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- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 2. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 6. |
- Francis, Monika K., et al.
(författare)
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Endocytic membrane turnover at the leading edge is driven by a transient interaction between Cdc42 and GRAF1
- 2015
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 128:22, s. 4183-4195
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Tidskriftsartikel (refereegranskat)abstract
- Changes in cell morphology require coordination of plasma membrane turnover and cytoskeleton dynamics, processes that are regulated by Rho GTPases. Here, we describe how a direct interaction between the Rho GTPase Cdc42 and the GTPase activating protein (GAP) GRAF1, facilitate rapid cell surface turnover at the leading edge. Both Cdc42 and GRAF1 were required for fluid phase uptake and regulated the generation of transient GRAF1-coated endocytic carriers, distinct from clathrin coated vesicles. GRAF1 was found to transiently assemble at discrete Cdc42-enriched punctae at the plasma membrane resulting in a corresponding decrease in Cdc42 microdomain association. However, Cdc42 captured in its active state was, via a GAP domain mediated interaction, localised together with GRAF1 on accumulated internal structures derived from the cell surface. Correlative fluorescence and electron tomography microscopy revealed that these structures were clusters of small membrane carriers affected in their endosomal processing. We conclude that a transient interaction between Cdc42 and GRAF1 drives endocytic turnover and controls the transition essential for endosomal maturation of plasma membrane internalised by this mechanism.
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| 7. |
- Henriksson, Hanna E., et al.
(författare)
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Meteorological parameters and air pollen count in association with self-reported peripartum depressive symptoms
- 2018
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Ingår i: European psychiatry. - : ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER. - 0924-9338 .- 1778-3585. ; 54, s. 10-18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meteorological parameters and air pollen count have been associated with affective disorders and suicide. Regarding peripartum depression, the literature is restricted and inconclusive.Methods: This cross-sectional study included women (pregnant, n = 3843; postpartum, n = 3757) who participated in the BASIC (Biology, Affect, Stress, Imaging, and Cognition) study 2010-2015 and the UPPSAT (Uppsala-Athens) study (postpartum, n = 1565) in 2006-2007. Cases were defined according to presence of depressive symptoms during pregnancy (gestational week 32) and 6 weeks postpartum, using the Edinburgh Postnatal Depression Scale (EPDS). Exposure of sunshine, temperature, precipitation, snow coverage, and air pollen counts of durations of 1, 7, and 42 days prior to the outcome were studied for associations with depressive symptoms, using negative binomial regression.Results: Prior to Bonferroni correction, the concentration of mugwort pollen, both one week and six weeks before the EPDS assessment at gestational week 32, was inversely associated with depressive symptoms in pregnancy, both before and after adjustment for season. No associations were found between the exposure to meteorological parameters and pollen and depressive symptoms, at the same day of depressive symptoms' assessment, the previous week, or the six weeks prior to assessment, either during pregnancy or postpartum after Bonferroni correction.Conclusions: There was no evidence that neither short-term nor long-term exposure to meteorological parameters or air pollen counts were associated with self-reported peripartum depressive symptoms in Uppsala, Sweden.
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| 8. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 10. |
- Odaga, John, et al.
(författare)
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Empowering districts to target priorities for improving child health service in Uganda using change management and rapid assessment methods
- 2016
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Ingår i: Global Health Action. - : Informa UK Limited. - 1654-9716 .- 1654-9880. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Local health system managers in low- and middle-income countries have the responsibility to set health priorities and allocate resources accordingly. Although tools exist to aid this process, they are not widely applied for various reasons including non-availability, poor knowledge of the tools, and poor adaptability into the local context. In Uganda, delivery of basic services is devolved to the District Local Governments through the District Health Teams (DHTs). The Community and District Empowerment for Scale-up (CODES) project aims to provide a set of management tools that aid contextualised priority setting, fund allocation, and problem-solving in a systematic way to improve effective coverage and quality of child survival interventions. Design: Although the various tools have previously been used at the national level, the project aims to combine them in an integral way for implementation at the district level. These tools include Lot Quality Assurance Sampling (LQAS) surveys to generate local evidence, Bottleneck analysis and Causal analysis as analytical tools, Continuous Quality Improvement, and Community Dialogues based on Citizen Report Cards and U reports. The tools enable identification of gaps, prioritisation of possible solutions, and allocation of resources accordingly. This paper presents some of the tools used by the project in five districts in Uganda during the proof-of-concept phase of the project. Results: All five districts were trained and participated in LQAS surveys and readily adopted the tools for priority setting and resource allocation. All districts developed health operational work plans, which were based on the evidence and each of the districts implemented more than three of the priority activities which were included in their work plans. Conclusions: In the five districts, the CODES project demonstrated that DHTs can adopt and integrate these tools in the planning process by systematically identifying gaps and setting priority interventions for child survival.
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