Compilation of somatic mutations of the CDKN2 gene in human cancers : non-random distribution of base substitutions

The CDKN2 gene, encoding the cyclin-dependent kinase inhibitor p16, is a tumour suppressor gene that maps to chromosome band 9p21-p22. The most common mechanism of inactivation of this gene in human cancers is through homozygous deletion; however, in a smaller proportion of tumours and tumour cell lines intragenic mutations occur. In this study we have compiled a database of over 120 published point mutations in the CDKN2 gene from a wide variety of tumour types. A further 50 deletions, insertions, and splice mutations in CDKN2 have also been compiled. Furthermore, we have standardised the numbering of all mutations according to the full-length 156 amino acid form of p16. From this study we are able to define several hot spots, some of which occur at conserved residues within the ankyrin domains of p16. While many of the hotspots are shared by a number of cancers, the relative importance of each position varies, possibly reflecting the role of different carcinogens in the development of certain tumours. As reported previously, the mutational spectrum of CDKN2 in melanomas differs from that of internal malignancies and supports the involvement of UV in melanoma tumorigenesis. Notably, 52% of all substitutions in melanoma-derived samples occurred at just six nucleotide positions. Nonsense mutations comprise a comparatively high proportion of mutations present in the CDKN2 gene, and possible explanations for this are discussed.

Mutation analysis of the CDKN2A promoter in Australian melanoma families

Approximately 50% of all melanoma families worldwide show linkage to 9p21-22, but only about half of these have been shown to contain germ line CDKN2A mutations. It has been hypothesized that a proportion of these families carry mutations in the noncoding regions of CDKN2A. Several Canadian families have been reported to carry a mutation in the 5' UTR, at position -34 relative to the start site, which gives rise to a novel AUG translation initiation codon that markedly decreases translation from the wild-type AUG (Liu et al., 1999). Haplotype sharing in these Canadian families suggested that this mutation is of British origin. We sequenced 1,327 base pairs (bp) of CDKN2A, making up 1,116 bp of the 5' UTR and promoter, all of exon 1, and 61 bp of intron 1, in at least one melanoma case from 110 Australian families with three or more affected members known not to carry mutations within the p16 coding region. In addition, 431 bp upstream of the start codon was sequenced in an additional 253 affected probands from two-case melanoma families for which the CDKN2A mutation status was unknown. Several known polymorphisms at positions -33, -191, -493, and -735 were detected, in addition to four novel variants at positions 120, -252, -347, and -981 relative to the start codon. One of the probands from a two-case family was found to have the previously reported Q50R mutation. No family member was found to carry the mutation at position -34 or any other disease-associated mutation. For further investigation of noncoding CDKN2A mutations that may affect transcription, allele-specific expression analysis was carried out in 31 of the families with at least three affected members who showed either complete or "indeterminate" 9p haplotype sharing without CDKN2A exonic mutations. Reverse transcription polymerase chain reaction and automated sequencing showed expression of both CDKN2A alleles in all family members tested. The lack of CDKN2A promoter mutations and the absence of transcriptional silencing in the germ line of this cohort of families suggest that mutations in the promoter and 5' UTR play a very limited role in melanoma predisposition.

Letter to the editor : likelihood of tetraplegia after CT clearance of the cervical spine in obtunded blunt trauma patients

...the probabilistic computer simulation study by Dunham and colleagues evaluating the impact of different cervical spine management (CSM) strategies on tetraplegia and brain injury outcomes.1 Based on literature findings, expert opinion and with use of advances programming techniques the authors conclude that early collar removal without cervical spine magnetic resonance imaging (MRI) is a preferable CSM strategy for comatose, blunt trauma patients with extremity movement and a negative cervical spine computed tomography(CT) scan. Although we do not have the required expertise to comment on the applied statistical approach, we would like to comment on one of the medical assumptions raised by the authors, namely the likelihood of tetraplegia in this specific population....

Modulation of the Chlamydia trachomatis In vitro transcriptome response by the sex hormones estradiol and progesterone

BACKGROUND:Chlamydia trachomatis is a major cause of sexually transmitted disease in humans. Previous studies in both humans and animal models of chlamydial genital tract infection have suggested that the hormonal status of the genital tract epithelium at the time of exposure can influence the outcome of the chlamydial infection. We performed a whole genome transcriptional profiling study of C. trachomatis infection in ECC-1 cells under progesterone or estradiol treatment.RESULTS:Both hormone treatments caused a significant shift in the sub-set of genes expressed (25% of the transcriptome altered by more than 2-fold). Overall, estradiol treatment resulted in the down-regulation of 151 genes, including those associated with lipid and nucleotide metabolism. Of particular interest was the up-regulation in estradiol-supplemented cultures of six genes (omcB, trpB, cydA, cydB, pyk and yggV), which suggest a stress response similar to that reported previously in other models of chlamydial persistence. We also observed morphological changes consistent with a persistence response. By comparison, progesterone supplementation resulted in a general up-regulation of an energy utilising response.CONCLUSION:Our data shows for the first time, that the treatment of chlamydial host cells with key reproductive hormones such as progesterone and estradiol, results in significantly altered chlamydial gene expression profiles. It is likely that these chlamydial expression patterns are survival responses, evolved by the pathogen to enable it to overcome the host's innate immune response. The induction of chlamydial persistence is probably a key component of this survival response.

(Not) the Twitter election: The dynamics of the #ausvotes conversation in relation to the Australian media ecology

This paper draws on a larger study of the uses of Australian user-created content and online social networks to examine the relationships between professional journalists and highly engaged Australian users of political media within the wider media ecology, with a particular focus on Twitter. It uses an analysis of topic based conversation networks using the #ausvotes hashtag on Twitter around the 2010 federal election to explore the key themes and issues addressed by this Twitter community during the campaign, and finds that Twitter users were largely commenting on the performance of mainstream media and politicians rather than engaging in direct political discussion. The often critical attitude of Twitter users towards the political establishment mirrors the approach of news and political bloggers to political actors, nearly a decade earlier, but the increasing adoption of Twitter as a communication tool by politicians, journalists, and everyday users alike makes a repetition of the polarisation experienced at that time appear unlikely.

The role of the recycling endosome in regulating lamellipodia formation and macrophage migration

Cell migration is a highly complex process that requires the extension of cell membrane in the direction of travel. This membrane is continuously remodeled to expand the leading edge and alter its membrane properties. For a long time it has been known that there is a continual flow of polarized membrane traffic towards the leading edge during migration and that this trafficking is essential for cell migration. However, there is little information on how the cell coordinates exocytosis at the leading edge. It is also unclear whether these internal membranes are incorporated into the leading edge or are just delivering the necessary proteins for migration to occur. We have shown that recycling endosome membrane is incorporated into the plasma membrane at the leading edge to expand the membrane and at the same time delivers receptors to the leading edge to mediate migration. In order for this to happen the surface Q-SNARE complex Stx4/SNAP23 translocates to the leading edge where it binds to the R-SNARE VAMP3 on the recycling endosome allowing incorporation into the plasma membrane. Loss of any one of the components of this complex reduces efficient lamellipodia formation and restrains cell migration.

Do you see what I mean? charting changing representations and receptions of the disabled body in contemporary and pop cultural performance

The meaning of the body emerges through acts of seeing, looking and staring in daily and dramatic performances. Acts that are, as Maike Bleeker argues1, bound up with the scopic rules, regimes and narratives that apply in specific cultures at specific times. In Western culture, the disabled body has been seen as a sign of defect, deficiency, fear, shame or stigma. Disabled artists – Mat Fraser, Bill Shannon, Aaron Williamson, Katherine Araniello, Liz Crow and Ju Gosling – have attempted, via performances that co-opt conventional images of the disabled body, to challenge dominant ways of representing and responding such bodies from within. In this paper, I consider what happens when non-disabled artists co-opt images of the disabled body to draw attention to, affirm, and even exoticise, eroticise or beautify, other modalities of or desires for difference. As Carrie Sandahl has noted2, the signs, symbols and somatic idiosyncrasies of the disabled body are, today, transported or translated into theatre, film and television as a metaphor or "master trope" for every body’s experience of difference. This happens in performance art (Guillermo Gomez-Pena’s use of a wheelchair in Chamber of Confessions), performance (Marie Chouinard's use of crutches, canes and walkers to represent dancers’ experience of becoming different or mutant during training in bODY rEMIX /gOLDBERG vARIATIONS), and pop culture (characters in wheelchairs in Glee or Oz). In this paper, I chart changing representations and receptions of the disabled body in such contexts. I use analysis of this cultural shift as a starting point for a re-consideration of questions about whether a face-toface encounter with a disabled body is in fact a privileged site for the emergence of a politics, and whether co-opting disability as a metaphor for a range of difference differences reduces its currency as a category around which a specific group might mobilise a politics.

Child Victims of Sexual Abuse: Children's Experience of the Investigative Process in the Criminal Justice System

This paper is a selected review of research on issues surrounding the investigation of intra-familial child sexual abuse for children aged eight and above, in the criminal justice system. Particular attention is paid to features of the investigative interview in relation to the child's level of understanding, ability to report and likely emotional response when the proceedings take place. Best practice by police and social care agencies involves establishing valid and reliable information from children while attending to their developmental level and emotional state. The review aims to distil principles optimising this process from both the investigative judicial perspective and the child's focus, as well as from the inter-agency perspective and information sharing. Recommendations are made for improving the interview process based on research and methods from a range of disciplines and to optimise information recording in a format easily shared between agencies. Updated and ongoing training procedures are key to successful practice with training shared across police and social work agencies. The focus of this review is informed by preliminary findings from pilot research in progress on behalf of the Metropolitan Police Child Abuse Investigation Command.

They Say You are a Danger But You Are Not: Representations and Construction of the Moral Self in Narratives of 'Dangerous Individuals'

This article is based on an analysis of narratives of 26 offenders with mental health problems living in the United Kingdom. It explores the impact of an ascribed dangerous status and the construction of the self as moral and responsible in response to this label with reference to the literature on denial, deviance disavowal and other “techniques of neutralization” and Goffman's presentation of self. Two dominant strands are identified in relation to the construction of moral self-hood: “Not my fault” and “Good at heart” narratives. “Techniques of neutralization” are widely drawn on, particularly denial of responsibility in the “Not my fault” narratives that seek to explain anti-social behavior with reference to external forces such as a hostile environment inhibiting their ability to control their lives. In contrast, “Good at heart” narratives draw on the essentially good and moral nature of the inner-self. Both are used as evidence of sharing and adhering to moral norms in order to present an acceptable and credible self.

Reading images : the book club in the art gallery

This paper seeks to document and understand one instance of community-university engagement: that of an on-going book club organised in conjunction with public art exhibitions. The curator of the Queensland University of Technology (QUT) Art Museum invited the authors, three postgraduate research students in the faculty of Creative Writing and Literary Studies at QUT, to facilitate an informal book club. The purpose of the book club was to generate discussion, through engagement with fiction, around the themes and ideas explored in the Art Museum’s exhibitions. For example, during the William Robinson exhibition, which presented evocative images of the environment around Brisbane, Queensland, the book club explored texts that symbolically represented aspects of the Australian landscape in a variety of modes and guises. This paper emerges as a result of the authors’ observations during, and reflections on, their experiences facilitating the book club. It responds to the research question, how can we create a best practice model to engage readers through open-ended, reciprocal discussion of fiction, while at the same time encouraging interactions in the gallery space? To provide an overview of reading practices in book clubs, we rely on Jenny Hartley’s seminal text on the subject, The Reading Groups Book (2002). Although the book club was open to all members of the community, the participants were generally women. Elizabeth Long, in Book Clubs: Woman and the Uses of Reading in the Everyday (2003), offers a comprehensive account of women’s interactions as they engage in a reading community. Long (2003, 2) observes that an image of the solitary reader governs our understanding of reading. Long challenges this notion, arguing that reading is profoundly social (ibid), and, as women read and talk in book clubs, ‘they are supporting each other in a collective working-out of their relationship to a particular historical movement and the particular social conditions that characterise it’ (Long 2003, 22). Despite the book club’s capacity to act as a forum for analytical discussion, DeNel Rehberg Sedo (2010, 2) argues that there are barriers to interaction in such a space, including that members require a level of cultural capital and literacy before they feel comfortable to participate. How then can we seek to make book clubs more inclusive, and encourage readers to discuss and question outside of their comfort zone? How can we support interactions with texts and images? In this paper, we draw on pragmatic and self-reflective practice methods to document and evaluate the development of the book club model designed to facilitate engagement. We discuss how we selected texts, negotiating the dual needs of relevance to the exhibition and engagement with, and appeal to, the community. We reflect on developing questions and material prior to the book club to encourage interaction, and describe how we developed a flexible approach to question-asking and facilitating discussion. We conclude by reflecting on the outcomes of and improvements to the model.

Evaluation of the luminous environment in open-plan offices with skylights

High Dynamic Range (HDR) imaging was used to collect luminance information at workstations in 2 open-plan office buildings in Queensland, Australia: one lit by skylights, vertical windows and electric light, and another by skylights and electric light. This paper compares illuminance and luminance data collected in these offices with occupant feedback to evaluate these open-plan environments based on available and emerging metrics for visual comfort and glare. This study highlights issues of daylighting quality and measurement specific to open plan spaces. The results demonstrate that overhead glare is a serious threat to user acceptance of skylights, and that electric and daylight integration and controls have a major impact on the perception of daylighting quality. With regards to measurement of visual comfort it was found that the Daylight Glare Probability (DGP) gave poor agreement with occupant reports of discomfort glare in open-plan spaces with skylights, and the CIE Glare Index (CGI) gave the best agreement. Horizontal and vertical illuminances gave no indication of visual comfort in these spaces.