A novel role for BRCA1 in regulating breast cancer cell spreading and motility

BRCA1 interacts with ERM proteins at leading edges and focal adhesion sites and modulates motility via its ubiquitin ligase activity

Intestinal epithelial Suppressor of Cytokine Signaling (SOCS) 3 enhances microbial induced inflammatory TNFα, contributing to epithelial barrier dysfunction

A single layer of intestinal epithelial cells (IEC) lines the entire GI tract and provides the first line of defence and barrier against an abundance of microbial stimuli. IEC homeostasis and repair are mediated through microbe-sensing Toll-like receptor (TLR)-induced inflammatory pathways. Increasing evidence supports a role of suppressor of cytokine signaling 3 (SOCS3) as a modulator of IEC turnover, balancing controlled repair and replenishment with excessive IEC proliferation predisposing to dysplasia and cancer. Our data indicate that SOCS3 can limit microbial-induced epithelial repair, promote TNFα, possibly through limiting TNFR2 expression in intestinal epithelial cells (IEC). Activation of TLR5 signalling pathways, compared with other TLR, increase TNFα mRNA in a dose dependent manner and SOCS3 enhances TLR5-induced TNFα. We also show that flagellin promotes transcription of TNFR2 and that SOCS3 may limit this expression, presenting a mechanism of SOCS3 action. Our data also supports the role of microbial ligands in epithelial wound healing and suggests that a functional consequence of increased TNFα is reduced wound healing. These results provide further evidence to support the regulatory role of epithelial SOCS3 in intestinal health and suggest that the increased expression of SOCS3 observed in IBD may serve to perpetuate 'inflammation' by promoting TNFα production and limiting epithelial repair in response to commensal microflora

Reducing Decisional Conflict and Enhancing Satisfaction with Information among Women Considering Breast Reconstruction following Mastectomy: Results from the BRECONDA Randomized Controlled Trial

Background: Deciding whether or not to have breast reconstruction following breast cancer diagnosis is a complex decision process. This randomized controlled trial assessed the impact of an online decision aid [Breast RECONstruction Decision Aid (BRECONDA)] on breast reconstruction decision-making. Methods: Women (n = 222) diagnosed with breast cancer or ductal carcinoma in situ, and eligible for reconstruction following mastectomy, completed an online baseline questionnaire. They were then assigned randomly to receive either standard online information about breast reconstruction (control) or standard information plus access to BRECONDA (intervention). Participants then completed questionnaires at 1 and 6 months after randomization. The primary outcome was participants' decisional conflict 1 month after exposure to the intervention. Secondary outcomes included decisional conflict at 6 months, satisfaction with information at 1 and 6 months, and 6-month decisional regret. Results: Linear mixed-model analyses revealed that 1-month decisional conflict was significantly lower in the intervention group (27.18) compared with the control group (35.5). This difference was also sustained at the 6-month follow-up. Intervention participants reported greater satisfaction with information at 1- and 6-month follow-up, and there was a nonsignificant trend for lower decisional regret in the intervention group at 6-month follow-up. Intervention participants' ratings for BRECONDA demonstrated high user acceptability and overall satisfaction. Conclusions: Women who accessed BRECONDA benefited by experiencing significantly less decisional conflict and being more satisfied with information regarding the reconstruction decisional process than women receiving standard care alone. These findings support the efficacy of BRECONDA in helping women to arrive at their breast reconstruction decision

The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Drug Target Evaluation

Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors BAP1, NF2 and P16 may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses. Ten cell lines, representing the spectrum of histological subtypes and tumour suppressor status, were dual labelled for fluorescence/bioluminescence imaging and implanted on the CAM at E7. Bioluminescence was used to assess viability of primary tumours, which were excised at E14 for immunohistological staining or real-time PCR. All MPM cell lines engrafted efficiently forming vascularised nodules, however their size, morphology and interaction with chick cells varied. MPM phenotypes including local invasion, fibroblast recruitment, tumour angiogenesis and vascular remodelling were evident. Bioluminescence imaging could be used to reliably estimate tumour burden pre- and post-treatment, correlating with tumour weight and Ki-67 staining. In conclusion, MPM-CAM models recapitulate important features of the disease and are suitable to assess drug targets using a broad range of MPM cell lines that allow histological or genetic stratification. They are amenable to multi-modal imaging, potentially offering a time and cost-efficient, 3Rs-compliant alternative to rodent xenograft models to prioritise candidate compounds from in vitro studies

An expert-driven framework for applying eDNA tools to improve biosecurity in the Antarctic

Signatories to the Antarctic Treaty System’s Environmental Protocol are committed to preventing incursions of non-native species into Antarctica, but systematic surveillance is rare. Environmental DNA (eDNA) methods provide new opportunities for enhancing detection of non-native species and biosecurity monitoring. To be effective for Antarctic biosecurity, eDNA tests must have appropriate sensitivity and specificity to distinguish non-native from native Antarctic species, and be fit-for-purpose. This requires knowledge of the priority risk species or taxonomic groups for which eDNA surveillance will be informative, validated eDNA assays for those species or groups, and reference DNA sequences for both target non-native and related native Antarctic species. Here, we used an expert elicitation process and decision-by-consensus approach to identify and assess priority biosecurity risks for the Australian Antarctic Program (AAP) in East Antarctica, including identifying high priority non-native species and their potential transport pathways. We determined that the priority targets for biosecurity monitoring were not individual species, but rather broader taxonomic groups such as mussels (Mytilus species), tunicates (Ascidiacea), springtails (Collembola), and grasses (Poaceae). These groups each include multiple species with high risks of introduction to and/or establishment in Antarctica. The most appropriate eDNA methods for the AAP must be capable of detecting a range of species within these high-risk groups (e.g., eDNA metabarcoding). We conclude that the most beneficial Antarctic eDNA biosecurity applications include surveillance of marine species in nearshore environments, terrestrial invertebrates, and biofouling species on vessels visiting Antarctica. An urgent need exists to identify suitable genetic markers for detecting priority species groups, establish baseline terrestrial and marine biodiversity for Antarctic stations, and develop eDNA sampling methods for detecting biofouling organisms

An expert-driven framework for applying eDNA tools to improve biosecurity in the Antarctic

Signatories to the Antarctic Treaty System’s Environmental Protocol are committed to preventing incursions of non-native species into Antarctica, but systematic surveillance is rare. Environmental DNA (eDNA) methods provide new opportunities for enhancing detection of non-native species and biosecurity monitoring. To be effective for Antarctic biosecurity, eDNA tests must have appropriate sensitivity and specificity to distinguish non-native from native Antarctic species, and be fit-for-purpose. This requires knowledge of the priority risk species or taxonomic groups for which eDNA surveillance will be informative, validated eDNA assays for those species or groups, and reference DNA sequences for both target non-native and related native Antarctic species. Here, we used an expert elicitation process and decision-by-consensus approach to identify and assess priority biosecurity risks for the Australian Antarctic Program (AAP) in East Antarctica, including identifying high priority non-native species and their potential transport pathways. We determined that the priority targets for biosecurity monitoring were not individual species, but rather broader taxonomic groups such as mussels (Mytilus species), tunicates (Ascidiacea), springtails (Collembola), and grasses (Poaceae). These groups each include multiple species with high risks of introduction to and/or establishment in Antarctica. The most appropriate eDNA methods for the AAP must be capable of detecting a range of species within these high-risk groups (e.g., eDNA metabarcoding). We conclude that the most beneficial Antarctic eDNA biosecurity applications include surveillance of marine species in nearshore environments, terrestrial invertebrates, and biofouling species on vessels visiting Antarctica. An urgent need exists to identify suitable genetic markers for detecting priority species groups, establish baseline terrestrial and marine biodiversity for Antarctic stations, and develop eDNA sampling methods for detecting biofouling organisms.This work was supported as a Science Innovation Project by the Department of Agriculture, Water and the Environment’s Science Innovation Program funding 2021–22 (project team: A.J.M., L.J.C., D.M.B., C.K.K., J.S.S. and L.S.). Support was also provided (to J.D.S, E.L.J., S.A.R., J.S.S., M.I.S., J.M.S., N.G.W.) from Australian Research Council SRIEAS grant SR200100005. P.C. and K.A.H. are supported by NERC core funding to the BAS Biodiversity, Evolution and Adaptation Team and Environment Office, respectively. L.R.P. and M.G. are supported by Biodiversa ASICS funding

'Pedometers cost buttons': the feasibility of implementing a pedometer based walking programme within the community

Background: Recent studies have suggested that walking interventions may be effective (at least in the short term) at increasing physical activity amongst those people who are the most inactive. This is a leading objective of contemporary public health policy in the UK and worldwide. However, before committing money from limited budgets to implement walking interventions more widely in the community, policymakers will want to know whether similar impacts can be expected and whether any changes will be required to the process to ensure uptake and success. This paper utilises the findings from a recent community-based pedometer study (Walking for Wellbeing in the West - WWW) undertaken in Glasgow, Scotland to address issues of feasibility. Methods: An economic analysis of the WWW study assessed the costs of the interventions (minimal and maximal) and combined these with the effects to present incremental cost-effectiveness ratios (cost/person achieving the target of an additional 15,000 steps/week). A qualitative evaluation, involving focus group discussions with WWW participants and short interviews with members of the WWW research team, explored perceived benefits and barriers associated with walking, as well as the successful aspects and challenges associated with the interventions. Results: The incremental cost effectiveness associated with the interventions was estimated as (sic)92 and (sic)591 per person achieving the target for the minimal and maximal interventions respectively. The qualitative evaluation gave insight into the process by which the results were achieved, and identified several barriers and facilitators that would need to be addressed before implementing the interventions in the wider community, in order to ensure their effective transfer. These included assessing the impact of the relationship between researchers and participants on the results, and the motivational importance of monitoring and assessing performance. Conclusions: The results suggest that pedometer based walking interventions may be considered cost-effective and suitable for implementation within the wider community. However, several research gaps remain, including the importance and impact of the researcher/participant relationship, the impact of assessment on motivation and effectiveness, and the longer term impact on physical and mental health, resource utilisation and quality of life

A CO2 sensing module modulates β-1,3-glucan exposure in Candida albicans.

This work was funded by a program grant to A.J.P.B., N.A.R.G., L.P.E., and M.G.N. from the UK Medical Research Council [www.mrc.ac.uk: MR/M026663/1, MR/M026663/2]. The work was also supported by the Medical Research Council Centre for Medical Mycology [MR/N006364/1, MR/N006364/2], by a grant to C.d.E. from the European Commission [FunHoMic: H2020-MSCA-ITN-2018–812969], and by the Wellcome Trust via Investigator, Collaborative, Equipment, Strategic and Biomedical Resource awards [www.wellcome.ac.uk: 075470, 086827, 093378, 097377, 099197, 101873, 102705, 200208, 217163, 224323]. Work in the d’Enfert laboratory was supported by grants from the Agence Nationale de Recherche (ANR-10-LABX-62-IBEID) and the Swiss National Science Foundation (Sinergia CRSII5_173863/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD