| 1. |
- Gustafsson, Erika, et al.
(författare)
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Directed evolution of chemotaxis inhibitory protein of Staphylococcus aureus generates biologically functional variants with reduced interaction with human antibodies
- 2010
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 23:2, s. 91-101
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Tidskriftsartikel (refereegranskat)abstract
- Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is a protein that binds and blocks the C5a receptor (C5aR) and formylated peptide receptor, thereby inhibiting the immune cell recruitment associated with inflammation. If CHIPS was less reactive with existing human antibodies, it would be a promising anti-inflammatory drug candidate. Therefore, we applied directed evolution and computational/rational design to the CHIPS gene in order to generate new CHIPS variants displaying lower interaction with human IgG, yet retaining biological function. The optimization was performed in four rounds: one round of random mutagenesis to add diversity into the CHIPS gene and three rounds of DNA recombination by Fragment INduced Diversity (FIND((R))). Every round was screened by phage selection and/or ELISA for decreased interaction with human IgG and retained C5aR binding. The mean binding of human anti-CHIPS IgG decreased with every round of evolution. For further optimization, new amino acid substitutions were introduced by rational design, based on the mutations identified during directed evolution. Finally, seven CHIPS variants with low interaction with human IgG and retained C5aR blocking capacity could be identified.
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| 2. |
- Hedlund, Gunnar, et al.
(författare)
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The Tumor Targeted Superantigen ABR-217620 Selectively Engages TRBV7-9 and Exploits TCR-pMHC Affinity Mimicry in Mediating T Cell Cytotoxicity.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- The T lymphocytes are the most important effector cells in immunotherapy of cancer. The conceptual objective for developing the tumor targeted superantigen (TTS) ABR-217620 (naptumomab estafenatox, 5T4Fab-SEA/E-120), now in phase 3 studies for advanced renal cell cancer, was to selectively coat tumor cells with cytotoxic T lymphocytes (CTL) target structures functionally similar to natural CTL pMHC target molecules. Here we present data showing that the molecular basis for the anti-tumor activity by ABR-217620 resides in the distinct interaction between the T cell receptor β variable (TRBV) 7-9 and the engineered superantigen (Sag) SEA/E-120 in the fusion protein bound to the 5T4 antigen on tumor cells. Multimeric but not monomeric ABR-217620 selectively stains TRBV7-9 expressing T lymphocytes from human peripheral blood similar to antigen specific staining of T cells with pMHC tetramers. SEA/E-120 selectively activates TRBV7-9 expressing T lymphocytes resulting in expansion of the subset. ABR-217620 selectively triggers TRBV7-9 expressing cytotoxic T lymphocytes to kill 5T4 positive tumor cells. Furthermore, ABR-217620 activates TRBV7-9 expressing T cell line cells in the presence of cell- and bead-bound 5T4 tumor antigen. Surface plasmon resonance analysis revealed that ABR-217620 binds to 5T4 with high affinity, to TRBV7-9 with low affinity and to MHC class II with very low affinity. The T lymphocyte engagement by ABR-217620 is constituted by displaying high affinity binding to the tumor cells (KD approximately 1 nM) and with the mimicry of natural productive immune TCR-pMHC contact using affinities of around 1 µM. This difference in kinetics between the two components of the ABR-217620 fusion protein will bias the binding towards the 5T4 target antigen, efficiently activating T-cells via SEA/E-120 only when presented by the tumor cells.
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| 3. |
- Moberg, Christina, et al.
(författare)
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De unga gör helt rätt när de stämmer staten
- 2022
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Ingår i: Aftonbladet. - 1103-9000.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
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| 4. |
- Akselsson, Cecilia, et al.
(författare)
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Samordnad landskapsförvaltning : Ett nytt sätt att förvalta landskap för att uppnå hållbarhetsmålen
- 2020
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Ingår i: ; 6
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Annan publikation (populärvet., debatt m.m.)abstract
- Trycket på både skogs- och jordbruksmark ökar, bland annat som en följd av befolknings-ökningen, ändrade konsumtionsmönster och den pågående klimatförändringen. Detta leder till målkonflikter, där aktörer med olika intressen har olika syn på hur marken ska användas på bästa sätt. Dagens sektorsvisa planering, där beslut ofta tas på fastighetsnivå, gör det svårt att hitta lösningar på dessa målkonflikter. En övergång till en mer samordnad landskapsförvaltning har stor potential, men innebär också att en rad hinder först måste övervinnas.
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| 5. |
- Bourelius, Lars, et al.
(författare)
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Öppna digitala resurser (OER)
- 2012
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Ingår i: Nyheter & Debatt. - 1651-3363. ; :3, s. 4-4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Lärande sker i sociala sammanhang. Genom nätet är klassrummet idag globalt. Tusentals universitet, skolor och lärare i världen delar idag med sig av kursmaterial, föreläsningar, experiment, reportage och bilder så att andra kan återanvända materialet i sin undervisning.
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| 6. |
- Cerezo-Magaña, Myriam, et al.
(författare)
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Hypoxic induction of exosome uptake through proteoglycan-dependent endocytosis fuels the lipid droplet phenotype in Glioma
- 2021
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Ingår i: Molecular Cancer Research. - : American Association For Cancer Research (AACR). - 1541-7786 .- 1557-3125. ; 19:3, s. 528-540
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Tidskriftsartikel (refereegranskat)abstract
- As an adaptive response to hypoxic stress, aggressive tumors rewire their metabolic phenotype into increased malignant behavior through extracellular lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known as influential messengers in the tumor microenvironment, may also serve anabolic functions by transforming hypoxic, patient-derived human glioblastoma cell lines into the LDþ phenotype. EVs were internalized via a hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct lipid transfer, and independently of fatty acid synthase activity. EVs can enter cells through multiple and yet ill-defined pathways. On a mechanistic level, we found that hypoxia-mediated EV uptake depends on increased heparan sulfate proteoglycan (HSPG) endocytosis that preferentially followed the lipid raft pathway. The functional relevance of HSPG was evidenced by the reversal of EV-mediated LD loading by targeting of HSPG receptor function.
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| 7. |
- de Oliveira, Kelin Gonçalves, et al.
(författare)
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Decoding of the surfaceome and endocytome in primary glioblastoma cells identifies potential target antigens in the hypoxic tumor niche
- 2024
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Ingår i: Acta Neuropathologica Communications. - : BioMed Central (BMC). - 2051-5960. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapies with antibody-drug-conjugates (ADC) and CAR-T cells, targeted at tumor surface antigens (surfaceome), currently revolutionize clinical oncology. However, target identification warrants a better understanding of the surfaceome and how it is modulated by the tumor microenvironment. Here, we decode the surfaceome and endocytome and its remodeling by hypoxic stress in glioblastoma (GBM), the most common and aggressive brain tumor in adults. We employed a comprehensive approach for global and dynamic profiling of the surfaceome and endocytosed (endocytome) proteins and their regulation by hypoxia in patient-derived GBM cultures. We found a heterogeneous surface-endocytome profile and a divergent response to hypoxia across GBM cultures. We provide a quantitative ranking of more than 600 surface resident and endocytosed proteins, and their regulation by hypoxia, serving as a resource to the cancer research community. As proof-of-concept, the established target antigen CD44 was identified as a commonly and abundantly expressed surface protein with high endocytic activity. Among hypoxia induced proteins, we reveal CXADR, CD47, CD81, BSG, and FXYD6 as potential targets of the stressed GBM niche. We could validate these findings by immunofluorescence analyses in patient tumors and by increased expression in the hypoxic core of GBM spheroids. Selected candidates were finally confronted by treatment studies, showing their high capacity for internalization and ADC delivery. Importantly, we highlight the limited correlation between transcriptomics and proteomics, emphasizing the critical role of membrane protein enrichment strategies and quantitative mass spectrometry. Our findings provide a comprehensive understanding of the surface-endocytome and its remodeling by hypoxia in GBM as a resource for exploration of targets for immunotherapeutic approaches in GBM.
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| 8. |
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| 9. |
- Fagerberg, Linn, et al.
(författare)
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Contribution of antibody-based protein profiling to the human chromosome-centric proteome project (C-HPP)
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:6, s. 2439-2448
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Tidskriftsartikel (refereegranskat)abstract
- A gene-centric Human Proteome Project has been proposed to characterize the human protein-coding genes in a chromosome-centered manner to understand human biology and disease. Here, we report on the protein evidence for all genes predicted from the genome sequence based on manual annotation from literature (UniProt), antibody-based profiling in cells, tissues and organs and analysis of the transcript profiles using next generation sequencing in human cell lines of different origins. We estimate that there is good evidence for protein existence for 69% (n = 13985) of the human protein-coding genes, while 23% have only evidence on the RNA level and 7% still lack experimental evidence. Analysis of the expression patterns shows few tissue-specific proteins and approximately half of the genes expressed in all the analyzed cells. The status for each gene with regards to protein evidence is visualized in a chromosome-centric manner as part of a new version of the Human Protein Atlas (www.proteinatlas.org).
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| 10. |
- Forsberg, Anders, et al.
(författare)
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Landmark-Based Software for Anatomical Measurements : A Precision Study
- 2009
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Ingår i: Clinical anatomy (New York, N.Y. Print). - : Wiley. - 0897-3806 .- 1098-2353. ; 22:4, s. 456-462
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop a software program, called Landmarker, which would aid studies of complex anatomical morphometry by simplifying the manual identification of landmarks in 3D images. We also tested its precision on routine magnetic resonance imaging (MRI) scans. To understand human biological variation, there is a need to identify morphological characteristics from the exterior and the interior of human anatomy. MRI, as opposed to other radiographic methods (mainly based on X-ray techniques), supplies good soft tissue contrast, which allows for more complex assessments than what bony landmarks can provide. Because automation of this assessment is highly demanding, one of the primary goals for the new software was to enable more rapid identification of landmark sets in 3D image data. Repeat acquisition of head MRIs having a resolution of 0.94 x 0.94 x 1.20 mm3 were performed on 10 volunteers. Intra- and interoperator, as well as interacquisition variations of manual identification of exterior, craniofacial interior, and brain landmarks were studied. The average distances between landmarks were <1.8 mm, <2.3 mm, and <2.0 mm in the intra- and interoperator, and interacquisition evaluations, respectively. This study presents new software for time efficient identification of complex craniofacial landmarks in 3D MRI. To the best of our knowledge, no evaluation of software for rapid landmark-based analysis of complex anatomies from 3D MR data has yet been presented. This software may also be useful for studies in other anatomical regions and for other types of image data.
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