| 1. |
- Mischak, Harald, et al.
(författare)
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Implementation of proteomic biomarkers : making it work
- 2012
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Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 42:9, s. 1027-1036
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Tidskriftsartikel (refereegranskat)abstract
- While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.
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| 2. |
- d'Alessandro, Elisa, et al.
(författare)
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Thrombo-Inflammation in Cardiovascular Disease : An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis
- 2020
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:4, s. 538-564
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Tidskriftsartikel (refereegranskat)abstract
- Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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| 3. |
- Freischmidt, Axel, et al.
(författare)
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A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis
- 2021
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 144:4, s. 1214-1229
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D = G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS.
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| 4. |
- Rudbeck Jepsen, Martin, et al.
(författare)
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Transitions in European land-management regimes between 1800 and 2010
- 2015
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Ingår i: Land use policy. - : Elsevier BV. - 0264-8377 .- 1873-5754. ; 49:SI, s. 53-64
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Tidskriftsartikel (refereegranskat)abstract
- Land use is a cornerstone of human civilization, but also intrinsically linked to many global sustainability challenges—from climate change to food security to the ongoing biodiversity crisis. Understanding the underlying technological, institutional and economic drivers of land-use change, and how they play out in different environmental, socio-economic and cultural contexts, is therefore important for identifying effective policies to successfully address these challenges. In this regard, much can be learned from studying long-term land-use change. We examined the evolution of European land management over the past 200 years with the aim of identifying (1) key episodes of changes in land management, and (2) their underlying technological, institutional and economic drivers. To do so, we generated narratives elaborating on the drivers of land use-change at the country level for 28 countries in Europe. We qualitatively grouped drivers into land-management regimes, and compared changes in management regimes across Europe. Our results allowed discerning seven land-management regimes, and highlighted marked heterogeneity regarding the types of management regimes occurring in a particular country, the timing and prevalence of regimes, and the conditions that result in observed bifurcations. However, we also found strong similarities across countries in the timing of certain land-management regime shifts, often in relation to institutional reforms (e.g., changes in EU agrarian policies or the emergence and collapse of the Soviet land management paradigm) or to technological innovations (e.g., drainage pipes, tillage and harvesting machinery, motorization, and synthetic fertilizers). Land reforms frequently triggered changes in land management, and the location and timing of reforms had substantial impacts on land-use outcomes. Finally, forest protection policies and voluntary cooperatives were important drivers of land-management changes. Overall, our results demonstrate that land-system changes should not be conceived as unidirectional developments following predefined trajectories, but rather as path-dependent processes that may be affected by various drivers, including sudden events.
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| 5. |
- Bednar, Peter, et al.
(författare)
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Sustainability in IS: the case for an open systems approach
- 2011
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Ingår i: Governance and Sustainability in Information Systems. Managing the Transfer and Diffusion of IT. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783642241475 ; 366, s. 325-329
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Bokkapitel (refereegranskat)abstract
- Common sense tells us that cost cutting leads to saving, and spending should therefore be minimized. However, a little reflection tells us that this sometimes leads to false economies. In an organizational context, these can lead on to a downward spiral of organizational ‘suicide’. Examples of false economies may include: saving on maintenance; saving on research and development expenditure; saving on margins (waste or just-in-time management); and saving on ‘how’ we do things, as opposed to ‘what’ we do. Common sense cost cutting makes ‘how’ invisible, and only recognizes ‘what’. It is vital that we also remember to consider ‘why’ activities are undertaken. Professional competence implies not only skill/knowledge in a particular field, but also desire to apply that knowledge in accordance with certain values, and engagement with the context of application so that learning through reflection may take place. Professional work therefore includes scope for extra-role behaviour, such as suggesting innovative methods or identifying and developing new opportunities (Bednar and Welch, 2010). We suggest that a naïve pursuit of ‘efficiency’ is likely to constrict and curtail possibilities for extra-role behaviour, with disastrous consequences for the development and growth of the business. Creation of systems experienced as sustainable therefore requires us to focus attention on perceived usefulness, rather than efficiency.
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| 6. |
- Freischmidt, Axel, et al.
(författare)
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Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137:11, s. 2938-2950
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.
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| 7. |
- Helferich, Anika M., et al.
(författare)
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Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS
- 2018
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 75:23, s. 4301-4319
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Tidskriftsartikel (refereegranskat)abstract
- Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic (sALS) and familial ALS (fALS) patients. Combined transcriptomic and proteomic analysis revealed that reduced levels of microRNA-1825 caused a translational upregulation of tubulin-folding cofactor b (TBCB). Moreover, we found that excess TBCB led to depolymerization and degradation of tubulin alpha-4A (TUBA4A), which is encoded by a known ALS gene. Importantly, the increase in TBCB and reduction of TUBA4A protein was confirmed in brain cortex tissue of fALS and sALS patients, and led to motor axon defects in an in vivo model. Our discovery of a microRNA-1825/TBCB/TUBA4A pathway reveals a putative pathogenic cascade in both fALS and sALS extending the relevance of TUBA4A to a large proportion of ALS cases.
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| 8. |
- Kabliman, Evgeniya, et al.
(författare)
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Ab initio-based mean-field theory of the site occupation in the Fe-Cr sigma-phase
- 2011
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - : AMER PHYSICAL SOC. - 1098-0121 .- 1550-235X. ; 83:9, s. 092201-
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Tidskriftsartikel (refereegranskat)abstract
- An efficient first-principles-based mean-field theory is applied to study the site occupations in the Fe-Cr sigma phase. It is based on the expansion of the total energy of a random alloy close to the equiatomic composition in the paramagnetic state in terms of the effective on-site interactions and takes into account longitudinal spin fluctuations at high temperatures. The calculated site occupation is in very good agreement with the existing experimental data.
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| 9. |
- Kabliman, Evgeniya, et al.
(författare)
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Ab Initio Study of Lattice Site Occupancies in Binary Sigma Phases Using a Single-Site Mean Field Model
- 2012
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Ingår i: Applied Sciences. - : MDPI. - 2076-3417. ; 2:3, s. 654-668
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Tidskriftsartikel (refereegranskat)abstract
- The site occupation of binary Fe-Cr, Co-Cr, Re-W and Fe-V sigma phases is studied in the present work with a first-principles-based single-site mean field theory. We show that the alloy components in these systems exhibit similar site preferences except for the Re-W system, where the occupation of two sites is reversed in agreement with previously published works. In case of the FeV sigma phase, for which the size mismatch between the alloy components is large, we also include into our consideration the effect of local lattice relaxations. The obtained results are found in good agreement with the experimental data and previous theoretical studies.
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| 10. |
- Kabliman, Evgeniya, et al.
(författare)
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Configurational thermodynamics of the Fe-Cr sigma phase
- 2011
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 84:18, s. 184206-
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Tidskriftsartikel (refereegranskat)abstract
- Configurational thermodynamics of the Fe-Cr sigma phase is investigated on the basis of an Ising-type configurational Hamiltonian and a single-site mean-field model for the free energy. The parameters of the statistical models are obtained from efficient first-principles calculations using different computational techniques. We demonstrate that the effective pair and multisite interactions in the sigma phase are relatively small, which allows using a simplified model for distributing Fe and Cr atoms among sublattices. We also show that this system exhibits a nontrivial magnetic behavior at high temperatures, which affects the site occupation by Fe and Cr atoms. The structural variation (volume and c/a) that might be present due to neutron irradiation and thermal expansion can lead to an additional atomic redistribution.
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| 11. |
- Knauf, Wolfgang U., et al.
(författare)
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Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial
- 2012
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 159:1, s. 67-77
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Tidskriftsartikel (refereegranskat)abstract
- The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re-evaluated after a median observation time of 54months in May 2010. Overall survival (OS) was analysed for the first time. At follow-up, investigator-assessed complete response (CR) rate (21.0% vs 10.8%), median progression-free survival (21.2 vs 8.8months; P<0.0001; hazard ratio 2.83) and time to next treatment (31.7 vs 10.1months; P<0.0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those =65years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78.3% vs 63.6%; P=0.004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.
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| 12. |
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| 13. |
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| 14. |
- Lejaeghere, Kurt, et al.
(författare)
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Reproducibility in density functional theory calculations of solids.
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 351:6280, s. 1415-1422
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Tidskriftsartikel (refereegranskat)abstract
- The widespread popularity of density functional theory has given rise to an extensive range of dedicated codes for predicting molecular and crystalline properties. However, each code implements the formalism in a different way, raising questions about the reproducibility of such predictions. We report the results of a community-wide effort that compared 15 solid-state codes, using 40 different potentials or basis set types, to assess the quality of the Perdew-Burke-Ernzerhof equations of state for 71 elemental crystals. We conclude that predictions from recent codes and pseudopotentials agree very well, with pairwise differences that are comparable to those between different high-precision experiments. Older methods, however, have less precise agreement. Our benchmark provides a framework for users and developers to document the precision of new applications and methodological improvements.
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| 15. |
- Madsen, Georg K. H., et al.
(författare)
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Efficient linearization of the augmented plane-wave method
- 2001
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 64:19, s. 195134-
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Tidskriftsartikel (refereegranskat)abstract
- We present a detailed analysis of the APW+lo basis set for band-structure calculations. This basis set consists of energy independent augmented plane-wave (APW) functions. The linearization is introduced through local orbitals evaluated at the same linearization energy as the APW functions. It is shown that results obtained with the APW+lo basis set converge much faster and often more systematically towards the final value. The APW+lo thereby allows accurate treatment of systems that were previously unaccessible to linearized APW. Furthermore, it is shown that APW+lo converges to the same total energy as LAPW provided the higher angular momenta l are linearized, either by adding extra local orbitals or treating them by LAPW. It is illustrated that the APW basis functions are much closer to the true form of the eigenfunctions than the LAPW basis functions. This is especially true for basis functions that have a strong energy dependence inside the sphere.
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| 16. |
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