BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Bespoke video vignettes - an approach to enhancing reflective learning developed by dental undergraduates and their clinical teachers.

This study explores the selective use of video as a medium to support reflective processes as related to dental undergraduate learning. With the objective of developing and enhancing high-quality adult dental care, the use of compiled video materials created in an undergraduate clinical setting was investigated. Video cameras were used to capture elements of reflection-in-action and reflection-on-action typically found during everyday clinical practice. 'Gold standard' or 'textbook outcomes' are rarely, if ever, fully achieved in dental practice. Real-life clinical experiences offer challenges and opportunities for both teachers and students to engage with reflective learning processes. The materials generated allowed for an experience of individual reflective learning and the creation of a data bank or archive with potential use for the benefit of a wider student cohort. Various aspects of the students' views and comments on the process of reflection were reported and explored by means of a semi-structured focus group moderated by a linked educational advisor.

Why do general dental practitioners become involved in clinical teaching? A pilot study exploring the views of part-time practitioner teachers, King's College London.

INTRODUCTION: Dental schools in the United Kingdom are becoming increasingly reliant on the services of part-time teachers to deliver the clinical educational component of the dental course. Their background is predominantly from general dental practice but the opportunities to progress in the system are limited. The aim of this study was to ascertain the views and perceptions of such teachers at a dental school. MATERIALS AND METHODS: An anonymous, non-incentivised online survey was used to obtain both qualitative and quantitative views of the part timers. RESULTS: The department has n = 40 part-time teachers and there was a response rate of 78%. Overall 73% were satisfied with their current teaching position, whereas the remaining 27% of teachers were seeking higher rewards both in terms of recognition and status. CONCLUSIONS: This study demonstrated the need for formal teaching skills and training to be made available to part-time clinical teachers. Allied to this is the requirement for a clearly defined and achievable career pathway.

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.

BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy. METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations. RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib. CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

The use of inhaled corticosteroids in the wheezy under 5-year-old child.

Inhaled corticosteroids are established as the most effective long-term anti-inflammatory therapy for asthma. National and international treatment guidelines recommend the use of these agents for long-term asthma control in children. In children <5 years, there are significant difficulties in diagnosing asthma. There are multiple non-asthma causes of wheeze, and there remains a lack of consensus in the description of wheezing phenotypes in this group of children. There is also a relative paucity of data concerning the short- and long-term effectiveness and side-effects in the under-fives: treatment recommendations have drawn heavily from experience of asthma treatment in school-age children and remains controversial. This article discusses the important recent advances in the evidence-base and current expert opinions which are helping to delineate improved outcomes for young children with wheeze.

Perceptions of a simulated general dental practice facility - reported experiences from past students at the Maurice Wohl General Dental Practice Centre 2001-2008.

UNLABELLED: This article assesses the perceived value of a simulated general dental practice centre as reported by past undergraduates over five years. Various aspects of teaching and related outcomes are explored based on responses received from anonymous questionnaires. A team based approach to cooperative learning led by current practitioners experienced in primary dental care was seen as pivotal to the huge success of the teaching model. Moreover the role of cooperative learning and its influence on building individual clinical confidence and acumen was considered highly beneficial as part of the transition from novice to expert. METHODOLOGY: An anonymous questionnaire was distributed to students six months after qualification for a period of five years. The last registered postal address held by the Institute was used for this purpose. The years surveyed were: 2001-2002, 2002-2003, 2003-2004, 2005-2006 and 2007-2008. The questionnaire provided for both qualitative aspects of feedback and a quantitative representation of the overall perception of effectiveness of the General Dental Practice Centre, as expressed by a visual analogue scale. RESULTS: In total 135 questionnaires were returned representing a return rate of 53%. From the responses received 99% of the students reported that they enjoyed their sessions at the Centre with 96% expressing satisfaction with the teaching regime. The mean visual analogue scale rating the centre overall was reported as 83%, with a year on year increase ranging from 76-92%. Rich qualitative data were derived from free text responses. CONCLUSION: A simulated general dental practice centre was highly rated by past dental students in terms of the overall learning experience received and its relevance to later vocational training. By far the most consistently reported attribute was the opportunity to practise close support four handed dentistry with a nurse. Training in practice management and organisational skills were viewed as important with effective teamwork and a friendly environment seen as conducive to building up knowledge and confidence. The role of experienced current primary care practitioners as teachers was seen to be very effective in this setting.

Going interactive: six strategies to meet the challenge of teaching electrosurgery to general dental practitioners.

Mandatory continuing professional development has resulted in a recent expansion in postgraduate dental teaching. One popular type of teaching is the practical 'hands-on' course that combines the explanation of theory with the acquisition of practical skills in small groups. The challenge to dental teachers is to provide the best level of teaching on these courses where the course participants bring varied expectations and different levels of knowledge, skill or interest. This paper presents a new teaching model that has been developed for the postgraduate teaching of Electrosurgery. The key components of this course include an interactive theory lecture using multimedia, followed by hands-on practical teaching. The emphasis throughout is on the use of facilitation and group learning rather than traditional didactic teaching. A series of strategies for the effective delivery of such a hands-on course together with evaluation of findings from 31 courses are considered.

Gonadotropins mediate DNA synthesis and protection from spontaneous cell death in human ovarian surface epithelium.

Gonadotropins have been implicated in the development of epithelial ovarian cancers. These tumors are derived from ovarian surface epithelium (OSE). The purpose of this study was to determine the effects of these hormones on DNA synthesis and spontaneous cell death in primary cultures of OSE and three immortalized OSE cultures. Primary cultures of OSE cells were generated from the ovaries of women with benign disease. The effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on DNA synthesis and cell death were determined using [(3)H]thymidine incorporation and JAM assays. Significant inductions of DNA synthesis were demonstrated with LH in 4/12 (33%) primary cultures of OSE and 2/3 OSE cell lines and with FSH in 4/11 (36%) primary cultures of OSE and 2/3 OSE cell lines. A significant protection from cell death was also observed in the presence of FSH in 2/4 primary cultures of OSE and 1/3 OSE cell lines and in the presence of LH in 1/4 primary cultures of OSE and 2/3 OSE cell lines. The results indicate that while gonadotropins have the potential to induce cell proliferation and protect from cell death in OSE cells in vitro, their effects are variable in OSE cells from different women.

Cyclooxygenase-2 inhibition: a potential mechanism for increasing the efficacy of bacillus calmette-guerin immunotherapy for bladder cancer.

PURPOSE: Intravesical bacillus Calmette-Guerin (BCG) therapy is the principal treatment for high risk, noninvasive urothelial carcinoma and carcinoma in situ of the bladder. However, up to 40% of patients fail to respond to this treatment. In this study the potential for inhibition of PGE2 production by BCG treated dendritic cells (DCs) was studied in the context of preferential polarization of the immune response toward a cancer clearing T-helper type 1 immune response. MATERIALS AND METHODS: Murine bone marrow derived DCs were cultured with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor. After 7 days the cells were stimulated with BCG. Cell surface expression of co-stimulatory molecules and phagocytic ability were measured by flow cytometry analysis to verify cell activation. The production of IL-10 and IL-12 was measured after DC stimulation with BCG in the presence of IL-10, prostaglandin E2(Cayman Chemical, Ann Arbor, Michigan), antiIL-10 antibody (Insight Biotechnology, Wembley, United Kingdom), NS-398 and indomethacin (Sigma, Poole, United Kingdom). RESULTS: Prostaglandin E2 stimulated a dose dependent increase in the levels of IL-10 produced by BCG activated DCs (p <0.01). IL-10 significantly decreased IL-12 production (p <0.001), while IL-10 blockade significantly increased IL-12 levels (p <0.05). The COX-2 selective inhibitor NS-398 caused a dose dependent increase in the concentration of IL-12 produced by BCG activated DCs (p <0.01). This effect was also seen with the partially selective COX-1 inhibitor indomethacin (p <0.05). CONCLUSIONS: The inhibition of PGE2 synthesis by COX inhibition favored the production of IL-12 by BCG activated DC. This potentially will result in the generation of a T-helper type 1, polarized T-cell response that may improve the efficacy of BCG therapy.

Coercion or collaboration? Nurses doing research with people who have severe mental health problems.

Nurses should address the concerns of service users in research and engage in collaborative work with them. Doing this presents ethical dilemmas, not least around the issues of assessing capacity and informed consent to participation in research. The view that judgement regarding the capacity to consent is solely the responsibility of a consultant psychiatrist is challenged as inadequate. The concept of 'moral discourse' (Pike 1991) is used to understand the process by which the assessment of capacity may be carried out. This is illustrated by the application of the concept in a qualitative research study carried out to explore what makes mental health services accessible to women with children. The role of the mental health nurse entails surveillance and the development of expertise in negotiating compliance with treatment programmes. The paper outlines the measures taken to ensure that service users felt empowered, rather than coerced, to participate in this study. While Community Mental Health Team workers were engaged in 'moral discourse' in respect of participation by service users in the study, there were difficulties in engaging General Practitioners. However, there was evidence that women themselves felt empowered both to express interest in participating and to withdraw if they so wished.

Galectin-3 does not reliably distinguish benign from malignant thyroid neoplasms.

AIMS: To determine whether galectin-3 is a sensitive indicator of thyroid malignancy. It has been suggested as a potential marker for differentiating thyroid carcinoma from benign or non-neoplastic lesions in preoperative fine-needle aspirates (FNAs). METHODS: Galectin-3 protein expression was assessed by immunohistochemistry in formalin-fixed thyroid tissues from 124 patients with histological diagnoses of papillary carcinoma (n = 38), follicular carcinoma (n = 19), follicular adenoma (n = 32) and dominant nodules of multinodular goitre (n = 35). Expression of galectin-3 was also assessed by Western blotting in 24 fresh thyroid tissues. RESULTS: Galectin-3 expression was observed in the majority of carcinomas (papillary 92%; follicular 74%). However, a large proportion of follicular adenomas (72%) and multinodular goitres (57%) also expressed galectin-3. In addition, galectin-3 expression was observed in epithelial cells of normal thyroid tissue and Hashimoto's thyroiditis. Galectin-3 immunopositivity was significantly greater in papillary carcinomas than in dominant nodules or follicular adenomas (P < 0.0001, P = 0.0005, respectively). However, galectin-3 expression was no greater in follicular carcinomas than in follicular adenomas (P = 0.8735). Western blotting analysis confirmed both the specificity of the antiserum and expression of galectin-3 in multinodular goitres, follicular adenomas/carcinomas and papillary carcinomas. CONCLUSION: The data demonstrate that galectin-3 is not a reliable immunohistochemical marker to distinguish benign from malignant thyroid follicular lesions.

Reflective practice in the teaching of conservative dentistry to undergraduate dental students - perceptions derived from a pilot study using personal development diaries.

The aim of this study was to explore final-year student perceptions to the use of personal development diaries (PDDs) and to compare the findings with an established system of competitive continuous assessment, using open display of score ratings displayed on a clinic notice board. Focus groups in conjunction with personal development diaries (PDDs) were used to investigate the teaching of conservative dentistry to senior dental undergraduates. Thirty per cent of the statements made reference to the positive aspects of PDDs, while a small percentage (6%) was negative. Nineteen per cent of the comments derived from the focus groups showed that the undergraduates disliked the open display of their marks on the conservation clinic notice board. This compared with only 2% who claimed that they enjoyed the competitive method. A further 22% of the comments related to the fact that open display of marks was stressful, whereas 3% were unaffected. Eighteen per cent of the responses indicated that clinical conservative dentistry was a stressful experience.

Cell type-specific methylation of an intronic CpG island controls expression of the MCJ gene.

Over 50% of human genes are associated with CpG islands and DNA methylation within such CpG islands has been clearly correlated with inhibition of expression. Whereas changes in DNA methylation play a key role in a number of human diseases, in particular cancer, in normal DNA CpG islands are nearly always methylation free, regardless of the expression status of the associated gene. Only limited evidence supports a role for DNA methylation in controlling tissue-specific expression in adult somatic tissue. Loss of expression of the MCJ gene has previously been linked to increased chemotherapeutic drug resistance in ovarian cancer. We report that loss of expression of MCJ in drug-resistant ovarian cancer cell lines depends on methylation of a CpG island within its first exon, but is independent of methylation within the promoter region. Furthermore, cell type-specific expression of the MCJ gene in normal cells also depends on the methylation status of the CpG island within its first exon. The MCJ CpG island is methylated and the gene is not expressed in cells of epithelial origin, but unmethylated and expressed in cells of lymphocyte or fibroblast origin. Chromatin immunoprecipitation assays determined that MCJ CpG island methylation was associated with loss of histone acetylation in ovarian epithelial cells compared with unmethylated fibroblast cells. Reduced acetylation was observed not only within the CpG island, but also within the promoter region, suggesting that CpG island methylation may direct alterations in chromatin structure within the promoter region, leading to gene inactivation.

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy.

Intravesical bacillus Calmette-Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS- and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.

Gene products involved in metastasis of bladder cancer.

Metastasis is usually responsible for mortality in patients suffering from muscle invasive bladder cancer. Whilst expression of a great number of genes and their protein products have been associated with metastasis and/or poor prognosis in bladder cancer, evidence that they actively drive the metastatic process, and hence make potentially good therapeutic targets, is often lacking. This is due to the limited number and application of effective animal models which reflect the pathogenesis of the human disease. In this review I will discuss the processes involved in metastasis, consider the established animal models of bladder cancer progression and metastasis, and review the evidence for a role of various gene products in this process. Consideration of clinical studies in conjunction with evidence from experimental animal models reveals that the tyrosine kinase receptor erbB1/EGFR, the calcium binding protein S100A4 and the the cell cycle arrest/apoptosis-inducing p53 protein are amongst the most promising targets for therapy against metastatic disease in patients with bladder cancer.

The human ovarian surface epithelium is an androgen responsive tissue.

The pathogenesis of epithelial ovarian cancer remains unclear. From epidemiological studies raised levels of androgens have been implicated to increase the risk of developing the disease. The purpose of this study was to determine the responses of normal human ovarian surface epithelium to androgens. We have established primary cultures of human ovarian surface epithelium from patients undergoing oophorectomy for benign disease. Total RNA was isolated from these cultures and expression of mRNA encoding for the androgen receptor was demonstrated using reverse transcriptase polymerase chain reaction. The presence of androgen receptor in sections of normal ovary was also investigated using an antibody against androgen receptor. The effects of androgens on DNA synthesis and cell death were determined. Eight out of eight (100%) cultures expressed mRNA encoding the androgen receptor. The presence of androgen receptor in ovarian surface epithelium of sections of normal ovaries was demonstrated in all sections. Mibolerone, a synthetic androgen, caused a significant stimulation of DNA synthesis in 5 out of 9 (55%) cultures when used at a concentration of 1 nM. Mibolerone also caused a significant decrease in cell death in 2 out of 5 (40%) cultures tested. We have demonstrated that the ovarian surface epithelium is an androgen responsive tissue and that androgens can cause an increase in proliferation and a decrease in cell death. These findings have important implications for the pathophysiology of ovarian carcinogenesis.