Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing

We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

DRB2 is required for microRNA biogenesis in Arabidopsis thaliana

Background The Arabidopsis thaliana (Arabidopsis) DOUBLE-STRANDED RNA BINDING (DRB) protein family consists of five members, DRB1 to DRB5. The biogenesis of two developmentally important small RNA (sRNA) species, the microRNAs (miRNAs) and trans-acting small interfering RNAs (tasiRNAs) by DICER-LIKE (DCL) endonucleases requires the assistance of DRB1 and DRB4 respectively. The importance of miRNA-directed target gene expression in plant development is exemplified by the phenotypic consequence of loss of DRB1 activity (drb1 plants). Principal Findings Here we report that the developmental phenotype of the drb235 triple mutant plant is the result of deregulated miRNA biogenesis in the shoot apical meristem (SAM) region. The expression of DRB2, DRB3 and DRB5 in wild-type seedlings is restricted to the SAM region. Small RNA sequencing of the corresponding tissue of drb235 plants revealed altered miRNA accumulation. Approximately half of the miRNAs detected remained at levels equivalent to those of wild-type plants. However, the accumulation of the remaining miRNAs was either elevated or reduced in the triple mutant. Examination of different single and multiple drb mutants revealed a clear association between the loss of DRB2 activity and altered accumulation for both the elevated and reduced miRNA classes. Furthermore, we show that the constitutive over-expression of DRB2 outside of its wild-type expression domain can compensate for the loss of DRB1 activity in drb1 plants. Conclusions/Significance Our results suggest that in the SAM region, DRB2 is both antagonistic and synergistic to the role of DRB1 in miRNA biogenesis, adding an additional layer of gene regulatory complexity in this developmentally important tissue.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

The Nagle Royal Commission 25 years on : gaining perspective on two and a half decades of NSW prison reform

This article attempts an audit of changes in the NSW penal system over the last nearly 30 years. Taking the 1978 Nagle Royal Commission findings and analysis as the starting point a comparison is made between the Nagle era and the contemporary scene across a range of practices including imprisonment rates, violence, drug use, deaths in custody, prison conditions, prisoners rights, legal regulation, and others. It is suggested that developments since Nagle are mixed and cannot be attributed to a single logic or force. Major changes include a doubling of imprisonment rates, significant increases in Indigenous and women's imprisonment rates, the apparent ending of institutionalised bashings and the centrality of drug use to imprisonment and to the culture, health and security practices which characterise the current prison experience. The article may constitute a useful starting point for broader attempts to relate current penal practices to far wider changes in the conditions of life under late modernity.

Exploring pedestrian accessibility and walkability : insight from public place observations in inner-urban higher density Brisbane, Australia

As planners work to create more sustainable and liveable urban environments, a priority is to transition away from prioritising the automobile and towards enhancing the pedestrian experience. Thus, this research explores the experience of pedestrian accessibility in inner-urban higher-density Brisbane in Australia, drawing on findings from semi-structured in-depth interviews with 24 residents and over 100 hours of public place observations in three case-study neighbourhoods. The interviews took place in residents homes and explored their experience of higher density living and their neighbourhood, whilst observations were recorded through a combination of methods including photographs, sketch maps, recordings and field journals. Observation locations included retail and commercial space, roads, parkland and open space, with multiple observations at each location. A thematic analysis identified common themes in both interviews and the observations, with this paper focusing on residents’ lived experience in urban built environments. This analysis revealed that pedestrian accessibility is linked to access to local amenities and direct routes, aesthetics, sense of community, ownership of space and safety. In particular, observations revealed how pedestrian accessibility and route-taking works with, against or in spite of the design features of urban environments, as well as the importance of the social use of the built environment. Residents spoke about although walking quick and preferred for local amenities, the decision to walk was moderated by factors such as time of day and perceived safety. Measures to ensure and improve the pedestrian accessibility of urban areas needs to take into account the propensity for people to prefer and improvise direct routes (often to the detriment of traffic safety considerations), the importance of ongoing maintenance and upgrading of walking infrastructure and the importance of aesthetically pleasing and safe walking environments. By combining interviews and observations, this research highlights the current dominance of the automobile culture in Brisbane and the layers of meaning, experiences and complexity hidden within the pedestrian experience.

Reasons for non-urgent presentations to the emergency department in Saudi Arabia

Background The majority of patients who attend emergency departments (EDs) in Saudi Arabia have non-urgent problems, resulting in overcrowding, excessive waiting times and delayed care for more acutely ill patients. The purpose of this research was to examine the reasons for non-urgent visits to a Saudi ED and factors associated with patient perceptions of urgency. Methods We administered a survey to 350 consecutively presenting Canadian Triage and Acuity Scale (CTAS) IV or V adult patients at a large tertiary ED in Riyadh region, Saudi Arabia, during 25 days of data collection in March 2013. Results Over half of the sample usually visited the ED to access healthcare. The most common reasons for attending the ED were not having a regular healthcare provider (63%), being able to receive care on the same day (62%), and the convenience of and access to medical care 24/7 (62%). Approximately two-thirds of CTAS V patients and one-third of CTAS IV patients believed their condition was more urgent than their triage nurse rating. Conclusion Multiple factors influence non-urgent visits to the ED in the Saudi context including insufficient community awareness of the role of the ED and perceived lack of access to primary healthcare services.

Equal access to the opportunities available? Equity and diversity laws and policies in Australia

Australia has been populated for more than 40,000 years with Indigenous Australians joined by European settlers only 230 years ago. The first settlers consisted of convicts from more than 28 countries and members of the British army who arrived in 1788 to establish a British penal colony. Mass migration in the nineteenth century with one and a half million immigrants from Europe, principally from the United Kingdom and Ireland (Haines and Shlomowitz, 1992), established the continent as an Anglo society in the Pacific. In the twentieth century immigrants came from many European countries and in the latter decades from many parts of Asia and the Middle East (Collins, 1991, pp.10-13). In the 21st century Australia has an ethnically and culturally diverse population. The original Indigenous population of Australia accounts for approximately 460,000 or 2.5 per cent of the total population (ABS, 2006a). Estimates are that around 4.5m. persons in the population (close to 20 per cent), were born outside Australia with the majority of these arriving from Europe, principally the United Kingdom, and New Zealand (ABS, 2006b). Like many other countries, Australia has a legacy of discrimination and inequality in employment. Propelled by racist ideologies and the male breadwinner ideology, Indigenous Australians, and non-European immigrants, and women were barred from certain jobs and paid less for their work than any white male counterpart. These conditions were legally sanctioned through the industrial relations system and other laws in the nineteenth and first half of the twentieth century. Since the 1960s a dramatic change has occurred in social policy and national legislation and Australia today has an extensive array of laws which forbid employment discrimination on race, ethnicity, gender and many other characteristics, and other approaches which promote proactive organizational plans and actions to achieve equity in employment. This chapter outlines these developments.

Physical activity, self-regulation, and early academic achievement in preschool children

Research Findings The present study investigated whether active play during recess was associated with self-regulation and academic achievement in a prekindergarten sample. A total of 51 children in classes containing approximately half Head Start children were assessed on self-regulation, active play, and early academic achievement. Path analyses indicated that higher active play was associated with better self-regulation, which in turn was associated with higher scores on early reading and math assessments. Practice or Policy Results point to the benefits of active play for promoting self-regulation and offer insight into possible interventions designed to promote self-regulation and academic achievement.

Physical activity patterns of inner-city elementary schoolchildren

Purpose This study aimed to objectively measure the physical activity (PA) characteristics of a racially and ethnically diverse sample of inner-city elementary schoolchildren and to examine the influence of sex, race/ethnicity, grade level, and weight status on PA. Methods A total of 470 students in grades 4-6 from six inner-city schools in Philadelphia wore an ActiGraph GT3X+ accelerometer (Actigraph, Pensacola, FL) for up to 7 d. The resultant data were uploaded to a customized Visual Basic EXCEL macro to determine the time spent in sedentary (SED), light-intensity PA (LPA), and moderate- to vigorous-intensity PA (MVPA). Results On average, students accumulated 48 min of MVPA daily. Expressed as a percentage of monitoring time, students were sedentary for 63% of the time, in LPA 31% of the time, and in MVPA 6% of the time. Across all race/ethnicity and grade level groups, boys exhibited significantly higher levels of MVPA than girls did; fifth-grade boys exhibited significantly lower MVPA levels than fourth-and sixth-grade boys did, and sixth-grade girls exhibited significantly lower MVPA levels than fourth-and fifth-grade girls did. Hispanic children exhibited lower levels of MVPA than children from other racial/ethnic groups did, and overweight and obese children exhibited significantly lower MVPA levels than children in the healthy weight range did. Across the entire sample, only 24.3% met the current public health guidelines for PA. Physical inactivity was significantly greater among females, Hispanics, and overweight and obese students. Conclusions Fewer than one in four inner-city schoolchildren accumulated the recommended 60 min of MVPA daily. These findings highlight the need for effective and sustainable programs to promote PA in inner-city youth.

Developing agency in the creative career : a design-based framework for work integrated learning

Research shows that approximately half of creative practitioners operate as embedded creatives by securing gainful employment within organisations located in the field beyond their core discipline. This foregrounds the significance of having the skills necessary to successfully cross the disciplinary boundaries in order to negotiate a professional role. The multiple implications of such reframing for emerging creative practitioners who navigate uncertain professional boundaries include developing a skill of identifying and successfully targeting the shifting professional and industry coordinates while remaining responsive to changes. A further implication involves creative practitioners engaging in a continuous cycle of re-negotiation of their professional identity making the management of multiple professional selves - along with creating and recreating a meaningful frame of references such as the language around their emerging practice - a necessary skill. This chapter presents a case study of a set of Work Integrated Learning subjects designed to develop in creative industries practitioners the skills to manage their emerging professional identities in response to the shifts in the professional world.

Physical activity patterns of Singaporean adolescents

The purpose of this study was to document the level of physical activity and sedentary behavior in a representative sample of Singaporean adolescents. A random sample of 1,827 secondary school students from six secondary schools (929 boys, 898 girls, mean age 14.9 +/- 1.2 yr) completed the Three-Day Physical Activity Recall (3DPAR) self-report instrument. Approximately 63% of Singaporean high school students met current guidelines requiring 60 min of moderate to vigorous physical activity daily. Just over half (51.6%) met the guideline calling for regular vigorous physical activity. Across all grade levels, boys were consistently more active than girls. More than 70% of Singaporean high school students exceeded the recommended 2 hours per day of electronic media use. Collectively, these findings suggest that a significant proportion of Singaporean adolescents are not sufficiently active and are in need of programs to promote physical activity and decrease sedentary behavior.

Long-term stability of adipose tissue generated from a vascularized pedicled fat flap inside a chamber

Background Numerous studies demonstrate the generation and short-term survival of adipose tissue; however, long-term persistence remains elusive. This study evaluates long-term survival and transferability of de novo adipose constructs based on a ligated vascular pedicle and tissue engineering chamber combination. Methods Defined adipose tissue flaps were implanted into rats in either intact or perforated domed chambers. In half of the groups, the chambers were removed after 10 weeks and the constructs transferred on their vascular pedicle to a new site, where they were observed for a further 10 weeks. In the remaining groups, the tissue construct was observed for 20 weeks inside the chamber. Tissue volume was assessed using magnetic resonance imaging and histologic measures, and constructs were assessed for stability and necrosis. Sections were assessed histologically and for proliferation using Ki-67. Results At 20 weeks, volume analysis revealed an increase in adipose volume from 0.04 ± 0.001 ml at the time of insertion into the chambers to 0.27 ± 0.004 ml in the closed and 0.44 ± 0.014 ml in the perforated chambers. There was an additional increase of approximately 10 to 15 percent in tissue volume in flaps that remained in chambers for 20 weeks, whereas the volume of the transferred tissue not in chambers remained unaltered. Histomorphometric assessment of the tissues documented no signs of hypertrophy, fat necrosis, or atypical changes of the newly generated tissue. Conclusion This study presents a promising new method of generating significant amounts of mature, vascularized, stable, and transferable adipose tissue for permanent autologous soft-tissue replacement.

Minimization of bauxite residue neutralization products using nanofiltered seawater

Currently, open circuit Bayer refineries pump seawater directly into their operations to neutralize the caustic fraction of the Bayer residue. The resulting supernatant has a reduced pH and is pumped back to the marine environment. This investigation has assessed modified seawater sources generated from nanofiltration processes to compare their relative capacities to neutralize bauxite residues. An assessment of the chemical stability of the neutralization products, neutralization efficiency, discharge water quality, bauxite residue composition, and associated economic benefits have been considered to determine the most preferable seawater filtration process based on implementation costs, savings to operations and environmental benefits. The mechanism of neutralization for each technology was determined to be predominately due to the formation of Bayer hydrotalcite and calcium carbonate, however variations in neutralization capacity and efficiencies have been observed. The neutralization efficiency of each feed source has been found to be dependent on the concentration of magnesium, aluminium, calcium and carbonate. Nanofiltered seawater with approximately double the amount of magnesium and calcium required half the volume of seawater to achieve the same degree of neutralization. These studies have revealed that multiple neutralization steps occur throughout the process using characterization techniques such as X-ray diffraction (XRD), infrared (IR) spectroscopy and inductively coupled plasma optical emission spectroscopy (ICP-OES).

Challenges of responding to online fraud victimisation in Australia

Online fraud occurs when an individual or a business responds in some manner to an unsolicited invitation received via the internet and suffers financial or other detrimental effects as a result. In 2010–11, the Australian Bureau of Statistics (2012) found that over 1.2 million Australians (6.7% of the population aged 15 years and over) had been a victim of personal fraud, losing approximately $1.4b in the preceding 12 months. More than half of these victims (55.7%) were contacted via the internet or email (online victimisation). In addition to monetary losses, victims of online fraud suffer serious psychological, emotional, social and even physical problems as a consequence of their victimisation. This paper explores the challenges of responding to online fraud victimisation in Australia and describes some of the specific support services that have recently emerged to support victims of this crime.