| 1. |
- Geyer, C. E., et al.
(författare)
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Overall survival in the OlympiA phase Ill trial of adjuvant olaparib in patients with germime pathogenic variants in BRCA1/2 and high-risk, early breast cancer
- 2022
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 33:12, s. 1250-1268
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Tidskriftsartikel (refereegranskat)abstract
- Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDES and DDFS with no new safety signals.
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| 7. |
- Walker, Anthony P., et al.
(författare)
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Comprehensive ecosystem model-data synthesis using multiple data sets at two temperate forest free-air CO2 enrichment experiments: Model performance at ambient CO2 concentration
- 2014
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Ingår i: Journal of Geophysical Research - Biogeosciences. - 2169-8953 .- 2169-8961. ; 119:5, s. 937-964
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Tidskriftsartikel (refereegranskat)abstract
- Free-air CO2 enrichment (FACE) experiments provide a remarkable wealth of data which can be used to evaluate and improve terrestrial ecosystem models (TEMs). In the FACE model-data synthesis project, 11 TEMs were applied to two decadelong FACE experiments in temperate forests of the southeastern U.S.the evergreen Duke Forest and the deciduous Oak Ridge Forest. In this baseline paper, we demonstrate our approach to model-data synthesis by evaluating the models' ability to reproduce observed net primary productivity (NPP), transpiration, and leaf area index (LAI) in ambient CO2 treatments. Model outputs were compared against observations using a range of goodness-of-fit statistics. Many models simulated annual NPP and transpiration within observed uncertainty. We demonstrate, however, that high goodness-of-fit values do not necessarily indicate a successful model, because simulation accuracy may be achieved through compensating biases in component variables. For example, transpiration accuracy was sometimes achieved with compensating biases in leaf area index and transpiration per unit leaf area. Our approach to model-data synthesis therefore goes beyond goodness-of-fit to investigate the success of alternative representations of component processes. Here we demonstrate this approach by comparing competing model hypotheses determining peak LAI. Of three alternative hypotheses(1) optimization to maximize carbon export, (2) increasing specific leaf area with canopy depth, and (3) the pipe modelthe pipe model produced peak LAI closest to the observations. This example illustrates how data sets from intensive field experiments such as FACE can be used to reduce model uncertainty despite compensating biases by evaluating individual model assumptions.
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| 8. |
- De Kauwe, Martin G., et al.
(författare)
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Forest water use and water use efficiency at elevated CO2: a model-data intercomparison at two contrasting temperate forest FACE sites
- 2013
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 19:6, s. 1759-1779
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Tidskriftsartikel (refereegranskat)abstract
- Predicted responses of transpiration to elevated atmospheric CO2 concentration (eCO2) are highly variable amongst process-based models. To better understand and constrain this variability amongst models, we conducted an intercomparison of 11 ecosystem models applied to data from two forest free-air CO2 enrichment (FACE) experiments at Duke University and Oak Ridge National Laboratory. We analysed model structures to identify the key underlying assumptions causing differences in model predictions of transpiration and canopy water use efficiency. We then compared the models against data to identify model assumptions that are incorrect or are large sources of uncertainty. We found that model-to-model and model-to-observations differences resulted from four key sets of assumptions, namely (i) the nature of the stomatal response to elevated CO2 (coupling between photosynthesis and stomata was supported by the data); (ii) the roles of the leaf and atmospheric boundary layer (models which assumed multiple conductance terms in series predicted more decoupled fluxes than observed at the broadleaf site); (iii) the treatment of canopy interception (large intermodel variability, 215%); and (iv) the impact of soil moisture stress (process uncertainty in how models limit carbon and water fluxes during moisture stress). Overall, model predictions of the CO2 effect on WUE were reasonable (intermodel =approximately 28%+/- 10%) compared to the observations (=approximately 30%+/- 13%) at the well-coupled coniferous site (Duke), but poor (intermodel =approximately 24%+/- 6%; observations =approximately 38%+/- 7%) at the broadleaf site (Oak Ridge). The study yields a framework for analysing and interpreting model predictions of transpiration responses to eCO2, and highlights key improvements to these types of models.
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- Howes, Mark T, et al.
(författare)
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Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells
- 2010
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Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 190:4, s. 675-691
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Tidskriftsartikel (refereegranskat)abstract
- Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells.
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- Jackson, R B, et al.
(författare)
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Belowground consequences of vegetation change and their treatment in models
- 2000
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Ingår i: Ecological Applications. - 1051-0761. ; 10:2, s. 470-483
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Tidskriftsartikel (refereegranskat)abstract
- The extent and consequences of global land-cover and land-use change are increasingly apparent. One consequence not so apparent is the altered structure of plants belowground. This paper examines such belowground changes, emphasizing the interaction of altered root distributions with other factors and their treatment in models. Shifts of woody and herbaceous vegetation with deforestation, afforestation, and woody plant encroachment typically alter the depth and distribution of plant rests, influencing soil nutrients, the water balance, and net primary productivity (NPP). For example, our analysis of global soil data sets shows that the major plant nutrients C, N, P, and K are more shallowly distributed than are Ca, Mg, and Na, but patterns for each element vary with the dominant vegetation type. After controlling for climate, soil C and N are distributed more deeply in arid shrublands than in arid grasslands, and subhumid forests have shallower nutrient distributions than do subhumid grasslands. Consequently, changes in vegetation may influence the distribution of soil carbon and nutrients over time (perhaps decades to centuries). Shifts in the water balance are typically much more rapid. Catchment studies indicate that the water yield decreases 25-40 mm for each 10% increase in tree cover, and increases in transpiration of water taken up by deep roots may account for as much as 50% of observed responses. Because models are increasingly important for predicting the consequences of vegetation change, we discuss the treatment of belowground processes and how different treatments affect model outputs. Whether models are parameterized by biome or plant life form (or neither), use single or multiple soil layers, or include N and water limitation will all affect predicted outcomes. Acknowledging and understanding such differences should help constrain predictions of vegetation change.
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| 11. |
- Jonsson, Andreas P., et al.
(författare)
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CuZn-superoxide dismutase in D90A heterozygotes from recessive and dominant ALS pedigrees
- 2002
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Ingår i: Neurobiology of Disease. - : Academic Press. - 0969-9961 .- 1095-953X. ; 10:3, s. 327-333
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in CuZn-superoxide dismutase (CuZn-SOD) have been linked to ALS. In most cases ALS is inherited as a dominant trait and there is marked reduction in CuZn-SOD activity in samples from the patients. The D90A mutation, however, mostly causes ALS as a recessive trait and shows near normal CuZn-SOD activity. A few familial and sporadic ALS cases heterozygous for the D90A mutation have also been found. Haplotype analysis of both types of D90A families has suggested that all recessive cases share a common founder and may carry a protective factor located close to the D90A mutant CuZn-SOD locus. To search for effects of a putative protective factor we analysed erythrocytes from D90A heterozygous individuals for SOD activity by a direct assay, subunit composition by immunoblotting, and zymogram pattern formed by isoelectric focusing and SOD staining. Included were heterozygotes from 17 recessive families, and from 2 dominant families and 4 apparently sporadic cases. The CuZn-SOD activity in the recessive and dominant groups was found to be equal, and 95% of controls. The ratio between mutant and wildtype subunits was likewise equal and 0.8:1 in both groups. The zymograms revealed multiple bands representing homo- and heterodimers. There were, however, no differences between the groups in patterns or in ratios between the molecular forms. In conclusion we find no evidence from analyses in erythrocytes that the putative protective factor in recessive families acts by simply downregulating the synthesis or altering the molecular structure or turnover of the mutant enzyme.
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| 14. |
- Parton, Robert G., et al.
(författare)
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Caveolae : The FAQs
- 2020
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Ingår i: Traffic. - : John Wiley & Sons. - 1398-9219 .- 1600-0854. ; 21:1, s. 181-185
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are an abundant, but enigmatic, plasma membrane feature of vertebrate cells. In this brief commentary, the authors attempt to answer some key questions related to the formation and function of caveolae based on round‐table discussions at the first EMBO Workshop on Caveolae held in France in May 2019.
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| 16. |
- Walker, Anthony P., et al.
(författare)
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Predicting long-term carbon sequestration in response to CO2 enrichment: How and why do current ecosystem models differ?
- 2015
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Ingår i: Global Biogeochemical Cycles. - 0886-6236. ; 29:4, s. 476-495
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Tidskriftsartikel (refereegranskat)abstract
- Large uncertainty exists in model projections of the land carbon (C) sink response to increasing atmospheric CO2. Free-Air CO2 Enrichment (FACE) experiments lasting a decade or more have investigated ecosystem responses to a step change in atmospheric CO2 concentration. To interpret FACE results in the context of gradual increases in atmospheric CO2 over decades to centuries, we used a suite of seven models to simulate the Duke and Oak Ridge FACE experiments extended for 300 years of CO2 enrichment. We also determine key modeling assumptions that drive divergent projections of terrestrial C uptake and evaluate whether these assumptions can be constrained by experimental evidence. All models simulated increased terrestrial C pools resulting from CO2 enrichment, though there was substantial variability in quasi-equilibrium C sequestration and rates of change. In two of two models that assume that plant nitrogen (N) uptake is solely a function of soil N supply, the net primary production response to elevated CO2 became progressively N limited. In four of five models that assume that N uptake is a function of both soil N supply and plant N demand, elevated CO2 led to reduced ecosystem N losses and thus progressively relaxed nitrogen limitation. Many allocation assumptions resulted in increased wood allocation relative to leaves and roots which reduced the vegetation turnover rate and increased C sequestration. In addition, self-thinning assumptions had a substantial impact on C sequestration in two models. Accurate representation of N process dynamics (in particular N uptake), allocation, and forest self-thinning is key to minimizing uncertainty in projections of future C sequestration in response to elevated atmospheric CO2.
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| 17. |
- Zaehle, Soenke, et al.
(författare)
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Evaluation of 11 terrestrial carbon-nitrogen cycle models against observations from two temperate Free-Air CO2 Enrichment studies
- 2014
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Ingår i: New Phytologist. - : Wiley. - 1469-8137 .- 0028-646X. ; 202:3, s. 803-822
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Tidskriftsartikel (refereegranskat)abstract
- We analysed the responses of 11 ecosystem models to elevated atmospheric [CO2] (eCO(2)) at two temperate forest ecosystems (Duke and Oak Ridge National Laboratory (ORNL) Free-Air CO2 Enrichment (FACE) experiments) to test alternative representations of carbon (C)-nitrogen (N) cycle processes. We decomposed the model responses into component processes affecting the response to eCO(2) and confronted these with observations from the FACE experiments. Most of the models reproduced the observed initial enhancement of net primary production (NPP) at both sites, but none was able to simulate both the sustained 10-yr enhancement at Duke and the declining response at ORNL: models generally showed signs of progressive N limitation as a result of lower than observed plant N uptake. Nonetheless, many models showed qualitative agreement with observed component processes. The results suggest that improved representation of above-ground-below-ground interactions and better constraints on plant stoichiometry are important for a predictive understanding of eCO(2) effects. Improved accuracy of soil organic matter inventories is pivotal to reduce uncertainty in the observed C-N budgets. The two FACE experiments are insufficient to fully constrain terrestrial responses to eCO(2), given the complexity of factors leading to the observed diverging trends, and the consequential inability of the models to explain these trends. Nevertheless, the ecosystem models were able to capture important features of the experiments, lending some support to their projections.
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