| 1. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 2. |
- Pollard, K. Michael, et al.
(författare)
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Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN
- 2017
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 199:11, s. 3739-3747
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Tidskriftsartikel (refereegranskat)abstract
- Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.
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| 3. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 4. |
- Haraldsson, Katarina, 1958, et al.
(författare)
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Evaluation of a school-based health promotion programme for adolescents aged 12-15 years with focus on well-being related to stress.
- 2008
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Ingår i: Public health. - London : Elsevier BV. - 0033-3506 .- 1476-5616. ; 122:1, s. 25-33
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to evaluate a school-based adolescent health promotion programme with focus on well-being related to stress. STUDY DESIGN: Interventional and evaluative with tests before and after the intervention. The study was performed in two secondary schools in a town on the west coast of Sweden. METHODS: A health promotion programme comprising massage and mental training was implemented for a single academic year in one school (intervention school, 153 participants) in order to strengthen and maintain well-being. No intervention was implemented in the other school (non-intervention school, 287 participants). A questionnaire was developed and tested, resulting in 23 items distributed across the following six areas: self-reliance; leisure time; being an outsider; general and home satisfaction; school satisfaction; and school environment. RESULTS: A pre- and postintervention comparison of the six areas was made within each school. In the intervention school, the boys maintained a very good or good sense of well-being related to stress in all six areas, while the girls' sense of well-being was maintained in five areas and deteriorated in one area. In the non-intervention school, the boys maintained a very good or good sense of well-being related to stress in four areas and deteriorated in two areas, while the girls' sense of well-being was maintained in two areas and deteriorated in four areas. CONCLUSION: Massage and mental training helped to maintain adolescents' very good or good sense of well-being related to stress. A questionnaire with acceptable validity and reliability was developed and tested in order to evaluate the health promotional approach. However, there is a need for further study to develop both the intervention and the questionnaire for young people.
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| 5. |
- Haraldsson, Katarina, et al.
(författare)
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What makes the everyday life of Swedish adolescent girls less stressful: a qualitative analysis
- 2010
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Ingår i: HEALTH PROMOTION INTERNATIONAL. - Oxford : Oxford University Press. - 0957-4824 .- 1460-2245. ; 25:2, s. 192-199
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Tidskriftsartikel (refereegranskat)abstract
- Stress is a widespread phenomenon in society today, not least among children and adolescents. Stress-related ill-health has increased in this population and affects girls to a greater extent than boys. Against this background, it is important to acquire knowledge about measures that prevent stress, especially in girls. The aim of this study was therefore to illuminate adolescent girls' experiences and reflections about what makes everyday life less stressful. An explorative design, qualitative content analysis, was used. In-depth interviews were conducted with fifteen 17-year-old girls. The analysis comprised both manifest and latent content and revealed the girls' own experiences of and reflections about what makes everyday life less stressful. Three categories, ‘Enjoyment and Recovery’, ‘Trust’ and ‘Insight and Influence’, and nine subcategories emerged. The latent content of these categories is described by the theme ‘access to sources of strength’. It is essential that persons in the girls' surroundings are aware of all sources that provide the strength to resist and prevent stress in everyday life. A climate has to be created in all arenas of the girls' everyday life in which they can access these sources of strength. Utilizing the girls' experiences and views about what needs to be done is the first step towards a preventive and promotive mode of working on their own circumstances and wishes. This approach is consistent with the Ottawa Charter for Health Promotion, which emphasizes the importance of involving the target group.
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| 6. |
- Haraldsson, M Katarina, et al.
(författare)
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The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation.
- 2008
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 28:1, s. 40-51
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Tidskriftsartikel (refereegranskat)abstract
- Here, we show that a lupus-suppressing locus is caused by a nonsense mutation of the filamentous actin-inhibiting Coronin-1A gene. This mutation was associated with developmental and functional alterations in T cells including reduced migration, survival, activation, and Ca2+ flux. T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected. By transfer of T cells, it was shown that suppression of autoimmunity could be accounted for by the presence of the Coro1a(Lmb3) mutation in T cells. Our results demonstrate that Coronin-1A is required for the development of systemic lupus and identify actin-cytoskeleton regulatory proteins as potential targets for modulating autoimmune diseases.
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| 7. |
- Lindgren, Eva-Carin M, et al.
(författare)
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Voices from Pupil Participation in the Health Promotion Intervention "Pulse for Learning and Health PuLH" in Primary and Middle School
- 2019
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Ingår i: International Journal of Environmental Research and Public Health. - Basel : MDPI AG. - 1660-4601 .- 1661-7827. ; 16:22
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Tidskriftsartikel (refereegranskat)abstract
- In order to improve the learning conditions and health of schoolchildren, the Pulse for Learning and Health [PuLH] program in Sweden has introduced additional mandatory moderate to vigorous physical activity [MVPA] that lasts for 30 min three times a week. The PE teachers used a child-centered coaching approach to support all pupils. The aim of this study was to explore pupils' perception and experience of PuLH that has been implemented in primary and middle schools in Sweden. We have taken into account children's rights perspectives and adopted an exploratory and interpretive approach. In total, 73 pupils (34 girls, 39 boys, grades 4-9) were recruited through purposive sampling. 13 focus group interviews (n = 71) and individual interviews (n = 2) were carried out. All interviews were analyzed using qualitative content analysis. The analysis resulted in three major themes: 'promotes academic performance and a learning school environment', 'promotes health and well-being', and 'individual and structural barriers'. From children's perspective, the results highlight the importance of teachers and principals taking into account the interests and needs of all pupils, to have a well-planned MVPA intervention and to deal with issues regarding body ideals.
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