Transient receptor potential canonical 4 and 5 proteins as targets in cancer therapeutics

Novel approaches towards cancer therapy are urgently needed. One approach might be to target ion channels mediating Ca²+ entry because of the critical roles played by Ca²+ in many cell types, including cancer cells. There are several types of these ion channels, but here we address those formed by assembly of transient receptor potential canonical (TRPC) proteins, particularly those which involve two closely related members of the family: TRPC4 and TRPC5. We focus on these proteins because recent studies point to roles in important aspects of cancer: drug resistance, transmission of drug resistance through extracellular vesicles, tumour vascularisation, and evoked cancer cell death by the TRPC4/5 channel activator (−)-englerin A. We conclude that further research is both justified and necessary before these proteins can be considered as strong targets for anti-cancer cell drug discovery programmes. It is nevertheless already apparent that inhibitors of the channels would be unlikely to cause significant adverse effects, but, rather, have other effects which may be beneficial in the context of cancer and chemotherapy, potentially including suppression of innate fear, visceral pain and pathological cardiac remodelling

Framing child protection as a public health law issue

During their remarks for a University of Michigan symposium on “Rethinking Foster Care”1 a variety of participants addressed foster care, or even rethinking child protection policy as a whole, from ‘the ground up’. Several speakers referenced the model of public health as a useful framework for child welfare policy. During many formal and informal exchanges, many others alluded to public health, touching on themes such as the importance of promoting primary prevention over later intervention, reducing reliance on punitive models for intervention, and relying more on science as a foundation for child welfare policy development. Given the role of public health as a touchstone2 for these views, likely shared by many non-lawyers, this chapter revisits the nature of public health, and the related field of public health law, before considering briefly a few examples that have been raised as embodying a public health application to child welfare.3 A review of historic and recent public health practices and law cannot be comprehensive, but can be instructive for any who would apply public health to child welfare, and who need to be informed by the workings, achievements and weaknesses of the vast field of public health. Moreover, this can avoid oversimplification and maximize the utility of a public health perspective for child protection policy analysis.4</sup

The widespread dissemination of integrons throughout bacterial communities in a riverine system.

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordAnthropogenic inputs increase levels of antimicrobial resistance (AMR) in the environment, however, it is unknown how these inputs create this observed increase, and if anthropogenic sources impact AMR in environmental bacteria. The aim of this study was to characterise the role of waste water treatment plants (WWTPs) in the dissemination of class 1 integrons (CL1s) in the riverine environment. Using sample sites from upstream and downstream of a WWTP, we demonstrate through isolation and culture-independent analysis that WWTP effluent significantly increases both CL1 abundance and antibiotic resistance in the riverine environment. Characterisation of CL1-bearing isolates revealed that CL1s were distributed across a diverse range of bacteria, with identical complex genetic resistance determinants isolated from both human-associated and common environmental bacteria across connected sites. Over half of sequenced CL1s lacked the 3'-conserved sequence ('atypical' CL1s); surprisingly, bacteria carrying atypical CL1s were on average resistant to more antibiotics than bacteria carrying 3'-CS CL1s. Quaternary ammonium compound (QAC) resistance genes were observed across 75% of sequenced CL1 gene cassette arrays. Chemical data analysis indicated high levels of boron (a detergent marker) downstream of the WWTP. Subsequent phenotypic screening of CL1-bearing isolates demonstrated that ~90% were resistant to QAC detergents, with in vitro experiments demonstrating that QACs could solely select for the transfer of clinical antibiotic resistance genes to a naive Escherichia coli recipient. In conclusion, this study highlights the significant impact of WWTPs on environmental AMR, and demonstrates the widespread carriage of clinically important resistance determinants by environmentally associated bacteria.We gratefully acknowledge financial support from the Natural Environment Research Council (grant NE/E004482/1). GCAA was supported by a BBSRC studentship. WHG has been supported by the ERDF and ESF since moving to the University of Exeter