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- Apellániz-Ruiz, Maria, et al.
(författare)
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Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.
- 2017
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Ingår i: Clinical Cancer Research. - : American Association of Cancer Research. - 1078-0432 .- 1557-3265. ; 23:5, s. 1227-1235
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for inter-individual differences remain unexplained. In this study we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.EXPERIMENTAL DESIGN: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/ gene-based analyses were used to compare variant frequencies among neuropathy groups and Cox regression models were used to analyze neuropathy evolution along treatment.RESULTS: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low frequency non-synonymous variants in EPHA6 were present exclusively in patients with high neuropathy and all affected the ligand binding domain. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency non-synonymous variant carriers (HR=14.60, 95%CI=2.33-91.62, P=0.0042) and an independent cohort confirmed an increased neuropathy risk (HR=2.07, 95%CI=1.14-3.77, P=0.017). Combining the series gave an estimated 2.50-fold higher risk of neuropathy (95%CI=1.46-4.31; P=9.1x10(-4)).CONCLUSION: This first study sequencing EPHA genes revealed that low frequency variants in EPHA6, EPHA5 and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHAs neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.
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| 3. |
- Ahlberg, Beth Maina, 1949-, et al.
(författare)
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"A child, a tree" : Challenges in building collaborative relations in a community research project in a Kenyan context
- 2016
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Ingår i: Action Research. - : Sage Publications. - 1476-7503 .- 1741-2617. ; 14:3, s. 257-275
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Tidskriftsartikel (refereegranskat)abstract
- This paper highlights the potential for basing participatory action research on priorities identified by communities. The case builds on a research project by the Social Science Medicine Africa Network (Soma-net) focusing on AIDS prevention among school youth in Kajiado in Kenya during 2003-2006. It became clear from that study just how complex it is to promote open communication on issues of sexuality considered critical for sexual health promotion. Towards the end of that study a spin-off in the form of a concept a child, a tree or tree planting evolved and the research thereafter continued as a partnership between the school community and the researchers. The focus then was on understanding how health promotion could be integrated into other aspects of community life. The concept and tree planting when implemented created a sense of ownership among the pupils largely because they were placed at the centre of the development activities. The story illuminates the nature of change developing in the course of the project, but also the challenges and complexity of creating and maintaining collaborative relations in the face of cultural and gender power dynamics and interventions imposed from outside the community.
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| 6. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 7. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 8. |
- Björnander, Stefan, et al.
(författare)
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A Formal Analysis Framework for AADL
- 2011
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Ingår i: The Journal of Science and Technology. - : Vietnam Academy of Science and Technology. - 0866-708X. ; 49:5
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Tidskriftsartikel (refereegranskat)abstract
- As system failure of mission-critical embedded systems may result in serious consequences, the development process should include verification techniques already at the architectural design stage, in order to provide evidence that the architecture fulfils its requirements. The Architecture Analysis and Design Language (AADL) is a language designed for modeling embedded systems, and its Behavior Annex defines the behavior of the system. However, even though it is an internationally used industry standard, AADL still lacks a formal semantics and is not executable, which limits the possibility to perform formal verification. In this paper, we introduce a formal analysis framework for a subset of AADL and its Behavior Annex, which includes the following: a denotational semantics, its implementation in Standard ML, and a graphical Eclipse-based tool encapsulating the implementation. We also show how to perform model checking of AADL properties defined in the Computation Tree Logic (CTL).
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| 10. |
- Björnander, Stefan, 1968-
(författare)
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Methods and Tool Support for Analyzing Architectural Models of Embedded Systems
- 2012
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Embedded systems are ubiquitous in the modern world. They are microcomputers most often included incomplete devices consisting of software and hardware. Embedded systems range from small devices to large systems monitoring and controlling complex processes. Design and development of such systems is a complex task, since embedded systems often need to fulfill extra-functional requirements, on top of functional ones, within constrained amounts of platform resources. Some embedded systems are mission critical; hence, they are not allowed to fail during the mission. One way to ensure that a system works in accordance to its specification is to define the system in an Architecture Description Language (ADL) and apply formal verification methods. The Architecture Design and Analysis Language (AADL) has become popular in the avionic and automobile industry, and is equipped with several annexes, among them the Behavior Annex. However, AADL still misses a formal semantics, which prevents the possibility to prove correctness of architecture features by performing model checking on AADL models. Moreover, AADL does not support time annotations, which prevents modeling of real-time systems in AADL.In this thesis, we address these issues by presenting a formal analysis framework including a denotationalsemantics for a subset of the AADL and its Behavior Annex, which evaluates properties defined in Computation Tree Logic (CTL) by providing model checking. Model checking is a formal verification method that has proved to be powerful as well as effective. Our AADL-semantics is supported by a tool with an implementation of the semantics in Standard ML, which in turn is encapsulated in an Eclipse plugin.We also present a time annotation extension of AADL, implemented in a tool translating time annotated AADL and its Behavior Annex into the Timed Abstract State Machine (TASM) for simulation of real-time features. Another closely related problem is how to achieve optimal component distribution; in order to address this issue we have developed a tool that perform near-optional component distribution in regard to a series of parameters.The research results, which have been validated thought case studies, provides the possibility for a system engineer to model a system and prove its correctness. The research has been conducted in the context of the PROGRESS research center, for predictable embedded software systems.
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