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- Hansson, Emma K., 1980-
(författare)
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Pharmacometric Models for Biomarkers, Side Effects and Efficacy in Anticancer Drug Therapy
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- New approaches quantifying the effect of treatment are needed in oncology to improve the drug development process and to enable treatment optimization for existing therapies. This thesis focuses on the development of pharmacometric models for biomarkers, side effects and efficacy in order to identify predictors of clinical response in anti-cancer drug therapy. The variability in myelosuppression was characterized in six different cytotoxic anticancer treatments to evaluate a model-based dose individualization approach utilizing neutrophil counts as a biomarker. The estimated impact of inter-occasion variability was relatively low in relation to the inter-individual variability, indicating that myelosuppression is predictable from one treatment course to another. The approach may thereby be useful for dose optimization within an individual. To further study and to identify predictors for the severe side effect febrile neutropenia (FN), the relationship between the shape of the myelosuppression time-course and the probability of FN was characterized. Patients with a rapid decline in neutrophil counts and high drug sensitivity were identified to have a higher probability of developing FN compared with other patients who experience grade 4 neutropenia. Predictors of clinical response in patients receiving sunitinib for the treatment of gastro-intestinal stromal tumor (GIST) were identified by the development of an integrated modeling framework. Drug exposure, biomarkers, tumor dynamics, side effects and overall survival (OS) were linked in a unified structure, and univariate and multivariate exposure variables were tested for their predictive capacities. The soluble biomarker, sVEGFR-3 and tumor size at start of treatment were found to be promising predictors of overall survival, with decreased sVEGFR-3 levels and smaller baseline tumor size being predictive of longer OS. Also hypertension and neutropenia was identified as predictors of OS. The developed modeling framework may be useful to monitor clinical response, optimize dosing in sunitinib and to facilitate dose individualization.
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| 2. |
- Hansson, Klas, 1944-
(författare)
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Svenska kyrkans primas : Ärkebiskopsämbetet i förändring 1914–1990
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- When Nathan Söderblom became archbishop in 1914 he substantially altered and extended the office of archbishop. This study deals with how and why the office of archbishop has changed from Söderblom’s incumbency down to the introduction of an assistant bishop in the archdiocese in 1990. Is the archbishop mainly a diocesan bishop with some duties on the national level or is the archbishop mainly the primate with minor tasks in the diocese? The latter view has prevailed and the archbishop’s business as primate has come to be regarded as the most important.During the period studied seven archbishops have served in Uppsala. Their ex officio positions, their archiepiscopal arenas, are examined to find out how they shaped their office. Different leadership styles are uncovered and the archbishops’ differing performance and characteristics are examined. These ranged from expansion and renewal (Nathan Söderblom), cautiousness and withdrawal (Erling Eidem), restoration and consolidation (Yngve Brilioth), uniting and dividing (Gunnar Hultgren), institutionalisation and internationalization (Ruben Josefson), ecumenism and peace work (Olof Sundby), and expansion and clarification (Bertil Werkström). In this way the study also gives a comprehensive view of the 20th century Church of Sweden debates and conflicts.The study also covers formal changes that have been introduced to the office of archbishop. The concepts of fields, capital and habitus are used to analyse the patterns and structures of the office during the decades studied. The social position of the archbishop became stronger during the period while the formal position became weaker. The archbishop of Uppsala is since the Reformation the foremost representative and spokesperson of the Church of Sweden.
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| 3. |
- Hansson, Karin, 1970-
(författare)
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The Autonomous and the Passive Progressive in 20th-Century Irish
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study deals with the use of two Irish verb constructions, the autonomous (e.g. cuireadh litreacha chun bealaigh, ‘letters were dispatched’) and the passive progressive (e.g. bhí m’athair á leigheas acu, ‘my father was being cured by them’), in a corpus of 20th-century texts. From this corpus, 2,956 instances of the autonomous and 467 instances of the passive progressive were extracted and included in the analysis. Dialectal variation concerning the use of these two constructions is also surveyed.The study explores and compares the use of the autonomous and the passive progressive. The main aim of the study is to investigate the two constructions with regard to their textual functions. The features studied relate to verb and clause type, as well as the measuring of topicality of patients, implicit agents, and – in the passive progressive only – overt agents. The autonomous tends to be used when the patient is topical, or central, in the text. The passive progressive, on the other hand, is mainly used with an overt agent that is considerably more topical than the patient. In agent-less passive progressives, patients and implicit agents are equally low in topicality. The autonomous occurs about equally often in main and subclauses, while the passive progressive is used primarily in subclauses, mainly non-finite ones. This difference is connected to the finding that 24% of the clauses containing the autonomous denote events as part of a sequentially ordered chain of events, compared to 4% of those containing the passive progressive.The most salient dialectal variation concerns the frequency of the passive progressive: 73% of the instances of the passive progressive in the database occur in the Munster texts, compared to 22% in Connacht 5% in Ulster. The autonomous, in contrast, is fairly evenly distributed across the dialects.
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| 4. |
- Hansson, Lars O.
(författare)
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Redesign of substrate specificity of glutathione transferase and glutathione reductase : Enzyme engineering by directed mutagenesis, phage-display selection and DNA shuffling
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human glutathione transferase (GST) A1-1 was expressed in fusion with the phage gene IIIproduct and a library of phage-displayed GST mutants was constructed by randomization of fouractive-site residues. Variant GSTs were isolated by mechanism-based phage display selection, using an immobilized transition-state analog of a nucleophilic aromatic substitution (SNAr) reaction. One isolated mutant exhibited a 105-fold rate enhancement with the SNAr substrate l-chloro-2,4-dinitrobenzene (CDNB) compared to the uncatalyzed reaction. This mutant was further randomized, in a fifth active-site residue to further improve the catalytic efficiency. Activity screening of 18 GST variants identified one mutant, Met208Cys, that exhibited a 2-fold enhanced catalytic efficiency with CDNB.A library of chimeric random mutants was constructed by shuffling of cDNA encoding thehomologous human enzymes GST M1-1 and GST M2-2. Activity screening and DNA sequence analysis of sampled mutants provided information about the differential substrate specificities withaminochrome and 2-cyano-1,3-dimethyl-1-nitrosoguanidine of the two wild-type isoenzymes.Chimeric enzyme variants derived from the DNA-shuffled library were further analyzed together with point mutants having residues in GST M1-1 replaced by those of GST M2-2. The results indicated that Arg165 in human GST M2-2 is important for the substitution reactions with 2-cyano-1,3-dimethyl-l-nitrosoguanidine and 1,2-dichloro-4-nitrobenzene.The three-dimensional structure of Anabaena PCC 7120 glutathione reductase was modeled based on a sequence alignment with the Escherichia coli and human enzymes, for which crystalstructures are known. The model was used for redesigning the enzyme for structure-activity studies. Removal of a 10-residue loop, predicted to be situated next to the entrance of the pyridine-nucleotide-binding site, increased the catalytic efficiency with both coenzymes NADPH and NADH.
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