Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta

The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4(+)CD25(hi) T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4(+)CD25(-) T cells. This defect, however, was overcome after anti-tumor necrosis factor (TNF)-alpha antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4(+)CD25(hi)FoxP3(+) T reg cell population, which mediates suppression via transforming growth factor (TGF)-beta and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62L(-) T reg cells from CD4(+)CD25(-) T cells isolated from active RA patients, a process dependent on TGF-alpha. In spite of the potent suppressor capacity displayed by this CD62L(-) T reg cell population, the natural CD62L(+) T reg cells remained defective in infliximab-treated patients. These results suggest that anti-TNF-alpha therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance

Damage function for historic paper. Part I: Fitness for use

Background In heritage science literature and in preventive conservation practice, damage functions are used to model material behaviour and specifically damage (unacceptable change), as a result of the presence of a stressor over time. For such functions to be of use in the context of collection management, it is important to define a range of parameters, such as who the stakeholders are (e.g. the public, curators, researchers), the mode of use (e.g. display, storage, manual handling), the long-term planning horizon (i.e. when in the future it is deemed acceptable for an item to become damaged or unfit for use), and what the threshold of damage is, i.e. extent of physical change assessed as damage. Results In this paper, we explore the threshold of fitness for use for archival and library paper documents used for display or reading in the context of access in reading rooms by the general public. Change is considered in the context of discolouration and mechanical deterioration such as tears and missing pieces: forms of physical deterioration that accumulate with time in libraries and archives. We also explore whether the threshold fitness for use is defined differently for objects perceived to be of different value, and for different modes of use. The data were collected in a series of fitness-for-use workshops carried out with readers/visitors in heritage institutions using principles of Design of Experiments. Conclusions The results show that when no particular value is pre-assigned to an archival or library document, missing pieces influenced readers/visitors’ subjective judgements of fitness-for-use to a greater extent than did discolouration and tears (which had little or no influence). This finding was most apparent in the display context in comparison to the reading room context. The finding also best applied when readers/visitors were not given a value scenario (in comparison to when they were asked to think about the document having personal or historic value). It can be estimated that, in general, items become unfit when text is evidently missing. However, if the visitor/reader is prompted to think of a document in terms of its historic value, then change in a document has little impact on fitness for use

M3C: Monte Carlo reference-based consensus clustering

Genome-wide data is used to stratify patients into classes for precision medicine using clustering algorithms. A common problem in this area is selection of the number of clusters (K). The Monti consensus clustering algorithm is a widely used method which uses stability selection to estimate K. However, the method has bias towards higher values of K and yields high numbers of false positives. As a solution, we developed Monte Carlo reference-based consensus clustering (M3C), which is based on this algorithm. M3C simulates null distributions of stability scores for a range of K values thus enabling a comparison with real data to remove bias and statistically test for the presence of structure. M3C corrects the inherent bias of consensus clustering as demonstrated on simulated and real expression data from The Cancer Genome Atlas (TCGA). For testing M3C, we developed clusterlab, a new method for simulating multivariate Gaussian clusters

M3C: Monte Carlo reference-based consensus clustering.

Genome-wide data is used to stratify patients into classes for precision medicine using clustering algorithms. A common problem in this area is selection of the number of clusters (K). The Monti consensus clustering algorithm is a widely used method which uses stability selection to estimate K. However, the method has bias towards higher values of K and yields high numbers of false positives. As a solution, we developed Monte Carlo reference-based consensus clustering (M3C), which is based on this algorithm. M3C simulates null distributions of stability scores for a range of K values thus enabling a comparison with real data to remove bias and statistically test for the presence of structure. M3C corrects the inherent bias of consensus clustering as demonstrated on simulated and real expression data from The Cancer Genome Atlas (TCGA). For testing M3C, we developed clusterlab, a new method for simulating multivariate Gaussian clusters

Statistical analysis of coherent structures in transitional pipe flow

Numerical and experimental studies of transitional pipe flow have shown the prevalence of coherent flow structures that are dominated by downstream vortices. They attract special attention because they contribute predominantly to the increase of the Reynolds stresses in turbulent flow. In the present study we introduce a convenient detector for these coherent states, calculate the fraction of time the structures appear in the flow, and present a Markov model for the transition between the structures. The fraction of states that show vortical structures exceeds 24% for a Reynolds number of about Re=2200, and it decreases to about 20% for Re=2500. The Markov model for the transition between these states is in good agreement with the observed fraction of states, and in reasonable agreement with the prediction for their persistence. It provides insight into dominant qualitative changes of the flow when increasing the Reynolds number.Comment: 11 pages, 26 (sub)figure

Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus: A Randomized Controlled Trial

BACKGROUND: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. OBJECTIVE: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. DESIGN: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003). SETTING: England. PARTICIPANTS: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. INTERVENTION: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. MEASUREMENTS: The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. RESULTS: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. LIMITATIONS: Small sample size; biomarker primary end point. CONCLUSION: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. PRIMARY FUNDING SOURCE: Versus Arthritis