| 1. |
- Mume, Eskender, et al.
(författare)
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Evaluation of ((4-Hydroxyphenyl)ethyl)maleimide for Site-Specific Radiobromination of Anti-HER2 Affibody
- 2005
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 16:6, s. 1547-1555
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are a new class of small phage-display selected proteins using a scaffold domain of the bacterial receptor protein A. They can be selected for specific binding to a large variety of protein targets. An affibody molecule binidng with high affinity to a tumor antigen HER2 was recently developed for radionuclide diagnostics and therapy in vivo. The use of hte positron-emitting nuclide 76Br(T½ = 16.2 h) could imporve the sensitivity of detection of HER2-expressing tumors. A site-specific radiobromination o fa cysteine-containing variant of the anti-HER2 affibody, (ZHER2:4)2-Cys, using ((4-hydroxpyphenyl)ethyl)maleimide (HPEM), was evaluated in this study. It was found that HPEM can be radiobrominated with an efficiency of 83+0.4% and thereafter coupled to freshly reduced conjugate to exceed 97%. The label was stable against challenge with large excess of nonlabeled bromide and in a high molar strengt solution. In vitro cell tests demonstraded that radiobrominated affibody binds specifically to the HER2-expressing cel-line, SK-OV-3. Biodistribution studies in nude mice bearing SK-OV-3 xenografts have shown tumor accumulation of 4.8 ? 2.2% IA/g and good tumor-to-normal tissue ratios.
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| 2. |
- Sjöberg, Andreas P., et al.
(författare)
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Native, amyloid fibrils and β-oligomers of the C-terminal domain of human prion protein display differential activation of complement and bind C1q, factor H and C4b-binding protein directly
- 2008
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 45:11, s. 3213-3221
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Tidskriftsartikel (refereegranskat)abstract
- Prion protein (PrP) is an endogenous protein involved in the pathogenesis of bovine spongiform encephalopathy and Creutzfeldt–Jakob disease. Murine PrP has been reported to bind C1q and activate the classical pathway of complement in a copper-dependent manner. Here we show that various conformational isoforms (native, amyloid fibrils, and β-oligomers) of recombinant human PrP (90–231 and 121–231) bind C1q and activate complement. PrP binds both the globular head and collagenous stalk domains of C1q. Native, β-oligomeric and amyloid fibrils of PrP all activate the classical and alternative pathways of complement to different extent. However, they do not trigger the lectin pathway. Of the tested PrP conformational isoforms we find that β-oligomers bind C1q and activate complement most strongly. Membrane attack complex formation initiated by PrP is subdued in comparison to deposition of early complement components. This is most likely attributed to the interaction between human PrP and complement inhibitors factor H and C4b-binding protein. Accordingly, PrP-triggered complement activation in the terminal pathway was increased in serum lacking C4b-binding protein. Taken together the present study indicates that complement activation may be an important factor in human prion diseases, suggesting that complement induced activities may prove relevant therapeutic targets.
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| 3. |
- Sjöberg, Karin, et al.
(författare)
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Quantification of population exposure to nitrogen dioxide in Sweden 2005
- 2007
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Sweden is one of the countries in Europe which experiences the lowest concentrations of air pollutants in urban areas. However, the health impact of exposure to ambient air pollution is still an important issue in the country and the concentration levels, especially of nitrogen dioxide (NO 2) and particles (PM10,) exceed the air quality standards and health effects of exposure to air pollutants in many areas.IVL Swedish Environmental Research Institute and the Department of Public Health and Clinical Medicine at Umeå University have, on behalf of the Swedish EPA and the health-related environmental monitoring programme, performed a health impact assessment (HIA) for the year 2005. The population exposure to NO 2 in ambient air has been quantified (annual and daily mean concentrations) and the health and associated economical consequences have been calculated based on these results.The results from the urban modelling show that in 2005 most of the country had low NO 2 urban background concentrations compared to the environmental standard for the annual mean (40 μg/m3). In most of the small to medium sized cities the NO2 concentration was less than 15 μg/m3 in the city centre. In the larger cities and along the Skåne west coast the concentrations were higher, up to 20-25 μg/m3, which is of the same magnitude as the long-term environmental objective (20 μg/m3 as an annual mean).Almost 50% of the population were exposed to annual mean NO 2 concentrations of less than 5 μg/m3. A further 30% were exposed to concentration levels between 5-10 μg NO2/m3, and only about 5% of the Swedish inhabitants experienced exposure levels above 15 NO2 μg/m3.The health impact calculation has four components: a relevant effect estimate from epidemiologic data, a baseline rate for the health effect, the affected number of persons and their estimated "exposure" (here pollutant concentration). We have used 10 μg/m 3 as a lower cut off in our impact assessment scenarios for long-term exposure and mortality as well as in the assessment of short-term effects on hospital admissions. Exposure above 10 μg/m3 is therefore defined as excess exposure resulting in "excess cases".For our mortality assessment we have chosen to use the same estimate as in our previous similar HIA. The estimate came from a study in Auckland, and was 13% (95% CI: 11–15%) increase in non-external mortality per 10 μg/m3 increase in annual average NO2. This estimate is similar to what has been reported in some other referenced studies.For respiratory hospital admissions we have used the risk estimates from a Norwegian study reporting a relative risk of 2.9% per 10 μg/m3. For cardiovascular hospital admissions we have used a meta-analysis presented by an expert group in UK, assuming a relative risk of 1.0 % per 10 μg/m3 in the health impact assessment.Altogether we estimate that concentations of NO2 in urban air resulted in more than 3200 excess deaths per year. Almost 600 of these could have been avoided if annual mean concentrations above the environmental goal 20 μg/m3 did not exist. Most excess deaths are estimated to occur due to annual levels in the range of 10-15 μg/m3. We have crudely estimated the average years of life lost per excess death to be just over 11 years. In addition we estimated more than 300 excess hospital admissions for all respiratory disease and almost 300 excess hospital admissions for cardiovascular disease due to the short-term effect of levels above 10 μg/m3.The health effects related to high concentrations of NO 2 in ambient air are related to socio-economic costs, as are the costs for abating these high concentrations. It is important for decision 2 Quantification of population exposure to nitrogen dioxide IVL report B 1749 makers to use their economic resources in an efficient manner, which furthermore induces the need for assessments of what can be considered as an efficient use of resources. The socio-economic costs related to high levels of NO 2 in air are derived from the cost estimates of resources required for treatment of affected persons, productivity losses from work absence and most prominently from studies on the social Willingness To Pay for the prevention of health effects related to these high levels of NO2.In our study we have applied results from international socio-economic valuation studies to our calculated results on increased occurrences of hospital admissions and fatalities. The values from the studies have been adapted to Swedish conditions. The application of international results favours comparison with other estimates on economic valuation of health effects related to high levels of NO 2.The results suggest that the health effects related to annual mean levels of NO 2 higher than 10 μg / m3 can be valued to annual socio-economic costs of 18.5 billion Swedish crowns. These 18.5 billion Swedish crowns are to be considered as welfare losses. However, only 18 % of these costs are related to exceedance of the Swedish long term environmental objectives for NO2. The other 82 % of the costs are taken by the larger part of the Swedish population that are exposed to medium levels of NO2. This displacement in the distribution of the social costs indicates that the most cost effective abatement strategy for Sweden might be to reduce medium annual levels of NO2 rather than only focusing on abatement measures directed towards the highest annual mean levels.The trend analysis between 1990 and 2005 clearly shows an increasing number of people exposed to lower NO 2 concentration levels. Comparing 2005 with 1990, about 15% less people were exposed to annual mean NO2 levels above 15 μg/m3, while almost 20% more people were exposed to annual mean NO2 levels in the lowest concentration class, 0-5 μg/m3.In general, the improved URBAN model shows good performance. When using the actual weather instead of the normal weather the variability in air pollution concentrations governed by the meteorology is captured when applying the rather fine scaled meteorology. The difference between measurements and the calculated concentrations is less than 10%. It was determined that the use of normal year meteorology lead to much greater uncertainties and this method was therefore rejected.The comparison between the URBAN model and detailed calculations on a regional scale shows a good agreement as regards the annual mean concentrations. For concentrations above the cut off level used in the exposure studies (10 μg/m 3) the agreement between the two calculation methods lies within 5%. On the local scale the population weighted annual means correlate very well with the URBAN model calculations in Göteborg and Uppsala. For Umeå there are larger differences. The comparison of the number of people exposed to different concentration levels corresponds quite well (within 15%) in Göteborg, but the differences are larger in the two other cities (up to 45%). This may be due to uncertainties in the concentration distribution pattern.There are still a number of issues that can further improve the certainty of the calculations, i.e. the selection of population data to be used as well as application of relevant geographical areas and best degree of resolution to fit with the most valid epidemiological ER-functions. By increasing the asseessment frequency it is possible to minimize the uncertainties due to meteorological variations. Furthermore, the differences in exposure on the local level could be reduced if existing local dispersion concentration calculations were applied into the model.
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| 4. |
- Sjöberg, Karin, et al.
(författare)
-
Quantification of population exposure to nitrogen dioxide in Sweden 2005
- 2007
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The population exposure to NO2 in ambient air for the year 2005 has been quantified (annual and daily mean concentrations) and the health and associated economical consequences have been calculated based on these results. Almost 50% of the population were exposed to annual mean NO2 concentrations of less than 5 µg/m3. A further 30% were exposed to concentration levels between 5-10 µg NO2/m3, and only about 5% of the Swedish inhabitants experienced exposure levels above 15 NO2 µg/m3. Using 10 µg/m3 as a lower cut off for long-term exposure we estimate that concentations of NO2 in urban air resulted in more than 3200 excess deaths per year. Almost 600 of these could have been avoided if annual mean concentrations above the environmental goal 20 µg/m3 did not exist. Most excess deaths are estimated to occur due to annual levels in the range of 10-15 µg/m3. In addition we estimated more than 300 excess hospital admissions for all respiratory disease and almost 300 excess hospital admissions for cardiovascular disease due to the short-term effect of levels above 10 µg/m3. The results suggest that the health effects related to annual mean levels of NO2 higher than 10 µg/m3 can be valued to annual socio-economic costs of 18.5 billion Swedish crowns. These 18.5 billion Swedish crowns are to be considered as welfare losses. However, only 18 % of these costs are related to exceedance of the Swedish long term environmental objectives for NO2. The other 82 % of the costs are taken by the larger part of the Swedish population that are exposed to medium levels of NO2. This displacement in the distribution of the social costs indicates that the most cost effective abatement strategy for Sweden might be to reduce medium annual levels of NO2 rather than only focusing on abatement measures directed towards the highest annual mean levels.
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| 5. |
- Sjöberg, Karin, et al.
(författare)
-
Quantification of population exposure to PM2.5 and PM10 in Sweden 2005
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The population exposure to PM2.5 and PM10 in ambient air for the year 2005 has been quantified (annualand daily mean concentrations) and the health and associated economic consequences have beencalculated based on these results. The PM10 urban background concentrations are found to be ratherlow compared to the environmental standard for the annual mean (40 μg/m3) in most of the country.However, in some parts, mainly in southern Sweden, the concentrations were of the same magnitude asthe environmental objective (20 μg/m3 as an annual mean) for the year 2010. The majority of people,90%, were exposed to annual mean concentrations of PM10 less than 20 μg/m3. Less than 1% of theSwedish inhabitants experienced exposure levels of PM10 above 25 μg/m3. The urban backgroundconcentrations of PM2.5 were in the same order of magnitude as the environmental objective (12 μg/m3as an annual mean for the year 2010) in quite a large part of the country. About 50% of the populationwas exposed to PM2.5 annual mean concentrations less than 10 μg/m3, while less than 2% experiencedlevels above 15 μg/m3.Using a cut off at 5 μg/m3 of PM10 as the annual mean (roughly excluding natural PM) and sourcespecific ER-functions, we estimate approximately 3 400 premature deaths per year. Together with1 300 - 1 400 new cases of chronic bronchitis, around 1 400 hospital admissions and some 4.5-5 millionRADs, the societal cost for health impacts is estimated at approximately 26 billion SEK per year. ForPM2.5 we estimate somewhat lower numbers, approximately 3 100 premature deaths per year.The results suggest that the health effects related to high annual mean levels of PM can be valued toannual socio-economic costs (welfare losses) of ~26 billion Swedish crowns (SEK) during 2005.Approximately 1.4 of these 26 billion SEK consist of productivity losses for society. Furthermore, theamount of working and studying days lost constitutes some ~0.1% of the total amount of working andstudying days in Sweden during 2005.
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