| 1. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
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Hypoxia stimulates CXCR4 signalling in ileal carcinoids.
- 2010
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Ingår i: Endocrine-related cancer. - 1479-6821. ; 17:2, s. 303-316
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Tidskriftsartikel (refereegranskat)abstract
- Tumour hypoxia is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Ileal carcinoids are usually metastatic at the time of diagnosis and respond poorly to chemotherapy. The aim of this study was to investigate the extent of hypoxia in ileal carcinoids and the response of tumour cells to induced hypoxia. VEGF, CA-IX, HIF-1alpha and HIF-2alpha were studied by immunohistochemistry in biopsies from 24 patients with ileal carcinoids. All hypoxic markers were shown to be highly expressed in localized areas of the tumours irrespective of tumour location or stage. However, HIF-2alpha expression was significantly higher in distant metastases compared to primary tumours in the same patient. Global gene expression profiling of GOT1 carcinoid cells revealed a marked response to hypoxia. Expression of genes related to epithelial-to-mesenchymal transition (EMT) and development was altered including increased expression of the chemokine receptor CXCR4, an important regulator of invasive growth and metastasis formation. High expression of CXCR4 was confirmed by immunohistochemistry in tumour biopsies. Stimulation of GOT1 cells by the CXCR4 ligand CXCL12 (SDF-1) activated the MAPK p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1alpha, and HIF-2alpha and CXCR4. Signalling through the CXCL12-CXCR4 axis may contribute to the metastatic potential of ileal carcinoids. Targeting of HIFs and/or the CXCR4 signalling pathway may offer new therapeutic strategies for this carcinoid tumour disease.
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| 2. |
- Köster, Jan, et al.
(författare)
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The diagnostic utility of DNA copy number analysis of core needle biopsies from soft tissue and bone tumors
- 2022
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Ingår i: Laboratory Investigation. - : Elsevier BV. - 0023-6837. ; 102:8, s. 838-845
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Tidskriftsartikel (refereegranskat)abstract
- Morphologic and immunohistochemical analysis of preoperative core needle biopsies (CNB) is important in the management of patients with soft tissue and bone tumors (STBTs). Most SBTB subtypes have more or less extensive DNA copy number aberrations (CNA), potentially providing useful diagnostic information. To evaluate the technical feasibility of single nucleotide polymorphism (SNP) array analysis and the diagnostic usefulness of the copy number profiles, we studied CNBs from 171 patients with suspected STBTs. SNP array analysis could be performed on 168 (98%) of the samples. The CNA profile was compatible with the CNB diagnosis in 87% of the cases. Discrepant cases were dominated by false-negative results due to nonrepresentative material or contamination with normal cells. 70 genomic profiles were indicative of specific histopathologic tumor entities and in agreement with the corresponding CNB diagnoses in 83%. In 96 of the cases with aberrant CNA profiles, the SNP profiles were of sufficient quality for segmentation, allowing clustering analysis on the basis of the Jaccard similarity index. The analysis of these segment files showed three major CNA clusters, based on the complexity levels and the predominance of gains versus losses. For 43 of these CNB samples, we had SNP array data also from their corresponding surgical samples. In 33 of these pairs, the two corresponding samples clustered next to each other, with Jaccard scores ranging from 0.61 to 0.99 (median 0.96). Also, for those tumor pairs that did not cluster together, the Jaccard scores were relatively high (median 0.9). 10 cases showed discrepant results, mainly due to varying degrees of normal cell contamination or technical issues. Thus, the copy number profile seen in a CNB is typically highly representative of the major cell population in the tumor.
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| 3. |
- Almobarak, Bilal, et al.
(författare)
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Exposure to nonanoic acid alters small intestinal neuroendocrine tumor phenotype
- 2023
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSmall intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location.MethodsClinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology.ResultsTumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology.ConclusionOur results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.
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| 4. |
- 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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| 5. |
- Broström (red), Tor, et al.
(författare)
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Brandsäkerhet för byggnader med kulturvärden: En kunskapsöversikt
- 2021
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Abstract [sv] Arbetet med brandsäkerhet för byggnader med kulturvärden kräver anpassade lösningar som också kan tillgodose ett bevarande av byggnaderna och deras kulturvärden. Det finns, utspritt, mycket kunskap och erfarenhet inom det här området både i Sverige och internationellt. För att tillgodose ett behov av samlad kunskap inom detta område initierade Brandforsk en kunskapsöversikt tillsammans med Akademiska hus, Fortifikationsverket, Kammarkollegiet, Kyrkans försäkring, Riksantikvarieämbetet och Statens fastighetsverk. Den här kunskapsöversikten syftar till att sammanställa och presentera den kunskap som finns. Ett kompletterande syfte är att definiera områden där kunskap saknas. Kunskapsöversikten är indelad i sex områden: 2. Skydd mot brands uppkomst 3. Spridning av brand inom byggnad 4. Spridning av brand till byggnad 5. Brandens påverkan på byggnadens stomme 6. Utrymning 7. Räddningstjänstens insats Med utgångspunkt från workshops har en sammanställning av behovsbilden gjorts. Kunskapsöversikten och behovsbilden ligger till grund för en gap-analys vilken pekar på behov av fortsatt forskning och utveckling. Abstract [en] Working with fire safety in historic buildings requires adapted solutions that can also satisfy the preservation of the buildings and their cultural values. There is a lot of knowledge and experience in this area both in Sweden and internationally. In order to make this available to end users, Brandforsk initiated a literature review together with a group of national sponsors. This literature review aims to compile and present the documented knowledge in the field. A complementary purpose is to define knowledge gaps. The review is divided into six areas: 2. Fire prevention 3. Fire spread within buildings 4. Fire spread between structures 5. Structural fire resistance 6. Evacuation 7. Fire and rescue service activities Based on workshops the needs of end users have been compiled. A comparison of the outcome of the review and the end user needs defines a knowledge gap pointing to the need for continued research and development.
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| 6. |
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| 7. |
- Börjesson, Peter, 1980, et al.
(författare)
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The Merits of Situated Evaluation as an Alternative UX Evaluation Method to Understand Appropriation
- 2018
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Ingår i: Interaction Design and Architecture(s). - 2283-2998 .- 1826-9745. ; :37, s. 78-98
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Tidskriftsartikel (refereegranskat)abstract
- Oftentimes, technologies are not used in the ways designers had initially envisioned. Instead, people adapt technologies to their own needs, a phenomenon called ‘appropriation’. Appropriation is an important aspect of User Experience design, related to the situatedness and dynamics of the design, recognizing not only that initial needs and requirements may change over time, but also that a design may change the environment that it was designed for. Appropriation can also contribute to a sense of ownership as people use a design in their own way, sometimes in ways the designer did not intend. However, commonly used User Experience evaluation methods often do not focus on the appropriation process of a technology. Situated Evaluation is an approach that does focus on appropriation, although it has not yet been used extensively in the UX field. In this paper, we therefore present and critically discuss our use of the Situated Evaluation approach for the evaluation of a specific tool that aims to enhance the communication between children, parents, and teaching staff in special education. By presenting this case, we hope to inform other UX researchers and designer about the potential of the approach to understand appropriation is an important factor in UX design.
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| 8. |
- Danielsson, Henrik, et al.
(författare)
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A Systematic Review of Longitudinal Trajectories of Mental Health Problems in Children with Neurodevelopmental Disabilities
- 2024
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Ingår i: Journal of Developmental and Physical Disabilities. - : Springer. - 1056-263X .- 1573-3580. ; 36, s. 203-242
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Forskningsöversikt (refereegranskat)abstract
- To review the longitudinal trajectories - and the factors influencing their development - of mental health problems in children with neurodevelopmental disabilities. Systematic review methods were employed. Searches of six databases used keywords and MeSH terms related to children with neurodevelopmental disabilities, mental health problems, and longitudinal research. After the removal of duplicates, reviewers independently screened records for inclusion, extracted data (outcomes and influencing factors), and evaluated the risk of bias. Findings were tabulated and synthesized using graphs and a narrative. Searches identified 94,662 unique records, from which 49 publications were included. The median publication year was 2015. Children with attention deficit hyperactivity disorder were the most commonly included population in retrieved studies. In almost 50% of studies, trajectories of mental health problems changed by < 10% between the first and last time point. Despite multiple studies reporting longitudinal trajectories of mental health problems, greater conceptual clarity and consideration of the measures included in research is needed, along with the inclusion of a more diverse range of populations of children with neurodevelopmental disabilities.
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| 9. |
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| 10. |
- Hammar, Linus, 1979, et al.
(författare)
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A Probabilistic Model for Hydrokinetic Turbine Collision Risks: Exploring Impacts on Fish
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 10:3, s. e0117756-
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Tidskriftsartikel (refereegranskat)abstract
- A variety of hydrokinetic turbines are currently under development for power generation in rivers, tidal straits and ocean currents. Because some of these turbines are large, with rapidly moving rotor blades, the risk of collision with aquatic animals has been brought to attention. The behavior and fate of animals that approach such large hydrokinetic turbines have not yet been monitored at any detail. In this paper, we conduct a synthesis of the current knowledge and understanding of hydrokinetic turbine collision risks. The outcome is a generic fault tree based probabilistic model suitable for estimating population-level ecological risks. New video-based data on fish behavior in strong currents are provided and models describing fish avoidance behaviors are presented. The findings indicate low risk for small sized fish. However, at large turbines (≥5 m), bigger fish seem to have high probability of collision, mostly because rotor detection and avoidance is difficult in low visibility. Risks can therefore be substantial for vulnerable populations of large-sized fish, which thrive in strong currents. The suggested collision risk model can be applied to different turbine designs and at a variety of locations as basis for case-specific risk assessments. The structure of the model facilitates successive model validation, refinement and application to other organism groups such as marine mammals.
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