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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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- Hognert, Helena, 1973, et al.
(författare)
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Acute effects of transdermal 17beta-estradiol on hemostatic variables after 24-hour treatment.
- 2002
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Ingår i: Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. - 1076-0296. ; 8:3, s. 239-43
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the acute effects of transdermal 17beta-estradiol (Estraderm) on plasma levels of coagulatory and fibrinolytic factors in postmenopausal normotensive and hypertensive women. Eleven normotensive and 13 hypertensive women were included in this placebo-controlled crossover study. In a randomized order each subject was treated with a patch of 100 microg 17beta-estradiol or placebo for 24 hours. Serum levels of tissue type plasminogen activator (tPA) activity, plasminogen activator inhibitor-I (PAI-1) activity, tPA antigen, PAI-I antigen, FVII, FX, and fibrinogen were assayed after both treatments. There was no significant difference in serum levels of hemostatic variables after treatment with estrogen compared to levels after placebo treatment in either of the groups. Nor was there any measurable difference when comparing hypertensive and normotensive subjects.
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- Höjer, Ingrid, 1953, et al.
(författare)
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Recognition of education and schooling in case files for children and young people placed in out-of-home care
- 2018
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Ingår i: Children and youth services review. - : Elsevier BV. - 0190-7409. ; 93, s. 135-142
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 Elsevier Ltd The aim of the article is to describe and discuss how issues related to schooling and educational achievement are recognized and addressed in social services case files for children and young people placed in out-of-home care (OHC) in the city of Gothenburg, Sweden. Four cohorts were included in the study: children born 1967, 1977, 1987 and 1992. 40 case files were selected from each cohort (38 from the 1977 cohort), in total 158 cases. The analyses were made through a counting of rows related to schooling and education in the documents. Results were then processed in the statistical program SPSS. The results show that the level of recognition of schooling/education was low, and that it was more frequent when the child/young person had behaviour problems and/or was placed in residential care. Little attention was paid to changes of schools. On a positive note, there was an increased attention to education and schooling for the two latter cohorts (1987, 1992), and the involvement of children, young people and parents was also more visible. To conclude, the acknowledgement of schooling and education that should be present in all placements in OHC was not generally visible in the documents in the case files, although the level of attention had increased. The message for practice is that this issue need more attention on several levels: better planning for the transition between old and new school, a developed cooperation between social services, foster/residential care and schools and a pro-active approach from social services concerning education and schooling.
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- Andersson, Claes R., et al.
(författare)
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Quantitative Chemogenomics : Machine-Learning Models of Protein-Ligand Interaction
- 2011
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Ingår i: Current Topics in Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 1568-0266 .- 1873-4294. ; 11:15, s. 1978-1993
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Forskningsöversikt (refereegranskat)abstract
- Chemogenomics is an emerging interdisciplinary field that lies in the interface of biology, chemistry, and informatics. Most of the currently used drugs are small molecules that interact with proteins. Understanding protein-ligand interaction is therefore central to drug discovery and design. In the subfield of chemogenomics known as proteochemometrics, protein-ligand-interaction models are induced from data matrices that consist of both protein and ligand information along with some experimentally measured variable. The two general aims of this quantitative multi-structure-property-relationship modeling (QMSPR) approach are to exploit sparse/incomplete information sources and to obtain more general models covering larger parts of the protein-ligand space, than traditional approaches that focuses mainly on specific targets or ligands. The data matrices, usually obtained from multiple sparse/incomplete sources, typically contain series of proteins and ligands together with quantitative information about their interactions. A useful model should ideally be easy to interpret and generalize well to new unseen protein-ligand combinations. Resolving this requires sophisticated machine-learning methods for model induction, combined with adequate validation. This review is intended to provide a guide to methods and data sources suitable for this kind of protein-ligand-interaction modeling. An overview of the modeling process is presented including data collection, protein and ligand descriptor computation, data preprocessing, machine-learning-model induction and validation. Concerns and issues specific for each step in this kind of data-driven modeling will be discussed.
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- Axelsson, Viktoria, et al.
(författare)
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Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.
- 2006
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Ingår i: Biochem Biophys Res Commun. - 0006-291X. ; 345:3, s. 1068-74
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Tidskriftsartikel (refereegranskat)abstract
- In this study, a significant increase by 50% in intracellular free calcium concentration ([Ca(2+)](i)) was observed in differentiated human neuroblastoma (SH-SY5Y) cells after exposure to 0.25microM of the fungal metabolite gliotoxin for 72h. Further, the involvement of caspases and calpains was demonstrated to underlie the gliotoxin-induced cytotoxic and neurite degenerative effects. The caspase inhibitor Z-VAD-fmk almost completely reduced the neurite degeneration from 40% degeneration of neurites to 5% as compared to control. Inhibition of calpains with calpeptin significantly attenuated gliotoxin-induced cytotoxicity, determined as reduction in total cellular protein content, from 43% to 14% as compared to control cells. Western blot analyses of alphaII-spectrin breakdown fragments confirmed activity of the proteases, and that alphaII-spectrin was cleaved by caspases in gliotoxin-exposed cells. These results show that calpains and caspases have a role in the toxicity of gliotoxin in differentiated SH-SY5Y cells and that the process may be Ca(2+)-mediated.
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- Berg, Lisa, et al.
(författare)
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Health risk behaviours among migrants by duration of residence : protocol for a systematic review and meta-analysis
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 10:10
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Forskningsöversikt (refereegranskat)abstract
- Introduction International migrants’ health has often been found to deteriorate in new countries, partly due to changes in health risk behaviours such as alcohol consumption, tobacco use, physical inactivity, and poor dietary habits. However, limited efforts have been made to comprehensively evaluate the extent to which migrants adopt unhealthy risk behaviours with longer duration of residence. This systematic review and meta-analysis will summarise evidence on international migrants’ behavioural patterns by duration of residence in multiple country contexts.Methods and analysis PubMed/MEDLINE, Web of Science and ProQuest databases will be searched for quantitative or mixed-method observational studies published in peer-reviewed scientific journals between 1 January 2000 and 31 December 2019. Studies comparing foreign-born individuals by duration of residence will be included. Information on study characteristics, descriptive statistics and measures of effect will be extracted. All included studies will be quality assessed using a modified Newcastle-Ottawa scale. The review will include narrative synthesis and, if sufficient and comparable data are available, random effects meta-analyses. The review will be conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Ethics and dissemination Ethical approval is not required since previously published information from peer-reviewed studies will be assessed. The results of this review will be published in peer-reviewed journals and presented at scientific conferences. Other forms of dissemination will include communication to broader audiences using well-established channels, including through university-based press releases. Progress will be regularly updated on the International Prospective Register of Systematic Reviews to ensure full transparency.
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- Brandin, Lisa, 1974, et al.
(författare)
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Effects of estrogen plus progesterone on hemodynamic and vascular reactivity in hypertensive postmenopausal women.
- 2010
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Ingår i: Blood pressure. - : Informa UK Limited. - 1651-1999 .- 0803-7051. ; 19:3, s. 156-63
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate the medium-term effects of estrogen plus progesterone therapy (EPT) on vascular reactivity, endothelial function and hemodynamic responses in 20 hypertensive postmenopausal women. METHODS: This randomized, double-blind, cross-over, placebo-controlled study investigates the effect of 6 months of EPT (conjugated equine estrogen plus medroxyprogesterone). Blood pressure (office and ambulatory), heart rate and heart rate variability (HRV) were measured at baseline and following EPT/placebo treatment. In eight women, we used a wire-myograph to assess endothelial function and contractile response of subcutaneous arteries to transmural nerve stimulation (TNS) and exogenous noradrenaline. RESULTS: EPT decreased vascular reactivity to cumulative TNS compared with baseline (p<0.01) and placebo (p<0.05). Moreover, EPT diminished sensitivity to exogenous noradrenaline (p<0.05). Although EPT reinforced response to acetylcholine, we observed no difference in maximal relaxation induced by substance P or acetylcholine. EPT did not affect ambulatory blood pressure, heart rate or HRV. CONCLUSIONS: Oral combined medium-term EPT reduces adrenergic reactivity in subcutaneous arteries from treated hypertensive postmenopausal women. EPT might act postjunctionally at the adrenergic vascular receptor level. In the present study, EPT neither reduces sympathetic activity nor increases vagal tone, and thus does not support an effect on the central hemodynamic system.
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