| 31. |
- Abdallah, Qasem M. A., et al.
(författare)
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Minor structural modifications to alchemix influence mechanism of action and pharmacological activity
- 2012
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 83:11, s. 1514-1522
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Tidskriftsartikel (refereegranskat)abstract
- Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.
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| 32. |
- Adlarson, Patrik, et al.
(författare)
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Abashian-Booth-Crowe Effect in Basic Double-Pionic Fusion : A New Resonance?
- 2011
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 106:24, s. 242302-
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Tidskriftsartikel (refereegranskat)abstract
- We report on an exclusive and kinematically complete high-statistics measurement of the basic double-pionic fusion reaction pn -> d pi(0)pi(0) over the full energy region of the ABC effect, a pronounced low-mass enhancement in the pi pi-invariant mass spectrum. The measurements, which cover also the transition region to the conventional t- channel Delta Delta process, were performed with the upgraded WASA detector setup at COSY. The data reveal the Abashian-Booth-Crowe effect to be uniquely correlated with a Lorentzian energy dependence in the integral cross section. The observables are consistent with a narrow resonance with m = 2.37 GeV, Gamma approximate to 70 MeV and I(J(P)) = 0(3(+)) in both pn and Delta Delta systems. Necessary further tests of the resonance interpretation are discussed.
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| 33. |
- Ayatolahi, Fatemeh, 1984, et al.
(författare)
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A study of the impact of single bit-flip and double bit-flip errors on program execution
- 2013
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Ingår i: Lect. Notes Comput. Sci.. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 9783642407925 ; 8153 LNCS
-
Konferensbidrag (refereegranskat)abstract
- This paper presents the results of an extensive experimental study of bit-flip errors in instruction set architecture registers and main memory locations. Comprising more than two million fault injection experiments conducted with thirteen benchmark programs, the study provides insights on whether it is necessary to consider double bit-flip errors in dependability benchmarking experiments. The results show that the proportion of silent data corruptions in the program output, is almost the same for single and double bit errors. In addition, we present detailed statistics about the error sensitivity of different target registers and memory locations, including bit positions within registers and memory words. These show that the error sensitivity varies significantly between different bit positions and registers. An important observation is that injections in certain bit positions always have the same impact regardless of when the error is injected.
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| 34. |
- Backius, Stefan
(författare)
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Arbetare på scen : amatörteater som politiskt verktyg
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the political dimensions of aesthetic expression during the Long Sixties. The thesis deals with amateur theatre ventures both within and linked to the social democratic labour movement. ’Spelet om Norbergsstrejken’ (The Play about the Norberg Strike) had its première in 1977 in a small industrial village in the industrial region of Bergslagen. Similar plays appeared in many regions of the country and a wave of workers’ plays emerged and made an impact on the internal investments of the educational association ABF in amateur theatre. The empiricism of the thesis concludes in 1982 when a social democratic amateur theatre association was founded and after a breakaway from the social democratic movement was establishing a residential study centre in another small village in Bergslagen. Sixties radicalisation provides the social context of the study and the perspective of sociological social movement research is used and developed. Based on the perspective of cognitive practice and the concepts of cosmology and movement ideology attention is directed towards the theatre assets of performance hosts, expectation horizons and patterns of behaviour. The thesis argues for a deeper understanding of sixties radicalisation partly meaning that the periodisation needs to be extended backwards as well as forwards in terms of time and partly that the political dimensions of aesthetic expression should be focused on. Based upon the results of the thesis the concept of culturactivism was formulated which defines the specific approach that appeared in the space between political and cultural activism. This highlights the need for a concept that covers the cognitive free space that arose between aesthetic expression and political activism and which has not previously attracted the attention of historical studies about sixties radicalisation to any great degree.
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| 35. |
- Barlind, Jonas G, et al.
(författare)
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Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687)
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:23, s. 10610-10629
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Tidskriftsartikel (refereegranskat)abstract
- A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
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| 36. |
- Bengtsson, Sara, 1978-, et al.
(författare)
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Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
- 2013
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Ingår i: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050. ; 10:1, s. 38-47
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels. learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Ab in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Berntsson, Shala Ghaderi, et al.
(författare)
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Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas
- 2011
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 105:3, s. 531-538
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.
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