Targeting aurora kinases : a novel approach to curb the growth and chemoresistance of androgen refractory prostate cancer

Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.

Viable chimaeric viruses confirm the biological importance of sequence specific maize streak virus movement protein and coat protein interactions

Background. A variety of interactions between up to three different movement proteins (MPs), the coat protein (CP) and genomic DNA mediate the inter- and intra-cellular movement of geminiviruses in the genus Begomovirus. Although movement of viruses in the genus Mastrevirus is less well characterized, direct interactions between a single MP and the CP of these viruses is also clearly involved in both intra- and intercellular trafficking of virus genomic DNA. However, it is currently unknown how specific these MP-CP interactions are, nor how disruption of these interactions might impact on virus viability. Results. Using chimaeric genomes of two strains of Maize streak virus (MSV) we adopted a genetic approach to investigate the gross biological effects of interfering with interactions between virus MP and CP homologues derived from genetically distinct MSV isolates. MP and CP genes were reciprocally exchanged, individually and in pairs, between maize (MSV-Kom)- and Setaria sp. (MSV-Set)-adapted isolates sharing 78% genome-wide sequence identity. All chimaeras were infectious in Zea mays c.v. Jubilee and were characterized in terms of symptomatology and infection efficiency. Compared with their parental viruses, all the chimaeras were attenuated in symptom severity, infection efficiency, and the rate at which symptoms appeared. The exchange of individual MP and CP genes resulted in lower infection efficiency and reduced symptom severity in comparison with exchanges of matched MP-CP pairs. Conclusion. Specific interactions between the mastrevirus MP and CP genes themselves and/or their expression products are important determinants of infection efficiency, rate of symptom development and symptom severity. © 2008 van der Walt et al; licensee BioMed Central Ltd.

Generation and characterisation of Cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature

Introduction: Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. Methods: An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. Results: Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. Conclusion: Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer. © 2013 Barr et al.

Drug abusers perceptions of their parents.

Many clinicians in the area of drug addiction believe that emotional problems arise from particular styles of parenting. To investigate this link, 63 young male and female addicts who had sought treatment completed the Parental Bonding Instrument which tapped their perceptions of their relationship with each parent. Addicts reported early parental experiences differing from those of a control group. Drug abusers judged their parents as cold, indifferent, controlling and intrusive. In addition, these perceptions were shared by male and female addicts. These results, together with previous research suggest that these perceptions might well point to a general risk factor for the development of a broad range of psychological and psychiatric disorders. In addition, the issue of family factors in the design and implementation of drug treatment programs needs to be addressed.

Child rearing Inc : On the perils of political paralysis Down Under

In his 2007 PESA keynote address, Paul Smeyers discussed the increasing regulation of child-rearing through government intervention and the generation of “experts,” citing particular examples from Europe where cases of childhood obesity and parental neglect have stirred public opinion and political debate. In his paper (this issue), Smeyers touches on a number of tensions before concluding that child rearing qualifies as a practice in which liberal governments should be reluctant to intervene. In response, I draw on recent experiences in Australia and argue that certain tragic events of late are the result of an ethical, moral and social vacuum in which these tensions coalesce. While I agree with Smeyers that governments should be reluctant to “intervene” in the private domain of the family, I argue that there is a difference between intervention and support. In concluding, I maintain that if certain Western liberal democracies did a more comprehensive job of supporting children and their families through active social investment in primary school education, then both families and schools would be better equipped to deal with the challenges they now face.

(Re)visioning the centre : education reform and the “ideal” citizen of the future

Discourses of public education reform, like that exemplified within the Queensland Government’s future vision document, Queensland State Education-2010 (QSE-2010), position schooling as a panacea to pervasive social instability and a means to achieve a new consensus. However, in unravelling the many conflicting statements that conjoin to form education policy and inform related literature (Ball, 1993), it becomes clear that education reform discourse is polyvalent (Foucault, 1977). Alongside visionary statements that speak of public education as a vehicle for social justice are the (re)visionary or those reflecting neoliberal individualism and a conservative politics. In this paper, it is argued that the latter coagulate to form strategic discursive practices which work to (re)secure dominant relations of power. Further, discussion of the characteristics needed by the “ideal” future citizen of Queensland reflect efforts to ‘tame change through the making of the child’ (Popkewitz, 2004, p.201). The casualties of this (re)vision and the refusal to investigate the pathologies of “traditional” schooling are the children who, for whatever reason, do not conform to the norm of the desired school child as an “ideal” citizen-in-the-making and who become relegated to alternative educational settings.

The magic of numbers and the amazing disappearing act : the politics of counting youth homelessness

No-one wants to see young people who are no longer able to stay at home with their parents living in situations that are neither stable nor safe. Most Australians also appreciate that youth homelessness is typically a result of factors beyond the control of young people like poverty, lack of affordable housing, parental divorce or separation, family conflict and violence, sexual abuse, or mental health problems.1 Since the Burdekin Report of 1989 first put the issue on the national agenda, youth homelessness has been a point of some political sensitivity as the numbers of young homeless stayed stubbornly high through the 1990s and into the 2000s.

Calling for help : a responsive evaluation of Child Health Line

The project examined the responsiveness of the telenursing service provided by the Child Health Line (hereinafter referred to as CHL). It aimed to provide an account of population usage of the service, the call request types and the response of the service to the calls. In so doing, the project extends the current body of knowledge pertaining to the provision of parenting support through telenursing. Approximately 900 calls to the CHL were audio-recorded over the December 2005-2006 Christmas-New Year period. A protocol was developed to code characteristics of the call, the interactional features between the caller and nurse call-taker, and the extent to which there was (a) agreement on problem definition and the plan of action and (b) interactional alignment between nurse and caller. A quantitative analysis examined the frequencies of the main topics covered in calls to the CHL and any statistical associations between types of calls, length of calls and nurse-caller alignment. In addition, a detailed qualitative analysis was conducted on a subset of calls dealing with the nurse management of calls seeking medical advice and information. Key findings include: • Overall, 74% of the calls discussed parenting and child development issues, 48% discussed health/medical issues, and 16% were information-seeking calls. • More specifically: o 21% discussed health/medical and parenting and child development issues. o 3% discussed parenting and information-seeking issues. o 5% discussed health/medical, parenting/development and information issues. o 18% exclusively focussed on health and medical issues and therefore were outside the remit of the intended scope of the CHL. These calls caused interactional dilemmas for the nurse call-takers as they simultaneously dealt with parental expectations for help and the CHL guidelines indicating that offering medical advice was outside the remit of the service. • Most frequent reasons for calling were to discuss sleep, feeding, normative infant physical functions and parenting advice. • The average length of calls to the CHL was 7 minutes. • Longer calls were more likely to involve nurse call-takers giving advice on more than one topic, the caller displaying strong emotions, the caller not specifically providing the reason for the call, and the caller discussing parenting and developmental issues. • Shorter calls were characterised by the nurse suggesting that the child receive immediate medical attention, the nurse emphasising the importance or urgency of the plan of action, the caller referring to or requesting confirmation of a diagnosis, and caller and nurse call-taker discussion of health and medical issues. • The majority of calls, 92%, achieved parent-nurse alignment by the conclusion of the call. However, 8% did not. • The 8% of calls that were not aligned require further quantitative and qualitative investigation of the interactional features. The findings are pertinent in the current context where Child Health Line now resides within 13HEALTH. These findings indicate: 1. A high demand for parenting advice. 2. Nurse call-takers have a high level of competency in dealing with calls about parenting and normal child development, which is the remit of the CHL. 3. Nurse call-takers and callers achieve a high degree of alignment when both parties agree on a course of action. 4. There is scope for developing professional practice in calls that present difficulties in terms of call content, interactional behaviour and call closure. Recommendations of the project: 1. There are numerous opportunities for further research on interactional aspects of calls to the CHL, such as further investigations of the interactional features and the association of the features to alignment and nonalignment. The rich and detailed insights into the patterns of nurse-parent interactions were afforded by the audio-recording and analysis of calls to the CHL. 2. The regular recording of calls would serve as a way of increasing understanding of the type and nature of calls received, and provide a valuable training resource. Recording and analysing calls to CHL provides insight into the operation of the service, including evidence about the effectiveness of triaging calls. 3. Training in both recognising and dealing with problem calls may be beneficial. For example, calls where the caller showed strong emotion, appeared stressed, frustrated or troubled were less likely to be rated as aligned calls. In calls where the callers described being ‘at their wits end’, or responded to each proposed suggestion with ‘I’ve tried that’, the callers were fairly resistant to advice-giving. 4. Training could focus on strategies for managing calls relating to parenting support and advice, and parental well-being. The project found that these calls were more likely to be rated as being nonaligned. 5. With the implementation of 13HEALTH, future research could compare nurse-parent interaction following the implementation of triaging. Of the calls, 21% had both medical and parenting topics discussed and 5.3% discussed medical, parenting and information topics. Added to this, in 12% of calls, there was ambiguity between the caller and nurse call-taker as to whether the problem was medical or behavioural.

Dying for the bonds of marriage : forced marriages as a weapon of genocide

‘Forced marriages’ involve a woman or girl being abducted and declared the ‘wife’ of her captor without her consent or her family’s consent. The practice generally occurs during wartime and the ‘wife’ is normally subjected to rape, forced impregnation and sexual slavery. Moreover, she is coerced into an intimate relationship with a man who is often the perpetrator of crimes against her and her community. While forced marriages have recently been recognised as a crime against humanity, this Article contends that this does not constitute full recognition of the destructive nature of forced marriages. Instead, this Article mirrors and extends the Akayesu decision that rape can be used as a tool of genocide and maintains that forced marriages can also be a form of genocide.

Submission to the Queensland Department of Communities Review of the Juvenile Justices Act 1992 Issues Paper 2007

This submission addresses the Queensland Government’s Department of Communities Issues Paper regarding the Review of the Juvenile Justice Act 1992 (August 2007). The Queensland University of Technology Faculty of Law has a Criminal Justice Program within the Law and Justice Research Centre. The members of this Program wish to participate in the debate on these issues which are critically important to the Queensland community at large but especially to our young people.

The deep trauma of secondary victimisation : parents of sex offenders

The publication of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) introduced the notion that a life-threatening illness can be a stressor and catalyst for Posttraumatic Stress Disorder (PTSD). Since then a solid body of research has been established investigating the post-diagnosis experience of cancer. These studies have identified a number of short and long-term life changes resulting from a diagnosis of cancer and associated treatments. In this chapter, we discuss the psychosocial response to the cancer experience and the potential for cancer-related distress. Cancer can represent a life-threatening diagnosis that may be associated with aggressive treatments and result in physical and psychological changes. The potential for future trauma through the lasting effects of the disease and treatment, and the possibility of recurrence, can be a source of continued psychological distress. In addition to the documented adverse repercussions of cancer, we also outline the recent shift that has occurred in the psycho-oncology literature regarding positive life change or posttraumatic growth that is commonly reported after a diagnosis of cancer. Adopting a salutogenic framework acknowledges that the cancer experience is a dynamic psychosocial process with both negative and positive repercussions. Next, we describe the situational and individual factors that are associated with posttraumatic growth and the types of positive life change that are prevalent in this context. Finally, we discuss the implications of this research in a therapeutic context and the directions of future posttraumatic growth research with cancer survivors. This chapter will present both quantitative and qualitative research that indicates the potential for personal growth from adversity rather than just mere survival and return to pre-diagnosis functioning. It is important to emphasise however, that the presence of growth and prevalence of resilience does not negate the extremely distressing nature of a cancer diagnosis for the patient and their families and the suffering that can accompany treatment regimes. Indeed, it will be explained that for growth to occur, the experience must be one that quite literally shatters previously held schemas in order to act as a catalyst for change.

Effects of changes to child car restraint legislation in Australia on seating position and restraint use

Road trauma is a leading cause of child injury worldwide and in highly motorised countries, injury as a passenger represents a major proportion of all child road deaths and hospitalisations. Australia is no exception, particularly since motorised transport to school is at high levels in most Australian states. Recently the legislation governing the type of car restraints required for children aged under 7 years has changed in most Australian states aligning requirements better with accepted best practice. However, it is unclear what effect these changes have had on children’s seating positions or the types of restraints used. A mixed methods evaluation of the impact of the new legislation on compliance was conducted at three times: baseline (Time 1); after announcement that changes were going to be implemented but before enforcement began (Time 2); and after enforcement commenced (Time 3). Measures of compliance were obtained using two methods: road-side observations of vehicles with child passengers; and parental self-report (intercept interviews conducted at Time 2 and Time 3 only). Results from the observations suggested an overall positive effect. Proportions of children occupying front seats decreased overall and use of dedicated child seas increased to almost 40% of the observed children by Time 3. However, almost a quarter of the children observed were still occupying the front seat. These results were very different from those of the interview study where almost no children were reported as usually travelling in the front seat, and the reported use of dedicated restraints with children was almost 90%, more than twice that in the observations.

The population dynamics of the Galapagos Flightless Cormorant Phalacrocorax harrisi in relation to sea temperature

The Flightless Cormorant Phalacrocorax harrisi is restricted to c. 400 km of the western coastline of the Galápagos archipelago coinciding with the local occurrence of seasonal upwelling of oceanic currents. Individuals frequently make more than one breeding attempt per year, usually change mates, and when juveniles are raised, females desert them to the further care of their mates who complete the rearing alone. Here we report data from a ten-year historical study of a colony stretching c.2 km along the coast-line and representing c. 12% of the total population of the species. The number of clutches laid and juveniles fledged were linked to the occurrence of cold water in off-shore foraging grounds. Most Flightless Cormorants have attachments to local stretches of coastline several hundred metres long. However, a few birds travelled many kilometres, including between colonies, sometimes over open sea. We show that males invest more in nest-building and feeding of the offspring than their mates, and we relate this to the (presumed) in-bred nature of the colony and to male and female reproductive strategies. Our data validate a published demographic model of the species (Valle 1995).

The effects of cold air (-110°C) and water (8°C) cryotherapy on knee skin temperature

Exposure to cold air, whole body cryotherapy (WBC), is a novel treatment employed by athletes. In WBC individuals dressed in minimal clothing are exposed to a temperature below -100°C for 2-4 min. The use of WBC has been advocated as a treatment for various knee injuries. PURPOSE: To compare the effects of two modalities of cryotherapy, -110°C WBC and 8°C cold water immersion (CWI) on knee skin temperature (Tsk). METHODS: With ethical approval and written informed consent 10 healthy active male participants (26.5±4.9 yr, 183.5±6.0 cm, 90.7±19.9 kg, 26.8±5.0 kg/m2, 23.0±9.3% body fat (measured by DXA), 7.6 ± 2.0 mm patellar skin fold; mean±SD) were exposed to 4 min of CWI and WBC. The treatment order was randomised in a controlled crossover design, with a minimum of 7 days between treatments. During WBC participants stood in a chamber (-60±3°C) for 20 s before entering the main chamber (-110°C±3°C) where they remained for 3 min and 40 s. For CWI participants were seated in a tank filled with cold water (8±0.3°C) and immersed to the level of the sternum for 4 min. Right knee Tsk was assessed via non-contact, infrared thermal imaging. A quadrilateral region of interest was created using inert markers placed 5 cm above and below the most superior and inferior aspect of the patella. Tsk within this quadrilateral was recorded pre, immediately post and every 10 min thereafter for 60 min. Tsk changes were examined using a two-way (treatment x time) repeated measures analyses of variance. In addition, a paired sample t-test was used to compare baseline Tsk before both treatments. RESULTS: Knee Tsk was similar before treatment (WBC: 29.9±0.7°C, CWI: 29.6±0.9°C, p>0.05). There was a significant main effect for treatment (p<0.05) and time (p<0.001). Compared to baseline, Tsk was significantly reduced (p<0.05) immediately post and at 10, 20, 30, 40, 50 and 60 min after both cooling modalities. Knee Tsk was lower (p<0.05) immediately after WBC (19.0±0.9°C) compared to CWI (20.5±0.6°C). However, from 10 to 60 min post, knee Tsk was lower (p<0.05) following the CWI treatment. CONCLUSION: WBC elicited a greater decrease in knee Tsk compared to CWI immediately after treatment. However, both modalities display different recovery patterns and Tsk after CWI was significantly lower than WBC at 10, 20, 30, 40, 50 and 60 min after treatment.

Improving the measurement and surveillance of child abuse in Queensland emergency departments

There are no population studies of prevalence or incidence of child maltreatment in Australia. Child protection data gives some understanding but is restricted by system capacity and definitional issues across jurisdictions. Child protection data currently suggests that numbers of reports are increasing yearly, and the child protection system then becomes focussed on investigating all reports and diluting available resources for those children who are most in need of intervention. A public health response across multiple agencies enables responses to child safety across the entire population. All families are targeted at the primary level; examples include ensuring all parents know the dangers of shaking a baby or teaching children to say no if a situation makes them uncomfortable. The secondary level of prevention targets families with a number of risk factors, for example subsidised child care so children aren't left unsupervised after school when both parents have to be at work or home visiting for drug-addicted parents to ensure children are cared for. The tertiary response then becomes the responsibility of the child protection system and is reserved for those children where abuse and neglect are identified. This model requires that child safety is seen in a broader context than just the child protection system, and increasingly health professionals are being identified as an important component in the public health framework. If all injury is viewed as preventable and considered along a continuum of 'accidental' through to 'inflicted', it becomes possible to conceptualise child maltreatment in an injury context. Parental intent may not be to cause harm to the child, but by lack of insight or concern about risk, the potential for injury is high. The mechanisms for unintentional and intentional injury overlap and some suggest that by segregating child abuse (with the possible exception of sexual abuse) from unintentional injury, child abuse is excluded from the broader injury prevention initiative that is gaining momentum in the community. This research uses a public health perspective, specifically that of injury prevention, to consider the problem of child abuse. This study employed a mixed method design that incorporates secondary data analysis, data linkage and structured interviews of different professional groups. Datasets from the Queensland Injury Surveillance Unit (QISU) and The Department of Child Safety (DCS) were evaluated. Coded injury data was grouped according to intent of injury according to those with a code that indicated the ED presentation was due to child abuse, a code indicating that the injury was possibly due to abuse or, in the third group, the intent code indicated that the injury was unintentional and not due to abuse. Primary data collection from ED records was undertaken and information recoded to assess reliability and completeness. Emergency department data (QISU) was linked to Department of Child Safety Data to examine concordance and data quality. Factors influencing the collection and collation of these data were identified through structured interview methodology and analysed using qualitative methods. Secondary analysis of QISU data indicated that codes lacking specific information on the injury event were more likely to also have an intent code indicating abuse than those records where there was specific information on the injury event. Codes for abuse appeared in only 1.2% of the 84,765 records analysed. Unintentional injury was the most commonly coded intent (95.3%). In the group with a definite abuse code assigned at triage, 83% linked to a record with DCS and cases where documentation indicated police involvement were significantly more likely to be associated with a DCS record than those without such documentation. In those coded with an unintentional injury code, 22% linked to a DCS record with cases assigned an urgent triage category more likely to link than those with a triage category for resuscitation and children who presented to regional or remote hospitals more likely to link to a DCS record than those presenting to urban hospitals. Twenty-nine per cent of cases with a code indicating possible abuse linked to a DCS record. In documentation that indicated police involvement in the case, a code for unspecified activity when compared to cases with a code indicating involvement in a sporting activity and children less than 12 months of age compared to those in the 13-17 year old age group were all variables significantly associated with linkage to a DCS record. Only 13% of records contained documentation indicating that child abuse and neglect were considered in the diagnosis of the injury despite almost half of the sample having a code of abuse or possible abuse. Doctors and nurses were confident in their knowledge of the process of reporting child maltreatment but less confident about identifying child abuse and neglect and what should be reported. Many were concerned about implications of reporting, for the child and family and for themselves. A number were concerned about the implications of not reporting, mostly for the wellbeing of the child and a few in terms of their legal obligations as mandatory reporters. The outcomes of this research will help improve the knowledge of barriers to effective surveillance of child abuse in emergency departments. This will, in turn, ensure better identification and reporting practises; more reliable official statistical collections and the potential of flagging high-risk cases to ensure adequate departmental responses have been initiated.