| 31. |
- Eriksson, Mathilda, et al.
(författare)
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Utilization of a right-handed coiled-coil protein from archaebacterium Staphylothermus marinus as a carrier for cisplatin
- 2009
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 29:1, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The nano-sized right-handed coiled-coil (RHCC) protein, originating from the archaebacterium Staphylothermus marinus, is stable at high salt concentrations, high temperatures, high pressures and extremes of pH. Its crystal structure reveals four hydrophobic cavities which can incorporate heavy metals. Nano-sized compounds have been used to carry cytotoxic drugs to tumours, avoiding delivery to healthy tissue, in part due to enhanced permeability in tumour blood vessels (enhanced permeability and retention effect). MATERIALS AND METHODS: The ability of RHCC to carry the platinum-containing chemotherapeutic drug cisplatin to cells, while retaining the cytotoxic potential was tested both in vitro and in vivo. RESULTS: RHCC was able to bind and enter cells in vitro and was not severely toxic or immunogenic in mice. Moreover, RHCC incorporated cisplatin, without inhibiting the cytotoxic potential of the drug against tumour cell lines in vitro or in vivo. CONCLUSION: RHCC can be used as a carrier of cisplatin without abrogating the effect of the drug.
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| 32. |
- Faxälv, Lars, 1977-
(författare)
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Imaging methods for haemostasis research
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood is a vital part of the human physiology; a transport system that brings nutrients and oxygen to sustain living cells and simultaneously facilitates the removal of carbon dioxide and other waste products from the body. To assure the continuity of these functions, it is of uttermost importance to keep the flowing blood inside the vascular system at any cost. The principal components of the haemostatic system are the blood platelets and the plasma coagulation system, both working in concert to create a blood stopping haemostatic plug when a vessel is ruptured. In modern health care, methods for treatment and diagnostics often implicate the contact between blood and artificial materials (biomaterials). Biomaterial surfaces may activate platelets and the coagulation cascade by exposing a surface that during blood contact shares certain characteristics with surfaces found at the site of vascular injury. Therefore it is of great importance that the mechanisms behind the interactions between foreign surfaces and blood are studied in order to minimize, and if possible, prevent unnecessary reactions that may lead to thrombosis.This thesis describes two important methods to study blood – surface interactions in terms of surface induced plasma coagulation and platelet adhesion/aggregation. The method ‘Imaging of coagulation’, a coagulation assay based on time-lapse image capture of the coagulation process was developed during the course of this work. The use of images enables the method to answer questions regarding where coagulation was initiated and how fast coagulation propagates. Such questions are highly relevant in the study of blood-biomaterial interactions but also in general haemostasis research. In vivo, platelet adhesion and aggregation are events that always proceed under flow conditions. Therefore we also developed a cone-and-plate flow model to study these mechanisms under similar conditions in vitro. The cone-and-plate setup was found to be a flexible platform and was used for both blood compatibility testing of potential biomaterials as well as for general haemostasis research.With the above mentioned methods we tested the haemocompatibility of glycerol monooleate (GMO), a proposed substance for use in biomaterial applications. It was found that GMO did not activate coagulation to any great extent either in plasma or in whole blood.Surface induced coagulation and platelet adhesion was also studied on PEG-containing hydrogels and compared with hydrogels constructed from three different non-PEG-containing monomers. It was concluded that all the grafted hydrogels, in particular those produced from the monomers 2-hydroxyethyl methacrylate (HEMA) and/or PEG- methacrylate (PEGMA), demonstrated good haemocompatibility.Supported phospholipid bilayers were used to investigate the relationship between surface charge and procoagulant activity. The coagulation process was studied in a straightforward manner using the imaging of coagulation setup. We concluded that the content of negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) in the bilayer must exceed ~ 6% for the bilayer to exert procoagulant activity.The physiological role of factor XII in human haemostasis and thrombosis was investigated in the imaging of coagulation setup and the cone and plate setup by the use of surfaces with thrombogenic coatings. We found that tissue factor initiated coagulation could be greatly accelerated by the presence of contact activating agents in a platelet dependent manner.In conclusion, the method ‘Imaging of coagulation’ and platelet adhesion/aggregation in the cone-and-plate flow model are both versatile methods with many possible applications. The combination of the two methods provides a solid foundation for biomaterial and haemostasis research.
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| 33. |
- Fayad, Walid, et al.
(författare)
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Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10, s. e7238-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS: A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS: The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Fryknäs, Mårten, et al.
(författare)
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Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model
- 2006
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 11:5, s. 457-468
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Tidskriftsartikel (refereegranskat)abstract
- The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
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| 38. |
- Fryknäs, Mårten, et al.
(författare)
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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
- 2007
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195
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Tidskriftsartikel (refereegranskat)abstract
- The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
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| 39. |
- Granberg, Mikael, et al.
(författare)
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Dealing with uncertainty : a case study of controlling insect populations in natural ecosystems
- 2008
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Ingår i: Local Environment. - : Informa UK Limited. - 1354-9839 .- 1469-6711. ; 13:7, s. 641-652
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Tidskriftsartikel (refereegranskat)abstract
- This paper analyses the political process for handling an outbreak of an insect causing human allergic reactions. In the southern part of the Swedish island Gotland in the Baltic Sea, an outbreak of the northern pine processionary moth, Thaumetopoea pinivora, has occurred. With regard to the human nuisance and long-term effects on the tourist industry, demands have been raised for intervention to reduce and control the insect population. At the same time, there have been warnings against treating the insect population because there are knowledge gaps concerning the wider ecological consequences, including effects on biodiversity. This paper analyses the political process and its problemsolving efforts. Of particular interest is how it dealt with the issue of uncertainty. It was found that the uncertainty associated with the issue hindered the development of a shared understanding of the problem and a possible solution. There seems to be a growing need in society to develop the institutional capacity to handle complex issues that cross different sectors, regulatory frameworks and policy targets.
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| 40. |
- Hallböök, Helene, et al.
(författare)
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In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia
- 2005
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 16:6, s. 631-634
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.
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