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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 2. |
- Moberg, Christina, et al.
(författare)
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De unga gör helt rätt när de stämmer staten
- 2022
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Ingår i: Aftonbladet. - 1103-9000.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
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| 6. |
- 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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| 7. |
- Emilsson, Maria, 1966-, et al.
(författare)
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Experiences of using surveillance cameras as a monitoring solution at nursing homes : The eldercare personnel's perspectives.
- 2023
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Ingår i: BMC Health Services Research. - : Springer Science and Business Media LLC. - 1472-6963. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: As the number of older people increases, so does the need for care. However, the workforce in eldercare cannot increase at the rate required to match the needs. Welfare technologies, such as surveillance cameras, can replace physical visits and be used at night to monitor older people in order to keep them safe, while not disturbing their sleep. The aim of the paper is to analyze obstacles and opportunities associated with implementation and use of surveillance cameras at nursing homes from the perspectives of the practitioners who use the technology, their working environment and the conditions of the older people with cognitive impairment who live in nursing homes.METHODS: Individual semi-structured interviews were conducted with the eldercare personnel at nursing homes to understand their experiences of implementation and use of surveillance cameras. The transcribed interviews were analyzed using qualitative content analysis. The consolidated criteria for reporting qualitative research (COREQ) was used as a guidance tool.RESULTS: The results show that the eldercare personnel experienced lack of adequate information, education and support related to using surveillance cameras. Several benefits are highlighted, such as better working environment and that the residents were not unnecessarily disturbed at night. However, the results also show that it is important to clarify that surveillance cameras cannot replace the human presence.CONCLUSIONS: The conclusions from this study are the importance of prerequisites for implementation, and that using surveillance cameras contributed to improvements in the working environment at night and created possibilities to maintain security and integrity for older people living in nursing homes.
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| 8. |
- Holst, Anna, et al.
(författare)
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Cost-effectiveness analysis of internet-mediated cognitive behavioural therapy for depression in the primary care setting : results based on a controlled trial
- 2018
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective To perform a cost-effectiveness analysis of a randomised controlled trial of internet-mediated cognitive behavioural therapy (ICBT) compared with treatment as usual (Tall) for patients with mild to moderate depression in the Swedish primary care setting. In particular, the objective was to assess from a healthcare and societal perspective the incremental cost-effectiveness ratio (ICER) of ICBT versus TaU at 12 months follow-up. Design A cost-effectiveness analysis alongside a pragmatic effectiveness trial. Setting Sixteen primary care centres (PCCs) in south-west Sweden. Participants Ninety patients diagnosed with mild to moderate depression at the PCCs. Main outcome measure ICERs calculated as (Cost(ICBT)-Cost(TaU))/(Health outcome(ICBT)-Health outcome(TaU))=Delta Cost/Delta Health outcomes, the health outcomes being changes in the Beck Depression Inventory-II (BDI-II) score and quality-adjusted life-years (QALYs). Results The total cost per patient for ICBT was 4044 Swedish kronor (SEK) ((sic)426) (healthcare perspective) and SEK47679 ((sic)5028) (societal perspective). The total cost per patient for TaU was SEK4434 ((sic)468) and SEK50 343 ((sic)5308). In both groups, the largest cost was associated with productivity loss. The differences in cost per patient were not statistically significant. The mean reduction in BDI-ll score was 13.4 and 13.8 units in the ICBT and Tall groups, respectively. The mean QALYs per patient was 0.74 and 0.79 in the ICBT and TaU groups, respectively. The differences in BDI-11 score reduction and mean QALYs were not statistically significant. The uncertainty of the study estimates when assessed by bootstrapping indicated that no firm conclusion could be drawn as to whether ICBT treatment compared with Tall was the most cost-effective use of resources. Conclusions ICBT was regarded to be as cost-effective as TaU as costs, health outcomes and cost-effectiveness were similar for ICBT and TaU, both from a healthcare and societal perspective.
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- Litjens, Carlijn H. C., et al.
(författare)
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Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
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Tidskriftsartikel (refereegranskat)abstract
- Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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