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>

Symmetric supercapacitor: Sulphurized graphene and ionic liquid

Shaikh, Jasmin S.,Shaikh, Navajsharif S.,Kharade, Rohini,Beknalkar, Sonali A.,Patil, Jyoti V.,Suryawanshi, Mahesh P.,Kanjanaboos, Pongsakorn,Hong, Chang Kook,Kim, Jin Hyeok,Patil, Pramod S. Elsevier 2018 JOURNAL OF COLLOID AND INTERFACE SCIENCE - Vol.527 No.-

<P><B>Abstract</B></P> <P>Symmetric supercapacitor is advanced over simple supercapacitor device due to their stability over a large potential window and high energy density. Graphene is a desired candidate for supercapacitor application since it has a high surface area, good electronic conductivity and high electro chemical stability. There is a pragmatic use of ionic liquid electrolyte for supercapacitor due to its stability over a large potential window, good ionic conductivity and eco-friendly nature. For high performance supercapacitor, the interaction between ionic liquid electrolyte and graphene are crucial for better charge transportation. In respect of this, a three-dimensional (3D) nanoporous honeycomb shaped sulfur embedded graphene (S-graphene) has been synthesized by simple chemical method. Here, the fabrication of high performance symmetric supercapacitor is done by using S-graphene as an electrode and [BMIM-PF<SUB>6</SUB>] as an electrolyte. The particular architecture of S-graphene benefited to reduce the ion diffusion resistance, providing the large surface area for charge transportation and efficient charge storage. The S-graphene and ionic liquid-based symmetric supercapacitor device showed the large potential window of 3.2 V with high energy density 124 Wh kg<SUP>−1</SUP> at 0.2 A g<SUP>−1</SUP> constant applied current density. Furthermore, this device shows good cycling performance (stability) with a capacitive retention of 95% over 20,000 cycles at a higher current density of 2 A g<SUP>−1</SUP>.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

열처리 단백질-광물질 복합제제 첨가가 In Vitro 발효성상과 착유우의 유량 및 유성분에 미치는 영향

최낙진,배귀석,남경표,장문백,엄재상,고종렬,하종규 한국동물자원과학회 2002 한국축산학회지 Vol.44 No.5

본 연구의 in vitro 실험결과를 살펴보면, 배양액의 pH와 암모니아 생성량은 전 배양시간 동안 처리구간 통계적 유의차가 없었다. Total VFA, acetate, propionate, butyrate 생성량은 12 h에서 HPM을 0.2%, 1% 첨가한 시험구에서 대조구와 비교하여 증가하는 경향이 있었으나, 2% 첨가구에서는 오히려 감소되었고, 48 h 에서는 HPM 첨가한 세 처리구에서 대조구와 비교하여 모두 증가하는 경향을 보였다. 반면에, 다른 배양시간대에서는 처리구간 통계적 유의차는 발견되지 않았다. A/P ratio 경우에도 처리구간 유의차는 없었다. 총 gas 생성량은 배양시간 24 h과 48 h에 HPM 처리구에서 대조구와 비교하여 증가하였다 (P<0.05). 한편 사양실험은 열처리된 단백질 (대두박)과 광물질의 복합 제제 (HPM)가 젖소의 유생산량과 유성분에 끼치는 영향을 조사하기 위하여 수행되었는데 그 결과를 요약하면, 유생산량은 대조구와 비교하여 HPM 시험구에서 하루에 약 1㎏ 정도 더 높았고 (27. 7 vs 28.8 ㎏/d, P<0.001), 4% FCM 생성량 또한 대조구와 비교하여 볼 때 HPM 시험구에서 1.3㎏/d 이 더 높았다 (P<0.001). 유단백 (P<0.05)과 SNF (P<0.05)도 대조구와 비교하여 HPM 시험구에서 그 생산량이 증가되었다. 반면에, 유지방, MUN과 체세포수는 처리구간 통계적 유의차가 발견되지 않았다. 이상의 결과로 보아, HPM 첨가에 의한 반추위 발효 저해현상은 없었으며, HPM 내 함유되어 있는 열처리된 단백질과 광물질의 결합체와 잔여 광물질이 반추위 내 단백질과 결합하여 단백질 분해 속도를 지연시킴으로써, 단백질의 by-pass율을 증가시켜, 유생산량 증가와 유질을 개선 (유단백질, SNF 함량 증가 등) 하는 등 젖소의 생산성을 향상시킨 것으로 요약할 수 있다. This study, consisting of two experiments, was conducted to determine the effects of feeding heat treated protein and mineral complex (HPM) on milk production and composition, and ruminal fermentation of Holstein dairy cows. In in vitro experiment, HPM levels were 0, 0.2, 1 and 2%, and Timothy hay, which was substrate, was milled as 1 ㎜ size, and the effect of HPM on pH and ammonia and VFA were analyzed after incubation times of 0, 6, 12, 24 and 48 h, respectively. The pH and ammonia production were not significantly different between treatments during the incubation. In addition, generally, total VFA and individual VFA were not affected by HPM on 0, 6 and 24 h. While, total VFA and individual VFA were increased in 0.2% and 1% of HPM supplemented treatments, but decreased in 2% of HPM treatment compared with control on 12 h. On 48 h, total VFA and individual VFA were increased in HMP treatment compared to control(P<0.05). However, A/P ratio was not affected by HPM supplementation. Gas production was higher in HPM treatment compared to control on 24 h (P<0.05) and 48 h (P<0.05). In lactating experiment, fourteen lactating Holstein cows were used for 4 months in a cross over experimental design. There were two treatment; no added HPM as a control and 0.2% of HPM added as a test treatment. Daily milk yield (P<0.001), 4% FCM (P<0.001), milk protein (P<0.05) and SNF (solid not fat; P<0.05) were increased in HPM treatment compared to control. While, milk fat, MUN (milk urea nitrogen) and SCC (somatic cell count) were not significantly different between treatments.

Status of the KSTAR superconducting magnet system development

Kim, K.,Park, H.K.,Park, K.R.,Lim, B.S.,Lee, S.I.,Chu, Y.,Chung, W.H.,Oh, Y.K.,Baek, S.H.,Lee, S.J.,Yonekawa, H.,Kim, J.S.,Kim, C.S.,Choi, J.Y.,Chang, Y.B.,Park, S.H.,Kim, D.J.,Song, N.H.,Kim, K.P.,So International Atomic Energy Agency 2005 Nuclear fusion Vol.45 No.8

<P>The aim of the Korea superconducting tokamak advanced research (KSTAR) project is to develop a steady-state-capable advanced superconducting tokamak for establishing a scientific and technological basis for an attractive fusion reactor. Since the KSTAR mission includes the achievement of a steady-state-capable operation, the use of superconducting coils is an obvious choice for the magnet system. The KSTAR superconducting magnet system consists of 16 toroidal field (TF) and 14 poloidal field (PF) coils which include 8 central solenoid coils. Both the TF and PF coil systems use internally-cooled cable-in-conduit conductors (CICC). The TF coil system provides a magnetic field of 3.5 T at the plasma centre and the PF coil system provide a flux swing of 17 V s. The major achievement in the KSTAR magnet system development includes the development of CICC, a full size TF model coil, a background magnetic field generation coil system and the construction of a large scale superconducting magnet and the CICC test facility. TF and PF coils are at the stage of fabrication for the KSTAR completion in the year 2007.</P>

Immunolocalization of steroidogenic acute regulatory protein-related lipid transfer (START) domain-containing proteins in the developing cerebellum of normal and hypothyroid rats

Chang, I.Y.,Ohn, T.,Ko, G.S.,Yoon, Y.,Kim, J.W.,Yoon, S.P. Wiley Sons ; Elsevier Science Ltd ; Elsevier Scien 2012 Journal of chemical neuroanatomy Vol.43 No.1

Cholesterol transport proteins are a prerequisite for neurosteroidogenesis. Steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain-containing proteins, such as StAR and START domain-containing 6 (StarD6), are known to be distributed in the brain. Since perinatal hypothyroidism affects cerebellar development, we examined postnatal changes in StAR and StarD6 immunolocalization in the developing cerebellum of control and hypothyroid rats. Pregnant Sprague-Dawley rats were given 0.05% 6-propyl-2-thiouracil (PTU) or water from gestation day 11 until postnatal day (P) 28, and were then killed together with age-matched control rats. As shown by calbindin D-28k immunostaining, the developing cerebellar cytoarchitecture and Purkinje cells were affected by PTU-induced hypothyroidism as compared to control rats. The immunolocalization of StAR and StarD6 generally followed the maturation pattern of Purkinje cells from the vermis to the cerebellar hemisphere. StAR immunostaining first appeared in the Purkinje cells of the vermis at P7 in both control and hypothyroid rats. In control rats, a few StarD6 immunoreactive cells were seen at birth and a nuclear localization of StarD6 in Purkinje cells was obvious at P14. PTU-induced hypothyroidism delayed the appearance of StarD6 immunopositive cells until P7. Moreover, the nuclear localization of StarD6 in PTU-treated rats was not obvious at P14. An adult-like distribution of StAR and StarD6 was achieved by P21 in control and hypothyroid rats. These results suggest that StarD6 may affect the development of Purkinje cells during the first and second postnatal weeks, a known period of thyroid hormone action.

Prognostic value of chronic total occlusions detected on coronary computed tomographic angiography

Opolski, Maksymilian P,Gransar, Heidi,Lu, Yao,Achenbach, Stephan,Al-Mallah, Mouaz H,Andreini, Daniele,Bax, Jeroen J,Berman, Daniel S,Budoff, Matthew J,Cademartiri, Filippo,Callister, Tracy Q,Chang, Hy BMJ Group 2019 Heart Vol.105 No.3

<P><B>Objective</B></P><P>Data describing clinical relevance of chronic total occlusion (CTO) identified by coronary CT angiography (CCTA) have not been reported to date. We investigated the prognosis of CTO on CCTA.</P><P><B>Methods</B></P><P>We identified 22 828 patients without prior known coronary artery disease (CAD), who were followed for a median of 26 months. Based on CCTA, coronary lesions were graded as normal (no atherosclerosis), non-obstructive (1%–49%), moderate-to-severe (50%–99%) or totally occluded (100%). All-cause mortality, and major adverse cardiac events defined as mortality, non-fatal myocardial infarction and late coronary revascularisation (≥90 days after CCTA) were assessed.</P><P><B>Results</B></P><P>The distribution of patients with normal coronaries, non-obstructive CAD, moderate-to-severe CAD and CTO was 10 034 (44%), 7965 (34.9%), 4598 (20.1%) and 231 (1%), respectively. The mortality rate per 1000 person-years of CTO patients was non-significantly different from patients with moderate-to-severe CAD (22.95; 95% CI 12.71 to 41.45 vs 14.46; 95% CI 12.34 to 16.94; p=0.163), and significantly higher than of those with normal coronaries and non-obstructive CAD (p<0.001 for both). Among 14 382 individuals with follow-up for the composite end point, patients with CTO had a higher rate of events than those with moderate-to-severe CAD (106.56; 95% CI 76.51 to 148.42 vs 65.45; 95% CI 58.01 to 73.84, p=0.009). This difference was primarily driven by an increase in late revascularisations in CTO patients (27 of 35 events). After multivariable adjustment, compared with individuals with normal coronaries, the presence of CTO conferred the highest risk for adverse cardiac events (14.54; 95% CI 9.11 to 23.20, p<0.001).</P><P><B>Conclusions</B></P><P>The detection of CTO on non-invasive CCTA is associated with increased rate of late revascularisation but similar 2-year mortality as compared with moderate-to-severe CAD.</P><P><B>Trial registration number</B></P><P> NCT01443637.</P>

Ribonucleotide reductase small subunit p53R2 suppresses MEK–ERK activity by binding to ERK kinase 2

Piao, C,Jin, M,Kim, H B,Lee, S M,Amatya, P N,Hyun, J -W,Chang, I -Y,You, H J Macmillan Publishers Limited 2009 Oncogene Vol.28 No.21

The p53-dependent RR small subunit (p53R2) protein, a newly identified member of the ribonucleotide reductase family, plays a key role in the p53-dependent cellular response to DNA. Several recent studies have suggested that p53R2 also plays an important role in suppressing the invasive potential of human cancer cells. However, the cellular mechanism that regulates invasiveness remains largely unknown. In this study, we show that p53R2 interacts with MEK2 (extracellular signal-regulated kinase (ERK) kinase 2–mitogen-activated protein kinase (MAPK) kinase 2), the molecule immediately upstream of ERK in the Ras–Raf–MAPK signaling cascade. In co-immunoprecipitation and immunofluorescence analyses, we found that p53R2 and MEK2 interact physically in cultured mammalian cells, and that the p53R2 segment comprising amino acids 161–206 is critical for this interaction. Moreover, serum-induced phosphorylation of MEK1/2 and ERK1/2 was greatly augmented in human cancer cells expressing small-interfering RNA against p53R2. On the other hand, phosphorylation of MEK1/2 and ERK1/2 in human cancer cells was markedly attenuated by overexpression of p53R2. Furthermore, MEK2 was required for p53R2 knockdown-induced enhancement of the invasive ability and anchorage-independent growth of human lung cancer H1299 cells. Taken together, these findings show that p53R2 negatively modulates serum-induced MEK–ERK activity and inhibits the MEK–ERK-mediated malignancy potential of human cancer cells.Oncogene (2009) 28, 2173–2184; doi:10.1038/onc.2009.84; published online 27 April 2009

Studies on the Use of Wet Sorghum Distiller's Grains in Lactating Cows

Chiou, P.W.S.,Chang, S.H.,Chiang, J.K.,Yu, B.,Chen, C.R. Asian Australasian Association of Animal Productio 1999 Animal Bioscience Vol.12 No.6

The aim of this study was to evaluate the effect of incorporating wet sorghum distiller's grains (WSDG) as part of their diet on the lactating performance of dairy cows. Twenty-seven Holstein milking cows were selected, all in the early lactating stage, with an average weight of 550 kg, and producing an average of 30 kg of milk daily. The cows were divided into three groups according to milk yield and lactation and were fed different total mixed rations. The diets were formulated according to NRC (1989) recommendations in three rations to (1) control diet, (2) 15% WSDG diet and (3) 30% WSDG diet. The three different diets were all formulated as iso-nitrogen and iso-energetic diets. After one week adaptation period, the experimental feeding was conducted for 8 weeks. Three ruminal cannulated cows were also examined in order to investigate ruminal fermentation of the three total mixed rations. The results showed that the milk yield, as corrected to the 4.0% fat standard, had no significant difference among the control, 15% WSDG and 30% WSDG treatment groups (p>0.05). The daily dry matter intake of the control group was higher than the other groups (p<0.05). with respect to milk composition, milk fat, milk protein and total solids, there was no significant difference among the treatment groups (p>0.05). The energy efficiency of the 30% WSDG group were significantly higher than the other treatment groups (p<0.05). Ruminal pH value showed no difference among the treatment groups (p<0.05). Ammonia-nitrogen concentration in the control group was higher than the other treatment groups (p<0.05). The concentration of total ruminal volatile fatty acid was similar in all three dietary groups.

Alteration by p11 of mGluR5 localization regulates depression-like behaviors

Lee, K-W,Westin, L,Kim, J,Chang, J C,Oh, Y-S,Amreen, B,Gresack, J,Flajolet, M,Kim, D,Aperia, A,Kim, Y,Greengard, P Macmillan Publishers Limited 2015 Molecular psychiatry Vol.20 No.12

Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and it has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors. Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membrane, and p11 increases cell surface availability of the receptor. Whereas p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.

Late Quaternary transgressive deposits in a low-gradient environmental setting: Korea Strait shelf, SE Korea

Yoo, D.G.,Kim, S.P.,Lee, C.W.,Chang, T.S.,Kang, N.K.,Lee, G.S. Pergamon Press 2014 QUATERNARY INTERNATIONAL Vol.344 No.-

Analysis of high-resolution seismic profiles and sediment data from the Korea Strait shelf reveals that the late Quaternary deposits in this area consist of five sedimentary units deposited during transgression phases of sea-level changes between about 15 and 6 ka BP: ancient beach/shoreface complex (unit P1), estuarine deposits (unit P2), mid-shelf sand sheet (unit M1), sand ridge system (unit M2), and inner-shelf sand sheet (unit M3). They are paralic and marine, separated by a ravinement surface. The lower paralic component below the ravinement surface consists of two sedimentary units (P1 and P2) preserved from shoreface erosion. The top surface of the paralic unit is truncated by a sharp erosional surface. This surface is overlain by three sedimentary units (M1, M2, and M3), which were produced by shoreface erosion that shifted landward during transgression. The transgressive deposits in this area, considering geometries and distribution patterns, can be divided into three types (I, II, and III). Type I overlying the lowstand systems tract is confined to the shelf margin, and consists of a thick paralic unit P1 and a relatively thin marine unit M1. Type II on the mid shelf has no paralic component and the marine units M1 or M2 directly overly the sequence boundary. Type III, found in the inner shelf, includes a thick paralic (unit P2) and a thin marine (unit M3) component. It is completely covered by the highstand systems tract.