Developing novel agents targeting the NF-κB pathway for the treatment of multiple myeloma

The key aim was to characterise Nuclear factor-κB (NF-κB) inhibitors in four multiple myeloma (MM) cell lines to evaluate their use as potential therapeutic agents in this incurable haematological malignancy. The NF-κB inhibitors were characterised in terms of their effects on cytotoxicity, nuclear NF-κB activity, global gene expression changes and the survival protein Mcl-1. Using this workflow, the following inhibitors were investigated: the commercial non-specific NF-κB inhibitor BAY 11-7082; a series of first-in-class putative IKKα inhibitors (SU compounds); and a novel putative NIK inhibitor (CW15337) in MM cell lines. BAY 11-7082, CW15337 and most of the SU compounds induced dosedependent cytotoxicity in the MM cell lines. For BAY 11-7082 and CW15337, cytotoxicity was associated with dose-dependent changes in NF-κB activity, although BAY 11-7082 inhibited both the canonical and the non-canonical NF-κB pathway, whereas CW15337 specifically inhibited the non-canonical NF-κB activity. In addition, the apoptosis induced by CW15337 was accompanied by a dose-dependent decrease in Mcl-1 expression in all tested MM cell lines. In contrast, the cytotoxicity of the SU compounds did not correlate with the dose-dependent down-regulation of Mcl-1 expression or NF-κB activity, and could not be completely explained by the SU compounds IKKα, IKKβ and CDK9 inhibitory profiles. Microarray analysis indicated a large disparity between the numbers of genes differentially regulated by some of the SU compounds; the number altered and the magnitude of the changes was associated with their cytotoxicity. Therefore, it seems likely that the increased potency of some of the SU compounds was caused by off-target effects. Overall, this work supports the concept of NF-κB as a molecular target in MM and suggests that NIK inhibition may present the most promising therapeutic option for specific non-canonical NF-κB targeting in MM. However, a more detailed investigation of CW15337 across the kinome is merited

Applying remotely sensed habitat descriptors to assist reintroduction programs: A case study in the hazel dormouse

For reintroduction programs to succeed, it is vital to identify suitable release sites. This is especially true for low dispersing habitat specialists, which are at particular risk from habitat fragmentation. The habitat specialist Muscardinus avellanarius (hazel dormouse) is part of a large-scale reintroduction program in the UK. The program began in 1993 and has so far had varying levels of long-term success across 24 sites. Although the causes of population persistence at reintroduction sites are not well understood, continued habitat suitability is hypothesized to play an important role. Here, we establish broad-scale habitat descriptors associated with the current distribution of natural hazel dormouse populations in England, using ecological niche factor analysis and remotely sensed, open-source maps. We also apply generalized linear mixed effects models to long-term monitoring data for reintroduced hazel dormouse populations, revealing that broad-scale habitat factors strongly influence the number of animals present in nest boxes. To aid conservation practitioners in future site selection, we illustrate the practical application of habitat suitability mapping to help prioritize the most appropriate woodlands for future hazel dormouse reintroductions, using the county of Cheshire as an example. Although demonstrated here for the hazel dormouse, this approach to reintroduction site selection could be beneficial to a broad range of species

Land conflict in peri-urban areas: Exploring the effects of land reform on informal settlement in Mexico

Peri-urban areas are often subject to intensive construction, through both formal and informal processes. As land transitions from rural to urban status, different land tenure and administration systems may come into conflict, leading to disputes, contestation and, in some cases, violence. However, little is known about the precise causes of peri-urban land conflict. In Mexico, peri-urban growth has historically proceeded peacefully, owing to the control exerted by a corporatist system of government, and the political use of land tenure regularisation. However, the effects of land reforms on transactions at the peri-urban fringe, in the context of wider processes of liberalisation, may be increasing vulnerability to conflict over land. This paper explores these issues through a case study of an irregular settlement on the peri-urban fringe of the provincial Mexican city of Xalapa, where contestations over informally developed land have escalated into violent encounters between groups of settlers and the state. The findings show that vulnerability to conflict in peri-urban areas can be attributed to the interaction of macro-level processes with local-level factors, including diverse claims, overlapping legal and governance frameworks and, critically, local power relations

Erratum to: Mutation screening in 86 known X-linked mental retardation genes by droplet-based multiplex PCR and massive parallel sequencing

Item does not contain fulltext[This corrects the article DOI: 10.1007/s11568-010-9137-y.].1 december 200

Constructing ordinary places: Place-making in urban informal settlements in Mexico

Observers from a variety of disciplines agree that informal settlements account for the majority of housing in many cities of the global South. Urban informal settlements, usually defined by certain criteria such as self-build housing, sub-standard services, and residents’ low incomes, are often seen as problematic, due to associations with poverty, irregularity and marginalisation. In particular, despite years of research and policy, gaps in urban theory and limited understandings of urban informal settlements mean that they are often treated as outside ‘normal’ urban considerations, with material effects for residents including discrimination, eviction and displacement. In response to these considerations, this article uses a place-making approach to explore the spatial, social and cultural construction of place in this context, in order to unsettle some of the assumptions underlying discursive constructions of informal settlements, and how these relate to spatial and social marginalisation. Research was carried out using a qualitative, ethnographic methodology in two case study neighbourhoods in Xalapa, Mexico. Mexico offers fertile ground to explore these issues. Despite an extensive land tenure regularisation programme, at least 60 per cent of urban dwellers live in colonias populares, neighbourhoods with informal characteristics. The research found that local discourses reveal complex and ambivalent views of colonias populares, which both reproduce and undermine marginalising tendencies relating to ‘informality’. A focus on residents’ own place-making activities hints at prospects for rethinking urban informal settlements. By capturing the messy, dynamic and contextualised processes that construct urban informal settlements as places, the analytical lens of place-making offers a view of the multiple influences which frame them. Informed by perspectives from critical social geography which seek to capture the ‘ordinary’ nature of cities, this article suggests imagining urban informal settlements differently, in order to re-evaluate their potential contribution to the city as a whole

The UK stand together trial: protocol for a multicentre cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of KiVa to reduce bullying in primary schools

Background Reducing bullying is a public health priority. KiVa, a school-based anti-bullying programme, is effective in reducing bullying in Finland and requires rigorous testing in other countries, including the UK. This trial aims to test the effectiveness and cost-effectiveness of KiVa in reducing child reported bullying in UK schools compared to usual practice. The trial is currently on-going. Recruitment commenced in October 2019, however due to COVID-19 pandemic and resulting school closures was re-started in October 2020. Methods Design: Two-arm pragmatic multicentre cluster randomised controlled trial with an embedded process and cost-effectiveness evaluation. Participants: 116 primary schools from four areas; North Wales, West Midlands, South East and South West England. Outcomes will be assessed at student level (ages 7–11 years; n = approximately 13,000 students). Intervention: KiVa is a whole school programme with universal actions that places a strong emphasis on changing bystander behaviour alongside indicated actions that provide consistent strategies for dealing with incidents of bullying. KiVa will be implemented over one academic year. Comparator: Usual practice. Primary outcome: Student-level bullying-victimisation assessed through self-report using the extensively used and validated Olweus Bully/Victim questionnaire at baseline and 12-month follow-up. Secondary outcomes: student-level bullying-perpetration; student mental health and emotional well-being; student level of, and roles in, bullying; school related well-being; school attendance and academic attainment; and teachers’ self-efficacy in dealing with bullying, mental well-being, and burnout. Sample size: 116 schools (58 per arm) with an assumed ICC of 0.02 will provide 90% power to identify a relative reduction of 22% with a 5% significance level. Randomisation: recruited schools will be randomised on 1:1 basis stratified by Key-Stage 2 size and free school meal status. Process evaluation: assess implementation fidelity, identify influences on KiVa implementation, and examine intervention mechanisms. Economic evaluation: Self-reported victimisation, Child Health Utility 9D, Client Service Receipt Inventory, frequency of services used, and intervention costs. The health economic analysis will be conducted from a schools and societal perspective. Discussion This two-arm pragmatic multicentre cluster randomised controlled trial will evaluate the KiVa anti-bullying intervention to generate evidence of the effectiveness, cost-effectiveness and scalability of the programme in the UK. Our integrated process evaluation will assess implementation fidelity, identify influences on KiVa implementation across England and Wales and examine intervention mechanisms. The integrated health economic analysis will be conducted from a schools and societal perspective. Our trial will also provide evidence regarding the programme impact on inequalities by testing whether KiVa is effective across the socio-economic gradient