154 research outputs found
The pathway of cross-presentation is influenced by the particle size of phagocytosed antigen
No full textCross-presentation is the presentation by MHC class I of antigenic peptides from exogenous proteins that have been internalised and processed by professional antigen presenting cells, eg. dendritic cells (DC). We have investigated the influence of particle size and antigen load on cross-presentation following antigen delivery on microspheres (MS). Cross-presentation from small particles (0.8 ?m) is sensitive to proteasome inhibition and the blockade of ER-resident MHC class I complex export, whereas cross-presentation from larger particles (aggregated clumps of 0.8 ?m MS) is resistant to these antagonists. This observation may have been overlooked previously, due to the heterogeneity of particle size and MS uptake in unsorted DC populations. Whilst larger particles carry more antigen, we show that antigen load does not influence the cross-presentation pathway utilised. Whereas early endosome autoantigen 1 (EEA1) could be observed in all phagosomes, we observed endoplasmic reticulum SNARE of 24 kDa (ERS24) and cathepsin S in association with 3.0 ?m and aggregated 0.8 ?m MS, but not individual 0.8 ?m MS. A potential mechanism underlying our observations may be the activation of ?-catenin by disruption of E-cadherin-mediated adhesion. Activated ?-catenin was detected in the cytoplasm of cells after phagocytosis of MS (highest levels for the largest particles). We propose that particle size can direct the use of different pathways for the cross-presentation of an identical antigen. Furthermore, these pathways have differing yields of MHC class I-peptide complexes, which is an important variable in designing vaccination strategies for maximal antigen expression and CD8(+) T cell priming
Polymer microarrays: identification of substrates for phagocytosis assays
No full textA polymer microarray of 120 polyurethanes was used to identify polymers that promoted the adhesion of bone marrow dendritic cells (BMDC). Identified polymers were coated onto glass cover slips and shown to be efficient substrates for the immobilisation of these primary cells, which underwent efficient phagocytosis while still presumably maintaining their immature stat
What carcinoembryonic antigen level should trigger further investigation during colorectal cancer follow-up? A systematic review and secondary analysis of a randomised controlled trial
No full textBackground
Following primary surgical and adjuvant treatment for colorectal cancer, many patients are routinely followed up with blood carcinoembryonic antigen (CEA) testing.
Objective
To determine how the CEA test result should be interpreted to inform the decision to undertake further investigation to detect treatable recurrences.
Design
Two studies were conducted: (1) a Cochrane review of existing studies describing the diagnostic accuracy of blood CEA testing for detecting colorectal recurrence; and (2) a secondary analysis of data from the two arms of the FACS (Follow-up After Colorectal Surgery) trial in which CEA testing was carried out.
Setting and participants
The secondary analysis was based on data from 582 patients recruited into the FACS trial between 2003 and 2009 from 39 NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence and followed up for 5 years. CEA testing was undertaken in general practice.
Results
In the systematic review we identified 52 studies for meta-analysis, including in aggregate 9717 participants (median study sample size 139, interquartile range 72–247). Pooled sensitivity at the most commonly recommended threshold in national guidelines of 5 µg/l was 71% [95% confidence interval (CI) 64% to 76%] and specificity was 88% (95% CI 84% to 92%). In the secondary analysis of FACS data, the diagnostic accuracy of a single CEA test was less than was suggested by the review [area under the receiver operating characteristic curve (AUC) 0.74, 95% CI 0.68 to 0.80]. At the commonly recommended threshold of 5 µg/l, sensitivity was estimated as 50.0% (95% CI 40.1% to 59.9%) and lead time as about 3 months. About four in 10 patients without a recurrence will have at least one false alarm and six out of 10 tests will be false alarms (some patients will have multiple false alarms, particularly smokers). Making decisions to further investigate based on the trend in serial CEA measurements is better (AUC for positive trend 0.85, 95% CI 0.78 to 0.91), but to maintain approximately 70% sensitivity with 90% specificity it is necessary to increase the frequency of testing in year 1 and to apply a reducing threshold for investigation as measurements accrue.
Limitations
The reference standards were imperfect and the main analysis was subject to work-up bias and had limited statistical precision and no external validation.
Conclusions
The results suggest that (1) CEA testing should not be used alone as a triage test; (2) in year 1, testing frequency should be increased (to monthly for 3 months and then every 2 months); (3) the threshold for investigating a single test result should be raised to 10 µg/l; (4) after the second CEA test, decisions to investigate further should be made on the basis of the trend in CEA levels; (5) the optimal threshold for investigating the CEA trend falls over time; and (6) continuing smokers should not be monitored with CEA testing. Further research is needed to explore the operational feasibility of monitoring the trend in CEA levels and to externally validate the proposed thresholds for further investigation.
Study registration
This study is registered as PROSPERO CRD42015019327 and Current Controlled Trials ISRCTN93652154.
Funding
The main FACS trial and this substudy were funded by the National Institute for Health Research Health Technology Assessment programme
Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma
No full textBackground: APC 366, a selective inhibitor of mast cell tryptase, has been shown to inhibit antigen-induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR) in a sheep model of allergic asthma.Objective: The purpose of this study was to investigate the effects of APC 366 on antigen-induced EAR, LAR, and BHR in mild atopic asthmatics not on any anti-inflammatory therapy.Methods: Sixteen mild atopic asthmatics, each with a demonstrable antigen-induced EAR, LAR, and BHR to histamine, were recruited into this randomized, double-blinded, crossover study. APC 366 (5 mg)/placebo was administered by aerosol inhalation 3 times per day on treatment days 1 through 4. Allergen challenge was carried out on day 4. Histamine challenge was performed the following morning, 1 hour after final dosing.Results: Subjects were shown to have a significantly smaller overall mean area under the curve for the LAR (P = .012) and mean maximum fall in FEV? for the LAR (P = .007) after pretreatment with APC 366 in comparison with placebo. No significant effects on BHR were demonstrable. Although the EAR was reduced by 18% after treatment with APC 366 in comparison with placebo, this was not statistically significant.Conclusion: Short-term repeated administration of APC 366 significantly reduced the magnitude of antigen-induced LAR in atopic asthmatics, which supports the role of mast cell tryptase in the pathophysiology of the LAR
Crotalaria angulata Mill.
No full textCrotalaria biflora Linnaeus, Mantissa Plantarum Altera: 570. 1771. ["Habitat in Insula s. Johannae. Koenig. H.U."] Mant. Pl. Alt.: 273 (1771). RCN: 5257. Lectotype (Rudd in Dassanayake & Fosberg, Revised Handb. Fl. Ceylon 7: 204. 1991): Herb. Linn. No. 895.20 (LINN). Current name: Crotalaria angulata Mill. (Fabaceae: Faboideae). Note: This name appeared in the Appendix of Mant. Pl. Alt., and includes, in its synonymy, Astragalus biflorus L. (Mant. Pl. Alt.: 273. 1771). As the latter name was not accepted by the author, A. biflorus is not validly published, and C. biflora is not a new combination based on A. biflorus.Published as part of Jarvis, Charlie, 2007, Chapter 7: Linnaean Plant Names and their Types (part C), pp. 370-473 in Order out of Chaos. Linnaean Plant Types and their Types, London :Linnaean Society of London in association with the Natural History Museum on page 459, DOI: 10.5281/zenodo.29197
Stagmatoptera supplicaria
No full textStagmatoptera supplicaria (Burmeister, 1838) (Fig. 149) Mantis (Acontistes) supplicaria Burmeister, 1838: 542. = Mantis flavipennis Audinet-Serville, 1838: 128. Type locality. Unknown (Rodrigues & Cancello 2016). Records. MUSM: ♂, 230 m, lux, 27.IX.2016, leg. M. Falkenberg, M. Schlemm & R. Mörtter (ex. SMNK); 2 ♂♂, 230 m, lux, 28.IX.2016, leg. M. Falkenberg, M. Schlemm & R. Mörtter (ex. SMNK); 2 ♂♂, 230 m, lux, 02.X.2016, leg. M. Falkenberg, M. Schlemm & R. Mörtter (ex. SMNK); 2 ♂♂, 230 m, lux, 07.X.2016, leg. M. Falkenberg, M. Schlemm & R. Mörtter (ex. SMNK); ♂, 230 m, lux, 09.X.2016, leg. M. Falkenberg, M. Schlemm & R. Mörtter (ex. SMNK). NMB: ♂, 230 m, lux, leg. E.-G. Burmeister, 20. IX.–09.X.2007 (QR-NMB-Mant 1569, ex. ZSM). SMNK: ♂, 230 m, lux, 17.II.1984, leg. M. Verhaagh (SMNK-Mant 09690); ♂, 230 m, 26.IX.2014, leg. R. Mörtter (SMNK-Mant 12800); ♂, 230 m, lux, 28.IX.2014, leg. M. Falkenberg (SMNK-Mant 12548); ♂, 260 m, lux, 07.X.2016, leg. R. Mörtter (SMNK-Mant 12873); 4 ♂♂, 230 m, lux, 16.IV.2018, leg. M. Falkenberg (SMNK-Mant 12793–12796); 3 ♂♂, 230 m, lux, 17.IV.2018, leg. M. Falkenberg (SMNK-Mant 12797–12799); 3 ♂♂, 230 m, 14.IV.2018, leg. R. Mörtter (SMNK-Mant 12801–12803). ZSM: ♂, 230 m, lux, 20.IX.–09.X.2007, leg. E.-G. Burmeister, E. Diller, O. Gruler, M. Breitsameter & T. Kothe (genitalia preparation Rodrigues #GM0070); ♂, 230 m, lux, 20.IX.–09.X.2007, leg. E.-G. Burmeister; 4 ♂♂, 230 m, lux, 02.–18.X.2009, leg. E.-G. Burmeister; ♂, 230 m, lux, V.2013, leg. E. Diller. CSC: ♂, 230 m, lux, 17.IV.2018, leg. M. Falkenberg (ex. SMNK); ♂, 230 m, 20.IX.–06.X.2013, leg. E. Diller (ex. ZSM). Distribution. Bolivia, Brazil, Colombia, Ecuador, French Guiana, Peru, Suriname, Trinidad & Tobago, Venezuela (Rodrigues & Cancello 2016). Remarks. As pointed out by Rodrigues & Cancello (2016), Burmeister (1838) has to be credited as the author of the species, not Stoll (1813). While a female of St. supplicaria is figured in both Stoll (1787) and the 1813 reprint, it is misidentified as St. precaria (Linnaeus, 1758). Very common at the study site.Published as part of Schwarz, Christian J., Ehrmann, Reinhard, Stiewe, Martin B. D., Mörtter, Rolf & Falkenberg, Michael, 2020, Mantodea of Panguana (Insecta: Dictyoptera), pp. 1-66 in Zootaxa 4824 (1) on pages 43-44, DOI: 10.11646/zootaxa.4824.1.1, http://zenodo.org/record/440199
Is there a role of synovial biopsy in drug development?
No full textRheumatoid arthritis (RA) is an autoimmune disease which causes significant pain, joint deformity, functional disability. The pathological hallmark of RA is inflammation of the synovium characterized by involvement of inflammatory and resident stromal cells, soluble mediators and signalling pathways leading to irreversible joint destruction. The treatment goal in RA has evolved over the last decade towards a target of disease remission that is achieved in less than a third of patients in clinical trials. The lack of therapeutic response to current treatments is suggestive of alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. There are data to justify the use of synovial tissue in early drug development. Synovial tissue represents an appropriate compartment to be studied in patients with inflammatory arthritis and provides information that is distinct from peripheral blood. Modern techniques have made the procedure much more accessible and ultrasound guided biopsies represent a safe and acceptable option. Advances in analytic technologies allowing transcriptomic level of analysis can provide unique inside to target organ/tissue following the exposure to investigational medicinal product. However, there are still caveats with regard to both the choice of technique and analytical methods. Therefore the significance of synovial biopsy remains to be determined in future clinical trials. The aim of the current debate is to explore the potential for accessing and evaluating synovial tissue in early drug development, to summarize lessons we have learned from clinical trials and to discuss the challenges that have arisen so far.</p
Bone marrow transplantation for MHC class I deficiency corrects T-cell immunity but dissociates natural killer cell repertoire formation from function
No full text
Targeting of antithrombin in hemophilia A or B with RNAi therapy
No full textBACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.
METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.
RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.
CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .)
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