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- Ge, Changrong, et al.
(author)
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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
- 2019
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In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 210-221
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Journal article (peer-reviewed)abstract
- Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.
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- Gulyas, M., et al.
(author)
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COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer
- 2018
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In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 57:2, s. 244-250
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Journal article (peer-reviewed)abstract
- Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition. Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells. Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81-1.27 and HR 1.12; 95% CI 0.78-1.61, respectively). High COX-2 scores in tumor (n=71) or stromal cells (n=55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60-1.54; and HR =1.51; 95% CI 0.86-2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p=.48 and .25, respectively). Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.
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- Lagerkvist, Birgitta Json, et al.
(author)
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Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance.
- 2004
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In: Environmental health perspectives. - 0091-6765. ; 112:17, s. 1768-71
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Journal article (peer-reviewed)abstract
- Airway irritants such as ozone are known to impair lung function and induce airway inflammation. Clara cell protein (CC16) is a small anti-inflammatory protein secreted by the nonciliated bronchiolar Clara cells. CC16 in serum has been proposed as a noninvasive and sensitive marker of lung epithelial injury. In this study, we used lung function and serum CC16 concentration to examine the pulmonary responses to ambient O3 exposure and swimming pool attendance. The measurements were made on 57 children 10-11 years of age before and after outdoor exercise for 2 hr. Individual O3 exposure was estimated as the total exposure dose between 0700 hr until the second blood sample was obtained (mean O3 concentration/m3 times symbol hours). The maximal 1-hr value was 118 microg/m3 (59 ppb), and the individual exposure dose ranged between 352 and 914 microg/m3hr. These O3 levels did not cause any significant changes in mean serum CC16 concentrations before or after outdoor exercise, nor was any decrease in lung function detected. However, children who regularly visited chlorinated indoor swimming pools had significantly lower CC16 levels in serum than did nonswimming children both before and after exercise (respectively, 57 +/- 2.4 and 53 +/- 1.7 microg/L vs. 8.2 +/- 2.8 and 8.0 +/- 2.6 microg/L; p < 0.002). These results indicate that repeated exposure to chlorination by-products in the air of indoor swimming pools has adverse effects on the Clara cell function in children. A possible relation between such damage to Clara cells and pulmonary morbidity (e.g., asthma) should be further investigated.
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- Middeldorp, Christel M., et al.
(author)
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The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects
- 2019
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In: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 34:3, s. 279-300
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Journal article (peer-reviewed)abstract
- The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
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- Persson Vinnersten, T Z, et al.
(author)
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A six-year study of insect emergence from temporary flooded wetlands in central Sweden, with and without Bti-based mosquito control
- 2010
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In: BULLETIN OF ENTOMOLOGICAL RESEARCH. - : Cab International. - 0007-4853 .- 1475-2670. ; 100:6, s. 715-725
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Journal article (peer-reviewed)abstract
- In temporary wetlands in the River Dalalven floodplains, recurrent but irregular floods induce massive hatching of the flood-water mosquito Aedes sticticus, which causes enormous nuisance. Flood-water mosquito control using the biological larvicide Bacillus thuringiensis var. israelensis (Bti) was commenced in parts of the floodplains during 2002, and here we report the first six years of full-season monitoring of general insect emergence from temporary wetlands with and without treatment. Emergence traps, which were emptied weekly, were used from May to September each year. A total of 137,153 insects of 13 taxonomic orders were collected. Diptera was highly dominating and especially the sub-order Nematocera with 18 families was a very prominent taxon. Bti-treatment effects were analysed by taxonomic order, by sub-order in Diptera and Hemiptera, and by family for Nematocera and Coleoptera for the whole study period. We found no significant negative effects of Bti treatments on the production of insects by taxonomic order, with the exception of Coleoptera in the long term. However, no significant negative effects were found for the Coleoptera families, neither in the short term nor in the long term. There was no significant negative treatment effect on Nematocera production, neither when analyzed for the whole sub-order nor when analyzed by family. However, abundance of Ceratopogonidae was significantly higher in experimental than in reference wetlands. We conclude that Bti-treatment effects on insect production may be minute in comparison to other environmental factors structuring the insect fauna of the temporary wetlands studied.
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- Velander, Erik, et al.
(author)
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An IGBT Turn-ON Concept Offering Low Losses Under Motor Drive dv/dt Constraints Based on Diode Current Adaption
- 2018
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In: IEEE transactions on power electronics. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 0885-8993 .- 1941-0107. ; 33:2, s. 1143-1153
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Journal article (peer-reviewed)abstract
- In this paper, a new low-loss turn-ON concept for the silicon insulated-gate bipolar transistor (Si-IGBT) in combination with silicon p-i-n diode is presented. The concept is tailored for two-level motor converters in the 100 kW to 1 MW range under the constraint that the output voltages slopes are limited in order to protect the motor windings. Moreover, analyses of the IGBT turn-ON and diode reverse recovery voltage slopes are presented concluding that the diode reverse recovery is the worst case. The concept includes a low-cost measurement of the free-wheeling diode current and temperature by the gate driver without necessity of acquiring this information from the converter control board. By using this concept, the output dv/dt at the diode turn-OFF can be kept approximately constant regardless of the commutated current and junction temperature. Hence, the switching losses could be decreased for the currents and temperatures where the voltage slopes are lower when using a conventional gate driver optimized for the worst case. Moreover, results are shown for one such power semiconductor, showing a total switching loss reduction of up to 28% in comparison with a gate driver without current and temperature measurement. Finally, this concept is particularly suitable for high power semiconductor modules in half-bridge configuration which are recently proposed by several suppliers.
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