| 51. |
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| 52. |
- Somajo, Sofia, et al.
(författare)
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Protein S and factor V in regulation of coagulation on platelet microparticles by activated protein C
- 2014
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 134:1, s. 144-152
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Platelets are the main source of microparticles in plasma and the concentration of microparticles is increased in many diseases. As microparticles expose negatively charged phospholipids, they can bind and assemble the procoagulant enzyme-cofactor complexes. Our aim was to elucidate possible regulation of these complexes on microparticles by the anticoagulant protein C system.Materials and methods: Platelets were activated with thrombin ± collagen or the calcium ionophore A23187 ± thrombin to generate microparticles. The microparticles were analyzed using flow cytometry and functional coagulation assays to characterize parameters with importance for the activated protein C system.Results: Activation with A23187 + thrombin was most efficient, fully converting the platelets to microparticle-like vesicles, characterized by high lactadherin and protein S binding capacity. Suppression of thrombin generation by activated protein C in plasma spiked with these microparticles was dependent on the presence of plasma protein S. Experiments with purified components showed that activated protein C inhibited both factor Va and factor VIIIa on the microparticle surface. Inhibition of factor Va was stimulated by, but not fully dependent on, the presence of protein S. In the factor VIIIa-degradation, activated protein C was dependent on the addition of protein S, and exogenous factor V further increased the efficiency.Conclusions: Protein S is crucial for activated protein C-mediated inhibition of thrombin generation on platelet-derived microparticles in plasma. Moreover, protein S and factor V are synergistic cofactors in the inhibition of factor VIIIa. The results demonstrate that the activated protein C system has the capacity to counterbalance the procoagulant ability of microparticles.
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| 53. |
- Tegler, Gustaf, 1968-, et al.
(författare)
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4D-PET/CT with [11C]-PK11195 and [11C]-D-deprenyl does not identify the chronic inflammation in asymptomatic abdominal aortic aneurysms
- 2013
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 45:4, s. 351-356
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe aim of this study was to investigate the relevance of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) in vivo with two novel positron emission tomography (PET) tracers: [11C]-PK11195 which targets the translocator protein (18 kDa) expressed on macrophages and [11C]-d-deprenyl with a yet unknown target receptor expressed in chronic inflammation.DesignProspective clinical study.Materials/methodsFive patients were examined with [11C]-PK11195-positron emission tomography/computed tomography (PET/CT) and 10 with [11C]-d-deprenyl-PET/CT. Nine large AAAs (54–66 mm) scheduled for repair and six small AAA (35–44 mm). All 15 patients were male and the AAAs were all asymptomatic. Regional activity was measured as standardised uptake values (SUVs) and retention index was calculated. Biopsies were taken from the aneurysm wall for histological examinations, in the nine patients operated on.ResultsNo aortic uptake was recorded on the visual inspection, neither with [11C]-PK11195 nor with [11C]-d-deprenyl. For [11C]-PK11195 the median SUV of the AAA wall was 0.9 (range 0.8–1.0) and for [11C]-d-deprenyl, 0.7 (range 0.4–1.2). No increased uptake was seen in the aneurysmal infrarenal aorta compared with the non-aneurysmal suprarenal aorta. Histological examination of the aneurysm wall showed high inflammatory cell infiltration with lymphocytes and macrophages.ConclusionsThe chronic inflammation observed in the vessel wall was not detectable with [11C]-PK11195 and [11C]-d-deprenyl. In order to study the relevance of the inflammation in the pathogenesis of AAA in vivo other PET tracers need to be investigated.
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| 54. |
- Vikingsson, Svante, 1983-
(författare)
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Development of new methodology for therapeutic drug monitoring of thiopurine treatment
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The three thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat several diseases, including inflammatory bowel disease (IBD). They are pro-drugs and are believed to act through the formation of thioguanine nucleotides (TGNs). Other important metabolites are the methylthioinosine nucleotides (meTINs). These metabolites are active in the white blood cells (WBCs).Most patients respond well to the thiopurine drugs but up to a third have to modify or discontinue their treatment due to adverse events or a lack of therapeutic effects. This could be caused by inter-patient variability in the metabolism of the drugs. Therapeutic drug monitoring (TDM) of thiopurine nucleotides in red blood cells (RBCs) is used to guide treatment. Current routine assays measure the nucleotides after hydrolysation to nucleic bases and are therefore unable to distinguish between mono-, di-, and triphosphates. Recently it was shown that these assays failed to predict the clinical outcome in about 40% of the patients. It has been suggested that measuring thioguanosine triphosphate (TGTP) (believed to be the most active of the TGNs) separately might increase the clinical value.An assay suitable for measuring thioguanosine mono- (TGMP) and diphosphate (TGDP) and TGTP, as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) separately in RBCs in clinical samples has been developed. In clinical studies of 82 IBD patients, we found no correlation between the thiopurine dose and metabolite levels in RBCs, thus illustrating the importance of metabolite measurements in the TDM of thiopurines.The TGN peak measured by the routine assay during TDM of patients treated with thiopurines consisted of TGTP and TGDP with a small contribution from TGMP. The meTIN also consisted of mono-, di- and triphosphates, but in different proportions, indicating differences in the formation. The inter-individual differences in nucleotide distribution were very small and a strong correlation between the different nucleotides and their respective sums was observed. As a consequence, measuring the mono-, di- and triphosphates separately was not beneficial in predicting remission, which was confirmed by the results from the clinical study.Further research into the metabolism and mode of action of thiopurine drugs is needed to understand the inter-patient variability in response and metabolite formation. An assay suitable for such studies, measuring TGNs and meTINs in cultured cells, has also been developed.
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| 55. |
- Vincent, Royce P, et al.
(författare)
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Higher circulating bile acid concentrations in obese patients with type 2 diabetes.
- 2013
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Ingår i: Annals of clinical biochemistry. - : SAGE Publications. - 1758-1001. ; 50:Pt 4, s. 360-4
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids (BAs) play an important role in releasing incretin hormones via the enteroendocrine L-cell surface TGR5 receptors. The aim of this study was to investigate the difference in BA concentration at baseline and in response to a meal stimulus between type 2 diabetes mellitus (T2DM) and a matched normoglycaemic group.
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| 56. |
- Zackrisson, Theresa, 1971, et al.
(författare)
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Evaluation of the objective posturo-locomotor-manual method in patients with parkinsonian syndromes.
- 2013
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Objective methods for quantifying patients' movement capacity would be useful in evaluating progression and interventions in neurodegenerative diseases. The Posturo-Locomotor-Manual (PLM) test is a standardized automated movement test developed to measure hypokinetic movements in patients with Parkinsonism. Our hypotheses were that the PLM movement time (MT) correlates with the Unified Parkinson's disease rating scale (UPDRS III) motor section, and that the components of the PLM test correlate with the corresponding constructed domains of UPDRS III. We also evaluated the coherence between the results of the two assessment methods after a test dose of levodopa (l-DOPA). We assessed motor function using the PLM method and UPDRS III in parallel, in the absence of medication and after administration of 200 mg l-DOPA, in 73 patients with moderate to advanced Parkinsonism: 47 with Parkinson's disease (PD), 17 with multiple system atrophy (MSA), and 9 with progressive supranuclear palsy (PSP). There was a fair correlation between the two assessment tools in the PD patients but not in the MSA or PSP patients. In the full dataset, there was a fair to good correlation between UPDRS III and the PLM MT. At group level, the UPDRS III l-DOPA test differentiated PD from MSA/PSP, whereas the PLM l-DOPA test differentiated between all three diagnoses.
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| 57. |
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| 58. |
- Botling, Johan, et al.
(författare)
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Biomarker Discovery in Non-Small Cell Lung Cancer : Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 194-204
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.
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| 59. |
- Cahill, Nicola, et al.
(författare)
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450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
- 2013
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 27:1, s. 150-158
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Tidskriftsartikel (refereegranskat)abstract
- In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n = 36) and patient-matched peripheral blood and lymph node samples (n = 20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-beta and NF-kappa B/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event. Leukemia (2013) 27, 150-158; doi:10.1038/leu.2012.245
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| 60. |
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