BackgroundTebentafusp (IMCgp100) is a bispecific T cell redirector comprised of an affinity-enhanced TCR recognising melanocyte lineage antigen gp100 and a T cell engaging anti-CD3 scFv domain. ...Tebentafusp has shown activity as monotherapy in advanced cutaneous and uveal melanoma (Middleton et al., ASCO 2019), and we have previously reported that over half of uveal melanoma patients treated with tebentafusp display melanocyte-related adverse events (MRAE). These include vitiligo/skin hypopigmentation, leukotrichia, and hyperpigmentation and, collectively, are associated with better overall survival in uveal patients receiving tebentafusp (Orloff et al, AACR 2020). In this study, we dissected the mechanisms by which tebentafusp may induce MRAE and highlight the potential clinical significance.MethodsIn vitro studies were conducted to assess the direct and indirect effects of tebentafusp on epidermal melanocytes from healthy donors. Expression of gp100 and the gp100:HLA*02:01 target complex by melanocytes were quantified at the mRNA level and on the cell surface by confocal microscopy, respectively. Melanocytes co-cultured with PBMC and increasing concentrations of tebentafusp were assessed for their susceptibility to lysis and/or ability to stimulate cytokine production. These readouts were compared to gp100-positive and negative melanoma cancer cell lines. Melanin production by melanocytes was quantified and the melanin synthesis pathway interrogated at the mRNA and protein level following exposure to secretomes from tebentafusp-redirected PBMC against melanoma cancer cells.ResultsHealthy melanocytes expressed 2 to 3-fold lower levels of gp100 peptide-HLA complexes on their surface compared to gp100-positive melanoma cell lines. In the presence of tebentafusp, this lower target expression translated into 3–6 fold lower levels of IFNγ and more than 100 fold lower granzyme B production by redirected T cells and these melanocytes were resistant to direct tebentafusp-induced killing (EC50 for melanocytes greater than 1nM vs EC50 melanoma cell lines of 23–50 pM). Supernatants from T cells activated in response to melanoma cancer cells by tebentafusp downregulated the melanin content of healthy melanocytes (20–30% reduction). Western blotting revealed 30–40% inhibition of two key components of the melanin synthesis pathway; the tyrosinase-related protein (TRP)-1 and TRP-2. This inhibition was reversed by blocking IFNγ in supernatants from activated T cells.ConclusionsMRAEs, especially vitiligo, associated with response to tebentafusp, may be explained, at least in part, by the downregulation of melanin biosynthesis pathway genes by IFNγ secreted by tebentafusp-activated T cells.Ethics ApprovalThe study was approved by the South Central - Oxford A Research Ethics Committee (UK), REC reference 13/SC/0226ReferencesMiddleton, et al., Relationship between clinical efficacy and AEs of IMCgp100, a novel bispecific TCR–anti-CD3, in patients with advanced melanoma. Journal of Clinical Oncology. 2019.Orloff, et al., Vitiligo and other clinical melanocyte-related adverse events following tebentafusp (IMCgp100) exposure in patients with uveal melanoma. AACR (American Association for Cancer Research), 2020.
Aims
The effect of a distance‐learning package linked to educational credits on the rate and quality of spontaneous adverse drug reaction (ADR) reporting by general practitioners (GPs) and ...pharmacists in Wales was investigated.
Methods
In April 2000, 477 GPs and 261 pharmacists enrolled in the 12 month programme.
Results
The number and quality of yellow card reports improved compared with those of a control region in England (Northern Region).
Conclusions
We conclude that an educational initiative in drug safety linked to incentives may be associated with a significant but perhaps short‐lived improvement in the rate and quality of ADR reporting.
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Urban greenspaces Houghton, Jane; Thomas, Hazel
The Routledge Handbook of Urban Ecology,
2021, Volume:
1
Book Chapter
This chapter explores the patterns of people's usage of their local parks and greenspaces in urban areas in England, the benefits they enjoy, and the factors and attributes of greenspace provision ...that encourage or discourage visits. The findings of an annual national survey in England, called the 'Monitoring of Engagement in the Natural Environment Survey', are analyzed by demographic and socio-economic groups to better understand social equity and patterns of use of the urban natural environment. It is important that researchers and spatial planners understand the underlying determinants of the patterns of visiting. The ecosystems services provided by urban greenspaces that benefit local communities include flood resilience and water quality, urban cooling, air quality, and noise attenuation. The chapter concludes with recommendations on the use of the findings in urban planning to increase greenspace use benefits and social and economic equitability in access and recreational opportunities, and for further research.
This is an account the work of NetworkNorthWest, a £1m project at the University of Salford that ran between 2004 and 2007 and was developed to address the issues relating to poor take up of ...traditional business support by small to medium-sized enterprises (SMEs) and low levels of engagement of the business community with Institutes of Higher Education. Originally funded by the North West Development Agency (NWDA), NetworkNorthWest was specifically developed to improve innovation, entrepreneurship, enterprise and wealth creation in the Northwest's SME business community through educational micronetworking - networking to learn from, and with, others in a similar position in other SMEs using action learning techniques that allow the participants to set the agenda for what they need to learn. At the same time the project was able to benchmark best practice in this form of business support regionally, nationally and internationally. Working with six delivery partner universities across the North West of England, the support was multi-disciplinary and multifaceted (including applied research, knowledge transfer, management and professional development and provision of sector specific training for employees) and there was potential to deliver support in the form of face-to-face contact or online resources. The project, seen as exemplary by the NWDA, has since delivered support for Manchester Chamber Business Enterprises to a further cohort of SMEs across Greater Manchester and the core process has been adopted as the basis for the second level of intervention for leadership development by the Northern Leadership Academy. It also significantly improved the profitability of the SMEs who took part through the impact of innovative processes and developments enabled by action learning.
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