| 1. |
- Wickström, Malin, et al.
(författare)
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The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:9, s. 2409-2417
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
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| 2. |
- Andersson, Claes R., et al.
(författare)
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In vitro drug sensitivity-gene expression correlations involve a tissue of origin dependency
- 2007
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Ingår i: Journal of chemical information and modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 47:1, s. 239-248
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Tidskriftsartikel (refereegranskat)abstract
- A major concern of chemogenomics is to associate drug activity with biological variables. Several reports have clustered cell line drug activity profiles as well as drug activity-gene expression correlation profiles and noted that the resulting groupings differ but still reflect mechanism of action. The present paper shows that these discrepancies can be viewed as a weighting of drug-drug distances, the weights depending on which cell lines the two drugs differ in.
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| 3. |
- Andersson, Göran, et al.
(författare)
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Towards strategic inter-organisational management accounting.
- 2007
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Konferensbidrag (refereegranskat)abstract
- We argue that strategic management accounting (SMA) and inter-organisational management accounting (IOMA) have developed management accounting (MA) in two dimensions. In previous theory these concepts are rather vague and they are mainly treated independently. A concept analysis focused on attributes for SMA and IOMA is performed. Similarities and differences in earlier writings are identified. The analysis shows that SMA is an academic, theory-based conceptualisation with weak practical application. The opposite is valid for IOMA. SMA is strategy- and competitor-oriented, while IOMA is measurement- and supplier-oriented. We suggest an integration of the two. With strategic inter-organisational management accounting (SIOMA) a combination of the advantages of SMA and IOMA is achieved. We suggest using SIOMA as a conceptual tool, when an enterprise attempts to improve its competitiveness.
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| 4. |
- Angelov, Nikolay, et al.
(författare)
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Testing for unit root against stationarity using the likelihood ratio test
- 2007
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Ingår i: Communications in statistics. Simulation and computation. - : Informa UK Limited. - 0361-0918 .- 1532-4141. ; 36:2, s. 391-412
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Tidskriftsartikel (refereegranskat)abstract
- In a first order autoregressive model with drift, we derive the likelihood ratio test for a unit root against the stationary alternative. We also derive the test in a state space model with trend. Finite sample and asymptotic critical values are obtained by Monte Carlo simulations. A simulation study investigates the power performance of the likelihood ratio test and we also examine how a bias correction of the test affects the results.
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| 5. |
- Bornefalk Hermansson, Anna, 1971-
(författare)
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Resampling Evaluation of Signal Detection and Classification : With Special Reference to Breast Cancer, Computer-Aided Detection and the Free-Response Approach
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The first part of this thesis is concerned with trend modelling of breast cancer mortality rates. By using an age-period-cohort model, the relative contributions of period and cohort effects are evaluated once the unquestionable existence of the age effect is controlled for. The result of such a modelling gives indications in the search for explanatory factors. While this type of modelling is usually performed with 5-year period intervals, the use of 1-year period data, as in Paper I, may be more appropriate.The main theme of the thesis is the evaluation of the ability to detect signals in x-ray images of breasts. Early detection is the most important tool to achieve a reduction in breast cancer mortality rates, and computer-aided detection systems can be an aid for the radiologist in the diagnosing process.The evaluation of computer-aided detection systems includes the estimation of distributions. One way of obtaining estimates of distributions when no assumptions are at hand is kernel density estimation, or the adaptive version thereof that smoothes to a greater extent in the tails of the distribution, thereby reducing spurious effects caused by outliers. The technique is described in the context of econometrics in Paper II and then applied together with the bootstrap in the breast cancer research area in Papers III-V.Here, estimates of the sampling distributions of different parameters are used in a new model for free-response receiver operating characteristic (FROC) curve analysis. Compared to earlier work in the field, this model benefits from the advantage of not assuming independence of detections in the images, and in particular, from the incorporation of the sampling distribution of the system's operating point.Confidence intervals obtained from the proposed model with different approaches with respect to the estimation of the distributions and the confidence interval extraction methods are compared in terms of coverage and length of the intervals by simulations of lifelike data.
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| 6. |
- Cabric, Sanja, et al.
(författare)
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Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 2008-2015
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
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| 7. |
- Christensen, Kjeld, 1957-
(författare)
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Platelet Activation and Inhibition in Connection with Vascular Stents
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the Chandler loop, which makes it possible to conduct studies in vitro of molecular and cellular interactions between whole blood and stents. It was possible to monitor activation and inhibition of the cascades systems, leukocytes and platelets by combining different platelet inhibitors and heparin coating of stents. The clinical study was performed on patients with ACS undergoing PCI and stent implantation. In this study platelet activation markers P-selectin, and αIIb/β3 as well as inflammatory markers were followed from baseline during the first 48 hours post-PCI. The same parameters were evaluated in healthy controls for comparison at baseline. In vitro: The activation of blood in the Chandler loops were more pronounced for unmodified stent grafts than for partially heparin coated stent grafts. Heparin coated stent grafts dreated the same activation as the loops alone. This indicated that the Chandler loop system was a feasible tool for evaluation of blood compability of stents. Heparin coating of stents significantly reduced TAT, CD11b and platelet activation. The combination of a heparin coated stent and abciximab reduced TAT and contact activation, as compared to abciximab or heparin coating alone. Heparin coating of stents in combination with AR-C69931MX resulted in a significant reduction in TAT and preservation of the platelet count but had no effect on contact activation. Clinical study: Abciximab resulted in an almost total inhibition of fibrinogen binding to platelets and persisted throughout the observation period. Clopidogrel effectscould be observed at four hours but was more pronounced at 24 hours. P-selectin expression did not differ over time between groups, indicating that platelet activation with α-granule secretion was not affected by abciximab treatment. The hs-CRP, C3a and sC5b-9 levels increased 24 to 48 hours after PCI in patients with ACS. FXIIa-C1inh was reduced in ACS patients receiving abciximab as compared to controls. The elevated bFGF levels at baseline returned to the levels observed in controls four hours after PCI and stent implantation, whereas an increase in VEGF was observed 24 hours post-PCI.
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| 8. |
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| 9. |
- Fryknäs, Mårten, et al.
(författare)
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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
- 2007
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195
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Tidskriftsartikel (refereegranskat)abstract
- The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
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| 10. |
- 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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