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- Ljungberg, Kajsa B, et al.
(författare)
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Computational Modelling of Inhibitor Binding to Human Thrombin
- 2001
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Ingår i: Eur. J. Pharm. Sci.. ; 12:4, s. 441-446
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Tidskriftsartikel (refereegranskat)abstract
- Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types ofhuman thrombin inhibitors. Far a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms ofmicroscopic interactions of the ligands with the solvated enzyme.
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- Schulman, S., et al.
(författare)
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Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months
- 2006
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 4:4, s. 734-742
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Tidskriftsartikel (refereegranskat)abstract
- Background: The influence of the duration of anticoagulant therapy after venous thromboembolism (VTE) on the long-term morbidity and mortality is unclear. Aim: To investigate the long-term sequelae of VTE in patients randomized to different duration of secondary prophylaxis. Methods: In a multicenter trial comparing secondary prophylaxis with vitamin K antagonists for 6 weeks or 6 months, we extended the originally planned 2 years follow-up to 10 years. The patients had annual visits and at the last visit clinical assessment of the post-thrombotic syndrome (PTS) was performed. Recurrent thromboembolism was adjudicated by a radiologist, blinded to treatment allocation. Causes of death were obtained from the Swedish Death Registry. Results: Of the 897 patients randomized, 545 could be evaluated at the 10 years follow-up. The probability of developing severe PTS was 6% and any sign of PTS was seen in 56.3% of the evaluated patients. In multivariate analysis, old age and signs of impaired circulation at discharge from the hospital were independent risk factors at baseline for development of PTS after 10 years. Recurrent thromboembolism occurred in 29.1% of the patients with a higher rate among males, older patients, those with permanent gering risk factor - especially with venous insufficiency at baseline - signs of impaired venous circulation at discharge, proximal deep vein thrombosis, or pulmonary embolism. Death occurred in 28.5%, which was a higher mortality than expected with a standardized incidence ratio (SIR) of 1.43 (95% CI 1.28-1.58), mainly because of a higher mortality than expected from cancer (SIR 1.83, 95% CI 1.44-2.23) or from myocardial infarction or stroke (SIR 1.28, 95% CI 1.00-1.56).The duration of anticoagulation did not have a statistically significant effect on any of the long-term outcomes. Conclusion: The morbidity and mortality during 10 years after the first episode of VTE is high and not reduced by extension of secondary prophylaxis from 6 weeks to 6 months. A strategy to reduce recurrence of VTE as well as mortality from arterial disease is needed. © 2006 International Society on Thrombosis and Haemostasis.
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- Berglind, S.-A., Ehnstrom, B. and Ljungberg, H.
(författare)
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Riparian beetles, biodiversity, and stream flow regulation - the examples of Svartån and Mjällån streams, Central Sweden
- 1997
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Ingår i: Entomologisk Tidskrift. - : The Entomological Society of Sweden, Umeå. - 0013-886X. ; 118:4, s. 137-154
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden, 70% of running waters have been exploited for hydropower purposes. Although hydroelectric power plants in small running waters, i.e. streams, contribute only 1% of the total electric production in Sweden, and the prospects for increasing this p
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| 8. |
- Canovic, Sead, 1979, et al.
(författare)
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CVD TiC/alumina and TiN/alumina multilayer coatings grown on sapphire single crystals
- 2010
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Ingår i: International Journal of Refractory Metals & Hard Materials. - : Elsevier BV. - 0263-4368. ; 28:2, s. 163-173
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Tidskriftsartikel (refereegranskat)abstract
- Multilayers of TiC/alpha-Al2O3 and TiN/kappa-Al2O3, consisting of three (1 mm thick) alumina layers separated by thin TiC or TiN (similar to 20 nm thick) layers, have been deposited onto c- and r-surfaces of single crystals of alpha-Al2O3 by chemical vapour deposition (CVD). The aim of this paper is to describe and compare the detailed microstructure of the different multilayer coatings by using transmission electron microscopy (TEM). The general microstructure of the alumina layers is very different when deposited onto different surfaces of alpha-Al2O3 single crystal substrates. On the c-surface the alumina layers grew evenly resulting in growth of single crystal layers of TiC or TiN and alumina throughout the coating. However, when deposited on the r-surface the alumina layers generally grow unevenly. The kappa -> alpha transformation occurs in TiN/kappa-Al2O3 multilayer coatings when deposited on both c- and r-surface substrates. In each layer the transformation starts at the interfacial pores in the upper part and proceeds inwards. The inner layer starts to transform first before the transformation proceeds to the outer layers. The microstructure of the transformed alpha-Al2O3 layers is different compared to as-deposited alpha-Al2O3, e.g. several voids and dislocations are present within the transformed alpha-Al2O3 layers. No pores were observed within the as-deposited alumina layers while a small number of pores was observed at the interfaces below the TiC and TiN layers. However, linkage of pores was observed within the transformed alpha-Al2O3 layers. There are also pores present in the substrate below the innermost TiC and TiN layers. It is believed that they are formed due to chemical etching during the deposition of the TiC and TiN layers. Single crystal TiC/alumina and TiN/alumina layers grow epitaxially on the c-surface substrates with close-packed planes growing on close-packed planes. On the r-surface, epitaxy is present only at some rare locations in alpha(r-sub)-TiC/Al2O3. However, in alpha(r-sub)-TiN/Al2O3 no epitaxy was observed. (C) 2009 Elsevier Ltd. All rights reserved.
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| 9. |
- Harmenberg, U, et al.
(författare)
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Treatment and overall survival (OS) in metastatic renal cell carcinoma (mRCC): A Swedish population-based study (2000-2008).
- 2012
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Ingår i: JOURNAL OF CLINICAL ONCOLOGY. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 30:5
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- 389 Background: This retrospective register study assessed OS in all mRCC patients in Sweden diagnosed before (2000–2005) and after (2006–2008) the introduction of targeted therapies, plus factors and treatment options influencing OS. Methods: Three Swedish national health registers were used: the Swedish Cancer register (diagnosis and death), the National Patient Register (in-/out-patient data), and the Swedish Prescribed Drug Register. From 2000-2008, 3,243 patients were identified with mRCC; 602 were recorded as receiving 1st-line treatment. Cox proportional hazards regression analysis, including estimation of adjusted OS, was used in three models with the covariates: diagnosis period, age, gender, institution size, nephrectomy status, geographic region (all models); mRCC treatments, defined as any tyrosine kinase inhibitor (TKI; Model 1; n=417); sunitinib (SU), sorafenib (SO), and interferon-alfa (IFN-α) in the 1st-line setting (Model 2; n=602 [SU=244, SO=110, IFN-α=248]); and variations of these drugs as 1st- and 2nd-line treatment sequences (Model 3; n=602). Results: Amongst mRCC patients diagnosed from 2006–2008 compared with 2000–2005, median adjusted OS was 16.1 vs. 10.9 months, respectively (HR=0.76, 95% CI: 0.69, 0.83; P<0.001). In all three models, factors independently associated with significantly improved OS included female gender, large institution, and prior nephrectomy. Prescription of any TKI (Model 1: HR=0.82, 95% CI: 0.73, 0.93; P=0.002) and 1st-line SU treatment (Model 2: HR=0.79, 95% CI: 0.67, 0.94; P=0.007) were associated with significantly improved OS compared with other or no treatments. A similar significant improvement in OS was also confirmed for patients treated with SU only in Model 3; however, due to a low number of observations, the model had insufficient statistical power to be appropriate for all sequences. Conclusions: An improved OS for mRCC patients was demonstrated for the period 2006-2008 compared with 2000-2005. Although the observed survival advantage is multifactorial in origin, contribution of targeted therapies is highly probable. Of the drugs studied, given design limitations, only SU was associated with improved OS.
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| 10. |
- Hedberg, Y, et al.
(författare)
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Cyclin D3 protein content in human renal cell carcinoma in relation to cyclin D1 and clinico-pathological parameters
- 2002
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 41:2, s. 175-181
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Tidskriftsartikel (refereegranskat)abstract
- Aberrations in the G1/S checkpoint are common in malignancies and are probably important for tumor development. Few G1/S studies have been performed on renal cell carcinoma (RCC) and therefore in this study the cyclin D3 protein content in 80 RCCs and that in 12 corresponding normal kidney cortex tissues are characterized using Western blotting. High cyclin D3 protein content was observed in 16% of the tumors and was significantly associated with aneuploidy, high TNM stage, high nuclear grade, high proliferation and young age. There was no association between tumor cyclin D3 and patient survival. The cyclin D3 overexpression was confirmed by immunohistochemical staining of 72 tumors, showing both nuclear and cytoplasmic localization of cyclin D3 in a fraction of the tumors. The cyclin D1 content has earlier been characterized in this tumor material and there was no relation between cyclin D1 and cyclin D3 protein expression. In summary, a fraction of the tumors overexpressed cyclin D3, supporting that various aberrations in the G1/S transition are implicated in RCCs.
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