| 631. |
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| 632. |
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| 633. |
- Kashif, Muhammad, et al.
(författare)
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A Pragmatic Definition of Therapeutic Synergy Suitable for Clinically Relevant In Vitro Multicompound Analyses
- 2014
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 13:7, s. 1964-1976
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Tidskriftsartikel (refereegranskat)abstract
- For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perform TS analysis, via computational predictions of the reference cell responses, when only the target cell responses are available. In conclusion, the conventional error-prone search for promising drug combinations may be improved by replacing conventional (toxicology-rooted) synergy analysis with an analysis focused on (clinically motivated) TS.
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| 634. |
- Kashif, Muhammad, et al.
(författare)
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Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 103952-103967
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed survival effects for 15 different pairs of clinically relevant anticancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy (TM) II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.
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| 635. |
- Kashif, Muhammad, et al.
(författare)
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In vitro discovery of promising anti-cancer drug combinations using iterative maximisation of a therapeutic index
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- In vitro-based search for promising anti-cancer drug combinations may provide important leads to improved cancer therapies. Currently there are no integrated computational-experimental methods specifically designed to search for combinations, maximizing a predefined therapeutic index (TI) defined in terms of appropriate model systems. Here, such a pipeline is presented allowing the search for optimal combinations among an arbitrary number of drugs while also taking experimental variability into account. The TI optimized is the cytotoxicity difference (in vitro) between a target model and an adverse side effect model. Focusing on colorectal carcinoma (CRC), the pipeline provided several combinations that are effective in six different CRC models with limited cytotoxicity in normal cell models. Herein we describe the identification of the combination (Trichostatin A, Afungin, 17-AAG) and present results from subsequent characterisations, including efficacy in primary cultures of tumour cells from CRC patients. We hypothesize that its effect derives from potentiation of the proteotoxic action of 17-AAG by Trichostatin A and Afungin. The discovered drug combinations against CRC are significant findings themselves and also indicate that the proposed strategy has great potential for suggesting drug combination treatments suitable for other cancer types as well as for other complex diseases.
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| 636. |
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| 637. |
- Kashif, Muhammad
(författare)
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Integrated Computational and Experimental Approaches for Accelerated Drug Combination Discovery and Development : Applications in Cancer Pharmacology
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today the norm in modern cancer treatment is to use different forms of drug combinations. Recently anti-cancer treatment using drug combinations has gained increased attention due to the outstanding pharmacotherapeutic opportunities provided by combination therapies. However, the potential of this field is largely unexplored, partly due to the complexities associated with the astronomical number of possible combinations and partly due to the lack of means for quantifying clinically relevant adverse side effects in the early stages of the combination discovery and development process. This has resulted in relatively limited progress in this area. Motivated by this unfortunate state-of-affairs, the research reported in this thesis was aimed at developing and implementing computational and experimental methods to facilitate and accelerate the discovery and development of anti-cancer therapies. In paper I, the largely overlooked concept of therapeutic synergy is re-introduced and demonstrated to be useful already at the level of combination discovery by taking both curative and adverse effects into account. In paper II, a semiautomatic combination discovery platform was developed based on a tailored programming of a pipetting robot system and application of a new in-house developed combination search algorithm, the therapeutic algorithmic combinatorial screen (TACS) algorithm. TACS seems to be the first algorithm of its kind that takes experimental variability into account during the iterative search process. The semiautomatic hardware platform along with TACS can perform de novo or knowledge based combination drug discovery and development without brute force comprehensive search efforts. One promising discovery made using this platform is a combination of the drugs 17-AAG, afungin and trichostatin a for treatment of colorectal cancer carcinoma (CRC). In paper III, an algorithm is developed and applied in order to use single drug induced systemic gene expression profiles for rational drug combination design by assuming additive combination effects. The resulting algorithm, combo-CMap, is applied and validated using a slightly extended version of the freely available Connectivity Map (CMap) database which is currently containing 6190 chemically induced mRNA gene expression signatures. In paper IV, a software (R package) was developed and applied to perform improved synergy/antagonism analysis, in particular joint Loewe and Bliss analyses while taking associated experimental variability into account using non-parametric statistics including bootstrap intervals. Applying this software to the synergy analysis of interaction effects among clinically used and/or relevant drugs in CRC cell lines revealed complex patterns of synergy and antagonism. In conclusion, the work presented here offers important contributions and findings that may accelerate and/or improve different parts of the field of drug combination discovery and development.
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| 638. |
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| 639. |
- Kaveh, Shamal, 1964-
(författare)
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Det villkorade tillståndet : Centralförbundet för Socialt Arbete och liberal politisk rationalitet 1901–1921
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This is a dissertation about Swedish liberalism as a political rationality and, more specifically, the conditions that made the transition from an exclusionary society to an inclusive one possible at the beginning of the 20th century. I have made a case study of National Association of Social Work (Centralförbundet för Socialt Arbete, CSA), an association that played a significant role in the institutionalization of social politics in Sweden. The objectives are threefold. Firstly, to analyze CSA as a liberal political rationality. Secondly, to analyze its political ontology. Thirdly, to examine its motives for defending an including society.One of the main arguments in this dissertation is that the political rationality of CSA is characterized by a form of government that works in and through society, as well as through freedom. By using the concept of ”the state of suspension” I try to capture and analyze the ontological ambiguity of the individual in liberal thought; an ambiguity expressed in biopolitical categorizations of the population according to perceived capacities for rational thought. The inclusion of the excluded part, which I describe through the notion of “the social”, was possible due to a new political ontology, which considered the individual as being a product of social circumstances, and as someone possible to shape and govern in and through society. I argue that the political struggle of the excluded not only served to revise the political ontology of CSA, but also provided the rationale for the efforts to create an including society with universal suffrage. CSA did not regard citizenship as a right, but as a political technology and as a solution. Furthermore, I argue that citizenship shouldn’t be seen as a prerequisite for the politization of the excluded. On the contrary, this part of the population was already, at least partially, politicized and they became political subjects through their participation in the struggle for political rights.
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| 640. |
- Kawahara, Jun, et al.
(författare)
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Flexible active matrix addressed displays manufactured by printing and coating techniques
- 2013
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Ingår i: Journal of Polymer Science Part B. - : Wiley-Blackwell. - 0887-6266 .- 1099-0488. ; 51:4, s. 265-271
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Tidskriftsartikel (refereegranskat)abstract
- A flexible electrochromic active matrix addressed display, including 8 × 8 pixels, is demonstrated by using solution processing based on standard printing and coating manufacturing techniques. Each organic electrochromic display (OECD) pixel and its corresponding organic electrochemical transistor (OECT) are located on different sides of the flexible PET substrate. Electronic vias generated through the plastic substrate connects each OECD pixel with one addressing OECT. When comparing this display with actively addressed OECDs with all its components located on the same side, the present approach based on this electronic via substrate provides an enhanced pixel resolution and a relatively more simplified manufacturing process.
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