| 1. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 2. |
- Aasa, Mikael, et al.
(författare)
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Cost and health outcome of primary percutaneous coronary intervention versus thrombolysis in acute ST-segment elevation myocardial infarction-Results of the Swedish Early Decision reperfusion Study (SWEDES) trial.
- 2010
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Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 160:2, s. 322-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In ST-elevation myocardial infarction, primary percutaneous coronary intervention (PCI) has a superior clinical outcome, but it may increase costs in comparison to thrombolysis. The aim of the study was to compare costs, clinical outcome, and quality-adjusted survival between primary PCI and thrombolysis. METHODS: Patients with ST-elevation myocardial infarction were randomized to primary PCI with adjunctive enoxaparin and abciximab (n = 101), or to enoxaparin followed by reteplase (n = 104). Data on the use of health care resources, work loss, and health-related quality of life were collected during a 1-year period. Cost-effectiveness was determined by comparing costs and quality-adjusted survival. The joint distribution of incremental costs and quality-adjusted survival was analyzed using a nonparametric bootstrap approach. RESULTS: Clinical outcome did not differ significantly between the groups. Compared with the group treated with thrombolysis, the cost of interventions was higher in the PCI-treated group ($4,602 vs $3,807; P = .047), as well as the cost of drugs ($1,309 vs $1,202; P = .001), whereas the cost of hospitalization was lower ($7,344 vs $9,278; P = .025). The cost of investigations, outpatient care, and loss of production did not differ significantly between the 2 treatment arms. Total cost and quality-adjusted survival were $25,315 and 0.759 vs $27,819 and 0.728 (both not significant) for the primary PCI and thrombolysis groups, respectively. Based on the 1-year follow-up, bootstrap analysis revealed that in 80%, 88%, and 89% of the replications, the cost per health outcome gained for PCI will be <$0, $50,000, and $100,000 respectively. CONCLUSION: In a 1-year perspective, there was a tendency toward lower costs and better health outcome after primary PCI, resulting in costs for PCI in comparison to thrombolysis that will be below the conventional threshold for cost-effectiveness in 88% of bootstrap replications.
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| 5. |
- Ahnstedt, Hilda, et al.
(författare)
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Cytokines and growth factors modify the upregulation of contractile endothelin ET(A) and ET(B) receptors in rat cerebral arteries after organ culture.
- 2012
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708. ; 205:2, s. 266-278
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Experimental cerebral ischemia and organ culture of cerebral arteries induce an increased endothelin ET(B) receptor-mediated contraction. The aim of the present study was to examine if cytokines and growth factors, known to be activated in ischemia, can influence the expression and function of endothelin receptors after organ culture. Methods: Rat middle cerebral arteries were cultured for 24 h at 37°C in humidified 5% CO(2) and air in culture medium alone, or with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF). Concentration-response curves were obtained for sarafotoxin 6c (ET(B) receptor agonist) and endothelin-1 (here ET(A) receptor agonist, because of ET(B) receptor desensitization). The receptor mRNA expression was examined by real-time PCR and the protein expression by immunohistochemistry and Western blot. Results: TNF-α (100 ng/ml) and EGF (20 ng/ml) potentiated the ET(B) receptor-mediated contraction (increase in pEC(50) without change in E(max) ). bFGF (10 ng/ml) and IL-1β (10 ng/ml) induced an enhanced ET(A) receptor-mediated contraction. bFGF (10 ng/ml) significantly increased the ET(B) mRNA level, and EGF (20 ng/ml) increased the ET(A) receptor protein. Increased ET(B) receptor mRNA and protein level also were observed after treatment with IL-1β (10 ng/ml). Conclusion: The present study show that TNF-α, IL-1β, EGF and bFGF can modify the expression and function of endothelin receptors during organ culture. Since there is similar receptor upregulation in experimental stroke, the effect of cytokines and growth factors on endothelin receptor upregulation is an interesting aspect to study in vivo.
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| 6. |
- Alexandersson, Gunnar, et al.
(författare)
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Coopetition between commercial and subsidized railway services : The case of the greater Stockholm region
- 2018
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Ingår i: Research in Transportation Economics. - : Elsevier. - 1875-7979 .- 0739-8859. ; 69:SI, s. 349-359
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Tidskriftsartikel (refereegranskat)abstract
- An important ingredient of the Swedish railway system is the increased involvement of public actors in the provision of local and regional railway services. The local and regional railway services show the strongest growth of all market segments in the Swedish passenger railway market. The strong growth is due both to changes in travel patterns and improved subsidized railway services. One important factor in the success of the regional public transport authorities’ (PTA) railway services is the redefinition of the scope of these railway services by interconnecting regional railway networks into bigger entities.In 2017, nearly all local and regional railway services in Sweden's most populated region, Mälardalen, became part of a network of railway services subsidized by the PTAs in the greater region. We analyse the cooperative and competitive interactions between the stakeholders in the greater region using the key concepts in the theory of hybrid organizations. We find that despite moving towards a unified public transport market covering many counties the hybrid organizations use different governance structures and have different principles for sharing value creation. The closer cooperation paradoxically enhances competition in the regional railway market, both between subsidized travel cards and between subsidized and commercial railway services.
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| 7. |
- Alfalahi, Alyaa, et al.
(författare)
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Expanding a dictionary of marker words for uncertainty and negation using distributional semantics
- 2015
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Ingår i: EMNLP 2015 - 6th International Workshop on Health Text Mining and Information Analysis, LOUHI 2015 : Proceedings of the Workshop - Proceedings of the Workshop. - : Association for Computational Linguistics. - 9781941643327 ; , s. 90-96
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Konferensbidrag (refereegranskat)abstract
- Approaches to determining the factuality of diagnoses and findings in clinical text tend to rely on dictionaries of marker words for uncertainty and negation. Here, a method for semi-automatically expanding a dictionary of marker words using distributional semantics is presented and evaluated. It is shown that ranking candidates for inclusion according to their proximity to cluster centroids of semantically similar seed words is more successful than ranking them according to proximity to each individual seed word.
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| 8. |
- Bergman, Jon, 1978-
(författare)
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Concentrations in the EU pharmaceutical sector : The protection of effective competition under Council Regulation No 139/2004 on the control of concentrations between undertakings
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A central element of competition law consists in the control of concentrations, that is, the changes in the competitive structure resulting from mergers and acquisitions. By controlling concentrations with a Union Dimension, the European Commission ensures that effective competition will not be significantly impeded, in particular by the creation or strengthening of dominant positions. Within the EU, the central legislation is Council Regulation (EC) No 139/2004 of 20 January 2004 on the control of concentrations between undertakings. Under the Regulation, the Commission has the power to declare concentrations incompatible with the internal market and prohibit them in whole or in part. The dissertation examines the Commission's application of the Regulation in the pharmaceutical industry. The pharmaceutical industry exhibits many special features in comparison with other economic sectors, not least because it comprises extensive sector-specific regulation governing the development, manufacture and sale of pharmaceutical products.The study comprehensively explores situations where the control of concentrations is affected by the special conditions characterising the market for pharmaceuticals. Besides providing an overview of the reasons why mergers and acquisitions should be checked, the contents of the Merger Regulation, and the relevant sector-specific regulation, the dissertation examines the definition of the relevant market for pharmaceutical products, how the substantive test in the Regulation is interpreted and applied, and the remedies that may be necessary when pharmaceutical companies merge.
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| 9. |
- Bosch-Sijtsema, Petra, 1971, et al.
(författare)
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Managing projects with distributed and embedded knowledge through interactions
- 2014
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Ingår i: International Journal of Project Management. - : Elsevier BV. - 0263-7863. ; 32:8, s. 1432-1444
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Tidskriftsartikel (refereegranskat)abstract
- In project-based industries studies show difficulties in extracting, distributing and applying embedded and practice knowledge across structural and organisational boundaries. We focus on interorganisational projects consisting of distributed and embedded knowledge. Interaction becomes important in order to cooperate and share interorganisational and distributed knowledge. The aim of the research is to explore how sharing and generating practice based and distributed knowledge occurs through interaction in interorganisational projects and how this is managed. The study focuses on the design phase and relates traditional design practices to concurrent design practices. In the study we observed six cases of designmeetings in the construction and oil and gas industry and performed 31 interviews. The paper contributes with the following: (1) understanding and visualisation of interaction patterns, (2) insight in use of various forms of interaction, and (3) ways of managing distributed and embedded knowledge through interaction.
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