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  • 1.
    Buetti-Dinh, Antoine
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    S100A4 and its role in metastasis – computational integration of data on biological networks2015Other (Other academic)
  • 2. Clyne, N
    et al.
    Wibom, R
    Havu, N
    Hultman, E
    Lins, L-E
    Pehrsson, S K
    Persson, Bengt L.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rydström, J
    The effect of cobalt on mitochondrial ATP production and cellular morphology in the rat myocardium and skeletal muscle1990In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 50, p. 153-159Article in journal (Refereed)
  • 3.
    Dragan, Smiljic
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Studies of small bicoid knock-down and overexpression at early and late stage of development in Drosophila melanogaster.2016Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
  • 4.
    Duong-Thi, Minh-Dao
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Introducing weak affinity chromatography to drug discovery with focus on fragment screening2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Fragment-based drug discovery is an emerging process that has gained popularity in recent years. The process starts from small molecules called fragments. One major step in fragment-based drug discovery is fragment screening, which is a strategy to screen libraries of small molecules to find hits. The strategy in theory is more efficient than traditional high-throughput screening that works with larger molecules. As fragments intrinsically possess weak affinity to a target, detection techniques of high sensitivity to affinity are required for fragment screening. Furthermore, the use of different screening methods is necessary to improve the likelihood of success in finding suitable fragments. Since no single method can work for all types of screening, there is a demand for new techniques. The aim of this thesis is to introduce weak affinity chromatography (WAC) as a novel technique for fragment screening.

    WAC is, as the name suggests, an affinity-based liquid chromatographic technique that separates compounds based on their different weak affinities to an immobilized target. The higher affinity a compound has towards the target, the longer it remains in the separation unit, and this will be expressed as a longer retention time. The affinity measure and ranking of affinity can be achieved by processing the obtained retention times of analyzed compounds.

    In this thesis, WAC is studied for fragment screening on two platforms. The first system comprised a 24-channel affinity cartridge that works in cooperation with an eight-needle autosampler and 24 parallel UV detector units. The second system was a standard analytical LC-MS platform that is connected to an affinity column, generally called WAC-MS or affinity LC-MS. The evaluation criteria in studying WAC for fragment screening using these platforms were throughput, affinity determination and ranking, specificity, operational platform characteristics and consumption of target protein and sample. The model target proteins were bovine serum albumin for the first platform, thrombin and trypsin for the latter. Screened fragments were either small molecule drugs, a thrombin-directed collection of compounds, or a general-purpose fragment library. To evaluate WAC for early stages of fragment elaboration, diastereomeric mixtures from a thrombin-directed synthesis project were screened.

    Although both analytical platforms can be used for fragment screening, WAC-MS shows more useful features due to easy access to the screening platform, higher throughput and ability to analyze mixtures. Affinity data from WAC are in good correlation with IC50 values from enzyme assay experiments. The possibility to distinguish specific from non- specific interactions plays an important role in the interpretation of WAC results. In this thesis, this was achieved by inhibiting the active site of the target protein to measure off-site interactions. WAC proves to be a sensitive, robust, moderate in cost and easy to access technique for fragment screening, and can also be useful in the early stages of fragment evolution.

    In conclusion, this thesis has demonstrated the proof of principle of using WAC as a new tool to monitor affinity and to select hits in fragment-based drug discovery. This thesis has indicated the primary possibilities, advantages as well as the limitations of WAC in fragment screening procedures.  In the future, WAC should be evaluated on other targets and fragment libraries in order to realize more fully the potential of the technology.

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  • 5.
    Duong-Thi, Minh-Dao
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bergström, Maria
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Fex, Tomas
    Astra&Zeneca R&D, Sweden.
    Svensson, Susanne
    Chalmers University of Technology, Sweden.
    Ohlson, Sten
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Isaksson, Roland
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Weak Affinity Chromatography for Evaluation of Stereoisomers in Early Drug Discovery2013In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 18, no 6, p. 748-755Article in journal (Refereed)
    Abstract [en]

    In early drug discovery (e.g. in fragment screening), recognition of stereoisomeric structures is valuable and guides medicinal chemists to focus only on useful configurations. In this work, we concurrently screened mixtures of stereoisomers and estimated their affinities to a protein target (thrombin) using weak affinity chromatography-mass spectrometry (WAC-MS). Affinity determinations by WAC showed that minor changes in stereoisomeric configuration could have major impact on affinity. The ability of WAC-MS to provide instant information about stereoselectivity and binding affinities directly from analyte mixtures is a great advantage in fragment library screening and drug lead development.

  • 6.
    Duong-Thi, Minh-Dao
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Meiby, Elinor
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Bergström, Maria
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Fex, Tomas
    Isaksson, Roland
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Ohlson, Sten
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Weak affinity chromatography as a new approach for fragment screening in drug discovery2011In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 414, no 1, p. 138-146Article in journal (Refereed)
    Abstract [en]

    Fragment-based drug design (FBDD) is currently being implemented in drug discovery, creating a demand for developing efficient techniques for fragment screening. Due to the intrinsic weak or transient binding of fragments (mM–uM in dissociation constant (KD)) to targets, methods must be sensitive enough to accurately detect and quantify an interaction. This study presents weak affinity chromatography (WAC) as an alternative tool for screening of small fragments. The technology was demonstrated by screening of a selected 23 compound fragment collection of documented binders, mostly amidines, using trypsin and thrombin as model target protease proteins. WAC was proven to be a sensitive, robust, and reproducible technique that also provides information about affinity of a fragment in the range of 1 mM–10uM. Furthermore, it has potential for high throughput as was evidenced by analyzing mixtures in the range of 10 substances by WAC–MS. The accessibility and flexibility of the technology were shown as fragment screening can be performed on standard HPLC equipment. The technology can further be miniaturized and adapted to the requirements of affinity ranges of the fragment library. All these features of WAC make it a potential method in drug discovery for fragment screening.

  • 7.
    Elgström, Erika
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Preparation and characterization of pretargeting molecules: The antibody BR96-Streptavidin conjugate2010Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: In pretargeted radio immunotherapy, one molecule is administrated to bind to the target cell, e.g. a tumour cell, and after clearance another molecule, a radio labeled effecter molecule, which binds to the pretargeting molecule, is administrated.

    Aim: In this thesis work methods are tested and validated for conjugation of a monoclonal antibody with streptavidin by two separate conjugation methods. One of the methods involves sulfo-SMCC (sulfo-Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate) and SATA (S-acetylthioacetic acid) and the other one is based on the Staudinger reaction with NHS-azide and NHS-phosphine. Moreover, preparation of F(ab)2- and Fab-fragments of the monoclonal antibody with immobilized pepsin and papain, respectively,  is evaluated. The plan is that the antibody-streptavidin conjugate shall be used as a pretargeting molecule while radio labelled biotin will be used as an effecter molecule.

    Method: The formed conjugates are evaluated by using Agilent Bioanalyzer 2100, by  immunoreactivity investigations, and to some extent by gel filtration using an ÄKTA system.

    Result: The sulfo-SMCC reaction results in conjugates with higher immunoreactivity than the  Staudinger based reaction, which seems to be more efficient. The conjugates prepared by the later method might be less functional due to the fast reaction resulting in undetectable large multi-complexes.

    Conclusion: Streptavidin-IgG complexes were efficiently formed by both conjugation procedures used. However, it was difficult to characterize the obtained complexes by the utilised methods.

  • 8.
    Engström, Henrik
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Development of Flourescence-based Immunosensors for Continous Carbohydrate Monotoring: Applications for Maltose and Glucose2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Weak affinity interaction of monoclonal antibodies and carbohydrate antigens can be detected and quantified by alterations in the antibodies' intrinsic tryptophan fluorescence. These weak/transient binding events have been monitored by total internal reflection fluorescence (TlRF) by facilitating the change in intrinsic tryptophan fluorescence. This immunosensor followed instant changes in the antigen concentration with rapid association- and dissociation rate constants reaching equilibrium in a short time, without the need for regeneration. Furthermore, in a competition assay with extrinsic fluorescence labeling, it was established that Förster/fluorescence resonance energy transfer (FRET) can be applied for weak and transient interactions. By entrapping components in small semipermeable capsules, aconvenient flow system was fabricated allowing on-line measurements of maltose. Quantification of maltose concentration was achievable in the mM-range without need for regeneration.High specificty for maltose was exhibited in crude food-samples with quantification in accordance with batch analysis.

    Furthermore, a monoclonal antibody was developed for potential use as a glucose immunosensor for diabetes. Its ability to interact with glucose was determined by competitive weak affinity chromatography (WAC) to approximately 19 mM in dissociation constant. This antibody was developed to bind monosaccharides, especially glucose, by utilizing crossreation with a carbohydrate dextran polymer. Selectivity for glucose was greater than for the similar monosaccharides, mannose and galactose. This antibody, or a fragment, in a fluorescence platform is an alternative to monitor glucose in vivo where other glucose-binders might fail.

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  • 9.
    Götesson, Åsa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Cykloserins och ceftazidim/avibaktams effekt på multiresistenta gramnegativa bakterier2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Multiresistant gramnegative bacteria (MRGN) like Escherichia coli and Pseudomonas aeruginosa, constitute a global health issue. Due to the resistance development among bacteria, new options for treatment are needed. Extended Spectrum β-Lactamase (ESBL) is common among MRGN, and there are different types of ESBLs (as ESBLand ESBLCARBA). The increasing lack of treatment alternatives is mutual for the different ESBLs. The purpose of this study was to examine cycloserine and ceftazidime with the β-lactamase-inhibitor avibactam, two potentially new options for treatments effective against MRGN. To examine the minimum inhibitory concentration (MIC) for cycloserine (CYK) against E. coli (n=26) a in-house broth microdilution-method was used. Using two commercial broth microdilution-methods, isolates of P. aeruginosa with and without carbapenemaseproduction (n=23) were examined regarding MIC for ceftazidime/avibactam (CZA). 

    Regarding CYK, the median MIC-value of the E. coli-strains was 32 mg/L (16 - 64 mg/L), which is around the epidemiological cut-off-value (32 mg/L) for Mycobacterium tuberculosisfor which CYK is being used as treatment. The median of the MIC-values for CZA was 8 mg/L (<1 - ≥8 mg/L) for all P. aeruginosa-strains and 40% (2/5) of the carbapenemaseproducing isolates were sensitive according to the clinical breakpoint (S≤8 mg/L). In summary, this study shows that CYK has MIC-values against non-ESBL- and ESBL-producing E. coli at the same level as other pathogens where CYK is being used. Further, CZA may have effect against the isolates with reduced susceptibility against meropenem and ESBLCARBA-producing P. aeruginosa, although the isolates need to be susceptibility-determined before treatment. 

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  • 10.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Interaction between biomaterials and innate immunity with clinical implications2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today there is an increasing clinical demand and expectation of patients for biomaterials, which underscores the importance of discovering the correlations between biomaterials and biological systems, especially blood. When an artificial material makes contact with blood, the first event is a rapid adsorption of plasma protein on the material surface, on top of which the innate immune system is triggered, with potentially detrimental consequences. The work presented in this thesis, reported in four papers, was designed to investigate complications associated with (a) biomaterial-induced immune systems, including activation mechanisms and crosstalk between cascades on the biomaterial surface, and with (b) clinical investigations.

    In Paper I and Paper II, a series of studies led to the development of a direct prediction of the subsequent biological events based on the pattern of initially bound proteins. A reciprocal relationship was demonstrated between activation of the contact system and the complement system when they were induced on artificial material surfaces. Based on these studies, a robust and simple method for biocompatibility testing was proposed and validated, yielding high specificity and sensitivity when compared to today’s gold standard. Paper III investigated biomaterial-induced activation of complement and leukocytes in dialysis treatment-related conditions. The results suggested that citrate is more biocompatible than the conventionally used acetate. This reduction in activation could be further enhanced with higher citrate concentrations, suggesting that dialysis fluid containing citrate is a promising alternative to acetate dialysis fluid. Paper IV investigated complement initiation mechanisms with clinical implications. An experimental system was set up to revisit the initiation of the complement alternative pathway, and correlations were found between chaotropic or nucleophilic agents and iC3 generation under physiologically relevant conditions. A clinical study of hepatic encephalopathy patients indicated a direct correlation between elevated plasma ammonia and iC3 formation, as well as with complement activation in vivo

    Taken together, these studies have provided a model for a robust biomaterial test and have investigated biomaterial-induced complications in the fluid phase in clinically related conditions; furthermore, the basic mechanisms of complement activation have been dissected in relation to disease symptoms.

    Keywords: Complement system, contact system, blood, biomaterials, biocompatibility, in vitro screening, iC3, dialysis

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  • 11. Kroon, Martin
    Modelling of fibroblast-controlled restructuring of collagen gels2010In: Presented at 6th World Congress in Biomechanics, 1-6 August, 2010, 2010Conference paper (Refereed)
  • 12.
    Kroon, Martin
    et al.
    Royal Institute of Technology.
    Holzapfel, Gerhard
    Graz University of Technology, Austria.
    Estimation of the distributions of the anisotropic, elastic properties and wall stresses of saccular cerebral aneurysms by inverse analysis2008In: Proceedings of the Royal Society. Mathematical, Physical and Engineering Sciences, ISSN 1364-5021, E-ISSN 1471-2946, Vol. 464, no 2092, p. 807-825Article in journal (Refereed)
    Abstract [en]

    A new method is proposed for estimating the elastic properties of the inhomogeneous and anisotropic structure of saccular cerebral aneurysms by inverse analysis. The aneurysm is modelled as a membrane and the constitutive response of each individual layer of the passive tissue is characterized by a transversely isotropic strain energy function of exponential type. The collagen fibres in the aneurysm wall are assumed to govern the mechanical response. Four parameters characterize the constitutive behaviour of the tissue: two initial stiffnesses of the collagen fabric in the two in-plane principal directions, one parameter describing the degree of nonlinearity that the collagen fibres exhibit and the other structural parameter, i.e. the angle which defines the orientation of the collagen fibres. The parameter describing the fibre nonlinearity is assumed to be constant, while all others are assumed to vary continuously over the aneurysm surface. Two model aneurysms, with the same initial geometry, boundary and loading conditions, constitutive behaviour and finite-element discretization, are defined: a ‘reference model’ with known distributions of material and structural properties and an ‘estimation model’ whose properties are to be estimated. An error function is defined quantifying the deviations between the deformations from the reference and the estimation models. The error function is minimized with respect to the unknown parameters in the estimation model, and in this way the reference parameter distributions are re-established. In order to achieve a robust parameter estimation, a novel element partition method is employed. The accordance between the estimated and the reference distributions is satisfactory. The deviations of the maximum stress distributions between the two models are below 1%. Consequently, the wall stresses in the cerebral aneurysm estimated by inverse analysis are accurate enough to facilitate the assessment of the risk of aneurysm rupture.

  • 13.
    Kruse, Robert
    et al.
    Univ Örebro.
    Demirel, Isak
    Univ Örebro.
    Säve, Susanne
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Persson, Katarina
    Univ Örebro.
    IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria2014In: Purinergic Signalling Purinergic Signalling, ISSN 1573-9538, E-ISSN 1573-9546, Vol. 10, no 3, p. 499-508Article in journal (Refereed)
    Abstract [en]

    The recent recognition of receptor-mediated ATP signalling as a pathway of epithelial pro-inflammatory cytokine release challenges the ubiquitous role of the TLR4 pathway during urinary tract infection. The aim of this study was to compare cellular responses of renal epithelial cells infected with uropathogenic Escherichia coli (UPEC) strain IA2 to stimulation with ATP-gamma-S. A498 cells were infected or stimulated in the presence or absence of apyrase, that degrades extracellular ATP, or after siRNA-mediated knockdown of ATP-responding P2Y(2) receptors. Cellular IL-8 release and global gene expression were analysed. Both IA2 and A498 cells per se released ATP, which increased during infection. IA2 and ATP-gamma-S caused a similar to 5-fold increase in cellular release of IL-8 and stimulations performed in the presence of apyrase or after siRNA knockdown of P2Y(2) receptors resulted in attenuation of IA2-mediated IL-8 release. Microarray results show that both IA2 and ATP-gamma-S induced marked changes in gene expression of renal cells. Thirty-six genes were in common between both stimuli, and many of these are key genes belonging to classical response pathways of bacterial infection. Functional analysis shows that 88 biological function-annotated cellular pathways were identical between IA2 and ATP-gamma-S stimuli. Results show that UPEC-induced release of IL-8 is dependent on P2Y(2) signalling and that cellular responses elicited by UPEC and ATP-gamma-S have many identical features. This indicates that renal epithelial responses elicited by bacteria could be mediated by bacteria- or host-derived ATP, thus defining a key role of ATP during infection.

  • 14.
    Leila, Lahchaichi
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hur påverkas bindningen mellan transferrin och transferrinreceptorn med inverkan av det nyutvecklade proteinet TB08dm?2020Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Iron homeostasis is essential for all mammals to maintain basic physiological functions. The iron regulation mainly occurs in the liver, while uptake occurs in the small intestine. Free iron in the circulation can cause formation of free radicals and oxidative stress, which is avoided by an advanced iron transport system. Iron binds to the protein transferrin (TF), which in turn binds to the transferrin receptor (TFR1) expressed by numerous cell types. In the pathogenesis of iron related diseases, such as hereditary hemochromatosis, an imbalance in the iron homeostasis occurs as cells continue the uptake of TF via TFR1. Cancer is another example of a disease that exploits TFR1 as it favors cell proliferation of tumors. Studying TFR1 in connection to its role in the pathogenesis of different diseases has become of interest in the development of alternative treatments. The newly developed protein TB08dm has demonstrated improved binding to TFR1 after a round of directed evolution and selections. In this work, TB08dm single mutations were validated with respect to their effect on TB08dm complex formation with TFR1. Yeast cells were transformed to express the various single mutant variants for further studies of their binding potential to TFR1 by yeast display and flow cytometry. Of all the single amino acid variants studied, three showed clear binding to TFR1. Common to these variants was that they all were located on the opposite side from the predicted binding surface. Continued studies with TB08dm are required where the variants are combined in order to develop a TB08dm variant with optimal binding potential. 

  • 15.
    Meiby, Elinor
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Progress of Weak Affinity Chromatography as a Tool in Drug Development2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Weak Affinity Chromatography (WAC) is a technology that was developed to analyse weak (KD > 10-5 M) although selective interactions between biomolecules. The focus of this thesis was to develop this method for various applications in the drug development process.

     

    Fragment Based Drug Discovery is a new approach in finding new small molecular drugs. Here, relatively small libraries (a few hundreds to a few thousands of compounds) of fragments (150 – 300 Da) are screened against the target. Fragment hits are then developed into lead molecules by linking, growing or merging fragments binding to different locations of the protein’s active site. However, due to the weakly binding nature of fragments, methods that are able to detect very weak binding events are needed. In this thesis, WAC is presented as a new robust and highly reproducible technology for fragment screening. The technology is demonstrated against a number of different protein targets – proteases, kinases, chaperones and protein-protein interaction (PPI) targets. Comparison of data from fragment screening of 111 fragments by WAC and other more established technologies for fragment screening, such as surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR), validates WAC as a screening technology. It also points at the importance of performing fragment screening by multiple methods as they complement each other.

     

    Other applications of WAC in drug development are also presented. The method can be used for chiral separations of racemic mixtures during fragment screening, which enables affinity measurements of individual enantiomers binding to the target of interest. Further, analysis of crude reaction mixtures is shown. By these procedures, the affinity of the product can be assessed directly after synthesis without any time-consuming purification steps. In addition, a high performance liquid chromatography (HPLC) system for highly efficient drug partition studies was developed by stable immobilization of lipid bilayer disks – lipodisks – on a high performance silica support material. These lipodisks are recognized model membranes for drug partition studies. A WAC system with incorporated membrane proteins into immobilized lipodisks has also been produced and evaluated with the ultimate objective to study affinity interactions between ligands and membrane proteins.

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  • 16.
    Meiby, Elinor
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    M Zetterberg, Malin
    Uppsala University.
    Victor, Hernàndez
    Uppsala University.
    Ohlson, Sten
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.
    Edwards, Katarina
    Uppsala University.
    Immobilized lipodisks as model membranes in high-throughput HPLC-MS analysis.2013In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 14, p. 4859-4869Article in journal (Refereed)
    Abstract [en]

    Lipodisks, also referred to as polyethylene glycol (PEG)-stabilized bilayer disks, have previously been demonstrated to hold great potential as model membranes in drug partition studies. In this study, an HPLC-MS system with stably immobilized lipodisks is presented. Functionalized lipodisks were immobilized on two different HPLC support materials either covalently by reductive amination or by streptavidin-biotin binding. An analytical HPLC column with immobilized lipodisks was evaluated by analysis of mixtures containing 15 different drug compounds. The efficiency, reproducibility, and stability of the system were found to be excellent. In situ incorporation of cyclooxygenase-1 (COX-1) in immobilized lipodisks on a column was also achieved. Specific binding of COX-1 to the immobilized lipodisks was validated by interaction studies with QCM-D. These results, taken together, open up the possibility of studying ligand interactions with membrane proteins by weak affinity chromatography.

  • 17.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Hong, Jaan
    Uppsala University.
    Hamad, Osama
    Uppsala University.
    Larsson, Rolf
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Evaluation of the blood compatibility of materials, cells and tissues: Basic concepts, test models and practical guidelines2013In: Complement Therapeutics / [ed] J.D. Lambris, V.M. Holers & D. Ricklin, Springer, 2013, p. 257-270Chapter in book (Refereed)
    Abstract [en]

    Medicine today uses a wide range of biomaterials, most of which make contact with blood permanently or transiently upon implantation. Contact between blood and nonbiological materials or cells or tissue of nonhematologic origin initiates activation of the cascade systems (complement, contact activation/coagulation) of the blood, which induces platelet and leukocyte activation.

    Although substantial progress regarding biocompatibility has been made, many materials and medical treatment procedures are still associated with severe side effects. Therefore, there is a great need for adequate models and guidelines for evaluating the blood compatibility of biomaterials. Due to the substantial amount of cross talk between the different cascade systems and cell populations in the blood, it is advisable to use an intact system for evaluation.

    Here, we describe three such in vitro models for the evaluation of the biocompatibility of materials and therapeutic cells and tissues. The use of different anticoagulants and specific inhibitors in order to be able to dissect interactions between the different cascade systems and cells of the blood is discussed. In addition, we describe two clinically relevant medical treatment modalities, the integration of titanium implants and transplantation of islets of Langerhans to patients with type 1 diabetes, whose mechanisms of action we have addressed using these in vitro models.

  • 18.
    Oudah, Dayana
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Development of a Healthy and Satiating Snack2008Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    ABSTRACT

    The demand of healthier products is increasing, and more people are more interested of what they eat. Statistics show that the consumption of snacks is rising.

    Hyperglycemia leads to an increased risk for complications in type II diabetes mellitus. Increased levels of postprandial plasma glucose may also lead to equal or maybe more harmful effects than fasting hyperglycemia. When the levels of postprandial plasma glucose are decreased, the development of cardiovascular complications is delayed, why it is important to lower the snacks consumption especially snacks that brings hunger quickly after they are eaten. Because of these factors, healthier products were developed in this study. The aim was to develop a wafer chocolate product that gives higher satiating effect and healthier blood glucose levels compared to one of Cloetta’s chocolate products. Two raw materials were used, a new carbohydrate and a new fat. The new carbohydrate is a healthier sugar alternative than sucrose, since it leads to lower and prolonged increase in blood glucose and insulin levels. The new fat is based on natural oil that is believed to be healthy, mainly due to its satiating effect. The effects of these two materials on blood glucose response and satiety were examined in two products. Furthermore, the products were made of fat reduced milk chocolate in which sucrose in the chocolate mass was 100 % replaced with the new carbohydrate, dietary fibre and fruit concentrate. Only one of the products contained the new fat. The products, together with Cloetta’s chocolate product were consumed by 17 healthy subjects. Blood glucose response and satiating effect after product intake were examined during a period of 3 days.

    When blood glucose response was analyzed, a slight indication that the products were relatively healthier than placebo, due to placebo’s unhealthy fluctuations, was found. No clear differences regarding blood sugar maxima were found. Placebo showed, as expected, the highest blood glucose maxima and the largest incremental area under curve, but the maxima of the new fat-lacking product was less than half as high as that of the new fatcontaining product and the area was smaller too, which was not expected. The results regarding the hunger levels were not as expected either since the new fat-lacking product was most satiating while the new fatcontaining product was the least satiating. Despite that, 57 % of the subjects reported they would by such products in the future.

    Several biases may have played a role in the results, for example whether or not subjects followed the criteria (e.g. lunch time, exercise), stress, worry, individual energy requirement and how serious and focused the subjects were. However, for further research, increasing the new fat content to 3 g, a bigger sized product, different filling, more subjects and more repeats of same measurements is recommended.

     

     

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  • 19.
    Runeson, Marcus
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Can the selective PDGF-receptor antagonist STI571 reduce hypoxia in solid tumors, and enhance drug uptake of Taxol, by lowering the interstitial fluid pressure in stroma rich breast carcinoma, BT-4742015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background Solid tumors have high interstitial fluid pressure, IFP. This cause a dramatic loss in uptake of anti cancer drugs with poor clinical outcome as result. Treatment with PDGF-receptor antagonist STI-571 lowers tumor IFP and enhances uptake of small compounds. Elevated transvascular transport as result of a lowering in IFP thereby predicts less hypoxia intratumoral. Elevated oxygen levels in tumors enhances further therapeutic outcome from radiation therapy and treatment with Radio labeled antibodies.The Purpose was to investigate if treatment with STI-571 a high Mw compound, cytotoxic antibody Herceptin. Further aim was to investigate the use HIF-1α as a marker for hypoxia in solid KAT-4 tumors. A functional hypoxia marker can further be used in other IFP and cancer research fields.Methods Fox chase SCID mice were injected with BT-474. STI-571 was administrated 3 days prior 3H-Taxol injection, 3H-Taxol was measured in tumor and blood after 24 hours. Hypoxia was measured and compared by immunohistochemistry with HIF-1α monoclonal antibody on KAT-4 tumors treated with STI-571and untreated controls. IFP was measured in STI-571 treated animals.Results STI-571increases uptake of 3H-Taxol in BT-474 breast carcinomas. HIF-1α expression is slightly decreased in STI-571 treated KAT-4 tumors.Conclusions Measuring hypoxia through HIF-1α expression in tumor sections can be applied, but further optimization of protocol is needed. IFP lowering treatment with STI-571 probably affects the uptake of 3H-Taxol in BT-474. These minor experiments confirm the theory of elevated uptake and support the suggestions that combination treatment with STI-571and 3H-Taxol improves clinical outcome in tumor therapy.

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  • 20.
    Sävneby, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Reverse genetic studies of Enterovirus replication2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enteroviruses belong to the Picornaviridae family and are small icosahedral viruses with RNA genomes of positive polarity, containing a single open reading frame. They mostly cause mild or asymptomatic infections, but also a wide array of diseases including: poliomyelitis, encephalitis, gastroenteritis, aseptic meningitis, myocarditis, hand-foot-and-mouth disease, hepatitis and respiratory diseases, ranging from severe infections to the common cold. The projects described in this thesis have been carried out through reverse genetic studies of Enterovirus B and Rhinovirus C.

                      In Papers I and II, a cassette vector was used to study recombination and translation of the RNA genome. It was found that the non-structural coding region could replicate when combined with the structural protein-coding region of other viruses of the same species. Furthermore, the genome could be translated and replicated without the presence of the structural protein-coding region. Moreover, it was found that when two additional nucleotides were introduced, shifting the reading frame, the virus could revert to the original reading frame, restoring efficient replication. In Paper III, a vector containing the genome of echovirus 5 was altered to produce an authentic 5’end of the in vitro transcribed RNA, which increased efficiency of replication initiation 20 times. This result is important, as it may lead to more efficient oncolytic virotherapy. An authentic 5’end was further used in Paper IV, where replication of Rhinovirus C in cell lines was attempted. Although passaging of the virus was unsuccessful, the genome was replicated and cytopathic effect induced after transfection. The restriction of efficient replication was therefore hypothesized to lie in the attachment and entry stages of the replication cycle. In Paper V, a cytolytic virus was found to have almost 10 times larger impact on gene expression of the host cell than a non-cytolytic variant. Furthermore, the lytic virus was found to build up inside the host cell, while the non-cytolytic virus was efficiently released.

                      As a whole, this thesis has contributed to a deeper understanding of replication of enteroviruses, which may prove important in development of novel vaccines, antiviral agents and oncolytic virotherapies.

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  • 21. Åsberg, Marie
    et al.
    Nygren, Åke
    Leopardi, Rosario
    Rylander, Gunnar
    Peterson, Ulla
    Karolinska Institutet.
    Wilczek, Lukas
    Källmén, Håkan
    Ekstedt, Mirjam
    Karolinska Institute.
    Åkerstedt, Torbjörn
    Lekander, Mats
    Ekman, Rolf
    Novel biochemical markers of psychosocial stress in women2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 1, p. e3590-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prolonged psychosocial stress is a condition assessed through self-reports. Here we aimed to identify biochemical markers for screening and early intervention in women.

    METHODS: Plasma concentrations of interleukin (IL) 1-alpha, IL1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), prolactin, and testosterone were measured in: 195 women on long-term sick-leave for a stress-related affective disorder, 45 women at risk for professional burnout, and 84 healthy women.

    RESULTS: We found significantly increased levels of MCP-1, VEGF and EGF in women exposed to prolonged psychosocial stress. Statistical analysis indicates that they independently associate with a significant risk for being classified as ill.

    CONCLUSIONS: MCP-1, EGF, and VEGF are potential markers for screening and early intervention in women under prolonged psychosocial stress.

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