<i>In vitro</i> inhibitory effects of Wen‐pi‐tang‐Hab‐Wu‐ling‐san on human cytochrome P450 isoforms

Lee, H. W.,Kim, D. W.,Phapale, P. B.,Lim, M. ‐,S.,Park, J.,Seo, J. J.,Park, K. M.,Park, Y. ‐,K.,Yoon, Y. ‐,R. Blackwell Publishing Ltd 2011 Journal of clinical pharmacy and therapeutics Vol.36 No.4

<P><B>Summary</B></P><P><B>What is known and Objective: </B> Although Wen‐pi‐tang‐Hab‐Wu‐ling‐san (WHW), an oriental herbal medicine, has been prescribed for the treatment of chronic renal failure (CRF) in Korean clinics, no studies regarding WHW–drug interactions had been reported. The purpose of this study was to evaluate the possibility that WHW inhibits the catalytic activities of major cytochrome P450 (CYP) isoforms.</P><P><B>Methods: </B> The abilities of various WHW extracts to inhibit phenacetin O‐de‐ethylation (CYP1A2), tolbutamide 4‐methylhydroxylation (CYP2C9), omeprazole 4′‐hydroxylation (CYP2C19), dextromethorphan O‐demethylation (CYP2D6), chlorzoxazone 6‐hydroxylation (CYP2E1) and midazolam 1‐hydroxylation (CYP3A4) were assessed using human liver microsomes.</P><P><B>Results and Discussion: </B> WHW extract at concentrations up to 100 μ<SMALL>m</SMALL> showed negligible inhibition of the six CYP isoforms tested (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4), with apparent IC<SUB>50</SUB> values (concentration of the inhibitor causing 50% inhibition of the original enzyme activity) of 817.5, 601.6, 521.7, 310.2, 342.8 and 487.0 μg/mL, respectively.</P><P><B>What is new and Conclusion: </B> Our <I>in vitro</I> findings suggest that WHW extract at concentrations corresponding to a clinically recommended dosage range has no notable inhibitory effects on CYP isoforms. Therefore, we believe that WHW extract may be free of drug–herb interactions when co‐administered with other medicines. However, <I>in vivo</I> human studies are needed to confirm these results.</P>

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points—Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Bergmeijer, Thomas O.,Reny, Jean-Luc,Pakyz, Ruth E.,Gong, Li,Lewis, Joshua P.,Kim, Eun-Young,Aradi, Daniel,Fernandez-Cadenas, Israel,Horenstein, Richard B.,Lee, Ming Ta Michael,Whaley, Ryan M.,Montane Elsevier 2018 American Heart Journal Vol.198 No.-

<P><B>Rationale</B></P> <P>The P2Y<SUB>12</SUB> receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. <I>CYP2C19</I> polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response.</P> <P><B>Study design</B></P> <P>Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies.</P> <P><B>Results</B></P> <P>In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate–stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y<SUB>12</SUB> assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between <I>CYP2C19</I>*2 and platelet reactivity (<I>P</I> value=5.1 × 10<SUP>−40</SUP>).</P> <P><B>Conclusion</B></P> <P>The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.</P>

MicroRNA signatures associated with immortalization of EBV‐transformed lymphoblastoid cell lines and their clinical traits

Lee, J.‐,E.,Hong, E.‐,J.,Nam, H.‐,Y.,Kim, J.‐,W.,Han, B.‐,G.,Jeon, J.‐,P. Blackwell Publishing Ltd 2011 Cell proliferation Vol.44 No.1

<P><B>Abstract</B></P><P><B>Objective: </B> MicroRNAs (miRNAs) are negative regulators of gene expression that play important roles in cell processes such as proliferation, development and differentiation. Recently, it has been reported that miRNAs are related to development of carcinogenesis. The aim of this study was to identify miRNAs associated with terminal immortalization of Epstein–Barr virus (EBV)‐transformed lymphoblastoid cell line (LCL) and associated clinical traits.</P><P><B>Material and Methods: </B> Hence, we performed miRNA microarray approach with early‐ (p6) and late‐passage (p161) LCLs.</P><P><B>Results and Conclusion: </B> Microarray data showed that nine miRNAs (miR‐20b*, miR‐28‐5p, miR‐99a, miR‐125b, miR‐151‐3p, miR‐151:9.1, miR‐216a, miR‐223* and miR‐1296) were differentially expressed in most LCLs during long‐term culture. In particular, miR‐125b was up‐regulated in all the tested late‐passage LCLs. miR‐99a, miR‐125b, miR‐216a and miR‐1296 were putative negative regulators of <I>RASGRP3</I>, <I>GPR160</I>, <I>PRKCH</I> and <I>XAF1</I>, respectively, which were found to be differentially expressed in LCLs during long‐term culture in a previous study. Linear regression analysis showed that miR‐200a and miR‐296‐3p correlated with triglyceride and HbA1C levels, respectively, suggesting that miRNA signatures of LCLs could provide information on the donor’s health. In conclusion, our study suggests that expression changes of specific miRNAs may be required for terminal immortalization of LCLs. Thus, differentially expressed miRNAs would be a potential marker for completion of cell immortalization during EBV‐mediated tumorigenesis.</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>

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>

On the range kernel orthogonality of derivations

Duggal, B.P. TOPOLOGY AND GEOMETRY RESEARCH CENTER 1998 Proceedings of the Topology and Geometry Research Vol.9 No.-

Let H be a separable infinite dimensional complex Hilbert space, and let B(H) denote the algebra of operators on H into itself. The generalized derivation δA,B : B(H) → B(H) is defined by δA,B (X) = AX - XB; let △A,B : B(H) → B(H) be defined by △A,B (X) = AXB - X, and let d A,B denote δA,B or △A,B . Given that S ∈ Cp (the Schatten p-class, 1 < p < ∞) and that the pair of operators A and B* satisfies a Putnam-Fuglede commutativity theorem type property, we consider here a necessary and sufficient condition for ∥dA,B (X) + S∥p ≥ ∥S∥ p to hold for all X ∈ C p.

The Impact of Feeding Diets of High or Low Energy Concentration on Carcass Measurements and the Weight of Primal and Subprimal Lean Cuts

Schinckel, A.P.,Einstein, M.E.,Jungst, S.,Matthews, J.O.,Fields, B.,Booher, C.,Dreadin, T.,Fralick, C.,Tabor, S.,Sosnicki, A.,Wilson, E.,Boyd, R.D. Asian Australasian Association of Animal Productio 2012 Animal Bioscience Vol.25 No.4

Pigs from four sire lines were allocated to a series of low energy (LE, 3.15 to 3.21 Mcal ME/kg) corn-soybean meal-based diets with 16% wheat midds or high energy diets (HE, 3.41 to 3.45 Mcal ME/kg) with 4.5 to 4.95% choice white grease. All diets contained 6% DDGS. The HE and LE diets of each of the four phases were formulated to have equal lysine:Mcal ME ratios. Barrows (N = 2,178) and gilts (N = 2,274) were fed either high energy (HE) or low energy (LE) diets from 27 kg BW to target BWs of 118, 127, 131.5 and 140.6 kg. Carcass primal and subprimal cut weights were collected. The cut weights and carcass measurements were fitted to allometric functions (Y = A $CW^B$) of carcass weight. The significance of diet, sex or sire line with A and B was evaluated by linearizing the equations by log to log transformation. The effect of diet on A and B did not interact with sex or sire line. Thus, the final model was cut weight = (1+$b_D$(Diet)) A($CW^B$) where Diet = -0.5 for the LE and 0.5 for HE diets and A and B are sire line-sex specific parameters. Diet had no affect on loin, Boston butt, picnic, baby back rib, or sparerib weights (p>0.10, $b_D$ = -0.003, -0.0029, 0.0002, 0.0047, -0.0025, respectively). Diet affected ham weight (bD = -0.0046, p = 0.01), belly weight (bD = 0.0188, p = 0.001) three-muscle ham weight ($b_D$ = -0.014, p = 0.001), boneless loin weight (bD = -0.010, p = 0.001), tenderloin weight ($b_D$ = -0.023, p = 0.001), sirloin weight ($b_D$ = -0.009, p = 0.034), and fat-free lean mass ($b_D$ = -0.0145, p = 0.001). Overall, feeding the LE diets had little impact on primal cut weight except to decrease belly weight. Feeding LE diets increased the weight of lean trimmed cuts by 1 to 2 percent at the same carcass weight.

Preferential Binding to Elk-1 by SLE-Associated <i>IL10</i> Risk Allele Upregulates <i>IL10</i> Expression

Sakurai, Daisuke,Zhao, Jian,Deng, Yun,Kelly, Jennifer A.,Brown, Elizabeth E.,Harley, John B.,Bae, Sang-Cheol,Alarcό,n-Riquelme, Marta E.,Edberg, Jeffrey C.,Kimberly, Robert P.,Ramsey-Goldman, Ros Public Library of Science 2013 PLoS genetics Vol.9 No.10

<▼1><P>Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of <I>IL10</I> with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the <I>IL10</I> gene cluster including <I>IL19</I>, <I>IL20</I> and <I>IL24</I>, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported <I>IL10</I> variant, rs3024505 located at 1 kb downstream of <I>IL10</I>, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (<I>P</I> = 2.7×10<SUP>−8</SUP>, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of <I>IL10</I>, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of <I>IL10</I> mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating <I>IL10</I> expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the <I>IL10</I> rs3122605-G allele upregulates <I>IL10</I> expression and confers increased risk for SLE in European Americans.</P></▼1><▼2><P><B>Author Summary</B></P><P>Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the <I>IL10</I> gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing <I>IL10</I> and its gene family member <I>IL19</I>, <I>IL20</I> and <I>IL24</I> for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of <I>IL10</I> as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated <I>IL10</I> expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.</P></▼2>

Search for B→hνν¯ decays with semileptonic tagging at Belle

Grygier, J.,Goldenzweig, P.,Heck, M.,Adachi, I.,Aihara, H.,Al Said, S.,Asner, D. M.,Aushev, T.,Ayad, R.,Aziz, T.,Babu, V.,Badhrees, I.,Bahinipati, S.,Bakich, A. M.,Bansal, V.,Barberio, E.,Behera, P.,B American Physical Society 2017 Physical Review D Vol.96 No.9

<P>We present the results of a search for the rare decays B -> h nu(nu) over bar, where h stands for K+, K-S(0), K*(+); K*(0); pi(+); pi(0), rho(+) and rho(0). The results are obtained with 772 x 10(6) B (B) over bar pairs collected with the Belle detector at the KEKB e(+)e(-) collider. We reconstruct one B meson in a semileptonic decay and require a single h meson but nothing else on the signal side. We observe no significant signal and set upper limits on the branching fractions. The limits set on the B-0 -> K-S(0)nu(nu) over bar, B-0 -> K*(0)nu(nu) over bar, B+ -> pi(+)nu(nu) over bar, B-0 -> pi(0)nu(nu) over bar, B+ -> rho(+)nu(nu) over bar, and B-0 -> rho(0)nu(nu) over bar channels are the world's most stringent.</P>