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| 2. |
- Dimberg, Lina, 1972-
(författare)
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Apoptosis Regulation in Multiple Myeloma
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a virtually incurable B cell malignancy of the bone marrow. One important part of tumor progression and an obstacle for successful therapy is resistance to apoptosis. To combat this resistance, the mechanisms of apoptosis and survival in MM must be better defined. In this thesis, we identified Fas up-regulation as a mechanism underlying interferon (IFN)-mediated sensitization to Fas-induced apoptosis in the MM cell line U-266-1970. IFN treatment induced activation of signal transducer and activator of transcription (Stat)1 but, intriguingly, also attenuated activation of MM survival factor Stat3. Exploring the role of Stat1 further, we established sub-lines of U-266-1970 with a stable over-expression of Stat1 and of its active mutant Stat1C. These sub-lines displayed a decreased expression and activation of Stat3, and an altered expression of apoptosis-related genes Harakiri, Bcl-2 and Mcl-1. In a drug library screening, Stat1 over-expression was associated with an increased sensitivity to Fas-induced apoptosis and, conversely, an increased resistance to several drugs, including the cyclin dependent kinase (cdk)1 inhibitor CGP74514A. We conclude that Stat1 over-expression does not confer a general resistance or sensitivity to apoptosis in MM, but may strongly affect the response to some specific drugs.We also explored the effects of picropodophyllin (PPP), an inhibitor of the insulin-like growth factor I (IGF-I) receptor tyrosine kinase (RTK), in MM. PPP selectively inhibited the IGF-I RTK activity without inhibiting the insulin RTK activity. Furthermore, PPP potently induced cell cycle arrest and apoptosis in all MM cell lines and patient samples tested, also in the presence of survival factors IGF-I and IL-6. We conclude that PPP has great therapeutic potential in MM Finally, we examined the expression and regulation of the inhibitors of apoptosis proteins (IAPs) in a panel of MM cell lines and patient samples. The glucocorticoid dexamethasone, which is used in MM therapy, induced a transient up-regulation and a subsequent down-regulation of c-IAP2, as well as a down-regulation of XIAP, possibly influencing the sensitivity to apoptosis induced by this drug. Supporting this notion, abrogation of IGF-IR signaling by PPP, which sensitizes MM cells to dexamethasone-induced apoptosis, enhanced the down-regulation of c-IAP2 and XIAP.
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| 5. |
- Henriksson, Marie
(författare)
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Importance of MAPK and PKC in cerebrovascular endothelin receptor changes
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endothelin is a vasoactive peptide that exerts its effect through two receptors; the endothelin type A (ETA) and type B (ETB) receptor. The contractile ETA receptor is localized on smooth muscle cells in the vascular wall, while the ETB receptors are mainly situated on endothelial cells, mediating vasodilatation. The endothelin system is involved in several pathophysiological conditions, such as atherosclerosis and ischemic stroke. Previous studies have shown an upregulation of contractile ETB receptors in the ipsilateral middle cerebral artery (MCA) after experimental focal ischemia and a similar upregulation is also seen after organ culture of MCA. Furthermore, studies have shown an involvement of protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) 1/2 in ischemia. The aim of this thesis was to further elucidate the mechanisms underlying this receptor upregulation process, both in experimental ischemia and in organ culture of rat MCA. The results from the organ culture studies (paper I-III) show that the ETB receptor upregulation is time-dependent, reaching a maximum after 24 hours of organ culture. By adding inhibitors of PKC and ERK1/2 pathways to the culture medium, the ETB receptor upregulation was attenuated. In the experimental model of ischemia (paper IV-V), we administered PKC and ERK1/2 inhibitors to the rats in conjuction with the ischemic insult. Both inhibitors diminished the ETB receptor responses, as well as decreasing brain damage and improving neurological function. In conclusion, the results of this thesis may provide a new perspective on possible mechanisms of actions of PKC and ERK in cerebral ischemia.
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| 7. |
- Henriksson, Marie, et al.
(författare)
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MEK1/2 inhibition attenuates vascular ET(A) and ET (B) receptor alterations after cerebral ischaemia.
- 2007
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 178:4, s. 470-476
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.
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| 8. |
- Henriksson, Marie, et al.
(författare)
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Protein kinase C inhibition attenuates vascular ETB receptor upregulation and decreases brain damage after cerebral ischemia in rat.
- 2007
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 8, s. 7-7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Protein kinase C (PKC) is known to be involved in the pathophysiology of experimental cerebral ischemia. We have previously shown that after transient middle cerebral artery occlusion, there is an upregulation of endothelin receptors in the ipsilateral middle cerebral artery. The present study aimed to examine the effect of the PKC inhibitor Ro-32-0432 on endothelin receptor upregulation, infarct volume and neurology outcome after middle cerebral artery occlusion in rat. Results: At 24 hours after transient middle cerebral artery occlusion (MCAO), the contractile endothelin B receptor mediated response and the endothelin B receptor protein expression were upregulated in the ipsilateral but not the contralateral middle cerebral artery. In Ro-32-0432 treated rats, the upregulated endothelin receptor response was attenuated. Furthermore, Ro-32-0432 treatment decreased the ischemic brain damage significantly and improved neurological scores. Immunohistochemistry showed fainter staining of endothelin B receptor protein in the smooth muscle cells of the ipsilateral middle cerebral artery of Ro-32-0432 treated rats compared to control. Conclusion: The results suggest that treatment with Ro-32-0432 in ischemic stroke decreases the ischemic infarction area, neurological symptoms and associated endothelin B receptor upregulation. This provides a new perspective on possible mechanisms of actions of PKC inhibition in cerebral ischemia.
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| 10. |
- Hogh, Annie, et al.
(författare)
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A 5-year follow-up study of aggression at work and psychological health
- 2005
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Ingår i: International Journal of Behavioral Medicine. - : Lawrence Erlbaum Associates. - 1070-5503 .- 1532-7558. ; 12:4, s. 256-265
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Tidskriftsartikel (refereegranskat)abstract
- In a longitudinal cohort study, organizational climate and long-term effects of exposure to nasty teasing (aggression) at work were investigated. The baseline consisted of a representative sample of Danish employees in 1995 with a response rate of 80% (N = 5,652). Of these, 4,647 participated in the follow-up in 2000 (response rate 84%). In 1995, 6.3% were subjected to nasty teasing with no significant gender difference. At baseline, we found significant associations among nasty teasing, a negative organizational climate, and psychological health effects. In the follow-up analyses, associations were found between exposure to nasty teasing at baseline and psychological health problems at follow-up, even when controlled for organizational climate and psychological health at baseline and nasty teasing at follow-up. Stratified for gender, the follow-up associations were significant for women but not for men. Low coworker support and conflicts at baseline and teasing at follow-up mediated the effects on men. Key words: bullying, fatigue, gender differences, longitudinal study, mental health, teasing
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| 11. |
- Iresjö, Britt-Marie, 1963, et al.
(författare)
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Appearance of individual amino acid concentrations in arterial blood during steady-state infusions of different amino acid formulations to ICU patients in support of whole-body protein metabolism
- 2006
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Ingår i: JPEN. - 0148-6071. ; 30:4, s. 277-85
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous work has demonstrated a relationship between arterial amino acid concentrations and uptake of amino acids across peripheral tissues in healthy volunteers, as well as in chronically and acutely ill patients. The aim of the present study was to evaluate whether different amino acid profiles in commercially available amino acid formulations are translated into significantly different arterial amino acid concentrations presumably high enough to promote protein metabolism in intensive care unit (ICU) patients. METHODS: Nonprotein calories (60% glucose: 40% lipid) were simultaneously and constantly infused over 72 hours. Different free amino acid solutions were infused at random to each patient for 24 hours in order to determine the appearance of steady-state arterial concentrations of individual amino acids. Basal metabolic and nutrition states were defined after a 12-hour infusion period with glucose in each patient. Healthy volunteers receiving a standardized oral meal served as reference subjects in measurements of venous amino acid concentrations after normal oral food intake. RESULTS: The sum of all amino acids in arterial plasma increased significantly during steady-state infusions of all the free amino acid solutions vs basal state in ICU patients. Only glutamine, taurine, and tyrosine did not increase at all vs basal state during steady-state infusions of the 3 formulations. Alanine, arginine, citrulline, glycine, histidine, serine, methionine, phenylalanine, valine, and ornithine showed different concentration among the amino acid solutions during infusions. Healthy volunteers had significantly higher overall concentrations of amino acids in both fasted and fed state compared with ICU patients, which indicates that free amino acid solutions remain a limiting component in artificial nutrition to patients to promote arterial amino acid concentrations in the artificially fed state. CONCLUSIONS: It appears important to continue further improvement of composition profile in solutions of free amino acids to promote adequate uptake across organ beds in promotion of protein balance in artificially nourished patients.
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| 14. |
- Piens, Kathleen, et al.
(författare)
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Glycosynthase activity of hybrid aspen xyloglucan endo-transglycosylase PttXET16-34 nucleophile mutants
- 2007
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Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 5:24
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Tidskriftsartikel (refereegranskat)abstract
- Glycosynthases are active-site mutants of glycoside hydrolases that catalyse glycosyl transfer using suitable activated donor substrates without competing product hydrolysis ( S. M. Hancock, M. D. Vaughan and S. G. Withers, Curr. Opin. Chem. Biol., 2006, 10, 509-519). Site-directed mutagenesis of the catalytic nucleophile, Glu-85, of a Populus tremula x tremuloides xyloglucan endo-transglycosylase (PttXET16-34, EC 2.4.1.207) into alanine, glycine, and serine yielded enzymes with glycosynthase activity. Product analysis indicated that PttXET16-34 E85A in particular was able to catalyse regio- and stereospecific homo- and hetero- condensations of alpha-xylogluco-oligosaccharyl fluoride donors XXXG alpha F andXLLG alpha F to produce xyloglucans with regular sidechain substitution patterns. This substrate promiscuity contrasts that of the Humicola insolens Ce17B E197A glycosynthase, which was not able to polymerise the di-galactosylated substrate XLLG alpha F. The production of the PttXET16-34 E85A xyloglucosynthase thus expands the repertoire of glycosynthases to include those capable of synthesising structurally homogenenous xyloglucans
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| 16. |
- Shete, Sanjay, et al.
(författare)
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Genome-wide association study identifies five susceptibility loci for glioma.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:8, s. 899-904
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Tidskriftsartikel (refereegranskat)abstract
- To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.
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| 18. |
- Stenman, Emelie, et al.
(författare)
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Cooperative effect of angiotensin AT, and endothelin ETA receptor antagonism limits the brain damage after ischemic stroke in rat
- 2007
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 570:1-3, s. 142-148
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral ischemia results in enhanced expression of smooth muscle cell endothelin and angiotensin receptors in cerebral arteries. We hypothesise that this phenomenon may be detrimental and that acute treatment with a combined non-hypotensive dose of the angiotensin AT, receptor inhibitor candesartan and the endothelin ETA receptor antagonist ZD 1611 reduces the infarct in experimental ischemic stroke. Transient middle cerebral artery occlusion was induced in male Wistar rats by the intraluminal filament technique for 2 h followed by recirculation. The animals received systemic candesartan (0.05 mg/kg/day), ZD1611 (0.15 mg/kg/day), both combined or vehicle with start immediately after the occlusion. After 48 h the rats were sacrificed, the brains sliced and stained with 1% 2, 3, 5-triphenyltetrazolium chloride (TTC) and the volume of ischemic damage determined. The middle cerebral arteries were harvested for immunocytochemical studies of angiotensin AT, and endothelin ETA receptor expression. Candesartan or ZD1611 did alone not significantly decrease the brain damage or improve neurological scores as compared to vehicle controls. The combined inhibition of angiotensin AT, and endothelin ETA receptors however decreased the brain damage and improved the neurological scores (both P < 0.05). The treatment did not change resting mean arterial blood pressure. In addition, there was an upregulation of angiotensin AT, receptors in the ischemic middle cerebral artery smooth muscle cells, which was normalised by the combined treatment. In conclusion, the present study shows that combined inhibition of angiotensin AT, and endothelin ETA receptors reduces the brain damage and improves the neurological outcome after ischemic stroke in rat. (c) 2007 Elsevier B.V. All rights reserved.
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| 20. |
- Sundström, Anna, 1979-
(författare)
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Developing and validating self-report instruments : assessing perceived driver competence
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to develop and validate a self-report instrument for perceived driver competence. The thesis includes six papers and a summary. All papers focus on perceived driver competence from a measurement perspective; that is, how to develop an instrument for perceived driver competence and how to use and interpret the scores from the instrument in a reliable and valid manner.Study I reviews how perceived driver competence has been measured in other studies and discusses these methods from a measurement perspective. Most studies have examined perceived driver competence by asking drivers to compare their own skill to that of the average driver. That method is problematic, since it is not possible to determine if drivers are overconfident or not, when empirical information of their own skills is missing. In order to examine if drivers overestimate their skills or not, perceived driver competence should be compared with actual driving performance.Study II reports on the development and psychometric evaluation of a self-report instrument for perceived driver competence - the Self-Efficacy Scale for Driver Competence (SSDC). The findings provides support for construct validity, as the SSDC demonstrated sound psychometric properties and as the internal structure of the SSDC corresponded to the theoretical model used as a basis for instrument development.In study III, the psychometric properties of the SSDC were further examined using an item response theory (IRT) model. The findings confirmed the results indicated by the classical analyses in Study II. Additional information was provided by the IRT analyses, as it was indicated that the scale would benefit from fewer scale points or by putting labels on each scale point.In study IV, Swedish and Finnish candidates’ self-assessment accuracy was examined by comparing candidates’ scores on the SSDC and a similar instrument for self-assessment of driving skill used in Finland, with driving test performance. Unlike previous studies, in which drivers compared their perceived skills to that of the average driver, a relatively large proportion made a realistic assessment of their own skills. In addition, in contrast to previous studies, no gender differences were found. These results were also confirmed in study V, where the results from the Finnish instrument for self-assessment of driving skill were compared with the results from a similar instrument used in the Netherlands.Study VI further examined the construct validity of a revised version of the SSDC, combining qualitative and quantitative sources of evidence. There was a strong relationship between the SSDC and an instrument for self-assessment of driving skills, providing support for convergent validity. No relationship was found between the SSDC and driving test performance. Explanations of the lack of relationship were provided from semi-structured interviews, as they indicated that confidence in performing different tasks in the test are different from being confident of passing the test, and that the candidates are familiar neither with assessing their own skills nor with the requirements for passing the test.In conclusion, the results from this thesis indicated that the choice of methods for assessing perceived driver competence as well as the quality of these methods affect the validity. The results provided support for different aspects of construct validity of the SSDC. Moreover, the findings illustrated the benefits of combining different methods in test validation, as each method contributed information about the validity of the SSDC. The studies in this thesis mainly examined internal and external aspects of construct validity. Future studies should examine procedural validity of the SSDC.
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| 21. |
- Sundström, Anna, 1979-, et al.
(författare)
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"Ett givet inslag i förarutbildningen" : Umeå universitet försvarar självvärderingen
- 2008
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Ingår i: Mitt i trafiken. - Landskrona : Sveriges Trafikskolors Riksförbund. ; :1, s. 33-33
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Sammanfattningsvis framstår det som en självklarhet att självvärdering ska vara ett inslag i såväl förarutbildning som förarprov eftersom det utgör en väsentlig del i den nya kursplanen. Det står också klart att många vinster, både för lärandet och trafiksäkerheten, kan göras genom att införa självvärdering i utbildningen. Nästa steg är att diskutera hur detta ska genomföras i praktiken genom att finna sätt för hur självvärdering ska användas både i utbildning och i förarprov.
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| 22. |
- Vikman, Petter, et al.
(författare)
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Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries.
- 2007
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 183:4, s. 499-510
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral ischemia results in a local inflammatory response that contributes to the size of the lesion, however, the involvement of the cerebral vasculature is unknown. We hypothesise that the expression of inflammatory genes (Il6, iNOS, cxcl2, TNF-α and Il-1β) and extracellular-matrix-related genes (MMP9, MMP13) is induced in cerebral arteries following cerebral ischemia via activation of mitogen activated kinases (MAPKs). This hypothesis was tested in vivo by experimental subarachnoid haemorrhage (SAH) and temporal middle cerebral artery occlusion (MCAO), and by organ culture of isolated cerebral arteries with quantitative real time PCR (mRNA expression) and immunohistochemistry (localization of protein expression). The gene promoters were investigated in silica with computer analysis. The mRNA analysis revealed that the ischemic models, SAH and MCAO, as well as organ culture of isolated cerebral arteries resulted in transcriptional upregulation of the abovementioned genes. The protein expression involved phosphorylation of three different MAPKs signalling pathways (p38, ERK 1/2 and SAPK/JNK) and the downstream transcription factors (ATF-2, Elk-1, c-Jun) shown by immunohistochemistry and quantified by image analysis. All three models revealed the same pattern of activation in the cerebrovascular smooth muscle cells. The in silica analysis demonstrated binding sites for said transcription factors. The results suggest that cerebral ischemia and organ culture induce activation of p38, ERK 1/2 and SAPK/JNK in cerebral arteries which in turn activate the transcription factors ATF-2, Elk-1 and c-Jun and the expression of inflammatory and extracellular-matrix-related genes in the wall of cerebral arteries.
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