IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.

Perspectives on research in project management : the nine schools

This paper demonstrates that project management is a developing field of academic study in management, of considerable diversity and richness, which can make a valuable contribution to the development of management knowledge, as well as being of considerable economic importance. The paper reviews the substantial progress and trends of research in the subject, which has been grouped into nine major schools of thought: optimization, modelling, governance, behaviour, success, decision, process, contingency, and marketing. The paper addresses interactions between the different schools and with other related management fields, and provides insights into current and potential research in each and across these schools.

Engaging paramedic students in research: A case report

The use of volunteer undergraduate students to support simulated training for peers is common in Paramedic Science. However, there are limited examples of engaging paramedic student-volunteers in research as compared to that reported in cognate disciplines such as Medicine and Nursing. This case report shares our experience with engaging a penultimate year paramedic student in evaluation research. This information we hope will start the dialogue on the epistemology and pedagogies for effective engagement of undergraduate paramedic students as future researchers.

Cataract surgery in eyes with low corneal astigmatism : implantation of the AcrySof IQ Toric SN6AT2 intraocular lens

Purpose The aim of this study is to assess the refractive and visual outcomes following cataract surgery and implantation of the AcrySof IQ Toric SN6AT2 intraolcular lens (IOL) (Alcon Laboratories, Inc) in patients with low corneal astigmatism. Materials and Methods A retrospective, consecutive, single surgeon series of ninety-eight eyes of 88 patients following cataract surgery and implantation of the AcrySof IQ Toric SN6AT2 IOL in eyes with low preoperative corneal astigmatism. Postoperative measurements were obtained at one month post surgery. Main outcome measures were monocular distance visual acuity and residual refractive astigmatism. Results The mean preoperative corneal astigmatic power vector (APV) was 0.38 ± 0.09 D. Following surgery and implantation of the toric IOL, mean postoperative refractive APV was 0.13 ± 0.10 D. Mean postoperative distance uncorrected visual acuity (UCVA) was 0.08 ± 0.09 logMAR. Postoperative spherical equivalent refraction (SER) resulted in a mean of - 0.23 ± 0.22 D, with 96% of eyes falling within 0.50 D of the target SER. Conclusions The AcrySof IQ Toric SN6AT2 IOL is a safe and effective option for eyes undergoing cataract surgery with low amounts of preoperative corneal astigmatism.

The creativity imperative : implications for education research

Arguing for the importance of understanding the conditions under which certain forms of the social subject become visible and viable, this chapter conceptualises the current educational focus on ‘creativity’ as a technology of governmentality that has arisen from the perceived need for governing authorities to manage and responsibilise populations for the pervasive uncertainties of the global economy. With reference to the document, Tough Choices or Tough Times, a publication of the National Center on Education and the Economy in the United States, we show how creativity has been reframed as a programmable capacity of the modern student, citizen and worker primarily because it is considered an indispensible source of enterprise and innovation. Education and family life are an integral part of this bio-politics and the ongoing ‘economisation’ of social life. Our concern is that this reductionist understanding of creativity precludes other transgressive and culturally enriching creativities that represent the infinite range of subjectivities associated with imaginative human capacity and activity. It is vital therefore that educational research renders this historical process transparent and opens spaces for more socially inclusive, sustainable and productive ways of being such as those indicated by the three respondees.

Literacy in the Middle Years : Learning from Collaborative Classroom Research

Literacy in the Middle Years: Learning from Collaborative Classroom Research, showcases teachers' innovative literacy work across the curriculum. Classroom practice, teacher thinking and collaborative research are highlighted in ways of working with new curricula and rapidly changing literacy modes and platforms. Connections with place, critical engagement with digital literacies, using polymedia with EAL/D learners, and subject-specific literacies are detailed in teachers' stories of practice. Teacher wellbeing, for a sustainable workforce, underpins the case studies, aimed at equipping 'change ready' teachers with positive examples of literacy approaches and inquiry in practice.

Can ginger ameliorate chemotherapy-induced nausea? Protocol of a randomized double blind, placebo-controlled trial

Background Preliminary research shows ginger may be an effective adjuvant treatment for chemotherapy-induced nausea and vomiting but significant limitations need to be addressed before recommendations for clinical practice can be made. Methods/Design In a double–blinded randomised-controlled trial, chemotherapy-naïve patients will be randomly allocated to receive either 1.2 g of a standardised ginger extract or placebo per day. The study medication will be administrated as an adjuvant treatment to standard anti-emetic therapy and will be divided into four capsules per day, to be consumed approximately every 4 hours (300 mg per capsule administered q.i.d) for five days during the first three cycles of chemotherapy. Acute, delayed, and anticipatory symptoms of nausea and vomiting will be assessed over this time frame using a valid and reliable questionnaire, with nausea symptoms being the primary outcome. Quality of life, nutritional status, adverse effects, patient adherence, cancer-related fatigue, and CINV-specific prognostic factors will also be assessed. Discussion Previous trials in this area have noted limitations. These include the inconsistent use of standardized ginger formulations and valid questionnaires, lack of control for anticipatory nausea and prognostic factors that may influence individual CINV response, and the use of suboptimal dosing regimens. This trial is the first to address these issues by incorporating multiple unique additions to the study design including controlling for CINV-specific prognostic factors by recruiting only chemotherapy-naïve patients, implementing a dosing schedule consistent with the pharmacokinetics of oral ginger supplements, and independently analysing ginger supplements before and after recruitment to ensure potency. Our trial will also be the first to assess the effect of ginger supplementation on cancer-related fatigue and nutritional status. Chemotherapy-induced nausea and vomiting are distressing symptoms experienced by oncology patients; this trial will address the significant limitations within the current literature and in doing so, will investigate the effect of ginger supplementation as an adjuvant treatment in modulating nausea and vomiting symptoms. Trial registration

Numerical modelling and design of lipped channel beams subject to shear

Cold-formed steel members are increasingly used as primary structural elements in buildings due to the availability of thin and high strength steels and advanced cold-forming technologies. Cold-formed lipped channel beams (LCB) are commonly used as flexural members such as floor joists and bearers. Many research studies have been carried out to evaluate the behaviour and design of LCBs subject to pure bending actions. However, limited research has been undertaken on the shear behaviour and strength of LCBs. Hence a numerical study was undertaken to investigate the shear behaviour and strength of LCBs. Finite element models of simply supported LCBs with aspect ratios of 1.0 and 1.5 were considered under a mid-span load. They were then validated by comparing their results with test results and used in a detailed parametric study based on the validated finite element models. Numerical studies were conducted to investigate the shear buckling and post-buckling behaviour of LCBs. Experimental and numerical results showed that the current design rules in cold-formed steel structures design codes are very conservative for the shear design of LCBs. Improved design equations were therefore proposed for the shear strength of LCBs. This paper presents the details of this numerical study of LCBs and the results.

Numerical studies and design of hollow flange channel beams subject to combined bending and shear actions

LiteSteel beam (LSB) is a cold-formed steel hollow flange channel section produced using a patented manufacturing process involving simultaneous cold-forming and dual electric resistance welding. It is commonly used as floor joists and bearers in residential, industrial and commercial buildings. Design of the LSB is governed by the Australian cold-formed steel structures code, AS/NZS 4600. Due to the geometry of the LSB, as well as its unique residual stress characteristics and initial geometric imperfections resultant of manufacturing processes, currently available design equations for common cold-formed sections are not directly applicable to the LSB. Many research studies have been carried out to evaluate the behaviour and design of LSBs subject to pure bending actions and predominant shear actions. To date, however, no investigation has been conducted into the strength of LSB sections under combined bending and shear actions. Hence experimental and numerical studies were conducted to assess the combined bending and shear behaviour of LSBs. Finite element models of LSBs were developed to simulate their combined bending and shear behaviour and strength of LSBs. They were then validated by comparing the results with available experimental test results and used in a detailed parametric study. The results from experimental and finite element analyses were compared with current AS/NZS 4600 and AS 4100 design rules. Both experimental and numerical studies show that the AS/NZS 4600 design rule based on circular interaction equation is conservative in predicting the combined bending and shear capacities of LSBs. This paper presents the details of the numerical studies of LSBs and the results. In response to the inadequacies of current approaches to designing LSBs for combined bending and shear, two lower bound design equations are proposed in this paper.

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM × anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I–III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

The importance of accurate beam data measurement for SRT/SRS treatment planning

Introduction This study investigated the sensitivity of calculated stereotactic radiotherapy and radiosurgery doses to the accuracy of the beam data used by the treatment planning system. Methods Two sets of field output factors were acquired using fields smaller than approximately 1 cm2, for inclusion in beam data used by the iPlan treatment planning system (Brainlab, Feldkirchen, Germany). One set of output factors were measured using an Exradin A16 ion chamber (Standard Imaging, Middleton, USA). Although this chamber has a relatively small collecting volume (0.007 cm3), measurements made in small fields using this chamber are subject to the effects of volume averaging, electronic disequilibrium and chamber perturbations. The second, more accurate, set of measurements were obtained by applying perturbation correction factors, calculated using Monte Carlo simulations according to a method recommended by Cranmer-Sargison et al. [1] to measurements made using a 60017 unshielded electron diode (PTW, Freiburg, Germany). A series of 12 sample patient treatments were used to investigate the effects of beam data accuracy on resulting planned dose. These treatments, which involved 135 fields, were planned for delivery via static conformal arcs and 3DCRT techniques, to targets ranging from prostates (up to 8 cm across) to meningiomas (usually more than 2 cm across) to arterioveinous malformations, acoustic neuromas and brain metastases (often less than 2 cm across). Isocentre doses were calculated for all of these fields using iPlan, and the results of using the two different sets of beam data were evaluated. Results While the isocentre doses for many fields are identical (difference = 0.0 %), there is a general trend for the doses calculated using the data obtained from corrected diode measurements to exceed the doses calculated using the less-accurate Exradin ion chamber measurements (difference\0.0 %). There are several alarming outliers (circled in the Fig. 1) where doses differ by more than 3 %, in beams from sample treatments planned for volumes up to 2 cm across. Discussion and conclusions These results demonstrate that treatment planning dose calculations for SRT/SRS treatments can be substantially affected when beam data for fields smaller than approximately 1 cm2 are measured inaccurately, even when treatment volumes are up to 2 cm across.

Design of light gauge steel roofing systems subject to high wind forces

Light gauge steel roofing systems made of thin profiled roof sheeting and battens are used commonly in residential, industrial and commercial buildings. Their critical design load combination is that due to wind uplift forces that occur during high wind events such as tropical cyclones and thunderstorms. However, premature local failures at their screw connections have been a concern for many decades since cyclone Tracy that devastated Darwin in 1974. Extensive research that followed cyclone Tracy on the pull-through and pull-out failures of roof sheeting to batten connections has significantly improved the safety of roof sheeting. However, this has made the batten to rafter/truss connection the weakest, and recent wind damage investigations have shown the failures of these connections and the resulting loss of entire roof structures. Therefore an experimental research program using both small scale and full scale air-box tests is currently under way to investigate the pull-through failures of thin-walled steel battens under high wind uplift forces. Tests have demonstrated that occurrence of pull-through failures in the bottom flanges of steel batttens and the need to develop simple test and design methods as a function of many critical parameters such as steel batten geometry, thickness and grade, screw fastener sizes and other fastening details. This paper presents the details of local failures that occur in light fauge roofing systems, a review of the current design and test methods for steel battens and associated short comings, and the test results obtained to date on pull-through failures of battens from small scale and full scale tests. Finally, it proposes the use of suitable small scale test methods that can be used by both researchers and manufacturers of such screw-fastened light gauge steel batten systems.

Conducting accelerometer-based activity assessments in field-based research

Purpose The purpose of this review is to address important methodological issues related to conducting accelerometer-based assessments of physical activity in free-living individuals. Methods We review the extant scientific literature for empirical information related to the following issues: product selection, number of accelerometers needed, placement of accelerometers, epoch length, and days of monitoring required to estimate habitual physical activity. We also discuss the various options related to distributing and collecting monitors and strategies to enhance compliance with the monitoring protocol. Results No definitive evidence exists currently to indicate that one make and model of accelerometer is more valid and reliable than another. Selection of accelerometer therefore remains primarily an issue of practicality, technical support, and comparability with other studies. Studies employing multiple accelerometers to estimate energy expenditure report only marginal improvements in explanatory power. Accelerometers are best placed on hip or the lower back. Although the issue of epoch length has not been studied in adults, the use of count cut points based on 1-min time intervals maybe inappropriate in children and may result in underestimation of physical activity. Among adults, 3–5 d of monitoring is required to reliably estimate habitual physical activity. Among children and adolescents, the number of monitoring days required ranges from 4 to 9 d, making it difficult to draw a definitive conclusion for this population. Face-to-face distribution and collection of accelerometers is probably the best option in field-based research, but delivery and return by express carrier or registered mail is a viable option. Conclusion Accelerometer-based activity assessments requires careful planning and the use of appropriate strategies to increase compliance.

Alternate healing and medicine : the roles of naturopathy, homeopathy, osteopathy, chiropractic and medical practice in the health system

This thesis is concerned with understanding the roles of four alternate healing systems and medical practice in the community's health behaviour. The four alternate systems are naturopathy, homoeopathy, osteopathy and chiropractic. The research reported developed from work supported by the Committee of Inquiry into Chiropractic, Osteopathy, Homoeopathy and Naturopathy conducted under the chairmanship of Professor E. C. Webb set up by the Australian Government in 1975. The study concentrates on the factors which influence individual clients in their decisions to consult healers for treatment. An underlying assumption is that an analysis of the processes that effect such decisions will lead to further knowledge of the community's attitudes towards the functions of alternate healing and medicine. A review of the historical backgrounds and current status of the four alternate healing systems leads to the conclusion that they differ in a variety of areas. These areas include treatment modalities, historical backgrounds, occupational development and rapprochement with medicine. Homoeopathy, osteopathy and chiropractic emerged as distinct approaches to healing late in the nineteenth century. Naturopathy tends to be a philosophy or style of life as much as a health system in its own right. Their relationships with medicine also vary; osteopathy and naturopathy receive some acceptance, some homoeopaths are tolerated, whilst chiropractic is ostracised and vilified. A common paradigm of treatment underlies all four alternate approaches to healing. They all eschew the use of synthetic pharmaceuticals and invasive treatments and accept an indigenous theory of disease and a belief in the vis medicatrix naturae or the healing power of nature. An inevitable concomitant of this paradigm is that they believe that healing and health must be self-engendered. They rest within the client and his or her actions, not within the hands, skills or power of the healer. It is these characteristics combined with the alternate healers ' claims to espouse a similar scientific rationale for their approaches, and their functioning as parallel healers to medicine, that establishes their special relationship with medicine. This relationship become s more problematic in the face of medicine's hegemony and claim to unique legitimacy as the community's sole healing system. The interaction between these systems and medical practice can be gauged through articles related to the four alternate healing systems that have appeared in the medical literature. Interest has been cyclical but appears to have markedly increased in the past two decades. In this period it has included exploratory and descriptive writing; concern with controlling and/or eradicating the healers; desire to protect an ignorant and vulnerable public and. finally understanding and exploration of what the alternate healers might have to offer. At the same time, the public or institutionalized role has been one of denial and suppression through ostracism and legal constraints. In spite of medicine's position the alternate healing systems have found growing community acceptance so that it is problematical and probably unacceptable now to consider their use as a 'deviant ' health action. Increasing interest in the characteristics of clients has provided a consensus that they are similar to the adult population and are more likely to suffer from musculoskeletal and chronic illnesses. They are no more likely to be neurotic or gullible than the general community, but probably more practical and more oriented towards an active involvement in the healing process. The impact of these issues is explored, through comparing the strategies taken into account when choosing a treatment. These include attending one of the alternate healers exclusively for a condition; attending an alternate healer and a medical practitioner for the same problem; attending a medical practitioner solely or not consulting any healer. Respondents from surveys of alternate healer clients and the general community were classified according to their use of these four strategies, and the influences on their decisions at different stages of the treatment decision making process were compared.