| 1. |
- Glimelius, Bengt, et al.
(författare)
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Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer
- 2011
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 11:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).
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| 2. |
- Gunnlaugsson, Adalsteinn, et al.
(författare)
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Multicentre phase II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable colorectal cancer : The CORGI-L study
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:5, s. 807-813
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study assessed radiotherapy combined with capecitabine and oxaliplatin in patients with primary, inextirpable colorectal adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients entered the trial. Two cycles of XELOX (capecitabine 1000mg/m(2) bid d1-14+oxaliplatin 130mg/m(2) d1, q3w) were followed by radiotherapy (50.4Gy), combined with capecitabine 825mg/m(2) bid every radiotherapy day and oxaliplatin 60mg/m(2) once weekly. The primary end-point was objective response. RESULTS: Forty-seven patients were evaluable. Twenty-nine (62% [95% CI: 46-75%]) achieved complete or partial response. Thirty-eight (81%) went through surgery of whom 37 (97%) had an R0 resection and five (13%) had a pathological complete response. Seventy-eight percent were alive and estimated local progression rate was 11% at 2 years. The most common grade 3+ toxicity during chemoradiotherapy was diarrhoea (24%). CONCLUSIONS: XELOX-RT was feasible and showed promising efficacy when treating patients with primary inextirpable colorectal cancer, establishing high local control rate.
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| 3. |
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| 4. |
- Adawi, Tom, et al.
(författare)
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On context in phenomenographic research on understanding heat and temperate
- 2002
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Ingår i: EARLI, Bi-annual Symposium, Fribourg, Switzerland.
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Konferensbidrag (refereegranskat)abstract
- Starting from an empirical study of lay adults' understanding of heatand temperature, we distinguish between different meanings of "context" inphenomenographic research. To confuse the variation in ways of experiencingthe context(s) of the study with the variation in ways of experiencing thephenomenon of study is to risk losing fundamental insights. We discuss contextas experienced and as interwoven with the experience of the phenomenon, andanalyse its significance in two dimensions: (1) the stage of the research project:formulating the question, collecting data, analysing data and deploying results;and (2) "who is experiencing" the context: the individual, the collective, or theresearcher. The arguments are illustrated from the empirical study.
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| 5. |
- Adawi, Tom, 1970, et al.
(författare)
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On context in phenomenographic research on understanding heat and temperature
- 2001
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Ingår i: The 9th EARLI conference, Fribourg, August 2001, Fribourg, Switzerland.
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Konferensbidrag (refereegranskat)abstract
- Starting from an empirical study of lay adults' everyday understanding of the scientificconcepts of heat and temperature, we have found it necessary to distinguish betweendifferent meanings of the notion of context in phenomenographic research.In order to reveal interesting and important differences in the ways in which aphenomenon is experienced, the phenomenographic researcher relegates experience ofthe context to the background. To confuse the variation in ways of experiencing thecontext(s) of the study with the variation in ways of experiencing the phenomenon ofstudy is to risk losing fundamental insights.This does not mean, however, that the researcher can neglect the context(s), even if it isnot of main interest. Since the research object of a phenomenographic study is "variationin ways of experiencing something", we discuss context as experienced and interwovenwith the experience of the phenomenon. We argue that the experienced context, thecontext as created and understood by the researcher, and the relation between these arerelevant to varying degrees and in varying ways at different stages of the research project.In our paper we see the experienced context from the perspective of "who isexperiencing" the context: the individual, the collective, or the researcher (whether asphenomenographer or as physicist). This will be illustrated from the empirical data.The proposed distinctions provide a better ground for generalising the results of thestudy, since they help us to understand the differences between the research situation(s)and the research object(s).
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| 7. |
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| 8. |
- Aldulaymi, Bahir, et al.
(författare)
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High Plasma TIMP-1 and Serum CEA Levels during Combination Chemotherapy for Metastatic Colorectal Cancer Are Significantly Associated with Poor Outcome
- 2010
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Ingår i: Oncology. - : S. Karger AG. - 0030-2414 .- 1423-0232. ; 79:1-2, s. 144-149
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate whether combination chemotherapy leads to early changes in plasma TIMP-1 and serum carcinoembryonic antigen (CEA) levels in patients with metastatic colorectal cancer (mCRC), and whether such changes relate to subsequent objective response, time to progression (TTP) and overall survival. Materials and Methods: Eighty-eight patients with mCRC were included. Blood samples were collected before initiation and after 2, 4 and 6 weeks of treatment with an irinotecan-5-fluorouracil combination. Plasma TIMP-1 and serum CEA levels were determined by validated ELISA platforms. The first response evaluation was performed after 8 weeks of chemotherapy. Results: Median plasma TIMP-1 and serum CEA levels did not change significantly during 6 weeks of treatment. High plasma TIMP-1 and high serum CEA levels before treatment and at weeks 2, 4 and 6 were related to poor objective response. Moreover, high levels of plasma TIMP-1 before treatment and at weeks 2 and 4 were significantly associated with short TTP, while high levels of serum CEA at week 4 were significantly associated with short TTP. Finally, high levels of plasma TIMP- 1 before and during treatment were significantly associated with poor overall survival; p < 0.0001 in all 4 determinations. A similar association between serum CEA and overall survival could only be demonstrated before treatment. Conclusion: Median plasma TIMP-1 or serum CEA levels do not change significantly during the first 6 weeks of chemotherapy for mCRC. The results indicate that plasma TIMP-1 in particular and serum CEA may be valuable biomarkers even in samples collected during treatment with chemotherapy.
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| 9. |
- Bandmann, Nina, 1971-
(författare)
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Rational and combinatorial genetic engineering approaches for improved recombinant protein production and purification
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The bacterium Escherichia coli (E. coli) is in many situations an ideal host for production of recombinant proteins, since it generally provides a rapid and economical means to achieve sufficiently high product quantities. However, there are several factors that may limit this host’s ability to produce large amounts of heterologous proteins in a soluble and native form. For many applications a high purity of the recombinant protein is demanded, which implies a purification strategy where the product efficiently can be isolated from the complex milieu of host cell contaminants. In this thesis, different strategies based on both rational and combinatorial genetic engineering principles have been investigated, aiming at improving and facilitating recombinant E. coli protein production and purification. One objective was to improve the PEG/salt aqueous two-phase system (ATPS) purification process of the lipase cutinase, by increasing the selectivity of the protein for the system top-phase. Peptide tags, with varying properties, were designed and genetically fused to the C-terminal end of ZZ-cutinase. Greatly increased partitioning values were observed for purified protein variants fused to tryptophan containing peptide tags, particularly a (WP)4 peptide. The partitioning properties of the ZZ-cutinase-(WP)4 protein were also retained when added to the ATPS directly from an E. coli total cell disintegrate, emphasizing the applicability of this genetic engineering strategy for primary protein purification in ATPSs. Further on, a combinatorial library approach using phage display technology was investigated as a tool for identification of peptide tags capable of improving partitioning properties of ZZ-cutinase in an ATPS. Repeated ATPS-based partitioning-selection cycles of a large phagemid (pVIII) peptide library, resulted in isolation of phage particles preferentially decorated with peptides rich in tyrosine and proline residues. Both a peptide corresponding to a phage library derived peptide sequence as well as peptides designed based on information of amino acid appearance frequencies in later selection rounds, were shown to improve partitioning several-fold when genetically fused to the C-terminal end of ZZ-cutinase. From the two- to four–fold increased production yields observed for these fusion proteins compared to ZZ-cutinase-(WP)4, it was concluded that the selection system used allowed for selection of desired peptide properties related to both partitioning and E. coli protein production parameters. Bacterial protein production is affected by several different mRNA and protein sequence-related features. Attempts to address single parameters in this respect are difficult due to the inter-dependence of many features, for example between codon optimization and mRNA secondary structure effects. Two combinatorial expression vector libraries (ExLib1 and ExLib2) were constructed using a randomization strategy that potentially could lead to variations in many of these sequence-related features and which would allow a pragmatic search of vector variants showing positive net effects on the level of soluble protein production. ExLib1 was constructed to encode all possible synonymous codons of an eight amino acid N-terminal extension of protein Z, fused to the N-terminal of an enhanced green fluorescent reporter protein (EGFP). In ExLib2, the same eight positions were randomized using an (NNG/T) degeneracy code, which could lead to various effects on both the nucleotide and protein level, through the introduction of nucleotide sequences functional as e.g. alternative ribosome binding or translation initiation sites or as translated codons for an Nterminal extension of the target protein by a peptide sequence. Flow cytometric analyses and sorting of library cell cultures resulted in isolation of clones displaying several-fold increases in whole cell fluorescence compared to a reference clone. SDS-PAGE and western blot analyses verified that this was a result of increases (up to 24-fold) in soluble intracellular ZEGFP product protein content. Both position specific codon bias effects and the appearance of new ribosomal binding sites in the library sequences were concluded to have influenced the protein production. To explore the possibility of applying the same combinatorial library strategy for improving soluble intracellular production of heterologous proteins proven difficult to express in E. coli, three proteins with either bacterial (a transcriptional regulator (DntR)) or human (progesterone receptor ligand binding domain (PRLBD) and 11-β Hydroxysteroid dehydrogenase type I (11-β)) origin, were cloned into the ExLib2 library. Flow cytometric sorting of libraries resulted in isolation of DntR library clones showing increased soluble protein production levels and PR-LBD library clones with up to ten-fold increases in whole cell fluorescence, although the product under these conditions co-separated with the insoluble cell material.
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| 10. |
- Berglund, Anders, et al.
(författare)
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On insights into teaching and learning technological systems
- 2016
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Ingår i: Different horizons: setting directions for phenomenographic research, EARLI Special Interest Group 9, Phenomenography and Variation Theory, Gothenburg 24-26 Aug..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the ETSC project is to explore how pupils, aged 11 - 13, learn about technological systems, with a further goal of offering insights useful for designing good teaching. This is a complicated tak as there is only is little previous research, no jointly agreed definition of the object of the pupils’ learning or how it should be taught exists, and the research on learning situations where learners work in teams with a high degree of agency is methodologically not well developed. Inspired by phenomenography and variation theory, we have collected data from lessons in technological systems. To analyse this learning we have developed a framework, where the four positions on which it is based together offer insights in the pupils’ learning, valuable for teaching. • A core position is technology itself, as it is the object of the pupils’ learning. • A classic phenomenographic analysis reveals how the pupils experience technological systems. • The teaching emphasis three dimensions of variation in understanding technological systems (Svensson, 2011). We investigate to what extent these dimensions are mirrored in the pupils’ learning. • The phenomenographic distinction on deep and surface learning offers a way to express how the pupils approach their learning. In our presentation, we will exemplify how these positions, taken together, can offer insights in the pupils’ perspective on technological systems.
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