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- Albertsson, Per, 1964, et al.
(författare)
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Differential locomotion of long- and short-term IL-2-activated murine natural killer cells in a model matrix environment.
- 2007
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 66:4, s. 402-9
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Tidskriftsartikel (refereegranskat)abstract
- Tumour infiltration by activated natural killer (A-NK) cells is a pre-requisite for tumour eradication by adoptive NK cell transfer. Extravasated A-NK cells do not always succeed in reaching the crucial target cell conjugation. Therefore, we wished to study A-NK cell locomotion and interactions with melanoma cells in a matrix environment (Matrigel) by electron, confocal and fluorescence microscopy. Two distinct patterns of A-NK cell-mediated matrix disintegration were revealed during incubation of tumour cells and A-NK cells in Matrigel: (1) A-NK cells pre-cultured for 5 days altered the homogeneous texture of the Matrigel, an initial microporous appearance became a loose filamentous meshwork by 24 h. Matrix degrading protease inhibitors could not fully prevent this, but could delay the process; and (2) A-NK cells pre-cultured for 6 days or more, instead formed large excavations in the Matrigel leaving the remaining matrix less affected compared to the effects by the younger A-NK cells. By histochemical staining with Cupromeronic Blue, the excavations were shown to contain proteoglycan material. Protease inhibitors had no discernable effect on the development of the excavations. The conspicuous capacity of A-NK cells to disintegrate extracellular matrix and the formation of large excavations seems only partially to depend on matrix-degrading proteases. Formation of extracellular proteoglycan material is suggested to facilitate A-NK cell locomotion within a matrix environment.
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| 2. |
- Edsparr, Karin, 1979, et al.
(författare)
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Effects of IL-2 on MMP expression in freshly isolated human NK cells and the IL-2-independent NK cell line YT.
- 2010
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Ingår i: Journal of immunotherapy (Hagerstown, Md. : 1997). - 1537-4513. ; 33:5, s. 475-81
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-2 is an important activation factor for natural killer (NK) cells but its effect on NK cell matrix metalloproteinases (MMP) production and matrix degradation is less well investigated. We have used freshly isolated human NK cells and the IL-2-independent NK cell line, YT, to investigate the effects of IL-2 stimulation on NK cell invasion of Matrigel and on MMP expression and production. In YT cells, we found opposing early and late effects of IL-2 stimulation with an early (2 h) increase in MMP-9 protein level and enhanced migration in the Matrigel invasion assay and by 30 hours a decreased mRNA expression of MMP-2, MMP-9, MMP-13, MT3-MMP, and MT6-MMP. We also found a preculture period of 48 hours with IL-2 to negatively affect YT cell migration. We furthermore found that freshly isolated human NK cells Matrigel invasion was MMP-dependent and it increased in response to IL-2. Importantly, in freshly isolated human NK cells we did not see a downregulation of MMPs after 24 hours IL-2 stimulation, but instead a significant upregulation of MT6-MMP mRNA. Because of the cellular localisation of MT6-MMP, which ensures a focalized proteolytic activity, and its high expression compared with the other MMPs in freshly isolated human NK cells makes it of interest to study further.
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| 3. |
- Edsparr, Karin, 1979, et al.
(författare)
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Human NK cell lines migrate differentially in vitro related to matrix interaction and MMP expression.
- 2009
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Ingår i: Immunology and cell biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 87:6, s. 489-95
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinases (MMPs) are thought to be of importance for the migratory ability of natural killer (NK) cells. Their expression and production may influence the amount of tumour-infiltrating NK cells and thereby any therapeutic capability. In this study, we sought to investigate the importance of MMPs for human NK cells' ability to degrade and migrate through the extracellular matrix (ECM). The two human NK cell lines, NK-92 and YT, migratory ability, MMP expression and production as well as their morphological appearance when cultured in the ECM equivalent Matrigel were analysed and compared. The quantitatively more migratory NK-92 cells were found to express invadopodia/podosomes at a significantly higher degree when cultured in Matrigel and gave rise to a general disintegration of the Matrigel. The NK-92 cells had a higher mRNA expression of MMP-2, -9, -13, MT1-, MT3- and MT6-MMP and a significantly higher production of MMP-9 compared to YT cells. These differences could explain the substantial functional difference observed between the two cell lines with respect to migratory capacity. In addition, the number of Matrigel invading NK-92 cells decreased significantly in the presence of the MMP inhibitor GM6001, demonstrating that MMPs have a critical function in their migration.
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| 6. |
- Gillberg, M., et al.
(författare)
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Longitudinal changes in the sleep habits of Swedish adolescents
- 2006
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Ingår i: Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 15:Suppl. 1, s. 83-
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Sleep habits change during adolescence both for biological and psychological/social reasons. Longitudinal studies on suchhabits are, however, scarce. The aim of the present study was toinvestigate the longitudinal changes of subjective sleep habits in Swedish adolescents.Method: The present study was part of a larger investigation mainlyon food habits that originally included all (about 2500) 14 year oldfrom three representative middle-sized Swedish towns. The adolescents filled in questionnaires at 14, 15 and 18 years of age. The 638 adolescents that answered all the questions on their sleephabits at each of the three occasions were included in the present study.Results and discussion: The adolescents developed later weekday bed- and rise times with increasing age (bedtimes from 22:35 h to23:20 h; risetimes from 06:50 h to 07:05 h). Consequently, time inbed on weekday nights decreased (from 8:15 h to 7:45 h). On weekends the adolescents went to bed later (around 2 h) and stayed in bed longer (around 1:20 h) than during the weekdays. Weekend time in bed decreased with increasing age. Differences between genders indicated that the changes observed were more obvious among boys. A dropout analysis implied that those adolescents that only participated at one occasion (at the age of 14) or at two occasions (at 14 and 15 years of age), respectively, went to bed later, woke up later and had shorter sleep compared to those who participated at all three occasions. Hence, the results might not be completely representative.Conclusions: A delay of bedtimes and of shortening of sleep duration as a function of age was observed. Weekend changes showed a delay of bedtimes and a (presumably) compensatory increase in sleep duration. Boys seemed 'worse off'.
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| 8. |
- Lennernäs, Bo, 1963, et al.
(författare)
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Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.
- 2005
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Ingår i: British journal of clinical pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 59:2, s. 249-53
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS: Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. RESULTS: The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. CONCLUSION: With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.
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| 10. |
- Ayoun Alsoud, Rami, et al.
(författare)
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Model-based interspecies scaling for predicting human pharmacokinetics of CB 4332, a complement factor I protein
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The extrapolation of a protein pharmacokinetics (PK) from preclinical to clinical studies can be less reliable than for small molecules. CB 4332 is a 150 kDa recombinant complement factor I (CFI) protein. In order to support clinical development, interspecies scaling of CB 4332 using traditional and model-based approaches was performed to inform first-in-human (FIH) dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous (i.v.) and subcutaneous (s.c.) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modelling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. Using the traditional dose-by-factor approach, a maximum recommended starting s.c. dose of 0.9 mg/kg once weekly was calculated using the NOAEL observed in NHPs. The model-based clinical trial simulations predicted it to result in a trough concentration at steady state 12.8% of the determined efficacy target for CB 4332 in humans. Interspecies scaling was performed for CB 4332 using traditional and model-based scaling, where PK modeling allowed the inclusion of preclinical PK information from three species, accounted for potential effects of ADA and species differences in elimination, and allowed the prediction of human PK for FIH dose selection.
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