| 21. |
- Hassan, Saadia B., et al.
(författare)
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Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity
- 2007
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Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 21:6, s. 1174-1181
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Tidskriftsartikel (refereegranskat)abstract
- Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50–300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.
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| 22. |
- Hassan, Saadia, et al.
(författare)
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Gene expression signature-based chemcial genomics and activity pattern in a panel of tumour cell lines propose linalyl acetate as a protein kinase/NF-κB inhibitor
- 2008
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Ingår i: Gene Therapy and Molecular Biology. - 1529-9120. ; 12:B, s. 359-370
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Tidskriftsartikel (refereegranskat)abstract
- The essential oil of Lebanese sage, Salvia libanotica, was reported to have anti-tumour activity; however, the mechanism of action has not been identified yet. In this study, 14- cancer cell lines including drug-sensitive and resistant lung, leukaemia, and colon, as well as primary human tumours of chronic lymphocytic leukaemia (CLL) and primary normal mononuclear cells (PBMCs) were used to characterize the anti-tumour activity and mechanism of action of linalyl acetate, a component of the Lebanese sage essential oil. Drug activity and gene expression data sets were utilized to identify drugs with similar activity patterns and genes involved in drug sensitivity/resistance. In addition, the Connectivity Map, a gene expression signature-based screening approach, assisted in predicting further the molecular action of linalyl acetate. Small cell lung carcinoma and colorectal cancer cell lines were the most sensitive to the drug and greater tumour selectivity was observed against chronic lymphocytic leukaemia cells compared to normal mononuclear cells. Only limited effect of some of the classical mechanisms of multi-drug resistance on the activity of Linalyl acetate was noted which makes it potentially interesting for drug-resistant patients. There was high similarity between the activity-pattern/gene expression profile of linalyl acetate and that of protein kinase/NF-kappa B inhibitors. Validating this, linalyl acetate was found to strongly inhibit Janus kinase, JAK3, and p38 alpha kinases in a cell-free assay as well as the NF-kappa B translocation in a dose-dependent manner. Taken together, our results show that the NF-kappa B inhibitor, linalyl acetate, may represent a new therapeutic compound in the management of inflammation and cancer.
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| 23. |
- Hovstadius, Peter, 1962-
(författare)
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Preclinical and Clinical Development of the Novel Cyanoguanidine CHS 828 for Cancer Treatment
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- CHS 828 is a cyanoguanidine with anti-tumour properties which has shown promising effects in several preclinical models. This thesis describes both preclinical and clinical studies aiming to investigate disease specific activity, clinical tolerability and efficacy of CHS 828.In paper I we investigated CHS 828 activity in a cell line panel with human myeloma cells, three of these cell-lines were also tested in vivo using a hollow fibre rat-model. In paper II we investigated CHS 828 activity in primary human tumour samples from patients. CHS 828 showed an effect on all tumour cell types tested both the primary human tumour samples and the myeloma cell lines. Notably, CHS 828 showed a high relative in vitro activity against tumour cells from chronic lymphocytic leukaemia and high-grade lymphoma. In a phase I trial we determined the maximum tolerated dose (MTD) of CHS 828. Haematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Non-haematological toxicity was mostly of gastrointestinal origin. The recommended phase two dose (RPTD) of CHS 828 was estimated to be 20 mg once daily for five days in cycles of 28 days duration.In a phase II trial we investigated the effect of CHS 828 on patients diagnosed with B-CLL. In total 12 patients were enrolled. CHS 828 was found to be well tolerated and the most common haematological toxicity was thrombocytopenia. Non-haematological toxicities were generally mild. Transient decreases in lymphocyte counts could be discerned coinciding with drug dosing, but no sustained clinical responses could be achieved.In conclusion, CHS 828 demonstrated marked effects in the preclinical investigations suggesting haematological malignancies as the main target. The clinical phase I study established a safe dose and the subsequent phase II trial in B-CLL patients showed biological effect but with no clinical disease response.
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| 24. |
- Hägglund, Gösta, et al.
(författare)
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Estimation of the correlation coefficient based on selected data
- 2006
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Ingår i: Journal of educational and behavioral statistics. - : American Educational Research Association (AERA). - 1076-9986 .- 1935-1054. ; 31:4, s. 377-411
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Tidskriftsartikel (refereegranskat)abstract
- In psychometrics, if is often the case that one encounters data that may not be considered random but selected in a systematic way according to some explanatory variable. In this article, maximum likelihood estimation is considered when data are supposed to arise from a bivariate normal distribution that is truncated in an extreme way. Two methods are presented and compared, one of them being purely numerical, while the other is based on an approximation. Both methods are tried on both simulated and on real data. The purely numerical method is shown to be the most reliable over all, but in some cases, the computationally less burdensome approximate method turns out to work almost as well.
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| 25. |
- Itani, Wafica, et al.
(författare)
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Anti colon cancer components from lebanese sage (Salvia libanotica) essential oil : Mechanistic basis
- 2008
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Ingår i: Cancer Biology & Therapy. - : Informa UK Limited. - 1538-4047 .- 1555-8576. ; 7:11, s. 1765-1773
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Tidskriftsartikel (refereegranskat)abstract
- Lebanese sage essential oil possesses antitumor properties, however, the bioactive components and antitumor mechanisms are not known. Here we show that combining the three sage bioactive compounds, Linalyl acetate (Ly), Terpeniol (Te) and Camphor (Ca), caused synergistic inhibition of the growth of two isogenic human colon cancer cell lines HCT-116 (p53(+/+) and p53(-/-)), and had no effect on growth of FHs74Int normal human intestinal cell line. In p53(+/+) cells, the combination of Ly + Te + Ca (10(-3) M of each) caused significant accumulation of cells in PreG(1) (64% at 48 h); less preG(1) increase was observed in response to Ly + Te (25%) or Ly + Ca (14%). In p53(-/-) cells, Ly + Te + Ca caused cell accumulation in PreG(1) and G(2)/M phases. In response to the three components, 58% apoptosis occurred in p53(+/+) cells and 38% in p53(-/-) cells. Apoptosis by Ly + Te + Ca, in p53(+/+) cells, was associated with increased Bax/Bcl-2 ratio and pp53/p53 ratio, cleavage and activation of caspase-3, loss of mitochondrial membrane potential and cytochrome c release. In p53(-/-) cells, the disruption of mitochondrial membrane potential was observed but to a lesser extent than in p53(+/+) cells and caspase activation or cleavage did not appear to be involved in drug-induced apoptosis. Sage components induced poly(ADP-ribose)-polymerase (PARP) cleavage in both p53(+/+) and p53(-/-) cell lines. Pretreatment with the caspase-3 inhibitor and pan caspase inhibitor abrogated drug-mediated apoptosis and blocked procaspase-3 activation and partially blocked PARP cleavage in p53(+/+) cells. Conversely, in p53(-/-) cells, pre-incubation with caspase inhibitors potentiated drug-induced cell death. It appears that apoptosis in p53(+/+) cells is through the mitochondrial-mediated, caspase-dependent pathway, while in p53(-/-) cells apoptosis is mostly caspase independent despite the presence and features indicating caspase-dependent cell death, such as cytochrome c release and PARP cleavage. Our findings encourage further studies of sage oil components as promising chemotherapeutic agents against colon cancer.
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| 26. |
- Jacobson, Tor, et al.
(författare)
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Inflation, Exchange Rates and PPP in a Multivariate Panel Cointegration Model
- 2008
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Ingår i: Econometrics Journal. - 1368-4221 .- 1368-423X. ; 11:1, s. 58-79
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Tidskriftsartikel (refereegranskat)abstract
- New multivariate panel cointegration methods are used to analyze nominal exchange rates and prices in four major economies in Europe: France, Germany, Italy and the United Kingdom for the post-Bretton Woods period. We test for purchasing power parity (PPP) between these four countries and find that the theoretical PPP relationship does not hold. However, the estimated unrestricted relationship is found to be remarkably close to the theoretical one (1, -1.5, 0.9 instead of 1, -1,1). Relevant asymptotic results are stated, proved, and evaluated using Monte Carlo simulations. The asymptotic results are general and may hence be used in similar empirical contexts using the same model structure. Parametric bootstrap inference is used in order to deal with test size distortions.
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| 27. |
- Jensen Waern, Marianne, et al.
(författare)
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Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism
- 2009
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Ingår i: Laboratory Animals. - : SAGE Publications. - 0023-6772 .- 1758-1117. ; 43:3, s. 249-254
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Tidskriftsartikel (refereegranskat)abstract
- Streptozotocin (STZ) given intravenously destroys pancreatic beta cells and is widely used in animal models to mimic type 1 diabetes. The effects of STZ on the clinical state of health and metabolism were studied in six high health certified domestic pigs weighing 19 +/- 1.3 kg at the start of the experiment. A single STZ dose of 150 mg/kg of body weight successfully induced hyperglycaemia and alterations in amino acid metabolism. Within 9 h after STZ administration, the blood glucose values fell from 5.4-7.5 mmol/L to 0.8-2.2 mmol/L. Hypoglycaemia was treated with 0.5 g glucose/kg body weight. In all pigs, hyperglycaemia was produced 24 h after STZ treatment, and 3 days after STZ injection, the glucose concentration was >25 mmol/L. Mean C-peptide concentration was 0.25 +/- 0.16 mug/L since 2 days after STZ injection until the end of the study. The serum concentration of the branched-chain amino acids (BCAA) increased four-fold, and alanine and taurine decreased by approximately 70% and 50%, respectively, after STZ treatment. All but one pig remained brisk and the physical examination was normal except for a retarded growth rate and a reduction of the skeletal muscle. At the end of the study, the pigs were moderately emaciated. Postmortem examination confirmed muscle wasting and a reduction of abdominal and subcutaneous fat. In conclusion, STZ-induced diabetes in pigs fulfils the requirements for a good animal model for type 1 diabetes with respect to clinical signs of the disease and alterations in the carbohydrate and amino acid metabolism.
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| 28. |
- Klinth, J. E., et al.
(författare)
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A novel application of multi-wavelength TIRF spectroscopy for real time monitoring of antithrombin interactions with immobilized heparin
- 2006
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Ingår i: Biosensors & bioelectronics. - : Elsevier BV. - 0956-5663 .- 1873-4235. ; 21:10, s. 1973-80
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Tidskriftsartikel (refereegranskat)abstract
- Real time interactions of antithrombin (AT) with Corline Heparin Surfaces (CHS) with one and two layers of heparin conjugate have been examined using a multi-wavelength TIRF spectroscopy technique with continuous flow. Fluorescently labeled AT, adsorbed from citrated human blood plasma, showed significantly higher signals on CHS compared to the cationic surface used to attach the heparin conjugate. The AT binding to CHS was very stable, also after exposure to soluble heparin at a concentration of 1.5 IU/mL. Only a few percent of the bound AT were displaced from the surfaces by AT present in plasma after long-term exposure to plasma. In contrast, larger amounts of the freshly added AT had adsorbed to the surfaces, especially to the surface with two layers of heparin conjugate, indicating the presence of unsaturated AT binding sites. The amount of AT bound to the different surfaces was quantified after elution using an enzyme immunoassay (EIA). Characteristic emission spectra of proteins and fluorophores of labeled proteins, obtained at the surfaces after a long-term exposure to plasma, confirmed their presence at the surfaces. The multi-wavelength TIRF technique proved to be a useful tool when combined with other techniques to study the time course of interactions of fluorescently labeled proteins with biomaterials, even in a complex environment such as plasma.
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| 29. |
- Korsell, Nicklas, 1974-
(författare)
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Statistical Properties of Preliminary Test Estimators
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis investigates the statistical properties of preliminary test estimators of linear models with normally distributed errors. Specifically, we derive exact expressions for the mean, variance and quadratic risk (i.e. the Mean Square Error) of estimators whose form are determined by the outcome of a statistical test. In the process, some new results on the moments of truncated linear or quadratic forms in normal vectors are established.In the first paper (Paper I), we consider the estimation of the vector of regression coefficients under a model selection procedure where it is assumed that the analyst chooses between two nested linear models by some of the standard model selection criteria. This is shown to be equivalent to estimation under a preliminary test of some linear restrictions on the vector of regression coefficients. The main contribution of Paper I compared to earlier research is the generality of the form of the test statistic; we only assume it to be a quadratic form in the (translated) observation vector. Paper II paper deals with the estimation of the regression coefficients under a preliminary test for homoscedasticity of the error variances. In Paper III, we investigate the statistical properties of estimators, truncated at zero, of variance components in linear models with random effects. Paper IV establishes some new results on the moments of truncated linear and/or quadratic forms in normally distributed vectors. These results are used in Papers I-III. In Paper V we study some algebraic properties of matrices that occur in the comparison of two nested models. Specifically we derive an expression for the inertia (the number of positive, negative and zero eigenvalues) of this type of matrices.
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| 30. |
- Kristensen, Emma, 1976-
(författare)
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Characterization of Surfaces Designed for Biomedical Applications
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In order to develop blood biocompatible materials a heparin surface and a phosphorylcholine (PC) functionalized polymer surface were characterized using photoelectron spectroscopy (PES). The formation of the heparin surface was studied by quartz crystal microbalance with dissipation monitoring (QCM-D). This heparin surface consists of heparin conjugates deposited on a conditioning layer, applied once or twice. The PC functionalized polymer, poly(trimethylene carbonate), was linked to a silicon substrate through 3-amino- propyltrimethoxysilane (APTMS), also studied using PES. Synchrotron radiation based PES showed that the thicker heparin film resulted in complete coverage of the substrate, while the thinner did not. This could explain the difference in blood biocompatibility between the two films, as observed by others. It was also found that the heparin chains bend down towards the substrate (under vacuum). For the thinner heparin film the modifications, resulting from extensive irradiation of the sample, were studied with synchrotron radiation based PES. This was done at a pressure of about 10-7 mbar and in 0.5 mbar water vapor. It was found that the modification is slower under water vapor than at low pressures and that the damaged film incorporates water upon exposure.The heparin coating was found to be stable and wear resistant enough to still be present on artificial heart valves after three weeks testing in circulating plasma. It then had about the same antithrombin uptake as a non-tested surface. The film was, however, partly destroyed by the durability test and plasma proteins were deposited. The PC functionalized, APTMS linked polymer was found to be much shorter than could be expected from random reactions. One plausible explanation is an interaction between the PC group and the silane surface, favoring aminolysis close to the PC group. This is consistent with our finding that the PC group bends down towards the surface.
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