Identification of inflections in T-cell counts among HIV-1-infected individuals and relationship with progression to clinical AIDS

Studies of circulating T (CD3+) lymphocytes have shown that on a population basis T-cell numbers remain stable for many years after HIV-1 infection (blind T-cell homeostasis), but decline rapidly beginning approximately 1.5–2.5 years before the onset of clinical AIDS. We derived a general method for defining the loss of homeostasis on the individual level and for determining the prevalence of homeostasis loss according to HIV status and the occurrence of AIDS in more than 5,000 men enrolled in the Multicenter AIDS Cohort Study. We used a segmented regression model for log10 CD3+ cell counts that included separate T-cell trajectories before and after a time (the T-cell inflection point) where the loss of T-cell homeostasis was most likely to have occurred. The average slope of CD3+ lymphocyte counts before the inflection point was close to zero for HIV− and HIV+ men, consistent with blind T-cell homeostasis. After the inflection point, the HIV+ individuals who developed AIDS generally showed a dramatic decline in CD3+ cell counts relative to HIV− men and HIV+ men not developing AIDS. A CD3+ cell decline of greater than 10 percent per year was present in 77% of HIV+ men developing AIDS but in only 23% of HIV+ men with no onset of AIDS. Our findings at the individual level support the blind T-cell homeostasis hypothesis and provide strong evidence that the loss of homeostasis is an important mechanism in the pathogenesis of the severe immunodeficiency that characterizes the late stages of HIV infection.

Beyond individuals: a more effective structure for the Commission. EPC Commentary, 9 September 2014

In recent days, Brussels has been excited by the circulation of diagrams showing a re-organisation and allocation of posts in the new European Commission, reputedly coming from somewhere within Jean-Claude Juncker’s team. Many have pointed out that some of the appointments seem unlikely, also noting that the diagram seems to miss the Enterprise and Single Market portfolios, where it is difficult to envisage their complete merger into other portfolios, given their size and importance. In addition, not only is the source of the document unknown, it could have been leaked for a specific purpose, for example to test out the reactions in some Member States or to push individual EU countries into action, for example by appointing a woman to get a better portfolio.

Do Individuals or Firms Matter More? The Case of Patent Generation

This paper studies the relative importance of individual inventors’ human capital and firms’ organizational capital in promoting a firm’s innovation output. We decompose the variation in innovation output into inventor- and firm-specific components. Inventors’ human capital is about 13 times as important as firms’ organizational capital in explaining a firm’s innovation performance in terms of patent counts and citations, while inventors’ human capital is only about the same as important when explaining the firm’s innovation styles in terms of patent exploratory and exploitive scores. In the cross section, inventors contribute more to innovation output when they are better networked, in firms with higher inventor mobility, in industries in which innovation is more difficult to achieve, and in publicly traded firms. Additional tests suggest that our main findings continue to hold after accounting for inventors’ endogenous moving. This paper highlights the importance of individual inventors in enhancing firm innovation and sheds new light on the theory of the firm.

Understanding the genetic basis of phenotype variability in individuals with neurocognitive disorders

Thesis (Ph.D.)--University of Washington, 2016-06

Self-report depressive symptoms do not directly predict suicidality in nonclinical individuals: Contributions toward a more psychosocial approach to suicide risk

Although suicidality is associated with mental illness in general and depression in particular, many depressed individuals do not attempt suicide and some individuals who attempt to or do die by suicide do not present depressive symptoms. This article aims to contribute to a more psychosocial approach to understanding suicide risk in nonclinical populations. In advocating a psychosocial perspective rather than a depression-focused approach, this article presents four diverse studies that demonstrate sampling and measurement invariance in findings across different populations and specific measures. Study 1 tests the mediation effects of 2 interpersonal variables, thwarted belongingness and perceived burdensomeness, in the association between depressive symptoms and recent suicidality. Studies 2 and 3 evaluate the contribution of hopelessness and psychache, beyond depressive symptoms, to suicidality. Study 4 tests the contribution of life events behind depressive symptoms, and other relevant sociodemographic and clinical variables, to the estimation of “future suicidality.” Overall, results demonstrate that depressive symptoms do not directly predict suicidality in nonclinical individuals, but that other psychosocial variables mediate the association between depressive symptoms and suicidality or predict suicidality when statistically controlling for depressive symptoms. The article contributes to understanding some of the nonpsychopathological factors that potentially link depressive symptoms to suicide risk and that might themselves contribute to suicidality, even when controlling for depressive symptoms.

Membrane associated transporter protein gene (SLC45A2) and the genetic basis of normal human pigmentation variation

This work is concerned with the genetic basis of normal human pigmentation variation. Specifically, the role of polymorphisms within the solute carrier family 45 member 2 (SLC45A2 or membrane associated transporter protein; MATP) gene were investigated with respect to variation in hair, skin and eye colour ― both between and within populations. SLC45A2 is an important regulator of melanin production and mutations in the gene underly the most recently identified form of oculocutaneous albinism. There is evidence to suggest that non-synonymous polymorphisms in SLC45A2 are associated with normal pigmentation variation between populations. Therefore, the underlying hypothesis of this thesis is that polymorphisms in SLC45A2 will alter the function or regulation of the protein, thereby altering the important role it plays in melanogenesis and providing a mechanism for normal pigmentation variation. In order to investigate the role that SLC45A2 polymorphisms play in human pigmentation variation, a DNA database was established which collected pigmentation phenotypic information and blood samples of more than 700 individuals. This database was used as the foundation for two association studies outlined in this thesis, the first of which involved genotyping two previously-described non-synonymous polymorphisms, p.Glu272Lys and p.Phe374Leu, in four different population groups. For both polymorphisms, allele frequencies were significantly different between population groups and the 272Lys and 374Leu alleles were strongly associated with black hair, brown eyes and olive skin colour in Caucasians. This was the first report to show that SLC45A2 polymorphisms were associated with normal human intra-population pigmentation variation. The second association study involved genotyping several SLC45A2 promoter polymorphisms to determine if they also played a role in pigmentation variation. Firstly, the transcription start site (TSS), and hence putative proximal promoter region, was identified using 5' RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE). Two alternate TSSs were identified and the putative promoter region was screened for novel polymorphisms using denaturing high performance liquid chromatography (dHPLC). A novel duplication (c.–1176_–1174dupAAT) was identified along with other previously described single nucleotide polymorphisms (c.–1721C>G and c.–1169G>A). Strong linkage disequilibrium ensured that all three polymorphisms were associated with skin colour such that the –1721G, +dup and –1169A alleles were associated with olive skin in Caucasians. No linkage disequilibrium was observed between the promoter and coding region polymorphisms, suggesting independent effects. The association analyses were complemented with functional data, showing that the –1721G, +dup and –1169A alleles significantly decreased SLC45A2 transcriptional activity. Based on in silico bioinformatic analysis that showed these alleles remove a microphthalmia-associated transcription factor (MITF) binding site, and that MITF is a known regulator of SLC45A2 (Baxter and Pavan, 2002; Du and Fisher, 2002), it was postulated that SLC45A2 promoter polymorphisms could contribute to the regulation of pigmentation by altering MITF binding affinity. Further characterisation of the SLC45A2 promoter was carried out using luciferase reporter assays to determine the transcriptional activity of different regions of the promoter. Five constructs were designed of increasing length and their promoter activity evaluated. Constitutive promoter activity was observed within the first ~200 bp and promoter activity increased as the construct size increased. The functional impact of the –1721G, +dup and –1169A alleles, which removed a MITF consensus binding site, were assessed using electrophoretic mobility shift assays (EMSA) and expression analysis of genotyped melanoblast and melanocyte cell lines. EMSA results confirmed that the promoter polymorphisms affected DNA-protein binding. Interestingly, however, the protein/s involved were not MITF, or at least MITF was not the protein directly binding to the DNA. In an effort to more thoroughly characterise the functional consequences of SLC45A2 promoter polymorphisms, the mRNA expression levels of SLC45A2 and MITF were determined in melanocyte/melanoblast cell lines. Based on SLC45A2’s role in processing and trafficking TYRP1 from the trans-Golgi network to stage 2 melanosmes, the mRNA expression of TYRP1 was also investigated. Expression results suggested a coordinated expression of pigmentation genes. This thesis has substantially contributed to the field of pigmentation by showing that SLC45A2 polymorphisms not only show allele frequency differences between population groups, but also contribute to normal pigmentation variation within a Caucasian population. In addition, promoter polymorphisms have been shown to have functional consequences for SLC45A2 transcription and the expression of other pigmentation genes. Combined, the data presented in this work supports the notion that SLC45A2 is an important contributor to normal pigmentation variation and should be the target of further research to elucidate its role in determining pigmentation phenotypes. Understanding SLC45A2’s function may lead to the development of therapeutic interventions for oculocutaneous albinism and other disorders of pigmentation. It may also help in our understanding of skin cancer susceptibility and evolutionary adaptation to different UV environments, and contribute to the forensic application of pigmentation phenotype prediction.

The impact of change on careers in the 21st century : what do individuals need to do

There is a growing literature (Arthur, Inkson, & Pringle, 1999; Collin & Young, 2000; Hall & Associates, 1996; Peiperl, Arthur,& Anand, 2002) about the changing workplace and the consequent changes to our understanding of the place of career in individuals’ lives (Richardson, 1996, 2000) - “Careers are becoming more varied and more difficult to manage for both individuals and organisations” (Arnold et al, 2005, p. 523). This chapter will present the background to the changes in the world of work and the changes which inevitably impact individuals’ careers. It will then focus on the close relationship between career development and lifelong learning and the importance of ongoing professional learning for individuals to maintain employability in a changing work world.

Venture idea newness, relatedness and performance in nascent ventures

Principal Topic The study of the origin and characteristics of venture ideas - or ''opportunities'' as they are often called - and their contextual fit are key research goals in entrepreneurship (Davidsson, 2004). We define venture idea as ''the core ideas of an entrepreneur about what to sell, how to sell, whom to sell and how an entrepreneur acquire or produce the product or service which he/she sells'' for the purpose of this study. When realized the venture idea becomes a ''business model''. Even though venture ideas are central to entrepreneurship yet its characteristics and their effect to the entrepreneurial process is mysterious. According to Schumpeter (1934) entrepreneurs could creatively destruct the existing market condition by introducing new product/service, new production methods, new markets, and new sources of supply and reorganization of industries. The introduction, development and use of new ideas are generally called as ''innovation'' (Damanpour & Wischnevsky, 2006) and ''newness'' is a property of innovation and is a relative term which means that the degree of unfamiliarity of venture idea either to a firm or to a market. However Schumpeter's (1934) discusses five different types of newness, indicating that type of newness is an important issue. More recently, Shane and Venkataraman (2000) called for research taking into consideration not only the variation of characteristics of individuals but also heterogeneity of venture ideas, Empirically, Samuelson (2001, 2004) investigated process differences between innovative venture ideas and imitative venture ideas. However, he used only a crude dichotomy regarding the venture idea newness. According to Davidsson, (2004) as entrepreneurs could introduce new economic activities ranging from pure imitation to being new to the entire world market, highlighting that newness is a matter of degree. Dahlqvist (2007) examined the venture idea newness and made and attempt at more refined assessment of the degree and type of newness of venture idea. Building on these predecessors our study refines the assessment of venture idea newness by measuring the degree of venture idea newness (new to the world, new to the market, substantially improved while not entirely new, and imitation) for four different types of newness (product/service, method of production, method of promotion, and customer/target market). We then related type and degree of newness to the pace of progress in nascent venturing process. We hypothesize that newness will slow down the business creation process. Shane & Venkataraman (2000) introduced entrepreneurship as the nexus of opportunities and individuals. In line with this some scholars has investigated the relationship between individuals and opportunities. For example Shane (2000) investigates the relatedness between individuals' prior knowledge and identification of opportunities. Shepherd & DeTinne (2005) identified that there is a positive relationship between potential financial reward and the identification of innovative venture ideas. Sarasvathy's 'Effectuation Theory'' assumes high degree of relatedness with founders' skills, knowledge and resources in the selection of venture ideas. However entrepreneurship literature is scant with analyses of how this relatedness affects to the progress of venturing process. Therefore, we assess the venture ideas' degree of relatedness to prior knowledge and resources, and relate these, too, to the pace of progress in nascent venturing process. We hypothesize that relatedness will increase the speed of business creation. Methodology For this study we will compare early findings from data collected through the Comprehensive Australian Study of Entrepreneurial Emergence (CAUSEE). CAUSEE is a longitudinal study whose primary objective is to uncover the factors that initiate, hinder and facilitate the process of emergence and development of new firms. Data were collected from a representative sample of some 30,000 households in Australia using random digit dialing (RDD) telephone survey interviews. Through the first round of data collection identified 600 entrepreneurs who are currently involved in the business start-up process. The unit of the analysis is the emerging venture, with the respondent acting as its spokesperson. The study methodology allows researchers to identify ventures in early stages of creation and to longitudinally follow their progression through data collection periods over time. Our measures of newness build on previous work by Dahlqvist (2007). Our adapted version was developed over two pre-tests with about 80 participants in each. The measures of relatedness were developed through the two rounds of pre-testing. The pace of progress in the venture creation process is assessed with the help of time-stamped gestation activities; a technique developed in the Panel Study of Entrepreneurial Dynamics (PSED). Results and Implications We hypothesized that venture idea newness slows down the venturing process whereas relatedness facilitates the venturing process. Results of 600 nascent entrepreneurs in Australia indicated that there is marginal support for the hypothesis that relatedness assists the gestation progress. Newness is significant but is the opposite sign to the hypothesized. The results give number of implications for researchers, business founders, consultants and policy makers in terms of better knowledge of the venture creation process.

Test of the enemy release hypothesis: the native magpie moth prefers a native fireweed (Senecio pinnatifolius) to its introduced congener (S.Madagascariensis)

Abstract The enemy release hypothesis predicts that native herbivores will either prefer or cause more damage to native than introduced plant species. We tested this using preference and performance experiments in the laboratory and surveys of leaf damage caused by the magpie moth Nyctemera amica on a co-occuring native and introduced species of fireweed (Senecio) in eastern Australia. In the laboratory, ovipositing females and feeding larvae preferred the native S. pinnatifolius over the introduced S. madagascariensis. Larvae performed equally well on foliage of S. pinnatifolius and S. madagascariensis: pupal weights did not differ between insects reared on the two species, but growth rates were significantly faster on S. pinnatifolius. In the field, foliage damage was significantly greater on native S. pinnatifolius than introduced S. madagascariensis. These results support the enemy release hypothesis, and suggest that the failure of native consumers to switch to introduced species contributes to their invasive success. Both plant species experienced reduced, rather than increased, levels of herbivory when growing in mixed populations, as opposed to pure stands in the field; thus, there was no evidence that apparent competition occurred.

It's time to be more serious about activating youngsters : lessons for childhood obesity

The epidemic of obesity is impacting an increasing proportion of children, adolescents and adults with a common feature being low levels of physical activity (PA). Despite having more knowledge than ever before about the benefits of PA for health and the growth and development of youngsters, we are only paying lip-service to the development of motor skills in children. Fun, enjoyment and basic skills are the essential underpinnings of meaningful participation in PA. A concurrent problem is the reported increase in sitting time with the most common sedentary behaviors being TV viewing and other screen-based games. Limitations of time have contributed to a displacement of active behaviors with inactive pursuits, which has contributed to reductions in activity energy expenditure. To redress the energy imbalance in overweight and obese children, we urgently need out-of-the-box multisectoral solutions. There is little to be gained from a shame and blame mentality where individuals, their parents, teachers and other groups are singled out as causes of the problem. Such an approach does little more than shift attention from the main game of prevention and management of the condition, which requires a concerted, whole-of-government approach (in each country). The failure to support and encourage all young people to participate in regular PA will increase the chance that our children will live shorter and less healthy lives than their parents. In short, we need novel environmental approaches to foster a systematic increase in PA. This paper provides examples of opportunities and challenges for PA strategies to prevent obesity with a particular emphasis on the school and home settings.

Philanthropy for Indigenous causes : more than a 'cup of tea'?

In the face of improved First Nation outcomes in many western nations, Australia is still dealing with a seemingly intractable gap between the quality of life of its Aboriginal and Torres Strait Islander peoples and the non-Aboriginal and Torres Strait Islander population. Philanthropy in Australia provides a smaller proportion of funding for community projects than is the case in other countries and Aboriginal and Torres Strait Islander causes have been significantly under - represented as recipients. This paper reports on a qualitative study aimed at understanding the issues affecting the decisions and actions of grantmaking organisations and individuals who wish to support Aboriginal and Torres Strait Islander causes in the current Australian context. The aims were to build on the limited research in this arena, add to the future research agenda and contribute to practice and policy insights for Australia and beyond. The study found that while government funding programs are perceived as output driven, inflexible and dogmatic - ‘a cup of tea mob’- participants see the Australian philanthropic sector as capable of addressing the complex Aboriginal and Torres Strait Islander ‘problem’ with more innovative and independent thinking. From the point of view of contextual impacts, success criteria, barriers, structural imposts and emotional involvement, the practical experience in grantmaking for Indigenous causes of participants in this study reflects that found elsewhere. However the focus of many grantmakers on organisational rather than community capacity and the potentially elitist emphasis on established relationships continues to hamper Aboriginal and Torres Strait Islander access to philanthropic funding in Australia. Further, if the strategic changes currently visible in the sector are unsupported by a depth of policy and a proactive transfer and distribution of skill and knowledge they may be unsustainable.

Repeatability of measuring corneal subbasal nerve fiber length in individuals with Type 2 Diabetes

Purpose: To analyze the repeatability of measuring nerve fiber length (NFL) from images of the human corneal subbasal nerve plexus using semiautomated software. Methods: Images were captured from the corneas of 50 subjects with type 2 diabetes mellitus who showed varying severity of neuropathy, using the Heidelberg Retina Tomograph 3 with Rostock Corneal Module. Semiautomated nerve analysis software was independently used by two observers to determine NFL from images of the subbasal nerve plexus. This procedure was undertaken on two occasions, 3 days apart. Results: The intraclass correlation coefficient values were 0.95 (95% confidence intervals: 0.92–0.97) for individual subjects and 0.95 (95% confidence intervals: 0.74–1.00) for observer. Bland-Altman plots of the NFL values indicated a reduced spread of data with lower NFL values. The overall spread of data was less for (a) the observer who was more experienced at analyzing nerve fiber images and (b) the second measurement occasion. Conclusions: Semiautomated measurement of NFL in the subbasal nerve fiber layer is highly repeatable. Repeatability can be enhanced by using more experienced observers. It may be possible to markedly improve repeatability when measuring this anatomic structure using fully automated image analysis software.

Population structure of Bactrocera dorsalis s.s., B. papayae and B. philippinensis (Diptera: Tephritidae) in southeast Asia: evidence for a single species hypothesis using mitochondrial DNA and wingshape data

Background Bactrocera dorsalis s.s. is a pestiferous tephritid fruit fly distributed from Pakistan to the Pacific, with the Thai/Malay peninsula its southern limit. Sister pest taxa, B. papayae and B. philippinensis, occur in the southeast Asian archipelago and the Philippines, respectively. The relationship among these species is unclear due to their high molecular and morphological similarity. This study analysed population structure of these three species within a southeast Asian biogeographical context to assess potential dispersal patterns and the validity of their current taxonomic status. Results Geometric morphometric results generated from 15 landmarks for wings of 169 flies revealed significant differences in wing shape between almost all sites following canonical variate analysis. For the combined data set there was a greater isolation-by-distance (IBD) effect under a ‘non-Euclidean’ scenario which used geographical distances within a biogeographical ‘Sundaland context’ (r2 = 0.772, P < 0.0001) as compared to a ‘Euclidean’ scenario for which direct geographic distances between sample sites was used (r2 = 0.217, P < 0.01). COI sequence data were obtained for 156 individuals and yielded 83 unique haplotypes with no correlation to current taxonomic designations via a minimum spanning network. BEAST analysis provided a root age and location of 540kya in northern Thailand, with migration of B. dorsalis s.l. into Malaysia 470kya and Sumatra 270kya. Two migration events into the Philippines are inferred. Sequence data revealed a weak but significant IBD effect under the ‘non-Euclidean’ scenario (r2 = 0.110, P < 0.05), with no historical migration evident between Taiwan and the Philippines. Results are consistent with those expected at the intra-specific level. Conclusions Bactrocera dorsalis s.s., B. papayae and B. philippinensis likely represent one species structured around the South China Sea, having migrated from northern Thailand into the southeast Asian archipelago and across into the Philippines. No migration is apparent between the Philippines and Taiwan. This information has implications for quarantine, trade and pest management.

Investigating the dynamics of the psychological contract : how and why individuals' contract beliefs change

The overall objective of this thesis is to explore how and why the content of individuals' psychological contracts changes over time. The contract is generally understood as "individual beliefs, shaped by the organisation, regarding the terms of an exchange agreement between individuals and their organisation" (Rousseau, 1995, p. 9). With an overall study sampling frame of 320 graduate organisational newcomers, a mixed method longitudinal research design comprised of three sequential, inter-related studies is employed in order to capture the change process. From the 15 semi-structured interviews conducted in Study 1, the key findings included identifying a relatively high degree of mutuality between employees' and their managers' reciprocal contract beliefs around the time of organisational entry. Also, at this time, individuals had developed specific components of their contract content through a mix of social network information (regarding broader employment expectations) and perceptions of various elements of their particular organisation's reputation (for more firm-specific expectations). Study 2 utilised a four-wave survey approach (available to the full sampling frame) over the 14 months following organisational entry to explore the 'shape' of individuals' contract change trajectories and the role of four theorised change predictors in driving these trajectories. The predictors represented an organisational-level informational cue (perceptions of corporate reputation), a dyadic-level informational cue (perceptions of manager-employee relationship quality) and two individual difference variables (affect and hardiness). Through the use of individual growth modelling, the findings showed differences in the general change patterns across contract content components of perceived employer (exhibiting generally quadratic change patterns) and employee (exhibiting generally no-change patterns) obligations. Further, individuals differentially used the predictor variables to construct beliefs about specific contract content. While both organisational- and dyadic-level cues were focused upon to construct employer obligation beliefs, organisational-level cues and individual difference variables were focused upon to construct employee obligation beliefs. Through undertaking 26 semi-structured interviews, Study 3 focused upon gaining a richer understanding of why participants' contracts changed, or otherwise, over the study period, with a particular focus upon the roles of breach and violation. Breach refers to an employee's perception that an employer obligation has not been met and violation refers to the negative and affective employee reactions which may ensue following a breach. The main contribution of these findings was identifying that subsequent to a breach or violation event a range of 'remediation effects' could be activated by employees which, depending upon their effectiveness, served to instigate either breach or contract repair or both. These effects mostly instigated broader contract repair and were generally cognitive strategies enacted by an individual to re-evaluate the breach situation and re-focus upon other positive aspects of the employment relationship. As such, the findings offered new evidence for a clear distinction between remedial effects which serve to only repair the breach (and thus the contract) and effects which only repair the contract more broadly; however, when effective, both resulted in individuals again viewing their employment relationships positively. Overall, in response to the overarching research question of this thesis, how and why individuals' psychological contract beliefs change, individuals do indeed draw upon various information sources, particularly at the organisational-level, as cues or guides in shaping their contract content. Further, the 'shapes' of the changes in beliefs about employer and employee obligations generally follow different, and not necessarily linear, trajectories over time. Finally, both breach and violation and also remedial actions, which address these occurrences either by remedying the breach itself (and thus the contract) or the contract only, play central roles in guiding individuals' contract changes to greater or lesser degrees. The findings from the thesis provide both academics and practitioners with greater insights into how employees construct their contract beliefs over time, the salient informational cues used to do this and how the effects of breach and violation can be mitigated through creating an environment which facilitates the use of effective remediation strategies.

Prognostic significance of IGF and ECM induced signalling proteins in breast cancer patients

Breast cancer is a leading contributor to the burden of disease in Australia. Fortunately, the recent introduction of diverse therapeutic strategies have improved the survival outcome for many women. Despite this, the clinical management of breast cancer remains problematic as not all approaches are sufficiently sophisticated to take into account the heterogeneity of this disease and are unable to predict disease progression, in particular, metastasis. As such, women with good prognostic outcomes are exposed to the side effects of therapies without added benefit. Furthermore, women with aggressive disease for whom these advanced treatments would deliver benefit cannot be distinguished and opportunities for more intensive or novel treatment are lost. This study is designed to identify novel factors associated with disease progression, and the potential to inform disease prognosis. Frequently overlooked, yet common mediators of disease are the interactions that take place between the insulin-like growth factor (IGF) system and the extracellular matrix (ECM). Our laboratory has previously demonstrated that multiprotein insulin-like growth factor-I (IGF-I): insulin-like growth factor binding protein (IGFBP): vitronectin (VN) complexes stimulate migration of breast cancer cells in vitro, via the cooperative involvement of the insulin-like growth factor type I receptor (IGF-IR) and VN-binding integrins. However, the effects of IGF and ECM protein interactions on the dissemination and progression of breast cancer in vivo are unknown. It was hypothesised that interactions between proteins required for IGF induced signalling events and those within the ECM contribute to breast cancer metastasis and are prognostic and predictive indicators of patient outcome. To address this hypothesis, semiquantitative immunohistochemistry (IHC) analyses were performed to compare the extracellular and subcellular distribution of IGF and ECM induced signalling proteins between matched normal, primary cancer, and metastatic cancer among archival formalin-fixed paraffin-embedded (FFPE) breast tissue samples collected from women attending the Princess Alexandra Hospital, Brisbane. Multivariate Cox proportional hazards (PH) regression survival models in conjunction with a modified „purposeful selection of covariates. method were applied to determine the prognostic potential of these proteins. This study provides the first in-depth, compartmentalised analysis of the distribution of IGF and ECM induced signalling proteins. As protein function and protein localisation are closely correlated, these findings provide novel insights into IGF signalling and ECM protein function during breast cancer development and progression. Distinct IGF signalling and ECM protein immunoreactivity was observed in the stroma and/or in subcellular locations in normal breast, primary cancer and metastatic cancer tissues. Analysis of the presence and location of stratifin (SFN) suggested a causal relationship in ECM remodelling events during breast cancer development and progression. The results of this study have also suggested that fibronectin (FN) and ¥â1 integrin are important for the formation of invadopodia and epithelial-to-mesenchymal transition (EMT) events. Our data also highlighted the importance of the temporal and spatial distribution of IGF induced signalling proteins in breast cancer metastasis; in particular, SFN, enhancer-of-split and hairy-related protein 2 (SHARP-2), total-akt/protein kinase B 1 (Total-AKT1), phosphorylated-akt/protein kinase B (P-AKT), extracellular signal-related kinase-1 and extracellular signal-related kinase-2 (ERK1/2) and phosphorylated-extracellular signal-related kinase-1 and extracellular signal-related kinase-2 (P-ERK1/2). Multivariate survival models were created from the immunohistochemical data. These models were found to fit well with these data with very high statistical confidence. Numerous prognostic confounding effects and effect modifications were identified among elements of the ECM and IGF signalling cascade and corroborate the survival models. This finding provides further evidence for the prognostic potential of IGF and ECM induced signalling proteins. In addition, the adjusted measures of associations obtained in this study have strengthened the validity and utility of the resulting models. The findings from this study provide insights into the biological interactions that occur during the development of breast tissue and contribute to disease progression. Importantly, these multivariate survival models could provide important prognostic and predictive indicators that assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy. The outcomes of this study further inform the development of new therapeutics to aid patient recovery. The findings from this study have widespread clinical application in the diagnosis of disease and prognosis of disease progression, and inform the most appropriate clinical management of individuals with breast cancer.