| 1. |
- 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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| 2. |
- Scheffler, Julia M., et al.
(författare)
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ER alpha Signaling in a Subset of CXCL12-Abundant Reticular Cells Regulates Trabecular Bone in Mice
- 2022
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Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen has pronounced effects on the immune system, which also influences bone homeostasis. In recent years, stromal cells in lymphoid organs have gained increasing attention as they not only support the regulation of immune responses but also affect bone remodeling. A conditional knockout mouse model where estrogen receptor alpha (ER alpha) is deleted in CCL19-expressing stromal cells (Ccl19-Cre ER alpha(fl/fl) mice) was generated and bone densitometry was performed to analyze the importance of stromal cell-specific ER alpha signaling on the skeleton. Results showed that female Ccl19-Cre ER alpha(fl/fl) mice display reduced total bone mineral density and detailed X-ray analyses revealed that ER alpha expression in CCL19-expressing stromal cells is important for trabecular but not cortical bone homeostasis. Further analysis showed that the trabecular bone loss is caused by increased osteoclastogenesis. Additionally, the bone formation rate was reduced; however, the expression of osteoprogenitor genes was not altered. Analysis of the bone marrow stromal cell compartment revealed a deletion of ER alpha in a subgroup of CXCL12-abundant reticular (CAR) cells resulting in increased secretion of the pro-osteoclastogenic chemokine CXCL12. In conclusion, this study reveals the importance of ER alpha signaling in CAR cells for bone health. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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| 6. |
- Birberg Thornberg, Ulrika, et al.
(författare)
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A Placebo controlled, randomized study of PUFA (Poly Unsaturated Fatty Acids) as treatment for neurodevelopmental problems in 7-year-old children and cognitive performance in relation to an age-matched control group
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVE: The goal of the present randomized placebo controlled double-blind study was to investigate the potential effect of PUFA supplementation on cognitive and behavioural performance in children with neurodevelopmental problems at 7 years of age (n = 28) and to compare findings with an age matched healthy control group (n = 20). METHODS: Children were screened with parent and teacher rating scales (Conner’s and SNAP-IV), and were included if they showed a range of neurodevelopmental problems that reached ADHD criteria. The group with neurodevelopmental difficulties was randomized to treatment with an EPA rich formula (n = 13) or to placebo (n = 15). Cognitive performance was determined at baseline and after 15 weeks of supplementation with a cognitive test battery including executive function and theory of mind tasks. RESULTS: Children with neurodevelopmental problems differed from the control group regarding working memory, inhibition and language ability, but not on an advanced theory of mind task. Regarding the treatment with EPA supplement there were no significant advantages in the active treatment group compared to placebo in any of the cognitive measures or in parents or teacher rating scales. CONCLUSION: The significant differences in cognitive performance and rating scales between the group with neurodevelopmental problems and the healthy control group at baseline indicate problems at a clinical level and suitability for treatment. However we found no significant effects of PUFA supplementation. The study is small and limited by a number of drop-outs.
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| 7. |
- Birberg Thornberg, Ulrika, 1971-, et al.
(författare)
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Nutrition and cognitive development
- 2002
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Ingår i: Områdesgruppen för utvecklingspsykologi och neuropsykologi,2002.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Birberg Thornberg, Ulrika, et al.
(författare)
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Nutrition and theory of mind : The role of polyunsaturated fatty acids (PUFA) in the development of theory of mind
- 2006
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Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 0952-3278 .- 1532-2823. ; 75:1, s. 33-41
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Tidskriftsartikel (refereegranskat)abstract
- Breast-milk provides nutrients required for the development of the brain. n-6 and n-3 long-chain polyunsaturated fatty acids (LCPUFAs) have been suggested to be particularly involved. In this study levels of fatty acids in breast-milk were examined in relation to theory of mind (ToM) (n=13) and WISC-III (n=22) in six-year-old children. ToM tasks comprised four illustrated stories with questions about emotional (sad) events. Single polyunsaturated fatty acids (PUFA) were estimated as well as ratios between different fatty acids in order to describe putative associations between PUFA and psychological measures. Results show correlations between both ToM and WISC-III with single n-6 PUFA and the ratios DHA/AA and DHA/DPA. The correlations remained when socio-demographic factors were statistically controlled for. The positive findings related to the n-6 and n-3 LCPUFAs corroborate previous findings related to child cognitive development. © 2006 Elsevier Ltd. All rights reserved.
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| 9. |
- Bjursell, Magnus K., et al.
(författare)
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Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function
- 2011
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 89:4, s. 507-515
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Tidskriftsartikel (refereegranskat)abstract
- Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (Ado Met), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.
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