Mediation of transformation by the <i>v-fos</i> oncogene: regulation of the invasive phenotype by histone deacetylases

Transformation of fibroblasts with the v-fos oncogene produces a highly invasive phenotype. Accordingly, genes up- and down-regulated by v-Fos are of crucial importance in mediating a multigenic invasion programme. Differential expression studies revealed that components of histone deacetylase (HDAC) transcriptional co-repressor complexes are up-regulated in FBR-v-Fos-transformed (FBR) cells. Since HDACs facilitate gene silencing, we investigated the consequences of inhibiting their activity in terms of gene re-expression and phenotypic changes. We treated FBR cells with the HDAC inhibitors, trichostatin A (TSA) and valproic acid (VPA), at a range of sub-growth-inhibitory concentrations. At higher concentrations within this range, actin stress-fibres reform, transformed morphology reverts, cells are less motile and invasion is inhibited. Significantly, however, at lower concentrations within this range we inhibit invasion and actin stress-fibres reform but morphology, motility and chemotaxis are unaffected. This demonstrates the involvement of different groups of genes in different aspects of the transformed phenotype. In a limited study, we found several genes, down-regulated in FBR cells, which are then re-expressed as a consequence of HDAC inhibition. Ectopic re-expression (stable and transient) of three of these genes (RYBP, PCDHGC3 and STAT6) individually, in FBR cells, inhibits invasion without affecting morphology, motility or chemotaxis; nor do actin stress-fibres reform. These results demonstrate that the down-regulation of genes by Fos can be mediated by histone deacetylases and that many of these down-regulated genes, when normally expressed in fibroblasts, function to maintain the non-invasive state, in that their expression is incompatible with the invasive phenotype

A cell-permeable biscyclooctyne as a novel probe for the identification of protein sulfenic acids

Reactive oxygen species act as important second messengers in cell signaling and homeostasis through the oxidation of protein thiols. However, the dynamic nature of protein oxidation and the lack of sensitivity of existing molecular probes have hindered our understanding of such reactions; therefore, new tools are required to address these challenges. We designed a bifunctional variant of the strained bicyclo[6.1.0]nonyne (BCN-E-BCN) that enables the tagging of intracellular protein sulfenic acids for biorthogonal copper-free click chemistry. In validation studies, BCN-E-BCN binds the sulfenylated form of the actin-severing protein cofilin, while mutation of the cognate cysteine residues abrogates its binding. BCN-E-BCN is cell permeable and reacts rapidly with cysteine sulfenic acids in cultured cells. Using different azide-tagged conjugates, we demonstrate that BCN-E-BCN can be used in various applications for the detection of sulfenylated proteins. Remarkably, cycloaddition of an azide-tagged fluorophore to BCN-E-BCN labelled proteins produced in vivo can be visualized by fluorescence microscopy to reveal their subcellular localization. These findings demonstrate a novel and multifaceted approach to the detection and trapping of sulfenic acids

Mapping surgical coordinates of the sphenopalatine foramen : surgical navigation study

Aims to identify measurements that may help intra operative localisation of the sphenopalatine foramen. The study used three dimensional surgical navigation software to study radiological anatomy, in order to define the distances and angulations between identifiable bony landmarks and the sphenopalatine foramen. The distance from the anterior nasal spine to the sphenopalatine foramen was 59 mm (+4 mm; inter observer variation = 0.866; intra observer variation = 0.822). The distance from the piriform aperture to the sphenopalatine foramen was 48 mm (+4 mm; inter observer variation = 0.828; intra observer variation = 0.779). The angle of elevation from the nasal floor to the sphenopalatine foramen was 22 degrees (+3 degrees; inter observer variation = 0.441; intra observer variation = 0.499). The sphenopalatine foramen is consistently identifiable on three dimensional, reconstructed computed tomography scans. Repeatable measurements were obtained. The centre point of the foramen lies 59 mm from the anterior nasal spine at 22 degrees elevation above the plane of the hard palate and 48 mm from the piriform aperture. We discuss how these data could be used to facilitate intra operative location of the sphenopalatine foramen in difficult cases

Child and adolescent psychiatric nursing and the 'plastic man': Reflections on the implementation of change drawing insights from Lewin's theory of planned change

Child and adolescent psychiatric nursing (CAPN) as a discipline has been remarkably slow in the uptake of high fidelity human patient simulation (HFHPS) as an education tool. Assuming HFHPS has potential use, and the issue is one of change management, this paper speculates about how Lewin's paradigm for Planned Change might provide guidance to the specialty discipline of CAPN in development of strategies to promote adoption of HFHPS to education of pre-registration nurses. Kurt Lewin (1890-1947) was a seminal theorist of change, whose pioneering work has had significant impact across many disciplines. His theory of Planned Change has four components - field theory, group dynamics, action research and the three-step model of change. Each component is considered briefly and then combined within an example of application. © eContent Management Pty Ltd

Modelling of Atherosclerotic Plaque for Use in a Computational Test-Bed for Stent Angioplasty

A thorough understanding of the diseased tissue state is necessary for the successful treatment of a blocked arterial vessel using stent angioplasty. The constitutive representation of atherosclerotic tissue is of great interest to researchers and engineers using computational models to analyse stents, as it is this in silico environment that allows extensive exploration of tissue response to device implantation. This paper presents an in silico evaluation of the effects of variation of atherosclerotic tissue constitutive representation on tissue mechanical response during stent implantation. The motivation behind this work is to investigate the level of detail that is required when modelling atherosclerotic tissue in a stenting simulation, and to give recommendations to the FDA for their guideline document on coronary stent evaluation, and specifically the current requirements for computational stress analyses. This paper explores the effects of variation of the material model for the atherosclerotic tissue matrix, the effects of inclusion of calcifications and a lipid pool, and finally the effects of inclusion of the Mullins effect in the atherosclerotic tissue matrix, on tissue response in stenting simulations. Results indicate that the inclusion of the Mullins effect in a direct stenting simulation does not have a significant effect on the deformed shape of the tissue or the stress state of the tissue. The inclusion of a lipid pool induces a local redistribution of lesion deformation for a soft surrounding matrix and the inclusion of a small volume of calcifications dramatically alters the local results for a soft surrounding matrix. One of the key findings from this work is that the underlying constitutive model (elasticity model) used for the atherosclerotic tissue is the dominant feature of the tissue representation in predicting tissue response in a stenting simulation

Lice and tick in sheep

Body lice and so called ticks or keds are the most serious of the external parasites which infest sheep in Western Australia, and unless they are controlled by systematic dipping, these pests can be the cause of considerable financial loss to flocl owners. The sheep body louse (Damalinaia ovis), which is able to propagate under hot and dry conditions, has a wide distribution and occurs in both the agricultural and pastoral areas. The so-called tick or ked (Melophogus ovinus), has a much more restricted distribution and is confined to the higher rainall areas of the South-West proportion of the State

Is HIV/AIDS jeopardizing biodiversity?

The scourge of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) is most prevalent in southern Africa. South Africa has the highest number of people in the world living with HIV/AIDS and a prevalence rate of over 30 % for females presenting at antenatal clinics. There are now almost five million orphans within southern Africa, as a result of AIDS deaths of one or more or their parents. AIDS-related mortality and morbidity of care-givers may lead to increased reliance on wild sources of animal protein by surviving children. This increase in hunting pressure has unknown, but potentially important impacts on local animal populations

Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an abscopal effect although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This quadmodality approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy