| 1531. |
- Martinsson, Tommy, 1956, et al.
(författare)
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Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy.
- 2011
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Ingår i: Cancer research. - : American Association for Cancer Research. - 1538-7445 .- 0008-5472. ; 71:1, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here, we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behavior. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression, mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in 2 independent systems. First, PC12 cell lines expressing ALK(F1174S) display ligand-independent activation of ALK and further downstream signaling activation. Second, analysis of ALK(F1174S) in Drosophila models confirms that the mutation mediates a strong, rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALK(F1174S) mutation that displays ligand-independent activity in vivo, correlating with rapid and treatment-resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analysis, in particular in tumor progression and/or tumor relapse, is warranted for better understanding of the treatment of neuroblastoma patients.
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| 1532. |
- Masuda, Rui, et al.
(författare)
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Improvements in Optical Properties of (0001) ZnO Layers Grown on (0001) Sapphire Substrates by Halide Vapor Phase Epitaxy Using Thick Buffer Layers
- 2012
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Ingår i: Japanese Journal of Applied Physics. - : Japan Society of Applied Physics. - 0021-4922 .- 1347-4065. ; 51:3, s. 031103-
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Tidskriftsartikel (refereegranskat)abstract
- The optical properties of (0001) ZnO layers grown at 1000 degrees C on (0001) sapphire substrates by halide vapor phase epitaxy (HVPE) were investigated by various photoluminescence (PL) measurements. A layer grown with a H2O/ZnCl2 (VI/II) ratio of 20 on a 0.4-mu m-thick buffer layer exhibited a significant near-band-edge (NBE) peak blueshift and degraded internal quantum efficiency (eta(int)) due to residual compressive stress. Growth with a VI/II ratio of 600 diminished the NBE peak blueshift; however, deep level emission and a reduction of PL decay time (tau(PL)) were caused by point defects generated by excess O source supply. A layer without the NBE peak blueshift and deep level emission was realized by growth with a VI/II ratio of 20 and a buffer layer of 0.8 mu m. The eta(int) and tau(PL) for HVPE-grown layers could be improved to 4.1% and 122.8 ps by using the thick buffer layer and appropriate VI/II ratio.
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| 1533. |
- Mathioudaki, Argyri, Ph.D student, 1986-, et al.
(författare)
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Allele frequency spectrum of known ankylosing spondylitis associated variants in a Swedish population
- 2022
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 51:1, s. 21-24
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The genetic predisposition to ankylosing spondylitis (AS) has been most widely studied in cohorts with European ancestry. However, within Europe, disease prevalence is higher in Sweden. Given this, we aimed to characterize known AS susceptibility variants in a homogeneous Swedish data set, assessing reproducibility and direction of effect. Method: The power to detect association within an existing Swedish targeted sequencing study (381 controls; 310 AS cases) was examined, and a set of published associations (n = 151) was intersected with available genotypes. Association to disease was calculated using logistic regression accounting for population structure, and HLA-B27 status was determined with direct polymerase chain reaction genotyping. Results: The cases were found to be 92.3% HLA-B27 positive, with the data set showing >= 80% predictive power to replicate associations, with odds ratios >= 1.6 over a range of allele frequencies (0.1-0.7). Thirty-four markers, representing 23 gene loci, were available for investigation. The replicated variants tagged MICA and IL23R loci (p < 1.47 x 10(-3)), with variable direction of effect noted for gene loci IL1R1 and MST1. Conclusion: The Swedish data set successfully replicated both major histocompatibility complex (MHC) and non-MHC loci, and revealed a different replication pattern compared to discovery data sets. This was possibly due to population demographics, including HLA-B27 frequency and measured comorbidities.
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| 1534. |
- Mathioudaki, Argyri, Ph.D student, 1986-, et al.
(författare)
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Replication and fine mapping of ankylosing spondylitis replicated loci in the Swedish population reveal different CCHCR1 protective haplotypes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The genetics of ankylosing spondylitis (AS) derives mainly from studies performed in large cohorts of British origin. However, within Europe, disease prevalence is higher in Sweden, and so we investigated the reproducibility of known AS susceptibility patterns in a homogeneous Swedish cohort.Methods: The replication power of the Swedish cohort was examined and a set of published SNP associations intersected with genotypes from an existing targeted sequencing study using these individuals (381 controls; 310 AS cases). To elucidate whether replication patterns derived from population subsampling or genetic similarity, allele frequency data from additional British and Swedish control populations were examined for genetic differentiation (FST). Replicated loci were fine mapped to investigate associations in more detail, and signals were dissected with haplotype analysis and functional annotation.Results: The study had 80% power to find variants of strong effect (Odds ratio, OR>2) given a wide range of risk allele frequencies (0.2-3), tagging HLA-B,CCHCR1and IL23R. The replication pattern was not due to European population genetic distance and fine mapping revealed genome-wide repositioned associations in HLA-Band CCHCR1, independent from the published associations (p-value < 2 x10-8, r2 < 0.3). The CCHCR1 locus showed two protective haplotype blocks (B1-1 and B2-1), independent from HLA-B signals (B1-1: r2 = 0.39, B2-2:r2=0.07), where 74% of controls were carrying 2 copies of the protective haplotypes (B1-1 and B2-1: OR=0.3, p-value = 1.2 x 10-45). Interestingly, while both haplotypes span CCHCR1, the effect of each haplotype is likely in cis, with eQTL evidence pointing to the regulation of TCF19(B1-1) and POU5F1(B1-2).Conclusions: Both European populations share key disease loci, but the Swedish cohort revealed fine-scale genetic differences, that may point to gene regulation. This study utilized a different variant resolution, and by doing so demonstrated that smaller populations have the potential to reveal new AS pathogenesis mechanisms and that further study of the Swedish population is warranted.
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| 1535. |
- Matikainen, Niina, et al.
(författare)
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Genetic Variation in SULF2 Is Associated with Postprandial Clearance of Triglyceride-Rich Remnant Particles and Triglyceride Levels in Healthy Subjects.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Nonfasting (postprandial) triglyceride concentrations have emerged as a clinically significant cardiovascular disease risk factor that results from accumulation of remnant triglyceride-rich lipoproteins (TRLs) in the circulation. The remnant TRLs are cleared from the circulation by hepatic uptake, but the specific mechanisms involved are unclear. The syndecan-1 heparan sulfate proteoglycan (HSPG) pathway is important for the hepatic clearance of remnant TRLs in mice, but its relevance in humans is unclear.
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| 1536. |
- Matos, Francisco A., et al.
(författare)
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Deep learning for plasma tomography using the bolometer system at JET
- 2017
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Ingår i: Fusion engineering and design. - : ELSEVIER SCIENCE SA. - 0920-3796 .- 1873-7196. ; 114, s. 18-25
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Tidskriftsartikel (refereegranskat)abstract
- Deep learning is having a profound impact in many fields, especially those that involve some form of image processing. Deep neural networks excel in turning an input image into a set of high-level features. On the other hand, tomography deals with the inverse problem of recreating an image from a number of projections. In plasma diagnostics, tomography aims at reconstructing the cross-section of the plasma from radiation measurements. This reconstruction can be computed with neural networks. However, previous attempts have focused on learning a parametric model of the plasma profile. In this work, we use a deep neural network to produce a full, pixel-by-pixel reconstruction of the plasma profile. For this purpose, we use the overview bolometer system at JET, and we introduce an up-convolutional network that has been trained and tested on a large set of sample tomograms. We show that this network is able to reproduce existing reconstructions with a high level of accuracy, as measured by several metrics.
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| 1537. |
- Matsson, Elin M., et al.
(författare)
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Combined in Vitro-in Vivo Approach To Assess the Hepatobiliary Disposition of a Novel Oral Thrombin Inhibitor
- 2013
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 10:11, s. 4252-4262
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Tidskriftsartikel (refereegranskat)abstract
- Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [H-3]AZD0837 was administered to healthy male volunteers (n = 8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927), and the active form (AR-H067637) was investigated (n = 17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately 2-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDRI cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate, and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE!) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.
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| 1538. |
- Matthews, G. F., et al.
(författare)
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Dynamic power balance analysis in JET
- 2017
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Ingår i: Physica Scripta. - : IOP PUBLISHING LTD. - 0031-8949 .- 1402-4896. ; T170
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Tidskriftsartikel (refereegranskat)abstract
- The full scale realisation of nuclear fusion as an energy source requires a detailed understanding of power and energy balance in current experimental devices. In this we explore whether a global power balance model in which some of the calibration factors applied to the source or sink terms are fitted to the data can provide insight into possible causes of any discrepancies in power and energy balance seen in the JET tokamak. We show that the dynamics in the power balance can only be properly reproduced by including the changes in the thermal stored energy which therefore provides an additional opportunity to cross calibrate other terms in the power balance equation. Although the results are inconclusive with respect to the original goal of identifying the source of the discrepancies in the energy balance, we do find that with optimised parameters an extremely good prediction of the total power measured at the outer divertor target can be obtained over a wide range of pulses with time resolution up to similar to 25 ms.
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| 1539. |
- Matthews, G. F., et al.
(författare)
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Energy balance in JET
- 2017
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Ingår i: Nuclear Materials and Energy. - : Elsevier. - 2352-1791. ; 12, s. 227-233
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Tidskriftsartikel (refereegranskat)abstract
- In this paper we discuss results from the study of the energy balance in JET based on calculated heating energies, radiated energy from bolometry and tile calorimetry. Recent data enables us to be more confident in the numbers used and to exclude certain possibilities but the overall energy imbalance which typically amounts to 25% of total input remains unexplained. This shows that caution is required in interpreting fractional radiated powers which are commonly used to measure the effectiveness of impurity seeded scenarios at reducing divertor heat load.
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| 1540. |
- Matthews, G. F., et al.
(författare)
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Melt damage to the JET ITER-like Wall and divertor
- 2016
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Ingår i: Physica Scripta. - : IOP PUBLISHING LTD. - 0031-8949 .- 1402-4896. ; T167
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Tidskriftsartikel (refereegranskat)abstract
- In October 2014, JET completed a scoping study involving high power scenario development in preparation for DT along with other experiments critical for ITER. These experiments have involved intentional and unintentional melt damage both to bulk beryllium main chamber tiles and to divertor tiles. This paper provides an overview of the findings of concern for machine protection in JET and ITER, illustrating each case with high resolution images taken by remote handling or after removal from the machine. The bulk beryllium upper dump plate tiles and some other protection tiles have been repeatedly flash melted by what we believe to be mainly fast unmitigated disruptions. The flash melting produced in this way is seen at all toroidal locations and the melt layer is driven by j x B forces radially outward and upwards against gravity. In contrast, the melt pools caused while attempting to use MGI to mitigate deliberately generated runaway electron beams are localized to several limiters and the ejected material appears less influenced by j. x. B forces and shows signs of boiling. In the divertor, transient melting of bulk tungsten by ELMs was studied in support of the ITER divertor material decision using a specially prepared divertor module containing an exposed edge. Removal of the module from the machine in 2015 has provided improved imaging of the melt and this confirms that the melt layers are driven by ELMs. No other melt damage to the other 9215 bulk tungsten lamellas has yet been observed.
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