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961.
Holton S Merckx A Burgess D Doerig C Noble M Endicott J 《Structure (London, England : 1993)》2003,11(11):1329-1337
Plasmodium falciparum cell cycle regulators are promising targets for antimalarial drug design. We have determined the structure of PfPK5, the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. The fold and the mechanism of inactivation of monomeric CDKs are highly conserved across evolution. ATP-competitive CDK inhibitors have been developed as potential leads for cancer therapeutics. These studies have identified regions of the CDK active site that can be exploited to achieve significant gains in inhibitor potency and selectivity. We have cocrystallized PfPK5 with three inhibitors that target such regions. The sequence differences between PfPK5 and human CDKs within these inhibitor binding sites suggest that selective inhibition is an attainable goal. Such compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for antimalarial drug development. 相似文献
962.
Bakare O Ashendel CL Peng H Zalkow LH Burgess EM 《Bioorganic & medicinal chemistry》2003,11(14):3165-3170
Mitogen activated protein kinases are of interest as research tools and as therapeutic target for certain physiological disorders. In this study, we found 2-chloro-3-(N-succinimidyl)-1,4-naphthoquinone 6 to be a selective inhibitor of MEK1 with an IC(50) of 0.38 microM. An open-chain homologue, 10, showed selective cytotoxicity against renal cancer in the NCI in vitro tumor screening. Structure-activity relationship study of eight compounds showed the cyclic imido-substituted chloro-1,4-naphthoquinone as more potent and selective MEK1 inhibitors than the open chain homologues. The imido-substituted chloro-1,4-naphthoquinones were synthesized in a straightforward fashion by refluxing 2-amino-3-chloro-1,4-naphthoquinone with the appropriate acid chloride or diacyl dichloride. 相似文献
963.
Mary P. McGowan Jean-Claude Tardif Richard Ceska Lesley J. Burgess Handrean Soran Ioanna Gouni-Berthold Gilbert Wagener Scott Chasan-Taber 《PloS one》2012,7(11)
Objectives
Mipomersen, an antisense oligonucleotide targeting apolipoprotein B synthesis, significantly reduces LDL-C and other atherogenic lipoproteins in familial hypercholesterolemia when added to ongoing maximally tolerated lipid-lowering therapy. Safety and efficacy of mipomersen in patients with severe hypercholesterolemia was evaluated.Methods and Results
Randomized, double-blind, placebo-controlled, multicenter trial. Patients (n = 58) were ≥18 years with LDL-C ≥7.8 mmol/L or LDL-C ≥5.1 mmol/L plus CHD disease, on maximally tolerated lipid-lowering therapy that excluded apheresis. Weekly subcutaneous injections of mipomersen 200 mg (n = 39) or placebo (n = 19) were added to lipid-lowering therapy for 26 weeks. Main outcome: percent reduction in LDL-C from baseline to 2 weeks after the last dose of treatment. Mipomersen (n = 27) reduced LDL-C by 36%, from a baseline of 7.2 mmol/L, for a mean absolute reduction of 2.6 mmol/L. Conversely, mean LDL-C increased 13% in placebo (n = 18) from a baseline of 6.5 mmol/L (mipomersen vs placebo p<0.001). Mipomersen produced statistically significant (p<0.001) reductions in apolipoprotein B and lipoprotein(a), with no change in high-density lipoprotein cholesterol. Mild-to-moderate injection site reactions were the most frequently reported adverse events with mipomersen. Mild-to-moderate flu-like symptoms were reported more often with mipomersen. Alanine transaminase increase, aspartate transaminase increase, and hepatic steatosis occurred in 21%, 13% and 13% of mipomersen treated patients, respectively. Adverse events by category for the placebo and mipomersen groups respectively were: total adverse events, 16(84.2%), 39(100%); serious adverse events, 0(0%), 6(15.4%); discontinuations due to adverse events, 1(5.3%), 8(20.5%) and cardiac adverse events, 1(5.3%), 5(12.8%).Conclusion
Mipomersen significantly reduced LDL-C, apolipoprotein B, total cholesterol and non-HDL-cholesterol, and lipoprotein(a). Mounting evidence suggests it may be a potential pharmacologic option for lowering LDL-C in patients with severe hypercholesterolemia not adequately controlled using existing therapies. Future studies will explore alternative dosing schedules aimed at minimizing side effects.Trial Registration
ClinicalTrials.gov . NCT00794664相似文献964.
Simon Willcock Oliver L. Phillips Philip J. Platts Andrew Balmford Neil D. Burgess Jon C. Lovett Antje Ahrends Julian Bayliss Nike Doggart Kathryn Doody Eibleis Fanning Jonathan Green Jaclyn Hall Kim L. Howell Rob Marchant Andrew R. Marshall Boniface Mbilinyi Pantaleon K. T. Munishi Nisha Owen Ruth D. Swetnam Elmer J. Topp-Jorgensen Simon L. Lewis 《PloS one》2012,7(9)
Monitoring landscape carbon storage is critical for supporting and validating climate change mitigation policies. These may be aimed at reducing deforestation and degradation, or increasing terrestrial carbon storage at local, regional and global levels. However, due to data-deficiencies, default global carbon storage values for given land cover types such as ‘lowland tropical forest’ are often used, termed ‘Tier 1 type’ analyses by the Intergovernmental Panel on Climate Change (IPCC). Such estimates may be erroneous when used at regional scales. Furthermore uncertainty assessments are rarely provided leading to estimates of land cover change carbon fluxes of unknown precision which may undermine efforts to properly evaluate land cover policies aimed at altering land cover dynamics. Here, we present a repeatable method to estimate carbon storage values and associated 95% confidence intervals (CI) for all five IPCC carbon pools (aboveground live carbon, litter, coarse woody debris, belowground live carbon and soil carbon) for data-deficient regions, using a combination of existing inventory data and systematic literature searches, weighted to ensure the final values are regionally specific. The method meets the IPCC ‘Tier 2’ reporting standard. We use this method to estimate carbon storage over an area of33.9 million hectares of eastern Tanzania, reporting values for 30 land cover types. We estimate that this area stored 6.33 (5.92–6.74) Pg C in the year 2000. Carbon storage estimates for the same study area extracted from five published Africa-wide or global studies show a mean carbon storage value of ∼50% of that reported using our regional values, with four of the five studies reporting lower carbon storage values. This suggests that carbon storage may have been underestimated for this region of Africa. Our study demonstrates the importance of obtaining regionally appropriate carbon storage estimates, and shows how such values can be produced for a relatively low investment. 相似文献
965.
Gabriel N. Defang Nicholas J. Martin Timothy H. Burgess Eugene V. Millar LeNae A. Pecenka Janine R. Danko John C. Arnold Tadeusz J. Kochel Thomas C. Luke 《PloS one》2012,7(12)
Influenza-specific hemaggluitination inhibition (HAI) antibody titer, an indicator of immunity to influenza, is often used to measure exposure to influenza in surveillance and immunogenicity studies. Traditionally, serum has been the specimen of choice for HAI assays, but a desire to reduce the amount of blood collected during studies and the availability of plasma in archived sample collections warrant the evaluation of plasma for HAI titer. Therefore, the relationship between serum and plasma HAI titer values is of great interest. Here, we compare HAI titers determined on temporally matched serum and plasma (citrated and heparinized) using influenza A and B viruses. Bland-Altman plots, McNemar''s test, and geometric coefficient of variation were used respectively for evaluating agreement, correlation and variability in the serum-plasma titer results. We observed a high degree of agreement (80.5%–98.8%) and correlation (r = 0.796–0.964) in the serum and matched plasma titer values although plasma titers were generally lower than corresponding serum titers. Calculated seropositive (HAI ≥40) rates were higher using serum titers than with plasma titers, but seroconversion rates were unaffected by sample type. Stronger agreement and decreased variability in titers were seen between serum and citrated plasma than between serum and heparinized plasma. Overall, these data suggest that serum or plasma can be used in serodiagnostic HAI assays, but seropositive rates may be underestimated using plasma HAI titers. The type of anticoagulant present in plasma may affect HAI titer values and warrants further investigation. 相似文献
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