| 1. |
- Mueller, Stefanie H., et al.
(författare)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X .- 1756-994X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 2. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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| 3. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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| 4. |
- Fallah, Mahsa, 1986-, et al.
(författare)
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Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds
- 2020
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Ingår i: Cell Death and Disease. - : Nature Publishing Group. - 2041-4889 .- 2041-4889. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-β signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.
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| 5. |
- Gustafsson, Mats, 1966-, et al.
(författare)
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Effekt på dammförråd och PM10-halter av tunnelstädning
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Driftmetoder mot höga partikelhalter orsakade av vägdamm i gatu- och vägmiljöer har under lång tid utvärderats i vanlig gatumiljö. Resultaten är dock ofta förhållandevis svårtolkade på grund av inverkan av meteorologi och omfattande inblandning från andra partikelkällor än just den gata som studeras. För att komma vidare med mer detaljerade studier av metodik och strategi och för att få mer lättolkade resultat, kan studierna förflyttas in i vägtunnlar. Dessa har en mer kontrollerad miljö med små meteorologiska variationer och en tydlig och helt dominerande partikelkälla – trafiken. Projektet ”Utvärdering av tekniker och strategier för damningsminimerad väg- och gatudrift i tunnelmiljö” avsåg att utvärdera olika varianter av damningsminimerande åtgärder i Södra länken, med fokus på dammbindningsstrategier och städning. På grund av säkerhetsmotiv fick vi inte möjlighet att testa olika dammbindningsstrategier varför projektet har fokuserat enbart på städning och i föreliggande rapport presenteras resultatet från två utvärderingar; en genomförd i januari, då partikelkällorna är starka och dammförrådet stort och en i juni, då källorna är svaga och dammförrådet litet. I januari städade först den så kallade supersugen och sedan Disa-Clean och i juni städade maskinerna i omvänd ordning. För utvärdering av effekterna användes VTI:s vägdammsprovtagare WDS II och luftkvalitetsdata från den mätstation i tunneln som testerna genomfördes vid. Resultaten visar att dammförrådet minskas mer i kombinationen i januari, det vill säga av högtryckstvätt följt av vakuumsug, än tvärtom, som i juni. Även om PM10-data är mer svårtolkade finns indikationer på att halterna i januari minskar något, medan halterna i juni snarare ökar efter städinsatsen. Resultatet att högtryckstvätt följt av vakuumsug fungerar väl för att städa bort vägdamm styrks av snarlika studier genomförda i Norge med samma utvärderingsteknik (WDS).
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| 6. |
- Hogan, Aidan, et al.
(författare)
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Knowledge Graphs
- 2021
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Ingår i: ACM Computing Surveys. - : ASSOC COMPUTING MACHINERY. - 0360-0300 .- 1557-7341. ; 54:4
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Tidskriftsartikel (refereegranskat)abstract
- In this article, we provide a comprehensive introduction to knowledge graphs, which have recently garnered significant attention from both industry and academia in scenarios that require exploiting diverse, dynamic, large-scale collections of data. After some opening remarks, we motivate and contrast various graph-based data models, as well as languages used to query and validate knowledge graphs. We explain how knowledge can be represented and extracted using a combination of deductive and inductive techniques. We conclude with high-level future research directions for knowledge graphs.
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| 7. |
- Hogan, Aidan, et al.
(författare)
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Knowledge Graphs
- 2021
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- This book provides a comprehensive and accessible introduction to knowledge graphs, which have recently garnered notable attention from both industry and academia. Knowledge graphs are founded on the principle of applying a graph-based abstraction to data, and are now broadly deployed in scenarios that require integrating and extracting value from multiple, diverse sources of data at large scale.The book defines knowledge graphs and provides a high-level overview of how they are used. It presents and contrasts popular graph models that are commonly used to represent data as graphs, and the languages by which they can be queried before describing how the resulting data graph can be enhanced with notions of schema, identity, and context. The book discusses how ontologies and rules can be used to encode knowledge as well as how inductive techniques—based on statistics, graph analytics, machine learning, etc.—can be used to encode and extract knowledge. It covers techniques for the creation, enrichment, assessment, and refinement of knowledge graphs and surveys recent open and enterprise knowledge graphs and the industries or applications within which they have been most widely adopted. The book closes by discussing the current limitations and future directions along which knowledge graphs are likely to evolve.This book is aimed at students, researchers, and practitioners who wish to learn more about knowledge graphs and how they facilitate extracting value from diverse data at large scale. To make the book accessible for newcomers, running examples and graphical notation are used throughout. Formal definitions and extensive references are also provided for those who opt to delve more deeply into specific topics.
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| 8. |
- Poikonen-Saksela, Paula, et al.
(författare)
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Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1
- 2020
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 59:7, s. 825-832
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m(2)). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.
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| 9. |
- Sandinge, Anna, et al.
(författare)
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A modified specimen holder for cone calorimeter testing of composite materials to reduce influence from specimen edges
- 2022
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Ingår i: Fire and Materials. - : John Wiley and Sons Ltd. - 0308-0501 .- 1099-1018. ; 46:1, s. 80-
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Tidskriftsartikel (refereegranskat)abstract
- ISO 5660-1 specifies the cone calorimeter method for characterizing the ignition and surface burning behavior of materials. The specimen is irradiated through a square opening in the frame of the specimen holder. The frame is intended to protect the edges of the specimen from irradiation but covers the edges with only a few mm. In tests with products such as composite laminates and sandwich wall panels, the production of pyrolysis gases from the edges and, in many cases, burning have been observed. Early contribution from the edges in the test is not representative for surface burning. A modified specimen holder was developed with a larger specimen size to allow better protection of the edges. The opening for exposure to irradiance of the retainer frame is circular and of the same area as that of the original frame. The distance between the exposed surface and the specimen edges is larger in order to prevent early exposure of edges. Tests using the standard specimen holder resulted in pyrolysis and burning from edges that took place outside of the specimen holder. Comparative tests using the modified specimen holder showed that it prevented the exposure and pyrolysis from edges for an extended time. However, the influence on ignition time and peak heat release due to the increased size of the modified specimen holder has not been characterized fully, and test results should not be used for direct comparison with those of the standard holder.
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| 10. |
- Svensson, Johan, 1964, et al.
(författare)
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Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia.
- 2021
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 82:2, s. 781-790
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Tidskriftsartikel (refereegranskat)abstract
- Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.To study the diagnostic utility of CSF ST levels in SSVD.This was a mono-center, cross-sectional study of SSVD (n=16), Alzheimer's disease (n=40), mixed dementia (n=27), and healthy controls (n=33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r=0.64, p< 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r=0.30, p< 0.05), but it did not correlate with CSF NFL level.Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.
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