Targeting histone deacetylases for the treatment of disease : Epigenetics Review Series

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' recognized 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 that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Oxidative stress induced lung cancer and COPD : opportunities for epigenetic therapy

Reactive oxygen species (ROS) form as a natural by-product of the normal metabolism of oxygen and play important roles within the cell. Under normal circumstances the cell is able to maintain an adequate homeostasis between the formation of ROS and its removal through particular enzymatic pathways or via antioxidants. If however, this balance is disturbed a situation called oxidative stress occurs. Critically, oxidative stress plays important roles in the pathogenesis of many diseases, including cancer. Epigenetics is a process where gene expression is regulated by heritable mechanisms that do not cause any direct changes to the DNA sequence itself, and disruption of epigenetic mechanisms has important implications in disease. Evidence is emerging that histone deacetylases (HDACs) play decisive roles in regulating important cellular oxidative stress pathways including those involved with sensing oxidative stress and those involved with regulating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by HDACs may play critical roles in cancer progression. In this review we discuss the current evidence linking epigenetics and oxidative stress and cancer, using chronic obstructive pulmonary disease and non-small cell lung cancer to illustrate the importance of epigenetics on these pathways within these disease settings. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

A critical realist perspective of enterprise architecture evolution : preliminary findings

This paper investigates how Enterprise Architecture (EA) evolves due to emerging trends. It specifically explores how EA integrates the Service-oriented Architecture (SOA). Archer’s Morphogenetic theory is used as an analytical approach to distinguish the architectural conditions under which SOA is introduced, to study the relationships between these conditions and SOA introduction, and to reflect on EA evolution (elaborations) that then take place. The paper focuses on reasons for why EA evolution could take place, or not and what architectural changes could happen due to SOA integration. The research builds on sound theoretical foundations to discuss EA evolution in a field that often lacks a solid theoretical groundwork. Specifically, it proposes that critical realism, using the morphogenetic theory, can provide a useful theoretical foundation to study enterprise architecture (EA) evolution. The initial results of a literature review (a-priori model) were extended using explorative interviews. The findings of this study are threefold. First, there are five different levels of EA-SOA integration outcomes. Second, a mature EA, flexible and well-defined EA framework and comprehensive objectives of EA improve the integration outcomes. Third, the analytical separation using Archer’s theory is helpful in order to understand how these different integration outcomes are generated.

Service-oriented architecture integration within enterprise architecture : a-priori model

This paper proposes that critical realism can provide a useful theoretical foundation to study enterprise architecture (EA) evolution. Specifically it will investigate the practically relevant and academically challenging question of how EAs integrate the Service-oriented Architecture (SOA). Archer’s Morphogenetic theory is used as an analytical approach to distinguish the architectural conditions under which SOA is introduced, to study the relationships between these conditions and SOA introduction, and to reflect on EA evolution (elaborations) that then take place. The focus lies on the reasons why EA evolution takes place (or not) and what architectural changes happen. This paper uses the findings of a literature review to build an a-priori model informed by Archer’s theory to understand EA evolution in a field that often lacks a solid theoretical groundwork. The findings are threefold. First, EA can evolve on different levels (different integration outcomes). Second, the integration outcomes are classified into three levels: business architecture, information systems architecture and technology architecture. Third, the analytical separation using Archer’s theory is helpful in order to understand how these different integration outcomes are generated.

Acknowledging, moving toward and transcending psychophysiological angst during a paradox of conflicting desires

In this paper I integrate the work of a number of philosophers to clarify some psychological issues that can arise in human existence when a conflict of intrapersonal or interpersonal desires arises. This paper utilises the work of Deleuze, Freud, Jung, Heidegger, Hegel and Nietzsche to provide a conceptual framework as to how mental disturbances can arise if unconscious desires cannot be satisfied due to the experience of a resistance from a conflicting or opposing desire. This paper argues that the phenomenal experience of a conflict of desires can be unconcealed in moments of un-readiness-to-hand and from the awareness of the psychophysiological experience of stress or angst. The work that is presented, results in the conclusion that it is fundamentally necessary to embrace Nietzsche’s idea of the ‘will to power’ to overcome these difficulties and to achieve personal individuation and authentic wellbeing. This advice is in contrast to an inauthentic choice of depending on the use of Freudian defence mechanisms to conceal a conflict of desires from consciousness. A detailed theoretical example of the process involved in the resolution of a conflict of desires through self-transcendence is specifically informed by the ideas of Nietzsche and Jung.

Investigating the association between sun exposure and folate degradation in the human body

This thesis is the first study to investigate the associations between sun exposure and folate degradation in a group of childbearing age women in a high UV environment. It examined whether the degree of sun exposure experienced by women influenced blood folate levels following a period of folic acid supplementation and found a strong significant relationship between increased sun exposure and folate degradation. This relationship has strong implications for public health and the thesis has provided a foundation for further research in this area.

Playing with Grammar in the Early Years : Learning about Language in the Australian Curriculum : English

As teacher/researchers interested in the pursuit of socially-just outcomes in early childhood education, the form and function of language occupies a special position in our work. We believe that mastering a range of literacy competences includes not only the technical skills for learning, but also the resources for viewing and constructing the world (Freire and Macdeo, 1987). Rather than seeing knowledge about language as the accumulation of technical skills alone, the viewpoint to which we subscribe treats knowledge about language as a dialectic that evolves from, is situated in, and contributes to a social arena (Halliday, 1978). We do not shy away from this position just because children are in the early years of schooling. In ‘Playing with Grammar’, we focus on the Foundation to Year 2 grouping, in line with the Australian Curriculum, Assessment and Reporting Authority’s (hereafter ACARA) advice on the ‘nature of learners’ (ACARA, 2013). With our focus on the early years of schooling comes our acknowledgement of the importance and complexity of play. At a time where accountability in education has moved many teachers to a sense of urgency to prove language and literacy achievement (Genishi and Dyson, 2009), we encourage space to revisit what we know about literature choices and learning experiences and bring these together to facilitate language learning. We can neither ignore, nor overemphasise, the importance of play for the development of language through: the opportunities presented for creative use and practice; social interactions for real purposes; and, identifying and solving problems in the lives of young children (Marsh and Hallet, 2008). We argue that by engaging young children in opportunities to play with language we are ultimately empowering them to be active in their language learning and in the process fostering a love of language and the intricacies it holds. Our goal in this publication is to provide a range of highly practical strategies for scaffolding young children through some of the Content Descriptions from the Australian Curriculum English Version 5.0, hereafter AC:E V5.0 (ACARA, 2013). This recently released curriculum offers a new theoretical approach to building children’s knowledge about language. The AC:E V5.0 uses selected traditional terms through an approach developed in systemic functional linguistics (see Halliday and Matthiessen, 2004) to highlight the dynamic forms and functions of multimodal language in texts. For example, the following statement, taken from the ‘Language: Knowing about the English language’ strand states: English uses standard grammatical terminology within a contextual framework, in which language choices are seen to vary according to the topics at hand, the nature and proximity of the relationships between the language users, and the modalities or channels of communication available (ACARA, 2013). Put simply, traditional grammar terms are used within a functional framework made up of field, tenor, and mode. An understanding of genre is noted with the reference to a ‘contextual framework’. The ‘topics at hand’ concern the field or subject matter of the text. The ‘relationships between the language users’ is a description of tenor. There is reference to ‘modalities’, such as spoken, written or visual text. We posit that this innovative approach is necessary for working with contemporary multimodal and cross-cultural texts (see Exley and Mills, 2012). We believe there is enormous power in using literature to expose children to the richness of language and in turn develop language and literacy skills. Taking time to look at language patterns within actual literature is a pathway to ‘…capture interest, stir the imagination and absorb the [child]’ into the world of language and literacy (Saxby, 1993, p. 55). In the following three sections, we have tried to remain faithful to our interpretation of the AC:E V5.0 Content Descriptions without giving an exhaustive explanation of the grammatical terms. Other excellent tomes, such as Derewianka (2011), Humphrey, Droga and Feez (2012), and Rossbridge and Rushton (2011) provide these more comprehensive explanations as does the AC:E V5.0 Glossary. We’ve reproduced some of the AC:E V5.0 glossary at the end of this publication. Our focus is on the structure and unfolding of the learning experiences. We outline strategies for working with children in Foundation, Year 1 and Year 2 by providing some demonstration learning experiences based on texts we’ve selected, but maintain that the affordances of these strategies will only be realised when teaching and learning is purposively tied to authentic projects in local contexts. We strongly encourage you not to use only the resource texts we’ve selected, but to capitalise upon your skill for identifying the language features in the texts you and the children are studying and adapt some of the strategies we have outlined. Each learning experience is connected to one of the Content Descriptions from the AC:E V5.0 and contains an experience specific purpose, a suggested resource text and a sequence for the experience that always commences with an orientation to text followed by an examination of a particular grammatical resource. We expect that each of these learning experiences will take a couple if not a few teaching episodes to work through, especially if children are meeting a concept for the first time. We hope you use as much, or as little, of each experience as is needed. Our plans allow for focused discussion, shared exploration and opportunities to revisit the same text for the purpose of enhancing meaning making. We do not want the teaching of grammar to slip into a crisis of irrelevance or to be seen as a series of worksheet drills with finite answers. Strategies for effective practice, however, have much portability. We are both very keen to hear from teachers who are adopting and adapting these learning experiences in their classrooms. Please email us on b.exley@qut.edu.au or lkervin@uow.edu.au. We’d love to continue the conversation with you over time.

The bioeconomics of nutritional poverty and child labour

This paper provides a bio-economic foundation of fertility and child labor. Drawing on the clinical and physiological literature, the model highlights the interaction between work efforts of adults and children, their subsistence consumption, and fertility. The subsistence consumption requirements are endogenous to physical efforts. Parents engaged in physically demanding occupations (e.g. non-mechanized agriculture) are likely to suffer from energy deficiency, leading to reduced future work-capacity. Consumption smoothing occurs through bearing a large number of children who provide income support as adults. Although net cost of an additional child is positive, the cost is balanced by the additional income accruing though child employment. In contrast, parents in low-physical effort occupations are less likely to su¤er from nutritional deficiency, and thus tend to have lower fertility and child labor.

Exploring influencing factors of short-lived buildings in China's urban renewal : evidence from Chongqing

With the fast development of urban sprawl and renewal in China, many buildings are “non-nature” short-lived, i.e. demolished after only a few years. For this concern, this research explores the influencing factors of short-lived buildings and provides the scientific foundation for sustainable urban management and planning. Cases for this research are 1734 buildings demolished in Jiangbei district, the middle region of Chongqing City. Internal and external factors for the short-lived buildings are identified by applying logistic analysis. The results indicate that nine factors have significant influence on short-lived buildings. This research also find that buildings with low density, utilization and compensation while high land development potential are more likely to become short-lived buildings.

Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma : clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study

Background The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study. Methods MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524. Findings Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92-3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21-6·26; p=0·016). Median survival was 14·4 months (5·3-18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group. Interpretation In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients. Funding Cancer Research UK (CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust. © 2011 Elsevier Ltd.