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- Elhai, M, et al.
(author)
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Journal article (peer-reviewed)abstract
- To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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| 2. |
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| 3. |
- Becker, M, et al.
(author)
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Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:9, s. 1242-1248
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Journal article (peer-reviewed)abstract
- Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.MethodsInclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.ResultsOf 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.ConclusionsThe use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.
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| 4. |
- Ballmann, Mónika Z., et al.
(author)
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Human AdV-20-42-42, a promising novel adenoviral vector for gene therapy and vaccine product development
- 2021
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In: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 95:22
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Journal article (peer-reviewed)abstract
- Preexisting immune responses toward adenoviral vectors limit the use of a vector based on particular serotypes and its clinical applicability for gene therapy and/or vaccination. Therefore, there is a significant interest in vectorizing novel adenoviral types that have low seroprevalence in the human population. Here, we describe the discovery and vectorization of a chimeric human adenovirus, which we call HAdV-20-42-42. Full-genome sequencing revealed that this virus is closely related to human serotype 42, except for the penton base, which is derived from serotype 20. The HAdV-20-42-42 vector could be propagated stably to high titers on existing E1-complementing packaging cell lines. Receptor-binding studies revealed that the vector utilized both CAR and CD46 as receptors for cell entry. Furthermore, the HAdV-20-42-42 vector was potent in transducing human and murine cardiovascular cells and tissues, irrespective of the presence of blood coagulation factor X. In vivo characterizations demonstrate that when delivered intravenously (i.v.) in mice, HAdV-20-42-42 mainly targeted the lungs, liver, and spleen and triggered robust inflammatory immune responses. Finally, we demonstrate that potent T-cell responses against vector-delivered antigens could be induced upon intramuscular vaccination in mice. In summary, from the data obtained we conclude that HAdV-20-42-42 provides a valuable addition to the portfolio of adenoviral vectors available to develop efficacious products in the fields of gene therapy and vaccination.
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| 5. |
- Roos, Eva M., et al.
(author)
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ICRS recommendation document : Patient-reported outcome instruments for use in patients with articular cartilage defects
- 2011
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In: Cartilage. - : SAGE Publications. - 1947-6035 .- 1947-6043. ; 2:2, s. 122-136
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Journal article (peer-reviewed)abstract
- Objective: The purpose of this article is to describe and recommend patient-reported outcome instruments for use in patients with articular cartilage lesions undergoing cartilage repair interventions. Methods: Nonsystematic literature search identifying measures addressing pain and function evaluated for validity and psychometric properties in patients with articular cartilage lesions. Results: The knee-specific instruments, titled the International Knee Documentation Committee Subjective Knee Form and the Knee injury and Osteoarthritis and Outcome Score, both fulfill the basic requirements for reliability, validity, and responsiveness in cartilage repair patients. A major difference between them is that the former results in a single score and the latter results in 5 subscores. A single score is preferred for simplicity’s sake, whereas subscores allow for evaluation of separate constructs at all levels according to the International Classification of Functioning. Conclusions: Because there is no obvious superiority of either instrument at this time, both outcome measures are recommended for use in cartilage repair. Rescaling of the Lysholm Scoring Scale has been suggested, and confirmatory longitudinal studies are needed prior to recommending this scale for use in cartilage repair. Inclusion of a generic measure is feasible in cartilage repair studies and allows analysis of health-related quality of life and health economic outcomes. The Marx or Tegner Activity Rating Scales are feasible and have been evaluated in patients with knee injuries. However, activity measures require age and sex adjustment, and data are lacking in people with cartilage repair.
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| 6. |
- Ceder, R, et al.
(author)
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The application of normal, SV40 T-antigen-immortalised and tumour-derived oral keratinocytes, under serum-free conditions, to the study of the probability of cancer progression as a result of environmental exposure to chemicals
- 2007
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In: Alternatives to laboratory animals : ATLA. - : SAGE Publications. - 0261-1929 .- 2632-3559. ; 35:6, s. 621-639
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Journal article (peer-reviewed)abstract
- In vitro models are currently not considered to be suitable replacements for animals in experiments to assess the multiple factors that underlie the development of cancer as a result of environmental exposure to chemicals. An evaluation was conducted on the potential use of normal keratinocytes, the SV40 T-antigen-immortalised keratinocyte cell line, SVpgC2a, and the carcinoma cell line, SqCC/Y1, alone and in combination, and under standardised serum-free culture conditions, to study oral cancer progression. In addition, features considered to be central to cancer development as a result of environmental exposure to chemicals, were analysed. Genomic expression, and enzymatic and functional data from the cell lines reflected many aspects of the transition of normal tissue epithelium, via dysplasia, to full malignancy. The composite cell line model develops aberrances in proliferation, terminal differentiation and apoptosis, in a similar manner to oral cancer progression in vivo. Transcript and protein profiling links aberrations in multiple gene ontologies, molecular networks and tumour biomarker genes (some proposed previously, and some new) in oral carcinoma development. Typical specific changes include the loss of tumour-suppressor p53 function and of sensitivity to retinoids. Environmental agents associated with the aetiology of oral cancer differ in their requirements for metabolic activation, and cause toxic effects to cells in both the normal and the transformed states. The results suggest that the model might be useful for studies on the sensitivity of cells to chemicals at different stages of cancer progression, including many aspects of the integrated roles of cytotoxicity and genotoxicity. Overall, the properties of the SVpgC2a and SqCC/Y1 cell lines, relative to normal epithelial cells in monolayer or organotypic culture, support their potential applicability to mechanistic studies on cancer risk factors, including, in particular, the definition of critical toxicity effects and dose–effect relationships.
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| 7. |
- Hennigan, Christopher J., et al.
(author)
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New particle formation and growth in biomass burning plumes : An important source of cloud condensation nuclei
- 2012
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In: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 39, s. L09805-
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Journal article (peer-reviewed)abstract
- Experiments were performed in an environmental chamber to characterize the effects of photo-chemical aging on biomass burning emissions. Photo-oxidation of dilute exhaust from combustion of 12 different North American fuels induced significant new particle formation that increased the particle number concentration by a factor of four (median value). The production of secondary organic aerosol caused these new particles to grow rapidly, significantly enhancing cloud condensation nuclei (CCN) concentrations. Using inputs derived from these new data, global model simulations predict that nucleation in photo-chemically aging fire plumes produces dramatically higher CCN concentrations over widespread areas of the southern hemisphere during the dry, burning season (Sept.-Oct.), improving model predictions of surface CCN concentrations. The annual indirect forcing from CCN resulting from nucleation and growth in biomass burning plumes is predicted to be -0.2 W m(-2), demonstrating that this effect has a significant impact on climate that has not been previously considered. Citation: Hennigan, C. J., D. M. Westervelt, I. Riipinen, G. J. Engelhart, T. Lee, J. L. Collett Jr., S. N. Pandis, P. J. Adams, and A. L. Robinson (2012), New particle formation and growth in biomass burning plumes: An important source of cloud condensation nuclei, Geophys. Res. Lett., 39, L09805, doi: 10.1029/2012GL050930.
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