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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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- 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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- TORNEVIK, C, et al.
(author)
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ADSORPTION OF SN ON SI(111)7X7 - RECONSTRUCTIONS IN THE MONOLAYER REGIME
- 1994
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In: Surface Science. - : Elsevier BV. - 0039-6028 .- 1879-2758. ; 314:2, s. 179-187
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Journal article (peer-reviewed)abstract
- Different monolayer phases of Sn on Si(111)7 x 7 have been studied by means of scanning tunneling microscopy (STM), core-level photoelectron spectroscopy (XPS), and Rutherford backscattering spectrometry (RBS). The STM results show that square-root 3 x square-root 3 reconstructions are obtained for room-temperature deposition of 1/3 ML of Sn followed by sample annealing in a broad temperature range. A T4 Sn adatom square-root 3 x square-root 3 phase is formed for temperatures between 500 and 800-degrees-C, with a concentration of defects that is strongly dependent on the temperature and which is as high as 25% for the lowest temperatures. Above 825-degrees-C a second square-root 3 x square-root 3 adatom reconstruction is formed, a mosaic-like phase with a 1: 1 mixture of Si and Sn atoms in T4 positions. The results from investigations of the higher coverage 2 square-root 3 x 2 square-root 3 reconstruction by XPS and RBS support the theory that this phase is a two-layer epitaxial Sn structure with all Si(111) dangling bonds saturated. The Sn coverage for this phase was determined to be between 1 and 1.2 ML.
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- Cetinic, I., et al.
(author)
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Ultrasound Shear Wave Elastography, Shear Wave Dispersion and Attenuation Imaging of Pediatric Liver Disease with Histological Correlation
- 2022
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In: Children. - : MDPI AG. - 2227-9067. ; 9:5
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Journal article (peer-reviewed)abstract
- Aim: To evaluate the feasibility of multiple ultrasound markers for the non-invasive characterization of fibrosis, inflammation and steatosis in the liver in pediatric patients. Materials and methods: The quantitative ultrasound measures shear wave elastography (SWE), shear wave dispersion (SWD) and attenuation imaging (ATI) were compared and correlated with percutaneous liver biopsies and corresponding measures in a control cohort. Results: The median age of the 32 patients was 12.1 years (range 0.1-17.9), and that of the 15 controls was 11.8 years (range: 2.6-16.6). Results: There was a significant difference in SWE values between histologic grades of fibrosis (p = 0.003), with a positive correlation according to the grade (r = 0.7; p < 0.0001). Overall, a difference in SWD values between grades of inflammation was found (p = 0.009) but with a lack of correlation (r = 0.1; p = 0.67). Comparing inflammation grades 0-1 (median:13.6 m/s kHz [min; max; 8.4; 17.5]) versus grades 2-3 (16.3 m/s kHz [14.6; 24.2]) showed significant differences between the groups (p = 0.003). In the 30 individuals with a steatosis score of 0, ATI was measured in 23 cases with a median value of 0.56 dB/cm/MHz. Conclusion: Comprehensive ultrasound analysis was feasible to apply in children and has the potential to reflect the various components of liver affection non-invasively. Larger studies are necessary to conclude to what extent these image-based markers can classify the grade of fibrosis, inflammation and steatosis.
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- 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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- 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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