S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis

Kim, S Y,S Hong, Y,K Shim, E,Kong, S-Y,Shin, A,Baek, J Y,Jung, K H Nature Publishing Group 2013 The British journal of cancer Vol.109 No.6

<P><B>Background:</B></P><P>S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin.</P><P><B>Methods:</B></P><P>Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m<SUP>−2</SUP> followed by oxaliplatin 85 mg m<SUP>−2</SUP> on day 1 and S-1 80 mg m<SUP>−2</SUP> per day from day 1 to 14 every 3 weeks. Polymorphisms in the <I>UGT1A1</I>, <I>UGT1A6</I>, <I>UGT1A7</I> and <I>CYP2A6</I> genes were analysed.</P><P><B>Results:</B></P><P>Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4–81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of <I>UGT1A6*2</I> or <I>UGT1A7*3</I> and an improved tumour response was noted in those without variant alleles of <I>CYP2A6</I> or <I>UGT1A1*60</I>.</P><P><B>Conclusion:</B></P><P>The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.</P>

Metabolic engineering and adaptive evolution for efficient production of D-lactic acid in Saccharomyces cerevisiae

Baek, S. H.,Kwon, E. Y.,Kim, Y. H.,Hahn, J. S. Springer Science + Business Media 2016 Applied microbiology and biotechnology Vol.100 No.6

<P>There is an increasing demand for microbial production of lactic acid (LA) as a monomer of biodegradable poly lactic acid (PLA). Both optical isomers, D-LA and L-LA, are required to produce stereocomplex PLA with improved properties. In this study, we developed Saccharomyces cerevisiae strains for efficient production of D-LA. D-LA production was achieved by expressing highly stereospecific D-lactate dehydrogenase gene (ldhA, LEUM_1756) from Leuconostoc mesenteroides subsp. mesenteroides ATCC 8293 in S. cerevisiae lacking natural LA production activity. D-LA consumption after glucose depletion was inhibited by deleting DLD1 encoding D-lactate dehydrogenase and JEN1 encoding monocarboxylate transporter. In addition, ethanol production was reduced by deleting PDC1 and ADH1 genes encoding major pyruvate decarboxylase and alcohol dehydrogenase, respectively, and glycerol production was eliminated by deleting GPD1 and GPD2 genes encoding glycerol-3-phosphate dehydrogenase. LA tolerance of the engineered D-LA-producing strain was enhanced by adaptive evolution and overexpression of HAA1 encoding a transcriptional activator involved in weak acid stress response, resulting in effective D-LA production up to 48.9 g/L without neutralization. In a flask fed-batch fermentation under neutralizing condition, our evolved strain produced 112.0 g/L D-LA with a yield of 0.80 g/g glucose and a productivity of 2.2 g/(L center dot h).</P>

Efficient proteolytic cleavage by insertion of oligopeptide linkers and its application to production of recombinant human interleukin-6 in Escherichia coli

Lee, E.G.,Baek, J.E.,Lee, S.H.,Kim, T.W.,Choi, J.H.,Rho, M.C.,Ahn, J.O.,Lee, H.W.,Jung, J.K. IPC Science and Technology Press ; Elsevier Scienc 2009 Enzyme and microbial technology Vol.44 No.5

Efficient expression and purification of bioactive recombinant human interleukin-6 (hIL6) was successfully achieved in Escherichia coli (E. coli) by fusion of the maltose-binding protein (MBP) with hIL6 and the insertion of oligopeptide linkers. MBP/hIL6 was over-expressed in the soluble form at a concentration of approximately 2.5g/L. For hIL6 recovery, enterokinase, factor Xa, and thrombin were employed to cleavage MBP from the fusion constructs. However, undesired and non-specific cleavage fragments as well as rhIL6 were obtained following the cleavage. The introduction of oligopeptide linkers at the C-terminal end of the fusion construct could improve the efficiency and the rate of the enzymatic cleavage reaction, and the rhIL6 purification was achieved by using MBP affinity chromatography, factor Xa cleavage, and reverse-phase chromatography, resulting in an overall yield as high as 33% (equivalent to 0.27ghIL6/L) at purity over 98%. The biological activity of the purified recombinant hIL6 was demonstrated by confirming the presence of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This study suggests that the optimized peptide linker specifically designed for both fusion partner and target molecule has a great potential for efficient recombinant protein production.

보존형 형태의 S-A 난류 모델 방정식을 이용한 이차원 유동 해석

곽인근(E. Kwak),백지영(J.Y. Baek),이승수(S. Lee) 한국전산유체공학회 2012 한국전산유체공학회 학술대회논문집 Vol.2012 No.5

Numerical simulations of two dimensional flows are performed with a conservative form of S-A turbulence model and the simulation results are compared to those of the standard form and the compressible form. The conservative form is derived, from the standard form, which is in non-conservative form, using the continuity equation. The model constant of the conservative form is corrected to compensate for the differences between the conservative and the non-conservative discretizations. For verification of the conservative form of the equation, flows over a flat plate at various flow conditions are computed and the results are compared to those of the other forms as well as other computational results and theories. For subsonic flows, little difference is observed between the results of three forms. For supersonic and hypersonic flows, however, skin frictions of the compressible form and the conservative form are slightly larger than that of the standard form. Furthermore, numerical simulations of a transonic flow around an airfoil are performed with three forms and usefulness of the conservative form is confirmed by obtaining reasonable results.

Construction of Protein Chip to Detect Binding of Mitf Protein (Microphthalmia Transcription Factor) and E-box DNA

Yang, S. H.,Han, J. S.,Baek, S. H.,Kwak, E. Y.,Kim, H. J.,Shin, J. H.,Chung, B. H.,Kim, E. K. HUMANA PRESS INC 2008 Applied biochemistry and biotechnology Vol.151 No.2

Baicalin-induced Akt activation decreases melanogenesis through downregulation of microphthalmia-associated transcription factor and tyrosinase

Jeong, H.S.,Gu, G.E.,Jo, A.R.,Bang, J.S.,Yun, H.Y.,Baek, K.J.,Kwon, N.S.,Park, K.C.,Kim, D.S. North-Holland ; Elsevier Science Ltd 2015 european journal of pharmacology Vol.761 No.-

Scutellaria baicalensis has been used topically to treat inflammatory skin diseases in traditional East Asian medicine. Because post-inflammatory hyperpigmentation of the skin is difficult to manage, we investigated the effects of baicalin, a major component of S. baicalensis, on melanin synthesis in Mel-Ab cells. Our data showed that baicalin significantly inhibited melanin production and tyrosinase activity in a dose-dependent fashion, but it did not directly influence tyrosinase activity. Moreover, baicalin treatment triggered decreases in both mRNA and protein levels of microphthalmia-associated transcription factor (MITF) and tyrosinase. Although AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK) activation were induced in baicalin-treated Mel-Ab cells, they were not responsible for baicalin-induced hypopigmentation. Because the Akt pathway is also known to be involved in regulation of melanogenic protein expression and melanin synthesis, we examined the effects of baicalin on the Akt pathway. Our results showed that baicalin treatment stimulated Akt activation. Treatment with LY294002, a specific Akt inhibitor, restored baicalin-induced melanogenesis inhibition and abolished MITF and tyrosinase downregulation by baicalin. Taken together, our data suggest that Akt activation by baicalin inhibits melanin production via downregulation of MITF and tyrosinase in Mel-Ab cells.

Joint Asymptotic Distributions of Sample Autocorrelations for Time Series of Martingale Differences

황선영,J. S. Baek,K. E. Lim 한국통계학회 2006 Journal of the Korean Statistical Society Vol.35 No.4

It is well known fact for theiid data that the limiting standard errors ofsample autocorrelations are all unity for all time lags and they are asymptot-ically independent for dierent lags (Brockwell and Davis, 1991). It is alsousual practice in time series modeling that this fact continues to be valid forwhite noise series which is a sequence of uncorrelated random variables. Thispaper contradicts this usual practice for white noise. We consider a sequenceof martingale dierences which belongs to white noise time series and deriveexactjoint asymptotic distributions of sample autocorrelations. Some im-plications of the result are illustrated for conditionally heteroscedastic timeseries.AMS 2000 subject classications.Primary 62M10; Secondary 62E20.Keywords. Limiting standard errors, sample autocorrelations, exact joint asymp-totic distribution, conditionally heteroscedastic time series.1. IntroductionThe sample autocorrelation function (ACF) for a given time series plays acrucial role in identifying an appropriate model for the data. To evaluate theadequacy of the model, the \residual" is recommended to be carefully examined.Here the term residual is dened as the dierence of observations and the ttedvalues obtained after tting an appropriate model. As discussed by Box andPierce (1970), the ACF based on residuals can be used as a useful diagnostic tool.See also Hwanget al.(1994). For the case ofiid data, it is a well known fact thatReceived June 2006; accepted November 2006.yThis work was supported by the SRC program of KOSEF (R11-2000-073-0000).1Corresponding author. Department of Statistics, Sookmyung Women's University, Seoul140-742, Korea (e-mail: shwang@sookmyung.ac.kr)

Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect.

Kang, H E,Cho, Y K,Jung, H Y,Choi, K Y,Sohn, S I,Baek, S R,Lee, M G Taylor Francis 2009 Xenobiotica Vol.39 No.6

<P>Pharmacokinetics of liquiritigenin, a candidate for inflammatory liver disease, and its two glucuronide conjugates, M1 and M2, were evaluated in rats. The hepatic and gastrointestinal first-pass effects of liquiritigenin were also evaluated in rats. After oral administration of liquiritigenin at a dose of 20 mg kg(-1), 1.07% of the dose was not absorbed from the gastrointestinal tract up to 24 h, and the F-value was only 6.68%. In vitro metabolism of liquiritigenin in S9 fractions of rat tissues showed that the liver and intestine were major tissues responsible for glucuronidation of liquiritigenin. The hepatic and gastrointestinal first-pass effects of liquiritigenin were approximately 3.67% and 92.5% of the oral dose, respectively. Although the hepatic first-pass effect of liquiritigenin after absorption into the portal vein was 57.1%, the value was only 3.67% of the oral dose due to extensive gastrointestinal first-pass effect in rats. Therefore, the low F-value of liquiritigenin in rats was primarily attributable to an extensive gastrointestinal first-pass effect although liquiritigenin was well absorbed. Compared with rats, the higher F-value of liquiritigenin could be expected in humans.</P>

EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex

Lee, J.,Lee, Jason S.,Kim, H.,Kim, K.,Park, H.,Kim, J.Y.,Lee, S.,Kim, I.,Kim, J.,Lee, M.,Chung, C.,Seo, S.B.,Yoon, J.B.,Ko, E.,Noh, D.Y.,Kim, K.,Kim, K.,Baek, S. Cell Press 2012 Molecular cell Vol.48 No.4

Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing ''methyl degron''; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.

Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells

Jeon, T-Y,Han, M-E,Lee, Y-W,Lee, Y-S,Kim, G-H,Song, G-A,Hur, G-Y,Kim, J-Y,Kim, H-J,Yoon, S,Baek, S-Y,Kim, B-S,Kim, J-B,Oh, S-O Nature Publishing Group 2010 The British journal of cancer Vol.102 No.4

<P><B>Background:</B></P><P>Stathmin1 is a microtubule-regulating protein that has an important role in the assembly and disassembly of the mitotic spindle. The roles of stathmin1 in carcinogenesis of various cancers, including prostate and breast cancer, have been explored. However, its expression and roles in gastric cancer have not yet been described.</P><P><B>Methods:</B></P><P>Stathmin1 expression in paraffin-embedded tissue sections from 226 patients was analysed by immunohistochemistry. Roles of stathmin1 were studied using a specific small interfering RNA (siRNA).</P><P><B>Results:</B></P><P>The expression of stathmin1 was positively correlated with lymph node metastasis, TNM stages and vascular invasion, and negatively with recurrence-free survival, in the diffuse type of gastric cancer. The median recurrence-free survival in patients with a negative and positive expression of stathmin1 was 17.0 and 7.0 months, respectively (<I>P</I>=0.009). When the expression of stathmin1 was knocked down using siRNA, the proliferation, migration and invasion of poorly differentiated gastric cancer cells <I>in vitro</I> were significantly inhibited. Moreover, s<I>tathmin1</I> siRNA transfection significantly slowed the growth of xenografts in nude mice.</P><P><B>Conclusion:</B></P><P>These results suggest that stathmin1 can be a good prognostic factor for recurrence-free survival rate and is a therapeutic target in diffuse-type gastric cancer.</P>