Mathematical modeling of the cancer cell’s control circuitry : paving the way to individualized therapeutic strategies

Cancer is a disease of signal transduction in which the dysregulation of the network of intracellular and extracellular signaling cascades is sufficient to thwart the cells finely-tuned biochemical control mechanisms. A keen interest in the mathematical modeling of cell signaling networks and the regulation of signal transduction has emerged in recent years, and has produced a glimmer of insight into the sophisticated feedback control and network regulation operating within cells. In this review, we present an overview of published theoretical studies on the control aspects of signal transduction, emphasizing the role and importance of mechanisms such as ‘ultrasensitivity’ and feedback loops. We emphasize that these exquisite and often subtle control strategies represent the key to orchestrating ‘simple’ signaling behaviors within the complex intracellular network, while regulating the trade-off between sensitivity and robustness to internal and external perturbations. Through a consideration of these apparent paradoxes, we explore how the basic homeostasis of the intracellular signaling network, in the face of carcinogenesis, can lead to neoplastic progression rather than cell death. A simple mathematical model is presented, furnishing a vivid illustration of how ‘control-oriented’ models of the deranged signaling networks in cancer cells may enucleate improved treatment strategies, including patient-tailored combination therapies, with the potential for reduced toxicity and more robust and potent antitumor activity.

Delivery of therapeutic molecules using electrosprayed polymeric particles for applications in tissue engineering

This thesis has developed an innovative technology, electrospraying, that allows biodegradable microparticles to deliver pharmaceuticals that aid bone regeneration. The establishment, characterisation and optimisation of the technique are a step forward in developing an affordable and safe alternative to the products used currently in the clinical setting for the treatment of musculoskeletal disorders. The researcher has also investigated electrospraying as a coating technique on biodegradable structures that are used to replace damaged tissues, in order to provide localised and efficient drug delivery in the site of the defect to help tissue reconstruction.

The effectiveness of workshops as managerial learning opportunities

Purpose The purpose of this paper is to examine the effectiveness of workshops as a learning tool for small business owner‐managers (SBO‐Ms). It aims to concentrate on workshops delivered over 18 months from January 2007 to July 2008 as part of several publicly‐funded small business development programmes in two Australian local government areas (LGAs). Design/methodology/approach Effectiveness is measured in terms of meeting the overarching learning needs and expectations of participants in the context of the programme goals. The paper analyses data gathered from workshop participants either post‐workshop, in later focus groups or through a questionnaire as well as additional feedback from participants and the organisers' reflections. The thematic analysis is organised through an analogy of “going shopping”, where the SBO‐M shopper is buying “learning” when they attend a workshop. Findings Understanding motivation to participate or the “what's in it for me” is important as SBO‐Ms tend to be reluctant, resist or fail to engage with externally sponsored business support initiatives. Workshops were valued for the “space” they create to reflect on practice. For many SBO‐Ms, content “comes alive” with discussion while networking helps reduce the isolation SBO‐Ms can feel. Practical implications The shopping analogy suggests workshops must cater for purposeful shoppers as well as browsers, while interaction with others in the workshop is critical to realising the value of workshops. Originality/value Knowing whether, and how, workshops deliver learning can help to better target and refine these types of support initiatives to ensure they provide positive outcomes for individuals, organisations and economies.

Tetraspanins as regulators of the tumour microenvironment : implications for metastasis and therapeutic strategies

One of the hallmarks of cancer is the ability to activate invasion and metastasis (Hanahan et al., 2011). Cancer morbidity and mortality are largely related to the spread of the primary, localised tumour to adjacent and distant sites (Pantel et al., 2004). Appropriate management and treatment decisions of predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are common events that occur during metastasis: dissociation from the primary tumour mass, reorganisation/remodelling of extracellular matrix, cell migration, recognition and transversal of endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma (Wells, 2006). One of the key and initial events is the increased capability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanins play important roles in regulation of cancer migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis

Functions and therapeutic roles of exosomes in cancer

The role of exosomes in cancer development has become the focus of much research, due to the many emerging roles possessed by exosomes. These micro-vesicles that are ubiquitously released in to the extracellular milieu, have been found to regulate immune system function, particularly in tumorigenesis, as well as conditioning future metastatic sites for the attachment and growth of tumor tissue. Through an interaction with a range of host tissue, exosomes are able to generate a pro-tumor environment that is essential for carcinogenesis. Herein, we discuss the contents of exosomes and their contribution to tumorigenesis, as well as their role in chemotherapeutic resistance and the development of novel cancer treatments and the identification of cancer biomarkers.

Therapeutic options for metastatic castration resistant prostate cancer : has the situation improved?

Limited treatment options for Castration Resistant Prostate Cancer (CRPC) still remain a major challenge. Despite therapeutic advances, most patients with malignant PCa have a poor prognosis. Since the year 2000, we have rapidly expanded our understanding of the molecular mechanisms underlying CRPC and this has led to an unprecedented number of new drug approvals within a short span of time. Recently, four new agents namely Abiraterone Acetate, Enzalutamide, Cabazitaxel, and Radium-223 have been shown to be effective in the post-chemotherapy setting in CRPC. The continued dependency of CRPC on androgen synthesis has seen the development of a number of new anti-androgen therapies, with abiraterone acetate and Enzalutamide being the most promising discoveries. Immunotherapeutic approaches have also found their niche in PCa with Sipuleucel-T shown to be effective in minimally asymptomatic CRPC. Research focussed on bone-targeting therapies has witnessed the arrival of promising new drugs with Denosumab and Radium-223 displaying improved survival of patients with CRPC. This review briefly discusses the findings and limitations from ongoing and completed clinical trials of novel treatments and regimens. In addition, potential mechanisms of therapy resistance and future challenges are discussed.

Therapeutic practice with refugee clients: a qualitative study of therapist experience

Background There is limited research on the subjective experience of therapists and their understanding of therapeutic process when working with people from refugee backgrounds. Objective The present study provides a qualitative account of therapists’ conceptions of therapeutic practice and experiences of working therapeutically with refugee clients. Method Participants were 12 mental health workers who had worked therapeutically with people from refugee backgrounds, with an average of 7.6 years (range 1.5-16 years) experience in this field. Participants completed a semi-structured interview and completed a brief quantitative survey. Findings Thematic analysis revealed a number of super-ordinate themes. Four key themes are explored in the current study: principles of therapeutic practice; therapy as a relational experience; the role of context in informing therapeutic work with refugee clients; and the impact of therapeutic work on the therapist. Discussion The results revealed the complexity and demands of working with people from refugee backgrounds. Further, the lack of research evidence for the methods of therapeutic practice described in the current study highlights the distinction between naturalistic therapeutic practice and the current state of the evidence regarding therapeutic interventions for refugee clients. The findings have important implications for training and supporting therapists to work with people who have fled their countries of origin and who have often been exposed to highly traumatic events.

Antisocial personality disorder and therapeutic justice court programs

It has become commonplace for courts to supervise an offender as part of the sentencing process. Many of them have Anti Social Personality Disorder (ASPD). The focus of this article is how the work of specialist and/or problem solving courts can be informed by the insights of the psychology profession into the best practice in the treatment and management of people with ASPD. It is a legitimate purpose of legal work to consider and improve the well-being of the participants in the legal process. Programs designed specifically to deal with those with ASPD could be incorporated into existing Drug Courts, or implemented separately by courts to aid with reforming offenders with ASPD and in managing the re-entry of offenders into the community as part of their sentence. For the success of this initiative on the part of the court, ASPD will need to be specifically diagnosed and treated. Close co-operation between courts and psychologists is required to improve the effectiveness of court programs to treat people with ASPD and to evaluate their success.

Developing a therapeutic anti-dendritic cell antibody to prevent graft versus host disease

Host and donor dendritic cells (DC) stimulate alloreactive donor T lymphocytes, and initiate GVHD. We have shown that polyclonal antibody to the DC surface activation marker human CD83 (anti hCD83), which depletes activated DC, can prevent human DC and T cell induced lethal xenogeneic GVHD in SCID mice without impairing T cell mediated anti-leukaemic and anti-viral (CMV and influenza) immunity (J Exp Med 2009; 206: 387). Therefore, we made and tested a polyclonal anti mouse CD83 (RAM83) antibody in murine HSCT models and developed a human mAb against hCD83 as a potential new therapeutic immunosuppressive agent.

Non-Therapeutic Medication Omissions: Incidence and Predictors at an Australian Hospital

Background: The inconsistent definition of non-therapeutic medication omissions, under-reporting, and a poor understanding of their associated factors hamper efforts to improve medication administration practices. Aim: To examine the incidence of non-therapeutic medication omissions among acutely ill medical and surgical adult patients; and to identify the patient-, drug- and system-related predictors of these omissions. Method: A medication chart audit of 288 acutely ill adult medical and surgical patients admitted to 4 target wards (2 surgical and 2 medical) at an Australian hospital. Patients admitted to these wards from December 2008 to November 2009, with at least one regularly prescribed medication, were eligible. The sample was stratified according to gender, season and ward. A medication chart audit identified medication omissions, and data were collected on gender, age, length of stay, comorbidities, medication history and clinical pharmacy review. Results: Of the 288 medication charts audited, 220 (75%) had one or more medication omissions. Of the 15 020 medication administration episodes, there were 1687 omissions, resulting in an omission rate per medication administration episode of 11%. Analgesics and aperients were the most frequently omitted medications, with failure to sign the medication record and patient refusal, the main reasons for omission. Female gender (p < 0.001) and the number of medication administration episodes (p < 0.001) were statistically significant predictors of non-therapeutic medication omissions. Conclusion: The high incidence of medication omissions suggests there is need for an agreed definition of medication omission and its inclusion as a reportable incident. Increasing medication reconciliation via implementation of the Medication Management Plan may also reduce the opportunity for error. J Pharm Pract Res 2011; 41: 188-91.

When coroners care too much: Therapeutic jurisprudence and suicide findings

In common law countries such as England and Australia, violent and otherwise unnatural deaths are investigated by coroners who make findings as to the “manner of death”. This includes determining whether the deceased person intentionally caused their own death. Previous research (Tait and Carpenter 2013a, 2013b, 2014) has suggested that coroners are reluctant to reach such determinations, citing the stigma of suicide and a need for sensitivity to grieving and traumatized families. Based on interviews with both English and Australian coroners, this paper explores whether an ‘ethic of care’ evident in English and Australian coronial suicide determinations, can be understood as an application of the ‘practices and techniques’ of therapeutic jurisprudence. Based on the ways in which coroners position the law as a potential therapeutic agent, we investigate how they understand their role and position as legal actors, and the effects of their decision making in the context of suspected suicides.

Reframe Workshops 2014 End of Year Report

Reframe: QUT's Evaluation Framework has repositioned the evaluations model away from a single survey instrument to a richer, customisable model that enables and supports QUT's academics in implementing teaching strategies and also provides holistic strategic capability. The Framework has established an approach to evaluation wherein the central role is that of individual academics strategising evaluation to support students as learners, enabled and supported by faculty and learning and teaching specialists. QUT has sought to refocus academic centrality and planning while also ensuring anticipated external reporting obligations to agencies such as TEQSA are achieved. 2014 is the year for embedding the Framework as core business within the University, with the the following providing a detailed report of the staff workshops that have been designed and delivered to support academic and professional staff in engaging with and using the Framework.