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| 2. |
- Christensen, Kjeld, et al.
(författare)
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Evidence of contact activation in patients suffering from ST-elevation myocardial infarction
- 2016
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 141, s. 158-162
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. Methods and patients: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3 days post-percutaneous intervention (PCI) and, in one-third of the patients, 3 months after PCI. In order to investigate the degree of Factor XII (FXII) activation, changes in FXIIa/AT and FXIIa/C1INH complex levels were quantified by ELISA. Results: FXIIa/AT levels at admission (0.89 +/- 0.50; p < 0.01) were significantly higher than those in normal individuals (0.39 +/- 0.28), but the levels after 1-3 days (0.33 +/- 0.33; p < 0.05) were essentially normalized. In contrast, the FXII/C1INH levels at admission (1.40 +/- 0.72; p < 0.001) and after 1-3 days (0.83 +/- 0.59; p < 0.001) were both significantly higher than those in normal individuals (0.40 +/- 0.30). FXIIa/AT and FXIIa/C1INH complexes at admission (p < 0.001; p < 0.001) and after 1-3 days (p < 0.02; p < 0.001) were significantly different from those at 3 months. No significant differences were observed when the data were stratified for patency (open/closed culprit lesions). Conclusion: Both FXIIa/AT and FXIIa/C1INH complexes were significantly increased and reflected the activation of FXII in STEMI patients at admission. In particular, FXIIa/AT complex elevations support the hypothesis that clot propagation-mediated FXII activation had occurred, and this activation may be a target for anticoagulation in patients with cardiac infarction. Based on previous studies, the FXIIa/C1INH complex levels were primarily interpreted to reflex endothelial cell activation. (C) 2016 Published by Elsevier Ltd.
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| 3. |
- Hamad, Osama A., et al.
(författare)
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Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 114:6, s. 1207-1217
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Tidskriftsartikel (refereegranskat)abstract
- Complement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16(+)/CD42a(+) PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75-100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.
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| 4. |
- Kroon, Martin, et al.
(författare)
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A new constitutive model for multi-layered collagenous tissues
- 2008
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Ingår i: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 41:12, s. 2766-2771
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Tidskriftsartikel (refereegranskat)abstract
- Collagenous tissues Such as the aneurysmal wall or the aorta are multi-layered structures with the mean fibre alignments distinguishing one layer from another. A constitutive representation of the multiple collagen layers is not yet developed, and hence the aim of the present study. The proposed model is based on the constitutive theory of finite elasticity and is characterized by an anisotropic strain-energy function which takes the material structure into account. The passive tissue behaviour is modelled and the related mechanical response is assumed to be dominated by elastin and collagen. While elastin is modelled by the neo-Hookean material the constitutive response of collagen is assumed to be transversely isotropic for each individual layer and based on an exponential function. The proposed constitutive function is polyconvex which ensures material stability. The model has five independent material parameters, each of which has a clear physical interpretation: the initial stiffnesses of the collagen fabric in the two principal directions, the shear modulus pertaining to the non-collagenous matrix material, a parameter describing the level of nonlinearity of the collagen fabric, and the angle between the principal directions of the collagen fabric and the reference coordinate system. An extension-inflation test of the adventitia of a human femoral artery is simulated by means of the finite element method and an error function is minimized by adjusting the material parameters yielding a good agreement between the model and the experimental data.
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| 5. |
- Kroon, Martin, et al.
(författare)
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Modeling of saccular aneurysm growth in a human middle cerebral artery
- 2008
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Ingår i: Journal of Biomechanical Engineering. - : ASME International. - 0148-0731 .- 1528-8951. ; 130:5
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Tidskriftsartikel (refereegranskat)abstract
- Saccular aneurysm growth in a human middle cerebral artery is modeled. The aneurysm growth model was presented in a companion paper by Kroon and Holzapfel ("A Model for Saccular Cerebral Aneurysm Growth by Collagen Fibre Remodelling," J. Theor. Biol., in press) and was assessed there for axisymmetric growth. The aneurysm growth model is now evaluated for a more realistic setting. The middle cerebral artery is modeled as a two-layered cylinder, where the layers correspond to the media and the adventitia. An instant loss of the media in a region of the artery wall initiates the growth of the saccular aneurysm. The aneurysm wall is assumed to be a development of the adventitia of the original healthy artery, and collagen is assumed to be the only load-bearing constituent in the adventitia and in the aneurysm wall. The collagen is organized in a number of distinct layers where fibers in a specific layer are perfectly aligned in a certain fiber direction. The production of new collagen is taken to depend on the stretching of the aneurysm wall, and the continuous remodeling of the collagen fibers is responsible for the aneurysm growth. The general behavior of the growth model is investigated and also the influence of the structural organization of the collagen fabric. The analysis underlines the fact that the material behavior of aneurysmal tissue cannot be expected to be isotropic. The model predictions agree well with clinical and experimental results, for example, in terms of aneurysm size and shape, wall stress levels, and wall thickness.
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| 6. |
- Norda, Rut, et al.
(författare)
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Complement activation products in liquid stored plasma and C3a kinetics after transfusion of autologous plasma
- 2012
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Ingår i: Vox Sanguinis. - Malden : Wiley-Blackwell. - 0042-9007 .- 1423-0410. ; 102:2, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: Keeping a small stock of liquid plasma readily available for transfusion is common practise in Sweden. We report data on complement activation markers in plasma components during storage in the liquid state and the kinetics of C3a-desArg after transfusion of autologous plasma with high content of C3a-desArg.Material and Methods: Plasma components were prepared by apheresis or from whole blood. C3 fragments (C3a-desArg, C3d, g, iC3), and soluble terminal complement complex (sC5b-9) were investigated. C3a-desArg kinetics was investigated in regular apheresis donors.Results: Apheresis plasma prepared by membrane centrifugation had significantly higher level of C3a-desArg, C3d, g and sC5b-9 from day 0 and low iC3, than plasma prepared by other methods. By storage day 7, C3a-desArg -levels were above the reference value in 88% of all components. After re-infusion of autologous plasma with high C3a-desArg content, there were rapid a1 and a2-distribution followed by a slower b-elimination phase.Conclusion: Plasma components prepared by different methods and stored in the liquid phase differ significantly in the amount and timing of complement activation. C3a-desArg present in plasma is rapidly eliminated after transfusion. Autologous plasma could be used to study complement kinetics in different clinical situations.
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| 7. |
- Moll, Guido, et al.
(författare)
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Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?
- 2014
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 32:9, s. 2430-2442
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Tidskriftsartikel (refereegranskat)abstract
- We have recently reported that therapeutic mesenchymal stromal cells (MSCs) have low engraftment and trigger the instant blood mediated inflammatory reaction (IBMIR) after systemic delivery to patients, resulting in compromised cell function. In order to optimize the product, we compared the immunomodulatory, blood regulatory, and therapeutic properties of freeze-thawed and freshly harvested cells. We found that freeze-thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties. Freeze-thawed MSCs demonstrated reduced responsiveness to proinflammatory stimuli, an impaired production of anti-inflammatory mediators, increased triggering of the IBMIR, and a strong activation of the complement cascade compared to fresh cells. This resulted in twice the efficiency in lysis of thawed MSCs after 1 hour of serum exposure. We found a 50% and 80% reduction in viable cells with freshly detached as opposed to thawed in vitro cells, indicating a small benefit for fresh cells. In evaluation of clinical response, we report a trend that fresh cells, and cells of low passage, demonstrate improved clinical outcome. Patients treated with freshly harvested cells in low passage had a 100% response rate, twice the response rate of 50% observed in a comparable group of patients treated with freeze-thawed cells at higher passage. We conclude that cryobanked MSCs have reduced immunomodulatory and blood regulatory properties directly after thawing, resulting in faster complement-mediated elimination after blood exposure. These changes seem to be paired by differences in therapeutic efficacy in treatment of immune ailments after hematopoietic stem cell transplantation.
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| 8. |
- Yang, Jingmei, et al.
(författare)
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Combating drug resistance in acute myeloid leukaemia by drug rotations : the effects of quizartinib and pexidartinib
- 2021
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Acute myeloid leukaemia (AML) is an aggressive blood cancer. In approximately 30% of the cases, driver mutations in the FLT3 gene are identified. FLT3 inhibitors are used in treatment of such patients together with cytotoxic drugs or (in refractory AML) as single agents. Unfortunately, resistance to FLT3 inhibitors limits their efficacy. Resistance is often due to secondary mutations in the gene encoding the molecular target. The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations. In chronic myeloid leukaemia (CML), it has been suggested that rotation between drugs with a different landscape of resistance mutations might postpone the emergence of resistance. Methods We studied the effect of quizartinib and pexidartinib in AML cell lines that express FLT3 (MOLM-14 and MV4-11). Using a rotation protocol, we further examined whether the emergence of resistance could be postponed. Computational modelling was used to analyse the onset of resistance and suggest which mutations are most likely to occur in a quantitative fashion. Results The cells were sensitive to both inhibitors but quickly developed resistance that could be inherited, suggesting a genetic origin. Rotation protocols were not useful to postpone the emergence of resistance, which implies that such protocols, or changing from pexidartinib to quizartinib (or vice-versa) should not be used in patients. The computational modelling led to similar conclusions and suggested that F691L is the most common mutation to occur with quizartinib, and also when both drugs are used in rotation. Conclusions AML patients are not likely to benefit from a quizartinib/pexidartinib rotation protocol. A combination of tyrosine kinase inhibitors (with different molecular targets) might be more useful in the future. Development of specific FLT3 inhibitors that are less sensitive to resistance mutations might also lead to a better outcome.
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| 9. |
- Yang, Jingmei, et al.
(författare)
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Combination strategies to overcome drug resistance in FLT+ acute myeloid leukaemia
- 2023
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAcute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly.MethodsWe examined combination therapies aimed at FLT3(+)-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism.ResultsWe show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance.ConclusionsThis study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.
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| 10. |
- Banegas, José R, et al.
(författare)
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Achievement of lipoprotein goals among patients with metabolic syndrome at high cardiovascular risk across Europe. The EURIKA study.
- 2013
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 166:1, s. 210-214
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine for the first time the achievement of lipoprotein treatment goals in patients with metabolic syndrome and lipid abnormalities who are at elevated cardiovascular risk in Europe. METHODS: Cross-sectional study conducted in 2009-2010 in 12 European countries among outpatients aged ≥50years free of clinical cardiovascular disease. We assessed achievement of American Diabetes Association/American College of Cardiology lipid treatment goals in those with metabolic syndrome at highest risk (diabetes plus ≥1 additional major cardiovascular risk factor beyond lipid abnormalities) or high risk (no diabetes but ≥2 additional major cardiovascular risk factors). RESULTS: Among 1431 highest-risk patients, 64.6% (between-country range [BCR] 40-84.5%) were on lipid-lowering medication. Of them, 13.4% (BCR: 2.5-28.6%) had LDL-cholesterol<70mg/dl, non-HDL-cholesterol<100mg/dl, and apolipoprotein B<80mg/dl. Among 832 high-risk patients, 38.7% BCR: 27.5-55.3%) were on lipid-lowering medication. Of them, 20.5% (BCR: 5.5-57.6%) had LDL-cholesterol<100mg/dl, non-HDL-cholesterol<130mg/dl, and apolipoprotein B<90mg/dl. About 96% of highest-risk patients and 94% of high-risk patients were given at least one lifestyle advice (weight reduction, healthy diet, physical activity, no-smoking), but only 1.3% of the former and 4.9% of the latter reached all three lipid goals. CONCLUSION: There is a substantial gap between clinical guidelines and medical practice since only one in 5-7 patients met all treatment targets. Although most patients received lifestyle advice, the effectiveness of counseling was very low. Large between-country differences in outcomes suggest considerable room for improvement.
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