| 349571. |
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| 349572. |
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| 349573. |
- Steffen, Ann-Charlott, 1977-
(författare)
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Radiolabeled HER-2 Binding Affibody Molecules for Tumor Targeting : Preclinical Studies
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Conventional cancer treatment based on radiotherapy or chemotherapy affects all dividing cells. By directing the therapy specifically to the tumor cells, normal cells can be spared. Tumor targeting molecules carrying a cytotoxic moiety is then an attractive approach.In this thesis, an affibody molecule with high affinity for the protein HER-2, that is strongly associated with aggressive forms of breast cancer, was selected. After radiolabeling with 125I, the affibody molecule, in monovalent and bivalent form, was tested in vitro in HER-2 overexpressing tumor cells and in transplanted tumors in mice.It was shown that the HER-2 targeting affibody molecule bound its target in a specific manner, both in vitro and in vivo. The small size of the affibody molecule resulted in fast clearance through the kidneys. An impressive tumor-to-blood ratio of 10 eight hours post injection was achieved and the tumors could easily be visualized in a gamma camera.The biologic effects of the bivalent affibody molecule and a monovalent affinity maturated version was measured and compared with the effects of the monoclonal antibody trastuzumab. It was found that although all molecules target the same protein, the effects differed greatly.The affibody molecule was also labeled with the alpha-emitting radionuclide 211At. Specific decrease in survival was seen in HER-2 overexpressing cells receiving the 211At labeled affibody molecule. The sensitivity to the treatment differed between cell lines, probably as a result of differences between the cell lines in internalization and nuclear size. The 211At labeled affibody molecules were also tested in vivo, where stability of the 211At label was a problem. To circumvent this problem, more stable conjugation chemistry was tested, as well as strategies to prevent uptake of released 211At by normal organs.This thesis describes the selection and optimization of affibody molecules for medical use for the first time.
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| 349574. |
- Steffen, Karin, 1989-
(författare)
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Genomics and metabolomics in the North Atlantic deep-sea sponge Geodia barretti
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sponges are among the earliest diverging taxa in the animal tree of life. They are sessile, filter-feeding animals found in marine and freshwater habitats. Many species are characterized by a close, specific and consistent association with microbes, mainly Bacteria and Archaea. This feature has been known for a long time and is suggested to be a factor contributing to the rich and diverse chemical output of the sponges. This thesis explored the effect of the habitat, specifically water mass or depth on sponges, their associated microbes, and their combined chemical output. The focal species of this thesis was the North Atlantic deep-sea high microbial abundance (HMA) demosponge Geodia barretti.In Paper I, 16S rRNA gene amplicon sequencing and untargeted metabolomics were used to quantify variation in prokaryotic community composition and chemical output in three sponge species. Water masses structured the prokaryotic community composition in the HMA species G. barretti and Stryphnus fortis. The community composition of the low microbial abundance (LMA) sponge Weberella bursa was unaffected by depth. Untargeted metabolomic data was modelled by depth. This allowed for identification of individual compounds varying with depth. Among those compounds were many putative osmolytes as well as diketopiperazines. Bioactive peptides and brominated tryptophan derivatives were unaffected by depth.In Paper II the diversity of the barrettide peptide family was explored in DNA sequencing data and chemical profiles across a wide selection of sponge species and G. barretti in particular. Five new barrettides were predicted and one sequence, barrettide C, was confirmed by solid phase peptide synthesis and co-elution with a native extract, antifouling bioassays and NMR structure elucidation. The confidence gained from sequence analysis and validating predictions lead us to suggest barrettides are a family of antifouling peptides in G. barretti.In Paper III, a reduced representation sequencing approach was used to evaluate the Stacks de novo pipeline in HMA sponges with the help of a whole genome assembled for this purpose. With this data, gene flow and connectivity were investigated in G. barretti populations sampled across the North Atlantic. The de novo pipeline was found to assemble and retain many putatively microbial loci and should thus only be used with reservations in HMA sponges. However, regarding biological inferences, strong population structure was recovered despite the apparent contamination.
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| 349575. |
- Steffen, Karin, 1989-, et al.
(författare)
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Sea for yourself: evaluating the ddRADseq Stacks de novo pipeline with a reference genome in the deep-sea sponge Geodia barretti
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Reduced representation sequencing appraches such as ddRADseq allow to assess population connectivity and infer population summary statistics, both with and without a reference genome. However, as ddRADseq employs total DNA indiscriminate of the origin, the method warrants validation prior to application in microbial rich systems. One example of a complex system are sponges such as the North Atlantic high microbial abundance sponge Geodia barretti. This species is known to maintain large, putatively disjoint populations across the deep-sea, but its dispersal capabilities remain unclear as larvae have never been observed. To study the effect of microbial contamination on data processing and population genetic inference in ddRADseq, we produced a reference genome of G. barretti and collected 163 individuals across its habitat range and bathymetry (35–1560 m) in the North Atlantic. We processed the data with Stacks2 both with and without a reference genome (de novo and hybrid/‘reference-integrated’ approach). We found that strong population structures are recovered by both approaches and across different population genetic analyses (fastStructure, PCA, FST). Compared to previous work using microsatellites in shallow populations, we found only very weak population structure across large geographic stretches (>1000 km). However, over a third (34%) of the final loci produced by the de novo pipeline did not map to the reference genome indicating that these might be of microbial origin. For comparably complex systems this means that de novo RRS genotyping approaches may contain a considerable amount of off-target loci potentially biasing the results.
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| 349576. |
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| 349577. |
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| 349578. |
- Steffenburg-Nordenström, Joachim, 1962-
(författare)
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Process chain simulation of forming, welding and heat treatment of Alloy 718
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Manufacturing of aero engine components requires attention to residual stress and final shape of the product in order to meet high quality product standards.This sets very high demands on involved manufacturing steps to meet design requirements. Simulation of manufacturing processes can therefore be animportant tool to contribute to quality assurance.The focus in this work is on simulation of a manufacturing process chain comprising of sheet metal forming, welding and a stress relief heat treatment.Simulation of sheet metal forming can be used to design a forming tool design that accounts for the material behaviour, e.g. spring back, and avoid problems such as wrinkling, thinning and cracking. Moreover, the simulation can also show how the material is stretched and work hardened. The residual stresses after forming may be of local character or global depending on the shape that is formed. However, the heat affected zone due to welding is located near the weld.The weld also causes large residual stresses with the major component along the weld. It is found that the magnitude of the residual stresses after welding is affected by remaining stresses from the previous sheet metal forming. The final stress relieve treatment will relax these residual stresses caused by e.g. forming and welding. However, this causes additional deformations.The main focus of this study is on how a manufacturing process step affects the subsequent step when manufacturing a component of the nickel-based super alloy 718. The chosen route and geometry is a simplified leading edge of an exhaust case guide vane. The simulations were validated versus experiments. The computed deformations were compared with measurements after each manufacturing step. The overall agreement between experiments and measurement was good. However, not sufficiently accurate considering the required tolerance of the component. It was found from simulations that the residual stresses after each process affects the subsequent step. After a complete manufacturing process chain which ends with a stress relief heat treatment the residual stresses were not negligible. VIII Special experiments were performed for studying the stress relief in order to understand how the stresses evolve through the heat treatment cycle during relaxation. It was found that the stresses were reduced already during the beginning of the heating up sequence due to decreasing Young´s modulus and yield stress with increasing temperature. Relaxation due to creep starts when a certain temperature was reached which gave a permanent stress relief.
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| 349579. |
- Steffenburg-Nordenström, Joachim, 1962-, et al.
(författare)
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Simulation and validation of forming, edge milling, welding and heat treatment of an alloy 718 component
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- This paper describes finite element simulations of a manufacturing process chain consisting of forming, weld preparation by milling, laser welding and stress relief heat treatment of an alloy718 aero-engine part. The work also includes experimental validation with optical measurements of the part after each process step. Approximation and discretization errors were avoided by keeping the same mesh and constitutive model. The results show that the remaining stresses affect the subsequent manufacturing process step and therefore, simulation of the process chain is essential. The accuracy with respect to the geometry showed relatively good agreement between measurement and simulation.
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| 349580. |
- Steffenburg-Nordenström, Joachim, 1962-, et al.
(författare)
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Simulation of the influence of forming on residual stresses and deformations after welding and heat treatment in Alloy 718
- 2014
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Manufacturing of components in aero engines requires attention to residual stress and final shape of the product in order to meet high quality product standards. This sets very high demands on involved manufacturing steps. The manufacturing of a V-shaped leading edge of a vane is simulated. It is made of Alloy718, which is a nickel based heat resistant material commonly used in aerospace components. The manufacturing process chain consists of forming, welding and heat treatment. The results show that the remaining residual stresses after a manufacturing process chain are affected when the residual history from the formingprocess is considered. The residual stress decrease after heat treatment is about 55-65%. Moreover, the von Mises stress profile through thickness at the centre of the radius at the weld joint is about 25% higher when full forming history is considered.
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