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>

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>

<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>

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.

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.

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

Balanced intake of protein and carbohydrate maximizes lifetime reproductive success in the mealworm beetle, Tenebrio molitor (Coleoptera: Tenebrionidae)

Rho, M.S.,Lee, K.P. Pergamon Press 2016 Journal of insect physiology Vol.91 No.-

<P>Recent developments in insect gerontological and nutritional research have suggested that the dietary protein:carbohydrate (P:C) balance is a critical determinant of lifespan and reproduction in many insects. However, most studies investigating this important role of dietary P:C balance have been conducted using dipteran and orthopteran species. In this study, we used the mealworm beetles, Tenebrio molitor L. (Coleoptera: Tenebrionidae), to test the effects of dietary P:C balance on lifespan and reproduction. Regardless of their reproductive status, both male and female beetles had the shortest lifespan at the protein-biased ratio of P:C 5:1. Mean lifespan was the longest at P:C 1:1 for males and at both P:C 1:1 and 1:5 for females. Mating significantly curtailed the lifespan of both males and females, indicating the survival cost of mating. Age-specific egg laying was significantly higher at P:C 1:1 than at the two imbalanced P:C ratios (1:5 or 5:1) at any given age throughout their lives, resulting in the highest lifetime reproductive success at P:C 1:1. When given a choice, beetles actively regulated their intake of protein and carbohydrate to a slightly carbohydrate-biased ratio (P:C 1:1.54-1:1.64 for males and P:C 1:1.31:1.36 for females). The self-selected P:C ratio was significantly higher for females than males, reflecting a higher protein requirement for egg production. Collectively, our results add to a growing body of evidence suggesting the key role played by dietary macronutrient balance in shaping lifespan and reproduction in insects. (C) 2016 Elsevier Ltd. All rights reserved.</P>

Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

Keystone, E C,Genovese, M C,Klareskog, L,Hsia, E C,Hall, S T,Miranda, P C,Pazdur, J,Bae, S-C,Palmer, W,Zrubek, J,Wiekowski, M,Visvanathan, S,Wu, Z,Rahman, M U BMJ Publishing Group 2009 Annals of the Rheumatic Diseases Vol.68 No.6

<P><B>Objective:</B></P><P>The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy.</P><P><B>Methods:</B></P><P>Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24.</P><P><B>Results:</B></P><P>The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively.</P><P><B>Conclusion:</B></P><P>The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.</P>