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- Denekamp, Juliana, et al.
(author)
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Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy?
- 1998
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In: Advances in Enzyme Regulation. - 0065-2571 .- 1873-2437. ; 38:1, s. 281-299
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Journal article (peer-reviewed)abstract
- This paper illustrates how the concept of the malignant cell per se as the prime and only target in cancer therapy may be erroneous. The micro-vasculature evoked to satisfy nutritional requirements of solid tumors, and the inadequacy of this nutrition for all tumor cells, provide novel targeting concepts. The vascular architecture and the microenvironmental gradients (VAMP) will differ from one tumor to another and may determine whether current therapies succeed or fail. Many agents have a different toxicity or mode of action at the pathophysiological oxygen tensions that prevail in solid tumors. This warrants more attention. The hypoxic cell or the immature proliferating endothelial cell may provide tumor specificity that is more general than, and greater than, that conferred by the process of malignant transformation. The poor vasculature of solid tumors is often regarded as a problem by the oncologist. It limits the access of cytotoxic drugs, monoclonal antibodies, cytokines, etc. It also leads to hypoxic radioresistance because of diffusion limited chronic hypoxia and perfusion limited intermittent hypoxia, resulting from transient vessel closure. However, it can also be seen as a potential target, since prolonged vessel occlusion can lead to an avalanche of cell death. Strategies to prevent further expansion of the vascular network (anti-angiogenesis) should stabilize tumors and prevent further growth. Vascular targeting, aiming to damage the microvascular function and cause occlusion, can lead to extensive cell death. The target may relate to the excessive proliferation of endothelial cells in tumors or to abnormal functional aspects, such as altered cell shape (influencing permeability) adhesiveness to leukocytes or steps in the coagulation cascade. These microvascular features and microenvironmental gradients, and the phenotypic consequences of them, have been relatively neglected. The altered milieu and inadequate neovasculature is a common feature of all types of solid tumor, whereas the genetic changes that can give rise to a malignancy are very variable, from tumor site to site and even within a site from individual to individual. It seems, therefore, that therapies that could be of widespread general applicability might more easily be found from the micro-environmental or anti-vascular approaches than from gene therapy targeted at specific oncogenes. This approach will require cross fertilisation between scientists from quite disparate backgrounds, whose paths seldom cross, and who may not read, or even scan, each other's literature. If the endothelium or the low oxygen tension in subsets of tumor cells are the key to successful cancer treatment in mice, there are considerable implications for screening methods in vitro and for predictive and prognostic tests made on homogenized tumor samples.
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| 5. |
- Kimming, Marie, et al.
(author)
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Biomass from agriculture in small-scale combined heat and power plants - A comparative life cycle assessment
- 2011
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In: Biomass and Bioenergy. - : Elsevier BV. - 0961-9534 .- 1873-2909. ; 35, s. 1572-1581
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Journal article (peer-reviewed)abstract
- The results show that the biomass-based scenarios reduce greenhouse gas emissions considerably compared to the scenario based on fossil fuel, but have higher acidifying emissions. Scenario 1 has by far the best performance with respect to global warming potential and the advantage of utilizing a byproduct and thus not occupying extra land. Scenario 2 and 3 require less primary energy and less fossil energy input than 1, but set-aside land for willow production must be available. The low electric efficiency of scenario 3 makes it an unsuitable option. (C) 2011 Elsevier Ltd. All rights reserved.
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| 6. |
- Dedinszki, Dora, et al.
(author)
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Inhibition of protein phosphatase-1 and -2A decreases the chemosensitivity of leukemic cells to chemotherapeutic drugs
- 2015
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In: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 27:2, s. 363-372
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Journal article (peer-reviewed)abstract
- The phosphorylation of key proteins balanced by protein kinases and phosphatases are implicated in the regulation of cell cycle and apoptosis of malignant cells and influences anticancer drug actions. The efficacy of daunorubicin (DNR) in suppression of leukemic cell survival was investigated in the presence of tautomycin (TM) and calyculin A (CIA), specific membrane permeable inhibitors of protein phosphatase-1 (PP1) and -2A (PP2A), respectively. CIA (50 nM) or TM (1 mu M) suppressed viability of THP-1 and KG-1 myeloid leukemia cell lines to moderate extents; however, they significantly increased survival upon DNR-induced cell death. CLA increased the phosphorylation level of Erk1/2 and PKB/Akt kinases, the retinoblastoma protein (pRb), decreased caspase3 activation by DNR and increased the phosphorylation level of the inhibitory sites (Thr696 and Thr853) in the myosin phosphatase (MP) target subunit (MYPT1) as well as in a 25 kDa kinase-enhanced phosphatase inhibitor (KEPI)-like protein. TM induced enhanced phosphorylation of pRb only, suggesting that this event may be a common factor upon CIA-induced PP2A and TM-induced PP1 inhibitory influences on cell survival. Silencing PP1 by siRNA in HeLa cells, or overexpression of Flag-KEPI in MCF-7 cells coupled with inducing its phosphorylation by PMA or CIA, resulted in increased phosphorylation of pRb. Our results indicate that PP1 directly dephosphorylates pRb, while PP2A might have an indirect influence via mediating the phosphorylation level of PP1 inhibitory proteins:These data imply the importance of PP1 inhibitory proteins in controlling the phosphorylation state of key proteins and regulating drug sensitivity and apoptosis in leukemic cells.
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| 7. |
- Holt, Nina E., et al.
(author)
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Empirical evaluations on the cost-effectiveness of state-based testing: An industrial case study
- 2014
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In: Information and Software Technology. - : Elsevier BV. - 0950-5849 .- 1873-6025. ; 56:8, s. 890-910
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Journal article (peer-reviewed)abstract
- Context: Test models describe the expected behavior of the software under test and provide the basis for test case and oracle generation. When test models are expressed as UML state machines, this is typically referred to as state-based testing (SBT). Despite the importance of being systematic while testing, all testing activities are limited by resource constraints. Thus, reducing the cost of testing while ensuring sufficient fault detection is a common goal in software development. No rigorous industrial case studies of SBT have yet been published. Objective: In this paper, we evaluate the cost-effectiveness of SBT on actual control software by studying the combined influence of four testing aspects: coverage criterion, test oracle, test model and unspecified behavior (sneak paths). Method: An industrial case study was used to investigate the cost-effectiveness of SBT. To enable the evaluation of SBT techniques, a model-based testing tool was configured and used to automatically generate test suites. The test suites were evaluated using 26 real faults collected in a field study. Results: Results show that the more detailed and rigorous the test model and oracle, the higher the fault-detection ability of SBT. A less precise oracle achieved 67% fault detection, but the overall cost reduction of 13% was not enough to make the loss an acceptable trade-off. Removing details from the test model significantly reduced the cost by 85%. Interestingly, only a 24–37% reduction in fault detection was observed. Testing for sneak paths killed the remaining eleven mutants that could not be killed by the conformance test strategies. Conclusions: Each of the studied testing aspects influences cost-effectiveness and must be carefully considered in context when selecting strategies. Regardless of these choices, sneak-path testing is a neces- sary step in SBT since sneak paths are common while also undetectable by conformance testing.
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