Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.

The rules of autogeddon : sex death and law in J G Ballard’s Crash

It was reported that the manuscript of Crash was returned to the publisher with a note reading ‘The author is beyond psychiatric help’. Ballard took the lay diagnosis as proof of complete artistic success. Crash conflates the Freudian tropes of libido and thanatos, overlaying these onto the twentieth century erotic icon, the car. Beyond mere incompetent adolescent copulatory fumblings in the back seat of the parental sedan or the clichéd phallic locomotor of the mid-life Ferrari, Ballard engages the full potentialities of the automobile as the locus and sine qua non of a perverse, though functional erotic. ‘Autoeroticism’ is transformed into automotive, traumatic or surgical paraphilia, driving Helmut Newton’s insipid photo-essays of BDSM and orthopædics into an entirely new dimension, dancing precisely where (but more crucially, because) the ‘body is bruised to pleasure soul’. The serendipity of quotidian accidental collisions is supplanted, in pursuit of the fetishised object, by contrived (though not simulated) recreations of iconographic celebrity deaths. Penetration remains as a guiding trope of sexuality, but it is confounded by a perversity of focus. Such an obsessive pursuit of this autoerotic-as-reality necessitates the rejection of the law of human sexual regulation, requiring the re-interpretation of what constitutes sex itself by looking beyond or through conventional sexuality into Ballard’s paraphiliac and nightmarish consensual Other. This Other allows for (if not demands) the tangled wreckage of a sportscar to function as a transformative sexual agent, creating, of woman, a being of ‘free and perverse sexuality, releasing within its dying chromium and leaking engine-parts, all the deviant possibilities of her sex’.

An accessible method for teaching doctors about death certification

The World Health Organization recommends that data on mortality in its member countries are collected utilising the Medical Certificate of Cause of Death published in the instruction volume of the ICD-10. However, investment in health information processes necessary to promote the use of this certificate and improve mortality information is lacking in many countries. An appeal for support to make improvements has been launched through the Health Metrics Network’s MOVE-IT strategy (Monitoring of Vital Events – Information Technology) [World Health Organization, 2011]. Despite this international spotlight on the need for capture of mortality data and in the use of the ICD-10 to code the data reported on such certificates, there is little cohesion in the way that certifiers of deaths receive instruction in how to complete the death certificate, which is the main source document for mortality statistics. Complete and accurate documentation of the immediate, underlying and contributory causes of death of the decedent on the death certificate is a requirement to produce standardised statistical information and to the ability to produce cause-specific mortality statistics that can be compared between populations and across time. This paper reports on a research project conducted to determine the efficacy and accessibility of the certification module of the WHO’s newly-developed web based training tool for coders and certifiers of deaths. Involving a population of medical students from the Fiji School of Medicine and a pre and post research design, the study entailed completion of death certificates based on vignettes before and after access to the training tool. The ability of the participants to complete the death certificates and analysis of the completeness and specificity of the ICD-10 coding of the reported causes of death were used to measure the effect of the students’ learning from the training tool. The quality of death certificate completion was assessed using a Quality Index before and after the participants accessed the training tool. In addition, the views of the participants about accessibility and use of the training tool were elicited using a supplementary questionnaire. The results of the study demonstrated improvement in the ability of the participants to complete death certificates completely and accurately according to best practice. The training tool was viewed very positively and its implementation in the curriculum for medical students was encouraged. Participants also recommended that interactive discussions to examine the certification exercises would be an advantage.

The Tension between a constructed self and universal reason in considerations of elective death

Review of Coping with Choices to Die, by C. G. Prado. Cambridge: Cambridge University Press, 2011.

When does pain and distress relief hastening death become killing?

This paper discusses the question of when pain and distress relief known to hasten death would cross the line between permissible conduct and killing. The issue is discussed in the context of organ donation after cardiac death, and considers the administration of analgesics, sedatives, and the controversial use of paralysing agents in the provision and withdrawal of ventilation.

Plant programmed cell death : Can't live with it; Can't live without it

The decision of whether a cell should live or die is fundamental for the wellbeing of all organisms. Despite intense investigation into cell growth and proliferation, only recently has the essential and equally important idea that cells control/programme their own demise for proper maintenance of cellular homeostasis gained recognition. Furthermore, even though research into programmed cell death (PCD) has been an extremely active area of research there are significant gaps in our understanding of the process in plants. In this review, we discuss PCD during plant development and pathogenesis, and compare/contrast this with mammalian apoptosis. © 2008 Blackwell Publishing Ltd.

Do the myths still exist? Revisiting people’s negative beliefs about organ donation upon death

The prevalence of myths preventing people partial to donation in Australia from consenting is unknown. Respondents (N = 468: 381 donors, 26 non-donors, 61 undecided) were surveyed about their (negative) donation beliefs. Approximately 30% of donors were neutral or supported negative beliefs about organ allocation, especially donation to undesirable organ recipients and a black market organ trade. Confusion about brain death, lack of family and religious support, and discomfort with donation were negative beliefs endorsed by some respondents irrespective of donor preference. Proportionally, donors had greater trust in hospitals/doctors than other groups. Some myths still exist but may vary with donation preference.

Wolbachia-mediated resistance to dengue virus infection and death at the cellular level

Dengue is currently the most important arthropod-borne viral disease of humans. Recent work has shown dengue virus displays limited replication in its primary vector, the mosquito Aedes aegypti, when the insect harbors the endosymbiotic bacterium Wolbachia pipientis. Wolbachia-mediated inhibition of virus replication may lead to novel methods of arboviral control, yet the functional and cellular mechanisms that underpin it are unknown.

Polarized fluid movement and not cell death, creates luminal spaces in adult prostate epithelium

There are two predominant theories for lumen formation in tissue morphogenesis: cavitation driven by cell death, and membrane separation driven by epithelial polarity. To define the mechanism of lumen formation in prostate acini, we examined both theories in several cell lines grown in three-dimensional (3D) Matrigel culture. Lumen formation occurred early in culture and preceded the expression of cell death markers for apoptosis (active caspase 3) and autophagy (LC-3). Active caspase 3 was expressed by very few cells and inhibition of apoptosis did not suppress lumen formation. Despite LC-3 expression in all cells within a spheroid, this was not associated with cell death. However, expression of a prostate-secretory protein coincided with lumen formation and subsequent disruption of polarized fluid movement led to significant inhibition of lumen formation. This work indicates that lumen formation is driven by the polarized movement of fluids and proteins in 3D prostate epithelial models and not by cavitation.

Architecture post mortem : the diastolic architecture of decline, dystopia, and death

Architecture Post Mortem surveys architecture’s encounter with death, decline, and ruination following late capitalism. As the world moves closer to an economic abyss that many perceive to be the death of capital, contraction and crisis are no longer mere phases of normal market fluctuations, but rather the irruption of the unconscious of ideology itself. Post mortem is that historical moment wherein architecture’s symbolic contract with capital is put on stage, naked to all. Architecture is not irrelevant to fiscal and political contagion as is commonly believed; it is the victim and penetrating analytical agent of the current crisis. As the very apparatus for modernity’s guilt and unfulfilled drives-modernity’s debt-architecture is that ideological element that functions as a master signifier of its own destruction, ordering all other signifiers and modes of signification beneath it. It is under these conditions that architecture theory has retreated to an “Alamo” of history, a final desert outpost where history has been asked to transcend itself. For architecture’s hoped-for utopia always involves an apocalypse. This timely collection of essays reformulates architecture’s relation to modernity via the operational death-drive: architecture is but a passage between life and death. This collection includes essays by Kazi K. Ashraf, David Bertolini, Simone Brott, Peggy Deamer, Didem Ekici, Paul Emmons, Donald Kunze, Todd McGowan, Gevork Hartoonian, Nadir Lahiji, Erika Naginski, and Dennis Maher. Contents: Introduction: ‘the way things are’, Donald Kunze; Driven into the public: the psychic constitution of space, Todd McGowan; Dead or alive in Joburg, Simone Brott; Building in-between the two deaths: a post mortem manifesto, Nadir Lahiji; Kant, Sade, ethics and architecture, David Bertolini; Post mortem: building deconstruction, Kazi K. Ashraf; The slow-fast architecture of love in the ruins, Donald Kunze; Progress: re-building the ruins of architecture, Gevork Hartoonian; Adrian Stokes: surface suicide, Peggy Deamer; A window to the soul: depth in the early modern section drawing, Paul Emmons; Preliminary thoughts on Piranesi and Vico, Erika Naginski; architectural asceticism and austerity, Didem Ekici; 900 miles to Paradise, and other afterlives of architecture, Dennis Maher; Index.

Collaborative tagging in participatory webs : the death of information organisation?

Many organisations, companies and libraries started to use participatory webs to extend their services and engage more users. However, some librarians are still hesitated to implement participatory webs in their libraries, particularly in developing countries. This paper explores the advantages and disadvantages of participatory webs focusing on collaborative tagging. This paper draws from the literature of published articles discussing topics but not limited to participatory webs, participatory libraries, collaborative tagging, folksonomy and taxonomy. The advantages of implementation of the participatory webs in the library outweigh the disadvantages of it. Participatory webs do not necessarily mean the death of information organisation but it can supplement and improves information organisation in the library. This paper may help to broaden knowledge of LIS professionals in the implementation of participatory webs in the library.

ACE research vignette 022 : family business succession : when death takes a hand

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. In this vignette, Dr. Mervyn Morris considers the impact on family business operations due to the sudden and unexpected death of a key family member.