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>

<i>S100A9</i> and <i>EGFR</i> gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy

Kim, W. T.,Kim, J.,Yan, C.,Jeong, P.,Choi, S. Y.,Lee, O. J.,Chae, Y. B.,Yun, S. J.,Lee, S. C.,Kim, W. J. Oxford University Press 2014 Annals of Oncology Vol.25 No.5

<P>In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC. Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings. Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor-prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623-13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy. The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC.</P>

Bishop's property (<i>β</i>), a commutativity theorem and the dynamics of class A ( s , t ) operators

Duggal, B.P.,Kubrusly, C.S.,Kim, I.H. Elsevier 2015 Journal of mathematical analysis and applications Vol.427 No.1

<P><B>Abstract</B></P> <P>Given a Hilbert space operator A ∈ B ( H ) with polar decomposition A = U | A | , the class A ( s , t ) , 0 < s , t ≤ 1 , consists of operators A ∈ B ( H ) such that <SUP> | <SUP> A ⁎ </SUP> | 2 t </SUP> ≤ <SUP> ( <SUP> | <SUP> A ⁎ </SUP> | t </SUP> <SUP> | A | 2 s </SUP> <SUP> | <SUP> A ⁎ </SUP> | t </SUP> ) t t + s </SUP> . Every class A ( s , t ) operator is paranormal; prominent amongst the subclasses of A ( s , t ) operators are the class A ( 1 2 , 1 2 ) consisting of w-hyponormal operators and the class A ( 1 , 1 ) consisting of (semi-quasihyponormal [16, p. 93], or) class A operators. Our aim here is threefold. We prove that A ( s , t ) operators satisfy: (i) Bishop's property (<I>β</I>), thereby providing a proof of [6, Theorem 3.1], and (ii) a Putnam–Fuglede commutativity theorem, thereby answering a question posed in [18, Conjecture 2.4]; we prove also an extension of [3, Theorem 3.4] to prove that (iii) if an A ( s , t ) operator is weakly supercyclic then it is a scalar multiple of a unitary operator.</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>

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>

Disruption of a regulatory loop between DUSP1 and p53 contributes to hepatocellular carcinoma development and progression

Hao, P.P.,Li, H.,Lee, M.J.,Wang, Y.P.,Kim, J.H.,Yu, G.R.,Lee, S.Y.,Leem, S.H.,Jang, K.Y.,Kim, D.G. Elsevier Science Publishers 2015 Journal of hepatology Vol.62 No.6

Background & Aims: Altered expression of dual specificity phosphatase 1 (DUSP1) is common in tumors including hepatocellular carcinoma (HCC), and is predictive of tumor progression and poor prognosis. However, the tumor suppressive role of DUSP1 has yet to be clearly elucidated. Methods: The molecular mechanisms of tumor suppression that were investigated were induction of apoptosis, cell cycle inhibition, and regulation of p53. Additionally, the antitumor effect of DUSP1 was assessed using a mouse model. Associated signaling pathways in HCC cells and tissues were examined. Results: Downregulation of DUSP1 expression was significantly correlated with poor differentiation (p<0.001) and advanced HCC stage (p=0.023). DUSP1 expression resulted in HCC suppression and longer survival (p=0.0002) in a xenoplant mice model. DUSP1 inhibited p38 MAPK phosphorylation and subsequently suppressed HSP27 activation, resulting in enhanced p53 phosphorylation at sites S15, S20, and S46 in HCC cells. Enhanced p53 activation induced the expression of target genes p21 and p27, which are linked to cell cycle arrest and apoptosis. Thus, DUSP1 was potentially linked to p53 activation via the p38 MAPK/HSP27 pathway. Wild-type but not mutant p53 transcriptionally upregulated DUSP1 via its DNA-binding domain. DUSP1 and p53 might collaborate to suppress tumors in hepatocarcinogenesis via a positive regulatory loop. Conclusions: Our results revealed that disruption of a positive regulatory loop between DUSP1 and p53 promoted HCC development and progression, providing a rationale for a therapeutic agent that restores DUSP1 in HCC.

MINIMAL P-SPACES

Arya, S.P.,Bhamini, M.P. Department of Mathematics 1987 Kyungpook mathematical journal Vol.27 No.1

Minimal s-Urysohn and minimal s-regular spaces are studied. An s-Urysohn (respectively, s-regular) space (X, $\mathfrak{T}$) is said to be minimal s-Urysohn (respectively, minimal s-regular) if for no topology $\mathfrak{T}^{\prime}$ on X which is strictly weaker than $\mathfrak{T}$, (X, $\mathfrak{T}^{\prime}$) is s-Urysohn (respectively s-regular). Several characterizations and other related properties of these classes of spaces have been obtained. The present paper is a study of minimal P-spaces where P refers to the property of being an s-Urysohn space or an s-regular space. A P-space (X, $\mathfrak{T}$) is said to be minimal P if for no topology $\mathfrak{T}^{\prime}$ on X such that $\mathfrak{T}^{\prime}$ is strictly weaker than $\mathfrak{T}$, (X, $\mathfrak{T}^{\prime}$) has the property P. A space X is said to be s-Urysohn [2] if for any two distinct points x and y of X there exist semi-open set U and V containing x and y respectively such that $clU{\bigcap}clV={\phi}$, where clU denotes the closure of U. A space X is said to be s-regular [6] if for any point x and a closed set F not containing x there exist disjoint semi-open sets U and V such that $x{\in}U$ and $F{\subseteq}V$. Throughout the paper the spaces are assumed to be Hausdorff.

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

<i>K</i>-mixing in the doubly mid-shell nuclide ¹⁷⁰Dy and the role of vibrational degeneracy

Sö,derströ,m, P.-A.,Walker, P.M.,Wu, J.,Liu, H.L.,Regan, P.H.,Watanabe, H.,Doornenbal, P.,Korkulu, Z.,Lee, P.,Liu, J.J.,Lorusso, G.,Nishimura, S.,Phong, V.H.,Sumikama, T.,Xu, F.R.,Yagi, A.,Zha North-Holland Pub. Co 2016 Physics letters. Section B Vol.762 No.-

<P><B>Abstract</B></P> <P>A detailed study of the structure of the doubly mid-shell nucleus Dy 104 1 66 170 has been carried out, following isomeric and <I>β</I> decay. We have measured the yrast band up to the spin-parity <SUP> J π </SUP> = <SUP> 6 + </SUP> state, the K = 2 <I>γ</I>-vibration band up to the <SUP> 5 + </SUP> state, a low-lying negative-parity band based on a <SUP> 2 − </SUP> state that could be a candidate for the lowest energy octupole vibration state within this nucleus, and a candidate for the <SUP> K π </SUP> = <SUP> 6 + </SUP> two quasi-particle isomer. This state was determined to have an excitation energy of 1643.91(23) keV and a half life of 0.99(4) μs, with a reduced hindrance for its decay to the ground-state band an order of magnitude lower than predicted by <SUB> N p </SUB> <SUB> N n </SUB> systematics. This is interpreted as being due to <I>γ</I>-vibrational mixing from a near degeneracy of the isomer and the <SUP> 6 + </SUP> state of the <I>γ</I> band. Furthermore, the parent nucleus <SUP>170</SUP>Tb has been determined to have a half-life of 0.91 ( − 13 + 18 ) s with a possible spin-parity of <SUP> 2 − </SUP> .</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>