The role of DNA repair pathways in cisplatin resistant lung cancer

Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.

Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer

Background The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. Methods NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Results Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Conclusions Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.

A longitudinal study of employee adaptation to organizational change: The role of change-related information and change-related self-efficacy

This study examined the role of information, efficacy, and 3 stressors in predicting adjustment to organizational change. Participants were 589 government employees undergoing an 18-month process of regionalization. To examine if the predictor variables had long-term effects on adjustment, the authors assessed psychological well-being, client engagement, and job satisfaction again at a 2-year follow-up. At Time 1, there was evidence to suggest that information was indirectly related to psychological well-being, client engagement, and job satisfaction, via its positive relationship to efficacy. There also was evidence to suggest that efficacy was related to reduced stress appraisals, thereby heightening client engagement. Last, there was consistent support for the stress-buffering role of Time 1 self-efficacy in the prediction of Time 2 job satisfaction.

Responses to an in-basket activity: The role of work stress, behavioral control, and informational control

This study was undertaken to examine the main and interactive effects of work stress and work control on levels of adjustment. Work stress, behavioral control, and informational control were manipulated in an experimental setting in which participants (N = 192) completed an in-basket activity. Although minimal support was found for the main and interactive effects of objective work stress, behavioral control, and informational control on adjustment, analyses involving the subjective measures of these variables revealed strong support for the proposal that work stress, behavioral control, and informational control would exert main effects on adjustment. There was also evidence that subjective levels of behavioral control buffered the negative effects of subjective work stress on positive mood, subjective task performance, and task satisfaction.

A stress and coping approach to organisational change: Evidence from three field studies

In this paper, a stress and coping perspective is used to outline the processes that determine employee adaptation to organisational change. A theoretical framework that simultaneously considers the effects of event characteristics, situational appraisals, coping strategies, and coping resources is reviewed. Three empirical investigations of organisational change that have tested various components of the model are then presented. In the first study, there was evidence linking event characteristics, situational appraisals, coping strategies and coping resources to levels of employee adjustment in a sample of pilots employed in a newly merged airline company. In a more focused test of the model with a sample of employees experiencing a restructuring process in their organisation it was found that the provision of change-related information enhanced levels of efficacy to deal with the change process which, in turn, predicted psychological wellbeing, client engagement, and job satisfaction. In a study of managers affected by a new remuneration scheme, there was evidence to suggest that managers who received change-specific information and opportunities to participate in the change process reported higher levels of change readiness. Managers who reported higher levels of readiness for change also reported higher levels of psychological wellbeing and job satisfaction. These studies highlight ways in which managers and change agents can help employees to cope during times of organisational change.

The moderating role of task characteristics in determining responses to a stressful work simulation

Two experimental studies were conducted to examine whether the stress-buffering effects of behavioral control on work task responses varied as a function of procedural information. Study 1 manipulated low and high levels of task demands, behavioral control, and procedural information for 128 introductory psychology students completing an in-basket activity. ANOVA procedures revealed a significant three-way interaction among these variables in the prediction of subjective task performance and task satisfaction. It was found that procedural information buffered the negative effects of task demands on ratings of performance and satisfaction only under conditions of low behavioral control. This pattern of results suggests that procedural information may have a compensatory effect when the work environment is characterized by a combination of high task demands and low behavioral control. Study 2 (N=256) utilized simple and complex versions of the in-basket activity to examine the extent to which the interactive relationship among task demands, behavioral control, and procedural information varied as a function of task complexity. There was further support for the stress-buffering role of procedural information on work task responses under conditions of low behavioral control. This effect was, however, only present when the in-basket activity was characterized by high task complexity, suggesting that the interactive relationship among these variables may depend on the type of tasks performed at work.

An experimental study of the effects of work stress, work control, and task information on adjustment

The present study was designed to examine the main and interactive effects of task demands, work control, and task information on levels of adjustment. Task demands, work control, and task information were manipulated in an experimental setting where participants completed a letter-sorting activity (N= 128). Indicators of adjustment included measures of positive mood, participants' perceptions of task performance, and task satisfaction. Results of the present study provided some support for the main effects of objective task demands, work control, and task information on levels of adjustment. At the subjective level of analysis, there was some evidence to suggest that work control and task information interacted in their effects on levels of adjustment. There was minimal support for the proposal that work control and task information would buffer the negative effects of task demands on adjustment. There was, however, some evidence to suggest that the stress-buffering role of subjective work control was more marked at high, rather than low, levels of subjective task information.

The effects of prediction, understanding, and control: A test of the stress antidote model

A study was undertaken to examine further the effects of perceived work control on employee adjustment. On the basis of the stress antidote model, it was proposed that high levels of prediction, understanding, and control of work-related events would have direct, indirect, and interactive effects on levels of employee adjustment. These hypotheses were tested in a short-term longitudinal study of 137 employees of a large retail organization. The stress antidote measures appeared to be indirectly related to employee adjustment, via their effects on perceptions of work stress. There was weak evidence for the proposal that prediction, understanding, and control would buffer the negative effects of work stress. Additional analyses indicated that the observed effects of prediction, understanding, and control were independent of employees' generalized control beliefs. However, there was no support for the proposal that the effects of the stress antidote measures would be dependent on employees' generalized control beliefs.

A longitudinal investigation of coping processes during a merger: Implications for job satisfaction and organizational identification

This study tested the utility of a stress and coping model of employee adjustment to a merger. Two hundred and twenty employees completed both questionnaires (Time 1: 3 months after merger implementation; Time 2: 2 years later). Structural equation modeling analyses revealed that positive event characteristics predicted greater appraisals of self-efficacy and less stress at Time 1. Self-efficacy, in turn, predicted greater use of problem-focused coping at Time 2, whereas stress predicted a greater use of problem-focused and avoidance coping. Finally, problem-focused coping predicted higher levels of job satisfaction and identification with the merged organization (Time 2), whereas avoidance coping predicted lower identification.

Copyright and creativity: An ongoing debate in the creative industries

This paper critically analyzes the divergent perspectives on how copyright and intellectual property laws impact creativity, innovation, and the creative industries. One perspective defines the creative industries based on copyright as the means by which revenues are generated from innovation and the dissemination of new ideas. At the same time, it has been argued that copyright and intellectual property regimes fetter creativity and innovation, and that this has become even more marked in the context of digital media convergence and the networked global creative economy. These issues have resonated in debates around the creative industries, particularly since the initial DCMS mapping study in the UK in 1998 defined creative industries as combining individual creativity and exploitable forms of intellectual property. The issue of competing claims for the relationship between copyright and the creative industries has also arisen in Australia, with a report by the Australian Law Reform Commission entitled Copyright and the Digital Economy. This paper will consider the competing claims surrounding copyright and the creative industries, and the implications for policy-makers internationally.

Patterned fen formation and development from the Great Sandy Region, south-east Queensland, Australia

The Great Sandy Region (incorporating Fraser Island and the Cooloola sand-mass), south-east Queensland, contains a significant area of Ramsar-listed coastal wetlands, including the globally important patterned fen complexes. These mires form an elaborate network of pools surrounded by vegetated peat ridges and are the only known subtropical, Southern Hemisphere examples, with wetlands of this type typically located in high northern latitudes. Sedimentological, palynological and charcoal analysis from the Wathumba and Moon Point complexes on Fraser Island indicate two periods of swamp formation (that may contain patterned fens), one commencing at 12 000 years ago (Moon Point) and the other ~4300 years ago (Wathumba). Wetland formation and development is thought to be related to a combination of biological and hydrological processes with the dominant peat-forming rush, Empodisma minus, being an important component of both patterned and non-patterned mires within the region. In contrast to Northern Hemisphere paludifying systems, the patterning appears to initiate at the start of wetland development or as part of an infilling process. The wetlands dominated by E. minus are highly resilient to disturbance, particularly burning and sea level alterations, and appear to form important refuge areas for amphibians, fish and birds (both non-migratory and migratory) over thousands of years.

Access to essential medicines: Public health and international law

Historically, there have been intense conflicts over the ownership and exploitation of pharmaceutical drugs and diagnostic tests dealing with infectious diseases. Throughout the 1980’s, there was much scientific, legal, and ethical debate about which scientific group should be credited with the discovery of the human immunodeficiency virus, and the invention of the blood test devised to detect antibodies to the virus. In May 1983, Luc Montagnier, Françoise Barré-Sinoussi, and other French scientists from the Pasteur Institute in Paris, published a paper in Science, detailing the discovery of a virus called lymphadenopathy (LAV). A scientific rival, Robert Gallo of the National Cancer Institute, identified the AIDS virus and published his findings in the May 1984 issue of Science. In May 1985, the United States Patent and Trademark Office awarded the American patent for the AIDS blood test to Gallo and the Department of Health and Human Services. In December 1985, the Institut Pasteur sued the Department of Health and Human Services, contending that the French were the first to identify the AIDS virus and to invent the antibody test, and that the American test was dependent upon the French research. In March 1987, an agreement was brokered by President Ronald Reagan and French Prime Minister Jacques Chirac, which resulted in the Department of Health and Human Services and the Institut Pasteur sharing the patent rights to the blood test for AIDS. In 1992, the Federal Office of Research Integrity found that Gallo had committed scientific misconduct, by falsely reporting facts in his 1984 scientific paper. A subsequent investigation by the National Institutes of Health, the United States Congress, and the US attorney-general cleared Gallo of any wrongdoing. In 1994, the United States government and French government renegotiated their agreement regarding the AIDS blood test patent, in order to make the distribution of royalties more equitable... The dispute between Luc Montagnier and Robert Gallo was not an isolated case of scientific rivalry and patent races. It foreshadowed further patent conflicts over research in respect of HIV/AIDS. Michael Kirby, former Justice of the High Court of Australia diagnosed a clash between two distinct schools of philosophy - ‘scientists of the old school... working by serendipity with free sharing of knowledge and research’, and ‘those of the new school who saw the hope of progress as lying in huge investments in scientific experimentation.’ Indeed, the patent race between Robert Gallo and Luc Montagnier has been a precursor to broader trade disputes over access to essential medicines in the 1990s and 2000s. The dispute between Robert Gallo and Luc Montagnier captures in microcosm a number of themes of this book: the fierce competition for intellectual property rights; the clash between sovereign states over access to medicines; the pressing need to defend human rights, particularly the right to health; and the need for new incentives for research and development to combat infectious diseases as both an international and domestic issue.

Welcome to Media Industries

An introduction to the journal, its goals, mission, and vision.