Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Oropharyngeal dysphagia in an elderly post-operative hip fracture population : a prospective cohort study

Background: normal ageing processes impact on oropharyngeal swallowing function placing older adults at risk of developing oropharyngeal dysphagia (OD). Anecdotal clinical experience has observed that older patients recovering from hip fracture surgery commonly develop OD post-operatively. Objective: to document the presence of OD following hip fracture surgery, and the factors associated with OD. Methods: one hundred and eighty-one patients with a mean age of 83 years (range: 65–103) admitted to a specialised orthogeriatric unit were assessed for OD post-surgery for hip fracture. Pre-admission, intra-operative and post-operative factors were examined to determine their relationship with the presence of OD. Results: OD was found to be present post-operatively in 34% (n = 61) of the current population. Multivariate logistic regression analyses revealed the presence of pre-existing neurological and respiratory medical co-morbidities, presence of post-operative delirium, age and living in a residential aged care facility prior to hospital admission to be associated with the post-operative OD. Conclusion: these results highlight that OD is present in a large number of the older hip fracture population. Early identification of OD has important implications for the provision of timely dysphagia management that may prevent secondary complications and potentially reduce the hospital length of stay.

Nursing practice environment, quality of care and morale of hospital nurses in Japan

The purpose of this study was to describe Japanese hospital nurses’ perceptions of the nursing practice environment and examine its association with nurse-reported ability to provide quality nursing care, quality of patient care and ward morale. A cross-sectional survey design was used including 223 nurses working in 12 acute inpatient wards in a large Japanese teaching hospital. Nurses rated their work environment favorably overall using the Japanese version of the Practice Environment Scale of the Nursing Work Index. Subscale scores indicated high perceptions of physician relations and quality of nursing management, but lower scores for staffing and resources. Ward nurse managers generally rated the practice environment more positively than staff nurses except for staffing and resources. Regression analyses found the practice environment was a significant predictor of quality of patient care and ward morale, whereas perceived ability to provide quality nursing care was most strongly associated with years of clinical experience. These findings support interventions to improve the nursing practice environment, particularly staffing and resource adequacy, to enhance quality of care and ward morale in Japan.

New Knowledge for Advancing Practice in Pain Management

This chapter contains sections titled: Introduction Advancing practice in pain management Conclusions References

MITIE C-Arm - Advanced innovation in education

Aim: In 2013 QUT introduced the Medical Imaging Training Immersive Environment (MITIE) as a virtual reality (VR) platform that allowed students to practice general radiography. The system software has been expanded to now include C-Arm. The aim of this project was to investigate the use of this technology in the pedagogy of undergraduate medical imaging students who have limited to no experience in the use of the C-Arm clinically. Method: The Medical Imaging Training Immersive Environment (MITIE) application provides students with realistic and fully interactive 3D models of C-Arm equipment. As with VR initiatives in other health disciplines (1–2) the software mimics clinical practice as much as possible and uses 3D technology to enhance 3D spatial awareness and realism. The application allows students to set up and expose a virtual patient in a 3D environment as well as creating the resultant “image” for comparison with a gold standard. Automated feedback highlights ways for the student to improve their patient positioning, equipment setup or exposure factors. The students' equipment knowledge was tested using an on line assessment quiz and surveys provided information on the students' pre-clinical confidence scale, with post-clinical data comparisons. Ethical approval for the project was provided by the university ethics panel. Results: This study is currently under way and this paper will present analysis of initial student feedback relating to the perceived value of the application for confidence in a high risk environment (i.e. operating theatre) and related clinical skills development. Further in-depth evaluation is ongoing with full results to be presented. Conclusion: MITIE C-Arm has a development role to play in the pre-clinical skills training for Medical Radiation Science students. It will augment their theoretical understanding prior to their clinical experience. References 1. Bridge P, Appleyard R, Ward J, Phillips R, Beavis A. The development and evaluation of a virtual radiotherapy treatment machine using an immersive visualisation environment. Computers and Education 2007; 49(2): 481–494. 2. Gunn T, Berry C, Bridge P et al. 3D Virtual Radiography: Development and Initial Feedback. Paper presented at the 10th Annual Scientific Meeting of Medical Imaging and Radiation Therapy, March 2013 Hobart, Tasmania.

Doctor’s knowledge and practices of traumatic brain injury management in Chinese prehospital settings

Objectives: The incidence and mortality of traumatic brain injury (TBI) has increased rapidly in the last decade in China. Appropriate ambulance service can reduce case-fatality rates of TBI significantly. This study aimed to explore the factors (age, gender, education level, clinical experience, professional title, organization, specialty before prehospital care, and training frequency) that could influence prehospital doctors’ knowledge level and practices in TBI management in China, Hubei Province. Methods: A cross-sectional questionnaire survey was conducted in two cities in Hubei Province. The self-administered questionnaire consisted of demographic information and questions about prehospital TBI management. Independent samples t-test and one-way ANOVA were used to analyze group differences in the average scores in terms of demographic character. General linear regression was used to explore associated factors in prehospital TBI management. Results: A total of 56 questionnaires were handed out and 52 (93%) were returned. Participants received the lowest scores in TBI treatment (0.64; SD=0.08) and the highest scores in TBI assessment (0.80; SD=0.14). According to the regression model, the education level was associated positively with the score of TBI identification (P=.019); participants who worked in the emergency department (ED; P=.011) or formerly practiced internal medicine (P=.009) tended to get lower scores in TBI assessment; participants’ scores in TBI treatment were associated positively with the training frequency (P=.011); and no statistically significant associated factor was found in the overall TBI management. Conclusion: This study described the current situation of prehospital TBI management. The prehospital doctors’ knowledge level and practices in TBI management were quantified and the influential factors hidden underneath were explored. The results indicated that an appropriate continuing medical education (CME) program enables improvement of the quality of ambulance service in China.

A construção da demanda por ajuda psicológica e o trabalho psicanalítico com as classes populares

Esta dissertação tem como objeto de exame a psicanálise exercida nas instituições públicas de saúde, com o público das classes populares, a partir do atual cenário da seguridade social brasileira e das políticas de saúde do Sistema Único de Saúde (SUS). Visando encontrar o que a psicanálise tem de mais fundamental, no consultório privado ou fora dele, analisa-se a obra de Freud e de autores contemporâneos, em busca de subsídios ao presente debate. Além de revisão bibliográfica, extratos de casos clínicos são também incluídos, sejam estes a partir de literatura ou de experiência própria. As classes populares, em sua condição de principais usuários dos ambulatórios públicos, são examinadas a partir de sua relação com seu sofrimento, seja este corporal ou psíquico, expressa em seu discurso dirigido ao profissional que as recebe. Ao longo deste percurso foram encontrados alguns elementos e/ou figuras essenciais de análise como o corpo, o campo do trabalho e a doença dos nervos. Ambos os debates acima convergem para um terceiro, de natureza prática, no qual psicanálise e classes populares unem-se no cotidiano destes serviços. Busca-se encontrar o significado de se trabalhar com psicanálise nestes espaços, e, consequentemente, o que faz este psicanalista manter a marca de sua atuação, ao mesmo tempo em que abre espaço para a reinvenção da mesma, sempre que assim se fizer necessário. Este estudo é finalizado pela análise desta prática, frente a alguns de seus obstáculos. Conclui-se que a mesma só é possível se os profissionais se afastarem de uma postura que, além de limitar o potencial da clínica psicanalítica, encara os pacientes como não propensos à autorreflexão, ou então, como limitados em sua capacidade de comunicação.

Aferição de competências em Endodontia percepcionadas pelos finalistas em Medicina Dentária e pelos Médicos Dentistas licenciados na Faculdade de Ciências de Saúde da Universidade Fernando Pessoa

Monografia apresentada à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Licenciada em Medicina Dentária

Os motivos da não erupção dos terceiros molares

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina Dentária

Contemporary results of focal therapy for prostate cancer using cryoablation.

The concept of focal therapy is rapidly evolving and gaining popularity from both physician and patient perspectives. We review the rationale, candidate selection, and results of the first clinical studies of focal cryoablation for selected patients with low volume and low- to low-moderate-risk features of prostate cancer as an alternative to whole-gland treatment. In spite of improved understanding of the tumor biology of early stage disease, we currently have limited tools to select appropriate patients with low- to low-moderate risk unifocal or unilateral prostate cancer who may be amenable to focal therapy. From a technical point, a number of ablative treatment options for focal therapy are available, with cryoablation having the most clinical experience. Recently, several reports have been published from single and multi-institutional studies that discuss focal therapy as a reasonable balance between cancer control and quality-of-life outcomes. Retrospective pathologic data from large prostatectomy series, however, do not clearly reveal valid and reproducible criteria to select appropriate candidates for focal cryoablation because of the complexity of tumorigenesis in early stage disease. At this time, a more feasible option remains hemiablation of the prostate with reasonable certainty about the absence of clinically significant cancer lesion(s) on the contralateral side of the prostate based on three-dimensional transperineal prostate biopsy mapping studies. Minimally invasive, parenchyma-preserving cryoablation can be considered as a potential feasible option in the treatment armamentarium of early stage, localized prostate cancer in appropriately selected candidates. There is a need to further test this technique in randomized, multicenter clinical trials.

Determinants of protection among HIV‐exposed seronegative persons: an overview.

Both clinical experience and a growing medical literature indicate that some persons who have been exposed to human immunodeficiency virus (HIV) infection remain uninfected. Although in some instances this may represent good fortune, cohorts of uninfected persons have been reported who are considered at high risk for infection. In these cohorts a variety of characteristics have been proposed as mediating protection, but to date only the 32–base pair deletion in the chemokine (C‐C motif) receptor 5 gene, which results in complete failure of cell surface expression of this coreceptor, has been associated with high‐level protection from HIV infection. With this in mind, there are probably many other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. Because some of these factors are probably incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high‐risk uninfected cohorts, who should undergo targeted studies of plausible mediators and broad screening for unexpected determinants of protection.

Verbal abuse experienced by student nurses

Aim: This paper is a report of a study to describe the nature, severity, frequency and sources of verbal abuse experienced by nursing students while gaining clinical experience. Background: Verbal abuse of healthcare workers is currently receiving considerable attention and nursing students have been identified as a group vulnerable to experiencing workplace verbal abuse. Method: Questionnaires were distributed in 2005 to a convenience sample of 156 third year nursing students from one pre-registration nursing programme in England. A total of 114 questionnaires were returned, giving a response rate of 73.0%. Findings: Experience of verbal abuse was reported by 45.1% of respondents, 34.5% had witnessed other students experiencing this and 65.5% reported that they were aware of other students experiencing verbal abuse. The incidents involved patients in 64.7% of cases, 15.7% involved visitors or relatives and 19.6% involved other healthcare workers. Students reported experiencing threats to kill them, racial abuse and sexually oriented verbal abuse, with the majority of incidents occurring in general medical, mental health and general surgical clinical areas. Conclusion: Education and healthcare providers should prepare students to manage negative verbal exchanges during nursing education, and policies and support networks relating to managing verbal abuse in clinical practice should be available to nursing students.

Effect of angiotensin-related antihypertensives on brain neurotransmitter levels in rats.

The extensive clinical experience of angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists as antihypertensive agents provide numerous examples of anecdotal evidence of improvements in cognition and mood. This study aimed to determine the effect of chronic treatment with the angiotensin converting enzyme inhibitor, perindopril, and the angiotensin AT(1) receptor antagonist, candesartan, on central neurotransmitter levels in the rat. Perindopril (1.0mg/kg/day) or candesartan (10mg/kg/day) was administered via the drinking water at for 1 week, while controls received water alone. At the end of treatment rats were sacrificed, brains removed and discrete regions dissected and analysed for noradrenaline, dopamine and its major metabolites, and serotonin content. As shown previously we found an increase in striatal dopamine levels after perindopril treatment, though this did not extend to the mesolimbic system with neurotransmitter levels unchanged in the hippocampus, nucleus accumbens and frontal cortex. Conversely, candesartan administration produced no change in dopamine, but significant decreases in both DOPAC and HVA in the striatum. In addition chronic candesartan infusion produced a significant increase in the levels of hippocampal noradrenaline and serotonin; and frontal cortex serotonin content. These results demonstrate that while angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists act as antihypertensives by affecting the renin-angiotensin system, they have divergent actions on brain neurochemistry.

Educating the dental team:exploring perceptions of roles and identities

Interprofessional education (IPE) should help to promote a team-based approach to professional practice but there are barriers to its implementation including professional identity. The aim of this study was to use a qualitative research methodology to explore dental and dental care professional (DCP) students' perceptions of professional roles and identities in the dental team. Data were collected by means of focus groups from a purposive sample of dental and DCP students and were audio recorded, transcribed and analysed using an explanatory framework. Five common themes emerged around the issue of professional roles and identity in the dental team. The results indicate that professional identity was an important factor in team development and was determined by direct responsibility for patient care and by the amount of clinical experience acquired. Professional identity within a team context was perceived as different from professional identity per se. Dental students were found to lack confidence in their role as team leaders which was related to their lack of knowledge of team roles, responsibilities and experience. The role of the dental technician was perceived as 'outside' the dental team due to lack of patient interaction.

Stress and eustress in nursing students

Aim. This paper is a report of a study to identify experiences that led to both distress and eustress and to make recommendations to help students cope with course demands.

Background. Much of the research on stress in nursing students is quantitative in focus and all draws on their experience of distress, with little attempt to understand experiences of eustress.

Method. A series of focus groups were carried out with a volunteer sample of final year nursing students (n = 16) in the United Kingdom in 2007. The data were thematically analysed.

Findings. The themes identified were clinical experience, support, learning and teaching experience and course structure. There were experiences within each that were perceived as sources of distress and eustress. Many of the sources of distress concur with earlier findings but they are more likely to be experienced and commented on because the demands of present-day programmes and the profile of many nursing students mean that more effort is invested in meeting educational demands. The experiential learning and patient-care opportunity that placements provided was an important source of eustress.

Conclusion. Students who coped well drew on effective support networks and adopted a positive, optimistic perspective towards programme issues. Effective educators did not offer more time than those perceived as less effective but seemed more effective at tuning into students' concerns, showing more empathy and offering clearer guidance.