Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer.

INTRODUCTION: Programmed cell death through apoptosis plays an essential role in the hormone-regulated physiological turnover of mammary tissue. Failure of this active gene-dependent process is central both to the development of breast cancer and to the appearance of the therapy-resistant cancer cells that produce clinical relapse. Functional expression cloning in two independent laboratories has identified Finkel-Biskis-Reilly murine sarcoma virus-associated ubiquitously expressed gene (Fau) as a novel apoptosis regulator and candidate tumour suppressor. Fau modifies apoptosis-controller Bcl-G, which is also a key target for candidate oncoprotein maternal embryonic leucine zipper kinase (MELK). METHODS: We have used RNA interference to downregulate Fau and Bcl-G expression, both simultaneously and independently, in breast cancer cells in vitro to determine the importance of their roles in apoptosis. Expression of Fau, Bcl-G and MELK was measured by quantitative RT-PCR in breast cancer tissue and in matched breast epithelial tissue from the same patients. Expression data of these genes obtained using microarrays from a separate group of patients were related to patient survival in Kaplan-Meier analyses. RESULTS: siRNA-mediated downregulation of either Fau or Bcl-G expression inhibited apoptosis, and the inhibition produced by combining the two siRNAs was consistent with control of Bcl-G by Fau. Fau expression is significantly reduced in breast cancer tissue and this reduction is associated with poor patient survival, as predicted for a candidate breast cancer tumour suppressor. In addition, MELK expression is increased in breast cancer tissue and this increase is also associated with poor patient survival, as predicted for a candidate oncogene. Bcl-G expression is reduced in breast cancer tissue but decreased Bcl-G expression showed no correlation with survival, indicating that the most important factors controlling Bcl-G activity are post-translational modification (by Fau and MELK) rather than the rate of transcription of Bcl-G itself. CONCLUSIONS: The combination of in vitro functional studies with the analysis of gene expression in clinical breast cancer samples indicates that three functionally interconnected genes, Fau, Bcl-G and MELK, are crucially important in breast cancer and identifies them as attractive targets for improvements in breast cancer risk prediction, prognosis and therapy.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Smell-related quality of life changes after total laryngectomy : a multi-centre study

Purpose: A total laryngectomy creates an alternate airway for gas exchange that bypasses the upper aerodigestive tract. The subsequent reduction in nasal airflow, and therefore, reduction in deposition of particles to the olfactory neuroepithelium leads to hyposmia or anosmia. The aim of this study was to assess the quality of life impairment conferred by anosmia following laryngectomy and identify any specific patient-related risk factors that are associated with poorer outcomes. Methods: Consecutive patients with a total laryngectomy presenting for review at three tertiary head and neck services (in Australia, the United Kingdom and India) over a 12-month period were recruited. Patient demographic and clinical data were collected, and each subject completed the validated assessment of self-reported olfactory functioning and olfaction-related quality of life questionnaire (ASOF). Dichotomous comparisons were performed using the student's unpaired t-test for continuous variables (SRP), a chi-squared test for categorical variables, and a Kendall's tau-b for ordinal variables (SOC) to assess for a correlation with poorer questionnaire scores. Results: A total of 66 laryngectomees (13.4% female; age 65.7 ± 8.6 years) were included in the study. The mean SRP score of the cohort was found to be 15.6 ± 7.4, while the mean ORQ score was noted to be 16.4 ± 8.1. No other specific risk factors associated with poorer quality of life were identified. Conclusion: A significant quality of life detriment from hyposmia is conferred following laryngectomy. Further research to assess treatment options and the patient population that would best benefit from these interventions is required

Data from: Real-time characterization of the molecular epidemiology of an influenza pandemic

Early characterization of the epidemiology and evolution of a pandemic is essential for determining the most appropriate interventions. During the 2009 H1N1 influenza A pandemic, public databases facilitated widespread sharing of genetic sequence data from the outset. We employ Bayesian phylogenetics to simulate real-time estimation of the evolutionary rate, date of emergence and intrinsic growth rate (r0) of the pandemic from whole-genome sequences. We investigate the effects of temporal range of sampling and dataset size on the precision and accuracy of parameter estimation. Parameters can be accurately estimated as early as two months after the first reported case, from 100 genomes. Early deleterious mutations were purged from the population during the second pandemic wave and the choice of growth model is important for accurate estimation of r0. This demonstrates the utility of simple coalescent models to rapidly inform intervention strategies during a pandemic