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>

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>

Identification of a novel <i>FAM83H</i> mutation and microhardness of an affected molar in autosomal dominant hypocalcified amelogenesis imperfecta

Hyun, H.-K.,Lee, S.-K.,Lee, K.-E.,Kang, H.-Y.,Kim, E.-J.,Choung, P.-H.,Kim, J.-W. Blackwell Publishing Ltd 2009 International endodontic journal Vol.42 No.11

<P>Abstract</P><P>Aim </P><P>To determine the underlying molecular genetic aetiology of a family with the hypocalcified form of amelogenesis imperfecta and to investigate the hardness of the enamel and dentine of a known <I>FAM83H</I> mutation.</P><P>Methodology </P><P>Mutational screening of the <I>FAM83H</I> on the basis of candidate gene approach was performed. All exons and exon–intron boundaries was amplified and sequenced. A microhardness test was performed to measure the Vickers microhardness value.</P><P>Results </P><P>A novel nonsense mutation (c.1354C>T, p.Q452X) was identified in the last exon of <I>FAM83H</I>, which resulted in soft, uncalcified enamel. The affected enamel was extremely soft (about 17% of the normal control), but the underlying dentine was as hard as the normal control.</P><P>Conclusions </P><P>Mutational analysis revealed a novel mutation in <I>FAM83H</I> gene. Hardness of dentine was not affected by the mutation, whilst the enamel was extremely soft.</P>

FAM83H mutations cause ADHCAI and alter intracellular protein localization.

Lee, S-K,Lee, K-E,Jeong, T-S,Hwang, Y-H,Kim, S,Hu, J C-C,Simmer, J P,Kim, J-W Journal of Dental Research, Inc 2011 Journal of dental research Vol.90 No.3

<P>Mutations in a family with sequence similarity 83 member H (FAM83H) cause autosomal-dominant hypocalcification amelogenesis imperfecta (ADH CAI). All FAM83H ADHCAI-causing mutations terminate translation or shift the reading frame within the specific exon 5 segment that encodes from Ser(287) to Glu(694). Mutations near Glu(694) cause a milder, more localized phenotype. We identified disease-causing FAM83H mutations in two families with ADHCAI: family 1 (g.3115C>T, c.1993 C>T, p.Q665X) and family 2 (g.3151C>T, c.2029 C>T, p.Q677X). We also tested the hypothesis that truncation mutations alter the intracellular localization of FAM83H. Wild-type FAM83H and p.E694X mutant FAM83H fused to green fluorescent protein (GFP) localized in the cytoplasm of HEK293T cells, but the mutant FAM83H proteins (p.R325X, p.W460X, and p.Q677X) fused to GFP localized mainly in the nucleus with slight expression in the cytoplasm. We conclude that nuclear targeting of the truncated FAM83H protein contributes to the severe, generalized enamel phenotype.</P>

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>

Selection for Duration of Fertility and Mule Duck White Plumage Colour in a Synthetic Strain of Ducks (Anas platyrhynchos)

H.C. Liu,J.F. Huang,S.R. Lee,H.L. Liu,C.H. Hsieh,C.W. Huang,M.C. Huang,C. Tai,J.P. Poivey,R. Rouvier,Y.S. Cheng 아세아·태평양축산학회 2015 Animal Bioscience Vol.28 No.5

A synthetic strain of ducks (Anas platyrhynchos) was developed by introducing genes for long duration of fertility to be used as mother of mule ducklings and a seven-generation selection experiment was conducted to increase the number of fertile eggs after a single artificial insemination (AI) with pooled Muscovy semen. Reciprocal crossbreeding between Brown Tsaiya LRI-2 (with long duration of fertility) and Pekin L-201 (with white plumage mule ducklings) ducks produced the G0. Then G1 were intercrossed to produce G2 and so on for the following generations. Each female duck was inseminated 3 times, at 26, 29, and 32 weeks of age. The eggs were collected for 14 days from day 2 after AI. Individual data regarding the number of incubated eggs (Ie), the number of fertile eggs at candling at day 7 of incubation (F), the total number of dead embryos (M), the maximum duration of fertility (Dm) and the number of hatched mule ducklings (H) with plumage colour were recorded. The selection criterion was the breeding values of the best linear unbiased prediction animal model for F. The results show high percentage of exhibited heterosis in G2 for traits to improve (19.1% for F and 12.9% for H); F with a value of 5.92 (vs 3.74 in the Pekin L-201) was improved in the G2. Heritabilities were found to be low for Ie (h2 = 0.07±0.03) and M (h2 = 0.07±0.01), moderately low for Dm (h2 = 0.13±0.02), of medium values for H (h2 = 0.20±0.03) and F (h2 = 0.23±0.03). High and favourable genetic correlations existed between F and Dm (rg = 0.93), between F and H (rg = 0.97) and between Dm and H (rg = 0.90). The selection experiment showed a positive trend for phenotypic values of F (6.38 fertile eggs in G10 of synthetic strain vs 5.59 eggs in G4, and 3.74 eggs in Pekin L-201), with correlated response for increasing H (5.73 ducklings in G10 vs 4.86 in G4, and 3.09 ducklings in Pekin L-201) and maximum duration of the fertile period without increasing the embryo mortality rate. The average predicted genetic response for F was 40% of genetic standard deviation per generation of selection. The mule ducklings’ feather colour also was improved. It was concluded that this study provided results for a better understanding of the genetics of the duration of fertility traits in the common female duck bred for mule and that the selection of a synthetic strain was effective method of improvement.

Report of the CCQM-K97: measurement of arsenobetaine standard solution and arsenobetaine content in fish tissue (tunafish)

Ma, L D,Wang, J,WEI, C,Kuroiwa, T,Narukawa, T,Ito, N,HIOKI, A,CHIBA, K,Yim, Y H,Lee, K S,Lim, Y R,Turk, G C,Davis, C W,Mester, Z,Yang, L,McCooeye, M,Maxwell, P,Cankur, O,Tokman, N,Coskun, F G BUREAU INTERNATIONAL DES POIDS ET MESURES 2017 METROLOGIA -BERLIN- Vol.54 No.-

<P></P> <P>The CCQM-K97 key comparison was organized by the inorganic analysis working group (IAWG) of CCQM as a follow-up to completed pilot study CCQM-P96 and P96.1 to test the abilities of the national metrology institutes to accurately quantitate the mass fraction of arsenobetaine (AsB) in standard solution and in fish tissue. A pilot study CCQM-P133 was parallelized with this key comparison. National Institute of Metrology (NIM), China and National Metrology Institute of Japan (NMIJ) acted as the coordinating laboratories.</P> <P>Six NMIs participated in CCQM-K97 and two institutes participated in CCQM-P133, and all of them submitted the results. Some NMIs submitted more than one results by different methods. The results were in excellent agreement with each other, and obviously better than those of previous P96 and P96.1. Therefore the calibrant which each NMI used was comparable. It shows that the capabilities of some of the participants have been improved after the previous pilot studies.</P> <H2>Main text</H2> <P> To reach the main text of this paper, click on <A HREF='http://www.bipm.org/utils/common/pdf/final_reports/QM/K97/CCQM-K97.pdf'>Final Report</A>. Note that this text is that which appears in Appendix B of the BIPM key comparison database <A HREF='http://kcdb.bipm.org/'>kcdb.bipm.org/</A>.</P> <P>The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).</P>

<i>In vitro</i> inhibitory effects of Wen‐pi‐tang‐Hab‐Wu‐ling‐san on human cytochrome P450 isoforms

Lee, H. W.,Kim, D. W.,Phapale, P. B.,Lim, M. ‐,S.,Park, J.,Seo, J. J.,Park, K. M.,Park, Y. ‐,K.,Yoon, Y. ‐,R. Blackwell Publishing Ltd 2011 Journal of clinical pharmacy and therapeutics Vol.36 No.4

<P><B>Summary</B></P><P><B>What is known and Objective: </B> Although Wen‐pi‐tang‐Hab‐Wu‐ling‐san (WHW), an oriental herbal medicine, has been prescribed for the treatment of chronic renal failure (CRF) in Korean clinics, no studies regarding WHW–drug interactions had been reported. The purpose of this study was to evaluate the possibility that WHW inhibits the catalytic activities of major cytochrome P450 (CYP) isoforms.</P><P><B>Methods: </B> The abilities of various WHW extracts to inhibit phenacetin O‐de‐ethylation (CYP1A2), tolbutamide 4‐methylhydroxylation (CYP2C9), omeprazole 4′‐hydroxylation (CYP2C19), dextromethorphan O‐demethylation (CYP2D6), chlorzoxazone 6‐hydroxylation (CYP2E1) and midazolam 1‐hydroxylation (CYP3A4) were assessed using human liver microsomes.</P><P><B>Results and Discussion: </B> WHW extract at concentrations up to 100 μ<SMALL>m</SMALL> showed negligible inhibition of the six CYP isoforms tested (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4), with apparent IC<SUB>50</SUB> values (concentration of the inhibitor causing 50% inhibition of the original enzyme activity) of 817.5, 601.6, 521.7, 310.2, 342.8 and 487.0 μg/mL, respectively.</P><P><B>What is new and Conclusion: </B> Our <I>in vitro</I> findings suggest that WHW extract at concentrations corresponding to a clinically recommended dosage range has no notable inhibitory effects on CYP isoforms. Therefore, we believe that WHW extract may be free of drug–herb interactions when co‐administered with other medicines. However, <I>in vivo</I> human studies are needed to confirm these results.</P>

Amphiphilic triblock copolymer poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol), enhancement of gene expression and inhibition of lung metastasis by aerosol delivery

Bhattarai, S R,Kim, S Y,Jang, K Y,Yi, H K,Lee, Y H,Bhattarai, N,Nam, S-Y,Lee, D Y,Kim, H Y,Hwang, P H Nature Publishing Group 2007 Gene Therapy Vol.14 No.6

<P>We describe the development of an aerosol system for topical gene delivery to the lungs of C57BL/6 mice. This system is based on the combination of the commercial cationic lipid Lipofectin with a novel amphiphilic triblock copolymer, poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol) (PPDO/PLLA-b-PEG, and abbreviated in the text as polymeric micelles). After optimizing conditions for DNA delivery to the lungs of mice using the combination of polymeric micelles with Lipofectin and LacZ DNA, we used the Lipofectin/polymeric micelle system to deliver the tumor suppressor gene PTEN to the lungs of C57BL/6 mice bearing the B16-F10 melanoma. Lipofectin/PTEN/polymeric micelles significantly improved gene expression of PTEN in the lungs of mice with no evidence of cell toxicity or acute inflammation. Importantly, lung metastasis, as measured by lung weight, was significantly reduced (P<0.001), as were total tumor foci in the lungs (P<0.001) and size of individual tumor nodules in animals treated with Lipofectin/PTEN/polymeric micelles compared with control animals. Survival time was also extended. These results suggest that the Lipofectin/polymeric micelle system is appropriate for enhancing gene delivery in vivo and that it can be applied as a non-invasive gene therapy for lung cancer.</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>