Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

More men than women make mucosal IgA antibodies to human papillomavirus type 16 (HPV-16) and HPV-18: A study of oral HPV and oral HPV antibodies in a normal healthy population

Background: We have previously shown the high prevalence of oral anti-human papillomavirus type 16 (HPV-16) antibodies in women with HPV-associated cervical neoplasia. It was postulated that the HPV antibodies were initiated after HPV antigenic stimulation at the cervix via the common mucosal immune system. The present study aimed to further evaluate the effectiveness of oral fluid testing for detecting the mucosal humoral response to HPV infection and to advance our limited understanding of the immune response to HPV. Methods: The prevalence of oral HPV infection and oral antibodies to HPV types 16, 18 and 11 was determined in a normal, healthy population of children, adolescents and adults, both male and female, attending a dental clinic. HPV types in buccal cells were determined by DNA sequencing. Oral fluid was collected from the gingival crevice of the mouth by the OraSure method. HPV-16, HPV-18 and HPV-11 antibodies in oral fluid were detected by virus-like particle-based enzyme-linked immunosorbent assay. As a reference group 44 women with cervical neoplasia were included in the study. Results: Oral HPV infection was h ighest in children (9/114, 7.9%), followed by adolescents (4/78, 5.1%), and lowest in normal adults (4/116, 3.5%). The predominant HPV type found was HPV-13 (7/22, 31.8%) followed by HPV-32 (5/22, 22.7%). The prevalence of oral antibodies to HPV-16, HPV-18 and HPV-11 was low in children and increased substantially in adolescents and normal adults. Oral HPV-16 IgA was significantly more prevalent in women with cervical neoplasia (30/44, 68.2%) than the women from the dental clinic (18/69, 26.1% P = 0.0001). Significantly more adult men than women displayed oral HPV-16 IgA (30/47 compared with 18/69, OR 5.0, 95% CI 2.09-12.1, P < 0.001) and HPV-18 IgA (17/47 compared with 13/69, OR 2.4, 95% CI 0.97-6.2, P = 0.04). Conclusion: The increased prevalence of oral HPV antibodies in adolescent individuals compared with children was attributed to the onset of sexual activity. The increased prevalence of oral anti-HPV IgA in men compared with women was noteworthy considering reportedly fewer men than women make serum antibodies, and warrants further investigation. © 2006 Marais et al; licensee BioMed Central Ltd.

Detaining the usual suspects : charting the use of segregated settings in New South Wales government schools, Australia

In this paper, we examine the increase in segregated placements in the New South Wales government school sector. Using disaggregated enrolment data, we point to the growing over-representation of boys in special schools and classes; particularly those of a certain age in certain support categories. In the discussion that follows, we question the role of special education in the development of new and additional forms of being “at risk.” In effect, we invert the traditional concept by asking: Who is at risk of what? In focusing on the containment of risk, are modern practices of diagnosis and segregation perpetuating risks that already disproportionately affect certain groups of individuals? Do these perceptions of and responses to risk in local schools now place these students at greater personal risk of school failure and a future marked by social exclusion? And, finally, is that risk worth the cost?

I sang Amazing Grace for about 3 hours that day : understanding Indigenous Australians’ experience of seclusion

Research shows that Indigenous Australians suspicion and fear of being ‘locked up’ may influence mental health service avoidance. Given this, the aim of this study was to explore, by qualitative analysis of in depth interviews (N = 3), how three Indigenous people experienced the controversial practice of seclusion Hans-Georg Gadamer’s phenomenology guided analysis of the material, and allowed narrated experiences to be understood within their cultural and historical context. Participants viewed seclusion negatively: police involvement in psychiatric care; perceptions of being punished and powerless; occasions of extreme use of force; and lack of care were prominent themes throughout the interviews. While power imbalances inherent in seclusion are problematic for all mental health clients, the distinguishing factor in the Indigenous clients’ experience is that seclusion is continuous with the discriminatory and degrading treatment by governments, police and health services that many Indigenous people have experienced since colonisation. The participants’ experiences echoed Goffman’s (1961) findings that institutional practices act to degrade and dehumanise clients whose resulting conformity eases the work of nursing staff. While some nurses perceive that seclusion reduces clients’ agitation (Meehan, Bergen & Fjeldsoe, 2004; Wynaden et al., 2001), one must ask at what cost to clients’ dignity, humanity and basic human rights.

The minority report : disproportionate representation in Australia’s largest education system

The overrepresentation of students from minority ethnic groups in separate special education settings has been extensively documented in North America, yet little research exists for Australian school systems. To address this gap, we systematically analyzed 13 years of enrolment data from the state of New South Wales. Stark differences are seen in patterns of enrolment between Indigenous students, students from a Language Background Other than English (LBOTE), and non-Indigenous English speaking students. Moreover, these differences are increasing. While enrollments of Indigenous students in separate settings increased faster across time than did enrollments of Indigenous students in mainstream, enrollments of LBOTE students in mainstream increased faster than did enrollments of LBOTE students in separate settings.

Modulation of LPS-induced chorioamnionitis by ureaplasma parvum in sheep chorioamnionitis in sheep

ABSTRACT Objective: Ureaplasma parvum colonization in the setting of polymicrobial flora is common in women with chorioamnionitis, and is a risk factor for preterm delivery and neonatal morbidity. We hypothesized that ureaplasma colonization of amniotic fluid will modulate chorioamnionitis induced by E.coli lipopolysaccharide (LPS). Methods: Sheep received intra-amniotic (IA) injections of media (control) or live ureaplasma either 7 or 70d before delivery. Another group received IA LPS 2d before delivery. To test for interactions, U.parvum exposed animals were challenged with IA LPS, and delivered 2d later. All animals were delivered preterm at 125±1 day gestation. Results: Both IA ureaplasmas and LPS induced leukocyte infiltration of chorioamnion. LPS greatly increased the expression of pro-inflammatory cytokines and myeloperoxidase in leukocytes, while ureaplasmas alone caused modest responses. Interestingly, 7d but not 70d ureaplasma exposure significantly downregulated LPS induced pro-inflammatory cytokines and myeloperoxidase expression in the chorioamnion. Conclusion: U.parvum can suppress LPS induced experimental chorioamnionitis.

The art of being a fan : complicity and criticality in contemporary art and fandom

This practice-led research project aims to use contemporary art processes and concepts of fandom to construct a space for the critical and creative exploration of the relationship between them. Much of the discourse addressing the intersection of these spaces over the last three decades tends to treat art and fan studies as separate areas of critical and theoretical research. There has also been very little consideration of the critical interface that art practice and fandom share in their engagement with one another – or how the artist as fan might creatively exploit this relationship. Approaching these issues through a practice-led methodology that combines studio based explorations and traditional modes of research, the project aims to demonstrate how my 'fannish' engagements with popular culture can generate new responses to, and understandings of, the relationship between fandom, affect and visual art. The research acts as a performative and creative investigation of fandom as I document the complicit tendencies that arise out of my affective relationship with pop cultural artefacts. It does this through appropriating and reconfiguring content from film, television and print media, to create digital video installations aimed at engendering new experiences and critical interpretations of screen culture. This approach promotes new possibilities for creative engagements with art and popular culture, and these are framed through the lens of what I term the digital-bricoleur. The research will be primarily contextualised by examining other artists' practices as well as selected theoretical frameworks that traverse my investigative terrain. The key artists that are discussed include Douglas Gordon, Candice Brietz, Pierre Huyghe, Paul Pfieffer, and Jennifer and Kevin McCoy. The theoretical developments of the project are drawn from a pluralistic range of ideas ranging from Johanna Drucker's discussion of critical complicity in contemporary art, Matt Hills' discussion of subjectivity in fandom and academia, Nicolas Bourriaud's discussion of Postproduction art practices, and Jacques Rancière's ideas about aesthetics and politics. The methodology and artworks developed over the course of this project will also demonstrate how digital-bricolage leads to new understandings of the relationships between contemporary art and entertainment. The research aims to exploit these apparently contradictory positions to generate a productive site for rethinking the relationship between the creative and critical possibilities of art and fandom. The outcomes of the research consists of a body of artworks – 75% – that demonstrate new contributions to knowledge, and an exegetical component – 25% – that acts to reflect on, analyse and critically contextualise the practice-led findings.

An examination of the legislative framework governing commuter safety in the Queensland Mining Industry

Commuting in the mining industry -Background -The problem -Journey management -The structure of the legislative framework Legislation and Regulation -Workplace safety in Queensland mining -Risk management -Mining legislation and journey management -Commuting and employee responsibilities -Queensland Workers’ Compensation Scheme Industry standards -Industry standards and journey management Regulated and organisational policy documents -Policy documents and journey management Observations & Conclusions

Cultural Policy

The development of cultural policy during the twentieth century is underscored by three key developments. First, the formation of the Arts Council of Great Britain in 1946, first headed by the Cambridge economist Lord Keynes, saw the scaffolding developed for ongoing government support for the arts. In doing so, it established the principle of an “arm’s length” relationship between the government of the day and individual artists, through the development of independent arts boards engaged in the peer review of creative works. Second, the formation of the Fifth Republic in France in 1958 saw the creation of a Ministry of Culture, headed by the writer André Malraux. Malraux and his successors have seen three major tasks for a national cultural policy: government support for the creation of new artistic and cultural works; the promotion and maintenance of cultural heritage; and enabling equitable access to creative works and creative opportunities through all segments of society. Finally, at a global level, agencies such as UNESCO have sought to promote national cultural policies as an element of national sovereignty, particularly in the developing world, and this has involved addressing sources of structural inequality in the distribution of global cultural and communications resources...

Prevention and treatment of acute radiation-induced skin reactions : a systematic review and meta-analysis of randomized controlled trials

Background Radiation-induced skin reaction (RISR) is a common side effect that affects the majority of cancer patients receiving radiation treatment. RISR is often characterised by swelling,redness, pigmentation, fibrosis, and ulceration, pain, warmth, burning, and itching of the skin. The aim of this systematic review was to assess the effects of interventions which aim to prevent or manage RISR in people with cancer. Methods We searched the following databases up to November 2012: Cochrane Skin Group Specialised Register, CENTRAL (2012, Issue 11), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), CINAHL (from 1981) and LILACS (from 1982). Randomized controlled trials evaluating interventions for preventing or managing RISR in cancer patients were included. The primary outcomes were development of RISR, and levels of RISR and symptom severity. Secondary outcomes were time taken to develop erythema or dry desquamation; quality of life; time taken to heal, a number of skin reaction and symptom severity measures; cost, participant satisfaction; ease of use and adverse effects. Where appropriate, we pooled results of randomized controlled trials using mean differences (MD) or odd ratios (OR) with 95% confidence intervals (CI). Results Forty-seven studies were included in this review. These evaluated six types of interventions (oral systemic medications; skin care practices; steroidal topical therapies; non-steroidal topical therapies; dressings and other). Findings from two meta-analyses demonstrated significant benefits of oral Wobe-Mugos E for preventing RISR (OR 0.13 (95% CI 0.05 to 0.38)) and limiting the maximal level of RISR (MD −0.92 (95% CI −1.36 to −0.48)). Another meta-analysis reported that wearing deodorant does not influence the development of RISR (OR 0.80 (95% CI 0.47 to 1.37)). Conclusions Despite the high number of trials in this area, there is limited good, comparative research that provides definitive results suggesting the effectiveness of any single intervention for reducing RISR. More research is required to demonstrate the usefulness of a wide range of products that are being used for reducing RISR. Future efforts for reducing RISR severity should focus on promising interventions, such as Wobe-Mugos E and oral zinc.

Mitigation of harmonics of DFIGs in DC-Microgrids

During the last few years, there has been an increased attention paid on the developments of DC microgrids (DCMGs) and their applications. For economical and more flexible wind power generation, doubly fed induction generator (DFIG) is regarded as a most commonly used generator in wind farms. This paper presents a configuration and operation method for a DCMG connected with DFIGs, in which the controller of the DFIG is designed for maximum power point tracking (MPPT). The generation of harmonics and their effects on the generator in this configuration are analyzed and a harmonic compensation method is proposed. Furthermore, the simulation results are presented to show that the DFIG can be operated effectively in DCMGs and harmonic currents can be reduced.

Physical activity, walking and quality of life in women with depressive symptoms

Background Physical activity (PA) has a positive association with health-related quality of life (HRQL) in the general population. The association between PA and HRQL in those with poor mental health is less clear. Purpose To examine the concurrent and prospective dose-response relationships between total physical activity (TPA) and walking only with HRQL in women aged 50-55 with depressive symptoms in 2001. Methods Participants were 1904 women born in 1946-1951 who completed mailed surveys for the Australian Longitudinal Study on Women's Health in 2001, 2004, 2007 and 2010 and who, in 2001, reported depressive symptoms. At each time point, they reported their weekly minutes of walking, moderate PA, and vigorous PA. A summary TPA score was created that accounted for differences in energy expenditure among the three PA types. Mixed models were used to examine associations between TPA and HRQL (SF-36 component and subscale scores) and between walking and HRQL, for women who reported walking as their only PA. Analyses were conducted in 2013-2014. Results Concurrently, higher levels of TPA and walking were associated with better HRQL (p<0.05). The strongest associations were found for physical functioning, vitality, and social functioning subscales. In prospective models, associations were attenuated, yet compared with women doing no TPA or walking, women doing “sufficient” TPA or walking had significantly better HRQL over time for most SF-36 scales. Conclusions This study extends previous work by demonstrating trends between both TPA and walking and HRQL in women reporting depressive symptoms.

“To educate you to be smart”: disaffected students and the purpose of school in the (not so clever) “lucky country”

This paper contributes to conversations about school, post-compulsory and further education policy by reporting findings from a three-year study with disaffected students who have been referred to special “behaviour” schools. Contrary to popular opinion, our research finds that these “ignorant yobs” (Tomlinson, 2012) do value education and know what it is for. They also have aspirations for a secure, productive and fulfilled life, although it may not involve university level study. Importantly, we found that students who responded negatively with regard to the importance of schooling tended to envision future lives and occupations for which they believed school knowledge was unnecessary. The implications of this research for school, post-compulsory and further education policy are discussed.

The psychology of containment : mis/representing emotional and behavioural difficulties in Australian schools

The number of students in special schools has increased at a rapid rate in some Australian states, due in part to increased enrolment under the categories of emotional disturbance (ED) and behaviour disorder (BD). Nonetheless, diagnostic distinctions between ED and BD are unclear. Moreover, despite international findings that students with particular backgrounds are over-represented in special schools, little is known about the backgrounds of students entering such settings in Australia. This study examined the government school enrolment data from New South Wales, the most populous of the Australian states. Linear and quadratic trends were used to describe the numbers and ages of students enrolled in special schools in the ED and BD categories. Changes between 1997 and 2007 were observed. Results showed an over-representation of boys that increased across the decade and a different pattern across age for boys and girls. Consistent with international findings, these results indicate that trends in special school placements are unrelated to disability prevalence in the population. Rather, it is suggested that schools act to preserve time and resources for others by removing their more challenging students: most typically, boys.

Can measures of limb loading and dynamic stability during the squat maneuver provide an index of early functional recovery following unilateral total hip arthroplasty?

Objective: To investigate limb loading and dynamic stability during squatting in the early functional recovery of total hip arthroplasty (THA) patients. Design: Cohort study Setting: Inpatient rehabilitation clinic. Participants: A random sample of 61 THA patients (34♂/27♀; 62±9 yrs, 77±14 kg, 174±9 cm) was assessed twice, 13.2±3.8 days (PRE) and 26.6±3.3 days post-surgery (POST), and compared with a healthy reference group (REF) (22♂/16♀; 47±12yrs; 78±20kg; 175±10cm). Interventions: THA patients received two weeks of standard in-patient rehabilitation. Main Outcome Measure(s): Inter-limb vertical force distribution and dynamic stability during the squat maneuver, as defined by the root mean square (RMS) of the center of pressure in antero-posterior and medio-lateral directions, of operated (OP) and non-operated (NON)limbs. Self-reported function was assessed via FFb-H-OA 2.0 questionnaire. Results: At PRE, unloading of the OP limb was 15.8% greater (P<.001, d=1.070) and antero-posterior and medio-lateral center of pressure RMS were 30-34% higher in THA than REF P<.05). Unloading was reduced by 12.8% towards a more equal distribution from PRE to POST (P<.001, d=0.874). Although medio-lateral stability improved between PRE and POST (OP: 14.8%, P=.024, d=0.397; NON: 13.1%, P=.015, d=0.321), antero-posterior stability was not significantly different. Self-reported physical function improved by 15.8% (P<.001, d=0.965). Conclusion(s): THA patients unload the OP limb and are dynamically more unstable during squatting in the early rehabilitation phase following total hip replacement than healthy adults. Although loading symmetry and medio-lateral stability improved to the level of healthy adults with rehabilitation, antero-posterior stability remained impaired. Measures of dynamic stability and load symmetry during squatting provide quantitative information that can be used to clinically monitor early functional recovery from THA.