Insulin increases De Novo Steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women

Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

Composing maternal identities : the living realities of mothers with young adult-children in twenty-first century Australia

There is an abundance of books available on the topic of motherhood and mothering; the majority of these books focus on the vulnerability of babies and young children and the motherwork such vulnerability demands. In particular they focus on what it is right to do in the interests of the child, and particularly his or her growth and development. Such a focus is consistent in Western culture with modern moral frameworks where understandings of goodness have been assimilated to dimensions of human action rather than dimensions of human being, selfhood, or specific forms of life. As Charles Taylor has observed, much modern moral philosophy has focused =on what it is right to do rather than the nature of the good life‘ (1989, 13). The master narratives of motherhood and the prevailing social discourses of intensive1 and sacrificial2 mothering exemplify this view as such narratives and discourses depict =what mothers are expected to do [and] how mothers are supposed to be‘ (Nelson 2001, 140). From such infant/child-focused accounts a canonical maternal identity can be discerned; arguably, it is a restricted one. The majority of these books fail to address questions related to what it means be a mother in particular situated, existing, living realities. For instance, ask a mother with young children what being a mother means to her and she may speak of the challenges she faces balancing paid employment and her role as a mother, or the impact of the demands being made on her time and energy. However, ask a mother with young adult-children3 what being a mother means to her and she may speak in similar tones, but she may also speak in differing tones. For example, a "mature" mother may speak of the "empty nest", the "crowded house" and/or "its revolving front door". She may speak of issues related to the vulnerability of the long term marriage, elder care, or grandparenting, or even disillusionment and disenchantment. The purpose of this research is to explore the identity challenges and prospects of some mothers with young adult-children aged between 18 and 30 years of age in twenty-first century Australia. In interpreting the identity challenges and prospects this particular cohort of mothers encounter in their ordinary, everyday living, a diverse and particular range of maternal experiences.my own included5.have been traced, along with the social and ethical meanings ascribed in them. With an understanding and appreciation of voice as the medium which connects one's inner and outer worlds, this research illuminates the plurality of voices and the multiple layers of meaning in each of these mother's particular living and existing realities. Specifically, this research addresses the narrowly constructed, canonical maternal identity through a critical exploration and reflection on stories, shared in a research context, of the living realities of a group of self-identified "mature", middle-class, Australian mothers with children aged between 18 and 30 years of age6. By appraising the broader familial, historical, social, cultural, institutional, and, importantly, moral contexts in which these mothers are situated, 'thick descriptions' (Geertz 1973, 27)7 of maternal identities, and the challenges and prospects these mothers are negotiating, are provided. In terms of its ethical orientation, the frameworks which support and frame this research reject, repudiate and contest (Nelson 2001) the reduction of ethical concerns to individual or intellectual problems or dilemmas to be solved through the application of a theory derived from reasoned thinking. In dismissing deductive and =theoretical-juridical‘8 approaches, the individualistic orientation entrenched in contemporary Western moral thinking, expressed in the notion of '"what ought I to do" when faced with a problem, issue or dilemma of practical urgency' (Isaacs & Massey 1994, 1), is simultaneously rejected, repudiated and contested (Nelson 2001). In countering such understandings, this research reorients us to the illumination and articulation of who it is good to be, for each of these mothers, in allegiance with those goods which guide and inspire her orientations towards living a good life—a life which embraces and enhances the flourishing of herself and her significant others. With an understanding and appreciation that 'mind is never free of precommitment[—t]here is no innocent eye, nor is there one that penetrates aboriginal reality' (Bruner 1987, 32), this thesis is written with the voices of other interlocutors9. These interlocutors include the voices of my research participants whom I refer to as "research interlocutors", my textual "friends" — those scholars whose work resonates strongly with my orientations—as well as the myriad other voices that speak to mothers, for mothers and about mothers, such as those found in popular and mainstream press and culture. Sometimes these voices resonate; other times dissonance may be heard. In situating this research within these complementary frameworks, this research invites readers to join with me in considering, appreciating and appraising the narrow construction of maternal identity. I seek for this engagement, like the engagements with my research interlocutors, to be 'a meeting of voices, an authentic dialogue that is inclusive of the voices of all concerned participants' (Isaacs 2001, 6). I hope that the voices in this thesis resonate with yours (although, at times, you may feel some dissonance) and that together we can draw closer to the accounting, re-counting and re-stor(y)ing of maternal identities; like concentric circles of witness, the dialogue, ...will thus be expanded rippling into corners where one might both imagine, and least expect. Possibilities, then, are vast; the future exciting (Smith 2007, 397). This research is also shaped and guided by maternal scholarship, a relatively new field of inquiry known as 'motherhood studies' (O'Reilly 2011, xvii) which has its origins within the broader terrain of feminist scholarship. As a work of maternal scholarship, this thesis draws upon and continues the tradition of examining motherhood as it is experienced 'in a social context, as embedded in a political institution: in feminist terms' (Rich 1995, ix). It values mothers, their experiences, their stories, their lives. As such, this research is oriented towards 'matricentric feminism', a particular form of feminist inquiry, politics and theory which is consistent with and receptive to feminist frameworks of care and equal rights (O‘Reilly 2011, 25). A number of complementary conceptual frameworks have been engaged in this research with the thesis presented in three parts: the pre-figurative, configurative and re-configurative. As my particular living experiences provided the initial motivation for this research, an account of the challenges I experienced as a mother with young adult-children are outlined as a Prelude to this thesis. Attention then turns to Part One – Pre-figuring Maternal Identities in which the contextual, conceptual and methodological foundations underpinning this research are explored and outlined. In Chapter One, the prevailing cultural narratives and social discourses supporting and shaping the construction of the canonical maternal identity are outlined. Next, in setting the scholarly context, the critiques — arising from feminist and maternal scholarship — of motherhood as a patriarchal institution, mothering as experience, and mothering as work, are explored. As this research engaged with participants who are embedded in particular middle-class, heterosexual, familial and cultural structures, an exploration of family life cycle theory and main stream media accounts are also incorporated. The terrain in which "mature" mothering within an Australian context is experienced is also outlined, including the notions of "empty nests" and "crowded houses", grandparenting, elder care and women's midlife transition. Chapter Two gives an account of the conceptual ontological, ethical, identity and narrative frameworks underpinning this research. In setting the context for rich interpretations, the characteristics of being human10 are outlined before attention turns to our embodiment and embeddedness in our shared human condition11. From this point, attention then turns to understanding the moral form of human living12. In appreciating the vulnerability inherent in our shared human condition, the ways in which we may experience trouble in our lives is noted. The framing of identity constitution13 as complex, multi-faceted, relationally negotiated and composed is then outlined, followed by an understanding of why narrative is a valuable interpretive tool for interpreting and understanding human experiences. This chapter concludes with an appreciation of the ethical significance of storytelling. The research methodology is then outlined in Chapter Three. The rationale underpinning the adoption of the narrative interviewing technique of in-depth interviewing is explored. In exploring these methodological frameworks, the recruitment and interview processes involved in gathering and interpreting the recorded transcripts of ten Australian mothers with young adult-children are outlined. The method of analysis known as the Listening Guide14 best complements the multi-layered, pluri-vocal nature of narrative accounting. The final section of Chapter Three outlines The Guide, with one mother's recorded transcript used to illustrate this method's step-by-step process. Having gathered an understanding and appreciation of the pluri-vocal, multi-layered nature of narrative and identity constitution, the tone of this thesis changes in Part Two . Configuring Maternal Identities. This section consists of Chapters Four and Five and seeks to find meaning in, and make sense of, the differences and commonalities across these particular accounts. Chapter Four explores the living realities of four Australian mothers with young adult-children: Poppy, Honey, Lily and Heather. In presenting a thick description of these mothers' situated realities, the frameworks.the familial, social, cultural, historical and institutional backgrounds.which have supported and shaped each mother's experiences are illuminated. Simultaneously revealed through these particular accounts are the plurality of goods focusing and moving each mother to the moral form of life, a life of meaning and purpose. The harms challenging some mothers' moral motivations are also revealed in this chapter. Specifically illustrated in Chapter Four are the unique and qualitative differences of particular maternal identity configurations. Chapter Five reveals the commonalities amongst all of the research interlocutors' accounts. This chapter contests the individualistic orientation of many contemporary accounts of motherhood which are aimed at defining or contesting what a "good" mother ought to do. By turning away from such individualistic orientations, the chapter does not seek to define 'the content of obligation' (Taylor 1989, 3) but rather seeks to illuminate and articulate a richer, deeper understanding and appreciation of maternal be-ing and be-coming - that is, who it is good to be, for each of these mothers - in allegiance with those goods that focus and inspire her moral motivations. Part Three - Re-Configuring Maternal Identities, which is comprised of Chapter Six, draws this thesis to a close. In this final chapter, the preconceptions, conditions and aspirations for this mother-centred account of the living realities of a small, local cohort of mothers are reiterated. The insights gathered from the rich, descriptive accounts are illuminated and articulated, and the chapter closes with some suggestions for future research. In a Postlude, I reflect on how this research has been a transformative learning experience in my own life.an experience in which I have been able to not only deeply understand and appreciate the challenges and disorientation I was experiencing but also to identify and reorient my stance in relation to the good. In a practical sense, by offering thick descriptions of the living realities of this cohort of "mature" mothers, this research challenges the canonical maternal identity and questions its relevance for, and effect on, "mature" mothers' identity constitution. By bringing to light the complex existing realities of these particular mothers, this research critiques the canonical maternal identity by illustrating that each mother's life and her identity constitutions are complex, relationally negotiated and composed and that motherhood is an enduring way of being. Through these illustrations, this research engages with and extends understandings of difference feminism. This research, however, not only rejects, repudiates and contests (Nelson 2001) the narrowly defined canonical maternal identity. By illuminating and articulating the goods which shape and inspire these "mature" mothers' motherwork, this research offers a matricentric account which is consistent with and respectful of the particular, situated realities—the broader familial, social, institutional, but most importantly, moral values and frameworks—in which each mother‘s life is embedded and her motherwork oriented. By understanding and appreciating the complex and multiple webs of relationships in which each mother exists, this matricentric re-stor(y)ing of maternal experiences not only understands and appreciates the unique nature of each mother‘s existing realities, it is oriented to the continuing enhancing of the shared pursuit of the good which underpins particular maternal practices and particular maternal ways of being.

Joining the dots : piloting the work diary as a data collection tool for educational research

This paper demonstrates the affordances of the work diary as a data collection tool for both pilot studies and qualitative research of social interactions. Observation is the cornerstone of many qualitative, ethnographic research projects (Creswell, 2008). However, determining through observation, the activities of busy school teams could be likened to joining dots of a child’s drawing activity to reveal a complex picture of interactions. Teachers, leaders and support personnel are in different locations within a school, performing diverse tasks for a variety of outcomes, which hopefully achieve a common goal. As a researcher, the quest to observe these busy teams and their interactions with each other was daunting and perhaps unrealistic. The decision to use a diary as part of a wider research project was to overcome the physical impossibility of simultaneously observing multiple team members. One reported advantage of the use of the diary in research was its suitability as a substitute for lengthy researcher observation, because multiple data sets could be collected at once (Lewis et al, 2005; Marelli, 2007).

Variations on a routine : how selection-adaptation-retention dynamics create variety in organisational routines

The question "what causes variety in organisational routines" is of considerable interest to organisational scholars, and one to which this thesis seeks to answer. To this end an evolutionary theory of change is advanced which holds that the dynamics of selection, adaptation and retention explain the creation of variety in organisational routines. A longitudinal, multi-level, multi-case analysis is undertaken in this thesis, using multiple data collection strategies. In each case, different types of variety were identified, according to a typology, together with how selection, adaptation and retention contribute to variety in a positive or negative sense. Methodologically, the thesis makes a contribution to our understanding of variety, as certain types of variety only become evident when examined by specific types of research design. The research also makes a theoretical contribution by explaining how selection, adaptation and retention individually and collectively contribute to variety in organisational routines. Moreover, showing that routines could be stable, diverse, adaptive and dynamic at the same time; is a significant, and novel, theoretical contribution.

Strategizing public sector human resource management : the implications of working network

Networks have come to the fore as a means by which government can achieve its strategic objectives, particularly when addressing complex or “wicked” issues. Such joined-up arrangements differ in their operations from other forms of organizing as they require collaborative effort to deliver the collaborative advantage. Strategic Human Resource Management is concerned with the matching of human resource practices to the strategic direction of organizations. It is argued that the strategic direction of government has been towards network involvement and that, as a result, a reconfiguration of Human Resource Management practices is needed to support this new direction. Drawing on eight network case studies findings are presented in relation to the roles government is expected to play in networks and conclusions are drawn about what types of human resource management practices would best support those roles. Implications for Strategic Human Resource Management are posited.

The applicability of aesthetic knowledge in organizational decision making processes

We argue that aesthetic knowledge, which is a form of tacit knowledge of beauty and related concepts, is an important, yet under-researched, topic in the study of organizational decision making processes. The significance of aesthetic knowledge for decision making processes is derived from its universal application by humans to commonplace practices; its use as the basis of decision criteria in complex situations to which the effective application of logic and reason is difficult; and its role both in assisting cognition in general and in enabling the choice of solutions generated from rational decision making processes. Despite its importance, the empirical research examining the application of aesthetic knowledge in organizational decision making processes is limited. Further detailed study of aesthetic knowledge in the context of organizational decision making processes is required to extend the recent movement in the field aimed at examining the role that extrarational, human-centered factors play in organizational decisions.