Insight Report: Online public involvement session on proposed cardiovascular research programmes

A group of researchers across Imperial College London (some of whom are also part of the Imperial Biomedical Research Centre (BRC)) are applying for £5 million funding over 5 years from the British Heart Foundation (BHF) to fund a BHF Centre for Research Excellence at Imperial to support research on various aspects of cardiovascular medicine. The four research themes the funding proposal will cover are as follows: 1. Societal and Environmental Factors 2. Learning from Heart Patients 3. Vascular Ageing (Blood vessels) 4. Remote (at home) personal monitorin

Report 14: Online community involvement in COVID-19 research & outbreak response: early insights from a UK perspective

The Patient Experience Research Centre (PERC) at Imperial College London is developing research to explore and understand people’s views about, experiences of and behavioural responses to the outbreak in the UK and elsewhere. To guide that effort and to help inform COVID-19 research and responses more broadly - for example in mathematical modelling and policy - PERC launched an online community involvement initiative that sought rapid, early insight from members of the public and aimed to establish a network for ongoing community engagement. Priority areas for COVID-19 research Vaccine development was considered the most urgent research priority for many respondents. Social studies exploring the public’s experiences, risk perceptions and behaviours during this outbreak were necessary and important according to 95% of the respondents. Such research could: Improve the way the current outbreak response is planned and implemented; Improve the way information and guidance is provided to and understood by the public; Optimise the support provided to communities and vulnerable groups; and Improve future outbreak preparedness. Other recommended areas of research included: Understanding the role of the media in influencing how people react and respond; Furthering our basic understanding of the virus – how it spreads, who it affects the most and why, and whether people achieve and maintain immunity after being infected; Critiquing the UK’s response to the pandemic against that of other countries; and Ensuring lessons can be learnt from this outbreak to better equip us for future outbreaks, and public health emergencies in general. Key unmet needs amongst communities The main challenges described by respondents were ineffective communication, including access to information and information overload; and conflicting guidance and misinformation. Respondents’ described feelings of concern, confusion and, in some cases, panic as a result of these communication and information challenges. Others shared their frustration that there was nowhere to post their concerns or questions. In addition, respondents expressed a need for more detailed and bespoke practical guidance about their risk and how best to prepare and protect themselves and their loved ones. Almost half (47%) wanted to hear about the latest research on the virus, and 45% wanted a dedicated internet portal where they could access the latest information and trusted guidance. Making information more accessible to different communities, including those who are not online and those who have English as a second language was also highlighted as a priority

Andy's Algorithms: new automated digital image analysis pipelines for FIJI.

Quantification of cellular antigens and their interactions via antibody-based detection methods are widely used in scientific research. Accurate high-throughput quantitation of these assays using general image analysis software can be time consuming and challenging, particularly when attempted by users with limited image processing and analysis knowledge. To overcome this, we have designed Andy's Algorithms, a series of automated image analysis pipelines for FIJI, that permits rapid, accurate and reproducible batch-processing of 3,3'-diaminobenzidine (DAB) immunohistochemistry, proximity ligation assays (PLAs) and other common assays. Andy's Algorithms incorporates a step-by-step tutorial and optimization pipeline to make batch image analysis simple for the untrained user and adaptable across laboratories. Andy's algorithms provide a simpler, faster, standardized work flow compared to existing programs, while offering equivalent performance and additional features, in a free to use open-source application of FIJI. Andy's Algorithms are available at GitHub, publicly accessed at https://github.com/andlaw1841/Andy-s-Algorithm

Groundnut: ICRISAT and East Timor

Although it is widely grown in small plots as an upland crop with little or no inputs, groundnut is not a major crop in East Timor. The cultivars that are grown have low yield potential and there is a great potential to increase the cultivation of groundnut in the country. Under the ACIAR ‘Seeds of life — East Timor’ project, new groundnut cultivars were introduced and trialled in the 2000–2001 and 2001–2002 seasons at a number of locations. Many of the introduced varieties outperformed the local variety at all the locations. As well as stimulating the local food and oil processing industry, increased groundnut production would provide an opportunity to export the produce to neighboring countries in the region. To enable a sufficient supply of good quality seed of the improved varieties farmers should be encouraged to produce and save their own seed. For this to happen, they need training in seed production and processing as the seed crop requires different handling than the commercial crop

ELF5 modulates the estrogen receptor cistrome in breast cancer.

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance

Voice and resistance: coalminers' struggles to represent their health and safety interests in Australia and New Zealand 1871–1925

The activism of coalmining unions in Australia, the UK, the USA and elsewhere securing improvements in safety including better legislation in the 19th and 20th centuries, has been widely researched and acknowledged. However, a relatively neglected aspect of this history was a campaign to secure worker inspectors (check-inspectors). These began in coalmining a century before similar measures were introduced for workers more generally as part of overhauling occupational health and safety laws in the 1970s/1980s. We document this struggle for mine safety in Australia and New Zealand, and the activities of check-inspectors in the period to 1925. Notwithstanding strong opposition from coal-owners and conservative governments, check-inspectors played an important role in safeguarding coalminers and improving the regulatory oversight of coalmines. Check-inspectors not only gave coalminers a ‘voice’ in OHS, but they also provided an exemplar of the value and legitimacy of worker’s ‘knowledge activism’. This system remains. Furthermore, the struggle is relevant to understanding contemporary debates about collective worker involvement in occupational health and safety

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation

The role of public involvement in the design of the first SARS-CoV-2 human challenge study during an evolving pandemic

High quality health care research must involve patients and the public. This ensures research is important, relevant and acceptable to those it is designed to benefit. The world’s first human challenge study with SARS-CoV-2 undertook detailed public involvement to inform study design despite the urgency to review and establish the study. The work was integral to the UK Research Ethics Committee review and approval of the study. Discussion with individuals from ethnic minorities within the UK population supported decision-making around the study exclusion criteria. Public review of study materials for consent processes led to the addition of new information, comparisons and visual aids to help volunteers consider the practicalities and risks involved in participating. A discussion exploring the acceptability of a human challenge study with SARS-CoV-2 taking place in the UK, given the current context of the pandemic, identified overall support for the study. Public concern for the wellbeing of trial participants, as a consequence of isolation, was identified. We outline our approach to public involvement and its impact on study design

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer