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>

Accelerated cosmological expansion without tension in the Hubble parameter : Fast evolution of the Hubble parameter <i>H(z)</i>

van Putten, Maurice H.P.M.,Gwak, B.,Kang, G.,Kim, C.,Kim, H.-C.,Lee, C.-H.,Lee, J.,Lee, S.,Lee, W. EDP Sciences 2018 The European Physical Journal Conferences Vol.168 No.-

<P>The <I>H</I>0-tension problem poses a confrontation of dark energy driving latetime cosmological expansion measured by the Hubble parameter<I> H</I>(<I>z</I>) over an extended range of redshifts <I>z</I>. Distinct values <I>H</I>0 ≃ 73 km s<SUP>-1</SUP> Mpcs<SUP>-1</SUP> and <I>H</I>0 ≃ 68 km s<SUP>-1</SUP> Mpcs<SUP>-1</SUP> obtain from surveys of the Local Universe and, respectively, ΛCBM analysis of the CMB. These are representative of accelerated expansion with <I>H</I>′(0) ≃ 0 by [see formula in PDF] and, respectively, <I>H</I>′(0) > 0 in ΛCDM, where [see formula in PDF] is a fundamental frequency of the cosmological horizon in a Friedmann-Robertson-Walker universe with deceleration parameter <I>q</I>(<I>z</I>) = -1 + (1+z)<I>H</I><SUP>-1</SUP><I>H</I>′(z). Explicit solution <I>H</I>(z) = <I>H</I>0 [see formula in PDF] and, respectively, <I>H</I>(z) = <I>H</I>0[see formula in PDF] are here compared with recent data on <I>H</I>(<I>z</I>) over 0 ≲ z ≲ 2.The first is found to be free of tension with H0 from local surveys, while the latter is disfavored at 2:7σ A further confrontation obtains in galaxy dynamics by a finite sensitivity of inertia to background cosmology in weak gravity, putting an upper bound of <I>m</I> ≲ 10<SUP>-30</SUP> eV on the mass of dark matter. A <I>C</I><SUP>0</SUP> onset to weak gravity at the de Sitter scale of acceleration <I>adS</I> = <I>cH</I>(<I>z</I>), where <I>c</I> denotes the velocity of light, can be seen in galaxy rotation curves covering 0 ≲ <I>z</I> ≲ 2 Weak gravity in galaxy dynamics hereby provides a proxy for cosmological evolution.</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>

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>

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>

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

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.

Decomposition of hydrogen sulfide (H₂S) on Ni(100) and Ni₃Al(100) surfaces from first-principles

Hernandez, J.M.,Lim, D.H.,Nguyen, H.V.P.,Yoon, S.P.,Han, J.,Nam, S.W.,Yoon, C.W.,Kim, S.K.,Ham, H.C. Pergamon Press ; Elsevier Science Ltd 2014 International journal of hydrogen energy Vol.39 No.23

Spin-polarized density functional theory studies of hydrogen sulfide (H<SUB>2</SUB>S) adsorption and decomposition on Ni(100) and Ni<SUB>3</SUB>Al(100) surfaces were conducted to understand the aluminum (Al) alloying effect on H<SUB>2</SUB>S dissociation. For such purpose, we first determined the near surface structure of fully ordered Ni<SUB>3</SUB>Al alloy along the [100] direction by calculating the Al segregation energy to the surface and then examined the adsorption energies of the adsorbates (H<SUB>2</SUB>S, HS, S, and H) and the activation barriers for the H<SUB>2</SUB>S and HS decomposition by using Climbing Image-Nudged Elastic Band method. We found that regardless of the way to terminate the surface, Al atom in bimetallic Ni<SUB>3</SUB>Al(100) tends to exist in the first surface layer, rather than in the second or third layer, and the Ni<SUB>3</SUB>Al(100) surface can substantially retard the H<SUB>2</SUB>S decomposition by reducing the adsorption energy of sulfur compounds compared to the pure Ni(100) case. Finally, we presented how the Al in Ni<SUB>3</SUB>Al modifies the activity of surface Ni atoms toward the sulfur compounds by calculating the local density of states and charge distribution in alloying components. This work hints the importance of knowing how to properly tailor the reactivity of Ni based materials to enhance the resistance for sulfur poisoning.

Identification of stathmin 1 expression induced by Epstein–Barr virus in human B lymphocytes

Baik, S. Y.,Yun, H. S.,Lee, H. J.,Lee, M. H.,Jung, S. E.,Kim, J. W.,Jeon, J. P.,Shin, Y. K.,Rhee, H. S.,Kimm, K. C.,Han, B. G. Blackwell Publishing Ltd 2007 Cell proliferation Vol.40 No.2

<P>Abstract. </P><P><I>Introduction</I>: The Epstein–Barr virus transforms resting B cells into proliferating lymphoblastoid cells, the origin of cell lines. <I>Method and results</I>: Our cDNA microarray analyses led to the identification of 232 up-regulated and 112 down-regulated genes with more than a 3-fold difference in lymphoblastoid cell lines compared to resting B cells. The functional classification of these genes exhibited the distinct expression signature for cell proliferation, cell cycle and an immune response. Among them, we verified the differential expression of several oncogenes such as <I>stathmin 1</I> (<I>STMN1</I>), <I>RAB27A</I>, <I>RAB9A</I>, <I>BACH1</I> and <I>BACH2</I> using quantitative real-time reverse transcriptase-polymerase chain reactions or Western blot analysis. Expression of <I>STMN1</I> (which is involved in regulation of the microtubule filament system, cell growth and S-phase of cell cycle) was increased in lymphoblastoid cell line as well as in 7-day post-Epstein–Barr virus infection B cells, compared to resting B cells. <I>Conclusion</I>: Thus, this study suggests that Epstein–Barr virus infection induces <I>STMN1</I> expression, which play a role in cell cycle progression and proliferation in the human B lymphocyte.</P>

Variants in hormone-related genes and the risk of biliary tract cancers and stones: a population-based study in China

Park, S. K.,Andreotti, G.,Sakoda, L. C.,Gao, Y.-T.,Rashid, A.,Chen, J.,Chen, B. E.,Rosenberg, P. S.,Shen, M.-C.,Wang, B.-S.,Han, T.-Q.,Zhang, B.-H.,Yeager, M.,Chanock, S.,Hsing, A. W. Oxford University Press 2009 Carcinogenesis Vol.30 No.4

<P>Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single-nucleotide polymorphisms (SNPs) in nine genes involved in steroid hormone biosynthesis, metabolism and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled 411 biliary tract cancer and 893 biliary stone patients and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder [odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.3-3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1-3.1), whereas the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5-5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (P = 0.004) and ampulla of Vater cancers (P = 0.01), but borderline with bile duct cancer (P = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (body mass index < 23) (OR = 3.3, 95% CI = 1.8-6.1; P interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2-20.5; P interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1-4.9; P-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones, possibly by modulating hormone metabolism.</P>