Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment

Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs)

Triple Negative Breast Cancer (TNBC) is defined by the lack of ERα, PR expression and HER2 overexpression and is the breast cancer subtype with the poorest clinical outcomes. Our aim was to identify genes driving TNBC proliferation and/or survival which could represent novel therapeutic targets. We performed microarray profiling of primary TNBCs and generated differential genelists based on clinical outcomes following the chemotherapy regimen FEC (5-Fluorouracil/Epirubicin/Cyclophosphamide -‘good’ outcome no relapse > 3 years; ‘poor’ outcome relapse < 3 years). Elevated expression of thromboxane A2 receptor (TBXA2R) was observed in ‘good’ outcome TNBCs. TBXA2R expression was higher specifically in TNBC cell lines and TBXA2R knockdowns consistently showed dramatic cell killing in TNBC cells. TBXA2R mRNA and promoter activities were up-regulated following BRCA1 knockdown, with c-Myc being required for BRCA1-mediated transcriptional repression. We demonstrated that TBXA2R enhanced TNBC cell migration, invasion and activated Rho signalling, phenotypes which could be reversed using Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. In summary, TBXA2R is a novel breast cancer-associated gene required for the survival and migratory behaviour of a subset of TNBCs and could provide opportunities to develop novel, more effective treatments

Measles virus host invasion and pathogenesis

Measles virus is a highly contagious negative strand RNA virus that is transmitted via the respiratory route and causes systemic disease in previously unexposed humans and non-human primates. Measles is characterised by fever and skin rash and usually associated with cough, coryza and conjunctivitis. A hallmark of measles is the transient immune suppression, leading to increased susceptibility to opportunistic infections. At the same time, the disease is paradoxically associated with induction of a robust virus-specific immune response, resulting in lifelong immunity to measles. Identification of CD150 and nectin-4 as cellular receptors for measles virus has led to new perspectives on tropism and pathogenesis. In vivo studies in non-human primates have shown that the virus initially infects CD150+ lymphocytes and dendritic cells, both in circulation and in lymphoid tissues, followed by virus transmission to nectin-4 expressing epithelial cells. The abilities of the virus to cause systemic infection, to transmit to numerous new hosts via droplets or aerosols and to suppress the host immune response for several months or even years after infection make measles a remarkable disease. This review briefly highlights current topics in studies of measles virus host invasion and pathogenesis

Employer demands from business graduates

This paper reports on research carried out with employers to determine demand for graduate business and management skills in the Scottish workforce.The research found that the factors which were most important to employers when recruiting graduates, with a business school first degree, were: personal attitude, employability skills, relevant work experience, and degree result. The most important transferable skills to employers when recruiting graduates were: trustworthiness, reliability, motivation, communication skills and a willingness to learn

Regionally Coherent Access and Employability Provision:Employer Demand for Business and Management Graduates.

This report presents findings from research with 71 employers of Edinburgh Napier University Business School (ENUBS) graduates across Scotland. Employers were asked to identify the academic, vocational and soft skills they sought when recruiting graduates

A new geodemographic classification of commuting flows for England and Wales

This paper aims to contribute to the area of geodemographic research through the development of a new and novel flow-based classification of commuting for England and Wales. In doing so, it applies an approach to the analysis of commuting in which origin-destination flow-data, collected as part of the 2011 census of England and Wales, are segmented into groups based on shared similarities across multiple demographic and socioeconomic attributes. K-means clustering was applied to 49 flow-based commuter variables for 513,892 interactions that captured 18.4 million of the 26.5 million workers recorded as part of the 2011 census of England and Wales. The final classification resulted in an upper-tier of nine ‘Supergroups’ which were subsequently partitioned to derive a lower-tier of 40 ‘Groups’. A nomenclature was developed and associated pen-portraits derived to provide basic signposting to the dominant characteristics of each cluster. Analysis of a selection of patterns underlying the nine-fold Supergroup configuration revealed a highly variegated structure of commuting in England and Wales. The classification has potentially wide-ranging descriptive and analytical applications within research and policy domains and the approach would be equally transferable to other countries and contexts where origin-destination data is disaggregated based on commuter characteristics

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

Acknowledgments The samples used in this research were received from the Northern Ireland Biobank, which has ethical approval to use de-identified tissue samples from the Belfast Health and Social Care Tissue Pathology archive (REC:11/NI/0013). The Northern Ireland Molecular Pathology Laboratory, was responsible for construction of tissue microarrays, slide staining, and scanning. We are grateful to the NVIDIA Corporation for supporting our research via the GPU Grant Program for researchers. The research leading to these results has also received funding from Invest Northern Ireland. The authors thank Mr. Ken Arthur for the construction of the original tissue microarrays used in this study. Funding This study was funded by a CRUK Accelerator Grant (A20256) to JJ and MST. CRUK had no role in the study design, collection, analysis, and interpretation of the data or in the writing of the report.Peer reviewedPublisher PD