Genetic polymorphisms in DPF3 associated with risk of breast cancer and lymph node metastases

Background Several studies have identified rare genetic variations responsible for many cases of familial breast cancer but their contribution to total breast cancer incidence is relatively small. More common genetic variations with low penetrance have been postulated to account for a higher proportion of the population risk of breast cancer. Methods and Results In an effort to identify genes that influence non-familial breast cancer risk, we tested over 25,000 single nucleotide polymorphisms (SNPs) located within approximately 14,000 genes in a large-scale case-control study in 254 German women with breast cancer and 268 age-matched women without malignant disease. We identified a marker on chromosome 14q24.3-q31.1 that was marginally associated with breast cancer status (OR = 1.5, P = 0.07). Genotypes for this SNP were also significantly associated with indicators of breast cancer severity, including presence of lymph node metastases ( P = 0.006) and earlier age of onset ( P = 0.01). The association with breast cancer status was replicated in two independent samples (OR = 1.35, P = 0.05). High-density association fine mapping showed that the association spanned about 80 kb of the zinc-finger gene DPF3 (also known as CERD4 ). One SNP in intron 1 was found to be more strongly associated with breast cancer status in all three sample collections (OR = 1.6, P = 0.003) as well as with increased lymph node metastases ( P = 0.01) and tumor size ( P = 0.01). Conclusion Polymorphisms in the 5' region of DPF3 were associated with increased risk of breast cancer development, lymph node metastases, age of onset, and tumor size in women of European ancestry. This large-scale association study suggests that genetic variation in DPF3 contributes to breast cancer susceptibility and severity.

Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus

We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using a collection of German cases and matched controls and >25,000 single nucleotide polymorphisms located within 16,000 genes. One of the candidate loci identified was located on chromosome 19p13.2 [odds ratio (OR) = 1.5, P = 0.001]. The effect was substantially stronger in the subset of cases with reported family history of breast cancer (OR = 3.4, P = 0.001). The finding was subsequently replicated in two independent collections (combined OR = 1.4, P < 0.001) and was also associated with predisposition to prostate cancer in an independent sample set of prostate cancer cases and matched controls (OR = 1.4, P = 0.002). High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5. Although genetic variants in ICAM5 showed the strongest association with disease status, ICAM1 is expressed at highest levels in normal and tumor breast tissue. A variant in ICAM5 was also associated with disease progression and prognosis. Because ICAMs are suitable targets for antibodies and small molecules, these findings may not only provide diagnostic and prognostic markers but also new therapeutic opportunities in breast and prostate cancer.

Identification of TFG (TRK-fused gene) as a putative metastatic melanoma tumor suppressor gene

High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation ‘‘hotspot’’ at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

Urban consolidation : reality or fantasy

Urban consolidation has been a policy objective of many local and state governments in Australia for the past decade. Densification of city centres and other identified activity centres is a sensible solution to a plethora of policy objectives including: growth management, housing affordability, housing choice and infrastructure utilisation etc whilst preserving the fabric of existing neighbourhoods. However despite the plethora of supportive policies and ripe redevelopment sites, urban sprawl continues to permeate city fringes and affordable urban densification in the post GFC environment slips into the “too hard” basket. This article discusses current issues facing the development industry, highlighting factors contributing to the disequilibrium between demand and supply in the medium to high density residential markets.

Ongoing outbreak of dengue serotype 3 in Solomon Islands, January to May 2013

Introduction In January 2013, clinicians in Honiara, Solomon Islands noted several patients presenting with dengue-like illness. Serum from three cases tested positive for dengue by rapid diagnostic test. Subsequent increases in cases were reported, and the outbreak was confirmed as being dengue serotype-3 by further laboratory tests. This report describes the ongoing outbreak investigation, findings and response. Methods Enhanced dengue surveillance was implemented in the capital, Honiara, and in the provinces. This included training health staff on dengue case definitions, data collection and reporting. Vector surveillance was also conducted. Results From 3 January to 15 May 2013, 5254 cases of suspected dengue were reported (101.8 per 10 000 population), including 401 hospitalizations and six deaths. The median age of cases was 20 years (range zero to 90), and 86% were reported from Honiara. Both Aedes aegyti and Aedes albopictus were identified in Honiara. Outbreak response measures included clinical training seminars, vector control activities, implementation of diagnostic and case management protocols and a public communication campaign. Discussion This was the first large dengue outbreak documented in Solomon Islands. Factors that may have contributed to this outbreak include a largely susceptible population, the presence of a highly efficient dengue vector in Honiara, a high-density human population with numerous breeding sites and favourable weather conditions for mosquito proliferation. Although the number of cases has plateaued since 1 April, continued enhanced nationwide surveillance and response activities are necessary.

Advance transit oriented development typology : case study in Brisbane, Australia

Internationally, transit oriented development (TOD) is characterised by moderate to high density development with diverse land use patterns and well connected street networks centred around high frequency transit stops (bus and rail). Although different TOD typologies have been developed in different contexts, they are based on subjective evaluation criteria derived from the context in which they are built and typically lack a validation measure. Arguably there exist sets of TOD characteristics that perform better in certain contexts, and being able to optimise TOD effectiveness would facilitate planning and supporting policy development. This research utilises data from census collection districts (CCDs) in Brisbane with different sets of TOD attributes measured across six objectively quantified built environmental indicators: net employment density, net residential density, land use diversity, intersection density, cul-de-sac density, and public transport accessibility. Using these measures, a Two Step Cluster Analysis was conducted to identify natural groupings of the CCDs with similar profiles, resulting in four unique TOD clusters: (a) residential TODs, (b) activity centre TODs, (c) potential TODs, and; (d) TOD non-suitability. The typologies are validated by estimating a multinomial logistic regression model in order to understand the mode choice behaviour of 10,013 individuals living in these areas. Results indicate that in comparison to people living in areas classified as residential TODs, people who reside in non-TOD clusters were significantly less likely to use public transport (PT) (1.4 times), and active transport (4 times) compared to the car. People living in areas classified as potential TODs were 1.3 times less likely to use PT, and 2.5 times less likely to use active transport compared to using the car. Only a little difference in mode choice behaviour was evident between people living in areas classified as residential TODs and activity centre TODs. The results suggest that: (a) two types of TODs may be suitable for classification and effect mode choice in Brisbane; (b) TOD typology should be developed based on their TOD profile and performance matrices; (c) both bus stop and train station based TODs are suitable for development in Brisbane.

Design, construction, and analysis of cell line arrays and tissue microarrays for gene expression analysis

Cell line array (CMA) and tissue microarray (TMA) technologies are high-throughput methods for analysing both the abundance and distribution of gene expression in a panel of cell lines or multiple tissue specimens in an efficient and cost-effective manner. The process is based on Kononen's method of extracting a cylindrical core of paraffin-embedded donor tissue and inserting it into a recipient paraffin block. Donor tissue from surgically resected paraffin-embedded tissue blocks, frozen needle biopsies or cell line pellets can all be arrayed in the recipient block. The representative area of interest is identified and circled on a haematoxylin and eosin (H&E)-stained section of the donor block. Using a predesigned map showing a precise spacing pattern, a high density array of up to 1,000 cores of cell pellets and/or donor tissue can be embedded into the recipient block using a tissue arrayer from Beecher Instruments. Depending on the depth of the cell line/tissue removed from the donor block 100-300 consecutive sections can be cut from each CMA/TMA block. Sections can be stained for in situ detection of protein, DNA or RNA targets using immunohistochemistry (IHC), fluorescent in situ hybridisation (FISH) or mRNA in situ hybridisation (RNA-ISH), respectively. This chapter provides detailed methods for CMA/TMA design, construction and analysis with in-depth notes on all technical aspects including tips to deal with common pitfalls the user may encounter. © Springer Science+Business Media, LLC 2011.

Antioestrogens and breast cancer

Antioestrogens are among the most widely used agents in the treatment of breast cancer. There has been a recent surge of interest in these compounds because of their potential breast cancer chemopreventive properties. The newer generation of antioestrogens, with increased selectivity and better toxicity profiles, have the potential to increase the effectiveness of hormonal treatment of breast cancer. The selective oestrogen receptor modulators (SERMs) hold the promise of revolutionising the care of healthy postmenopausal women with their beneficial effects on bone and lipids in addition to the chemoprevention of breast cancer.

Primary stability of two uncemented acetabular components of different geometry : hemispherical or peripherally enhanced?

Objective This study compared the primary stability of two commercially available acetabular components from the same manufacturer, which differ only in geometry; a hemispherical and a peripherally enhanced design (peripheral self-locking (PSL)). The objective was to determine whether altered geometry resulted in better primary stability. Methods Acetabular components were seated with 0.8 mm to 2 mm interference fits in reamed polyethylene bone substrate of two different densities (0.22 g/cm3 and 0.45 g/cm3). The primary stability of each component design was investigated by measuring the peak failure load during uniaxial pull-out and tangential lever-out tests. Results There was no statistically significant difference in seating force (p = 0.104) or primary stability (pull-out p = 0.171, lever-out p = 0.087) of the two components in the low-density substrate. Similarly, in the high-density substrate, there was no statistically significant difference in the peak pull-out force (p = 0.154) or lever-out moment (p = 0.574) between the designs. However, the PSL component required a significantly higher seating force thanthe hemispherical cup in the high-density bone analogue (p = 0.006). Conclusions Higher seating forces associated with the PSL design may result in inadequate seating and increased risk of component malpositioning or acetabular fracture in the intra-operative setting in high-density bone stock. Our results, if translated clinically, suggest that a purely hemispherical geometry may have an advantage over a peripherally enhanced geometry in high density bone stock.

Lattice-free descriptions of collective motion with crowding and adhesion

Cell-to-cell adhesion is an important aspect of malignant spreading that is often observed in images from the experimental cell biology literature. Since cell-to-cell adhesion plays an important role in controlling the movement of individual malignant cells, it is likely that cell-to-cell adhesion also influences the spatial spreading of populations of such cells. Therefore, it is important for us to develop biologically realistic simulation tools that can mimic the key features of such collective spreading processes to improve our understanding of how cell-to-cell adhesion influences the spreading of cell populations. Previous models of collective cell spreading with adhesion have used lattice-based random walk frameworks which may lead to unrealistic results, since the agents in the random walk simulations always move across an artificial underlying lattice structure. This is particularly problematic in high-density regions where it is clear that agents in the random walk align along the underlying lattice, whereas no such regular alignment is ever observed experimentally. To address these limitations, we present a lattice-free model of collective cell migration that explicitly incorporates crowding and adhesion. We derive a partial differential equation description of the discrete process and show that averaged simulation results compare very well with numerical solutions of the partial differential equation.

Increase in prevalence of obesity and diabetes and decrease in plasma cholesterol in a central Australian Aboriginal community

Objective: To document change in prevalence of obesity, diabetes and other cardiovascular diease (CVD) risk factors, and trends in dietary macronutrient intake, over an eight-year period in a rural Aboriginal community in central Australia. Design: Sequential cross-sectional community surveys in 1987, 1991 and 1995. Subjects: All adults (15 years and over) in the community were invited to participate. In 1987, 1991 and 1995, 335 (87% of eligible adults), 331 (76%) and 304 (68%), respectively, were surveyed. Main outcome measures: Body mass index and waist : hip ratio; blood glucose level and glucose tolerance; fasting total and high density lipoprotein (HDL) cholesterol and triglyceride levels; and apparent dietary intake (estimated by the store turnover method). Intervention: A community-based nutrition awareness and healthy lifestyle program, 1988-1990. Results: At the eight-year follow-up, the odds ratios (95% CIs) for CVD risk factors relative to baseline were obesity, 1.84 (1.28-2.66); diabetes, 1.83 (1.11-3.03); hypercholesterolaemia, 0.29 (0.20-0.42); and dyslipidaemia (high triglyceride plus low HDL cholesterol level), 4.54 (2.84-7.29). In younger women (15-24 years), there was a trebling in obesity prevalence and a four- to fivefold increase in diabetes prevalence. Store turnover data suggested a relative reduction in the consumption of refined carbohydrates and saturated fats. Conclusion: Interventions targeting nutritional factors alone are unlikely to greatly alter trends towards increasing prevalences of obesity and diabetes. In communities where healthy food choices are limited, the role of regular physical activity in improving metabolic fitness may also need to be emphasised.

In vitro assessment of surface congruency and integration of chondrocytes at adjacent edges of micro-fabricated clefts on cartilage

Osteochondral grafts are common treatment options for joint focal defects due to their excellent functionality. However, the difficulty is matching the topography of host and graft(s) surfaces flush to one another. Incongruence could lead to disintegration particularly when the gap reaches subchondoral region. The aim of this study is therefore to investigate cell response to gap geometry when forming cartilage-cartilage bridge at the interface. The question is what would be the characteristics of such a gap if the cells could bridge across to fuse the edges? To answer this, osteochondral plugs devoid of host cells were prepared through enzymatic decellularization and artificial clefts of different sizes were created on the cartilage surface using laser ablation. High density pellets of heterologous chondrocytes were seeded on the defects and cultured with chondrogenic differentiation media for 35 days. The results showed that the behavior of chondrocytes was a function of gap topography. Depending on the distance of the edges two types of responses were generated. Resident cells surrounding distant edges demonstrated superficial attachment to one side whereas clefts of 150 to 250 µm width experienced cell migration and anchorage across the interface. The infiltration of chondrocytes into the gaps provided extra space for their proliferation and laying matrix; as the result faster filling of the initial void space was observed. On the other hand, distant and fit edges created an incomplete healing response due to the limited ability of differentiated chondrocytes to migrate and incorporate within the interface. It seems that the initial condition of the defects and the curvature profile of the adjacent edges were the prime determinants of the quality of repair; however, further studies to reveal the underlying mechanisms of cells adapting to and modifying the new environment would be of particular interest.

Developing sustainable ‘liveable’ buildings, cities and communities for a sub-tropical context : residents’ perspectives

A key challenge for the 21st Century is to make our cities more liveable and foster economically sustainable, environmentally responsible, and socially inclusive communities. Design thinking, particularly a human-centred approach, offers a way to tackle this challenge. Findings from two recent Australian research projects highlight how facilitating sustainable, liveable communities in a humid sub-tropical environment requires an in-depth understanding of people’s perspectives, experiences and practices. Project 1 (‘Research House’) documents the reflections of a family who lived in a ‘test’ sustainable house for two years, outlining their experience and evaluations of universal design and sustainable technologies. The study family was very impressed with the natural lighting, natural ventilation, spaciousness and ease of access, which contributed significantly to their comfort and the liveability of their home. Project 2 (‘Inner-Urban High Density Living’) explored Brisbane residents’ opinions about high-density living, through a survey (n=636), interviews (n=24), site observations (over 300 hours) and environmental monitoring, assessing opinions on the liveability of their individual dwelling, the multi-unit host building and the surrounding neighbourhood. Nine areas, categorised into three general domains, were identified as essential for enhancing high density liveability. In terms of the dwelling, thermal comfort/ventilation, natural light, noise mitigation were important; shared space, good neighbour protocols, and support for environmentally sustainable behaviour were desired in the building/complex; and accessible/sustainable transport, amenities and services, sense of community were considered important in the surrounding neighbourhood. Combined, these findings emphasise the importance and complexity associated with designing liveable building, cities and communities, illustrating how adopting a design thinking, human-centred approach will help create sustainable communities that will meet the needs of current and future generations.

Diabetes, hyperinsulinemia, and hyperlipidemia in small aboriginal community in northern Australia

A small rural Aboriginal community in northern Australia was surveyed for diabetes, impaired glucose tolerance (IGT), hyperinsulinemia, and lipid levels. Of the 122 adults >17 yr of age who participated (95% response rate), 11.5% had diabetes, 7.4% had IGT, and the remaining 81.1% had normal glucose tolerance. Both diabetes and IGT were strongly age related. This high frequency of diabetes occurred, despite the population being relatively lean. Although the body mass index (BMI) increased with age in both men and women, only 25% of the population overall had BMI >25 kg/m2. There were wide ranges of insulin responses to glucose, with the upper fertile of 2-h insulin levels being more than seven times higher than the lower fertile (144 ± 13 vs. 19 ± 1 mLI/L). Hyperinsulinemia was associated with IGT, elevated triglycerides, and lower high-density lipoprotein cholesterol levels. Lipid abnormalities were much more frequent among men than women. Cholesterol levels were an average of 0.55 mM higher and triglycerides an average of 1.05 mM higher in men than in women, and both increased with age. In conclusion, this small isolated Aboriginal population from northern Australia had an unexpectedly high frequency of diabetes (in view of their relative leanness) in association with a high frequency of metabolic abnormalities indicative of insulin resistance (hyperinsulinemia, IGT, hypertriglyceridemia).

Considering a whole-of-community approach to integrating nature in cities, an international case study of Vauban, Germany

Globally, cities face a convergence of complex and rapidly evolving challenges, including climate change, resource shortages, population growth and urbanization, and financial pressures. Biophilic urbanism is an emerging design principle capable of considering the multidimensional and interdependent complexities of urban systems and infrastructure, which through the use of natural design features, can meet society’s inherent need for contact with nature, and assist efforts to respond to these growing challenges. Considering the imperative for addressing these challenges, this paper proposes that significant lessons can be learned from existing examples of biophilic urbanism, avoiding ‘re-invention of the wheel’ and facilitating accelerated innovation in other areas. Vauban is a 38-hectare brownfield development located 3 kilometers from the centre of Germany’s ‘ecological capital’ of Freiburg city. It was developed using an innovative process with strong community participation and reinterpreted developer roles to produce an example of integrated sustainability. Innovation in transport, energy, housing, development and water treatment has enabled a relatively high-density, mixed-use development that integrates a considerable amount of nature. This paper discusses Vauban in light of research undertaken over the last two years through the Sustainable Built Environment National Research Centre in Australia, to investigate emerging elements of ‘biophilic urbanism’ (nature-loving cities), and their potential to be mainstreamed within urban environments. The paper considers the interplay between the policies, community dynamics and innovations in Vauban, within the context of the culture, history and practice of sustainability in Germany, and how these have enabled nature to be integrated into the urban environment of Vauban while achieving other desirable goals for urban areas. It highlights potential applications from Vauban for Australian cities.