| 1. |
- Tykesson, Emil, et al.
(author)
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Recombinant dermatan sulfate is a potent activator of heparin cofactor II-dependent inhibition of thrombin
- 2019
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In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423. ; 29:6, s. 446-451
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Journal article (peer-reviewed)abstract
- The glycosaminoglycan dermatan sulfate (DS) is a well-known activator of heparin cofactor II-dependent inactivation of thrombin. In contrast to heparin, dermatan sulfate has never been prepared recombinantly from material of non-animal origin. Here we report on the enzymatic synthesis of structurally well-defined DS with high anticoagulant activity. Using a microbial K4 polysaccharide and the recombinant enzymes DS-epimerase 1, dermatan 4-O-sulfotransferase 1, uronyl 2-O-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase, several new glycostructures have been prepared, such as a homogenously sulfated IdoA-GalNAc-4S polymer and its 2-O-, 6-O- and 2,6-O-sulfated derivatives. Importantly, the recombinant highly 2,4-O-sulfated DS inhibits thrombin via heparin cofactor II, approximately 20 times better than heparin, enabling manipulation of vascular and extravascular coagulation. The potential of this method can be extended to preparation of specific structures that are of importance for binding and activation of cytokines, and control of inflammation and metastasis, involving extravasation and migration.
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| 2. |
- Elowsson Rendin, Linda, et al.
(author)
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Matrisome Properties of Scaffolds Direct Fibroblasts in Idiopathic Pulmonary Fibrosis
- 2019
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 20:16
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Journal article (peer-reviewed)abstract
- In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). Scaffolds were repopulated with healthy fibroblasts cultured under static stretch with heavy isotope amino acids (SILAC), to examine newly synthesized proteins over time. IPF scaffolds were characterized by increased tissue density, stiffness, ultimate force, and differential expressions of matrisome proteins compared to healthy scaffolds. Collagens, proteoglycans, and ECM glycoproteins were increased in IPF scaffolds, however while specific basement membrane (BM) proteins such as laminins and collagen IV were decreased, nidogen-2 was also increased. Findings were confirmed with histology, clearly showing a disorganized BM. Fibroblasts produced scaffold-specific proteins mimicking preexisting scaffold composition, where 11 out of 20 BM proteins were differentially expressed, along with increased periostin and proteoglycans production. We demonstrate how matrisome changes affect fibroblast activity using novel approaches to study temporal differences, where IPF scaffolds support a disorganized BM and upregulation of disease-associated proteins. These matrix-directed cellular responses emphasize the IPF matrisome and specifically the BM components as important factors for disease progression.
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| 3. |
- Nilsson Åhman, Hanna, et al.
(author)
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An Enhanced Understanding of the Powder Bed Fusion-Laser Beam Processing of Mg-Y-3.9wt%-Nd-3wt%-Zr-0.5wt% (WE43) Alloy through Thermodynamic Modeling and Experimental Characterization
- 2022
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In: Materials. - : MDPI AG. - 1996-1944. ; 15:2
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Journal article (peer-reviewed)abstract
- Powder Bed Fusion-Laser Beam (PBF-LB) processing of magnesium (Mg) alloys is gaining increasing attention due to the possibility of producing complex biodegradable implants for improved healing of large bone defects. However, the understanding of the correlation between the PBF-LB process parameters and the microstructure formed in Mg alloys remains limited. Thus, the purpose of this study was to enhance the understanding of the effect of the PBF-LB process parameters on the microstructure of Mg alloys by investigating the applicability of computational thermodynamic modelling and verifying the results experimentally. Thus, PBF-LB process parameters were optimized for a Mg WE43 alloy (Mg-Y-3.(9wt%)-Nd-3wt%-Zr-0.5wt%) on a commercially available machine. Two sets of process parameters successfully produced sample densities >99.4%. Thermodynamic computations based on the Calphad method were employed to predict the phases present in the processed material. Phases experimentally established for both processing parameters included alpha-Mg, Y2O3, Mg3Nd, Mg24Y5 and hcp-Zr. Phases alpha-Mg, Mg24Y5 and hcp-Zr were also predicted by the calculations. In conclusion, the extent of the applicability of thermodynamic modeling was shown, and the understanding of the correlation between the PBF-LB process parameters and the formed microstructure was enhanced, thus increasing the viability of the PBF-LB process for Mg alloys.
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| 4. |
- Nilsson Åhman, Hanna, et al.
(author)
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Computational and Experimental Microstructural Characterization of A Magnesium WE43 Alloy Processed on A Commercially Available PBF-LB Machine
- 2020
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In: Proceedings - Euro PM2020 Congress and Exhibition. - : European Powder Metallurgy Association (EPMA).
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Conference paper (peer-reviewed)abstract
- Magnesium (Mg) has gained a lot of attention for its biodegradable properties. Additive manufacturing of Mg would further provide an opportunity to manufacture optimized structures for implants. However, much work remains to ensure stable processes and to understand the correlation between processing parameters, microstructure and related properties. The aim of this study was to process gas-atomized WE43 powder by Powder Bed Fusion-Laser Beam (PBF-LB) in a commercially available machine (EOS M290). The built material was characterized in terms of microstructure and composition and compared with the virgin powder. Thermodynamic computations based on the Calphad-method were for the first time employed to an additively manufactured Mg-alloy to predict phases present. Samples with above 99% density were successfully manufactured. The phases predicted using computational thermodynamics partly overlapped with phases observed experimentally. The study confirms the feasibility of using commercial PBF-LB systems for processing Mg-alloys, and the applicability of thermodynamic modelling to this system.
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| 5. |
- Sandén, Carl, et al.
(author)
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Clonal competition within complex evolutionary hierarchies shapes AML over time
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.
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| 6. |
- von Palffy, Sofia, et al.
(author)
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The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML
- 2023
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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:7, s. 1204-1218
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Journal article (peer-reviewed)abstract
- Mutated Nucleophosmin 1 (NPM1) is the most common genetic alteration in acute myeloid leukemia (AML), found in approximately 30% of cases. Although mutations in this gene are considered favorable according to current risk stratification guidelines, a large fraction of patients will suffer from relapse, demonstrating the urgent need for new treatment options. Therefore, we aimed to identify cell surface proteins specifically expressed on NPM1)-mutated AML cells, allowing for potential targeting with antibody-based therapies. Herein, we performed an arrayed flow cytometry-based screen directed to 362 cell surface markers. Comparing the cell surface expression on NPM1-mutated AML cells to primitive (CD34+ CD38-) normal bone marrow cells, we identified the complement receptor C3AR as specifically expressed in NPM1-mutated AML. By flow cytometry and single cell RNA-sequencing, we further show that normal hematopoietic stem and progenitor cells lack detectable C3AR gene and protein expression, making it particularly suitable as a target for antibody therapy. We also demonstrate that C3AR in combination with GPR56 distinguishes the leukemic stem cells (LSCs) in NPM1-mutated AML from the normal hematopoietic stem cells, defining the LSC population, as shown by transplantation into immunodeficient mice. Mechanistically, stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit NK cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.
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| 7. |
- Zimmerman, Malin, et al.
(author)
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Temporal trend of autonomic nerve function and HSP27, MIF and PAI-1 in type 1 diabetes
- 2017
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In: Journal of Clinical and Translational Endocrinology. - : Elsevier BV. - 2214-6237. ; 8, s. 15-21
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Journal article (peer-reviewed)abstract
- Aim Diabetes mellitus type 1 (T1D) has numerous complications including autonomic neuropathy, i.e. dysfunction of the autonomous nervous system. This study focuses on Heat Shock Protein 27 (HSP27), Macrophage Migration Inhibitory Factor (MIF), Plasminogen Activator Inhibitor-1 (PAI-1) and HbA1c and their possible roles in effects of diabetes on the autonomic nervous system. Methods Patients with T1D (n = 32, 41% women) were recruited in 1985 and followed up on four occasions (1989, 1993, 1998, and 2005). Autonomic function was tested using expiration/inspiration (E/I-ratio). Blood samples, i.e. HSP27 (last three occasions), MIF, PAI-1 (last two occasions) and HbA1c (five occasions), were analyzed. Results Autonomic nerve function deteriorated over time during the 20-year-period, but levels of HSP27, MIF, and PAI-1 were not associated with cardiovascular autonomic neuropathy. MIF and PAI-1 were lower in T1D than in healthy controls in 2005. Increased HbA1c correlated with a decrease in E/I-ratio. Conclusions Neither the neuroprotective substance HSP27 nor the inflammatory substances, MIF and PAI-1 were associated with measures of cardiovascular autonomic nerve function, but a deterioration of such function was observed in relation to increasing HbA1c in T1D during a 20-year follow-up period. Improved glucose control might be associated with protection against autonomic neuropathy in T1D.
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