Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor

Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of b-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy.

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.

Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing

Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx⁻/⁻ revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.

Using enterprise information architecture methods to model wicked problems in information systems design research

Design Science is the process of solving ‘wicked problems’ through designing, developing, instantiating, and evaluating novel solutions (Hevner, March, Park and Ram, 2004). Wicked problems are described as agent finitude in combination with problem complexity and normative constraint (Farrell and Hooker, 2013). In Information Systems Design Science, determining that problems are ‘wicked’ differentiates Design Science research from Solutions Engineering (Winter, 2008) and is a necessary part of proving the relevance to Information Systems Design Science research (Hevner, 2007; Iivari, 2007). Problem complexity is characterised as many problem components with nested, dependent and co-dependent relationships interacting through multiple feedback and feed-forward loops. Farrell and Hooker (2013) specifically state for wicked problems “it will often be impossible to disentangle the consequences of specific actions from those of other co-occurring interactions”. This paper discusses the application of an Enterprise Information Architecture modelling technique to disentangle the wicked problem complexity for one case. It proposes that such a modelling technique can be applied to other wicked problems and can lay the foundations for proving relevancy to DSR, provide solution pathways for artefact development, and aid to substantiate those elements required to produce Design Theory.

Life story work and social work practice : a case study with ex-prisoners labelled as having an intellectual disability

In common with other professions social workers have the power to articulate certain ‘‘truths’’ about the people who use their services (Hare Mustin, 1994). These knowledge statements about people, often situated in case files may become the only background information of the lived experience for people with disability (Gillman, Swain, & Heyman, 1997). Social workers need to develop interviewing, assessment and recording practices that give precedent to the worldview of service users, if they are to truly understand and respond effectively to people's lives (Bigby, 2007). One such way of doing this is by adopting a life story approach to working with vulnerable people, which can provide a holistic stance to a person's social reality (Ortiz, 1985). This article outlines the use of this approach in research with Queensland ex-prisoners who were labelled as having an intellectual disability. By explaining the process used by the first author (hereafter known as the researcher), the methodological findings of this study illustrate how life story work can contribute to social work practice.

Effective responses to offenders with intellectual disabilities : generalist and specialist services working together

Despite policies of deinstitutionalisation, many people with intellectual disabilities in developed western countries continue to live in mainstream institutional settings, such as correctional facilities, rather than in the community with support from disability services. This paper reports on the life stories of 10 people with intellectual disabilities, who had been imprisoned in adult correctional facilities in Queensland. The pathways taken by these 10 people into and out of prison are marked by significant abuse, neglect, and poverty. Significant disparity and disconnection is also displayed between the policies and service approaches, particularly between the disability, mental health, and correctional systems in Queensland. Based on these findings, a framework for practice, which spans both generic and specialist services, is suggested.

Social work with marginalised people who have a mild or borderline intellectual disability : practicing gentleness and encouraging hope

People with mild or borderline intellectual disabilities are a group of people who usually do not meet the eligibility criteria for specialist disability services, yet are high users of many generalist services, such as mental health, child protection, and criminal justice systems. They may traverse many services, often entering, exiting, and returning to the same service providers with few positive results. This article explores the practice approach of the Meryton Association, a medium-sized nongovernment agency located in Brisbane, Australia. The Meryton Association provides social work support to people with mild to borderline intellectual disabilities, actively assisting this group to build relationships, resources, knowledge, and autonomy in their everyday lives. Using qualitative in-depth interviews with Meryton Association staff and secondary analysis of Meryton Association policy and practice documents, the challenges and opportunities of using this practice approach have been documented. The article proposes that specialist services are needed that use a developmental approach, stress the importance of relationship, and the need to practice gentleness and hope in social worker-client interaction.

On-road driver sleepiness : what are Australian drivers experiences and awareness of sleepiness while driving?

Objectives: Driver sleepiness contributes substantially to road crash incidents. Simulator and on-road studies clearly reveal an impairing effect from sleepiness for driving ability. However, drivers might not appreciate the dangerousness of driving while sleepy and this could translate to their on-road driving behaviours. This study sought to determine drivers’ on-road experiences of sleepiness, their sleep habits, and personal awareness of the signs of sleepiness. Methods: Participants were a random selection of 92 drivers travelling on a major highway in the state of Queensland, Australia, who were stopped by Police as part of routine drink driving operations. Participants completed a brief questionnaire that included: demographic details, awareness and on-road experiences of sleepy driving, and sleep habits. A modified version of the Karolinska Sleepiness Scale (KSS) was used to assess subjective sleepiness during the last 15 minutes of driving. Results: Participants rating of subjective sleepiness was quite low with 90% reporting at or below 3 on the KSS. Participants were reasonably aware of the signs of sleepiness; with a number of these correlated with on-road experiences. The participants sleep debt correlated with their alertness (r = -.30) and the hours spent driving (r = .38). Conclusions: These results suggest that drivers had moderate or substantial experience of driving when sleepy and many were aware of the signs of sleepiness. As many of the participants reported driving long distances after suboptimal sleep durations, it is possible that their risk perception of the dangerousness of sleepy driving maybe erroneous.

Optimisation methods for coupled thermodynamic and 1D design of radial-inflow turbines

Optimisation is a fundamental step in the turbine design process, especially in the development of non-classical designs of radial-inflow turbines working with high-density fluids in low-temperature Organic Rankine Cycles (ORCs). The present work discusses the simultaneous optimisation of the thermodynamic cycle and the one-dimensional design of radial-inflow turbines. In particular, the work describes the integration between a 1D meanline preliminary design code adapted to real gases and the performance estimation approach for radial-inflow turbines in an established ORC cycle analysis procedure. The optimisation approach is split in two distinct loops; the inner operates on the 1D design based on the parameters received from the outer loop, which optimises the thermodynamic cycle. The method uses parameters including brine flow rate, temperature and working fluid, shifting assumptions such as head and flow coefficients into the optimisation routine. The discussed design and optimisation method is then validated against published benchmark cases. Finally, using the same conditions, the coupled optimisation procedure is extended to the preliminary design of a radial-inflow turbine with R143a as working fluid in realistic geothermal conditions and compared against results from commercially-available software RITAL from Concepts-NREC.

Role of the N-terminal region in G protein-coupled receptor functions : negative modulation revealed by 5-HT2B receptor polymorphisms

The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family

Can larger cemented femoral components reduce periprosthetic fractures?

Introduction The risk for late periprosthetic fractures is higher in patients treated for a neck of femur fracture compared to those treated for osteoarthritis. It has been hypothesised that osteopenia and consequent decreased stiffness of the proximal femur are responsible for this. We investigated if a femoral component with a bigger body would increase the torque to failure in a biaxially loaded composite sawbone model. Method A biomechanical composite sawbone model was used. Two different body sizes (Exeter 44-1 vs 44-4) of a polished tapered cemented stem were implanted by an experienced surgeon, in 7 sawbones each and loaded at 40 deg/s internal rotation until failure. Torque to fracture and fracture energy were measured using a biaxial materials testing device (Instron 8874). Data are non-parametric and tested with Mann-Whitney U-test. Results The mean torque load to fracture was 154.1 NM (SD 4.4) for the 44-1 stem and 229 NM (SD10.9) for the 44-4 stem (p = 0.01). The mean fracture energy was 9.6 J (SD1.2) for the 44-1 stem and 17.2 J (SD2.0) for the 44-4 stem (p = 0.14). Conclusion the use of a large body polished tapered cemented stem for neck of femur fractures increases the torque to failure in a biomechanical model and therefore is likely to reduce late periprosthetic fracture risk in this vulnerable cohort.

Fracture load for short versus standard cemented hip stems : an experimental in vitro study

Introduction: In an attempt to reduce stress shielding in the proximal femur multiple new shorter stem design have become available. We investigated the load to fracture of a new polished tapered cemented short stem in comparison to the conventional polished tapered Exeter stem. Method: A total of forty-two stems, twenty-one short stems and twenty-one conventional stems both with three different offsets were cemented in a composite sawbone model and loaded to fracture. Results: study showed that femurs will break at a significantly lower load to failure with a shorter compared to conventional length Exeter stem. Conclusion: This Both standard and short stem design are safe to use as the torque to failure is 7–10 times as much as the torques seen in activities of daily living.

Emerging Opportunities for "Design Thinking" to Deliver Sustainable Solutions in the Built Environment

In the built environment sector, a range of innovations are delivering environmental improvements with mixed success worldwide. The authors of this paper argue that a more “disruptive” form of innovation is needed to bring about significant and systemic change within the sector. Critical to this transition is the development of new behaviours and values. In particular, built environment professionals need to become active change agents in cultivating these new behaviours and values through the development of collaborative visions, scenarios, practices, and ideas. This paper identifies and discusses the critical role that design (in its broadest sense) can play in this process. Drawing on a comprehensive review of literature, the authors highlight a number of transformational opportunities for cross professional learning and sharing between design and built environment disciplines in achieving environmental innovation (eco-innovation). The paper also considers several design-based concepts that have a potential application in the built environment sector including: design thinking, social innovation (human-centered), and disruptive innovation (transformational) approaches. The research findings will assist in building the capabilities of designers and innovators to create sustainable solutions to global problems, and in supporting the social diffusion of systems-changing ideas in the built environment sector.