| 1. |
- Schuette, Moritz, et al.
(författare)
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Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling 44,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
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| 2. |
- Alagöz, Ibrahim, et al.
(författare)
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Validating Test Cases for Safety Relevant ECUs using Simulation Models
- 2017
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Ingår i: 4th International Symposium on Future Active Safety Technology towards Zero-Traffic-Accidents (FAST-zero).
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Konferensbidrag (refereegranskat)abstract
- Software Components responsible for active safety require extensive testing using multiple steps from unit level to integration level. As the hardware involved in this process is costly and limited, it is important that test cases used in this environment are valid. In this study, we present a novel approach towards validating test cases for active safety software components in vehicles. Simulation models from the integration testing step are re-used for validating test cases early in the process. The approach builds upon the SimTAny framework that conducts a test-driven agile simulation. However, simulation models are available in their Matlab/Simulink simulation environment. Thus a distributed simulation of the test and the system model is required. Accordingly, an extended framework for distributed simulation is created using the high- level architecture / run-time infrastructure standard. We validate the approach by applying it to a test for reversible belt tensioning and the respective simulation model. We were able to reuse an existing simulation model and validate connected test cases. We show that the framework has the potential to save valuable time on expensive hardware resources and time to review test results.
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| 3. |
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| 4. |
- Auffray, Charles, et al.
(författare)
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Making sense of big data in health research: Towards an EU action plan
- 2016
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Ingår i: Genome Medicine. - : BIOMED CENTRAL LTD. - 1756-994X. ; 8:71
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Tidskriftsartikel (refereegranskat)abstract
- Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health arid healthcare for all Europearis.
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| 6. |
- Larhammar, Martin, 1985-, et al.
(författare)
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SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
- 2015
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 77:6, s. 526-536
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.MethodsWe used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.ResultsWe show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.ConclusionsOur results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.
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| 7. |
- Ueda, Kiyoshi, et al.
(författare)
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Roadmap on photonic, electronic and atomic collision physics : I. Light-matter interaction
- 2019
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Ingår i: Journal of Physics B. - : IOP PUBLISHING LTD. - 0953-4075 .- 1361-6455. ; 52:17
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Tidskriftsartikel (refereegranskat)abstract
- We publish three Roadmaps on photonic, electronic and atomic collision physics in order to celebrate the 60th anniversary of the ICPEAC conference. In Roadmap I, we focus on the light-matter interaction. In this area, studies of ultrafast electronic and molecular dynamics have been rapidly growing, with the advent of new light sources such as attosecond lasers and x-ray free electron lasers. In parallel, experiments with established synchrotron radiation sources and femtosecond lasers using cutting-edge detection schemes are revealing new scientific insights that have never been exploited. Relevant theories are also being rapidly developed. Target samples for photon-impact experiments are expanding from atoms and small molecules to complex systems such as biomolecules, fullerene, clusters and solids. This Roadmap aims to look back along the road, explaining the development of these fields, and look forward, collecting contributions from twenty leading groups from the field.
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| 8. |
- van de Luijtgaarden, Moniek W. M., et al.
(författare)
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Trends in dialysis modality choice and related patient survival in the ERA-EDTA Registry over a 20-year period
- 2016
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Ingår i: Nephrology, Dialysis and Transplantation. - : OXFORD UNIV PRESS. - 0931-0509 .- 1460-2385. ; 31:1, s. 120-128
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Tidskriftsartikel (refereegranskat)abstract
- Background. Although previous studies suggest similar patient survival for peritoneal dialysis (PD) and haemodialysis (HD), PD use has decreased worldwide. We aimed to study trends in the choice of first dialysis modality and relate these to variation in patient and technique survival and kidney transplant rates in Europe over the last 20 years. Methods. We used data from 196 076 patients within the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry who started renal replacement therapy (RRT) between 1993 and 2012. Trends in the incidence rate and prevalence on Day 91 after commencing RRT were quantified with Joinpoint regression. Crude and adjusted hazard ratios (HRs) for 5-year dialysis patient and technique survival were calculated using Cox regression. Analyses were repeated using propensity score matching to control for confounding by indication. Results. PD prevalence dropped since 2007 and HD prevalence stabilized since 2009. Incidence rates of PD and HD decreased from 2000 and 2009, respectively, while the incidence of kidney transplantation increased from 1993 onwards. Similar 5-year patient survival for PD versus HD patients was found in 1993-97 [adjusted HR: 1.02, 95% confidence interval (95% CI): 0.98-1.06], while survival was higher for PD patients in 2003-07 (HR: 0.91, 95% CI: 0.88-0.95). Both PD (HR: 0.95, 95% CI: 0.91-1.00) and HD technique survival (HR: 0.93, 95% CI: 0.87-0.99) improved in 2003-07 compared with 1993-97. Conclusions. Although initiating RRT on PD was associated with favourable patient survival when compared with starting on HD treatment, PD was often not selected as initial dialysis modality. Over time, we observed a significant decline in PD use and a stabilization inHD use. These observations were explained by the lower incidence rate of PD and HD and the increase in pre-emptive transplantation.
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| 9. |
- Warnke, Clemens, et al.
(författare)
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Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF
- 2015
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 21:8, s. 1036-1044
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Tidskriftsartikel (refereegranskat)abstract
- Background: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML). Objective: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37). Methods: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid. Results: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid. Conclusions: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.
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