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- 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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- Gustafsson, Anna, et al.
(författare)
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The antisecretory factor in plasma and breast milk in breastfeeding mothers : a prospective cohort study in Sweden
- 2018
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation and infection postpartum threaten the mother and her infant. Human milk provides a defense for the infant, but inflammatory complications like mastitis may lead to the cessation of breastfeeding. Antisecretory factor (AF) has a role in the regulation of secretory processes and inflammation. The objective of the study was to describe AF-levels in plasma and breast milk, and in relation to breast complications. Breastfeeding mothers (n = 95) were consecutively recruited at a Well Baby Clinic in Umeå, Sweden. At inclusion four weeks postpartum, samples of venous blood (10 mL) and breast milk (10 mL) were collected. Active AF was analyzed with ELISA using a monoclonal antibody mAb43, and was detected in all samples of plasma and breast milk with a positive correlation (Spearman coefficient = 0.40, p < 0.001; Pearson correlation = 0.34, p < 0.01). High AF-levels in plasma correlated with high AF-levels in breast milk. The results suggest a co-regulation between active AF in plasma and breastmilk, and/or a local regulation of AF in the breast. Further studies are needed to determine the pathways for the activation of AF-levels in breast milk and plasma.
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- 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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- Abelsson, Anna, 1971-, et al.
(författare)
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Physical stress triggers in simulated emergency care situations
- 2021
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Ingår i: Nursing Open. - : John Wiley & Sons. - 2054-1058. ; 8:1, s. 156-162
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Tidskriftsartikel (refereegranskat)abstract
- AimTo practise emergency care situations during the education can be stressful. The aim of this study is to identify factors that cause stress in simulated emergency care.DesignA descriptive observational study.MethodsVideo recordings (N = 26) subjected to observation with written field notes in turn subjected to interpretive qualitative content analysis.ResultsTo assess the patient's condition and decide what measures to take trigger stress reactions. If the students failed to connect the correct and relevant information in the conversation with the physician, the students showed signs of stress. Also, to calculate medication dosages stress the students.
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- Aboagye, Emmanuel, et al.
(författare)
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Exhaustion and Impaired Work Performance in the Workplace : Associations With Presenteeism and Absenteeism
- 2019
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Ingår i: Journal of Occupational and Environmental Medicine. - : Wolters Kluwer. - 1076-2752 .- 1536-5948. ; 61:11, s. 438-444
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to investigate the association between presenteeism and absenteeism during the previous year and the current levels of exhaustion and impaired work performance in a Swedish university setting.Methods: In a study of 3525 employees, an ordinal logistic regression and general linear model was used to examine the association between presenteeism and absenteeism during the previous year and the current exhaustion and impaired work performance, respectively.Results: Presenteeism, but not absenteeism, during the previous year independently increased the risk of having moderate or severe exhaustion. Presenteeism, absenteeism, and exhaustion remained positively associated with impaired work performance when health status and other confounders had been adjusted for.Conclusions: Presenteeism, but not absenteeism, was associated with exhaustion. Both presenteeism and absenteeism were the salient correlates of impaired work performance.
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