EVERSUN: A phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

Background We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.

A candidate gene association study for growth performance in an improved Giant Freshwater Prawn (Macrobrachium rosenbergii) culture line

A candidate gene approach using type I single nucleotide polymorphism (SNP) markers can provide an effective method for detecting genes and gene regions that underlie phenotypic variation in adaptively significant traits. In the absence of available genomic data resources, transcriptomes were recently generated in Macrobrachium rosenbergii to identify candidate genes and markers potentially associated with growth. The characterisation of 47 candidate loci by ABI re-sequencing of four cultured and eight wild samples revealed 342 putative SNPs. Among these, 28 SNPs were selected in 23 growth-related candidate genes to genotype in 200 animals selected for improved growth performance in an experimental GFP culture line in Vietnam. The associations between SNP markers and individual growth performance were then examined. For additive and dominant effects, a total of three exonic SNPs in glycogen phosphorylase (additive), heat shock protein 90 (additive and dominant) and peroxidasin (additive), and a total of six intronic SNPs in ankyrin repeats-like protein (additive and dominant), rolling pebbles (dominant), transforming growth factor-β induced precursor (dominant), and UTP-glucose-1-phosphate uridylyltransferase 2 (dominant) genes showed significant associations with the estimated breeding values in the experimental animals (P =0.001−0.031). Individually, they explained 2.6−4.8 % of the genetic variance (R2=0.026−0.048). This is the first large set of SNP markers reported for M. rosenbergii and will be useful for confirmation of associations in other samples or culture lines as well as having applications in marker-assisted selection in future breeding programs.

Do repeated rumble strip hits improve driver alertness?

Driving while sleepy is associated with increased crash risk. Rumble strips are designed to alert a sleepy or inattentive driver when they deviate outside their driving lane. The current study sought to examine the effects of repeated rumble strip hits on levels of physiological and subjective sleepiness as well as simulated driving performance. In total, 36 regular shift workers drove a high-fidelity moving base simulator on a simulated road with rumble strips installed at the shoulder and centre line after a working a full night shift. The results show that on average, the first rumble strip occurred after 20 minutes of driving, with subsequent hits occurring 10 minutes later, with the last three occurring approximately every 5 minutes thereafter. Specifically, it was found that the first rumble strip hit reduced physiological sleepiness; however, subsequent hits did not increase alertness. Moreover, the results also demonstrate that increased subjective sleepiness levels, via the Karolinska Sleepiness Scale, were associated with a greater probability of hitting a rumble strip. The present results suggest that sleepiness is very resilient to even strongly arousing stimuli, with physiologicl and subjective sleepiness increasing over the duration of the drive, despite the interference by rumble strips.

Effectiveness of on-line resources to enhance student learning and engagement

BACKGROUND For engineering graduates to be work-ready with marketable skills they must not only be well-versed with engineering science and its applications, but also able to adapt to using commercial software that is widely used in engineering practice. Hydrological/hydraulic modelling is one aspect of engineering practice which demands the ability to apply fundamentals into design and construction using software. The user manuals for such software are usually tailored for the experienced engineer but not for undergraduates who typically are novices to concepts of modelling and software tools. As the focus of a course such as Advanced Water Engineering is on the wider aspects of engineering application of hydrological and hydraulic concepts, it is ineffective for the lecturers to direct the students to user manuals as students have neither the time nor the desire to sift through numerous pages in a manual. An alternative and efficient way to demonstrate the use of the software is enabling students to develop a model to simulate real-world scenario using the tools of the software and directing them to make informed decisions based on outcomes. PURPOSE Past experience of the lecturer showed that the resources available for the students left a knowledge gap leading to numerous student queries outside contact hours. The purpose of this study is to assess how effective purpose-built video resources can be in supplementing the traditional learning resources to enhance student learning. APPROACH Short-length animated video clips comprising guided step-by-step instructions were prepared using screen capture software to capture screen activity and later edited to focus on specific features using pop-up annotations; Vocal narration was purposely excluded to avoid disturbances due to noise and allow different learning paces of individual students. The video clips were made available to the students alongside the traditional resources/approaches such as in-class demonstrations, guideline notes, and tips for efficient and error-free procedural descriptions. The number of queries the lecturer received from the student cohort outside the lecture times was recorded. An anonymous survey to assess the usefulness and adequacy of the courseware was conducted. OUTCOMES While a significant decline in the number of student queries was noted, an overwhelming majority of the survey respondents confirmed the usefulness of the purpose-developed courseware. CONCLUSIONS/RECOMMENDATIONS/SUMMARY The survey and lecturer’s experience indicated that animated demonstration video clips illustrating the various steps involved in developing hydrologic and hydraulic models and simulating design scenarios is an effective supplement for traditional learning resources. Among the many advantages of the custom-made video clips as a learning resource are that they (1) highlight the aspects that are important to undergraduate learning but not available in the software manuals as the latter are designed for more mature users/learners; (2) provide short, to-the point communication in a step-by-step manner; (3) allow students flexibility to self-learn at their own pace; (4) enhance student learning; and (5) enable time savings for the lecturer in the long term by avoiding queries of a repetitive nature. It is expected that these newly developed resources will be improved to incorporate students’ suggestions before being offered to future cohorts of students. The concept can also be expanded to other relevant courses where animated demonstrations of key modelling steps are beneficial to student learning.

Natural convection in a triangular enclosure heated from below and non-uniformly cooled from top

This study is concerned with transient natural convection in an isosceles triangular enclosure subject to non-uniformly cooling at the inclined surfaces and uniformly heating at the base. The numerical simulations of the unsteady flows over a range of Rayleigh numbers and aspect ratios are carried out using Finite Volume Method. Since the upper inclined surfaces are linearly cooled and the bottom surface is heated, the flow is potentially unstable. It is revealed from the numerical simulations that the transient flow development in the enclosure can be classified into three distinct stages; an early stage, a transitional stage, and a steady stage. The flow inside the enclosure depends significantly on the governing parameters, Rayleigh number and aspect ratio. The effect of Rayleigh number and aspect ratio on the flow development and heat transfer rate are discussed. The key finding for this study is to analyze the pitchfork bifurcation of the flow about the geometric center line. The heat transfer through the roof and the ceiling as a form of Nusselt number is reported in this study.

Moffatt vortices induced by the motion of a contact line

A recent hydrodynamic theory of liquid slippage on a solid substrate (Kirkinis & Davis, Phys. Rev. Lett., vol. 110, 2013, 234503) gives rise to a sequence of eddies (Moffatt vortices) that co-move with a moving contact line (CL) in a liquid wedge. The presence of these vortices is established through secular equations that depend on the dynamic contact angle α and capillary number Ca. The limiting case α→O is associated with the appearance of such vortices in a channel. The vortices are generated by the relative motion of the interfaces, which in turn is due to the motion of the CL. This effect has yet to be observed in experiment.

Controlling routine front line service workers: an Australian retail supermarket case

Food retail is known for its use of flexible labour and for the centralisation of functions at head office, resulting in a reduction of managerial autonomy at store level. This article employs a typology of controls developed from labour process scholarship to explore how retail managers negotiate the control of their predominantly part-time workforce. Using an Australian supermarket chain as a case, and mixed methods, the article demonstrates that supermarkets use a multiplicity of forms of control across their workforce. For front line service workers, the article identifies a new configuration of controls which intersects with employment status and acts differentially for checkout operators on different employment contracts.

An N-ethyl-n-nitrosourea induced corticotropin-releasing hormone promoter mutation provides a mouse model for endogenous glucocorticoid excess

Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, maybe due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumors, respectively. ACTH secretion is stimulated by CRH, and we report a mouse model for Cushing's syndrome due to an N-ethyl-N-nitrosourea (ENU) induced Crh mutation at -120 bp of the promoter region, which significantly increased luciferase reporter activity and was thus a gain-of-function mutation. Crh -120/+ mice, when compared with wild-type littermates, had obesity, muscle wasting, thin skin, hair loss, and elevated plasma and urinary concentrations of corticosterone. In addition, Crh-120/+ mice had hyperglycemia, hyperfructosaminemia, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia but normal adiponectin. Crh -120/+ mice also had low bone mineral density, hypercalcemia, hypercalciuria, and decreased concentrations of plasma PTH and osteocalcin. Bone histomorphometry revealed Crh-120/+ mice to have significant reductions in mineralizing surface area, mineral apposition, bone formation rates, osteoblast number, and the percentage of corticoendosteal bone covered by osteoblasts, which was accompanied by an increase in adipocytes in the bone marrow. Thus, a mouse model for Cushing's syndrome has been established, and this will help in further elucidating the pathophysiological effects of glucocorticoid excess and in evaluating treatments for corticosteroid-induced osteoporosis.

hSSB1 (NABP2/ OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway

The maintenance of genome stability is essential to prevent loss of genetic information and the development of diseases such as cancer. One of the most common forms of damage to the genetic code is the oxidation of DNA by reactive oxygen species (ROS), of which 8-oxo-7,8-dihydro-guanine (8-oxoG) is the most frequent modification. Previous studies have established that human single-stranded DNA-binding protein 1 (hSSB1) is essential for the repair of double-stranded DNA breaks by the process of homologous recombination. Here we show that hSSB1 is also required following oxidative damage. Cells lacking hSSB1 are sensitive to oxidizing agents, have deficient ATM and p53 activation and cannot effectively repair 8-oxoGs. Furthermore, we demonstrate that hSSB1 forms a complex with the human oxo-guanine glycosylase 1 (hOGG1) and is important for hOGG1 localization to the damaged chromatin. In vitro, hSSB1 binds directly to DNA containing 8-oxoguanines and enhances hOGG1 activity. These results underpin the crucial role hSSB1 plays as a guardian of the genome.

Submission to the draft Migration Assurance Policy - Improving the transition to the fixed-line national broadband network review

The rights of individuals to self-determination and participation in social, political and economic life are recognised and supported by Articles 1, 3 and 25 of the International Covenant on Civil and Political Rights 1966.4 Article 1 of the United Nations’ Human Rights Council’s Resolution on the Promotion and Protection of Human Rights on the Internet of July 2012 confirms individuals have the same rights online as offline. Access to the internet is essential and as such the UN: Calls upon all States to promote and facilitate access to the Internet and international cooperation aimed at the development of media and information and communications facilities in all countries (Article 3) Accordingly, access to the internet per se is a fundamental human right, which requires direct State recognition and support.5 The obligations of the State to ensure its citizens are able, and are enabled, to access the internet, are not matters that should be delegated to commercial parties. Quite simply – access to the internet, and high-speed broadband, by whatever means are “essential services” and therefore “should be treated as any other utility service”...

Pacific Journalism Review : Twenty years on the front line of regional identity and freedom

Pacific Journalism Review has consistently, at a good standard, honoured its 1994 founding goal: to be a credible peer-reviewed journal in the Asia-Pacific region, probing developments in journalism and media, and supporting journalism education. Global, it considers new media and social movements; ‘regional’, it promotes vernacular media, human freedoms and sustainable development. Asking how it developed, the method for this article was to research the archive, noting authors, subject matter, themes. The article concludes that one answer is the journal’s collegiate approach; hundreds of academics, journalists and others, have been invited to contribute. Second has been the dedication of its one principal editor, Professor David Robie, always somehow providing resources—at Port Moresby, Suva, and now Auckland—with a consistent editorial stance. Eclectic, not partisan, it has nevertheless been vigilant over rights, such as monitoring the Fiji coups d’etat. Watching through a media lens, it follows a ‘Pacific way’, handling hard information through understanding and consensus. It has 237 subscriptions indexed to seven databases. Open source, it receives more than 1000 site visits weekly. With ‘clientele’ mostly in Australia, New Zealand and ‘Oceania’, it extends much further afield. From 1994 to 2014, 701 articles and reviews were published, now more than 24 scholarly articles each year.

Single 2×1 domain orientation on Si(001) surfaces using aperiodic Bi line arrays

Studies of Bi heteroepitaxy on Si(001) have shown that lines grow to lengths of up to 500nm if the substrate is heated to above the Bi desorption temperature (500°C) during or after Bi deposition. Unlike many other nanoline systems, the lines formed by this nonequilibrium growth process have no detectable width dispersion. Although much attention has been given to the atomic geometery of the line, in this paper, we focus on how the lines can be used to create a majority 2×1 domain orientation. It is demonstrated that the Bi lines can be used to produce a single-domain orientation on Si(001) if the lines are grown on Si(001) surfaces with a regular distribution of single height steps. This is a compelling example of how a nanoscale motif can be used to modify mesoscopic surface structure on Si(001).

Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line

This study aimed to investigate the effects of arsenic trioxide (As2O3) on the mitochondrial DNA (mtDNA) of acute promyelocytic leukemia (APL) cells. The NB4 cell line was treated with 2.0 μmol/L As2O3in vitro, and the primary APL cells were treated with 2.0 μmol/L As2O3in vitro and 0.16 mg kg-1 d-1 As2O3in vivo. The mitochondrial DNA of all the cells above was amplified by PCR, directly sequenced and analyzed by Sequence Navigatore and Factura software. The apoptosis rates were assayed by flow cytometry. Mitochondrial DNA mutation in the D-loop region was found in NB4 and APL cells before As2O3 use, but the mutation spots were remarkably increased after As2O3 treatment, which was positively correlated to the rates of cellular apoptosis, the correlation coefficient: rNB4-As2O3=0.973818, and rAPL-As2O3=0.934703. The mutation types include transition, transversion, codon insertion or deletion, and the mutation spots in all samples were not constant and regular. It is revealed that As2O3 aggravates mtDNA mutation in the D-loop region of acute promyelocytic leukemia cells both in vitro and in vivo. Mitochondrial DNA might be one of the targets of As2O3 in APL treatment.

Base material characterisation of spoil piles at BMA coal mines

This project was an initiation to investigate slaking induced properties detrition of spoil pile materials with overburden pressure and time. The changes in the material properties over time are important parameters that control the behaviour and performance of the piles. The time dependent mechanical and hydraulic properties reported together with mineralogical changes. One chamber designed to apply slaking in the laboratory and geotechnical investigation conducted to fulfil the objective of this project.

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.