| 1. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells
- 2013
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Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylation of receptor tyrosine kinases (RTKs) has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL). Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38) applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature) and glycosylated (mature) ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03). The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa) isoform was significantly higher in progressive than in non-progressive disease (p<0.001). Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.
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| 2. |
- Holmberg, Lars, et al.
(författare)
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National comparisons of lung cancer survival in England, Norway and Sweden 2001-2004 : differences occur early in follow-up
- 2010
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 65:5, s. 436-441
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Countries with a similar expenditure on healthcare within Europe exhibit differences in lung cancer survival. Survival in lung cancer was studied in 2001-2004 in England, Norway and Sweden. METHODS Nationwide cancer registries in England, Norway and Sweden were used to identify 250 828 patients with lung cancer from England, 18 386 from Norway and 24 886 from Sweden diagnosed between 1996 and 2004, after exclusion of patients registered through death certificate only or with missing, zero or negative survival times. 5-Year relative survival was calculated by application of the period approach. The excess mortality between the countries was compared using a Poisson regression model. RESULTS In all subcategories of age, sex and follow-up period, the 5-year survival was lower in England than in Norway and Sweden. The age-standardised survival estimates were 6.5%, 9.3% and 11.3% for men and 8.4%, 13.5% and 15.9% for women in the respective countries in 2001-2004. The difference in excess risk of dying between the countries was predominantly confined to the first year of follow-up. The relative excess risk ratio during the first 3 months of follow-up comparing England with Norway 2001-2004 varied between 1.23 and 1.46, depending on sex and age, and between 1.56 and 1.91 comparing England with Sweden. CONCLUSION Access to healthcare and population awareness are likely to be major reasons for the differences, but it cannot be excluded that diagnostic and therapeutic activity play a role. Future improvements in lung cancer management may be seen early in follow-up.
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| 3. |
- Möller, Henrik, et al.
(författare)
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Breast cancer survival in England, Norway and Sweden : a population-based comparison
- 2010
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 127:11, s. 2630-2638
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Tidskriftsartikel (refereegranskat)abstract
- Several international studies have found that survival from breast cancer is lower in the United Kingdom than in some other European countries. We have compared breast cancer survival between the national populations of England, Norway and Sweden, with a view to identifying subsets of patients with particularly good or adverse survival outcomes. We extracted cases of breast cancer in women diagnosed 1996-2004 from the national cancer registries of the 3 countries. The study comprised 303,657 English cases, 24,919 Norwegian cases and 57,512 cases from Sweden. Follow-up was in 2001-2004. The main outcome measures were 5-year cumulative relative survival and excess death rates, stratified by age and period of follow-up. In comparison with Norway and Sweden, the excess mortality in England was particularly pronounced in the first month and in the first year after diagnosis, and generally more marked in the oldest age groups. Compared with Norwegian patients, 81% of the excess deaths in the English patients occurred in the first 2 years after diagnosis. Our findings emphasise the importance of awareness of symptoms and early detection as the main strategy to improve breast cancer survival in the United Kingdom.
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| 4. |
- Pettersson, Åsa
(författare)
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TV FOR CHILDREN : How the Swedish Public Service Television Imagines a Child Audience
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The study explores how the Swedish public service TV institution imagines a child audience in a societal context where the broadcasting landscape hastransformed greatly over the past thirty years and where TV is seen to constitute both risks and benefits for children. The concept of TV for children is established to broaden the scope for studying what has been broadcast for a child audience on public service TV. The empirical material consists of both broadcasting policy documents and an extensive selection of public service TV programmes targeting children, selected from 1980, 1992 and 2007, which marked before, during and after the abolishment of the Swedish public service broadcasting monopoly. The policy texts, as well as TV content, TV talk and TV visuality, have been studied to investigate how the imagined child audience is configured. The study shows that when the category ‘children’ is mentioned in the broadcasting legislation, they are seen foremost as being at risk of being harmed by commercial messages and only gradually as explicitly entitled to TV programme content meant for them. The broadcasting companies, however, have broadcast programming for the child audience during the whole research period. Adult notions form how children are represented. In the TV programmes, these notions have remained largely unchanged over the studied years, even if technology, legislative demands and approaches to narration also provide opportunities for change. The imagined child TV audience configured in TV for children is knowledgeable, but wanting and in need of more knowledge. This audience is also imagined as being close to nature, eager to interact with the programmes and activate on basically all occasions, which opposes the discursive view according to which children are passivized by television. This study of public service TV for children points to and questions discursive ideas about what it means to be a child in a mediated society.
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| 5. |
- Sandin, Åsa
(författare)
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PTPs : redox controlled regulators of cell signaling and transformation
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protein tyrosine phosphatases (PTPs) are important redox regulated enzymes that control the tyrosine phosphorylation status in the cell. These studies aimed to increase the understanding on how PTPs are controlled by reversible oxidation in different pathological settings such as hypoxia and restenosis and to which extent oxidized PTPs contribute to certain diseases. Low levels of oxygen - hypoxia - can occur in tumors due to poor vascularization as well as in myocardial infarction and is associated with increased levels of reactive oxygen species (ROS). In our study we found that hypoxia followed by reoxygenation caused reversible oxidation of PTPs. This created an increased amount of inactivated PTPs and was followed by prolonged PDGF receptor activation. The hypoxia induced increase in phosphorylation lead to elevated ERK signaling as well as increased formation of cytoskeletal re-arrangements which could be inhibited by addition of the antioxidant N-acetylcysteine. Decreased phosphatase activity was also seen when analyzed in heart tissues from an ex-vivo model of rat heart exposed to ischemia-reperfusion. Atherosclerosis is a disease characterized by artery wall thickening due to a buildup of fatty materials. A common treatment is to open up the vessel with a balloon catheter and thereby increase the blood flow. A problem with this treatment is that restenosis occur after some time. Restenosis is associated with an elevated ROS production and increase in PDGFβ-receptor signaling. Using a rabbit restenosis model we could show that restenosis could be attenuated by administration of antioxidants. Tissue analysis from vessels in combination with cell culture experiments showed that the beneficial effect of antioxidant treatment was prevention of PTP inactivation. Peroxidized lipids have been found in increased amounts in several diseases with inflammatory components, like atherosclerosis and diabetes. The amounts of peroxidized lipids are tightly regulated by the glutathione peroxidase 4 (GPx4). In an inducible knock out model of GPx4 in cells we found that the rapid accumulation of peroxidized lipids caused PTP oxidation and lead to increased cell signaling. This was the first time peroxidized lipids were shown to oxidize and inactivate PTPs. PTPs are often regarded as inhibitors of cell signaling and therefore as potential tumor suppressors. SHP-2 is however, an exception and is a bona fida oncogene in which phosphatase-activating mutations have been associated with different forms of leukemia and to a smaller proportion with solid tumors. We found that PDGF-BB dependent growth of subcutaneous tumors was compromised when SHP-2 levels were repressed by shRNA. Cell culture experiments indicated that compromised Src activity and reduced ERK activation underlie the inability of these cells to form tumors.
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