Target acquired: Progress and promise of targeted therapeutics in the treatment of prostate cancer

Cancer is fundamentally a genomic disease caused by mutations or rearrangements in the DNA or epigenetic machinery of a patient. An emerging field in cancer treatment targets key aberrations arising from the mutational landscape of an individual patient’s disease rather than employing a cancer-wide cytotoxic therapy approach. In prostate cancer in particular, where there is an observed variation in response to standard treatments between patients with disease of a similar pathological stage and grade, mutationdirected treatment may grow to be a viable tool for clinicians to tailor more effective treatments. This review will describe a number of mutations across multiple forms of cancer that have been successfully antagonised by targeted therapeutics including their identification, the development of targeted compounds to combat them and the development of resistance to these therapies. This review will continue to examine these same mutations in the treatment and management of prostate cancer; the prevalence of targetable mutations in prostate cancer, recent clinical trials of targeted-agents and the potential or limitations for their use.

Fusion transcript loci share many genomic features with non-fusion loci

Background Fusion transcripts are found in many tissues and have the potential to create novel functional products. Here, we investigate the genomic sequences around fusion junctions to better understand the transcriptional mechanisms mediating fusion transcription/splicing. We analyzed data from prostate (cancer) cells as previous studies have shown extensively that these cells readily undergo fusion transcription. Results We used the FusionMap program to identify high-confidence fusion transcripts from RNAseq data. The RNAseq datasets were from our (N = 8) and other (N = 14) clinical prostate tumors with adjacent non-cancer cells, and from the LNCaP prostate cancer cell line that were mock-, androgen- (DHT), and anti-androgen- (bicalutamide, enzalutamide) treated. In total, 185 fusion transcripts were identified from all RNAseq datasets. The majority (76 %) of these fusion transcripts were ‘read-through chimeras’ derived from adjacent genes in the genome. Characterization of sequences at fusion loci were carried out using a combination of the FusionMap program, custom Perl scripts, and the RNAfold program. Our computational analysis indicated that most fusion junctions (76 %) use the consensus GT-AG intron donor-acceptor splice site, and most fusion transcripts (85 %) maintained the open reading frame. We assessed whether parental genes of fusion transcripts have the potential to form complementary base pairing between parental genes which might bring them into physical proximity. Our computational analysis of sequences flanking fusion junctions at parental loci indicate that these loci have a similar propensity as non-fusion loci to hybridize. The abundance of repetitive sequences at fusion and non-fusion loci was also investigated given that SINE repeats are involved in aberrant gene transcription. We found few instances of repetitive sequences at both fusion and non-fusion junctions. Finally, RT-qPCR was performed on RNA from both clinical prostate tumors and adjacent non-cancer cells (N = 7), and LNCaP cells treated as above to validate the expression of seven fusion transcripts and their respective parental genes. We reveal that fusion transcript expression is similar to the expression of parental genes. Conclusions Fusion transcripts maintain the open reading frame, and likely use the same transcriptional machinery as non-fusion transcripts as they share many genomic features at splice/fusion junctions.

Introducing a new limit states design concept to railway concrete sleepers: An Australian experience

Over 50 years, a large number of research and development projects with respect to the use of cementitious and concrete materials for manufacturing railway sleepers have been significantly progressed in Australia, Europe, and Japan (Wang, 1996; Murray and Cai, 1998; Wakui and Okuda, 1999; Esveld, 2001; Freudenstein and Haban, 2006; Remennikov and Kaewunruen, 2008). Traditional sleeper materials are timber, steel, and concrete. Cost-efficiency, superior durability, and improved track stability are the main factors toward significant adoption of concrete materials for railway sleepers. The sleepers in a track system, as shown in Figure 1, are subjected to harsh and aggressive external forces and natural environments across a distance. Many systemic problems and technical issues associated with concrete sleepers have been tackled over decades. These include pre-mature failures of sleepers, concrete cancer or ettringite, abrasion of railseats and soffits, impact damages by rail machinery, bond-slip damage, longitudinal and lateral instability of track system, dimensional instability of sleepers, nuisance noise and vibration, and so on (Pfeil, 1997; Gustavson, 2002; Kaewunruen and Remennikov, 2008a,b, 2013). These issues are, however, becoming an emerging risk for many countries (in North and South Americas, Asia, and the Middle East) that have recently installed large volumes of concrete sleepers in their railway networks (Federal Railroad Administration, 2013). As a result, it is vital to researchers and practitioners to critically review and learn from previous experience and lessons around the world.

Design and Development of an In-Vehicle Human Machine Interface to Improve Fuel Efficiency & Safety

Road transport plays a significant role in various industries and mobility services around the globe and has a vital impact on our daily lives. However it also has serious impacts on both public health and the environment. In-vehicle feedback systems are a relatively new approach to encouraging driver behaviour change for improving fuel efficiency and safety in automotive environments. While many studies claim that the adoption of eco-driving practices, such as eco-driving training programs and in-vehicle feedback to drivers, has the potential to improve fuel efficiency, limited research has integrated safety and eco-driving. Therefore, this research seeks to use human factors related theories and practices to inform the design and evaluation of an in-vehicle Human Machine Interface (HMI) providing real-time driver feedback with the aim of improving both fuel efficiency and safety.

Playing alone, playing with others: Differences in player experience and indicators of wellbeing

Video game play is becoming an increasingly social experience, yet we have little understanding of how social and solitary modes of play differ in terms of the player experience or interact with player wellbeing. An online survey (n = 446) collected data on players' current mode of play, their game play experience, social capital gained from game play and wellbeing. The results indicate that social and solitary players differ in terms of degree of autonomy, presence and relatedness experienced, while the different types of social play are associated with differences in relatedness and social capital experienced. Different predictors of wellbeing were also present across solitary and social player samples. People who play games on their own experience greater wellbeing when experiencing in-game autonomy. Social players experience greater wellbeing when playing with strangers, and when experiencing in-game bridging social capital. All players experienced increased wellbeing with age and decreased wellbeing with greater amounts of play.

Indicators of wellbeing in recreational video game players

Video game play is a popular entertainment choice, yet we have a limited understanding of the potential wellbeing benefits associated with recreational play. An online survey (final sample, n = 297) addresses this by investigating how the player experience related to wellbeing. The impact of amount of play, game genre, mode of play (social or solitary play) and the psychological experience of play (flow and need satisfaction) on a multi-dimensional measure of wellbeing (emotional, psychological and social) was examined via hierarchical regression. Age, gender, the play of casual games compared to shooters, and in-game experiences of flow, autonomy and relatedness were associated with increases in dimensions of wellbeing.

Designing for collections : Building histories, sharing the spectacle

The hobby of collecting represents the passionate acquisition and possession of a specific type(s) of object; creating a ‘spectacle’, to be shared with others. The fundamentality of the physical objects in collections against the backdrop of the growing ubiquity of computing provides a unique and compelling avenue for design. Based on interviews with 11 self-identified collectors, this paper discusses the role collectors have in informing HCI design and in turn, the potential HCI has in designing technology to assist collectors in sharing what we term the ‘spectacle’ of collecting. Toward this, we suggest two ideas for future designs, including building personal histories of individual collectable items and developing a simple digital means of connecting proximate collectors with those who stand to benefit from collectors’ unique and item-specific knowledge.

A noticeboard in "both worlds" unsurprising interfaces supporting easy bi-cultural content publication

We describe the design of a digital noticeboard to support communication within a remote Aboriginal community whose aspiration is to live in "both worlds", nurturing and extending their Aboriginal culture and actively participating in Western society and economy. Three bi-cultural aspects have emerged and are presented here: the need for a bi-lingual noticeboard to span both oral and written language traditions, the tension between perfunctory information exchange and social, embodied protocols of telling in person and the different ways in which time is represented in both cultures. The design approach, developed iteratively through consultation, demonstration and testing led to an "unsurprising interface", aimed at maximizing use and appropriation across cultures by unifying visual, text and spoken contents in both passive and interactive displays in a modeless manner.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

Combining unsupervised and invigilated assessment of introductory programming

We compared student performance on large-scale take-home assignments and small-scale invigilated tests that require competency with exactly the same programming concepts. The purpose of the tests, which were carried out soon after the take home assignments were submitted, was to validate the students' assignments as individual work. We found widespread discrepancies between the marks achieved by students between the two types of tasks. Many students were able to achieve a much higher grade on the take-home assignments than the invigilated tests. We conclude that these paired assessments are an effective way to quickly identify students who are still struggling with programming concepts that we might otherwise assume they understand, given their ability to complete similar, yet more complicated, tasks in their own time. We classify these students as not yet being at the neo-Piagetian stage of concrete operational reasoning.

The internet of playful things

This one-day workshop brings together researchers and practitioners to share knowledge and practices on how people can connect and interact with the Internet of Things in a playful way. Open to participants with a diverse range of interests and expertise, and by exploring novel ways to playfully connect people through their everyday objects and activities, the workshop will facilitate discussion across a range of HCI discipline areas. The outcomes from the workshop will include an archive of participants' initial position papers along with the materials created during the workshop. The result will be a road map to support the development of a Model of Playful Connectedness, focusing on how best to design and make playful networks of things, identifying the challenges that need to be addressed in order to do so.

Reflections from East Asia's ageing population: An interaction designers' challenge

As Asia experiences the demographic imbalance between working and ageing populations, the need for attention in this area is highlighted. The shift of a country's age structure that results from people having small families and living long lives, where previously they had large families and lived short lives, results in more workers and fewer dependents creating economic growth, known as the demographic dividend. However for a generation after this bulge and dividend, a disproportionate number of older people must be supported by a smaller working population, a current concern in Asia with its rapidly growing number of older adults. This extended abstract draws practical and unique insights from three of the oldest and richest nations in Asia - Japan, South Korea and China, on the perspective of interactive technology design for older adults. ICT has powerful potential to ameliorate the imbalance in the population demographic through its potential to leverage various kinds of support. As HCI researchers, this is a challenge we embrace; a challenge for the ageing society of unique individuals to exploit the technologies that they have helped to create. The paper draws lessons from key sample studies, one from each country, which aimed to understand their ageing population. The insights for interaction designers are presented in the form of a practical set of reflections to guide the authors, who are in the early stages of research on technology design for older adults.

Examination of EXOSC4 as a new prognostic marker and a novel therapeutic avenue in lung adenocarcinoma

Although prevention and early detection of the disease greatly improved over the past few years, lung cancer remains the leading cause of cancer deaths. In order to be able to treat a larger population, we are in urgent need for novel treatments. While it is known that DNA repair genes play a major role in the oncogenic transformation, they also represent a weakness of cancers that constitute a therapeutic opportunity. To identify novel DNA repair genes implicated in Lung cancers, we conducted an in silico investigation to identify genes co-regulated with two DNA repair factors, BRCA2 and hSSB1. This approach allowed for the identification of EXOSC4, a component of the RNA Exosome machinery, as a potential factor involved in the maintenance of genome stability and that is deregulated in lung cancer.

Vendors' perspectives of coordination in the information technology offshore outsourcing industry : An exploratory study from the Philippines

This study investigates how offshore information technology (IT) service providers (vendors) coordinate work with their clients (employers) in order to succeed in the global IT offshore outsourcing industry. We reviewed literature on coordination studies, interviewed offshore service providers in the Philippines, and used thematic analysis to analyse coordination practices from the point of view of these individual vendors in a newly industrialized country. We used Olson and Olson's framework on 'collaboration at a distance' as a lens to structure the results. The study provides an understanding of vendors' individual attitudes towards the coordination of distributed work and draws attention to how differences in power affect the work situation of vendors, and by implication all stakeholders. We offer this insight as a way to enhance existing CSCW frameworks, by imbuing them with the perspective of non-equal relationships. The study found that vendors were generally able to produce outputs that satisfy their clients, however these results were only achieved because individuals were willing to take risks and make sacrifices in their personal lives. The relationship was further characterised by a complex interplay between the client's control of the overall work arrangements and the vendors' ability to establish a level of autonomy in their work practices and their flexible use of coordination tools.