PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

Education and training of medical physicists in south East Asia: Accomplishments and challenges

John Cameron has made significant contributions to the field of Medical Physics. His contributions encompassed research and development, technical developments and education. He had a particular interest in the education of medical physicists in developing countries. Structured clinical training is also an essential component of the professional development of a medical physicist. This paper considers aspects of the clinical training and education of medical physicists in South-East Asia and the challenges facing the profession in the region if it is to keep pace with the rapid increase in the amount and technical complexity of medical physics infrastructure in the region.

The impact of English as a Foreign Language (EFL) listening comprehension through first language (L1) listening strategy training

Listening is the basic and complementary skill in second language learning. The term listening is used in language teaching to refer to a complex process that allows us to understand spoken language. Listening, the most widely used language skill, is often used in conjunction with the other skills of speaking, reading and writing. Listening is not only a skill area in primary language performance (L1), but is also a critical means of acquiring a second language (L2). Listening is the channel in which we process language in real time – employing pacing, units of encoding and decoding (the 2 processes are central to interpretation and meaning making) and pausing (allows for reflection) that are unique to spoken language. Despite the wide range of areas investigated in listening strategies during training, there is a lack of research looking specifically at how effectively L1 listening strategy training may transfer to L2. To investigate the development of any such transfer patterns the instructional design and implementation of listening strategy of L1 will be critical.

Polycaprolactone-based scaffold plus recombinant human bone morphogenetic protein (rhBMP-2) in an ovine model of anterior spinal fusion

Synthetic scaffolds combined with growth factors have the potential to replace allograft or autograft as a graft material for spinal interbody fusion. Such tissue engineering approaches may be useful in Adolescent Idiopathic Scoliosis (AIS) surgery, however there are no studies to date examining the use of such biodegradable implants in combination with biologics in a thoracic spine model. This in vivo study examines the use of biodegradable polycaprolactone (PCL) based scaffolds with rhBMP-2 as a bone graft substitute in a sheep thoracic fusion model, where an anterior approach is used to simulate minimally invasive surgical deformity correction in the setting of AIS.

Recruitment and training of board members for the 90's and beyond

An historical analysis of the management of the arts in Australia in the last fifty years demonstrates clearly the problems faced by arts organisations which have poorly selected and trained Boards of Directors. Traditionally Board members were selected because they represented the various facets and skills involved in business (marketing, law, accountancy, management, entrepreneurship) or they were arts practitioners or patrons, or they had some particular social standing. Arts organisations recruited Board members like a "mixed bag of lollies - one of these and one of those". No consideration was given to the vital qualities of enthusiasm, reliability, empathy, capacity for hard work, strong arts interest, effective communication skills and respect for organisational processes.

Incident investigation training needs for the Australasian rail industry

A core component for the prevention of re-occurring incidents within the rail industry is rail safety investigations. Within the current Australasian rail industry, the nature of incident investigations varies considerably between organisations. As it stands, most of the investigations are conducted by the various State Rail Operators and Regulators, with the more major investigations in Australia being conducted or overseen by the Australian Transport Safety Bureau (ATSB). Because of the varying nature of these investigations, the current training methods for rail incident investigators also vary widely. While there are several commonly accepted training courses available to investigators in Australasia, none appear to offer the breadth of development needed for a comprehensive pathway. Furthermore, it appears that no single training course covers the entire breadth of competencies required by the industry. These courses range in duration between a few days to several years, and some were run in-house while others are run by external consultants or registered training organisations. Through consultations with rail operators and regulators in Australasia, this paper will identify capabilities required for rail incident investigation and explore the current training options available for rail incident investigators.

Risk taking by motorcyclists : rider training and stages of change

Motorcyclists in Australia have been found to be 30 times more likely to be killed per kilometre travelled than car occupants and 40 times more likely to be seriously injured. One approach to preventing motorcycle-related injury is through training and education. While there is traditionally a major focus on developing riding skills during training for motorcyclists, there is also a need for training to promote safe riding to reduce subsequent risk taking. The Transtheoretical Model, commonly known as the ‘Stages of Change’ model, provides a rationale to support incremental behaviour change for risky riding that may be facilitated through motorcycle rider training and education. A sample of 438 learner motorcyclists attended a rider training program in Queensland, Australia, with the stages of change to adopt a safe riding mindset and safe riding practices being measured upon commencement of the course (Time 1) and then again upon completion (Time 2). A small subset of the original sample (n=45) responded at follow up 24 months post training (Time 3). Consistent with the aims of training, results showed a significant shift from the contemplation stage to the subsequent stages of change for participants between Time 1 and Time 2. Progression to the later stages in the model was found for the subset of participants that responded at the Time 3 follow up. Issues of questionnaire design and the utility of the Transtheoretical Model for motorcycle rider training are discussed.

Multiuser virtual safety training system for tower crane dismantlement

Tower crane dismantling is one of the most dangerous activities in the construction industry. Tower crane erection and dismantlement causes 10–12% of the fatalities of all crane accidents. The nature of the task is such that off-the-job training is not practicable, and the knowledge and expertise needed has to be gained on the job. However, virtual trainers such as Microsoft Flight Simulator for airplane pilots and mission rehearsal exercise (MRE) for army personnel have been developed and are known to provide a highly successful means of overcoming the risks involved in such on-the-job learning and clearly have potential in construction situations. This paper describes the newly developed multiuser virtual safety training system (MVSTS) aimed at providing a similar learning environment for those involved in tower crane dismantlement. The proposed training system is developed by modifying an existing game engine. Within the close-to-reality virtual environment, trainees can participate in a virtual dismantling process. During the process, they learn the correct dismantling procedure and working location and to cooperate with other trainees by virtually dismantling the crane. The system allows the trainees to experience the complete procedure in a risk-free environment. A case study is provided to demonstrate how the system works and its practical application. The proposed system was evaluated by interviews with 30 construction experts with different backgrounds, divided into three groups according to their experience and trained by the traditional and virtual methods, respectively. The results indicate that the trainees of the proposed system generally learned better than those using the traditional method. The ratings also indicate that the system generally has great potential as a training platform.

Inflammatory cytokine responses to progressive resistance training and supplementation with fortified milk in men aged 50+ years : an 18-month randomized controlled trial

We examined the effects of progressive resistance training (PRT) and supplementation with calcium-vitamin D(3) fortified milk on markers of systemic inflammation, and the relationship between inflammation and changes in muscle mass, size and strength. Healthy men aged 50-79 years (n = 180) participated in this 18-month randomized controlled trial that comprised a factorial 2 x 2 design. Participants were randomized to (1) PRT + fortified milk supplement, (2) PRT, (3) fortified milk supplement, or (4) a control group. Participants assigned to PRT trained 3 days per week, while those in the supplement groups consumed 400 ml day(-1) of milk containing 1,000 mg calcium plus 800 IU vitamin D(3). We collected venous blood samples at baseline, 12 and 18 months to measure the serum concentrations of IL-6, TNF-alpha and hs-CRP. There were no exercise x supplement interactions, but serum IL-6 was 29% lower (95% CI, -62, 0) in the PRT group compared with the control group after 12 months. Conversely, IL-6 was 31% higher (95% CI, -2, 65) in the supplement group compared with the non-supplemented groups after 12 and 18 months. These between-group differences did not persist after adjusting for changes in fat mass. In the PRT group, mid-tibia muscle cross-sectional area increased less in men with higher pre-training inflammation compared with those men with lower inflammation (net difference similar to 2.5%, p < 0.05). In conclusion, serum IL-6 concentration decreased following PRT, whereas it increased after supplementation with fortified milk concomitant with changes in fat mass. Furthermore, low-grade inflammation at baseline restricted muscle hypertrophy following PRT.

The effects of increased endurance training load on biomarkers of heat intolerance during intense exercise in the heat

The effects of increased training (IT) load on plasma concentrations of lipopolysaccharides (LPS), proinflammatory cytokines, and anti-LPS antibodies during exercise in the heat were investigated in 18 male runners, who performed 14 days of normal training (NT) or 14 days of 20% IT load in 2 equal groups. Before (trial 1) and after (trial 2) the training intervention, all subjects ran at 70% maximum oxygen uptake on a treadmill under hot (35 degrees C) and humid (similar to 40%) conditions, until core temperature reached 39.5 degrees C or volitional exhaustion. Venous blood samples were drawn before, after, and 1.5 h after exercise. Plasma LPS concentration after exercise increased by 71% (trial 1, p < 0.05) and 21% (trial 2) in the NT group and by 92% (trial 1, p < 0.01) and 199% (trial 2, p < 0.01) in the IT group. Postintervention plasma LPS concentration was 35% lower before exercise (p < 0.05) and 47% lower during recovery (p < 0.01) in the IT than in the NT group. Anti-LPS IgM concentration during recovery was 35% lower in the IT than in the NT group (p < 0.05). Plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha concentrations after exercise (IL-6, 3-7 times, p < 0.01, and TNF-alpha, 33%, p < 0.01) and during recovery (IL-6, 2-4 times, p < 0.05, and TNF-alpha, 30%, p < 0.01) were higher than at rest within each group. These data suggest that a short-term tolerable increase in training load may protect against developing endotoxemia during exercise in the heat.

The use of computerised simulators for training of transthoracic and transoesophageal echocardiography. The future of echocardiographic training?

Echocardiography is the commonest form of non-invasive cardiac imaging and is fundamental to patient management. However, due to its methodology, it is also operator dependent. There are well defined pathways in training and ongoing accreditation to achieve and maintain competency. To satisfy these requirements, significant time has to be dedicated to scanning patients, often in the time pressured clinical environment. Alternative, computer based training methods are being considered to augment echocardiographic training. Numerous advances in technology have resulted in the development of interactive programmes and simulators to teach trainees the skills to perform particular procedures, including transthoracic and transoesophageal echocardiography. 82 sonographers and TOE proceduralists utilised an echocardiographic simulator and assessed its utility using defined criteria. 40 trainee sonographers assessed the simulator and were taught how to obtain an apical 2 chamber (A2C) view and image the superior vena cava (SVC). 100% and 88% found the simulator useful in obtaining the SVC or A2C view respectively. All users found it easy to use and the majority found it helped with image acquisition and interpretation. 42 attendees of a TOE training day utilising the simulator assessed the simulator with 100% finding it easy to use, as well as the augmented reality graphics benefiting image acquisition. 90% felt that it was realistic. This study revealed that both trainee sonographers and TOE proceduralists found the simulation process was realistic, helped in image acquisition and improved assessment of spatial relationships. Echocardiographic simulators may play an important role in the future training of echocardiographic skills.