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| 3. |
- Jevnikar, Z., et al.
(author)
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
- 2019
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 577-590
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Journal article (peer-reviewed)abstract
- Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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| 4. |
- Al-Khalili, L, et al.
(author)
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Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes
- 2014
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In: American journal of physiology. Cell physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 307:9, s. C774-C787
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Journal article (peer-reviewed)abstract
- Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system.
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- Mikus, MS, et al.
(author)
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Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
- 2022
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In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 59:2
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Journal article (peer-reviewed)abstract
- Asthma phenotyping requires novel biomarker discovery.ObjectivesTo identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs).MethodsAn antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED.ResultsIn U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.ConclusionsThe plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.
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- Jadersten, M., et al.
(author)
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Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
- 2022
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 292:6, s. 925-940
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Journal article (peer-reviewed)abstract
- Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission. Conclusion Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study.
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| 12. |
- Brahme, A., et al.
(author)
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Evaluation of a GEM and CAT-based detector for radiation therapy beam monitoring
- 2000
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In: Nuclear Instruments and Methods in Physics Research Section A. - 0168-9002 .- 1872-9576. ; 454, s. 136-141
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Journal article (peer-reviewed)abstract
- We are developing a radiation therapy beam monitor for the Karolinska Institute. This monitor will consist of two consecutive detectors confined in one gas chamber: a keV-photon detector, which will allow diagnostic quality visualization of the patient, and a MeV-photon detector, that will measure the absolute intensity of the therapy beam and its position with respect to the patient. Both detectors are based on highly radiation resistant gas and solid photon to electron converters, combined with GEMs and a CAT as amplification structures. We have performed systematic studies of the high-rate characteristics of the GEM and the CAT, as well as tested the electron transfer through these electron multipliers and various types of converters. The tests show that the GEM and the CAT satisfy all requirements for the beam monitoring system. As a result of these studies we successfully developed and tested a full section of the beam monitor equipped with a MeV-photon converter placed between the GEM and the CAT.
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| 17. |
- HUDNER, J, et al.
(author)
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PREPARATION OF YBA2CU3O7-X FILMS AND YBA2CU3O7-X/Y2O3 MULTILAYERS USING COEVAPORATION AND ATOMIC OXYGEN
- 1993
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In: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 73, s. 3096-3098
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Journal article (peer-reviewed)abstract
- Thin layers of YBa2Cu3O7-x (YBCO) deposited on LaAlO3 substrates have been prepared in situ by coevaporation of Y, Ba, and Cu. Incorporation of oxygen was accomplished by an atomic oxygen beam source with high cracking efficiency. The total oxygen flow at the substrate could be kept low enough to permit the use of a quadrupole mass spectrometer for evaporation rate monitoring. Films were strongly c-axis oriented with rocking curve full width at half-maximum values of 0.6-degrees. Transport measurements on patterned films yielded critical current densities of 6 x 10(6) A/cm2 at 77 K. The deposition method was demonstrated to be feasible for preparation of Y2O3/YBCO heterostructures.
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| 18. |
- Iacobaeus, C., et al.
(author)
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A high position resolution X-ray detector : An Edge on illuminated capillary plate combined with a gas amplification structure
- 2006
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In: IEEE Transactions on Nuclear Science. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9499 .- 1558-1578. ; 53:2, s. 554-561
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Journal article (peer-reviewed)abstract
- We have developed and successfully tested a prototype of a new high position resolution hybrid X-ray detector. It contains a thin-wall lead glass capillary plate converter of X-rays combined with a microgap parallel-plate avalanche chamber operating in various gas mixtures at 1 atm. The operation of these converters was studied in a wide range of X-ray energies (from 6 to 60 keV) at incident angles varying from 0-90 degrees. The detection efficiency, depending on the geometry, photon's energy, incident angle and the mode of operation was between 5-30% in single step mode and up to 50% in a multi-layered combination. Depending on the capillary's geometry, the position resolution achieved was between 50-250 mu m in digital form and was practically independent of the photon's energy or gas mixture. The usual lead glass capillary plates operated without noticeable charging up effects at counting rates of 50 Hz/mm(2) and hydrogen treated capillaries-up to 10(5) Hz/mm(2). The developed detector has several important potential advantages over the exciting X-ray detectors and may open new possibilities for medical imaging, for example in mammography, portal imaging, radiography (including security devices), as well as many other applications.
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| 20. |
- Iacobaeus, C., et al.
(author)
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Advances in capillary-based gaseous UV imaging detectors
- 2004
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In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 525:02-jan, s. 42-48
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Journal article (peer-reviewed)abstract
- We studied gain and position resolution of gaseous UV-photon detectors combining single- and cascaded-glass capillary-plate multipliers and CsI photocathodes. Two modes of operation were investigated: a conventional one, where the main amplification occurs within capillary holes and a parallel-plate amplification mode, where the main amplification occurs between the capillary plate and the readout anode. Results of these studies demonstrate that in the parallel-plate amplification mode one can reach both high gains (> 10(5)) and good position resolutions (similar to 100 mum) even with a single-element multiplier. This offers a compact amplification structure, which can be used in many applications.
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| 21. |
- Iacobaeus, C., et al.
(author)
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An X-ray scanner based on an "edge on" illuminated capillary plate combined with a gas amplification structure
- 2004
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In: 2004 IEEE Nuclear Science Symposium Conference Record. ; , s. 489-492
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Conference paper (peer-reviewed)abstract
- We have developed and successfully tested a prototype of a new type of high position resolution X-ray scanner. It contains a thin wall lead glass capillary plate converter of X-rays combined with a microgap parallel-plate avalanche chamber operating in various gas mixtures at 1 atm. The operation of these converters was studied in a wide range of X-ray energies (from 6 to 60 keV) at incident angles varying from 0-90°. The detection efficiency, depending on the geometry, photon's energy, incident angle and the mode of operation, was between 5-30% in a single step mode and up to 50% in a multi-layered combination. Depending on the capillary's geometry, the position resolution achieved was between 50-250 μm in digital form and was practically independent of the photon's energy or gas mixture. The usual lead glass capillary plates operated without noticeable charging up effects at counting rates of 50 Hz/mm2, and hydrogen treated capillaries up to 10 5 Hz/mm2. Finally, a prototype of the X-ray scanner based on an "edge-on" illumination capillary plate was built and tested. The developed detector open new possibilities for medical imaging, for example in mammography, portal imaging, radiography (including security devices), crystallography and many other applications.
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| 22. |
- Iacobaeus, C., et al.
(author)
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Sporadic electron jets from cathodes - The main breakdown-triggering mechanism in gaseous detectors
- 2002
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In: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 49:4, s. 1622-1628
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Journal article (peer-reviewed)abstract
- We have demonstrated experimentally that the main breakdown-triggering mechanism in most gaseous detectors, including micropattern gaseous detectors, is sporadic electron jets from the cathode surfaces. Depending on the counting rate and applied voltages, each jet contains randomly from a few primary electrons up to 10(5), emitted in a time interval ranging between 0.1 mus to milliseconds. After the emission, these primary electrons experience a full gas multiplication in the detector and create spurious pulses. The rate of these jets increases with applied voltage and very sharply at voltages close to the breakdown limit. In our measurements, we found that these jets are responsible for the breakdown-triggering at any counting rate between 10(-2) Hz/mm(2) and 10(8) Hz/mm(2). We demonstrated on a few detectors that an optimized cathode-geometry, a high electrode surface quality, and a proper choice of the gas mixture considerably improve the performance characteristics and provide the highest possible gains. Results from this work were helpful in the construction of high-performance gaseous detectors for medical imaging applications.
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| 30. |
- Ostling, J., et al.
(author)
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Study of hole-type gas multiplication structures for portal imaging and other high count rate applications
- 2003
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In: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 50:4, s. 809-819
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Journal article (peer-reviewed)abstract
- We performed studies in the operation of various hole-type gaseous multiplication structures (GEM, capillary plates, and others) at very high fluxes of X-rays (<60 keV-bremsstrahlung) and pulsed gamma radiation (<50 MeV-bremsstrahlung). In the case of X-rays, the counting rate was 10(5)-10(6) Hz/mm(2); in the case of gammas it reached levels of up to 10(9) Hz/mm(2) during the pulses. In most measurements, the entire area of the detector was exposed to these extremely high fluxes. Results obtained so far indicate that the GEM and the hydrogen-treated capillary plates could be successfully used in medical imaging applications.
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| 31. |
- Peskov, V., et al.
(author)
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The study and optimization of new micropattern gaseous detectors for high-rate applications
- 2001
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In: IEEE Transactions on Nuclear Science. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9499 .- 1558-1578. ; 48:4, s. 1070-1074
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Journal article (peer-reviewed)abstract
- We performed a new series of systematic studies of gain and rate characteristics of several micropattern gaseous detectors. Extending earlier studies, characteristics were measured at various pressures and gas mixtures at a wide range of primary charges, and also when the whole area of the detectors was irradiated with a high-intensity X-ray beam. Several new effects were discovered, common to all tested detectors, which define fundamental limits of operation. The results of these studies allow us to identify several concrete ways of improving the performance of micropattern detectors and to suggest that in some applications, resistive plate chambers may constitute a valid alternative. Being protected from damaging discharges by the resistive electrodes, these detectors feature high gain, high rate capability (10(5) Hz/mm(2)), good position resolution (better than 30 mum), and excellent timing (50 ps sigma).
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| 37. |
- Wallmark, M., et al.
(author)
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Operating range of a gas electron multiplier for portal imaging
- 2001
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In: Nuclear Instruments and Methods in Physics Research Section A. - 0168-9002 .- 1872-9576. ; 471:02-jan, s. 151-155
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Journal article (peer-reviewed)abstract
- At the Karolinska Institute in Stockholm, Sweden a new detector for portal imaging is under development, which could greatly improve the alignment of the radiation beam with respect to the tumor during radiation treatment. The detector is based on solid converters combined with gas electron multipliers (GEMs) as an amplification structure. The detector has a large area and will be operated in a very high rate environment in the presence of heavy ionizing particles. As was discovered recently high rates and alpha particles could cause discharges in GEM and discharge propagation from GEM to GEM and to the readout electronics. Since reliability is one of the main requirements for the portal imaging device, we performed systematic studies to find a safe operating range of the device, free from typical high rate problems, such as discharges.
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