Biomarker analysis in stage III–IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor ( <i>EGFR</i> ) associated with favourable survival

Kim, J-S,Kim, M-A,Kim, T M,Lee, S-H,Kim, D-W,Im, S-A,Kim, T-Y,Kim, W H,Yang, H-K,Heo, D S,Bang, Y-J,Lee, K-U,Choe, K-J,Kim, N K Nature Publishing Group 2009 The British journal of cancer Vol.100 No.5

<P>The aim of this study was to analyse the impact of epidermal growth factor receptor (<I>EGFR</I>), thymidylate synthase (<I>TS</I>), dihydropyrimidine dehydrogenase (<I>DPD</I>), thymidine phosphorylase (<I>TP</I>), aurora kinase (ARK) A/B, and excision repair cross-complementing gene 1 (<I>ERCC1</I>) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III–IV (M0) who subsequently treated with adjuvant FP chemotherapy. <I>TS</I>, <I>DPD</I>, <I>TP</I>, <I>ERCC1</I>, and ARK proteins were measured by immunohistochemistry (IHC). <I>EGFR</I> expression was investigated using a standardized IHC with the <I>EGFR</I> PharmDx assay. Amplification of <I>EGFR</I> gene was analysed using fluorescent <I>in situ</I> hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and <I>EGFR</I> expression were significant prognostic factors for overall survival. Patients with higher <I>EGFR</I> expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282–0.791, <I>P</I>=0.005). Low <I>EGFR</I> expression might be a predictive marker for relapse in curative resected stage III–IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.</P>

Effect of Antimuscarinic Autoantibodies in Primary Sjögren’s Syndrome

Kim, N.,Shin, Y.,Choi, S.,Namkoong, E.,Kim, M.,Lee, J.,Song, Y.,Park, K. SAGE Publications 2015 Journal of dental research Vol.94 No.5

<P>The presence of functional autoantibodies against the muscarinic type 3 receptor (M3R) has been reported in primary Sjogren's syndrome (pSS). However, the pathogenic role of these autoantibodies in pSS development remains to be elucidated. In this experiment, we investigated a pathologic role of pSS autoantibodies (pSS IgG) associated with downregulation of the major histocompatibility complex I (MHC I) molecule with M3R through internalization. Anti-M3R autoantibodies in purified control and pSS IgG were detected using 4 synthesized cyclic M3R peptides by enzyme-linked immunosorbent assay. The binding reactivity of pSS IgG to M3R in situ was analyzed by a dual immunostaining method. Surface expression, interaction, and internalization of M3R with MHC I were analyzed by immunofluorescence confocal microscopy and biochemical assays. Synthetic cyclic peptides M3RP(205-221) and M3RP(520-527) showed significantly high reactivity with pSS IgG compared to the control IgG or the other 3 peptides (P < 0.05). Significantly high reactivity of pSS IgG to M3R in situ was observed. PSS IgG increased the interaction of membrane M3R with MHC I and induced their internalization in primary human submandibular gland cells. The pSS IgG-induced internalization of M3R with MHC I was significantly inhibited by the cholesterol-sequestering drug filipin. Our novel findingnamely, strong downregulation of the membrane MHC I with M3R through internalization of the cholesterol-rich microdomain associating with anti-M3R autoantibodiescould be an important mechanism contributing to the impaired salivation seen in pSS and linking secretory hypofunction to autoimmune pathogenesis.</P>

Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection

Kim, M.C.,Lee, J.S.,Kwon, Y.M.,O, E.,Lee, Y.J.,Choi, J.G.,Wang, B.Z.,Compans, R.W.,Kang, S.M. Elsevier/North-Holland 2013 Antiviral research Vol.99 No.3

The influenza M2 ectodomain (M2e) is poorly immunogenic and has some amino acid changes among isolates from different host species. We expressed a tandem repeat construct of heterologous M2e sequences (M2e5x) derived from human, swine, and avian origin influenza A viruses on virus-like particles (M2e5x VLPs) in a membrane-anchored form. Immunization of mice with M2e5x VLPs induced protective antibodies cross-reactive to antigenically different influenza A viruses and conferred cross protection. Anti-M2e antibodies induced by heterologous M2e5x VLPs showed a wider range of cross reactivity to influenza A viruses at higher levels than those by live virus infection, homologous M2e VLPs, or M2e monoclonal antibody 14C2. Fc receptors were found to be important for mediating protection by immune sera from M2e5x VLP vaccination. The present study provides evidence that heterologous recombinant M2e5x VLPs can be more effective in inducing protective M2e immunity than natural virus infection and further supports an approach for developing an effective universal influenza vaccine.

Fatigue performance of deepwater SCR under short-term VIV considering various S-N curves

Kim, D.K.,Choi, H.S.,Shin, C.S.,Liew, M.S.,Yu, S.Y.,Park, K.S. Techno-Press 2015 Structural Engineering and Mechanics, An Int'l Jou Vol.53 No.5

In this study, a method for fatigue performance estimation of deepwater steel catenary riser (SCR) under short-term vortex-induced vibration was investigated for selected S-N curves. General tendency between S-N curve capacity and fatigue performance was analysed. SCRs are generally used to transport produced oil and gas or to export separated oil and gas, and are exposed to various environmental loads in terms of current, wave, wind and others. Current is closely related with VIV and it affects fatigue life of riser structures significantly. In this regards, the process of appropriate S-N curve selection was performed in the initial design stage based on the scale of fabrication-related initial imperfections such as welding, hot spot, crack, stress concentration factor, and others. To draw the general tendency, the effects of stress concentration factor (SCF), S-N curve type, current profile, and three different sizes of SCRs were considered, and the relationship between S-N curve capacity and short-term VIV fatigue performance of SCR was derived. In case of S-N curve selection, DNV (2012) guideline was adopted and four different current profiles of the Gulf of Mexico (normal condition and Hurricane condition) and Brazil (Amazon basin and Campos basin) were considered. The obtained results will be useful to select the S-N curve for deepwater SCRs and also to understand the relationship between S-N curve capacity and short-term VIV fatigue performance of deepwater SCRs.

Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPβ and potentiates breast cancer progression

Kim, E-S,Cha, Y,Ham, M,Jung, J,Kim, S G,Hwang, S,Kleemann, R,Moon, A Macmillan Publishers Limited 2014 Oncogene Vol.33 No.27

A crucial role of the inflammatory lipid sphingosine-1-phosphate (S1P) in breast cancer aggressiveness has been reported. Recent clinical studies have suggested that C-reactive protein (CRP) has a role in breast cancer development. However, limited information is available on the molecular basis for the expression of CRP and its functional significance in breast cell invasion. The present study aimed to elucidate the molecular link between S1P and CRP during the invasive process of breast epithelial cells. This is the first report showing that transcription of CRP was markedly activated by S1P in breast cells. Our data suggest that not only S1P treatment but also the endogenously produced S1P may upregulate CRP in breast carcinoma cells. Transcription factors CCAAT/enhancer-binding protein beta and c-fos were required for S1P-induced CRP expression. Coupling of S1P<SUB>3</SUB> to heterotrimeric G<SUB>αq</SUB> triggered the expression of CRP, utilizing signaling pathways involving reactive oxygen species (ROS), Ca<SUP>2+</SUP> and extracellular signal-related kinases (ERKs). S1P-induced CRP expression was crucial for the transcriptional activation of matrix metalloproteinase-9 through ERKs, ROS and c-fos, leading to breast cell invasion. Using a xenograft mice tumor model, we demonstrated that S1P induced CRP expression both in vitro and in vivo. Taken together, our findings have revealed a molecular basis for S1P-induced transcriptional activation of CRP and its functional significance in the acquisition of the invasive phenotype of human breast epithelial cells under inflammatory conditions. Our findings may provide useful information on the identification of useful therapeutic targets for inflammatory breast cancer.

Optical subthreshold current method for extracting the interface states in MOS systems

Kim, M.S.,Nam, I.C.,Kim, H.T.,Shin, H.T.,Kim, T.E.,Park, H.S.,Kim, K.S.,Kim, K.H.,Choi, J.B.,Min, K.S.,Kim, D.J.,Kang, D.W.,Kim, D.M. IEEE 2004 IEEE electron device letters Vol.25 No.2

Optical subthreshold current method (OSCM) is proposed for characterizing the interface states in MOS systems using the current-voltage characteristics under a photonic excitation. An optical source with a subbandgap (E<SUB>ph</SUB>>E<SUB>g</SUB>) photonic energy (E<SUB>ph</SUB>=0.943 eV, P<SUB>opt</SUB>=+5 dBm), which is less than the silicon bandgap (E<SUB>g</SUB>=1.12;eV), is employed for the optical subthreshold current characterization of interface states in the photoresponsive energy band. We applied the OSCM method under a subbandgap photonic excitation to MOS systems with a poly-Si gate and verified a U-shaped distribution of interface trap density D<SUB>it</SUB>=10<SUP>10</SUP>∼10<SUP>12</SUP> eV<SUP>-1</SUP>cm<SUP>-2</SUP> for n- and p-type MOSFETs with W/L=30 μm/1.2 μm.

Phase II study of S-1 combined with oxaliplatin as therapy for patients with metastatic biliary tract cancer: influence of the <i>CYP2A6</i> polymorphism on pharmacokinetics and clinical activity

Kim, K-p,Jang, G,Hong, Y S,Lim, H-S,Bae, K-s,Kim, H-S,Lee, S S,Shin, J-G,Lee, J-L,Ryu, M-H,Chang, H-M,Kang, Y-K,Kim, T W Nature Publishing Group 2011 The British journal of cancer Vol.104 No.4

<P><B>Background:</B></P><P>Advanced biliary cancer is often treated with fluoropyrimidine-based chemotherapy. In this study, we evaluated the efficacy and tolerability of a combination of S-1, an oral fluoropyrimidine prodrug, and oxaliplatin in patients with metastatic biliary cancer.</P><P><B>Methods:</B></P><P>Patients with histologically confirmed metastatic biliary cancer and no history of radiotherapy or chemotherapy were enrolled. Oxaliplatin was administered intravenously (130 mg m<SUP>−2</SUP>), followed by 14-day administration of oral S-1 (40 mg m<SUP>−2</SUP> twice daily) with a subsequent 7-day rest period every 21 days. Pharmacokinetic analysis of S-1 was performed at cycle 1. Patients were genotyped for <I>CYP2A6</I> polymorphisms (<SUP>*</SUP>1, <SUP>*</SUP>4, <SUP>*</SUP>7, <SUP>*</SUP>9 or <SUP>*</SUP>10), and pharmacokinetic and clinical parameters compared according to the <I>CYP2A6</I> genotype.</P><P><B>Results:</B></P><P>In total, 49 patients were evaluated, who received a median of four cycles. The overall response rate was 24.5%. Median progression-free and overall survival was 3.7 and 8.7 months, respectively. The most common haematological grade 3 out of 4 toxicity was neutropenia (14%), while non-hematological grade 3 out of 4 toxicities included anorexia (14%), nausea (12%), asthenia (10%), vomiting (10%), and diarrhoea (4%). Biotransformation of S-1 (AUC<SUB>0−24 h</SUB> of 5-fluorouracil/AUC<SUB>0−24 h</SUB> of tegafur) was 1.85-fold higher for the <I>*1/*1</I> group than for the other groups (90% confidence interval 1.37–2.49). Diarrhoea (<I>P</I>=0.0740), neutropenia (<I>P</I>=0.396), and clinical efficacy (response rate, <I>P</I>=0.583; PFS, <I>P</I>=0.916) were not significantly associated with <I>CYP2A6</I> genotype, despite differences in 5-FU exposure.</P><P><B>Conclusion:</B></P><P>The combination of S-1 and oxaliplatin appears to be active and well tolerated in patients with metastatic biliary cancer, and thus is feasible as a therapeutic modality. <I>CYP2A6</I> genotypes are associated with differences in the biotransformation of S-1. However, the impact of the <I>CYP2A6</I> polymorphism on variations in clinical efficacy or toxicity requires further evaluation.</P>

Disposition and metabolism of (2S,3S,4R)-N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N'-benzylguanidine, a novel neuroprotective agent for ischemia-reperfusion damage, in rats

Kim, N. S.,Yoo, H. H.,Lee, M. W.,Kim, H. S.,Kim, D. H. Taylor & Francis 2007 Xenobiotica Vol.37 No.5

<P> The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [14C]-KR31378 to rats. [14C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24 h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24 h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.</P>

ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding

Jeon, B.N.,Yoon, J.H.,Han, D.,Kim, M.K.,Kim, Y.,Choi, S.H.,Song, J.,Kim, K.S.,Kim, K.,Hur, M.W. Elsevier Science 2017 Biochimica et biophysica acta. Gene regulatory mec Vol.1860 No.9

Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.

Butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1 with high butyric acid yield and selectivity

Kim, M.,Kim, K.Y.,Lee, K.M.,Youn, S.H.,Lee, S.M.,Woo, H.M.,Oh, M.K.,Um, Y. Elsevier Applied Science 2016 Bioresource technology Vol.218 No.-

The aim of this work was to study the butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1. Results showed that Clostridium sp. S1 produced butyric acid by simultaneously utilizing glucose and mannose in softwood hydrolysate and, more remarkably, it consumed acetic acid in hydrolysate. Clostridium sp. S1 utilized each of glucose, mannose, and xylose as well as mixed sugars simultaneously with partially repressed xylose utilization. When softwood (Japanese larch) hydrolysate containing glucose and mannose as the main sugars was used, Clostridium sp. S1 produced 21.17g/L butyric acid with the yield of 0.47g/g sugar and the selectivity of 1 (g butyric acid/g total acids) owing to the consumption of acetic acid in hydrolysate. The results demonstrate potential of Clostridium sp. S1 to produce butyric acid selectively and effectively from hydrolysate not only by utilizing mixed sugars simultaneously but also by converting acetic acid to butyric acid.