LRH-1 as a Key Regulator of Estrogen Responses in Breast Cancer Cells

Liver receptor homolog-1 (LRH-1; NR5A2) is an orphan member of the Ftz-F1 family of nuclear receptors, which comprises four members (NR5A1-NR5A4). LRH- 1 has been linked to a number of key developmental, metabolic and proliferative processes and is known to play an important role in the regulation of cholesterol biosynthesis, lipid homeostasis and the control of steroid aromatisation. In this respect, LRH-1 is recognised to play an important role in breast cancer, where it acts to regulate aromatase activity, leading to the paracrine production of estrogen. Recent findings have also suggested a direct role for LRH-1 in cancer, where LRH-1 is found to be involved in the induction of intestinal tumours and LRH-1 has been found by immunohistochemistry in tumour cells of human mammary ductal carcinomas. Recently, a gene expression microarray analysis of estrogen responses in an engineered breast cancer cell line, where Estrogen Receptor-α (ERα) activity can be conditionally repressed, provisionally identified LRH-1 as an estrogen responsive gene that may be important in the estrogen-regulated growth of breast cancer cells. Based on this initial observation, I have gone on to study the role of LRH-1 in the estrogen response in breast cancer cells. Using ERα-positive breast cancer cell lines, I have confirmed that LRH-1 levels increase in response to estrogen and are inhibited by anti-estrogens (tamoxifen and ICI 182,780). Using 5`RNA Ligase Mediated Rapid Amplification of cDNA Ends (5`RLM-RACE) to characterise the 5’ end of the LRH-1 mRNA, I have found that the estrogen regulation of LRH-1 is mediated through a previously undescribed gene promoter, which results in the production of a variant LRH-1 mRNA species that initiates transcription just upstream of exon 2 of the LRH-1 gene. Further, reverse transcriptase polymerase chain reaction (RT-PCR) showed that the newly identified variant LRH-1 transcript is expressed in tissues in which LRH-1 expression has previously been described. Moreover, this variant was seen to be the major form of LRH-1 expressed in breast cancer cell lines. Having established the estrogen regulation of LRH-1, studies were carried out to investigate the role of LRH-1 in growth and gene expression in breast cancer cells. siRNA-mediated inhibition of LRH-1 expression inhibited proliferation of MCF-7, ZR-75-1 and T47-D breast cancer cell lines but did not inhibit BT474 and MDAMB- 231 breast cancer cells, in which LRH-1 is not expressed. Further, a group of recently described synthetic agonists for LRH-1 stimulated the growth of breast cancer cell lines expressing LRH-1 in a dose dependent manner, but did not stimulate growth in those breast cancer cell lines which do not express LRH-1. Finally, RNA interference experiments directed against LRH-1 identified ERα as an important LRH-1 regulated gene. These results show that LRH-1 potentially plays a key role in regulating estrogen responses in ERα–positive breast cancer cells, primarily through the direct regulation of ERα gene expression. These new findings, taken together with the previously described role for LRH-1 in regulating aromatase gene expression identify LRH-1 as a potentially important target for the development of new therapies for the treatment of breast cancer

Continuous low-dose antibiotic prophylaxis for adults with repeated urinary tract infections (AnTIC): a randomised, open-label trial

Funder: UK National Institute for Health Research. Open Access funded by Department of Health UK Acknowledgments We thank all the participants for their commitment to the study, Sheila Wallace for updating the systematic review, members of the Trial Steering Committee and members of the Data Monitoring Committee for their valuable guidance. We thank the National Health Service organisations, principal investigators and local research staff who hosted and ran the study at site. We thank the Health Technology Assessment Programme of the UK NIHR for funding the study (no. 11/72/01). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Government Department of Health. A full report of the study30 has been published by the NIHR Library.Peer reviewedPublisher PD

Continuous low-dose antibiotic prophylaxis to prevent urinary tract infection in adults who perform clean intermittent self-catheterisation: the AnTIC RCT

Peer reviewedPublisher PD

Pesticides and Parkinson’s Disease—Is There a Link?

Parkinson’s disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. In this article we present a comprehensive review of the published epidemiologic and toxicologic literature and critically evaluate whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. However, both the epidemiology and toxicology studies were limited by methodologic weaknesses. Particular issues of current and future interest include multiple exposures (both pesticides and other exogenous toxicants), developmental exposures, and gene–environment interactions. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure

Co-regulated gene expression by oestrogen receptor α and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells.

Oestrogen receptor α (ERα) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, regulates breast cancer cell proliferation and promotes motility and invasion. To determine the mechanisms of LRH-1 action in breast cancer, we performed gene expression microarray analysis following RNA interference for LRH-1. Interestingly, gene ontology (GO) category enrichment analysis of LRH-1-regulated genes identified oestrogen-responsive genes as the most highly enriched GO categories. Remarkably, chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1 showed LRH-1 binding at many ERα binding sites. Analysis of select binding sites confirmed regulation of ERα-regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ERα recruitment, while LRH-1 knockdown reduced ERα recruitment to ERα binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERα target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERα at oestrogen response elements controls the expression of oestrogen-responsive genes

Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000

BACKGROUND: Head and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors. METHODS: We are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires. DISCUSSION: This large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Data from: The importance of a medical chaperone: a quality improvement study exploring the use of a note stamp in a tertiary breast surgery unit

Objectives :The project aim was to determine current use and documentation of medical chaperones within a major breast service unit. It explored ways of improving adherence to professional guidelines concerning chaperones. Setting: The single centre quality improvement project was completed in a tertiary breast service unit in North West London. It was a three-stage project with initial audit in October 2013, 1st postintervention cycle in November 2013 and 2nd postintervention cycle in October 2014. Participants: In each study cycle, data were collected from entries in clinic notes until at least 155 encounters with documented clinical examination were analysed. All notes were of female patients. Interventions: (1) Intervention 1st cycle: presentation and discussion of chaperone guidelines alongside reminder posters and introduction of note stamp. (2) Intervention 2nd cycle: note stamp alone. Primary and secondary outcome measures: Documentation of chaperone offer, documentation of patient preference regarding chaperone, identifier (name or signature) of chaperone present and gender of examining clinician. Results: In the 1st postintervention cycle, 69.95% documentation of chaperone offer was recorded, p<0.001, CI (59.04% to 80.76%). This result was replicated in the 2nd postintervention cycle a year later with 74.86% documentation of chaperone offer recorded, p<0.001, CI (66.41% to 83.31%). The 4.91% difference was insignificant; p=0.294, CI (14.03% to 4.21%). Conclusions: The authors suggest that a proforma approach to medical chaperones is an effective means of ensuring adherence to best practice guidelines. A stamp, or similar, that can be embedded into documentation structure is an effective example of such an approach. Improved documentation allows any problems with adherence to guidelines to be more easily identified, helping to ensure the safeguarding of patients and staff involved in intimate examinations

Raw data for three parts of a QIP study

Data was collected in paper format by researchers at the end of an outpatient clinic and inputted each day into a cumulative excel spreadsheet. The raw data is included in these files. Statistical calculations for this data were calculated using an open access software. Results of a two tailed z-calculation have also been included. Confidence intervals where relevant were included in the paper and calculated by hand