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- Boussemart, Lise, et al.
(författare)
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eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 513:7516, s. 105-109
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Tidskriftsartikel (refereegranskat)abstract
- In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.
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| 4. |
- Mineur, Therese, 1970-
(författare)
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Skolformens komplexitet : elevers erfarenheter av skolvardag och tillhörighet i gymnasiesärskolan
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Swedish upper secondary education consists of different types of schools. One type of school is the upper secondary for pupils who have assessed as having an intellectual disability. The aim of this study is to increase the knowledge and understanding of pupils’ experiences of everyday life in school, and how they perceive the significance of their sense of belonging to this type of school. An additional aim of the study is to increase the knowledge about different ways of organizing the education and teaching. The collection of data started with a national questionnaire survey which was directed to headteachers at the schools. Based on the results from the survey five schools were selected. By participant observations at the schools and repeated interviews with 14 young women and 12 young men, the first person perspective has been studied and analysed through an interpretive approach. The analysis showed that knowledge about the schools different ways of organizing the teaching are of importance, to understand pupils’ diverse experiences of school life. As an example it has an impact on how the pupils evaluate different types of knowledge, but also how they view their future opportunities. Any clear connection between the schools different ways of organizing the education and teaching and pupils’ experiences of their sense of belonging to this type of school has not emerged. Instead pupils’ awareness, confidence, uncertainty, dejection and determination are to be seen as a framework of understanding, telling us about their experiences of their school affiliation. Together they demonstrate a complexity surrounding pupils’ situation, associated to both advantages and disadvantages in school, but also their thoughts about identity and how they perceive being categorized as deviant by others. The analysis also showed that expectations on the pupils, and their possibilities in the school context, are related to a special school culture and to gender differences.
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- Tinghög, Petter, 1973-
(författare)
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Migration, Stress and Mental Ill Health : Post-migration Factors and Experiences in the Swedish Context
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This predominantly empirical dissertation deals with how socio-economic living conditions and immigrant-specific factors can be linked to immigrants’ mental ill health. It is also explored how cultural representations can affect stress and whether mental ill health is expressed differently among immigrants from Iraq and Iran than among individuals of Nordic origin. Moreover, a conceptual analysis is conducted, where a phenomenological conceptualisation of stress is outlined with a special focus on how this stress approach can be related to culture and migration.The empirical material consists of eleven in-depth interviews with Iraqi and Iranian immigrant women and two population-based surveys.The main findings of this thesis suggest as follows: 1) Mental ill health is more common among foreign-born than among native-born Swedes and can to a great extent be attributed to their poorer socio-economic living conditions. 2) Immigrants’ mental health is independently associated with different types of factors, such as traumatic episodes, socio-cultural adaptation level and socioeconomic living conditions. 3) The self-reporting mental health instruments, HSCL-25 and WHO (ten) Wellbeing Index, produce scores that are comparable between Scandinavians and immigrants of Middle Eastern descent. 4) Nonuniversal representations that can be found in Iraq and Iran can amplify, or even be necessary ingredients in certain types of stressful experiences among immigrant women from these countries. 5) The distinctions between universal and non-universal stress, and between immigrant/minority and non-immigrant/nonminority stress appear to be crucial for an adequate comprehension of immigrants’ stressful experiences.
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