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>

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>

Molecular identification and functional delineation of a glutathione reductase homolog from disk abalone (<i>Haliotis discus discus</i>): Insights as a potent player in host antioxidant defense

Herath, H.M.L.P.B.,Wickramasinghe, P.D.S.U.,Bathige, S.D.N.K.,Jayasooriya, R.G.P.T.,Kim, Gi-Young,Park, Myoung Ae,Kim, Chul,Lee, Jehee Elsevier 2017 FISH AND SHELLFISH IMMUNOLOGY Vol.60 No.-

<P><B>Abstract</B></P> <P>Glutathione reductase (GSR) is an enzyme that catalyzes the biochemical conversion of oxidized glutathione (GSSG) into the reduced form (GSH). Since the ratio between the two forms of glutathione (GSH/GSSG) is important for the optimal function of GSH to act as an antioxidant against H<SUB>2</SUB>O<SUB>2</SUB>, the contribution of GSR as an enzymatic regulatory agent to maintain the proper ratio is essential. Abalones are marine mollusks that frequently encounter environmental factors that can trigger the overproduction of reactive oxygen species (ROS) such as H<SUB>2</SUB>O<SUB>2</SUB>. Therefore, we conducted the current study to reveal the molecular and functional properties of a GSR homolog in the disk abalone, <I>Haliotis discus discus</I>. The identified cDNA sequence (2325 bp) has a 1356 bp long open reading frame (ORF), coding for a 909 bp long amino acid sequence, which harbors a pyridine nucleotide-disulfide oxidoreductase domain (171–246 aa), a pyridine nucleotide-disulfide oxidoreductase dimerization domain, and a NAD(P)(+)-binding Rossmann fold superfamily signature domain. Four functional residues: the FAD binding site, glutathione binding site, NADPH binding motif, and assembly domain were identified to be conserved among the other species. The recombinant abalone GSR (rAbGSR) exhibited detectable activity in a standard glutathione reductase activity assay. The optimum pH and optimal temperature for the reaction were found to be 7.0 and 50 °C, respectively, while the ionic strength of the medium had no effect. The enzymatic reaction was vastly inhibited by Cu<SUP>+2</SUP> and Cd<SUP>+2</SUP> ions. A considerable effect of cellular protection was detected with a disk diffusion assay conducted with rAbGSR. Moreover, an MTT assay and flow cytometry confirmed the significance of the protective role of rAbGSR in cell function. Furthermore, <I>AbGSR</I> was found to be ubiquitously distributed in different types of abalone tissues. <I>AbGSR</I> mRNA expression was significantly upregulated in response to three immune challenges: <I>Vibrio parahaemolyticus</I>, <I>Listeria monocytogenes</I>, and lipopolysaccharide (LPS), thus indicating its possible involvement in host defense mechanisms during pathogenic infections. Taken together, the results of the current study suggest that AbGSR plays an important role in antioxidant-mediated host defense mechanisms and also provide insights into the immunological contribution of AbGSR.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We identified a glutathione reductase homolog (AbGSR) from disk abalone. </LI> <LI> AbGSR resembled functionally important domain architecture of GSR family. </LI> <LI> Recombinant AbGSR confirmed its biochemical properties via enzymatic assays. </LI> <LI> First functional antioxidant properties assessment of a molluscan GSR. </LI> <LI> <I>AbGSR</I> expression was modulated upon induced pathogen stress in gill and hemocytes. </LI> </UL> </P>

Search for Λc+→ϕpπ0 and branching fraction measurement of Λc+→K−π+pπ0

Pal, B.,Schwartz, A. J.,Adachi, I.,Aihara, H.,Al Said, S.,Asner, D. M.,Aushev, T.,Ayad, R.,Badhrees, I.,Bakich, A. M.,Bansal, V.,Behera, P.,Berger, M.,Bhardwaj, V.,Biswal, J.,Bobrov, A.,Bozek, A.,Bra& American Physical Society 2017 Physical review. D Vol.96 No.5

<P>We have searched for the Cabibbo-suppressed decay Lambda(+)(c) -> pi p(0) in e(+) e(-) collisions using a data sample corresponding to an integrated luminosity of 915 fb(-1). The data were collected by the Belle experiment at the KEKB e(+) e(-) asymmetric-energy collider running at or near the (4S) and (5S) resonances. No significant signal is observed, and we set an upper limit on the branching fraction of B(Lambda(+)(c) -> phi p(0)) < 15.3 x 10(-5) at 90% confidence level. The contribution of nonresonant Lambda(+)(c) -> K+ K- p pi(0) decays is found to be consistent with zero, and the corresponding upper limit on its branching fraction is set to be B(Lambda(+)(c) ->. K+ K- p pi(0))(NR) < 6.3 x 10(-5) at 90% confidence level. We also search for an intermediate hidden-strangeness pentaquark decay P-s(+) -> phi p. We see no evidence for this intermediate decay and set an upper limit on the product branching fraction of B(Lambda(+)(c) -> P-s(+) pi(0)) x B(P-s(+) -> phi p) < 8.3 x 10(-5) at 90% confidence level. Finally, we measure the branching fraction for the Cabibbo-favored decay Lambda(+)(c) -> K- pi(+) p pi(0); the result is B(Lambda(+)(c) -> K- pi(+) p pi(0)) = (4.42 +/- 0.05(stat)+/- 0.12(syst)+/- 0.16(norm))%, which is the most precise measurement to date.</P>

Multisite campaign on the open cluster M67 – III. δ Scuti pulsations in the blue stragglers

Bruntt, H.,Stello, D.,Suá,rez, J. C.,Arentoft, T.,Bedding, T. R.,Bouzid, M. Y.,Csubry, Z.,Dall, T. H.,Dind, Z. E.,Frandsen, S.,Gilliland, R. L.,Jacob, A. P.,Jensen, H. R.,Kang, Y. B.,Kim, S.-L. Blackwell Publishing Ltd 2007 MONTHLY NOTICES- ROYAL ASTRONOMICAL SOCIETY Vol.378 No.4

<P>ABSTRACT</P><P>We have made an asteroseismic analysis of the variable blue stragglers in the open cluster M67. The data set consists of photometric time-series from eight sites using nine 0.6–2.1 m telescopes with a time-baseline of 43 d. In two stars, EW Cnc and EX Cnc, we detect the highest number of frequencies (41 and 26) detected in δ Scuti stars belonging to a stellar cluster, and EW Cnc has the second highest number of frequencies detected in any δ Scuti star. We have computed a grid of pulsation models that take the effects of rotation into account. The distribution of observed and theoretical frequencies shows that in a wide frequency range a significant fraction of the radial and non-radial low-degree modes are excited to detectable amplitudes. Despite the large number of observed frequencies we cannot constrain the fundamental parameters of the stars. To make progress we need to identify the degrees of some of the modes from either multicolour photometry or spectroscopy.</P>

15-lipoxygenase metabolites play an important role in the development of a T-helper type 1 allergic inflammation induced by double-stranded RNA

Jeon, S. G.,Moon, H.-G.,Kim, Y.-S.,Choi, J.-P.,Shin, T.-S.,Hong, S.-W.,Tae, Y.-M.,Kim, S.-H.,Zhu, Z.,Gho, Y. S.,Kim, Y.-K. Blackwell Publishing Ltd 2009 Clinical and experimental allergy Vol.39 No.6

<P>Summary</P><P>Background</P><P>We recently demonstrated that the T-helper type 1 (Th1) immune response plays an important role in the development of non-eosinophilic inflammation induced by airway exposure of an allergen plus double-stranded RNA (dsRNA). However, the role of lipoxygenase (LO) metabolites in the development of Th1 inflammation is poorly understood.</P><P>Objective</P><P>To evaluate the role of LO metabolites in the development of Th1 inflammation induced by sensitization with an allergen plus dsRNA.</P><P>Methods</P><P>A Th2-allergic inflammation mouse model was created by an intraperitoneal injection of lipopolysaccharide-depleted ovalbumin (OVA, 75 μg) and alum (2 mg) twice, and the Th1 model was created by intranasal application of OVA (75 μg) and synthetic dsRNA [10 μg of poly(I : C)] four times, followed by an intranasal challenge with 50 μg of OVA four times. The role of LO metabolites was evaluated using two approaches: a transgenic approach using 5-LO<SUP>−/−</SUP> and 15-LO<SUP>−/−</SUP> mice, and a pharmacological approach using inhibitors of cysteinyl leucotriene receptor-1 (cysLTR1), LTB4 receptor (BLT1), and 15-LO.</P><P>Results</P><P>We found that the Th1-allergic inflammation induced by OVA+dsRNA sensitization was similar between 5-LO<SUP>−/−</SUP> and wild-type (WT) control mice, although Th2 inflammation induced by sensitization with OVA+alum was reduced in the former group. In addition, dsRNA-induced Th1 allergic inflammation, which is associated with down-regulation of 15-hydroxyeicosateraenoic acids production, was not affected by treatment with cysLTR1 or BLT1 inhibitors, whereas it was significantly lower in 12/15-LO<SUP>−/−</SUP> mice compared with WT control mice. Moreover, dsRNA-induced allergic inflammation and the recruitment of T cells following an allergen challenge were significantly inhibited by treatment with a specific 15-LO inhibitor (PD146176).</P><P>Conclusion</P><P>15-LO metabolites appear to be important mediators in the development of Th1-allergic inflammation induced by sensitization with an allergen plus dsRNA. Our findings suggest that the 15-LO pathway is a novel therapeutic target for the treatment of virus-associated asthma characterized by Th1 inflammation.</P>

Multisite campaign on the open cluster M67 – I. Observations and photometric reductions

Stello, D.,Arentoft, T.,Bedding, T. R.,Bouzid, M. Y.,Bruntt, H.,Csubry, Z.,Dall, T. H.,Dind, Z. E.,Frandsen, S.,Gilliland, R. L.,Jacob, A. P.,Jensen, H. R.,Kang, Y. B.,Kim, S.-L.,Kiss, L. L.,Kjeldsen, Blackwell Publishing Ltd 2006 MONTHLY NOTICES- ROYAL ASTRONOMICAL SOCIETY Vol.373 No.3

<P>ABSTRACT</P><P>We report on an ambitious multisite campaign aimed at detecting stellar variability, particularly solar-like oscillations, in the red giant stars in the open cluster M67 (NGC 2682). During the six-week observing run, which comprised 164 telescope nights, we used nine 0.6-m to 2.1-m class telescopes located around the world to obtain uninterrupted time series photometry. We outline here the data acquisition and reduction, with emphasis on the optimization of the signal-to-noise ratio of the low-amplitude (50–500 μmag) solar-like oscillations. This includes a new and efficient method for obtaining the linearity profile of the CCD response at ultrahigh precision (∼10 parts per million). The noise in the final time series is 0.50 mmag per minute integration for the best site, while the noise in the Fourier spectrum of all sites combined is 20 μmag. In addition to the red giant stars, this data set proves to be very valuable for studying high-amplitude variable stars such as eclipsing binaries, W UMa systems and δ Scuti stars.</P>

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>

Si film electrodes with surface-modified Cu current collectors for micro Li batteries

Lee, M.j.,Chae, M.r.,Jeong, J.s.,Noh, J.p.,Ahn, H.j.,Cho, K.k.,Choi, H.k.,Nam, T.h.,Kim, K.w.,Cho, G.b. Pergamon Press 2016 Materials research bulletin Vol.82 No.-

<P>Si film electrodes were fabricated onsurface-modified Cu current collectors using an oxidation-reduction process. Flower-like nanostructures (FLNSs) with diameters of 2-3 mu m and plate-like nanostructures (PLNSs) with lengths of 1 m were formed on the Cu foil oxidized at 423 K for 0.5 h, but only the PLNSs remained after sonication. Reduction of the preoxidized Cu foil at 673 K resulted in the formation of platelike and coral -like nanostructures on the Cu foils reduced for 1 and 3 h and a smooth surface without specific structures on the Cu foil reduced for 6 h. The best electrochemical properties in terms of the first columbic efficiency (85.4%) and the cycle performance (67.3% at 50 cycles) were obtained from the Si film electrode fabricated on the Cu foil that had been reduced for 3 h because the coral -like nanostructures on the Cu foil enhanced the adhesion of the Si film and improved the structural stability of the Si film electrode during the electrochemical reactions. (C) 2016 Elsevier Ltd: All rights reserved.</P>

SEARCH FOR PULSED γ-RAY EMISSION FROM GLOBULAR CLUSTER M28

Wu, J. H. K.,Hui, C. Y.,Wu, E. M. H.,Kong, A. K. H.,Huang, R. H. H.,Tam, P. H. T.,Takata, J.,Cheng, K. S. IOP Publishing 2013 ASTROPHYSICAL JOURNAL LETTERS - Vol.765 No.2

<P>Using the data from the Large Area Telescope on board the Fermi Gamma-ray Space Telescope, we have searched for gamma-ray pulsations from the direction of the globular cluster M28 (NGC 6626). We report the discovery of a signal with a frequency consistent with that of the energetic millisecond pulsar (MSP) PSR B1821-24 in M28. A weighted H-test test statistic of 28.8 is attained, which corresponds to a chance probability of similar to 10(-5) (4.3 sigma detection). With a phase-resolved analysis, the pulsed component is found to contribute similar to 25% of the total observed gamma-ray emission from the cluster. However, the unpulsed level provides a constraint for the underlying MSP population and the fundamental plane relations for the scenario of inverse Compton scattering. Follow-up timing observations in radio/X-ray are encouraged to further investigate this periodic signal candidate.</P>