| 1. |
- 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. |
- Kliger, Robert, 1950, et al.
(författare)
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Vibration response of long cable-stayed timber footbridge – case study
- 2013
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Ingår i: Proceedings of International Conference on Timber Bridges 2013- Las Vegas, Nevada USA.
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Konferensbidrag (refereegranskat)abstract
- Timber footbridges with a span larger than 30 meters are sensitive to vibrations and dynamic factors must therefore be taken into considerations in the design. A case study of a cable-stayed footbridge, Älvsbacka Bridge, with a free span of 130 meters, is presented. The dynamic design of the bridge is compared, based on the old Swedish code, BRO 2004 and the Eurocode 5. Simplified force models presented in BRO 2004 and the ISO 10137 international standard are compared. Vertical and lateral accelerations are measured on the bridge with accelerometers attached to the bridge deck. According to the simplified force model, the vertical acceleration limit was met for a group of twenty pedestrians, which was regarded as a reasonable design situation. From the measured accelerations, the damping factor was calculated as 1.2% of critical damping, which is twice the value used in design.
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| 5. |
- Amer-Wåhlin, Isis, et al.
(författare)
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Slutrapport för EVIDIGVO
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Den här texten presenterar resultat från tre aktiviteter för kunskapsinsamling om implementering av digitala verktyg inom vård- och omsorg: en litteratursammanställning, en workshopserie i två delar och en enkätundersökning. Den primära målgruppen har varit verksamhetsutvecklare och projektledare i regioner och kommuner. Antalet svarande i enkätstudien var för lågt för att kunna dra några statistiska slutsatser, men resultatet kan, tillsammans med workshopserien, ändå användas för att identifiera områden där det verkar finnas utmaningar. Både litteratursammanställningen och enkätundersökningen pekar på ett behov av att utveckla strukturerade utvärderingsmodeller för implementering. Även under workshoppen diskuterades den bristande förmågan att ”samla in evidens under projektens gång”, och det fanns en önskan om att ett sådant arbetssätt skulle utvecklas. Enkäten och workshoppen pekar även på flera återkommande problem under implementeringsprojekts olika faser. I den inledande fasen efterfrågas bättre analyser och förankringsarbete. Analyser med användarfokus missas speciellt ofta, så som användarresa, hållbarhetsanalys och intressent- och behovsanalys. Även i andra ändan av processen, då system och arbetssätt ska avvecklas, finns utmaningar och förbättringsförslag, t.ex. saknas ofta beslut om utfasning av gamla lösningar, och ett förslag är att man redan när man skriver kontakt med en leverantör ska säkerställa att leverantören hjälper till med migrering vid utfasning. En annan genomgående problematik är osäkerhet, och ibland avsaknad, av roller, ansvar och kommunikation. Detta handlar om att man inte riktigt vet varför man ska göra saker, eller att verksamheten och personerna som ska göra förändringen inte är tillräckligt inblandade. Det kan också handla om att support och förvaltning inte är tillräckligt väl utvecklat, och om att man inte vet hur man kan samarbeta med leverantörer. Här identifieras även förändringsledning som ett viktigt verktyg för att underlätta en god implementering.
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| 6. |
- Andersson, Karin, 1952, et al.
(författare)
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Methods and Tools for Environmental Assessment.
- 2016
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Ingår i: Shipping and the Environment: Improving Environmental Performance in Marine Transportation; Andersson, K., Brynolf, S., Lindgren, F.J. & Wilewska-Bien (eds.).. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783662490457 ; , s. 265-293
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Selecting measures to reduce the overall environmental impact associated with shipping can be a difficult task, and a systematic approach is needed. There is risk of sub-optimisation and counteraction of different measures with one another if decisions are made based on fragmented decision support. An example of a system effect is the long lifetime of ships, which slows the introduction of new technologies. Therefore, design and retrofits must fulfil not only present but also future requirements for environmental sustainability. This chapter describes the basic details of several methods and tools that can be used in environmental assessments within the shipping industry. The methods and tools described are grouped into three categories: (1) procedural tools, (2) analytical tools and (3) aggregated tools. Examples of procedural tools are environmental impact assessment, multi-criteria decision analysis and risk management; life cycle assessment (LCA) and environmental risk assessment are examples of analytical tools. Aggregated tools include indicators, indices, and footprints.
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| 8. |
- Appelros, Frida, et al.
(författare)
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On the role of the frontal projection in videoradiography of velopharynx in decision-making for a velopharyngeal flap plasty in patients with cleft palate
- 2020
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - 2000-656X. ; 54:4, s. 255-259
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Tidskriftsartikel (refereegranskat)abstract
- Despite uneventful primary surgery, patients with cleft palate may experience velopharyngeal insufficiency (VPI) and hypernasal speech. Videoradiography of velopharynx is a commonly used method to visualize velopharyngeal function and a velopharyngeal flap is often used to counteract VPI. The aim of this study was to investigate whether the frontal projection on videoradiography plays a role in the decision-making about velopharyngeal flap surgery, or possibly the width and orientation of the flap. A secondary aim was to evaluate the effect of the flap in improving velopharyngeal function. Between 2007 and 2016, 75 patients had received a flap at our department. During the same period of time, 41 patients who had undergone videoradiography did not receive a flap. Medical records, particularly regarding speech assessments, videoradiography statements and operating records, were scrutinised to seek information about the factors leading up to the decision about whether or not to perform a flap. In only one instance, reduced lateral pharyngeal wall movement found on the frontal projection was clearly taken into account when deciding to refrain from performing a velopharyngeal flap. Only a slight agreement was found between pre-operative speech assessment and findings in videoradiography. Hypernasality was reduced by flap surgery in 97% of the patients. We conclude the frontal projection of the videoradiographic examination seems to have no crucial role in the decision-making on performing a velopharyngeal flap or not in patients with cleft palate. Even with reduced lateral pharyngeal wall movement, a velopharyngeal flap effectively reduces hypernasality and VPI.
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| 9. |
- Armstrong, Andrea, et al.
(författare)
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Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
- 2014
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Ingår i: Neuromolecular medicine. - : Humana Press. - 1535-1084 .- 1559-1174. ; 16:1, s. 150-160
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Tidskriftsartikel (refereegranskat)abstract
- The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.
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