<i>Lrig1</i> expression identifies airway basal cells with high proliferative capacity and restricts lung squamous cell carcinoma growth

Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival.Using an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression.Together, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes

It's all in the details: methods in breast development and cancer

The inaugural European Network for Breast Development and Cancer (ENBDC) meeting on 'Methods in Mammary Gland Development and Cancer' was held in Weggis, Switzerland last April. The goal was to discuss the details of techniques used to study mammary gland biology and tumourigenesis. Highlights of this meeting included the use of four-colour fluorescence for protein co-localisation in tissue microarrays, genome analysis at single cell resolution, technical issues in the isolation of normal and tumour stem cells, and the use of mouse models and mammary gland transplantations to elucidate gene function in mammary development and to study drug resistance in breast cancer

Estrogen receptor-α and progesterone receptor are expressed in label-retaining mammary epithelial cells that divide asymmetrically and retain their template DNA strands

INTRODUCTION: Stem cells of somatic tissues are hypothesized to protect themselves from mutation and cancer risk through a process of selective segregation of their template DNA strands during asymmetric division. Mouse mammary epithelium contains label-retaining epithelial cells that divide asymmetrically and retain their template DNA. METHOD: Immunohistochemistry was used in murine mammary glands that had been labeled with [(3)H]thymidine during allometric growth to investigate the co-expression of DNA label retention and estrogen receptor (ER)-α or progesterone receptor (PR). Using the same methods, we investigated the co-localization of [(3)H]thymidine and ER-α or PR in mammary tissue from mice that had received treatment with estrogen, progesterone, and prolactin subsequent to a long chase period to identify label-retaining cells. RESULTS: Label-retaining epithelial cells (LRECs) comprised approximately 2.0% of the entire mammary epithelium. ER-α-positive and PR-positive cells represented about 30–40% of the LREC subpopulation. Administration of estrogen, progesterone, and prolactin altered the percentage of LRECs expressing ER-α. CONCLUSION: The results presented here support the premise that there is a subpopulation of LRECs in the murine mammary gland that is positive for ER-α and/or PR. This suggests that certain mammary LRECs (potentially stem cells) remain stably positive for these receptors, raising the possibility that LRECs comprise a hierarchy of asymmetrically cycling mammary stem/progenitor cells that are distinguished by the presence or absence of nuclear steroid receptor expression

Stop! In the name of transforming growth factor-β: keeping estrogen receptor-α-positive mammary epithelial cells from proliferating

Recent genetic and cell biological studies illustrate the importance of active transforming growth factor-β signaling in preventing the proliferation of estrogen receptor-positive cells in the normal mammary gland, and suggest how the loss of this inhibition may be important in early breast cancer progression

Who are the 'middle actors' in sustainable construction and what do they need to know?

This paper explores what knowledge and skills are needed, and how those skills and knowledge might be gained, in order to deliver more sustainable outcomes from construction, using the concept of ‘middle actors’. ‘Middle actors’ are the individuals who occupy the space between ‘top-down’ policy and instruction, and ‘bottom-up’ norms. In construction, ‘middle actors’ with influence on building performance include clerks of works, project managers, tradespeople and technical advisers. There is a relentless drive for more sustainable buildings that use less energy, generate less waste during construction and use, and provide healthy environments for people to live and work in. This direction of travel can no longer be considered ‘new’ and yet it remains far from the mainstream. To create buildings which are sustainable, we need to consider not only technology and design changes, but how to alter the wider system of construction. We use middle actors as the lens through which to examine these non-technical changes, and the skills and knowledge required to achieve them. A review of the concept of middle actors as it has been applied to construction and an overview of skills and knowledge needs for sustainable construction is followed by identifying middle actors in new build and retrofit, commercial and domestic projects currently under way with one developer in Leeds, UK. The skills and knowledge needed by ‘middle actors’ to deliver more sustainable outcomes from their projects are described, based on empirical data gathered from project teams, and further structured by considering when in the project cycle they are needed, and what routes to gaining the required skills and knowledge might be most effective. This analysis reinforces that there is no single route to achieving more sustainable buildings and instead the activities, responsibilities and networks of individuals need to be carefully considered in developing training programmes for construction teams

Birth weight in relation to endometrial and breast cancer risks in Swedish women

An examination of birth weight in a Swedish cohort study of 38 566 women showed no significant association between birth weight and endometrial cancer, but supported a protective role for low birth weight for premenopausal breast cancer

Sirenomelia in a Nigerian triplet: a case report

<p>Abstract</p> <p>Introduction</p> <p>Sirenomelia, also known as mermaid syndrome, is a very rare fatal congenital abnormality in which the legs are fused together, giving them the appearance of a mermaid's tail. It is commonly associated with abnormal kidney development, genital and rectal abnormalities. A handful of cases have been reported in other parts of the world, however, no cases have previously been reported in a Nigerian neonate. To the best of our knowledge, we believe that this is the first case reported from West Africa and in a triplet.</p> <p>Case presentation</p> <p>A 16-hour-old baby boy, the second of a set of Nigerian triplets, presented to our facility with fusion of the entire lower limbs, imperforate anus, indiscernible genital structures, single umbilical artery and a neural tube defect. His parents were from the Hausa ethnic group and not related.</p> <p>Conclusion</p> <p>Sirenomelia has not been previously described in a set of triplets, and it is hoped that this report from West Africa will give information about the non-racial predilection of this condition.</p

Salvage radiotherapy after radical prostatectomy: analysis of toxicity by dose-fractionation in the RADICALS-RT trial

ABSTRACT: Emerging data indicate comparable disease control and toxicity of postoperative normo-fractionation and moderate hypofractionation radiotherapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66Gy in 33 fractions over 6.5 weeks or 52.5Gy in 20 fractions over 4 weeks. In this non-randomized, exploratory analysis, we explore the toxicity of these two schedules in patients who had adjuvant RT. METHODS: Information on RT dose was collected in all patients. Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, 6-monthly until 5 years, then annually until 15 years. Patient-reported data were collected at baseline, 1, 5, and 10 years with use of standard questionnaires including Vaizey (bowel) and International Continence Society Male Short-Form (urinary incontinence). The highest grade of event was recorded within the first 2 years, and beyond 2 years, and compared between treatment groups using the χ² test. RESULTS: 217/634 (34%) patients were planned for 52.5Gy/20f and 417/634 (66%) for 66Gy/33f. In the first two years, grade 1 - 2 cystitis was reported more frequently among the 66Gy/33f group (52.5Gy/20f: 20% vs 66Gy/33f: 30%, p=0.04). After two years, grade 1-2 cystitis was reported in 16% in the 66Gy group, and 9% in the 52.5Gy group (p=0.08). Other toxicities were similar in the two groups and very few patients had any grade 3 - 4 toxicity. Patients reported slightly higher urinary and faecal incontinence scores at one year than at baseline, but no clinically meaningful differences were reported between 52.5Gy/20f and 66Gy/33f groups. Patient reported health was similar at baseline and at one year, and similar between 52.5Gy/20f and 66Gy/33f groups. CONCLUSION: Severe toxicity is rare after prostate bed radiotherapy with either 52.5Gy/20f or 66Gy/33f. Only modest differences were recorded in toxicity or in patient reported outcomes between these two schedules

Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial

The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research arms and 1 control arm. The trial has a pilot stage assessing safety and feasibility, 3 intermediate “activity” stages (I-III) where the outcome measure is failure-free survival (FFS) and one final “efficacy” stage (IV) with overall survival as primary outcome measure. At the end of each stage, each research arm is formally compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to arms showing activity with acceptable safety. The stopping guideline compares the treatment effect against a pre-defined cut-off value using the hazard ratio when the hazards are proportional and restricted-mean survival time otherwise. This interim hurdle becomes increasingly stringent stage-by-stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is independent of any of the original research arms stopping accrual early subject to adequate recruitment to support the overall trial aims

Keratin 6 is not essential for mammary gland development

INTRODUCTION: Keratin 6 (K6) has previously been identified as a marker of early mammary gland development and has also been proposed to be a marker of mammary gland progenitor cells. However, the function of K6 in the mammary gland was not known, so we examined the expression pattern of the protein during both embryonic and postnatal mammary development, as well as the mammary gland phenotype of mice that were null for both K6a and K6b isoforms. METHOD: Immunostaining was performed to determine the expression pattern of K6a throughout mammary gland development, from the embryonic mammary bud to lactation. Double immunofluorescence was used to co-localize K6 with known markers of mammary gland development. Wild-type and K6ab-null mammary tissues were transplanted into the cleared fat pads of nude mice and the outgrowths were analyzed for morphology by whole-mount staining and for markers of mammary epithelium by immunostaining. Finally, progesterone receptor (PR) and bromodeoxyuridine co-localization was quantified by double immunofluorescence in wild-type and K6ab-null mammary outgrowths. RESULTS: Here we report that K6 is expressed earlier than described previously, by embryonic day 16.5. K6a is the predominant isoform expressed in the mammary gland, localized in the body cells and luminal epithelial cells but not in the cap cells or myoepithelial cells. Co-localization studies showed that most K6a-positive cells express steroid receptors but do not proliferate. When both the K6a and K6b genes are deleted, mammary gland development appears normal, with similar expression of most molecular markers examined in both the pubertal gland and the mature gland. Loss of K6a and K6b, however, leads to an increase in the number of steroid-receptor-positive cells, and increased co-localization of steroid receptor expression and proliferation was observed. CONCLUSION: Although K6a was not essential for mammary gland development, loss of both K6a and K6b resulted in an increase in PR-positive mammary epithelial cells and decreased proliferation after exposure to steroid hormones. There was also increased co-localization of PR and bromodeoxyuridine, suggesting alterations in patterning events important for normal lobuloalveolar development