gastric cancer.</P><P><B>Background.</B></P><P>Microsatellite instability (MSI)‐high (MSI‐H) colorectal cancer is known to be associated with increased tumor‐infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response.</P><P><B>Materials and Methods.</B></P><P>We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti‐CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.</P><P><B>Results.</B></P><P>Of the 345 patients, 57 demonstrated MSI‐H tumors and 288 demonstrated non‐MSI‐H tumors. MSI‐H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI‐H tumors and those with non‐MSI‐H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence‐free survival (RFS) or overall survival (OS) in the MSI‐H tumor group. In the non‐MSI‐H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS.</P><P><B>Conclusions.</B></P><P>The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response.</P><P><B>Implications for Practice.</B></P><P>This study demonstrates that the density of each subset of tumor‐infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)‐high and non‐MSI‐high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI‐high (MSI‐H) and non‐MSI‐H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI‐high gastric cancer.</P>

Phosphatase of regenerating liver‐3 promotes migration and invasion by upregulating matrix metalloproteinases‐7 in human colorectal cancer cells

Lee, Su‐,Kyung,Han, Young&#x2010,Min,Yun, Jieun,Lee, Chang Woo,Shin, Dae&#x2010,Seop,Ha, Young&#x2010,Ran,Kim, Jina,Koh, Jong Sung,Hong, Su‐,Hyung,Han, Dong Cho,Kwon, Byoung&#x2010,Mog Wiley Subscription Services, Inc., A Wiley Company 2012 International journal of cancer: Journal internati Vol.131 No.3

<P><B>Abstract</B></P><P>Phosphatase of regenerating liver (PRL)‐3, a member of a subgroup of protein tyrosine phosphatases that can stimulate the degradation of the extracellular matrix, is over‐expressed in metastatic colorectal cancer (CRC) relative to primary tumors. To determine whether PRL‐3‐induced enhancement of migration and invasion is dependent on the expression of matrix metalloproteinases (MMPs), PRL‐3 was expressed in DLD‐1 human CRC cells. The motility, migration and invasion characteristics of the cells were examined, and metastasis to the lung was confirmed in a nude mouse using PRL‐3‐overexpressing DLD‐1 cells [DLD‐1 (PRL‐3)]. Migration and invasion of the cells were inhibited by phosphatase and farnesyltransferase inhibitors. Expression of MMPs was enhanced 3‐ to 10‐fold in comparison to control cells, and migration and invasion were partially inhibited by small interfering RNA (siRNA) knockdown of MMP‐2, ‐13 or ‐14. Importantly, siRNA knockdown of MMP‐7 completely inhibited the migration and invasion of DLD‐1 (PRL‐3) cells, whereas overexpression of MMP‐7 increased migration. The expression of MMP‐7 was also downregulated by phosphatase and farnesyltransferase inhibitors. It was found that PRL‐3 induced MMP‐7 through oncogenic pathways including PI3K/AKT and ERK and that there is a relationship between the expression of PRL‐3 and MMP‐7 in human tumor cell lines. The expression of MMP‐13 and ‐14 was very sensitive to the inhibition of farnesyltransferase; however, the migration and invasion of DLD‐1 (PRL‐3) cells did not strongly depend on the expression of MMP‐13 or ‐14. These results suggest that the migration and invasion of PRL‐3‐expressing CRC cells depends primarily on the expression of MMP‐7.</P>

Enhanced production of 2,3‐butanediol in pyruvate decarboxylase‐deficient <i>Saccharomyces cerevisiae</i> through optimizing ratio of glucose/galactose

Choi, Eun&#x2010,Ji,Kim, Jin&#x2010,Woo,Kim, Soo&#x2010,Jung,Seo, Seung&#x2010,Oh,Lane, Stephan,Park, Yong&#x2010,Cheol,Jin, Yong&#x2010,Su,Seo, Jin&#x2010,Ho WILEY‐VCH Verlag 2016 Biotechnology Journal Vol.11 No.11

<P><B>Abstract</B></P><P>Galactose and glucose are two of the most abundant monomeric sugars in hydrolysates of marine biomasses. While <I>Saccharomyces cerevisiae</I> can ferment galactose, its uptake is tightly controlled in the presence of glucose by catabolite repression. It is desirable to construct engineered strains capable of simultaneous utilization of glucose and galactose for producing biofuels and chemicals from marine biomass. The <I>MTH1</I> gene coding for transcription factor in glucose signaling was mutated in a pyruvate decarboxylase (Pdc)‐deficient <I>S. cerevisiae</I> expressing heterologous 2,3‐butanediol (2,3‐BD) biosynthetic genes. The engineered <I>S. cerevisiae</I> strain consumed glucose and galactose simultaneously and produced 2,3‐BD as a major product. Total sugar consumption rates increased with a low ratio of glucose/galactose, though, occurrence of the glucose depletion in a fed‐batch fermentation decreased 2,3‐BD production substantially. Through optimizing the profiles of sugar concentrations in a fed‐batch cultivation with the engineered strain, 99.1 ± 1.7 g/L 2,3‐BD was produced in 143 hours with a yield of 0.353 ± 0.022 g 2,3‐BD/g sugars. This result suggests that simultaneous and efficient utilization of glucose and galactose by the engineered yeast might be applicable to the economical production of not only 2,3‐BD, but also other biofuels and chemicals from marine biomass.</P>

XIAP inhibitor embelin induces autophagic and apoptotic cell death in human oral squamous cell carcinoma cells

Lee, You&#x2010,Jin,Park, Bong&#x2010,Soo,Park, Hae&#x2010,Ryoun,Yu, Su‐,Bin,Kang, Hae&#x2010,Mi,Kim, In&#x2010,Ryoung John Wiley and Sons Inc. 2017 Environmental toxicology Vol.32 No.11

<P><B>Abstract</B></P><P>Embelin is an active ingredient of traditional herbal remedies for cancer and other diseases. Recently, it has been suggested that autophagy may play an important role in cancer therapy. However, little data are available regarding the role of autophagy in oral cancers. Therefore, we conducted this study to examine whether Embelin modulates autophagy in Ca9‐22. Our results showed that Embelin had anticancer activity against the Ca9‐22 human tongue squamous cell, and we observed that autophagic vacuoles were formed by MDC and AO. We also analyzed Embelin‐treated Ca9‐22 cells for the presence of biochemical markers and found that it directly affected the conversion of LC3‐II, the degradation of p62/SQSTM1, full‐length cleavage formation of ATG5‐ATG12 complex and Beline‐1, and caspase activation. Rescue experiments using an autophagy inhibitor showed Embelin‐induced cell death in Ca9‐22, confirming that autophagy acts as a pro‐death signal. Furthermore, Embelin exhibited anticancer activity against Ca9‐22 via both autophagy and apoptosis. These findings suggest that Embelin may potentially contribute to oral cancer treatment and provide useful information for the development of a new therapeutic agent.</P>

Delphinidin induces apoptosis and inhibits epithelial‐to‐mesenchymal transition via the ERK/p38 MAPK‐signaling pathway in human osteosarcoma cell lines

Kang, Hae&#x2010,Mi,Park, Bong&#x2010,Soo,Kang, Hyun&#x2010,Kyung,Park, Hae&#x2010,Ryoun,Yu, Su‐,Bin,Kim, In&#x2010,Ryoung John Wiley and Sons Inc. 2018 Environmental toxicology Vol.33 No.6

<P><B>Abstract</B></P><P>Delphinidin is major anthocyanidin that is extracted from many pigmented fruits and vegetables. This substance has anti‐oxidant, anti‐inflammatory, anti‐angiogenic, and anti‐cancer properties. In addition, delphinidin strongly suppresses the migration and invasion of various cancer cells during tumorigenesis. Although delphinidin has anti‐cancer effects, little is known about its functional roles in osteosarcoma (OS). For these reasons, we have demonstrated the effects of delphinidin on OS cell lines. The effects of delphinidin on cell viability and growth of OS cells were assessed using the MTT assay and colony formation assays. Hoechst staining indicated that the delphinidin‐treated OS cells were undergoing apoptosis. Flow cytometry, confocal microscopy, and a western blot analysis also indicated evidence of apoptosis. Inhibition of cell migration and invasion was found to be associated with epithelial‐to‐mesenchymal transition (EMT), observed by using a wound healing assay, an invasion assay, and a western blot analysis. Furthermore, delphinidin treatment resulted in a profound reduction of phosphorylated forms of ERK and p38. These findings demonstrate that delphinidin treatment suppressed EMT through the mitogen‐activated protein kinase (MAPK) signaling pathway in OS cell lines. Taken together, our results suggest that delphinidin strongly inhibits cell proliferation and induces apoptosis. Delphinidin treatment also suppresses cell migration and prevents EMT via the MAPK‐signaling pathway in OS cell lines. For these reasons, delphinidin has anti‐cancer effects and can suppress metastasis in OS cell lines, and it might be worth using as an OS therapeutic agent.</P>