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- Azimi, Alireza, et al.
(författare)
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Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors
- 2018
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines. Unbiased proteomics and phosphoproteomics analyses identified CDK2 as a driver of resistance to both BRAF and Hsp90 inhibitors and its expression is regulated by the transcription factor MITF upon XL888 treatment. The CDK2 inhibitor, dinaciclib, attenuated resistance to both classes of inhibitors and combinations thereof. Notably, we found that MITF expression correlates with CDK2 upregulation in patients; thus, dinaciclib would warrant consideration for treatment of patients unresponsive to BRAF-MEK and/or Hsp90 inhibitors and/or harboring MITF amplification/overexpression.
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- Bengtsson Boström, Kristina, et al.
(författare)
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Polymorphisms in α- And β-adrenergic receptor genes, hypertension, and obstructive sleep apnea : The skaraborg sleep study
- 2010
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Ingår i: International Journal of Hypertension. - : Hindawi Limited. - 2090-0384 .- 2090-0392. ; 2010
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Tidskriftsartikel (refereegranskat)abstract
- The sympathetic nervous system and the adrenergic receptors play an important role in regulation of blood pressure. This study explored the associations between functional polymorphisms of the α 2B -, β 1 -, and β 2 -adrenergic receptor genes and obstructive sleep apnea (OSA) in hypertensive patients and hypertension in patients with OSA in a populationbased sample of 157 hypertensive patients and 181 healthy control subjects. Only the Arg389Gly polymorphism of the β 1 -adrenergic receptor gene was associated with increased risk for mild OSA in hypertensive patients (Arg/Arg versus Gly/Arg/Gly/Gly, 2.1, 95% CI, 1.02-4.7). Hypertensive men carrying the Arg389Arg genotype had higher crude and age-adjusted AHI than carriers of the Arg389Gly/Gly389Gly genotypes. When adjusted also for BMI this difference became borderline significant. This difference was not observed in women. The risk of hypertension in mild OSA was associated with increasing number of Arg-alleles (Arg/Arg OR 5.4, 95 CI 1.4-21.2).
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- Boman, Christoffer, et al.
(författare)
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Development of innovative small(micro)-scale biomass-based CHP technologies
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- To enhance the overall efficiency of the use of biomass in the energy sector in Europe, the large electricity production potential from small-scale biomass heating systems should be utilised. So far, no technologically sound (in terms of efficiency and reliability) and economically affordable micro- and small-scale biomass CHP technologies are, however, available. Therefore, the present ERA-NET project (MiniBioCHP) aimed at the further development and test of new CHP technologies based on small-scale biomass combustion in the electric capacity range between some W and 100 kW. Within the project, an international consortium consisting of 12 partners from 4 countries, including university institutions, institutes and industry (both engineering and manufacturing), collaborated closely to perform high level R&D on three promising micro/small-scale biomass based CHP technologies which are covering a broad range of applications in the residential heating sector. The Austrian engineering company BIOS, coordinated the international project. The project was based on earlier basic research and development work related to these promising new technologies and aimed at the achievement of a technological level which allows a first (commercial) demonstration after the end of the project. The three CHP concepts included in the MiniBioCHP project were;1. Pellet stoves with a thermoelectric generator (TEG)2. Small-scale biomass boilers (10-30 kWth) with a micro-ORC process3. High temperature heat exchanger (HT-HE) for an externally fired gas turbine (EFGT)The Swedish part of the project was focused on the development of the concept of biomass based EFGT with dedicated R&D activities related to the development of the HT-HE system. The Swedish project consisted of the research partners Umeå University (project leader), Luleå University of Technology, Chalmers University of Technology and RISE Research Institutes of Sweden, together with the industrial partners Enertech AB/Osby Parca and Ecergy. The expertise of the Swedish partners regarding ash related problems, grate boiler combustion and modelling, deposit formation and high temperature corrosion, were combined with the know-how of a Polish partner regarding HT-HE design, construction, testing and optimisation.The HT-HE is the most crucial component in EFGT processes significantly influencing the investment costs, availabilities as well as the efficiencies that can be achieved. With a thermal capacity from several hundred kW up to 2-3 MWth) the CHP technology based on a biomass boiler and an EFGT is suitable for district heating systems, or process heat consumers. The electricity produced by the gas turbine (up to some 100 kWel) can be used to cover the own electricity consumption of a company and/or fed into the grid. Even though the concept of biomass based EFGT has been an interesting alternative for small-scale CHP production for some decades, and R&D activities have been undertaken, tackling both economic and technical aspects, only a few pilot-plants have been in operation and no initiative has so far reached the level of commercial implementation. Thus, the concept of EFGT fed with biomass is still considered to be in a rather early development stage and the main technical challenges are related to alkali deposit induced corrosion and thermal stress of the HT-HE material, turbine design/operation and system integration.Within the present project, a HT-HE prototype aimed for an EFGT system was therefore designed, constructed and successfully tested at flue gas temperatures up to 900°C. Thus, appropriate guidelines for a compact design of the HT-HE and recommendations have been worked out to minimize thermal stresses as well as ash related problems regarding ash deposit formation and high temperature corrosion in a biomass boiler system. Furthermore, different concepts for the overall biomass based EFGT system have been worked out and evaluated. The outcome of the project will hopefully be used in the further development work and form the basis for a first testing and demonstration plant within the coming years.
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- Boström, Fredrik, et al.
(författare)
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Cerebrospinal fluid total tau is associated with shorter survival in dementia with Lewy bodies.
- 2009
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 28:4, s. 314-9
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Tidskriftsartikel (refereegranskat)abstract
- A pathology typical of dementia with Lewy bodies (DLB) has been demonstrated to increase mortality to a greater extent than the pathology of Alzheimer's disease (AD). However, mortality in DLB has also been shown to increase with concomitant AD pathology. Furthermore, in a recent publication, we showed that there is a robust and specific increase in CSF calcium and magnesium in DLB patients compared to both AD patients and controls. Thus, in order to explore the influence of CSF AD markers and trace element concentrations on mortality in DLB, we undertook a longitudinal prospective study of 47 clinically diagnosed DLB patients and 157 AD patients as well as 49 healthy volunteers. Both AD and DLB patients showed an increased mortality compared to the healthy controls (relative risk: 10 and 8, respectively; p < 0.001). Increased levels of CSF total tau were associated with increased mortality among the DLB patients (p < 0.05), but not among the AD patients or controls. Gender, age, MMSE score, Abeta42 concentration and phosphorylated tau, and CSF trace element concentrations did not influence survival in the obtained models.
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- Boström, Fredrik, et al.
(författare)
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CSF Mg and Ca as diagnostic markers for dementia with Lewy bodies.
- 2008
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:8, s. 1265-1271
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence implicates a role for altered metal homeostasis in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, few investigations have addressed this issue in dementia with Lewy bodies (DLB). The aim of the present study was to investigate metal concentrations in cerebrospinal fluid (CSF) and plasma from patients with DLB and other neurodegenerative disorders. To that end, CSF and plasma samples were collected from 29 patients with DLB, 174 patients with AD, 90 patients with AD with minor vascular components, and 51 healthy volunteers. Total concentrations of Mg, Ca, Mn, Fe, Cu, Zn, Rb, Sr, and Cs were determined using mass spectrometry. Patients with DLB had elevated Ca and Mg levels in CSF and Mg levels in plasma as compared to all other groups (p<0.001). Furthermore, a combination of CSF-Mg and CSF-Ca could distinguish DLB from AD with a sensitivity of 93% and a specificity of 85%. Cu levels in both CSF and plasma tended to be higher in DLB compared to the other groups, but these trends failed to reach significance after correction for multiple comparisons. Mn, Fe, Zn, Rb, and Sr concentration in CSF or plasma were similar in all groups. The observed elevations of CSF-Mg, CSF-Ca and CSF-Cu may contribute to or be associated with the neurodegenerative process in DLB. Furthermore, determination of CSF-Mg and CSF-Ca concentration may be a valuable tool in distinguishing DLB from AD.
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| 9. |
- Boström, Fredrik
(författare)
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Dementia with Lewy bodies —an Investigation of Cause and Consequence
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dementia with Lewy bodies (DLB) is today considered to be the second most common primary neurodegenerative dementia after Alzheimer’s disease. However, the disease has only been a clearly defined entity for 13 years. Due to its recent recognition, DLB is still not as extensively studied as are other major dementia disorders such as Alzheimer’s disease (AD), vascular dementia, and fronto-temporal dementia. In summary, this thesis demonstrates important differences between AD and DLB. Paper I and II focus on the ultimate consequences of the disease, including resource consumption and impact on quality of life, and demonstrate much more severe consequences of DLB. Paper III and IV focus on diagnosis and prediction of disease progression through CSF analysis, and demonstrate a robust increase of CSF Ca and Mg in DLB but not in AD. Furthermore, CSF t-tau, a marker of AD and neurodegeneration, is demonstrated to increase mortality in DLB, but not in AD. These DLB specific CSF findings give us further understanding of the factors that may trigger the disease and determine disease course. Furthermore, CSF Mg and Ca may be a valuable tool in making a DLB diagnosis, especially when the considered differential diagnosis is AD.
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