60 research outputs found
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The role of Syk-family protein tyrosine kinases in B cell development.
The related Syk and Zap70 tyrosine kinases play an important role in lymphocyte development and signalling. Gene targeted mutant mice revealed that Syk plays a significant role in B cell development. Syk'1' mice show a partial block in B cell development at the pro-B to pre-B cell transition and a complete block at the immature to mature B cell transition. In contrast, mice deficient for Zap70 were reported to have normal numbers of B cells, but no T cells due to a block in thymic positive selection. Unexpectedly, mice deficient for both Syk and Zap70 show a complete block in B cell development at the pro-B to pre-B cell transition, indicating that Zap70 plays a role in the B cell lineage as well. I have now further explored the role of Zap70 in B cell development and function. I found that Zap70 is expressed in all developing and mature B cell subsets, although pro-B cells express higher levels of Zap70 than other populations. Analysis of B cell development showed an increase in Bib and marginal zone B cells in Zap70 '1' mice, which was due to the lack of Zap70 in the B cell lineage. In contrast, Zap70-deficient B cells were able to mount normal T-dependent and T-independent immune responses and had unaffected BCR-induced calcium release. Furthermore, I asked whether the distinct effects of Syk and Zap70 mutations on B cell development were due to intrinsic differences in the function of the two kinases, or rather reflected differences in levels of expression. I found that overexpression of Zap70 in Syk'1' mice completely rescued B cell development, arguing that the two kinases are able to perform the same function during B cell development, and that the distinct B cell phenotypes of Syk'1' and Zap 70'1' mice are caused mainly by differences in levels of expression. Finally, to be able to address the role of Syk in mature B cells, I set up a system where I made Syk inducible by fusing the protein to the hormone-binding domain of the estrogen receptor (ER-HBD). Three different Syk-ER fusion constructs were expressed in Syk'1' DT40 cells and one of these was found to restore BCR-induced calcium fluxes in a hormone-dependent manner
Treatment of Psoriasis with Fumarates and other Systemic Therapies
In this era of expensive biologics, which have gained popularity among dermatologists as effective treatments for chronic, moderate to severe plaque psoriasis, there is a great need for an effective, safe, long-term and low-cost therapy such as fumarates.
In this book the authors have investigated its efficacy, safety, adverse-events, popularity among Dutch dermatologists, combination therapy and alternative treatment options
RAG-mediated DNA double-strand breaks activate a cell type-specific checkpoint to inhibit pre-B cell receptor signals
DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre–B cell receptor (pre–BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre–BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre–B cells. Here, we show that RAG DSBs inhibit pre–BCR signals through the ATM- and NF-κB2–dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre–BCR signaling. This regulatory circuit prevents the pre–BCR from inducing additional Igl chain gene rearrangements and driving pre–B cells with RAG DSBs into cycle. We propose that pre–B cells toggle between pre–BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes
Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation
Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme
Blockade of OX40-OX40L Interactions Attenuates Allograft Rejection Mediated by CD4 T Cells That Recognize Alloantigen through the Direct but Not Indirect Pathway of Allorecognition
Reliable marine power cables are imperative for the cost-effective operation of marine energy conversion systems. There is considerable experience with marine power cables under static and dynamic load conditions but the loading regimes for floating marine energy converters are not well understood, due to a lack of field experience. This paper aims to assess mechanical load conditions and failure modes for a dynamic power cable that is connected to a floating wave energy converter. The applied approach combines experimental tank test data with numerical modelling and site-specific wave characteristics to identify maximum load points and to quantify the fatigue life. The effect of varying wave parameters on maximum loads and fatigue cycles is investigated and results are presented for two common umbilical configurations: catenary and lazy wave. In situations with limited field experience, the presented approach provides a tool to determine if critical components are fit for purpose and to assess the expected level of reliability prior to deployment. The cable conductor’s fatigue life is estimated for the lazy wave configuration and highlights component fatigue failure as a major concern that must be addressed in floating marine energy applications
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