High-resolution metabolomics to identify urine biomarkers in corticosteroid-resistant asthmatic children

Park, Youngja H.,Fitzpatrick, Anne M.,Medriano, Carl Angelo,Jones, Dean P. Elsevier 2017 The Journal of allergy and clinical immunology Vol.139 No.5

<P><B>Background</B></P> <P>Corticosteroid (CS) treatment has been established as the first anti-inflammatory treatment for adults and children with asthma. However, a subset of patients fails to respond to combined systemic and inhaled CS treatment.</P> <P><B>Objective</B></P> <P>This study was aimed at further understanding CS resistance among children with severe asthma.</P> <P><B>Methods</B></P> <P>High-resolution metabolomics was performed on urine samples from CS-respondent (n = 15) and CS-nonrespondent (n = 15) children to determine possible urine biomarkers related to CS resistance. The metabolic phenotypes of CS responders and CS nonresponders were analyzed using bioinformatics including Manhattan plot with false- discovery rate, hierarchical cluster analysis, Kyoto Encyclopedia Genes and Genomes, and Mummichog pathway analysis.</P> <P><B>Results</B></P> <P>The 2-way hierarchical cluster analysis study determined 30 metabolites showing significantly different levels between CS responders and CS nonresponders. The important metabolites annotated were 3,6-dihydronicotinic acid (126.05 <I>m</I>/<I>z</I>, RT: 106, [M+H]<SUP>+</SUP>), 3-methoxy-4-hydroxyphenyl(ethylene)glycol (185.05 <I>m</I>/<I>z</I>, RT: 155, [M+H]<SUP>+</SUP>), 3,4-dihydroxy-phenylalanine (198.07 <I>m</I>/<I>z</I>, RT: 446, [M+H]<SUP>+</SUP>), γ-glutamylcysteine (236.06 <I>m</I>/<I>z</I>, RT: 528, [M+S(34)+H]<SUP>+</SUP>), Cys-Gly, (253.06 <I>m</I>/<I>z</I>, RT: 528, [M-NH<SUB>3</SUB>+H]<SUP>+</SUP>), and reduced Flavin mononucleotide (517.0794 <I>m/z</I>, RT: 533, [M+NaCl]<SUP>+</SUP>). Tyrosine metabolism, degradation of aromatic compounds, and glutathione metabolism are suggested to be significant pathways relating to CS resistance.</P> <P><B>Conclusions</B></P> <P>High-resolution metabolomics is a promising approach in asthma research. Five candidate markers were identified to be related to CS-resistant children with severe asthma. These compounds, upon validation, may contribute further in the understanding of CS resistance among children with severe asthma through the use of urine.</P>

Seasonal and geographical toxicity of Indoxacarb against Helicoverpa armigera and influence of different host plants against Indoxacarb in India, 2005–2007

Basweshwar S. GHODKI,Shivcharan M. THAKARE,Mangesh P. MOHARIL,Nagarjuna G. V. RAO 한국곤충학회 2009 Entomological Research Vol.39 No.1

Indoxacarb, an oxadiazine insecticide, was evaluated for its effectiveness against Helicoverpa armigera collected from selected locations in India. Determination of Indoxacarb efficacy was done using a log-dose probit (LDP) bioassay against third instars collected from cotton (Gossypium arborium) fields near Akola, India. Monthly levels of toxicity of Indoxacarb were determined from July 2005 to March 2007. The maximum tolerance level of Indoxacarb was reported for the Amaravati strain (5.09 p.p.m.) and the minimum tolerance level for the Fatehbad strain (0.22 p.p.m.). Seasonal monitoring of Indoxacarb toxicity revealed an increased trend in tolerance from July 2005 to February 2006, which decreased from March 2006. The LC50 of Indoxacarb was 2.71 p.p.m. in July 2005 and 17.14 p.p.m. in February 2006. During 2006–007, the LC50 was 3.84 p.p.m. at the start of the season and in March 2007 it was 13.51 p.p.m. The minimum LC50 of Indoxacarb was reported for H. armigera larvae fed on Legasca spp. (1.62 p.p.m.) and the maximum LC50 was reported for H. armigera reared on chickpea (Cicer arietium) (8.45 p.p.m.). LC50 of 2.73 and 4.56 p.p.m. were reported for H. armigera fed on cotton (Gossypium arborium) and pigeonpea (Cajanus cajan), respectively.

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>

Non-traditional Straws: Alternate Feedstuffs for Ruminants

Kaushal, S.,Wadhwa, M.,Bakshi, M.P.S. Asian Australasian Association of Animal Productio 2006 Animal Bioscience Vol.19 No.12

The nutritive value of 4 straws, obtained after thrashing of seeds from fodder crops, was assessed as complete feed for ruminants. Sixteen male Murrah buffaloes (liveweight 365.8${\pm}$19.5 kg), were divided into 4 equal groups and offered ad lib. straw of either Trifolium resupinatum, Trifolium alexandrium, Medicago sativa or Lolium perenne, supplemented with minerals and vitamin A, for 40 days in a completely randomized design. Simultaneously, each straw was offered to 3 rumen fistulated male buffaloes in order to assess the biochemical changes in the rumen. Compared to other straws M. sativa straw had higher (p<0.05) organic matter (OM), crude protein (CP), acid-detergent fiber (ADF) and cellulose content. L .perenne had the highest (p<0.05) hemicellulose and lowest (p<0.05) CP and acid-detergent lignin (ADL) content. T. resupinatum had the lowest concentration of cell wall constituents (CWC). The digestibility of nutrients of T. resupinatum and L. perenne straw was similar, but higher (p<0.05) than that of other straws. M.sativa straw showed highest (p<0.05) digestibility of CP. The highest OM digestibility of T. resupinatum and CP digestibility of M. sativa were responsible for highest (p<0.05) total volatile fatty acids and trichloroacetic acid precipitable nitrogen in the strained rumen liquor. The digestible crude protein (DCP) was highest (p<0.05) in M. sativa followed by that in T. alexandrium. The total purine derivatives excreted in urine varied from 0.22-0.32 mmol/kg $W^{.75}/d$. The efficiency of microbial protein synthesis indicated that OM of straws of M. sativa and that of T. alexandrium was used more (p<0.05) efficiently. The microbial protein synthesized was highest in T. resupinatum, but statistically similar to other groups. The values for N-retention and apparent biological value were highest for L. perenne, though comparable with that of M. sativa and T. alexandrium. The available metabolizable energy (ME) was highest (p<0.05) in T. resupinatum followed by that in L. perenne and lowest in M. sativa. It was concluded that all the straws, supplemented with minerals and vitamin A, could be fed exclusively to adult ruminants with no adverse affect, as animals were able to maintain body weight (372${\pm}$20.1 kg).

Expression phenotype changes of EBV-transformed lymphoblastoid cell lines during long-term subculture and its clinical significance

Lee, J.-E.,Nam, H.-Y.,Shim, S.-M.,Bae, G.-R.,Han, B.-G.,Jeon, J.-P. Blackwell Publishing Ltd 2010 Cell proliferation Vol.43 No.4

<P>Abstract</P><P>Objectives: </P><P>The EBV-transformed lymphoblastoid cell line (LCL) is a useful resource for population-based human genetic and pharmacogenetic studies. The principal objective here was to assess expression phenotype changes during long-term subculture of LCLs, and its clinical significance.</P><P>Materials and methods: </P><P>We searched for genes that were differentially expressed in 17 LCLs at late (p161) passage compared to early passage (p4) using microarray assay, then validated them by real-time RT-PCR analysis. In addition, we estimated correlations between expression phenotypes of 20 LCL strains at early passage and 23 quantitative clinical traits from blood donors of particular LCL strains.</P><P>Results: </P><P>Transcript sequences of 16 genes including nuclear factor-&kgr;B (NF-&kgr;B) pathway-related genes (such as <I>PTPN13</I>, <I>HERC5</I> and miR-146a) and carcinogenesis-related genes (such as <I>XAF1</I>, <I>TCL1A</I>, <I>PTPN13</I>, <I>CD38</I> and miR-146a) were differentially expressed (>2-fold change) in at least 15 of the 17 LCL strains. In particular, <I>TC2N</I>, <I>FCRL5</I>, <I>CD180</I>, <I>CD38</I> and miR-146a were downregulated in all 17 of the evaluated LCL strains. In addition, we identified clinical trait-associated expression phenotypes in LCLs.</P><P>Conclusion: </P><P>Our results showed that LCLs acquired expression phenotype changes involving expression of NF-&kgr;B pathway- and carcinogenesis-related genes during long-term subculture. These differentially expressed genes can be considered to be a gene signature of LCL immortalization or EBV-induced carcinogenesis. Clinical trait-associated expression phenotypes should prove useful in the discovery of new candidate genes for particular traits.</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>

Determination of N* amplitudes from associated strangeness production in p+p collisions

Mü,nzer, R.,Fabbietti, L.,Epple, E.,Lu, S.,Klose, P.,Hauenstein, F.,Herrmann, N.,Grzonka, D.,Leifels, Y.,Maggiora, M.,Pleiner, D.,Ramstein, B.,Ritman, J.,Roderburg, E.,Salabura, P.,Sarantsev, A.,B North-Holland Pub. Co 2018 Physics letters. Section B Vol.785 No.-

<P><B>Abstract</B></P> <P>We present the first determination of the energy-dependent amplitudes of N<SUP>⁎</SUP> resonances extracted from their decay in KΛ pairs in p+p → <SUP> pK + </SUP> Λ reactions. A combined Partial Wave Analysis of seven data samples with exclusively reconstructed p+p → <SUP> pK + </SUP> Λ events measured by the COSY-TOF, DISTO, FOPI and HADES Collaborations in fixed target experiments at kinetic energies between 2.14 to 3.5 GeV is used to determine the amplitude of the resonant and non-resonant contributions into the associated strangeness final state. The contribution of seven N<SUP>⁎</SUP> resonances with masses between 1650 MeV/c<SUP>2</SUP> and 1900 MeV/c<SUP>2</SUP> for an excess energy between 0 and 600 MeV has been considered. The Σ–p cusp and final state interactions for the p–Λ channel are also included as coherent contributions in the PWA. The N<SUP>⁎</SUP> contribution is found to be dominant with respect to the phase space emission of the pK Λ + final state at all energies demonstrating the important role played by both N<SUP>⁎</SUP> and interference effects in hadron–hadron collisions.</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>

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>

Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors

Westhovens, R,Robles, M,Ximenes, A C,Nayiager, S,Wollenhaupt, J,Durez, P,Gomez-Reino, J,Grassi, W,Haraoui, B,Shergy, W,Park, S-H,Genant, H,Peterfy, C,Becker, J-C,Covucci, A,Helfrick, R,Bathon, J BMJ Group 2009 Annals of the Rheumatic Diseases Vol.68 No.12

<P><B>Objectives:</B></P><P>To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis (RA) and poor prognostic factors.</P><P><B>Methods:</B></P><P>In this double-blind, phase IIIb study, patients with RA for 2 years or less were randomly assigned 1 : 1 to receive abatacept (∼10 mg/kg) plus methotrexate, or placebo plus methotrexate. Patients were methotrexate-naive and seropositive for rheumatoid factor (RF), anti-cyclic citrullinated protein (CCP) type 2 or both and had radiographic evidence of joint erosions. The co-primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission (C-reactive protein) and joint damage progression (Genant-modified Sharp total score; TS) at year 1. Safety was monitored throughout.</P><P><B>Results:</B></P><P>At baseline, patients had a mean DAS28 of 6.3, a mean TS of 7.1 and mean disease duration of 6.5 months; 96.5% and 89.0% of patients were RF or anti-CCP2 seropositive, respectively. At year 1, a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission (41.4% vs 23.3%; p<0.001) and there was significantly less radiographic progression (mean change in TS 0.63 vs 1.06; p = 0.040) versus methotrexate alone. Over 1 year, the frequency of adverse events (84.8% vs 83.4%), serious adverse events (7.8% vs 7.9%), serious infections (2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%) and malignancies (0.4% vs 0%) was comparable for abatacept plus methotrexate versus methotrexate alone.</P><P><B>Conclusions:</B></P><P>In a methotrexate-naive population with early RA and poor prognostic factors, the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable, favourable safety profile.</P>