| 1. |
- Aits, Sonja, et al.
(författare)
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HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:5, s. 1008-1019
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.
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| 2. |
- Ahlquist, Mårten, et al.
(författare)
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Rhodium(I) hydrogenation in water : Kinetic studies and the detection of an intermediate using C-13{H-1} PHIPNMR spectroscopy
- 2007
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Ingår i: Inorganica Chimica Acta. - : Elsevier BV. - 0020-1693 .- 1873-3255. ; 360:5, s. 1621-1627
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism for hydrogenation of dimethylmaleate in water using cationic rhodium complexes with water-soluble bi-dentate phosphines has been investigated using kinetics and a novel method for the indirect detection of intermediates in catalytic hydrogenation reactions, whereby a late intermediate was detected. A mechanism is proposed involving fast, irreversible substrate binding followed by a rate-determining reaction with dihydrogen.
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| 3. |
- Düringer, Caroline, et al.
(författare)
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HAMLET; a novel tool to identify apoptotic pathways in tumor cells.
- 2005
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Ingår i: Application of apoptosis to cancer treatment.. - Berlin/Heidelberg : Springer-Verlag. - 9781402033032 ; , s. 223-245
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Tumor cells often carry mutations in genes that control cell survival, and become resistant to signals that trigger cell death. Yet, some cell death pathways remain intact in tumor cells. If identified, these pathways might be exploited to selectively remove tumor cells. HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex derived from human milk that activates cell death programs in tumor cells but not in healthy differentiated cells. We use HAMLET as a tool to identify apoptosis and apoptosis-like cell death mechanisms in tumor cells and to understand if these mechanisms differ between tumor and healthy cells. HAMLET interacts with the cell surface, translocates into the cytoplasm and accumulates in cell nuclei, where it disrupts the chromatin. Recent in vivo studies have shown that HAMLET maintains the tumoricidal activity in glioblastoma, papilloma and bladder cancer models, with no significant side effects. The results suggest that HAMLET should be explored as a new therapeutic agent with selectivity for the tumor and with little toxicity for adjacent healthy tissue. Such therapies are a much-needed complement to conventional treatments, to reduce the side effects and improve the selectivity.
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| 4. |
- Gustafsson, Lotta, et al.
(författare)
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HAMLET kills tumor cells by apoptosis: Structure, cellular mechanisms, and therapy
- 2005
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Ingår i: Journal of Nutrition. - 1541-6100. ; 135:5, s. 1299-1303
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Tidskriftsartikel (refereegranskat)abstract
- New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human a-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, α-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.
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| 5. |
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| 6. |
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| 7. |
- Hallgren, Oskar, et al.
(författare)
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Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
- 2008
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Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 606, s. 217-240
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Forskningsöversikt (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.
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| 9. |
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| 10. |
- Leijon, Mats, et al.
(författare)
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Wave Energy from the North Sea : Experiences from the Lysekil Research Site
- 2008
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Ingår i: Surveys in geophysics. - : Springer Science and Business Media LLC. - 0169-3298 .- 1573-0956. ; 29:3, s. 221-240
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Forskningsöversikt (refereegranskat)abstract
- This paper provides a status update on the development of the Swedish wave energy research area located close to Lysekil on the Swedish West coast. The Lysekil project is run by the Centre for Renewable Electric Energy Conversion at Uppsala University. The project was started in 2004 and currently has permission to run until the end of 2013. During this time period 10 grid-connected wave energy converters, 30 buoys for studies on environmental impact, and a surveillance tower for monitoring the interaction between waves and converters will be installed and studied. To date the research area holds one complete wave energy converter connected to a measuring station on shore via a sea cable, a Wave Rider™ buoy for wave measurements, 25 buoys for studies on environmental impact, and a surveillance tower. The wave energy converter is based on a linear synchronous generator which is placed on the sea bed and driven by a heaving point absorber at the ocean surface. The converter is directly driven, i.e. it has no gearbox or other mechanical or hydraulic conversion system. This results in a simple and robust mechanical system, but also in a somewhat more complicated electrical system.
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