Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Creating a common approach to safety management through structured training development

The successful management of workplace safety has many benefits for employees, employers and the community. Similar to other areas of job performance, safety performance can be enhanced through appropriate and well-designed training. The foundation of the development of effective training is a thorough training needs analysis (TNA). Currently, the application of psychometrically valid TNA practices for the management of workplace safety is an under-researched topic and limited guidance is available for implementing appropriate strategies. To address this gap in the literature, this chapter will provide an overview of TNA practices, including the purpose and benefits associated with implementing the systematic procedure. A case study will then be presented to illustrate how the TNA process was successfully applied to investigate the training needs of Australasian rail incident investigators to achieve an industry-approved national training package. Recommendations will be made to assist practitioners with implementing TNA practices with the goal of enhancing workplace safety management through targeted workforce development.

Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium

Regeneration and growth of the human endometrium after shedding of the functional layer during menstruation depends on an adequate angiogenic response. We analysed the mRNA expression levels of all known vascular endothelial growth factor (VEGF) ligands and receptors in human endometrium collected in the menstrual and proliferative phases of the menstrual cycle. In addition, we evaluated the expression of VEGF-A, VEGF-R2 and NRP-1 at the protein level. Two periods of elevated mRNA expression of ligands and receptors were observed, separated by a distinct drop at cycle days (CDs) 9 and 10. Immunohistochemical staining showed that VEGF and VEGF-R2 were expressed in epithelial, stromal and endothelial cells. NRP-1 was mainly confined to stroma and blood vessels; only in late-proliferative endometrium, epithelial staining was also observed. Except for endothelial VEGF-R2 expression in CDs 6-8, there were no significant differences in the expression of VEGF, VEGF-R2 or NRP-1 in any of the cell compartments. In contrast, VEGF release by cultured human endometrium explants decreased during the proliferative phase. This output was significantly reduced in menstrual and early-proliferative endometrium by estradiol (E2) treatment. Western blot analysis indicated that part of the VEGF-A was trapped in the extracellular matrix (ECM). Changes in VEGF ligands and receptors were associated with elevated expression of the hypoxia markers HIF1 alpha and CA-IX in the menstrual and early proliferative phases. HIF1 alpha was also detected in late-proliferative phase endometrium. Our findings indicate that VEGF-A exerts its actions mostly during the first half of the proliferative phase. Furthermore, VEGF-A production appears to be triggered by hypoxia in the menstrual phase and subsequently suppressed toy estrogen during the late proliferative phase.

Olfactomedin-4 regulation by estrogen in the human endometrium requires epidermal growth factor signaling

Olfactomedin-4 (OLFM-4) is an extracellular matrix protein that is highly expressed in human endometrium. We have examined the regulation and function of OLFM-4 in normal endometrium and in cases of endometriosis and endometrial cancer. OLFM-4 expression levels are highest in proliferative-phase endometrium, and 17 beta-estradiol up-regulates OLFM-4 mRNA in endometrial explant cultures. Using the luciferase reporter under control of the OLFM-4 promoter, it was shown that both 17 beta-estradiol and OH-tamoxifen induce luciferase activity, and epidermal growth factor receptor-1 is required for this estrogenic response. In turn, EGF activates the OLFM-4 promoter, and estrogen receptor-alpha is needed for the complete EGF response. The cellular functions of OLFM-4 were examined by its expression in OLFM-4-negative HEK-293 cells, which resulted in decreased vimentin expression and cell adherence as well as increased apoptosis resistance. In cases of endometriosis and endometrial cancer, OLFM-4 expression correlated with the presence of epidermal growth factor receptor-1 and estrogen receptor-alpha (or estrogen signaling). An increase of OLFM-4 mRNA was observed in the endometrium of endometriosis patients. No change in OLFM-4 expression levels were observed in patients with endometrial cancer relative with controts. In conclusion, cross-talk between estrogen and EGF signaling regulates OLFM-4 expression. The role of OLFM-4 in endometrial tissue remodeling before the secretory phase and during the predisposition and early events in endometriosis can be postulated but requires additional investigation. (Am J Pathol 2010, 177:2495-2508: DOI: 10.2353/ajpath.2010.100026

Maternal concern about her toddler undereating and becoming underweight and use of feeding practices - analysis of the NOURISH and SAIDI cohorts using structural equation modeling

The chubby baby who eats well is desirable in our culture. Perceived low weight gains and feeding concerns are common reasons mothers seek advice in the early years. In contrast, childhood obesity is a global public health concern. Use of coercive feeding practices, prompted by maternal concern about weight, may disrupt a child’s innate self regulation of energy intake, promoting overeating and overweight. This study describes predictors of maternal concern about her child undereating/becoming underweight and feeding practices. Mothers in the control group of the NOURISH and South Australian Infants Dietary Intake studies (n = 332) completed a self-administered questionnaire when the child was aged 12–16 months. Weight-for-age z-score (WAZ)was derived from weight measured by study staff. Mean age (SD) was 13.8 (1.3) months, mean WAZ (SD), 0.58 (0.86) and 49% were male. WAZ and two questions describing food refusal were combined in a structural equation model with four items from the Infant feeding Questionnaire (IFQ) to form the factor ‘Concern about undereating/weight’. Structural relationships were drawn between concern and IFQ factors ‘awareness of infant’s hunger and satiety cues’, ‘use of food to calm infant’s fussiness’ and ‘feeding infant on a schedule’, resulting in a model of acceptable fit. Lower WAZ and higher frequency of food refusal predicted higher maternal concern. Higher maternal concern was associated with lower awareness of infant cues (r = −.17, p = .01) and greater use of food to calm (r = .13, p = .03). In a cohort of healthy children, maternal concern about undereating and underweight was associated with practices that have the potential to disrupt self-regulation.

Common hazards and their mitigating measures in work zones : a qualitative study of worker perceptions

Road construction and maintenance activities present challenges for ensuring the safety of workers and the traveling public alike. Hazards in work zones are typically studied using historical crash records but the current study took a qualitative approach by interviewing 66 workers from various work zones in Queensland, Australia. This supplemented and enhanced the limited available data regarding the frequency and nature of work zone crashes in Australia, provided worker insights into contributing factors, and assessed their opinions on the likely effectiveness of current or future approaches to hazard mitigation. Workers may not be aware of objective data regarding effectiveness, but their attitudes and consequent levels of compliance can influence both the likelihood of implementation and the outcomes of safety measures. Despite the potential importance of worker perceptions, they have not been studied comprehensively to date, and thus this study fills a significant gap in the literature. Excessive vehicle speeds, driver distraction and aggression towards roadworkers, working in wet weather, at night and close to traffic stream were among the most common hazards noted by workers. The safety measures perceived to be most effective included police presence, active enforcement, and improving driver awareness and education about work zones. Worker perceptions differed according to their level of exposure to hazards.

Association study of MTHFD1 coding polymorphisms R134K and R653Q with migraine susceptibility

Objective There is evidence that folate metabolism has a role in migraine pathophysiology, particularly in the migraine with aura subtype. In this study we investigate whether two non-synonymous single nucleotide polymorphisms (SNPs), rs1950902 (C401T; R134K) and rs2236225 (G1958A; R653Q), in MTHDF1 are associated with migraine in an Australian case-control population. Background Increased plasma levels of homocysteine (HCy), one of the metabolites produced in the folate pathway, has been found to be a risk factor for migraine. There is also a genetic link, as a common polymorphism (C667T) that reduces the catalytic activity of MTHFR, the enzyme that catalyses the formation of HCy, is associated with an increase in risk of the migraine with aura (MA) subtype. MTHFD1 is a crucial multifunctional enzyme that catalyses three separate reactions of the folate pathway and therefore variants in MTHFD1 may also influence migraine susceptibility. Methods The R134K and R653Q variants in MTHFD1 were genotyped in an Australian cohort of 520 unrelated migraineurs (162 were diagnosed with migraine without aura [MO] and 358 with MA) and 520 matched controls. Data were analysed for association with migraine and for interaction with the MTHFR C667T polymorphism. Results We find no significant differences in genotype or allele frequencies for either SNP between migraineurs and controls, or when either MO or MA cases were compared to controls. In addition these MTHFD1 polymorphisms did not appear to influence the risk of MA conferred by the MTHFR 667T allele. Conclusions We find no evidence for association of the MTHFD1 R134K and R653Q polymorphisms with migraine in our Australian case-control population. However, as folate metabolism appears to be important in migraine, particularly with respect to the aura component, future studies using high throughput methods to expand the number of SNPs in folate-related genes genotyped and investigation of interactions between SNPs may be justified.

The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.

Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Moderate physical activity level as a protective factor against metabolic syndrome in middle-aged and older women

Aims and objectives To investigate whether physical activity is a protective factor against metabolic syndrome in middle-aged and older women. Background Socio-demographic and lifestyle behaviour factors contribute to metabolic syndrome. To minimise the risk of metabolic syndrome, several global guidelines recommend increasing physical activity level. However, only limited research has investigated the relationship between physical activity levels and metabolic syndrome in middle-aged and older women after adjusting for socio-demographic and lifestyle behaviour factors. Design Cross-sectional design. Methods A convenience sample of 326 middle-aged and older women was recruited. Metabolic syndrome was confirmed according to the National Cholesterol Education Program, Adult Treatment Panel III guidelines, and physical activity levels were measured by the International Physical Activity Questionnaire. Results The sample had a mean age of 60•9 years, and the prevalence of metabolic syndrome was 43•3%. Postmenopausal women and women with low socioeconomic status (low-education background, without personal income and currently unemployed) had a significantly higher risk of developing metabolic syndrome. After adjusting for significant socio-demographic and lifestyle behaviour factors, the women with moderate or high physical activity levels had a significantly lower (OR = 0•10; OR = 0•11, p < 0•001) risk of metabolic syndrome and a lower risk for each specific component of metabolic syndrome, including elevated fasting plasma glucose (OR = 0•29; OR = 0•26, p = 0•009), elevated blood pressure (OR = 0•18; OR = 0•32, p = 0•029), elevated triglycerides (OR = 0•41; OR = 0•15, p = 0•001), reduced high-density lipoprotein (OR = 0•28; OR = 0•27, p = 0•004) and central obesity (OR = 0•31; OR = 0•22, p = 0•027). Conclusions After adjusting for socio-demographic and lifestyle behaviour factors, physical activity level was a significant protective factor against metabolic syndrome in middle-aged and older women. Higher physical activity levels (moderate or high physical activity level) reduced the risk of metabolic syndrome in middle-aged and older women. Relevance to clinical practice Appropriate strategies should be developed to encourage middle-aged and older women across different socio-demographic backgrounds to engage in moderate or high levels of physical activity to reduce the risk of metabolic syndrome.

Development of the OnTrack Diabetes program

Background: Type 2 diabetes affects an estimated 347 million people worldwide and often leads to serious complications including blindness, kidney disease, and limb amputation. Comorbid dysphoria is common and is an independent risk factor for poor glycaemic control. Professional support for diabetes self-management and dysphoria has limited availability and involves high costs, especially after regular hours, and in rural and remote areas. Web-based cognitive behavior therapy offers highly accessible, acceptable, and cost-effective support for people with diabetes. This paper describes the development of OnTrack Diabetes, a self-guided, Web-based program to promote improved physical and emotional self-management in people with Type 2 diabetes. Objective: The objective of the study is to describe the development of the OnTrack Diabetes program, which is a self-guided, Web-based program aimed to promote euthymia and improved disease self-management in people with Type 2 diabetes. Methods: Semistructured interviews with 12 general practitioners and 13 patients with Type 2 diabetes identified enablers of and barriers to effective diabetes self-management, requirements for additional support, and potential program elements. Existing resources and research data informed the development of content, and consultants from relevant disciplines provided feedback on draft segments and reviewed the program before release. Using a self-guided delivery format contained costs, in addition to adapting program features and modules from an existing OnTrack program. Results: A separate paper describes the protocol for a randomized controlled trial to provide this required evaluation. Conclusions: Development of the OnTrack Diabetes program demonstrates strategies that help ensure that a program is acceptable to users. The next stages involve testing users’ experiences and examining the program’s effectiveness and cost-effectiveness in randomized controlled trials.

Analyzing causes for reworks in construction projects in China

Although rework is a common phenomenon in the Chinese construction industry and significantly affects project success, the reasons for rework remain largely unknown and most construction companies are unable to manage the issue effectively. To investigate the causes of rework in construction projects, a total of 39 causes were first identified through a comprehensive literature review and semi-structured interviews with 13 experienced construction professionals in China. A questionnaire survey was further conducted to prioritize these causes, in which unclear project process management, poor quality of construction technology, and the use of poor construction materials rank the highest. Finally, a factor analysis revealed 11 major underlying dimensions of these causes, relating to design management, communication management, field management, project scope management, project process management, active rework, project plan changes, subcontractor management, contract management, owner capability, and the external environment. The contribution of this work lies in its examination of the underlying causes of rework perceived by construction professionals in the world’s largest developing country, which is characterized by its unique economic and social systems. In particular, newly identified causes of contract management, active rework, and scope management help expand existing knowledge of the underlying causes of rework for the global construction community.

Combustion analysis of microalgae methyl ester in a common rail direct injection diesel engine

In this study, the biodiesel properties and effects of blends of oil methyl ester petroleum diesel on a CI direct injection diesel engine is investigated. Blends were obtained from the marine dinoflagellate Crypthecodinium cohnii and waste cooking oil. The experiment was conducted using a four-cylinder, turbo-charged common rail direct injection diesel engine at four loads (25%, 50%, 75% and 100%). Three blends (10%, 20% and 50%) of microalgae oil methyl ester and a 20% blend of waste cooking oil methyl ester were compared to petroleum diesel. To establish suitability of the fuels for a CI engine, the effects of the three microalgae fuel blends at different engine loads were assessed by measuring engine performance, i.e. mean effective pressure (IMEP), brake mean effective pressure (BMEP), in cylinder pressure, maximum pressure rise rate, brake-specific fuel consumption (BSFC), brake thermal efficiency (BTE), heat release rate and gaseous emissions (NO, NOx,and unburned hydrocarbons (UHC)). Results were then compared to engine performance characteristics for operation with a 20% waste cooking oil/petroleum diesel blend and petroleum diesel. In addition, physical and chemical properties of the fuels were measured. Use of microalgae methyl ester reduced the instantaneous cylinder pressure and engine output torque, when compared to that of petroleum diesel, by a maximum of 4.5% at 50% blend at full throttle. The lower calorific value of the microalgae oil methyl ester blends increased the BSFC, which ultimately reduced the BTE by up to 4% at higher loads. Minor reductions of IMEP and BMEP were recorded for both the microalgae and the waste cooking oil methyl ester blends at low loads, with a maximum of 7% reduction at 75% load compared to petroleum diesel. Furthermore, compared to petroleum diesel, gaseous emissions of NO and NOx, increased for operations with biodiesel blends. At full load, NO and NOx emissions increased by 22% when 50% microalgae blends were used. Petroleum diesel and a 20% blend of waste cooking oil methyl ester had emissions of UHC that were similar, but those of microalgae oil methyl ester/petroleum diesel blends were reduced by at least 50% for all blends and engine conditions. The tested microalgae methyl esters contain some long-chain, polyunsaturated fatty acid methyl esters (FAMEs) (C22:5 and C22:6) not commonly found in terrestrial-crop-derived biodiesels yet all fuel properties were satisfied or were very close to the ASTM 6751-12 and EN14214 standards. Therefore, Crypthecodinium cohnii- derived microalgae biodiesel/petroleum blends of up to 50% are projected to meet all fuel property standards and, engine performance and emission results from this study clearly show its suitability for regular use in diesel engines.

Expertise in the illustrative context of BPM

As Business Process Management (BPM) is evolving and organisations are becoming more process oriented, the need for Expertise in BPM amongst practitioners has increased. Proactively managing Expertise in BPM is essential to unlock the potential of BPM as a management paradigm and competitive advantage. Whilst great attention is being paid by the BPM community to the technological aspects of BPM, relatively little research or work has been done concerning the expertise aspect of BPM. There is a substantial body of knowledge on expertise itself, however there is no common framework in existence at the time of writing, describing the fundamental attributes characterising Expertise in the illustrative context of BPM. There are direct implications of the understanding and characterisation of Expertise in the context of BPM as a key strategic component and success factor of BPM itself, as well as for those involved in BPM. Expertise in the context of BPM needs to be characterised to understand it, and be able to proactively manage it. Given the relative infancy of research into Expertise in the context of BPM, an exploration of the relevance and importance of Expertise in the context of BPM was considered essential, to ensure the study itself was of value to the BPM field. The aims of this research are firstly to address the two research questions 'why is expertise important and relevant in the context of BPM?', and 'how can Expertise in the context of BPM be characterised?', and secondly, the development of a comprehensive and validated A-priori model characterising Expertise in the illustrative context of BPM. The study is theory-guided. It has been undertaken via an extensive literature review across relevant literature domains, and a revelatory case study utilising several methods: informal discussions, an open-ended survey, and participant observation. An a-priori model was then developed which comprised of several Constructs and Sub-constructs, and several overall aspects of Expertise in BPM. This was followed by the conduct of interviews in the validation phase of the revelatory case study. The primary contributions of this study are to the fields of expertise, BPM and research. Contributions to the field of expertise include a comprehensive review of expertise literature in general and synthesised critique on expertise research, characterisation of expertise in an illustrative context as a system, and a comprehensive narrative of the dynamics and interrelationships of the core attributes characterising expertise. Contributions to the field of BPM include firstly, the establishment of the importance of understanding Expertise in the context of BPM, including a comprehensive overview of the role the relevance and importance of Expertise in the context of BPM, through explanation of the effect of Expertise in BPM. Secondly, a model characterising Expertise in the context of BPM, which can be used by BPM practitioners to clearly articulate and illuminate the state of Expertise in BPM in organisations. Contributions to the field of research include an extended view of Systems Theory developed, reflecting the importance of the system context in systems thinking, and a narrative on ontological innovation through the positioning of ontology as a meta-model of Expertise in the context of BPM.