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The challenge of cross-trial comparisons using limited data.
Laubach JP, Faber EA, Voorhees P, Moslehi J, Varga C, Niculescu L, Anderson KC, Richardson PG
(2014) Haematologica 99: e145-6
MeSH Terms: Female, Humans, Male, Multiple Myeloma, Oligopeptides, Proteasome Inhibitors
Added March 4, 2015
0 Communities
1 Members
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6 MeSH Terms
Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
Johnson DH, Venuto C, Ritchie MD, Morse GD, Daar ES, McLaren PJ, Haas DW
(2014) Pharmacogenet Genomics 24: 195-203
MeSH Terms: Acquired Immunodeficiency Syndrome, Adult, Antiretroviral Therapy, Highly Active, Atazanavir Sulfate, Bilirubin, Female, Genome-Wide Association Study, Glucuronosyltransferase, HIV Protease Inhibitors, Humans, Hyperbilirubinemia, Male, Middle Aged, Multivariate Analysis, Oligopeptides, Polymorphism, Single Nucleotide, Prospective Studies, Pyridines, Ritonavir
Show Abstract · Added March 13, 2015
BACKGROUND - Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
METHODS - Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available.
RESULTS - Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance.
CONCLUSION - Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.
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1 Members
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19 MeSH Terms
Nature of KaiB-KaiC binding in the cyanobacterial circadian oscillator.
Pattanayek R, Yadagiri KK, Ohi MD, Egli M
(2013) Cell Cycle 12: 810-7
MeSH Terms: Bacterial Proteins, Circadian Clocks, Circadian Rhythm Signaling Peptides and Proteins, Histidine, Models, Molecular, Nanostructures, Negative Staining, Oligopeptides, Protein Binding, Scattering, Small Angle, Static Electricity, Synechococcus, X-Ray Diffraction
Show Abstract · Added March 7, 2014
In the cyanobacteria Synechococcus elongatus and Thermosynechococcus elongatus, the KaiA, KaiB and KaiC proteins in the presence of ATP generate a post-translational oscillator (PTO) that can be reconstituted in vitro. KaiC is the result of a gene duplication and resembles a double doughnut with N-terminal CI and C-terminal CII hexameric rings. Six ATPs are bound between subunits in both the CI and CII ring. CI harbors ATPase activity, and CII catalyzes phosphorylation and dephosphorylation at T432 and S431 with a ca. 24-h period. KaiA stimulates KaiC phosphorylation, and KaiB promotes KaiC subunit exchange and sequesters KaiA on the KaiB-KaiC interface in the final stage of the clock cycle. Studies of the PTO protein-protein interactions are convergent in terms of KaiA binding to CII but have led to two opposing models of the KaiB-KaiC interaction. Electron microscopy (EM) and small angle X-ray scattering (SAXS), together with native PAGE using full-length proteins and separate CI and CII rings, are consistent with binding of KaiB to CII. Conversely, NMR together with gel filtration chromatography and denatured PAGE using monomeric CI and CII domains support KaiB binding to CI. To resolve the existing controversy, we studied complexes between KaiB and gold-labeled, full-length KaiC with negative stain EM. The EM data clearly demonstrate that KaiB contacts the CII ring. Together with the outcomes of previous analyses, our work establishes that only CII participates in interactions with KaiA and KaiB as well as with the His kinase SasA involved in the clock output pathway.
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3 Members
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13 MeSH Terms
Gas-phase reactivity of carboxylic acid functional groups with carbodiimides.
Prentice BM, Gilbert JD, Stutzman JR, Forrest WP, McLuckey SA
(2013) J Am Soc Mass Spectrom 24: 30-7
MeSH Terms: Carbodiimides, Carboxylic Acids, Dendrimers, Edetic Acid, Gases, Ions, Mass Spectrometry, Oligopeptides
Show Abstract · Added August 17, 2016
Gas-phase modification of carboxylic acid functionalities is performed via ion/ion reactions with carbodiimide reagents [N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide (CMC) and [3-(3-Ethylcarbodiimide-1-yl)propyl]trimethylaminium (ECPT)]. Gas-phase ion/ion covalent chemistry requires the formation of a long-lived complex. In this instance, the complex is stabilized by an electrostatic interaction between the fixed charge quaternary ammonium group of the carbodiimide reagent cation and the analyte dianion. Subsequent activation results in characteristic loss of an isocyanate derivative from one side of the carbodiimide functionality, a signature for this covalent chemistry. The resulting amide bond is formed on the analyte at the site of the original carboxylic acid. Reactions involving analytes that do not contain available carboxylic acid groups (e.g., they have been converted to sodium salts) or reagents that do not have the carbodiimide functionality do not undergo a covalent reaction. This chemistry is demonstrated using PAMAM generation 0.5 dendrimer, ethylenediaminetetraacetic acid (EDTA), and the model peptide DGAILDGAILD. This work demonstrates the selective gas-phase covalent modification of carboxylic acid functionalities.
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8 MeSH Terms
Impact of UGT1A1 Gilbert variant on discontinuation of ritonavir-boosted atazanavir in AIDS Clinical Trials Group Study A5202.
Ribaudo HJ, Daar ES, Tierney C, Morse GD, Mollan K, Sax PE, Fischl MA, Collier AC, Haas DW, DS Clinical Trials Group
(2013) J Infect Dis 207: 420-5
MeSH Terms: Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Atazanavir Sulfate, Bilirubin, Genetic Variation, Genotype, Glucuronosyltransferase, HIV Infections, HIV-1, Humans, Jaundice, Oligopeptides, Pyridines, Ritonavir
Show Abstract · Added March 13, 2015
The UGT1A1*28 variant has been associated with hyperbilirubinemia and atazanavir discontinuation. Protocol A5202 randomly assigned human immunodeficiency virus type 1 (HIV-1)-infected patients to receive atazanavir/ritonavir (atazanavir/r) or efavirenz, with tenofovir/emtricitabine or abacavir/lamivudine. A total of 646 atazanavir/r recipients were evaluable for UGT1A1. Homozygosity for *28/*28 was present in 8% of whites, 24% of blacks, and 18% of Hispanics and was associated with increased bilirubin concentrations. There was an association between *28/*28 and increased atazanavir/r discontinuation among Hispanic participants (P = .005) but not among white or black participants (P = .79 and P = .46, respectively). The positive predictive value of 28*/28* for atazanavir/r discontinuation among Hispanic participants was only 32% (95% confidence interval, 16%-52%).
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1 Members
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14 MeSH Terms
A sequential mechanism for exosite-mediated factor IX activation by factor XIa.
Geng Y, Verhamme IM, Messer A, Sun MF, Smith SB, Bajaj SP, Gailani D
(2012) J Biol Chem 287: 38200-9
MeSH Terms: Arginine, Binding Sites, Binding, Competitive, Biocatalysis, Calcium, Catalytic Domain, Electrophoresis, Polyacrylamide Gel, Factor IX, Factor IXa, Factor XIa, HEK293 Cells, Humans, Kinetics, Mutation, Oligopeptides, Protein Multimerization, Proteolysis, Pyrrolidonecarboxylic Acid, Recombinant Proteins, Substrate Specificity
Show Abstract · Added May 19, 2014
During blood coagulation, the protease factor XIa (fXIa) activates factor IX (fIX). We describe a new mechanism for this process. FIX is cleaved initially after Arg(145) to form fIXα, and then after Arg(180) to form the protease fIXaβ. FIXα is released from fXIa, and must rebind for cleavage after Arg(180) to occur. Catalytic efficiency of cleavage after Arg(180) is 7-fold greater than for cleavage after Arg(145), limiting fIXα accumulation. FXIa contains four apple domains (A1-A4) and a catalytic domain. Exosite(s) on fXIa are required for fIX binding, however, there is lack of consensus on their location(s), with sites on the A2, A3, and catalytic domains described. Replacing the A3 domain with the prekallikrein A3 domain increases K(m) for fIX cleavage after Arg(145) and Arg(180) 25- and ≥ 90-fold, respectively, and markedly decreases k(cat) for cleavage after Arg(180). Similar results were obtained with the isolated fXIa catalytic domain, or fXIa in the absence of Ca(2+). Forms of fXIa lacking the A3 domain exhibit 15-fold lower catalytic efficiency for cleavage after Arg(180) than for cleavage after Arg(145), resulting in fIXα accumulation. Replacing the A2 domain does not affect fIX activation. The results demonstrate that fXIa activates fIX by an exosite- and Ca(2+)-mediated release-rebind mechanism in which efficiency of the second cleavage is enhanced by conformational changes resulting from the first cleavage. Initial binding of fIX and fIXα requires an exosite on the fXIa A3 domain, but not the A2 or catalytic domain.
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1 Members
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20 MeSH Terms
The human metapneumovirus fusion protein mediates entry via an interaction with RGD-binding integrins.
Cox RG, Livesay SB, Johnson M, Ohi MD, Williams JV
(2012) J Virol 86: 12148-60
MeSH Terms: Amino Acid Motifs, Cell Line, Flow Cytometry, Humans, Integrins, Membrane Fusion, Metapneumovirus, Microscopy, Electron, Oligopeptides, Protein Binding, Receptors, Vitronectin, Recombinant Proteins, Viral Fusion Proteins, Virion, Virus Internalization
Show Abstract · Added March 7, 2014
Paramyxoviruses use a specialized fusion protein to merge the viral envelope with cell membranes and initiate infection. Most paramyxoviruses require the interaction of two viral proteins to enter cells; an attachment protein binds cell surface receptors, leading to the activation of a fusion (F) protein that fuses the viral envelope and host cell plasma membrane. In contrast, human metapneumovirus (HMPV) expressing only the F protein is replication competent, suggesting a primary role for HMPV F in attachment and fusion. We previously identified an invariant arginine-glycine-aspartate (RGD) motif in the HMPV F protein and showed that the RGD-binding integrin αVβ1-promoted HMPV infection. Here we show that both HMPV F-mediated binding and virus entry depend upon multiple RGD-binding integrins and that HMPV F can mediate binding and fusion in the absence of the viral attachment (G) protein. The invariant F-RGD motif is critical for infection, as an F-RAE virus was profoundly impaired. Further, F-integrin binding is required for productive viral RNA transcription, indicating that RGD-binding integrins serve as receptors for the HMPV fusion protein. Thus, HMPV F is triggered to induce virus-cell fusion by interactions with cellular receptors in a manner that is independent of the viral G protein. These results suggest a stepwise mechanism of HMPV entry mediated by the F protein through its interactions with cellular receptors, including RGD-binding integrins.
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2 Members
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15 MeSH Terms
ßarrestin1-biased agonism at human δ-opioid receptor by peptidic and alkaloid ligands.
Aguila B, Coulbault L, Davis A, Marie N, Hasbi A, Le bras F, Tóth G, Borsodi A, Gurevich VV, Jauzac P, Allouche S
(2012) Cell Signal 24: 699-707
MeSH Terms: Arrestins, Cell Line, Endocytosis, Enkephalin, D-Penicillamine (2,5)-, Etorphine, Humans, Ligands, Oligopeptides, RNA Interference, RNA, Small Interfering, Receptors, Opioid, delta, Signal Transduction, beta-Arrestins
Show Abstract · Added December 10, 2013
We have previously reported on the differential regulation of the human δ-opioid receptor (hDOR) by alkaloid (etorphine) and peptidic (DPDPE and deltorphin I) ligands, in terms of both receptor desensitization and post-endocytic sorting. Since ßarrestins are well known to regulate G protein-coupled receptors (GPCRs) signaling and trafficking, we therefore investigated the role of ßarrestin1 (the only isoform expressed in our cellular model) in the context of the hDOR. We established clonal cell lines of SK-N-BE cells over-expressing ßarrestin1, its dominant negative mutant (ßarrestin1(319-418)), and shRNA directed against endogenous ßarrestin1. Interestingly, both binding and confocal microscopy approaches demonstrated that ßarrestin1 is required for hDOR endocytosis only when activated by etorphine. Conversely, functional experiments revealed that ßarrestin1 is exclusively involved in hDOR desensitization promoted by the peptides. Taken together, these results provide substantial evidence for a ßarrestin1-biased agonism at hDOR, where ßarrestin1 is differentially involved during receptor desensitization and endocytosis depending on the ligand.
Copyright © 2011 Elsevier Inc. All rights reserved.
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1 Members
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13 MeSH Terms
Engineering streptokinase for generation of active site-labeled plasminogen analogs.
Laha M, Panizzi P, Nahrendorf M, Bock PE
(2011) Anal Biochem 415: 105-15
MeSH Terms: Biocatalysis, Catalytic Domain, Endopeptidases, Enzyme Precursors, Fluorescent Dyes, Histidine, Imino Acids, Kinetics, Oligopeptides, Plasminogen, Protein Binding, Protein Engineering, Recombinant Fusion Proteins, Streptokinase
Show Abstract · Added January 20, 2015
We previously demonstrated that streptokinase (SK) can be used to generate active site-labeled fluorescent analogs of plasminogen (Pg) by virtue of its nonproteolytic activation of the zymogen. The method is versatile and allows stoichiometric and active site-specific incorporation of any one of many molecular probes. The limitation of the labeling approach is that it is both time-consuming and low yield. Here we demonstrate an improved method for the preparation of labeled Pg analogs by the use of an engineered SK mutant fusion protein with both COOH- and NH(2)-terminal His(6) tags. The NH(2)-terminal tag is followed by a tobacco etch virus proteinase cleavage site to ensure that the SK Ile(1) residue, essential for conformational activation of Pg, is preserved. The SK COOH-terminal Lys(414) residue and residues Arg253-Leu260 in the SK β-domain were deleted to prevent cleavage by plasmin (Pm) and to disable Pg substrate binding to the SK·Pg(∗)/Pm catalytic complexes, respectively. Near elimination of Pm generation with the SKΔ(R253-L260)ΔK414-His(6) mutant increased the yield of labeled Pg 2.6-fold and reduced the time required more than 2-fold. The versatility of the labeling method was extended to the application of Pg labeled with a near-infrared probe to quantitate Pg receptors on immune cells by flow cytometry.
Copyright © 2011 Elsevier Inc. All rights reserved.
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1 Members
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14 MeSH Terms
Methods for peptide and protein quantitation by liquid chromatography-multiple reaction monitoring mass spectrometry.
Zhang H, Liu Q, Zimmerman LJ, Ham AJ, Slebos RJ, Rahman J, Kikuchi T, Massion PP, Carbone DP, Billheimer D, Liebler DC
(2011) Mol Cell Proteomics 10: M110.006593
MeSH Terms: Adenocarcinoma, Alkaline Phosphatase, Amino Acid Sequence, Biomarkers, Tumor, Carcinoma, Squamous Cell, Cell Line, Tumor, Chromatography, Liquid, Humans, Isotope Labeling, Lung Neoplasms, Mass Spectrometry, Molecular Sequence Data, Oligopeptides, Peptide Fragments, Peptides, Proteins, Reference Standards
Show Abstract · Added March 5, 2014
Liquid chromatography-multiple reaction monitoring mass spectrometry of peptides using stable isotope dilution (SID) provides a powerful tool for targeted protein quantitation. However, the high cost of labeled peptide standards for SID poses an obstacle to multiple reaction monitoring studies. We compared SID to a labeled reference peptide (LRP) method, which uses a single labeled peptide as a reference standard for all measured peptides, and a label-free (LF) approach, in which quantitation is based on analysis of un-normalized peak areas for detected MRM transitions. We analyzed peptides from the Escherichia coli proteins alkaline phosphatase and β-galactosidase spiked into lysates from human colon adenocarcinoma RKO cells. We also analyzed liquid chromatography-multiple reaction monitoring mass spectrometry data from a recently published interlaboratory study by the National Cancer Institute Clinical Proteomic Technology Assessment for Cancer network (Addona et al. (2009) Nat. Biotechnol. 27: 633-641), in which unlabeled and isotopically labeled synthetic peptides or their corresponding proteins were spiked into human plasma. SID displayed the highest correlation coefficients and lowest coefficient of variation in regression analyses of both peptide and protein spike studies. In protein spike experiments, median coefficient of variation values were about 10% for SID and 20-30% for LRP and LF methods. Power calculations indicated that differences in measurement error between the methods have much less impact on measured protein expression differences than biological variation. All three methods detected significant (p < 0.05) differential expression of three endogenous proteins in a test set of 10 pairs of human lung tumor and control tissues. Further, the LRP and LF methods both detected significant differences (p < 0.05) in levels of seven biomarker candidates between tumors and controls in the same set of lung tissue samples. The data indicate that the LRP and LF methods provide cost-effective alternatives to SID for many quantitative liquid chromatography-multiple reaction monitoring mass spectrometry applications.
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3 Members
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17 MeSH Terms