| 1. |
- Larsson, Dhana E., et al.
(författare)
-
Combination analyses of anti-cancer drugs on human neuroendocrine tumor cell lines
- 2009
-
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 65:1, s. 5-12
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: There is a large need for better pharmacological treatment of neuroendocrine tumors. The aim of this study was to investigate and quantify the cytotoxic potentiating effects resulting from a combination of five substances, NSC 95397, emetine, CGP-74514A hydrochloride, Brefeldin A and sanguinarine chloride, chosen from a previous screening of 1,280 pharmacologically active agents on neuroendocrine tumor cells, with standard cytotoxic agents currently used in the treatment of neuroendocrine tumors. METHOD: The human pancreatic carcinoid cell line BON-1, human typical bronchial carcinoid cell line NCI-H727 and the human atypical bronchial carcinoid cell line NCI-H720 were used. Combinations between doxorubicin, etoposide, oxaliplatin, docetaxel, and each one of the five agents were studied and simultaneous exposures were explored using the median-effect method. RESULTS: Most of the combinations of NSC-95397 and emetine with doxorubicin, etoposide, docetaxel, and oxaliplatin showed synergism, and their remaining combinations were additive. Almost all of the CGP-74514A hydrochloride interactions were additive, while brefeldin A and sanguinarine displayed less synergy but more additive and antagonistic interactions in combination with the standard drugs. CONCLUSION: The synergistic and additive interactions make NSC-95397, emetine, and CGP-74514A hydrochloride potential candidates for incorporation into combination chemotherapy regimens and these drugs might be the suitable candidates for further clinical studies in patients with bronchial carcinoids and pancreatic endocrine tumors.
|
|
| 2. |
- Baranowska, Izabella, et al.
(författare)
-
Sensory ataxic neuropathy in golden retriever dogs is caused by a deletion in the mitochondrial tRNATyr gene
- 2009
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 5:5, s. e1000499-
-
Tidskriftsartikel (refereegranskat)abstract
- Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNA(Tyr) gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0-11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNA(Tyr) had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNA(Tyr) gene is the causative mutation for SAN.
|
|
| 3. |
- Berndtsson, Maria, et al.
(författare)
-
Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome system
- 2009
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:6, s. 1463-1469
-
Tidskriftsartikel (refereegranskat)abstract
- The lysosomal apoptosis pathway is a potentially interesting therapeutic target. Since apoptosis involving the lysosomal pathway has been described to involve cathepsins, we screened a drug library for agents that induce cathepsin-dependent apoptosis. Using pharmacological inhibitors and siRNA, we identified 2 structurally related agents (NSC687852 and NSC638646) that induced cathepsin D-dependent caspase-cleavage activity in human breast cancer cells. Both agents were found to induce the mitochondrial apoptosis pathway. NSC687852 and NSC638646 were found to inhibit the activity of ubiquitin isopeptidases and to induce the accumulation of high-molecular-mass ubiquitins in cells. We show that 3 other inhibitors of the proteasome degradation pathway induce lysosomal membrane permeabilization (LMP) and that cathepsin-D siRNA inhibits apoptosis induced by these agents. We conclude that a screen for cathepsin-dependent apoptosis-inducing agents resulted in the identification of ubiquitin isopeptidase inhibitors and that proteasome inhibitors with different mechanisms of action induce LMP and cathepsin D-dependent apoptosis.
|
|
| 4. |
- Ekström, Joakim, 1982-
(författare)
-
Contributions to the Theory of Measures of Association for Ordinal Variables
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, we consider measures of association for ordinal variables from a theoretical perspective. In particular, we study the phi-coefficient, the tetrachoric correlation coefficient and the polychoric correlation coefficient. We also introduce a new measure of association for ordinal variables, the empirical polychoric correlation coefficient, which has better theoretical properties than the polychoric correlation coefficient, including greatly enhanced robustness. In the first article, entitled ``On the relation between the phi-coefficient and the tetrachoric correlation coefficient'', we show that under given marginal probabilities there exists a continuous bijection between the two measures of association. Furthermore, we show that the bijection has a fixed point at zero for all marginal probabilities. Consequently, the choice of which of these measures of association to use is for all practical purposes a matter of preference only. In the second article, entitled ``A generalized definition of the tetrachoric correlation coefficient'', we generalize the tetrachoric correlation coefficient so that a large class of parametric families of bivariate distributions can be assumed as underlying distributions. We also provide a necessary and sufficient condition for the generalized tetrachoric correlation coefficient to be well defined for a given parametric family of bivariate distributions. With examples, we illustrate the effects on the polychoric correlation coefficient of different distributional assumptions. In the third article, entitled ``A generalized definition of the polychoric correlation coefficient'', we generalize the polychoric correlation coefficient to a large class of parametric families of bivariate distributions, and show that the generalized and the conventional polychoric correlation coefficients agree on the family of bivariate normal distributions. With examples, we illustrate the effects of different distributional assumptions on the polychoric correlation coefficient. In combination with goodness-of-fit p-values, the association analysis can be enriched with a consideration of possible tail dependence. In the fourth article, we propose a new measure of association for ordinal variables, named the empirical polychoric correlation coefficient. The empirical polychoric correlation coefficient relaxes the fundamental assumption of the polychoric correlation coefficient so that an underlying joint distribution is only assumed to exist, not to be of a particular parametric family. We also provide an asymptotical result, by which the empirical polychoric correlation coefficient converges almost surely to the true polychoric correlation under very general conditions. Thus, the proposed empirical polychoric correlation coefficient has better theoretical properties than the polychoric correlation coefficient.
|
|
| 5. |
- Eriksson, Mathilda, et al.
(författare)
-
Utilization of a right-handed coiled-coil protein from archaebacterium Staphylothermus marinus as a carrier for cisplatin
- 2009
-
Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 29:1, s. 11-18
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The nano-sized right-handed coiled-coil (RHCC) protein, originating from the archaebacterium Staphylothermus marinus, is stable at high salt concentrations, high temperatures, high pressures and extremes of pH. Its crystal structure reveals four hydrophobic cavities which can incorporate heavy metals. Nano-sized compounds have been used to carry cytotoxic drugs to tumours, avoiding delivery to healthy tissue, in part due to enhanced permeability in tumour blood vessels (enhanced permeability and retention effect). MATERIALS AND METHODS: The ability of RHCC to carry the platinum-containing chemotherapeutic drug cisplatin to cells, while retaining the cytotoxic potential was tested both in vitro and in vivo. RESULTS: RHCC was able to bind and enter cells in vitro and was not severely toxic or immunogenic in mice. Moreover, RHCC incorporated cisplatin, without inhibiting the cytotoxic potential of the drug against tumour cell lines in vitro or in vivo. CONCLUSION: RHCC can be used as a carrier of cisplatin without abrogating the effect of the drug.
|
|
| 6. |
- Faxälv, Lars, 1977-
(författare)
-
Imaging methods for haemostasis research
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood is a vital part of the human physiology; a transport system that brings nutrients and oxygen to sustain living cells and simultaneously facilitates the removal of carbon dioxide and other waste products from the body. To assure the continuity of these functions, it is of uttermost importance to keep the flowing blood inside the vascular system at any cost. The principal components of the haemostatic system are the blood platelets and the plasma coagulation system, both working in concert to create a blood stopping haemostatic plug when a vessel is ruptured. In modern health care, methods for treatment and diagnostics often implicate the contact between blood and artificial materials (biomaterials). Biomaterial surfaces may activate platelets and the coagulation cascade by exposing a surface that during blood contact shares certain characteristics with surfaces found at the site of vascular injury. Therefore it is of great importance that the mechanisms behind the interactions between foreign surfaces and blood are studied in order to minimize, and if possible, prevent unnecessary reactions that may lead to thrombosis.This thesis describes two important methods to study blood – surface interactions in terms of surface induced plasma coagulation and platelet adhesion/aggregation. The method ‘Imaging of coagulation’, a coagulation assay based on time-lapse image capture of the coagulation process was developed during the course of this work. The use of images enables the method to answer questions regarding where coagulation was initiated and how fast coagulation propagates. Such questions are highly relevant in the study of blood-biomaterial interactions but also in general haemostasis research. In vivo, platelet adhesion and aggregation are events that always proceed under flow conditions. Therefore we also developed a cone-and-plate flow model to study these mechanisms under similar conditions in vitro. The cone-and-plate setup was found to be a flexible platform and was used for both blood compatibility testing of potential biomaterials as well as for general haemostasis research.With the above mentioned methods we tested the haemocompatibility of glycerol monooleate (GMO), a proposed substance for use in biomaterial applications. It was found that GMO did not activate coagulation to any great extent either in plasma or in whole blood.Surface induced coagulation and platelet adhesion was also studied on PEG-containing hydrogels and compared with hydrogels constructed from three different non-PEG-containing monomers. It was concluded that all the grafted hydrogels, in particular those produced from the monomers 2-hydroxyethyl methacrylate (HEMA) and/or PEG- methacrylate (PEGMA), demonstrated good haemocompatibility.Supported phospholipid bilayers were used to investigate the relationship between surface charge and procoagulant activity. The coagulation process was studied in a straightforward manner using the imaging of coagulation setup. We concluded that the content of negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) in the bilayer must exceed ~ 6% for the bilayer to exert procoagulant activity.The physiological role of factor XII in human haemostasis and thrombosis was investigated in the imaging of coagulation setup and the cone and plate setup by the use of surfaces with thrombogenic coatings. We found that tissue factor initiated coagulation could be greatly accelerated by the presence of contact activating agents in a platelet dependent manner.In conclusion, the method ‘Imaging of coagulation’ and platelet adhesion/aggregation in the cone-and-plate flow model are both versatile methods with many possible applications. The combination of the two methods provides a solid foundation for biomaterial and haemostasis research.
|
|
| 7. |
- Fayad, Walid, et al.
(författare)
-
Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters
- 2009
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10, s. e7238-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology. METHOD AND FINDINGS: A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo. CONCLUSIONS: The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.
|
|
| 8. |
- Jensen Waern, Marianne, et al.
(författare)
-
Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism
- 2009
-
Ingår i: Laboratory Animals. - : SAGE Publications. - 0023-6772 .- 1758-1117. ; 43:3, s. 249-254
-
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.
|
|
| 9. |
|
|
| 10. |
- Karlsson, Peter
(författare)
-
On the Asymptotics of Increasing Dimension Models : Methods for Complete or Incomplete Data
- 2009
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In some multivariate contexts there is a close relation between the number of parameters (p) and the number of observations (n). In a situation where p grows with n it frequently happens that the statistic does not converge to its true parameter. An additional issue is if the data set also contain missing observations and , for example, as p grows with n so does the number of missing observations. This situation arises in the context of empirical applications of the Arbitrage Pricing Theory model, where the data is incomplete due to the nature of stocks leaving or entering the stock exchange. In this thesis two situations of increasing dimension are considered: firstly, the case of complete data sets where the statistic of interest is the inverse covariance matrix where three types of shrinkage estimators of the inverse covariance matrix are investigated, particularly as an ingredient of a composite estimator, specifically Zellners seemingly unrelated regression models and the Mahalanobis distance. Secondly, the case arising in empirical application of the APT model where the data set is incomplete and the interest is to model the underlying covariance structure among the variables by a few factors. Two possible solutions to the problem are considered and a case study using the Swedish OMX data is conducted for demonstration.
|
|
