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.

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.

Induction of metastatic ability in a stably diploid benign rat mammary epithelial cell line by transfection with DNA from human malignant breast carcinoma cell lines.

Transfection of the stably diploid rat mammary epithelial cell line, Rama 37, which yields nonmetastasizing, adenomatous tumors in syngeneic rats with HindIII-fragmented DNA from malignant or nonmalignant human breast epithelial cell lines and the drug-resistance plasmid pSV2neo, yields transformants with a frequency of 10(-4) to 10(-5). The resultant cell lines form tumors with varying frequencies when injected s.c. into the mammary fat pads of syngeneic rats. Cells transfected with DNA from the malignant human breast carcinoma cell line, Ca2-83, or DNA from the human pleural effusion-derived cell lines, MCF-7 or ZR-75-1, yield transformants which metastasize to lungs and/or lymph nodes at high frequency, whereas transfection of HindIII-fragmented DNA from nonmetastatic human mammary epithelial cell lines, transfection of the drug-resistance plasmid pSV2neo alone, or nonspecific DNA such as salmon sperm DNA fails to yield transformants expressing the metastatic phenotype. Transfectants which metastasized were reestablished in culture and reinjected into syngeneic rats to confirm their metastatic properties. These transfectants yield rapidly growing tumors with reduced latent periods, which give rise to significant numbers of metastases. The karyotype of selected transfectants after passage in vivo remains stably diploid. Hybridization of a 32P-labeled oligonucleotide probe specific for the human Alu family of sequences to DNA from these transfectants reveals the presence of human-specific DNA sequences integrated into the genome. It is suggested that transfection of specific genomic DNA sequences from the malignant human cell lines can induce the metastatic phenotype in the nonmetastatic Rama 37 cell line in a genetically dominant manner, whereas genomic DNA from the nonmetastatic cells cannot confer metastatic properties to the Rama 37 cell line.

Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1.

The rat mammary epithelial cell line, Rama 37, yields benign, non-metastasizing adenomatous tumours in syngeneic Wistar-Furth rats. Transfection of this line with a drug resistance plasmid containing both the gene for resistance to Geneticin (neo) and the gene for p9Ka (pSV2neo-p9Ka), a rat calcium-binding protein, or with a similar plasmid containing neo and the oncogene EJ-ras-1 (pSV2neo-ras) yields drug-resistant transformants that express high levels of the p9Ka or EJ-ras-1 mRNAs and proteins. These transfected cells all produce tumours when injected at subcutaneous sites with a shorter median latent period than the tumours produced by the parental untransfected Rama 37 cells in syngeneic hosts. Cells transfected with pSV2neo-p9Ka yield a higher incidence of tumours than untransfected Rama 37 cells, many of which metastasize to lungs and/or lymph nodes in syngeneic rats. However, cells transfected with pSV2-neo-ras or pSV2neo plasmid alone yield tumours that fail to metastasize. Immunofluorescent studies suggest an association of p9Ka with the cytoskeleton, as depicted by F-actin staining with the reagent phalloidin. It is suggested that the transfection of copies of the gene for the rat calcium-binding protein p9Ka can enhance the tumorigenic potential and induce the metastatic phenotype in this rat mammary model, whereas transfection of control plasmid DNA or the oncogene EJ-ras-1 fails to induce the metastatic phenotype, although EJ-ras-1 transfectants, like those containing p9Ka, possess increased growth properties in vivo.

Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer.

Epithelial ovarian cancers (EOCs) arise in the Ovarian Surface Epithelium (OSE). This tissue is a simple, poorly committed mesothelium which exhibits characteristics of epithelial and mesenchymal cells when grown in culture. In contrast, EOCs frequently exhibit properties of complex epithelial tissues of the female reproductive tract, such as oviductal, endometrial and cervical epithelia, and show induction of expression of epithelial markers such as E-cadherin. Fibroblast Growth Factor Receptor 2 isoform IIIb (FGF receptor 2-IIIb) is a spliced variant of FGF receptor 2 that binds the ligands FGF-1 and FGF-7 with high affinity, and is expressed exclusively by epithelial cells. We have studied the expression of FGF receptor 2-IIIb and its ligands in primary cultures of normal human OSE, EOC cell lines and snap frozen tissue from EOCs. Expression of FGF receptor 2-IIIb mRNA is undetectable in normal OSE, but is expressed in 16/20 (80%) of EOCs. FGFs 1 and 7 mRNAs are expressed in normal OSE, whilst only 4/20 (20%) and 12/20 (60%) of EOCs demonstrated expression for these ligands respectively. However, FGF-7 protein was detected in 70% (mean level=0.7 ng/ml) of ascitic fluids obtained from patients with EOC. FGFs 1 and 7 stimulate DNA synthesis in EOC cell lines that express FGF receptor 2-IIIb. Moreover, DNA synthesis in these cell lines can be partially blocked by blocking antisera to FGFs 1 and 7. It is suggested that induction of expression of FGF receptor 2-IIIb may play a role in the development of EOCs by rendering the OSE susceptible to paracrine and/or autocrine stimulation by its requisite FGF ligands.

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.

Induction of a variety of preneoplasias and tumours in the mammary glands of transgenic rats.

Although transgenic mouse models for breast cancer have frequently been reported in the literature, transgenic rat models have not been described. We have generated transgenic rats overexpressing the human transforming growth factor alpha (TGF alpha) and c-erbB-2 genes in the mammary gland under the control of the mouse mammary tumour virus (MMTV) long terminal repeat promoter, and have analysed multiple lines of these rats to the second (F2) generation. Female MMTV/TGF alpha rats frequently develop severe hyperplasias during pregnancy, and a variety of tumours of long latency. The mammary glands of MMTV/TGF alpha rats fail to involute fully after the completion of lactation. Expression of the TGF alpha transgene is highest in the hyperplasias. MMTV/c-erbB-2 female rats develop a spectrum of benign and malignant lesions, including ductal carcinoma in situ and carcinomas. Expression of the c-erbB-2 transgene is found in benign tumours such as fibroadenomas, but is highest in the carcinomas. These animals model a spectrum of lesions found in human breasts and suggest that TGF alpha overexpression can act at a relatively early stage in the pathogenesis of breast cancer in the rat, resulting in a predominantly hyperplastic response, whereas overexpression of c-erbB-2 plays a role in the induction of various benign lesions and more advanced breast carcinomas.

Use of DNA transfer in the induction of metastasis in experimental mammary systems.

The metastatic spread of cancer is a little understood process, in part because it is difficult to model the entire process using experimental approaches in vitro. The ability to transfer DNA into non-metastatic mammary cells and to observe the induction of metastasis in vivo provides a means for identifying DNA sequences that are associated with the development of metastatic capability. Using these techniques, a metastasis-associated cytoskeletal calcium binding protein, S100A4 (p9Ka), has been identified as an inducer of metastatic capability in benign rat mammary epithelial cells. Metastasis can also be induced in the rat mammary epithelial cells by fragments of DNA from metastatic, but not from benign, human breast tumour cells. These non-coding fragments of DNA act via the induction of osteopontin, an extracellular, integrin binding, calcium binding protein. Since both osteopontin and S100A4 are thought to be associated with malignancy in human breast cancer specimens, gene transfer techniques can identify genes for metastasis-inducing proteins that may play a role in breast cancer, and further suggest that cell migration/motility might be important in the metastatic process.

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 seasonal conception of lethal congenital malformations.

BACKGROUND: The objective of the study was to investigate the possibility of the effect of seasonal temperature on the incidence of lethal congenital malformations in a retrospective study. METHODS: At the National Institute of Perinatology in Mexico City, perinatal deaths due to congenital malformations were compared with the the remainder of perinatal deaths over a period of 3 years in relation to the average temperature of the months in which the fifth week of gestation occurred. RESULTS: The division between the average temperature of the individual months was 18 degrees C, as there were no months with an average between 17.9 and 18.8 degrees C. An average of 0.86 perinatal deaths with lethal malformations had spent their embryonic life in a cold month, whereas an average of 1.54 had spent their embryonic life in a hot month; in contrast, an average of 10.24 perinatal deaths with lethal malformations had spent their embryonic life in a cold month, and a smaller number (9.23) in a hot month. CONCLUSIONS: The perinatal deaths with lethal malformations therefore showed a significant tendency to have spent their embryonic lives during the hotter months in comparison with the other perinatal fetal deaths (p = 0.04). Further studies should be made with larger numbers of cases, maintaining careful attention to early perinatal data and local temperatures.

Fetal amniotic adhesions. Their topographic concordance with regionally clustered malformations.

BACKGROUND: The amniotic band disruption complex (ABDC) has been segregated recently into various phenotypes. In view of the pathogenic mechanisms that have been proposed, this study was designed to assess if it is one variable process or is composed of several distinct complexes. METHODS: The 48 cases of fetuses with bands or placenta attached to fetal parts cited in this paper included nine new cases and 39 from the literature. They were organized first according to the embryonal topography of the malformations, then according to the position of the adhesions, and finally by the assessment of distances between the cases and between the malformations using the squared Euclidean distances for binary variables and cluster analysis. RESULTS: In all three analyses, three groups were identified: 1) fetuses with cephalo-thoracic anomalies; 2) fetuses with caudal anomalies, and 3) fetuses with mixed anomalies. Nonetheless, overlap among the three groups was apparent. Thus, while fetuses with amniotic bands form three clusters, it appears that these are part of a spectrum and should be considered as variable manifestations of a single entity resulting from a single pathogenetic mechanism. An association was established between the localization of the adhesions and the malformations in various axes. Abdominoschisis, however, was not particularly related to adhesions at one or the other end of the fetus; a short umbilical cord was an almost universal finding. Single umbilical artery (SUA) was especially related to caudal adhesions and malformations (p = 0.004 and 0.001), as well as abdominoschisis (p = 0.002) and agenesis of the abdominal organs (p = 0.008). CONCLUSIONS: The association between amniotic adhesions to the fetus and multiple malformations occurring predominantly in the same area suggest that the former are the cause of the latter. The association of abdominoschisis, as well as a short umbilical cord, with malformations and adhesions in all areas, suggests that these are secondary phenomena to generalized embryonal and fetal tension. SUA, however, with a specifically regional association, is more likely to be due to disruption from exposure in cases with abdominoschisis, often accompanying the loss of abdominal organs.

Effects of the removal of composite resin restorations on Class II cavities.

Composite resin has such good aesthetic qualities that it is often difficult to identify the tooth-restoration interface, yet this is particularly important should the material require complete removal. Following the in-vitro removal of direct and indirect composite resin restorations from Class II cavities significant changes in cavity size and shape were recorded. Thirty-eight cavities were studied from both occlusal and proximal aspects and the final cavity size was compared to the original cavity. There was a significant increase in cavity size with a mean increase of 37% for the direct composite cavities and 35% for the indirect cavities, although the range of values is large. Following restoration removal, occlusal surfaces were seen to increase in 71% of teeth and proximal surfaces in 75% of teeth. There was no significant difference between the results for direct and indirect composite restorations. Occlusal dovetails and cavity undercuts were created in cavities which did not contain these features initially.

A survey of the effectiveness of dental light-curing units and a comparison of light testing devices.

The aims of this study were to: 1. survey the light output from 49 light-curing units in clinical use; 2. measure the effect on depth of cure of composite resin caused by a range of light outputs; 3. assess the relationship between radiometer meter readings and depth of cure of composite resin in a human tooth model and a Heliotest. The mean meter reading produced by the 49 lights surveyed using a lampChecker radiometer was 4.4 (+/-2.4 SD), range 0.3 to 10.0. The manufacturer of the radiometer considers optimal light output to provide a meter reading within the range 5.0 to 7.0. Lights of very low output (0.7 +/- 0.1 SD) were found to be capable of curing, after 20 seconds, a 1.9 (+/-0.3 SD) mm thickness of composite resin. However, only approximately 50% of this thickness can be considered fully cured. Increasing the cure time from 20 seconds to 60 seconds increased the mean depths of cure by a factor of approximately 1.4. The mean depths of cure of composite resin placed in the Heliotest were greater than those observed in the natural tooth model, by a factor of approximately 1.3. Correlation coefficients of meter readings and depth of cure were greater for the Efos Cure Rite and Demetron 100 radiometers than the lampChecker unit.

Strength of secondary-cured resin composite inlay repairs.

A study was designed to simulate the repair of an indirect resin composite restoration with conventionally cured resin composite. Two-part specimens were prepared to test the diametral tensile strength of the repair interface between the base material of an indirectly cured resin composite (Herculite XRV) and repairs carried out with three directly cured materials (Herculite XRV, TPH, and Charisma). The repairs were carried out with and without use of the bonding resin for the repair material. The diametral tensile strengths of all repaired specimens were significantly less than those of bulk unrepaired specimens. There were no significant differences between the diametral tensile strengths of repaired blocks when the repair materials were used without bonding resin. The use of an intermediate layer of bonding resin significantly increased the bond strengths obtained when Herculite XRV and TPH were used for repair. There was no significant difference between the strength values of Herculite XRV and TPH, but Charisma exhibited the lowest strengths of repaired specimens.

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.