| 1711. |
|
|
| 1712. |
- van Erp, Nielka P, et al.
(författare)
-
Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib
- 2007
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:24, s. 7394-7400
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) mu g.h/mL and 41.2 (32.1-53.1) mu g.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 mu mol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.
|
|
| 1713. |
|
|
| 1714. |
- von Sydow, Lina, et al.
(författare)
-
BENCHOP—The BENCHmarking project in Option Pricing
- 2015
-
Ingår i: International Journal of Computer Mathematics. - : Informa UK Limited. - 1029-0265 .- 0020-7160. ; 92:12, s. 2361-2379
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the BENCHOP project is to provide the finance community with a common suite of benchmark problems for option pricing. We provide a detailed description of the six benchmark problems together with methods to compute reference solutions. We have implemented seventeen different numerical methods for these problems, and compare their relative performance. All implementations are available on line and can be used for future development and comparisons.
|
|
| 1715. |
- Wain, Louise V, et al.
(författare)
-
Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
- 2017
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:3, s. 416-425
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
|
|
| 1716. |
- Wain, Louise V., et al.
(författare)
-
Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
-
Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
-
Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
|
|
| 1717. |
|
|
| 1718. |
- Wang,, L., et al.
(författare)
-
Domino effect of a natural cascade alpine lake system on the Third Pole
- 2022
-
Ingår i: PNAS Nexus. - : Oxford University Press (OUP). - 2752-6542. ; 1:3
-
Tidskriftsartikel (refereegranskat)abstract
- Third Pole natural cascade alpine lakes (NCALs) are exceptionally sensitive to climate change, yet the underlying cryosphere-hydrological processes and associated societal impacts are largely unknown. Here, with a state-of-the-art cryosphere-hydrology-lake-dam model, we quantified the notable high-mountain Hoh-Xil NCALs basin (including Lakes Zonag, Kusai, Hedin Noel, and Yanhu, from upstream to downstream) formed by the Lake Zonag outburst in September 2011. We demonstrate that long-term increased precipitation and accelerated ice and snow melting as well as short-term heavy precipitation and earthquake events were responsible for the Lake Zonag outburst; while the permafrost degradation only had a marginal impact on the lake inflows but was crucial to lakeshore stability. The quadrupling of the Lake Yanhu area since 2012 was due to the tripling of inflows (from 0.25 to 0.76 km3/year for 1999 to 2010 and 2012 to 2018, respectively). Prediction of the NCALs changes suggests a high risk of the downstream Qinghai–Tibet Railway, necessitating timely adaptions/mitigations.
|
|
| 1719. |
|
|
| 1720. |
- Wang, Q., et al.
(författare)
-
Color-tunable single-fluorophore supramolecular system with assembly-encoded emission
- 2020
-
Ingår i: Nature Communications. - : Nature Research. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Regulating the fluorescent properties of organic small molecules in a controlled and dynamic manner has been a fundamental research goal. Although several strategies have been exploited, realizing multi-color molecular emission from a single fluorophore remains challenging. Herein, we demonstrate an emissive system by combining pyrene fluorophore and acylhydrazone units, which can generate multi-color switchable fluorescent emissions at different assembled states. Two kinds of supramolecular tools, amphiphilic self-assembly and γ-cyclodextrin mediated host-guest recognition, are used to manipulate the intermolecular aromatic stacking distances, resulting in the tunable fluorescent emission ranging from blue to yellow, including a pure white-light emission. Moreover, an external chemical signal, amylase, is introduced to control the assembly states of the system on a time scale, generating a distinct dynamic emission system. The dynamic properties of this multi-color fluorescent system can be also enabled in a hydrogel network, exhibiting a promising potential for intelligent fluorescent materials.
|
|
