A dose-finding study for oxaliplatin, irinotecan, and S-1 (OIS) in patients with metastatic or recurrent gastrointestinal cancer

Han, B.,Jung, J. Y.,Kim, H. S.,Cho, J. W.,Kim, K. C.,Lim, H.,Kang, H. S.,Ha, H. I.,Kim, M. J.,Kim, J. H. Springer Science + Business Media 2016 Cancer chemotherapy and pharmacology Vol.78 No.5

<P>To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined oxaliplatin, irinotecan, and S-1 chemotherapy for metastatic or recurrent gastrointestinal (GI) cancer. Oxaliplatin and irinotecan were administered intravenously on day 1, and S-1 was administered orally on days 1-7, every 2 weeks. This phase I study used the following dose levels for oxaliplatin/irinotecan/S-1: level 1, 85/120/60 mg/m(2); level 2, 85/120/80 mg/m(2); level 3, 85/120/100 mg/m(2); level 4, 85/150/100 mg/m(2); and level 5, 85/180/100 mg/m(2). Treatment was repeated for a maximum of 12 cycles, until disease progression, or until unacceptable toxicity. Twenty-four patients were enrolled between October 2012 and February 2014 (median age 59 years). During the first cycle, one of the six patients in levels 1, 3, and 4 developed a dose-limiting toxicity (grade 3 febrile neutropenia), and none of the three patients in level 5 developed a dose-limiting toxicity. As the planned maximum dose did not reach the MTD, the level 5 dose was defined as the RD. Twenty-one patients were evaluated for response, which included 2 cases of complete response and 8 cases of partial response, with an overall response rate of 47.6 %. The combination of oxaliplatin, irinotecan, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced GI cancer. The RD was 85 mg/m(2) of oxaliplatin, 180 mg/m(2) of irinotecan, and 100 mg/m(2) of S-1 every 2 weeks.</P>

Sphingosine-1-phosphate-induced Flk-1 transactivation stimulates mouse embryonic stem cell proliferation through S1P₁/S1P₃-dependent β-arrestin/c-Src pathways

Ryu, J.M.,Baek, Y.B.,Shin, M.S.,Park, J.H.,Park, S.H.,Lee, J.H.,Han, H.J. Elsevier 2014 Stem cell research Vol.12 No.1

Although recent findings showed that the bioactive lipid metabolites can regulate the ES cell functions, the physiological relevance of interaction between sphingosine-1-phosphate (S1P) and Flk-1 and its related signaling molecules are not yet clear in ES cell proliferation. In the present study, S1P<SUB>1-5</SUB> receptors were expressed in mouse ES cells and S1P increased S1P<SUB>1-3</SUB> receptor expression level. S1P treatment stimulated the cellular proliferation in S1P<SUB>1/3</SUB>-dependent manner, located in lipid rafts. In response to S1P, β-arrestin was recruited to S1P<SUB>1/3</SUB> receptor and c-Src was activated. S1P also increased the binding of S1P<SUB>1/3</SUB> receptor with Flk-1. Similar to responses for VEGF, S1P increased Flk-1 phosphorylation, which was blocked by β-arrestin siRNA, and PP2, but not by VEGF-A<SUB>164</SUB> antibody or VEGF siRNA. In addition, S1P induced VEGF expression and VEGFR2 kinase inhibitor (SU1498) blocked the S1P-induced cellular proliferation. However, VEGF-A<SUB>164</SUB> antibody or VEGF siRNA partially blocked S1P-induced cellular proliferation, suggesting that both VEGF-dependent Flk-1 activation and VEGF-independent Flk-1 activation are involved in S1P-induced ES cell proliferation. S1P and VEGF-induced phosphorylation of ERK and JNK were blocked by pretreatment with SU1498. Moreover, inhibition of ERK and JNK blocked S1P-induced cellular proliferation. In conclusion, S1P-elicited transactivation of Flk-1 mediated by S1P<SUB>1/3</SUB>-dependent β-arrestin/c-Src pathways stimulated mouse ES cell proliferation.

放射菌을 利用한 異種間 原形質體 融合과 그 融合體의 安定性에 관한 硏究(Ⅱ)

閔洪基,金昌珉,孫麗源,韓惠勝,崔英珠,丁大映,韓康玄,李相燮,李欽淑,元奉必 국립보건연구원 1992 국립보건원보 Vol.29 No.2

General trends of atmospheric mercury concentrations in urban and rural areas in Korea and characteristics of high-concentration events

Han, Y.J.,Kim, J.E.,Kim, P.R.,Kim, W.J.,Yi, S.M.,Seo, Y.S.,Kim, S.H. Pergamon Press ; Elsevier [distribution] 2014 Atmospheric environment Vol.94 No.-

Long-term measurement of speciated Hg concentrations is the first step toward identifying the seasonal and spatial characteristics of Hg concentrations; however, atmospheric Hg research is scarce in Korea. In this study, total gaseous mercury (TGM), gaseous oxidized mercury (GOM) and particle-bound mercury (PBM) were measured in urban (Seoul) and rural (Chuncheon) areas over a more than 3 year period in order to improve the understanding of speciated Hg transport. The mean concentrations of TGM, GOM and PBM were 3.72 +/- 2.96 (0.19-149.84) ng m<SUP>-3</SUP>, 11.3 +/- 9.5 (0.9-57.3) pg m<SUP>-3</SUP>, and 13.4 +/- 12.0 (2.1-64.3) pg m<SUP>-3</SUP> at the Seoul site and 2.12 +/- 1.47 (0.26-10.75) ng m<SUP>-3</SUP>, 2.7 +/- 2.7 (0.1-16.9) pg m<SUP>-3</SUP>, and 3.7 +/- 5.7 (0.1-30.0) pg m<SUP>-3</SUP> in Chuncheon. Both long-range transport and local sources caused high TGM concentration events, while local coal combustion was a main cause of enhancing the GOM and PBM concentrations in Seoul. However, there was no correlation between the pollutants emitted from coal combustion and the speciated Hg concentration in Chuncheon, indicating that other mechanisms were involved in the Hg increase. We found a positive correlation between the GOM and the O<SUB>3</SUB> concentrations and a negative correlation between the GEM and the GOM concentrations, especially on foggy days, suggesting that the oxidation of GEM was an important source for GOM in Chuncheon. In addition, the ratio of PBM/GOM was inversely proportional to the atmospheric temperature and directly proportional to the relative humidity, which suggests that the in-situ formation of PBM through gas-particle partitioning of GOM was important in rural areas.

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.

S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Yi, S.,Um, S.,Lee, J.,Yoo, J.,Bang, S.,Park, E.,Lee, M.,Nam, K.,Jeon, Y.,Park, J.,You, J.,Lee, S.J.,Bae, G.U.,Rhie, J.,Kozma, Sara C.,Thomas, G.,Han, J.W. Cell Press 2016 Molecular Cell Vol.62 No.3

S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer

Han, S-W,Oh, D-Y,Im, S-A,Park, S R,Lee, K-W,Song, H S,Lee, N-S,Lee, K H,Choi, I S,Lee, M H,Kim, M A,Kim, W H,Bang, Y-J,Kim, T-Y Nature Publishing Group 2009 The British journal of cancer Vol.100 No.2

<P>This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m<SUP>−2</SUP> at week 1 and 250 mg m<SUP>−2</SUP> weekly thereafter until disease progression. Oxaliplatin (100 mg m<SUP>−2</SUP>) and leucovorin (100 mg m<SUP>−2</SUP>) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m<SUP>−2</SUP>) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1–65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5–6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-<I>α</I> levels showed a 100% RR compared to 37.0% in the remaining 27 patients (<I>P</I><0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.</P>

Prevalence and different characteristics of two serotypes of <i>Streptococcus parauberis</i> isolated from the farmed olive flounder, <i>Paralichthys olivaceus</i> (Temminck and Schlegel), in Korea

Han, S Y,Kang, B K,Kang, B J,Shin, S P,Soen, B H,Kim, J M,Kim, J H,Choresca Jr, C H,Han, J E,Jun, J W,Park, S C Blackwell Publishing Ltd 2011 Journal of fish diseases Vol.34 No.10

<P><B>Abstract</B></P><P>The prevalence of two serotypes of <I>Streptococcus parauberis</I> isolated from the olive flounder, <I>Paralichthys olivaceus</I>, was evaluated in a total of 29 isolates between 2003 and 2010 in Korea. <I>Streptococcus parauberis</I> isolates were divided into two serologically distinct types (serotype 1 and serotype 2), except for one strain (S1091), using an agglutination assay with rabbit antiserum, and serotype 1 was identified as the dominant type (24 of 29 isolates) in this study. To identify the characteristics of the two serotypes of <I>S.?parauberis</I>, we conducted a biochemical test using the API 20 Strep kit, a transmission electron microscopy (TEM) assay, sequence analysis of 16S‐23S rRNA intergenic spacer region (ISR) and a pathogenicity test. In TEM, both serotypes possessed polysaccharide capsule layers around the cell surface when bacterial cells were treated with a homologous serotype of rabbit antiserum. However, we were unable to discriminate serotype‐specific biochemical characteristics and genetic characteristics of 16S‐23S rRNA ISR between the two serotypes. In the pathogenicity test, the serotype 1 strains induced significantly higher mortality than the serotype 2 strains in olive flounder when experimentally inoculated via the intraperitoneal route.</P>

OGLE-2015-BLG-0196: GROUND-BASED GRAVITATIONAL MICROLENS PARALLAX CONFIRMED BY SPACE-BASED OBSERVATION

Han, C.,Udalski, A.,Gould, A.,Zhu, Wei,Szymań,ski, M. K.,Soszyń,ski, I.,Skowron, J.,Mró,z, P.,Poleski, R.,Pietrukowicz, P.,Kozłowski, S.,Ulaczyk, K.,Pawlak, M.,Yee, J. C.,Beichman, C. American Astronomical Society 2017 The Astrophysical journal Vol.834 No.1

<P>In this paper, we present an analysis of the binary gravitational microlensing event OGLE-2015-BLG-0196. The event lasted for almost a year, and the light curve exhibited significant deviations from the lensing model based on the rectilinear lens-source relative motion, enabling us to measure the microlens parallax. The ground-based microlens parallax is confirmed by the data obtained from space-based microlens observations using the Spitzer telescope. By additionally measuring the angular Einstein radius from the analysis of the resolved caustic crossing, the physical parameters of the lens are determined up to the twofold degeneracy, u(0) < 0 and u(0) > 0, solutions caused by the well-known 'ecliptic' degeneracy. It is found that the binary lens is composed of two M dwarf stars with similar masses, M-1 = 0.38 +/- 0.04M(circle plus) (0.50 +/- 0.05M(circle plus)) and M-2 = 0.38 +/- 0.04M(circle plus) (0.55 +/- 0.06M(circle plus)), and the distance to the lens is D-L = 2.77. +/- 0.23 kpc (3.30 +/- 0.29 kpc). Here the physical parameters outside and inside the parentheses are for the u(0) < 0 and u(0) > 0 solutions, respectively.</P>

Sulfur to oxygen substitution in BiOCuSe and its effect on the thermoelectric properties

Han, M. K.,Jin, Y. S.,Yu, B.,Choi, W.,You, T. S.,Kim, S. J. Royal Society of Chemistry 2016 Journal of Materials Chemistry A Vol.4 No.36

<P>The effects of S doping at the oxygen site on the thermoelectric properties of BiOCuSe have been investigated. The partial substitution of S ions at the O sites of BiOCuSe was achieved by sulfurization using CS2 gas. Analysis of the powder X-ray diffraction data indicates that the ZrCuSiAs structure of BiOCuSe is retained after sulfurization. Substitution of O with S leads to an increase in the lattice parameters and a decrease in the band gap. The electrical conductivity rises due to the increase of the electronic contribution with doping. S-doped BiOCuSe materials behave as a p-type semiconductor. The thermoelectric properties of S-doped BiOCuSe materials can be understood through the analysis of the electronic band structure and the density of states close to the Fermi level. The substitution of O sites with S provides possible directions toward the enhancement of the thermoelectric figure of merit of oxide materials with low electrical conductivity.</P>