Foxp3 is a key downstream regulator of p53-mediated cellular senescence

Kim, J-E,Shin, J-S,Moon, J-H,Hong, S-W,Jung, D-J,Kim, J H,Hwang, I-Y,Shin, Y J,Gong, E-Y,Lee, D H,Kim, S-M,Lee, E Y,Kim, Y S,Kim, D,Hur, D,Kim, T W,Kim, K-p,Jin, D-H,Lee, W-J Macmillan Publishers Limited 2017 Oncogene Vol.36 No.2

<P>The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.</P>

Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis

Yu, K‐,H.,Hong, K‐,S.,Lee, B‐,C.,Oh, M‐,S.,Cho, Y‐,J.,Koo, J‐,S.,Park, J‐,M.,Bae, H‐,J.,Han, M‐,K.,Ju, Y‐,S.,Kang, D‐,W.,Appelros, P. Blackwell Publishing Ltd 2011 Acta neurologica Scandinavica Vol.123 No.5

<P>Yu K‐H, Hong K‐S, Lee B‐C, Oh M‐S, Cho Y‐J, Koo J‐S, Park J‐M, Bae H‐J, Han M‐K, Ju Y‐S, Kang D‐W, Appelros P, Norrving B, Terent A. Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis. 
Acta Neurol Scand: 2011: 123: 325–331. 
© 2010 John Wiley & Sons A/S.</P><P><B>Background – </B> It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case‐fatality between two PSM cohorts of Sweden and Korea.</P><P><B>Methods – </B> Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one‐to‐one matching based on propensity scores of each patient.</P><P><B>Results – </B> After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90‐day case‐fatality was identical 6.2% (HR 0.997, 95%CI 0.905–1.099) in Sweden and Korea.</P><P><B>Conclusions – </B> No difference is found in the 90‐day case‐fatality in propensity score‐matched Swedish and Korean patients with ischemic stroke.</P>

Phosphorylation and isoform use in p120-catenin during development and tumorigenesis

Hong, J.Y.,Oh, I.H.,McCrea, P.D. Elsevier Biomedical Press 2016 Biochimica et biophysica acta, Molecular cell rese Vol.1863 No.1

P120-catenin is essential to vertebrate development, modulating cadherin and small-GTPase functions, and growing evidence points also to roles in the nucleus. A complexity in addressing p120-catenin's functions is its many isoforms, including optional splicing events, alternative points of translational initiation, and secondary modifications. In this review, we focus upon how choices in the initiation of protein translation, or the earlier splicing of the RNA transcript, relates to primary sequences that harbor established or putative regulatory phosphorylation sites. While certain p120 phosphorylation events arise via known kinases/phosphatases and have defined outcomes, in most cases the functional consequences are still to be established. In this review, we provide examples of p120-isoforms as they relate to phosphorylation events, and thereby to isoform dependent protein-protein associations and downstream functions. We also provide a view of upstream pathways that determine p120's phosphorylation state, and that have an impact upon development and disease. Because other members of the p120 subfamily undergo similar processing and phosphorylation, as well as related catenins of the plakophilin subfamily, what is learned regarding p120 will by extension have wide relevance in vertebrates.

Serine palmitoyltransferase inhibitor myriocin induces growth inhibition of B16F10 melanoma cells through G₂/M phase arrest

Lee, Y.‐,S.,Choi, K.‐,M.,Choi, M.‐,H.,Ji, S.‐,Y.,Lee, S.,Sin, D.‐,M.,Oh, K.‐,W.,Lee, Y.‐,M.,Hong, J.‐,T.,Yun, Y.‐,P.,Yoo, H.‐,S. Blackwell Publishing Ltd 2011 Cell proliferation Vol.44 No.4

<P><B>Abstract</B></P><P><B>Objectives: </B> Melanoma is the most aggressive form of skin cancer, and it resists chemotherapy. Candidate drugs for effective anti‐cancer treatment have been sought from natural resources. Here, we have investigated anti‐proliferative activity of myriocin, serine palmitoyltransferase inhibitor, in the <I>de novo</I> sphingolipid pathway, and its mechanism in B16F10 melanoma cells.</P><P><B>Material and methods: </B> We assessed cell population growth by measuring cell numbers, DNA synthesis, cell cycle progression, and expression of cell cycle regulatory proteins. Ceramide, sphingomyelin, sphingosine and sphingosine‐1‐phosphate levels were analysed by HPLC.</P><P><B>Results: </B> Myriocin inhibited proliferation of melanoma cells and induced cell cycle arrest in the G<SUB>2</SUB>/M phase. Expressions of cdc25C, cyclin B1 and cdc2 were decreased in the cells after exposure to myriocin, while expression of p53 and p21<SUP>waf1/cip1</SUP> was increased. Levels of ceramide, sphingomyelin, sphingosine and sphingosine‐1‐phosphate in myriocin‐treated cells after 24 h were reduced by approximately 86%, 57%, 75% and 38%, respectively, compared to levels in control cells.</P><P><B>Conclusions: </B> Our results suggest that inhibition of sphingolipid synthesis by myriocin in melanoma cells may inhibit expression of cdc25C or activate expression of p53 and p21<SUP>waf1/cip1</SUP>, followed by inhibition of cyclin B1 and cdc2, resulting in G<SUB>2</SUB>/M arrest of the cell cycle and cell population growth inhibition. Thus, modulation of sphingolipid metabolism by myriocin may be a potential target of mechanism‐based therapy for this type of skin cancer.</P>

p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN

Hong, S-W,Moon, J-H,Kim, J-S,Shin, J-S,Jung, K-A,Lee, W-K,Jeong, S-Y,Hwang, J J,Lee, S-J,Suh, Y-A,Kim, I,Nam, K-Y,Han, S,Kim, J E,Kim, K-p,Hong, Y S,Lee, J-L,Lee, W-J,Choi, E K,Lee, J S,Jin, D-H,Kim, Macmillan Publishers Limited 2014 CELL DEATH AND DIFFERENTIATION Vol.21 No.1

PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.

Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer

Kim, J C,Ha, Y J,Roh, S A,Choi, E Y,Yoon, Y S,Kim, K P,Hong, Y S,Kim, T W,Cho, D H,Kim, S Y,Kim, Y S Nature Publishing Group 2013 The British journal of cancer Vol.108 No.9

<P><B>Background:</B></P><P>Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.</P><P><B>Methods:</B></P><P>A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.</P><P><B>Results:</B></P><P>For cetuximab regimens, patients homozygous for the wild-type alleles (<I>GG</I>) of <I>LIFR rs3729740</I> exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (<I>GA</I> and <I>AA</I>; <I>P</I>=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (<I>TT</I>) of <I>ANXA11 rs1049550</I> exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (<I>CC</I> and <I>CT</I>; <I>P</I>=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type <I>LIFR rs3729740</I> patients either with wild-type <I>KRAS</I> or skin toxicity (<I>P</I>=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type <I>LIFR rs3729740</I> (<I>P</I>=0.044) and in those expressing minor-type <I>ANXA11 rs1049550</I> (<I>P</I>=0.007), respectively.</P><P><B>Conclusion:</B></P><P><I>LIFR rs3729740</I> and possibly <I>ANXA11 rs1049550</I> may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.</P>

Eccentric morphology of jailed side-branch ostium after stent crossover in coronary bifurcation lesions: A three-dimensional optical coherence tomographic analysis

Yang, P.S.,Ha, J.,Kim, J.S.,Park, S.,Bae, J.,Shin, D.H.,Kim, B.K.,Ko, Y.G.,Choi, D.,Jang, Y.,Hong, M.K. Japanese College of Cardiology 2015 Journal of cardiology Vol.65 No.4

Background: Angiographic stenosis of a jailed side-branch ostium is usually observed after a single-stent crossover at coronary bifurcation lesions. However, the stenosis severity is typically overestimated due to the limited information obtained from two-dimensional morphology by angiography. We evaluated the actual stenosis of jailed side-branch ostium using three-dimensional (3D) optical coherence tomography (OCT). Methods: Using 3D reconstructions of OCT data, we analyzed minimal lumen area (MLA) and eccentricity of the jailed side-branch ostium in 41 patients who were treated with single stent crossover at coronary bifurcation lesions and subsequently underwent serial OCT follow-up. Results: The MLA of jailed side-branch ostium calculated from quantitative coronary angiography (QCA) assuming a circular lumen markedly decreased after stent implantation (1.73+/-1.22mm<SUP>2</SUP> pre-intervention to 0.84+/-0.91mm<SUP>2</SUP> post-intervention, p<0.001). However, the MLA of jailed side-branch ostium measured at post-intervention by 3D-OCT (2.67+/-1.75mm<SUP>2</SUP>) was significantly larger than that measured by QCA (p<0.001). There were no statistically significant changes in MLA of jailed side-branch ostium based on 3D-OCT measurements during the follow-up (2.35+/-1.50mm<SUP>2</SUP> at 3-6 months post-intervention; 2.44+/-1.27mm<SUP>2</SUP> at 1-2 years post-intervention, p=0.098). The shapes of the jailed side-branch ostium were nearly elliptical (mean eccentricity index: 2.97+/-1.27 post-intervention; 2.79+/-1.17 at 3-6 months post-intervention; 2.59+/-1.02 at 1-2 years post-intervention). Conclusions: Compared to 3D-OCT measurements, QCA measurements overestimated the jailed side-branch ostial stenosis after single stent crossover due to eccentric morphology from orthogonal projection in coronary angiography. Significant changes in the MLA of jailed side-branch ostium by 3D-OCT were not observed during the follow-up.

Tin porphyrin immobilization significantly enhances visible-light-photosensitized degradation of Microcystins: Mechanistic implications

Yoo, H.Y.,Yan, S.,Ra, J.W.,Jeon, D.,Goh, B.,Kim, T.Y.,Mackeyev, Y.,Ahn, Y.Y.,Kim, H.J.,Wilson, L.J.,Alvarez, P.J.J.,Lee, Y.,Song, W.,Hong, S.W.,Kim, J.,Lee, J. Elsevier 2016 Applied catalysis. B, Environmental Vol.199 No.-

<P>This study demonstrates that tin porphyrin (SnP) loading on a silica substrate (SnP/silica) markedly accelerates the degradation of Microcystins (MCs) under visible light irradiation, despite a reduction of photosensitized singlet oxygen (O-1(2)) production. A comparative study using Rose Bengal, SnP, and C-60 aminofullerene suggested that the MC-RR decay rate was directly proportional to the photosensitizing activity for triplet state-induced oxidation, while it exhibited poor correlation to singlet oxygenation efficiency. This implies that electron transfer from MC to the triplet state of SnP (facilitated by favorable MC sorption on silica) contributes to the photosensitized MC oxidation. Experiments to examine sensitizers for the one-electron oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) showed the superiority of SnP/silica for photo-initiated electron transfer as a possible MC oxidation route. This was corroborated by the negligible effects of reagents that quench or facilitate singlet oxygenation (e.g., azide ion, D2O) on the MC-RR degradation rate. Despite MC-RR removal below detection levels, residual toxicity (indicated by a significant decrease in protein phosphatase inhibition activity) was observed. Tandem mass spectrometric analysis suggests that this residual toxicity may be ascribed to byproducts resulting from addition of a single oxygen atom to the Adda moiety. (C) 2016 Elsevier B.V. All rights reserved.</P>

고속용 동기 릴럭턴스 전동기 특성

洪定杓(J. P. Hong),周秀元(S. W. Joo),韓聲鎭(S. C. Hahn),具大鉉(D. H. Koo) 대한전기학회 2006 전기학회논문지 B Vol.55 No.4

This paper presents characteristics of SynRM(Synchronous Reluctance Motor) that is compared with a high speed induction motor. SynRM is much suitable for high speed electric machines because of structural robustness. There are many kinds of SynRM according to the shape of rotors. Particularly, axially laminated anisotropic (ALA) rotor is suitable for high speed instruments. Characteristics of SynRM with ALA rotor is obtained from a governing voltage and torque equation mainly composed of d-axis and q-axis inductance that will be identified with finite element method.

One-year clinical outcomes of everolimus- versus sirolimus-eluting stents in patients with acute myocardial infarction

other Korea Acute Myocardial Infarction Registry Investigators,Chen, K.Y.,Rha, S.W.,Wang, L.,Li, Y.J.,Li, G.P.,Choi, C.U.,Park, C.G.,Seo, H.S.,Oh, D.J.,Jeong, M.H.,Ahn, Y.K.,Hong, T.J.,Kim, Y.J.,Chae, Elsevier/North-Holland Biomedical Press 2014 INTERNATIONAL JOURNAL OF CARDIOLOGY Vol.176 No.3

Background: In contrast to many studies comparing everolimus-eluting stent (EES) with paclitaxel-eluting stent (PES), data directly comparing EES with sirolimus-eluting stent (SES) are limited, especially in patients with acute myocardial infarction (AMI). Methods: This study includes 2911 AMI patients treated with SES (n=1264) or EES (n=1701) in Korea Acute Myocardial Infarction Registry (KAMIR). Propensity score matching was applied to adjust for baseline imbalance in clinical and angiographic characteristics, yielding a total of 2400 well-matched patients (1200 receiving SES and 1200 receiving EES). One-year clinical outcomes were compared between the two propensity score matched groups. Results: Baseline clinical and angiographic characteristics were similar between the two propensity score matched groups. One-year clinical outcomes of the propensity score matched cohort were comparable between the EES versus the SES groups including the rates of cardiac death (4.8% vs. 4.8%, P=1.000), recurrent myocardial infarction (1.4% vs. 1.7%, P=0.619), target lesion revascularization (1.4% vs. 1.6%, P=0.737), target lesion failure (7.0% vs. 7.3%, P=0.752), and probable or definite stent thrombosis (0.5% vs. 0.9%, P=0.224) except for a trend toward lower incidence of target vessel revascularization (1.9% vs. 3.0%, P=0.087) and a lower rate of total major adverse cardiac events (9.3% vs. 11.9%, P=0.034) in the EES group. Conclusions: The present propensity score matched analysis performed in a large-scale, prospective, multicenter registry suggests that the second-generation drug-eluting stent EES has at least comparable or even better safety and efficacy profiles as compared with SES in the setting of AMI.