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>

Identification of a novel <i>FAM83H</i> mutation and microhardness of an affected molar in autosomal dominant hypocalcified amelogenesis imperfecta

Hyun, H.-K.,Lee, S.-K.,Lee, K.-E.,Kang, H.-Y.,Kim, E.-J.,Choung, P.-H.,Kim, J.-W. Blackwell Publishing Ltd 2009 International endodontic journal Vol.42 No.11

<P>Abstract</P><P>Aim </P><P>To determine the underlying molecular genetic aetiology of a family with the hypocalcified form of amelogenesis imperfecta and to investigate the hardness of the enamel and dentine of a known <I>FAM83H</I> mutation.</P><P>Methodology </P><P>Mutational screening of the <I>FAM83H</I> on the basis of candidate gene approach was performed. All exons and exon–intron boundaries was amplified and sequenced. A microhardness test was performed to measure the Vickers microhardness value.</P><P>Results </P><P>A novel nonsense mutation (c.1354C>T, p.Q452X) was identified in the last exon of <I>FAM83H</I>, which resulted in soft, uncalcified enamel. The affected enamel was extremely soft (about 17% of the normal control), but the underlying dentine was as hard as the normal control.</P><P>Conclusions </P><P>Mutational analysis revealed a novel mutation in <I>FAM83H</I> gene. Hardness of dentine was not affected by the mutation, whilst the enamel was extremely soft.</P>

Foxp3 is a key downstream regulator of p53-mediated cellular senescence

Kim, J-E,Shin, J-S,Moon, J-H,Hong, S-W,Jung, D-J,Kim, J H,Hwang, I-Y,Shin, Y J,Gong, E-Y,Lee, D H,Kim, S-M,Lee, E Y,Kim, Y S,Kim, D,Hur, D,Kim, T W,Kim, K-p,Jin, D-H,Lee, W-J Macmillan Publishers Limited 2017 Oncogene Vol.36 No.2

<P>The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.</P>

Effect of the Length of Feed Withdrawal on Weight Loss, Yield and Meat Color of Broiler

Kim, D.H.,Yoo, Y.M.,Kim, S.H.,Jang, B.G.,Park, B.Y.,Cho, S.H.,Seong, P.N.,Hah, K.H.,Lee, J.M.,Kim, Y.K.,Hwang, I.H. Asian Australasian Association of Animal Productio 2007 Animal Bioscience Vol.20 No.1

The current study was conducted to determine the optimum length of feed withdrawal for pre-harvest broilers. A total of three hundred broilers were sampled from an industrial population, and 30 chicks for each weight group (e.g., 1.5 and 2.5 kg) were randomly assigned to feed withdrawal treatments for 0, 3, 6, 9 and 12 h. Weight loss, yield, muscle pH, objective meat color and weights of gastro intestinal contents, crop, gizzard, provenriculus, small intestine, caecum, and rectum were determined. Live weight loss was significantly (p<0.05) increased as length of feed withdrawal extended. A significant (p<0.05) carcass yield for both 1.5 and 2.5 kg groups coincided after 9 and 6 h feed withdrawal, respectively. Net weights of intestinal contents for crop and gizzard were significantly (p<0.05) reduced by 6 h, and the reduction for proventriculus and small intestine occurred from 3 h. A noticeable effect of feed withdrawal on pH for breast muscle at 3 h postmortem occurred only when chicks were fasted for 3 h of which pH (6.05) was significantly (p<0.05) higher than that for other groups including the control (5.74). There was a linear tendency of higher lightness (Hunter L* value) numerically for chicks fasted for longer periods. The highest coefficient of determinations of regression models to estimate weight loss as a function of fasting period and body weights were achieved, when the models included both linear and quadratic terms for fasting period, and linear term for both 1.5 ($R^2=0.76$) and 2.5 kg ($R^2=0.78$) body weight groups. Given the practical aspect, approximately 1.5 kg of body weight is dominant, weight loss could be predicted by the following function; live weight $loss=26.6-0.28{\times}(fasting period)^2+12.34{\times}pasting\;period-0.012{\times}body\;weight$, $R^2=0.76$. Current data implied that the optimum fasting time for pre-slaughter chicks varied depending on slaughter weight; 6 and 9-h fasting were recommendable for 2.5 and 1.5 kg chicks, with little effect on objective meat color.

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>

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>

Fam83h is Associated with Intracellular Vesicles and ADHCAI

Ding, Y.,Estrella, M.R.P.,Hu, Y.Y.,Chan, H.L.,Zhang, H.D.,Kim, J.-W.,Simmer, J.P.,Hu, J.C.-C. SAGE Publications 2009 Journal of dental research Vol.88 No.11

<P>Defects in <I>FAM83H</I> on human chromosome 8q24.3 cause autosomal-dominant hypocalcified amelogenesis imperfecta (ADHCAI). <I>FAM83H</I> does not encode a recognizable signal peptide, so we predicted that the Fam83h protein functions within the cell. We tested this hypothesis by constitutively expressing mouse Fam83h with green fluorescent protein (GFP) fused to its C-terminus in HEK293 and HeLa cell lines. Green fluorescent signal from the Fam83h-GFP fusion protein was associated with perinuclear vesicles, usually in the vicinity of the Golgi apparatus. No signal was observed within the nucleus. In addition, we identified <I> FAM83H</I> nonsense mutations in Hispanic (C1330C>T; p.Q444X) and Caucasian (c.1192C>T; p.Q398X) families with ADHCAI. We conclude that Fam83h localizes in the intracellular environment, is associated with vesicles, and plays an important role in dental enamel formation. <I>FAM83H</I> is the first gene involved in the etiology of amelogenesis imperfecta (AI) that does not encode a secreted protein.</P>

Toward high efficiency organic photovoltaic devices with enhanced thermal stability utilizing P3HT-b-P3PHT block copolymer additives

Zhu, M.,Kim, H.,Jang, Y.,Park, S.,Ryu, D.,Kim, K.,Tang, P.,Qiu, F.,Kim, D.,Peng, J. Royal Society of Chemistry 2016 Journal of Materials Chemistry A Vol.4 No.47

<P>Organic photovoltaics (OPVs) have drawn an extensive amount of attention due to their low cost, processibility and flexibility. However, a cell based on a blend of poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C-61-butyric acid methyl ester (PC61BM) has a limited power conversion efficiency (PCE) due to the short exciton diffusion length of similar to 10 nm. We address this issue by designing a series of all-conjugated diblock copolymers, poly(3-hexylthiophene)-b-poly(3-(6-diethylphosphonatohexyl) thiophene) (P3HT-b-P3PHT), intended for use as additives to improve the performance of P3HT:PC61BM-based photovoltaic devices. The PCE of the devices improved from 3.30% to 4.03% with the addition of P3HT-b-P3PHT (3 : 1). The thermal stability of devices with P3HT-b-P3PHT additives improved significantly relative to that of the P3HT:PC61BM reference device, where the devices including a copolymer with a higher P3PHT content exhibited a better thermal stability. It was found that the fill factor (FF) could be regulated by simply varying the block ratio of P3HT-b-P3PHT and played a crucial role in improving both the PCE and the thermal stability. The P3HT-b-P3PHT diffused at the P3HT:PC61BM interface, improved the miscibility between P3HT and PC61BM, optimized the nanoscale morphology of the photoactive layer, and reduced the active layer roughness, all of which improved the FF and thus contributed to an improvement in device performance.</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>

FAM83H mutations cause ADHCAI and alter intracellular protein localization.

Lee, S-K,Lee, K-E,Jeong, T-S,Hwang, Y-H,Kim, S,Hu, J C-C,Simmer, J P,Kim, J-W Journal of Dental Research, Inc 2011 Journal of dental research Vol.90 No.3

<P>Mutations in a family with sequence similarity 83 member H (FAM83H) cause autosomal-dominant hypocalcification amelogenesis imperfecta (ADH CAI). All FAM83H ADHCAI-causing mutations terminate translation or shift the reading frame within the specific exon 5 segment that encodes from Ser(287) to Glu(694). Mutations near Glu(694) cause a milder, more localized phenotype. We identified disease-causing FAM83H mutations in two families with ADHCAI: family 1 (g.3115C>T, c.1993 C>T, p.Q665X) and family 2 (g.3151C>T, c.2029 C>T, p.Q677X). We also tested the hypothesis that truncation mutations alter the intracellular localization of FAM83H. Wild-type FAM83H and p.E694X mutant FAM83H fused to green fluorescent protein (GFP) localized in the cytoplasm of HEK293T cells, but the mutant FAM83H proteins (p.R325X, p.W460X, and p.Q677X) fused to GFP localized mainly in the nucleus with slight expression in the cytoplasm. We conclude that nuclear targeting of the truncated FAM83H protein contributes to the severe, generalized enamel phenotype.</P>