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- Adolf, A., et al.
(författare)
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Release of astroglial vimentin by extracellular vesicles: Modulation of binding and internalization of C3 transferase in astrocytes and neurons
- 2019
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Ingår i: Glia. - : Wiley. - 0894-1491. ; 67:4, s. 703-717
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Tidskriftsartikel (refereegranskat)abstract
- Clostridium botulinum C3 transferase (C3bot) ADP-ribosylates rho proteins to change cellular functions in a variety of cell types including astrocytes and neurons. The intermediate filament protein vimentin as well as transmembrane integrins are involved in internalization of C3bot into cells. The exact contribution, however, of these proteins to binding of C3bot to the cell surface and subsequent cellular uptake remains to be unraveled. By comparing primary astrocyte cultures derived from wild-type with Vim(-/-) mice, we demonstrate that astrocytes lacking vimentin exhibited a delayed ADP-ribosylation of rhoA concurrent with a blunted morphological response. This functional impairment was rescued by the extracellular excess of recombinant vimentin. Binding assays using C3bot harboring a mutated integrin-binding RGD motif (C3bot-G89I) revealed the involvement of integrins in astrocyte binding of C3bot. Axonotrophic effects of C3bot are vimentin dependent and postulate an underlying mechanism entertaining a molecular cross-talk between astrocytes and neurons. We present functional evidence for astrocytic release of vimentin by exosomes using an in vitro scratch wound model. Exosomal vimentin+ particles released from wild-type astrocytes promote the interaction of C3bot with neuronal membranes. This effect vanished when culturing Vim(-/-) astrocytes. Specificity of these findings was confirmed by recombinant vimentin propagating enhanced binding of C3bot to synaptosomes from rat spinal cord and mouse brain. We hypothesize that vimentin+ exosomes released by reactive astrocytes provide a novel molecular mechanism constituting axonotrophic (neuroprotective) and plasticity augmenting effects of C3bot after spinal cord injury.
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| 2. |
- Lee, EF, et al.
(författare)
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BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival
- 2019
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:5, s. 342-
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Tidskriftsartikel (refereegranskat)abstract
- Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, though the outcomes of previous studies have been conflicting. To conclusively address this question, we tested a panel of established and early passage patient-derived cell lines against several BH3-mimetic drugs designed to target individual or subsets of pro-survival BCL-2 proteins, alone and in combination, in both 2D and 3D cell cultures. None of the drugs demonstrated significant activity as single agents, though combinations targeting MCL-1 plus BCL-XL, and to a lesser extent BCL-2, showed considerable synergistic killing activity that was elicited via both BAX and BAK. Genetic deletion of BFL-1 in cell lines that express it at relatively high levels only had minor impact on BH3-mimetic drug sensitivity, suggesting it is not a critical pro-survival protein in melanoma. Combinations of MCL-1 inhibitors with BRAF inhibitors also caused only minimal additional melanoma cell killing over each drug alone, whilst combinations with the proteasome inhibitor bortezomib was more effective in multiple cell lines. Our data show for the first time that therapies targeting specific combinations of BCL-2 pro-survival proteins, namely MCL-1 plus BCL-XL and MCL-1 plus BCL-2, could have significant benefit for the treatment of melanoma.
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| 3. |
- Kulkov, Ignat, et al.
(författare)
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Technology entrepreneurship in healthcare : Challenges and opportunities for value creation
- 2023
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Ingår i: Journal of Innovation and Knowledge. - : Elsevier B.V.. - 2530-7614 .- 2444-569X. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- The healthcare industry is nowadays increasingly forced to adapt to new fast-paced changes, despite its conservatism. Indeed, the number of new technology entrepreneurs and technology value is increasing. In this study, we use modern literature and illustrative cases to identify patterns of technological value creation in the healthcare industry with the purpose to form an understanding of the challenges and opportunities for technology entrepreneurs. Hence, we propose a new challenges-opportunities framework for understanding technology entrepreneurship (i.e., technology innovation, technology proactivity, and technology risk-taking) as a foundation for value creation concerning the needs of patients, medical personnel and hospitals, and the whole industry. We also end the article by outlining practical implications at the micro-level (i.e., patient advocacy and technology-enabled engagement strategies), meso-level (i.e., digital health solutions and motivation for collaboration), and macro-level (i.e., trust building and infrastructure).
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| 6. |
- Kulkova, J., et al.
(författare)
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Medicine of the future : How and who is going to treat us?
- 2023
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Ingår i: Futures. - : Elsevier Ltd. - 0016-3287 .- 1873-6378. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- Medicine’s ability to quickly respond to challenges raises questions from researchers, practitioners, and society as a whole. Our task in this study was to identify key and atypical current factors influencing the development of medicine and to predict the development of medicine in the short, medium, and long term. To implement our study, we selected 22 medical experts and applied the three-level Delphi method. The current trends caused by COVID-19 have a short-term impact, but they will launch other drivers that will transform the healthcare industry. Well-being technologies, data-informed personalization, and climate change will become key drivers for the development of medicine over the period of 1–50 years. Expert opinion is divided about the future of mass availability of advanced medical treatment and sustainable development of healthcare.
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