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- Abu-Bakar, A'edah, et al.
(författare)
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Metabolism of bilirubin by human cytochrome P450 2A6
- 2012
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 261:1, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.
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| 2. |
- Aleman, Dionne M., et al.
(författare)
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A fluence map optimization model for restoring traditional fractionation in IMRT treatment planning
- 2014
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Ingår i: Optimization Letters. - : Springer Science and Business Media LLC. - 1862-4472 .- 1862-4480. ; 8:4, s. 1453-1473
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Tidskriftsartikel (refereegranskat)abstract
- One of the core problems in intensity modulated radiation therapy (IMRT) treatment planning is the fluence map optimization (FMO) problem, which determines a fluence map (or profile) for each beam used in the delivery of treatment. Radiation therapy is administered in multiple so-called daily fractions to allow for healthy tissue to recover from damage caused by the treatment. Before the advent of IMRT, the treatment was designed to ensure a constant dose to cells in the target (the areas in the patient where cancerous cells are present or suspected). In the presence of multiple targets with different prescribed doses, this design meant that treatment had to be delivered in a sequence of unequal fractions, one per prescription dose level. For example, in case of two targets treatment would consist of an initial plan aimed at treating both targets to a lower total dose, followed by a so-called boost plan aimed at delivering the additional dose at the target with higher prescribed dose. In contrast, IMRT treatment plans are often delivered with equal treatment plan for each fraction, which means that the dose per fraction cannot be the same for all targets. The important problem of restoring traditional fractionation to IMRT treatments has not yet received much attention in the literature. In this paper we propose a new optimization model that explicitly restores fractionation into the FMO problem, yielding an optimal set of fluence maps for each fraction. We illustrate the capabilities of our approach on clinical head-and-neck cancer cases.
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| 3. |
- Aleman, Dionne M., et al.
(författare)
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Interior point algorithms : guaranteed optimality for fluence map optimization in IMRT
- 2010
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Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 0031-9155 .- 1361-6560. ; 55:18, s. 5467-5482
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Tidskriftsartikel (refereegranskat)abstract
- One of the most widely studied problems of the intensity-modulated radiation therapy (IMRT) treatment planning problem is the fluence map optimization (FMO) problem, the problem of determining the amount of radiation intensity, or fluence, of each beamlet in each beam. For a given set of beams, the fluences of the beamlets can drastically affect the quality of the treatment plan, and thus it is critical to obtain good fluence maps for radiation delivery. Although several approaches have been shown to yield good solutions to the FMO problem, these solutions are not guaranteed to be optimal. This shortcoming can be attributed to either optimization model complexity or properties of the algorithms used to solve the optimization model. We present a convex FMO formulation and an interior point algorithm that yields an optimal treatment plan in seconds, making it a viable option for clinical applications.
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