The Role of Whey Acidic Protein Four-Disulfide-Core Proteins in Respiratory Health and Disease

Abstract Members of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family of proteins are a relatively under-explored family of low molecular weight proteins. The two most prominent WFDC proteins, secretory leukocyte protease inhibitor (SLPI) and elafin (or the precursor, trappin-2), have been shown to possess multiple functions including anti-protease, anti-bacterial, anti-viral and anti-inflammatory properties. It is therefore of no surprise that both SLPI and elafin/trappin-2 have been developed as potential therapeutics. Given the abundance of SLPI and elafin/trappin-2 in the human lung, most work in the area of WFDC research has focused on the role of WFDC proteins in protecting the lung from proteolytic attack. In this review, we will outline the current evidence regarding the expanding role of WFDC protein function with a focus on WFDC activity in lung disease as well as emerging data regarding the function of some of the more recently described WFDC proteins.</jats:p

Definition of interfaces

The aim of this report is to define the interfaces for the tools used in the MT development and evaluation scenarios as included in the QTLaunchPad (QTLP) infrastructure. Specification of the interfaces is important for the interaction and interoperability of the tools in the developed QTLP infrastructure. In addressing this aim, the report provides: 1. Descriptions of the common aspects of the tools and their standardized data formats; 2. Descriptions of the interfaces for the tools for interoperability. where the tools are categorized into preparation, development, and evaluation categories including the human interfaces for quality assessment with multidimensional quality metrics. Interface specifications allow a modular tool infrastructure, flexibly selecting among alternative implementations, enabling realistic expectations to be made at different sections of the QTLP information flow pipeline, and supporting the QTLP infrastructure. D3.2.1 allows the emergence of the QTLP infrastructure and helps the identification and acquisition of existing tools (D4.4.1), the integration of identified language processing tools (D3.3.1), their implementation (D3.4.1), and their testing (D3.5.1). QTLP infrastructure will facilitate the organization and running of the quality translation shared task (D5.2.1). We also provide human interfaces for translation quality assessment with the multidimensional quality metrics (D1.1.1). D3.2.1 is a living document until M12, which is when the identification and acquisition of existing tools (D4.4.1) and the implementation of identified language processing tools (D3.4.1) are due

Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials : lessons learnt from the PROMETHEUS research programme

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.Peer reviewedPublisher PD

Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity

<p>Abstract</p> <p>Background</p> <p>Proteolytic enzymes have been implicated in driving tumor progression by means of their cancer cell microenvironment activity where they promote proliferation, differentiation, apoptosis, migration, and invasion. Therapeutic strategies have focused on attenuating their activity using small molecule inhibitors, but the association of proteases with the cell surface during cancer progression opens up the possibility of targeting these using antibody dependent cellular cytotoxicity (ADCC). Cathepsin S is a lysosomal cysteine protease that promotes the growth and invasion of tumour and endothelial cells during cancer progression. Our analysis of colorectal cancer patient biopsies shows that cathepsin S associates with the cell membrane indicating a potential for ADCC targeting.</p> <p>Results</p> <p>Here we report the cell surface characterization of cathepsin S and the development of a humanized antibody (Fsn0503h) with immune effector function and a stable <it>in vivo </it>half-life of 274 hours. Cathepsin S is expressed on the surface of tumor cells representative of colorectal and pancreatic cancer (23%-79% positive expression). Furthermore the binding of Fsn0503h to surface associated cathepsin S results in natural killer (NK) cell targeted tumor killing. In a colorectal cancer model Fsn0503h elicits a 22% cytotoxic effect.</p> <p>Conclusions</p> <p>This data highlights the potential to target cell surface associated enzymes, such as cathepsin S, as therapeutic targets using antibodies capable of elicitingADCC in tumor cells.</p

Staff training to improve participant recruitment into surgical randomised controlled trials : A feasibility study within a trial (SWAT) across four host trials simultaneously

The PROMoting THE Use of SWATs (PROMETHEUS) programme was funded by the Medical Research Council (MRC) [grant number MR/R013748/1]. The DISC host trial is funded by the Health Technology Assessment Programme (Grant Ref: 15/102/04). IntAct is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (Grant Ref: 14/150/62). The EME Programme is funded by the MRC and NIHR, with contributions from the CSO in Scotland and Health and Care Research Wales and the HSC R&D Division, Public Health Agency in Northern Ireland. PROFHER-2 is funded by the Health Technology Assessment Programme (Grant Ref: 16/73/03). START: REACTS is funded by the NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 16/61/18. The development of the training intervention was funded by the MRC Network of Hubs for Trials Methodology Research (MR/L004933/1- R53) and supported by the MRC ConDuCT-II Hub (Collaboration and innovation for Difficult and Complex randomized controlled Trials In Invasive procedures - MR/K025643/1). The online version of the training intervention was funded by the NIHR and is hosted on the NIHR Learn platform (https://learn.nihr.ac.uk/course/view.php?id=385). It is based on the face-to face GRANULE training course funded by the Bowel Disease Research Foundation in collaboration with the University of Birmingham, University of Bristol and former MRC ConDuCT-II Hub. This work was part-funded by the Wellcome Trust [ref: 204829] through the Centre for Future Health (CFH) at the University of York. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the MRC or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.Peer reviewedPublisher PD

Characterisation of eppin function: expression and activity in the lung

Eppin is a serine protease inhibitor expressed in male reproductive tissues. In this study we have demonstrated novel sites of eppin expression in myeloid and epithelial cell lines with further confirmation in primary myeloid cell types. Using immunohistochemistry and Western blotting, eppin was detected in the lungs of patients with Acute Respiratory Distress Syndrome and Cystic Fibrosis lung disease. Expression of eppin in monocytic cells was unaffected by stimulation with TLR agonists, cytokine stimulation and hormone receptor agonist stimulation. However, upregulated expression and secretion of eppin was observed following treatment of monocytes with epidermal growth factor (EGF). Incubation of recombinant eppin with monocytic cells resulted in significant inhibition of lipopolysaccharide (LPS)-induced chemokine production. Furthermore, eppin inhibited LPS- induced NF-κB activation by a mechanism which involved accumulation of phosphorylated IκBα. In an in vivo model of lung inflammation induced by LPS, eppin administration resulted in decreased recruitment of neutrophils to the lung with a concomitant reduction in the levels of the neutrophil chemokine MIP-2. Overall, these results suggest a role for eppin outside of the reproductive tract and that eppin may have a role in the innate immuneresponse in the lung

Undertaking studies within a trial to evaluate recruitment and retention strategies for RCTs : lessons learnt from the PROMETHEUS research programme

Background Randomised controlled trials (‘trials’) are susceptible to poor participant recruitment and retention. Studies Within A Trial (SWATs) are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Aims PROMoting THE USE of Studies Within A Trial (PROMETHEUS) aimed to facilitate at least 25 SWATs evaluating recruitment or retention strategies. We share our experience of delivering the PROMETHEUS programme, and the lessons learnt for undertaking randomised SWATs. Design A network of 10 Clinical Trials Units (CTUs) and one primary care research centre committed to conducting randomised controlled SWATs of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the SWAT Repository, and existing prioritisation exercises, which were reviewed by patient and public (PPI) members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMETHEUS team to undertake SWATs. We also tested the feasibility of undertaking coordinated SWATs, across multiple host trials simultaneously. Setting CTU-based trials recruiting or following up participants in any setting in the UK were eligible. Participants CTU-based teams undertaking trials in any clinical context in the UK. Interventions Funding of up to £5,000 and support from the PROMETHEUS team to design, implement, and report SWATs. Main outcome measures Number of host trials funde

The Irish Rover: Phil Lynott and the Search for Identity

Phil Lynott, the lead singer of the rock band Thin Lizzy, was a complex character. An illegitimate black child who grew up in a working-class, Catholic district of Dublin, Ireland in the 1950s, Lynott spent his life searching for a sense of belonging, something which he explored through rock and roll. This study uses Lynott’s song lyrics to investigate his quest for identity. In particular, it identifies the many recurring themes and archetypes in his music that offered multifaceted self-portraits of his internal conflict between being black, Irish, illegitimate, a rockstar, a Lothario, a son, a father, and a husband, all at the same time