Targeting histone deacetylases for the treatment of immune, endocrine and metabolic disorders

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The proinflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment. © 2009 Bentham Science Publishers Ltd.

Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer : potential targets for chemoprevention and systemic therapy

The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1β, Tumour Necrosis Factor (TNF)-α and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

The Enamovirus P0 protein is a silencing suppressor which inhibits local and systemic RNA silencing through AGO1 degradation

The P0 protein of poleroviruses and P1 protein of sobemoviruses suppress the plant's RNA silencing machinery. Here we identified a silencing suppressor protein (SSP), P0PE, in the Enamovirus Pea enation mosaic virus-1 (PEMV-1) and showed that it and the P0s of poleroviruses Potato leaf roll virus and Cereal yellow dwarf virus have strong local and systemic SSP activity, while the P1 of Sobemovirus Southern bean mosaic virus supresses systemic silencing. The nuclear localized P0PE has no discernable sequence conservation with known SSPs, but proved to be a strong suppressor of local silencing and a moderate suppressor of systemic silencing. Like the P0s from poleroviruses, P0PE destabilizes AGO1 and this action is mediated by an F-box-like domain. Therefore, despite the lack of any sequence similarity, the poleroviral and enamoviral SSPs have a conserved mode of action upon the RNA silencing machinery. © 2012 Elsevier Inc.

A systemic view of innovation adoption in the Australian beef industry

Significant investments in developing technological innovations have been made in the Australian beef industry but with low adoption rates. By modelling the key variables and their interactions in the innovation adoption process, this research seeks to demonstrate the complexity and dynamics of the process. This research uses causal loop modelling and develops a holistic model of the current innovation adoption system in the Australian beef industry to show the complexity of dynamic interactions among multiple variables. It is suggested that innovation adoption is such an extremely complex issue, and we need to shift our views on this issue from a paradigm of linear thinking to systems thinking. Innovation adoption is more likely to be enhanced based on a full understanding of the complexity and dynamics of the system as a whole. The paper demonstrates to practitioners and developers of innovation the multiple variables and interactions impacting innovation adoption.

An overview of Australian intrans*igence : a systemic Pandora’s Box

Despite the fact that Australia is a socially progressive country and boasts one of the largest Gender Dysphoria Clinics in the Southern Hemisphere, delivering services for almost four decades, Australian Governments fail to arrive at any consensus on the legal and human rights approaches to Trans*people. The subsequent lack of recognition does little more than increase the levels of frustration of and the continued discrimination to Trans*people, including adverse mental health problems, in this country. The purpose of this presentation is to provide an overview of the Australian systems that govern Trans*people and to identify how Trans*identities are manipulated in our Federal system of government; a system which offers little to protect the human rights of Trans*people. In order to contextualise the Australian situation, I commence with a brief description on the layers of government which will include how Australian Trans*people are currently protected under the law in those jurisdictions. I then present some of the impracticalities endured by the transitioning individual (single or married) including change of documentation and legal gender status before, during and after surgical transition for both those born on and off shore. This presentation will also include discussion of legislation that has been described by Trans*advocates as “Gesture”, “Cart before the Horse” and “Harmful”. I will conclude with a way forward by suggesting the development of a coordinated all of government approach in consultation with key stakeholders for “Trans* Friendly Legislation” to improve the human and legal rights, and ultimately the health and wellbeing of Australian Trans*identities.

Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas

Background: The present study aimed to evaluate the antitumor effectiveness of systemic interleukin (IL)-12 gene therapy in murine sarcoma models, and to evaluate its interaction with the irradiation of tumors and metastases. To avoid toxic side-effects of IL-12 gene therapy, the objective was to achieve the controlled release of IL-12 after intramuscular gene electrotransfer. Methods: Gene electrotransfer of the plasmid pORF-mIL12 was performed into the tibialis cranialis in A/J and C57BL/6 mice. Systemic release of the IL-12 was monitored in the serum of mice after carrying out two sets of intramuscular IL-12 gene electrotransfer of two different doses of plasmid DNA. The antitumor effectiveness of IL-12 gene electrotransfer alone or in combination with local tumor or lung irradiation with X-rays, was evaluated on subcutaneous SA-1 and LPB tumors, as well as on lung metastases. Results: A synergistic antitumor effect of intramuscular gene electrotransfer combined with local tumor irradiation was observed as a result of the systemic distribution of IL-12. The gene electrotransfer resulted in up to 28% of complete responses of tumors. In combination with local tumor irradiation, the curability was increased by up to 100%. The same effect was observed for lung metastases, where a potentiating factor of 1.3-fold was determined. The amount of circulating IL-12 was controlled by the number of repeats of gene electrotransfer and by the amount of the injected plasmid. Conclusions: The present study demonstrates the feasibility of treatment by IL-12 gene electrotransfer combined with local tumor or lung metastases irradiation on sarcoma tumors for translation into the clinical setting. Copyright © 2009 John Wiley & Sons, Ltd.

Targeted disruption of the JAK2/STAT3 pathway in combination with systemic administration of paclitaxel inhibits the priming of ovarian cancer stem cells leading to a reduced tumor burden

Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo,we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients.

Using the Event Analysis of Systemic Teamwork (EAST) to explore conflict between different road user groups when making right hand turns at urban intersections

Collisions between different types of road users at intersections form a substantial component of the road toll. This paper presents an analysis of driver, cyclist, motorcyclist and pedestrian behaviour at intersections that involved the application of an integrated suite of ergonomics methods, the Event Analysis of Systemic Teamwork (EAST) framework, to on-road study data. EAST was used to analyse behaviour at three intersections using data derived from an on-road study of driver, cyclist, motorcyclist and pedestrian behaviour. The analysis shows the differences in behaviour and cognition across the different road user groups and pinpoints instances where this may be creating conflicts between different road users. The role of intersection design in creating these differences in behaviour and resulting conflicts is discussed. It is concluded that currently intersections are not designed in a way that supports behaviour across the four forms of road user studied. Interventions designed to improve intersection safety are discussed.

Understanding declining science participation in Australia : a systemic perspective

In this chapter we describe the substantial declines in student participation in senior high school physics, chemistry and biology classes in Australia over the last two decades. We outline some of the explanations commonly offered to account for these declines, focusing on two contrasting positions: first, that they are due to today’s students holding less positive attitudes towards science classes and careers than their predecessors, and second, that the declines are related to policy and structural changes at the upper secondary and tertiary education levels which have affected the relative status of subjects and the dynamics of choice. We describe how the Choosing Science study investigated the extent to which the two hypotheses were supported by empirical evidence, and discuss our findings in the light of a third result from the study concerning the role of self-identity in subject choice. We conclude that the declines in high school science enrolments are most likely related to changes in school and university curriculum options and that within this expanded curriculum marketplace, identity becomes a very important reference point in students’ decisions about whether to take science in the final years of high school.

A biomarker panel to discriminate between systemic inflammatory response syndrome and sepsis and sepsis severity

Introduction: In this study, we report on initial efforts to discover putative biomarkers for differential diagnosis of a systemic inflammatory response syndrome (SIRS) versus sepsis; and different stages of sepsis. In addition, we also investigated whether there are proteins that can discriminate between patients who survived sepsis from those who did not. Materials and Methods: Our study group consisted of 16 patients, of which 6 died and 10 survived. We daily measured 28 plasma proteins, for the whole stay of the patients in the ICU. Results: We observed that metalloproteinases and sE-selectin play a role in the distinction between SIRS and sepsis, and that IL-1, IP-10, sTNF-R2 and sFas appear to be indicative for the progression from sepsis to septic shock. A combined measurement of MMP-3, -10, IL-1, IP-10, sIL-2R, sFas, sTNF-R1, sRAGE, GM-CSF, IL-1 and Eotaxin allows for a good separation of patients that survived from those that died (mortality prediction with a sensitivity of 79% and specificity of 86%). Correlation analysis suggests a novel interaction between IL-1a and IP-10. Conclusion: The marker panel is ready to be verified in a validation study with or without therapeutic intervention.

Proceedings of the Digital Cities 9 Workshop - Hackable Cities – From Subversive City Making to Systemic Change (Workshop) [Edited Proceedings]

The DC9 workshop takes place on June 27, 2015 in Limerick, Ireland and is titled “Hackable Cities: From Subversive City Making to Systemic Change”. The notion of “hacking” originates from the world of media technologies but is increasingly often being used for creative ideals and practices of city making. “City hacking” evokes more participatory, inclusive, decentralized, playful and subversive alternatives to often top-down ICT implementations in smart city making. However, these discourses about “hacking the city” are used ambiguously and are loaded with various ideological presumptions, which makes the term also problematic. For some “urban hacking” is about empowering citizens to organize around communal issues and perform aesthetic urban interventions. For others it raises questions about governance: what kind of “city hacks” should be encouraged or not, and who decides? Can city hacking be curated? For yet others, trendy participatory buzzwords like these are masquerades for deeply libertarian neoliberal values. Furthermore, a question is how “city hacking” may mature from the tactical level of smart and often playful interventions to the strategic level of enduring impact. The Digital Cities 9 workshop welcomes papers that explore the idea of “hackable city making” in constructive and critical ways.

Measuring industry clockspeed in the systemic industry context

Industry clockspeed has been used in earlier literature to assess the rate of change of industries but this measure remains limited in its application in longitudinal analyses as well as in systemic industry contexts. Nevertheless, there is a growing need for such a measure as business ecosystems replace standalone products and organisations are required to manage their innovation process in increasingly systemic contexts. In this paper, we firstly derive a temporal measure of technological industry clockspeed, which evaluates the time between successively higher levels of performance in the industry's product technology, over time. We secondly derive a systemic technological industry clockspeed for systemic industry contexts, which measures the time required for a particular sub-industry to utilise the level of technological performance that is provisioned by another, interdependent sub-industry. In turn, we illustrate the use of these measures in an empirical study of the systemic personal computer industry. The results of our empirical illustration show that the proposed clockspeeds together provide informative measures of the pace of change for sub-industries and systemic industry. We subsequently discuss the organisational considerations and theoretical implications of the proposed measures.

Adoption dynamics of increasing-return technologies in systemic contexts

Many systemic, complex technologies have been suggested to exhibit increasing returns to adoption, whereby the initial increase in adoption leads to increasing experience with the technology, which drives technological improvements and use, subsequently leading to further adoption. In addition, in the systemic context, mimetic behavior may lend support to increasing returns as technology adoption is witnessed among other agents in the systemic context. Finally, inter-dependencies in the systemic context also sensitize the adoption behavior to fundamental changes in technology provisioning, and this may lend support for the increasing returns type of dynamics in adoption. Our empirical study examines the dynamics of organizational technology adoption when technology is provisioned by organizations in another sub-system in a systemic context. We hypothesize that innovation, imitation, and technological change effects are present in creating increasing returns in the systemic context. Our empirical setting considers 24 technologies represented by 2282 data points in the computer industry. Our results provide support for our prediction that imitation effects are present in creating increasing returns to adoption. We further discuss the managerial and research implications of our results.

Systemic ideation: A playbook for creating innovative ideas more consciously

When looking for innovative ideas, we all wish we were Larry Page or Mark Zuckerberg with the “next big thingˮ. However, not all companies have geniuses like them, nor do they need them. What is needed is a systemic approach for consciously developing ideas.