Long-term efficacy of orthokeratology contact lens wear in controlling the progression of childhood myopia

Purpose: The primary outcome of this study is to compare the axial length growth of white European myopic children wearing orthokeratology contact lenses (OK) to a control group (CT) over a 7-year period. Methods: Subjects 6–12 years of age with myopia −0.75 to −4.00DS and astigmatism ≤1.00DC were prospectively allocated OK or distance single-vision spectacles (SV) correction. Measurements of axial length (Zeiss IOLMaster), corneal topography, and cycloplegic refraction were taken at 6-month intervals over a 2-year period. Subjects were invited to return to the clinic approximately 5 years later (i.e., 7 years after the beginning of the study) for assessment of their ocular refractive and biometric components. The CT consisted of 4 SV and 12 subjects who switched from SV to soft contact lens wear after the initial 2 years of SV lens wear. Changes in axial length relative to baseline over a 7-year period were compared between groups. Results: Fourteen and 16 subjects from the OK and CT groups, respectively, were examined 6.7 ± 0.5 years after the beginning of the study. Statistically significant changes in the axial length were found over time and between groups (both p <0.001), but not for the time*group interaction (p = 0.125). The change in the axial length for the OK group was 22% (p = 0.328), 42% (p = 0.007), 40% (p = 0.020), 41% (p = 0.013), and 33% (p = 0.062) lower than the CT group following 6, 12, 18, 24, and 84 months of lens wear, respectively. Conclusion: A trend toward a reduction in the rate of axial elongation of the order of 33% was found in the OK group in comparison to the CT group following 7 years of lens wear.

L'acide valproïque inhibe la progression dans le cycle cellulaire chez Saccharomyces cerevisiae

L’acétylation est une modification post-traductionnelle des protéines essentielles. Elle est impliquée dans bon nombre de processus cellulaires importants comme la régulation de la structure de la chromatine et le recrutement de protéines. Deux groupes d’enzymes, soient les lysines acétyltransférases et les lysines désacétylases, régulent cette modification, autant sur les histones que sur les autres protéines. Au cours des dernières années, de petites molécules inhibitrices des désacétylases ont été découvertes. Certaines d’entre elles semblent prometteuses contre diverses maladies telles le cancer. L’acide valproïque, un inhibiteur de deux des trois classes des désacétylases, a un effet antiprolifératif chez plusieurs organismes modèles. Toutefois, les mécanismes cellulaires sous-jacents à cet effet restent encore méconnus. Ce mémoire met en lumière l’effet pH dépendant de l’acide valproïque sur différentes voies cellulaires importantes chez la levure Saccharomyces cerevisiae. Il démontre que ce composé a la capacité d’inhiber la transition entre les phases G1 et S par son action sur l’expression des cyclines de la phase G1. De plus, il inhibe l’activation de la kinase principale de la voie activée suite à un stress à la paroi cellulaire. L’acide valproïque occasionne également un arrêt dans la réplication de l’ADN sans y causer de dommage. Il s’agit là d’un effet unique qui, à notre connaissance, n’est pas observable avec d’autres agents qui inhibent la progression en phase S.

Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology

Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.

Influence de l’hypoxie dans la régulation du pH et les conséquences dans la progression tumorale et la résistance à la chimiothérapie

Résumé : La formation de métastases s’inscrit comme la finalité d’un processus darwinien dans lequel les cellules tumorales subissent des altérations génétiques et épigénétiques dans l’unique but de préserver un avantage prolifératif. L’environnement hypoxique, caractéristique des tumeurs solides, se révèle comme une pression de sélection et un facteur déterminant dans la progression tumorale. Face à l’hypoxie, une des adaptations majeures des cellules tumorales est le déséquilibre du pH cellulaire qui mène à la formation de métastases et à la résistance à la chimiothérapie. Cette thèse met en lumière de nouveaux liens moléculaires entre l’hypoxie et la régulation du pH dans des contextes d’invasion cellulaire et de chimiorésistance. Les échangeurs d’ions NHE1 et NHE6 sont au cœur de ces études où de nouveaux rôles dans la progression du cancer leur ont été attribués. Premièrement, nous avons observé l’influence de l’hypoxie sur la régulation de NHE1 par p90RSK et les conséquences fonctionnelles de cette interaction dans l’invasion cellulaire par les invadopodes. En conditions hypoxiques, NHE1 est activé par p90RSK résultant en une acidification extracellulaire. En modifiant le pH, NHE1 stimule la formation des invadopodes et la dégradation de la matrice extracellulaire. Ainsi, la phosphorylation de NHE1 par p90RSK en hypoxie apparaît comme un biomarqueur potentiel des cancers métastatiques. Peu étudié, le pH endosomal peut intervenir dans la chimiorésistance mais les mécanismes sont inconnus. Nous avons développé une méthode pour mesurer précisément le pH endosomal par microscopie. Ceci a permis d’illuminer un nouveau mécanisme de résistance induit par l’hypoxie et mettant en vedette l’échangeur NHE6. L’hypoxie favorise l’interaction de NHE6 avec RACK1 à la membrane plasmique empêchant la localisation endosomale de l’échangeur. Cette interaction mène à la séquestration de la doxorubicine dans des endosomes sur-acidifiés. Ces travaux mettent en évidence pour la première fois le rôle du pH endosomal et l’échangeur NHE6 comme des éléments centraux de la chimiorésistance induite par l’hypoxie. Cette thèse renforce donc l’idée voulant que les interactions entre les cellules tumorales et le microenvironnement hypoxique sont le « talon d’Achille » du cancer et la régulation du pH cellulaire est primordiale dans l’adaptation des cellules à l’hypoxie et l’instauration du phénotype malin du cancer. La découverte de nouveaux rôles pro-tumoraux pour NHE1 et NHE6 les placent à l’avant-plan pour le développement de stratégies thérapeutiques orientées contre la formation de métastases et la chimiorésistance.

Creative design and the generative evolutionary paradigm

Design as seen from the designer's perspective is a series of amazing imaginative jumps or creative leaps. But design as seen by the design historian is a smooth progression or evolution of ideas that they seem self-evident and inevitable after the event. But the next step is anything but obvious for the artist/creator/inventor/designer stuck at that point just before the creative leap. They know where they have come from and have a general sense of where they are going, but often do not have a precise target or goal. This is why it is misleading to talk of design as a problem-solving activity - it is better defined as a problem-finding activity. This has been very frustrating for those trying to assist the design process with computer-based, problem-solving techniques. By the time the problem has been defined, it has been solved. Indeed the solution is often the very definition of the problem. Design must be creative-or it is mere imitation. But since this crucial creative leap seem inevitable after the event, the question must arise, can we find some way of searching the space ahead? Of course there are serious problems of knowing what we are looking for and the vastness of the search space. It may be better to discard altogether the term "searching" in the context of the design process: Conceptual analogies such as search, search spaces and fitness landscapes aim to elucidate the design process. However, the vastness of the multidimensional spaces involved make these analogies misguided and they thereby actually result in further confounding the issue. The term search becomes a misnomer since it has connotations that imply that it is possible to find what you are looking for. In such vast spaces the term search must be discarded. Thus, any attempt at searching for the highest peak in the fitness landscape as an optimal solution is also meaningless. Futhermore, even the very existence of a fitness landscape is fallacious. Although alternatives in the same region of the vast space can be compared to one another, distant alternatives will stem from radically different roots and will therefore not be comparable in any straightforward manner (Janssen 2000). Nevertheless we still have this tantalizing possibility that if a creative idea seems inevitable after the event, then somehow might the process be rserved? This may be as improbable as attempting to reverse time. A more helpful analogy is from nature, where it is generally assumed that the process of evolution is not long-term goal directed or teleological. Dennett points out a common minsunderstanding of Darwinism: the idea that evolution by natural selection is a procedure for producing human beings. Evolution can have produced humankind by an algorithmic process, without its being true that evolution is an algorithm for producing us. If we were to wind the tape of life back and run this algorithm again, the likelihood of "us" being created again is infinitesimally small (Gould 1989; Dennett 1995). But nevertheless Mother Nature has proved a remarkably successful, resourceful, and imaginative inventor generating a constant flow of incredible new design ideas to fire our imagination. Hence the current interest in the potential of the evolutionary paradigm in design. These evolutionary methods are frequently based on techniques such as the application of evolutionary algorithms that are usually thought of as search algorithms. It is necessary to abandon such connections with searching and see the evolutionary algorithm as a direct analogy with the evolutionary processes of nature. The process of natural selection can generate a wealth of alternative experiements, and the better ones survive. There is no one solution, there is no optimal solution, but there is continuous experiment. Nature is profligate with her prototyping and ruthless in her elimination of less successful experiments. Most importantly, nature has all the time in the world. As designers we cannot afford prototyping and ruthless experiment, nor can we operate on the time scale of the natural design process. Instead we can use the computer to compress space and time and to perform virtual prototyping and evaluation before committing ourselves to actual prototypes. This is the hypothesis underlying the evolutionary paradigm in design (1992, 1995).

A new measure to quantify chest wall deformity in scoliosis patients : does rib hump measurement correlate with anterior chest wall deformity post surgery?

The primary aims of scoliosis surgery are to halt the progression of the deformity, and to reduce its severity (cosmesis). Currently, deformity correction is measured in terms of posterior parameters (Cobb angles and rib hump), even though the cosmetic concern for most patients is anterior chest wall deformity. In this study, we propose a new measure for assessing anterior chest wall deformity and examine the correlation between rib hump and the new measure. 22 sets of CT scans were retrieved from the QUT/Mater Paediatric Spinal Research Database. The Image J software (NIH) was used to manipulate formatted CT scans into 3-dimensional anterior chest wall reconstructions. A ‘chest wall angle’ was then measured in relation to the first sacral vertebral body. The chest wall angle was found to be a reliable tool in the analysis of chest wall deformity. No correlation was found between the new measure and rib hump angle. Since rib hump has been shown to correlate with vertebral rotation on CT, this suggests that there maybe no correlation between anterior and posterior deformity measures. While most surgical procedures will adequately address the coronal imbalance & posterior rib hump elements of scoliosis, they do not reliably alter the anterior chest wall shape. This implies that anterior chest wall deformity is to a large degree an intrinsic deformity, not directly related to vertebral rotation.

Experience of problem-based learning (PBL) in virtual space : a phenomenographical study

This thesis reports the outcomes of an investigation into students’ experience of Problem-based learning (PBL) in virtual space. PBL is increasingly being used in many fields including engineering education. At the same time many engineering education providers are turning to online distance education. Unfortunately there is a dearth of research into what constitutes an effective learning experience for adult learners who undertake PBL instruction through online distance education. Research was therefore focussed on discovering the qualitatively different ways that students experience PBL in virtual space. Data was collected in an electronic environment from a course, which adopted the PBL strategy and was delivered entirely in virtual space. Students in this course were asked to respond to open-ended questions designed to elicit their learning experience in the course. Data was analysed using the phenomenographical approach. This interpretative research method concentrated on mapping the qualitative differences in students’ interpretations of their experience in the course. Five qualitatively different ways of experiencing were discovered: Conception 1: ‘A necessary evil for program progression’; Conception 2: ‘Developing skills to understand, evaluate, and solve technical Engineering and Surveying problems’; Conception 3: ‘Developing skills to work effectively in teams in virtual space’; Conception 4: ‘A unique approach to learning how to learn’; Conception 5: ‘Enhancing personal growth’. Each conception reveals variation in how students attend to learning by PBL in virtual space. Results indicate that the design of students’ online learning experience was responsible for making students aware of deeper ways of experiencing PBL in virtual space. Results also suggest that the quality and quantity of interaction with the team facilitator may have a significant impact on the student experience in virtual PBL courses. The outcomes imply pedagogical strategies can be devised for shifting students’ focus as they engage in the virtual PBL experience to effectively manage the student learning experience and thereby ensure that they gain maximum benefit. The results from this research hold important ramifications for graduates with respect to their ease of transition into professional work as well as their later professional competence in terms of problem solving, ability to transfer basic knowledge to real-life engineering scenarios, ability to adapt to changes and apply knowledge in unusual situations, ability to think critically and creatively, and a commitment to continuous life-long learning and self-improvement.

Implication of 3D culture system for study of prostate cancer (CaP) mediated bone metastasis

Introduction : For the past decade, three dimensional (3D) culture has served as a foundation for regenerative medicine study. With an increasing awareness of the importance of cell-cell and cell-extracellular matrix interactions which are lacking in 2D culture system, 3D culture system has been employed for many other applications namely cancer research. Through development of various biomaterials and utilization of tissue engineering technology, many in vivo physiological responses are now better understood. The cellular and molecular communication of cancer cells and their microenvironment, for instance can be studied in vitro in 3D culture system without relying on animal models alone. Predilection of prostate cancer (CaP) to bone remains obscure due to the complexity of the mechanisms and lack of proper model for the studies. In this study, we aim to investigate the interaction between CaP cells and osteoblasts simulating the natural bone metastasis. We also further investigate the invasiveness of CaP cells and response of androgen sensitve CaP cells, LNCaP to synthetic androgen.----- Method : Human osteoblast (hOB) scaffolds were prepared by seeding hOB on medical grade polycaprolactone-tricalcium phosphate (mPLC-TCP) scaffolds and induced to produce bone matrix. CaP cell lines namely wild type PC3 (PC3-N), overexpressed prostate specific antigen PC3 (PC3k3s5) and LNCaP were seeded on hOB scaffolds as co-cultures. Morphology of cells was examined by Phalloidin-DAPI and SEM imaging. Gelatin zymography was performed on the 48 hours conditioned media (CM) from co-cultures to determine matrix metalloproteinase (MMP) activity. Gene expression of hOB/LNCaP co-cultures which were treated for 48 hours with 1nM synthetic androgen R1881 were analysed by quantitative real time PCR (qRT-PCR).----- Results : Co-culture of PCC/hOB revealed that the morphology of PCCs on the tissue engineered bone matrix varied from homogenous to heterogenous clusters. Enzymatically inactive pro-MMP2 was detected in CM from hOBs and PCCs cultured on scaffolds. Elevation in MMP9 activity was found only in hOB/PC3N co-culture. hOB/LNCaP co-culture showed increase in expression of key enzymes associated with steroid production which also corresponded to an increase in prostate specific antigen (PSA) and MMP9.----- Conclusions : Upregulation of MMP9 indicates involvement of ECM degradation during cancer invasion and bone metastases. Expression of enzymes involved in CaP progression, PSA, which is not expressed in osteoblasts, demonstrates that crosstalk between PCCs and osteoblasts may play a part in the aggressiveness of CaP. The presence of steroidogenic enzymes, particularly, RDH5, in osteoblasts and stimulated expression in co-culture, may indicate osteoblast production of potent androgens, fuelling cancer cell proliferation. Based on these results, this practical 3D culture system may provide greater understanding into CaP mediated bone metastasis. This allows the role of the CaP/hOB interaction with regards to invasive property and steroidogenesis to be further explored.

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.

Defining an Identity : The Evolution of Science Education

Research in science education is now an international activity. This book asks for the first time, Does this research activity have an identity?-It uses the significant studies of more than 75 researchers in 15 countries to see to what extent they provide evidence for an identity as a distinctive field of research.-It considers trends in the research over time, and looks particularly at what progression in the research entails.-It provides insight into how researchers influence each other and how involvement in research affects the being of the researcher as a person.-It addresses the relation between research and practice in a manner that sees teaching and learning in the science classroom as interdependent with national policies and curriculum traditions about science. It gives graduate students and other early researchers an unusual overview of their research area as a whole. Established researchers will be interested in, and challenged by, the identity the author ascribes to the research and by the plea he makes for the science content itself to be seen as problematic.

Property Education : an evaluation of how well undergraduate property students are prepared for commencing their careers

The evolution of property education to adapt to the changing business environment requires changes to course content, method of delivery and assessment. Many universities have a special interest in understanding how the students transition in and transition out of the property programs. The impact of the first year student experience is often easier to assess through students’ progression in the course and performance in their intermediate and advanced units. However, the students’ success in transitioning from university student to property professional is often more difficult to determine. In an environment where many property students commence their professional careers while still completing their undergraduate property qualification, a survey of current final year students was undertaken to identify the students’ perception of their level of preparedness for entry into the professional world. This study has also been informed by feedback received from and informal discussions held with industry representative bodies, alumni and senior members of professional organisations. The QUT UD40 Bachelor of Urban Development, Property Economics course has been designed to achieve graduate capabilities in core technical skills and generic professional skills which are required by property professionals. The results of this study were that some units in the program were perceived to provide direct preparation for students commencing their professional careers whilst the impact of other units was less tangible. Valuable feedback received during the study included an assessment of the relevance of many multi-disciplinary units, the appropriateness of the programming of units within the course and the appropriateness of repetition of content during the course. The further research question arises as to how universities can better assist students in the transition to the professional environment when frequently this occurs prior to completion of the property course.

Modulation of the SHBG signalling axis

Sex hormone-binding globulin (SHBG) is a homodimeric plasma glycoprotein that is the major sex steroid carrier-protein in the bloodstream and functions also as a key regulator of steroid bioavailability within target tissues, such as the prostate. Additionally, SHBG binds to prostatic cell membranes via the putative and unidentified SHBG receptor (RSHBG), activating a signal transduction pathway implicated in stimulating both proliferation and expression of prostate specific antigen (PSA) in prostate cell lines in vitro. A yeast-two hybrid assay suggested an interaction between SHBG and kallikrein-related protease (KLK) 4, which is a serine protease implicated in the progression of prostate cancer. The potential interaction between these two proteins was investigated in this PhD thesis to determine whether SHBG is a proteolytic substrate of KLK4 and other members of the KLK family including KLK3/PSA, KLK7 and KLK14. Furthermore, the effects from SHBG proteolytic degradation on SHBG-regulated steroid bioavailability and the activation of the putative RSHBG signal transduction pathway were examined in the LNCaP prostate cancer cell line. SHBG was found to be a proteolytic substrate of the trypsin-like KLK4 and KLK14 in vitro, yielding several proteolysis fragments. Both chymotrypsin-like PSA and KLK7 displayed insignificant proteolytic activity against SHBG. The kinetic parameters of SHBG proteolysis by KLK4 and KLK14 demonstrate a strong enzyme-substrate binding capacity, possessing a Km of 1.2 ± 0.7 µM and 2.1 ± 0.6 µM respectively. The catalytic efficiencies (kcat/Km) of KLK4 and KLK14 proteolysis of SHBG were 1.6 x 104 M-1s-1 and 3.8 x 104 M-1s-1 respectively, which were comparable to parameters previously reported for peptide substrates. N-terminal sequencing of the fragments revealed cleavage near the junction of the N- and C-terminal laminin globulin-like (G-like) domains of SHBG, resulting in the division of the two globulins and ultimately the full degradation of these fragments by KLK4 and KLK14 over time. Proteolytic fragments that may retain steroid binding were rapidly degraded by both proteases, while fragments containing residues beyond the steroid binding pocket were less degraded over the same period of time. Degradation of SHBG was inhibited by the divalent metal cations calcium and zinc for KLK4, and calcium, zinc and magnesium for KLK14. The human secreted serine protease inhibitors (serpins), α1-antitrypsin and α2-antiplasmin, inhibited KLK4 and KLK14 proteolysis of SHBG; α1-antichymotrypsin inhibited KLK4 but not KLK14 activity. The inhibition by these serpins was comparable and in some cases more effective than general trypsin protease inhibitors such as aprotinin and phenylmethanesulfonyl fluoride (PMSF). The binding of 5α-dihydrotestosterone (DHT) to SHBG modulated interactions with KLK4 and KLK14. Steroid-free SHBG was more readily digested by both enzymes than DHT-bound SHBG. Moreover, a binding interaction exists between SHBG and pro-KLK4 and pro-KLK14, with DHT strengthening the binding to pro-KLK4 only. The inhibition of androgen uptake by cultured prostate cancer cells, mediated by SHBG steroid-binding, was examined to assess whether SHBG proteolysis by KLK4 and KLK14 modulated this process. Proteolytic digestion eliminated the ability of SHBG to inhibit the uptake of DHT from conditioned media into LNCaP cells. Therefore, the proteolysis of SHBG by KLK4 and KLK14 increased steroid bioavailability in vitro, leading to an increased uptake of androgens by prostate cancer cells. Interestingly, different transcriptional responses of PSA and KLK2, which are androgen-regulated genes, to DHT-bounsd SHBG treatment were observed between low and high passage number LNCaP cells (lpLNCaP and hpLNCaP respectively). HpLNCaP cells treated with DHT-bound SHBG demonstrated a significant synergistic upregulation of PSA and KLK2 above DHT or SHBG treatment alone, which is similar to previously reported downstream responses from RSHBG-mediated signaling activation. As this result was not seen in lpLNCaP cells, only hpLNCaP cells were further investigated to examine the modulation of potential RSHBG activity by KLK4 and KLK14 proteolysis of SHBG. Contrary to reported results, no increase in intracellular cAMP was observed in hpLNCaP cells when treated with SHBG in the presence and absence of either DHT or estradiol. As a result, the modulation of RSHBG-mediated signaling activation could not be determined. Finally, the identification of the RSHBG from both breast (MCF-7) and prostate cancer (LNCaP) cell lines was attempted. Fluorescently labeled peptides corresponding to the putative receptor binding domain (RBD) of SHBG were shown to be internalized by MCF-7 cells. Crosslinking of the RBD peptide to the cell surfaces of both MCF-7 and LNCaP cells, demonstrated the interaction of the peptide with several targets. These targets were then captured using RBD peptides synthesized onto a hydrophilic scaffold and analysed by mass spectrometry. The samples captured by the RBD peptide returned statistically significantly matches for cytokeratin 8, 18 and 19 as well as microtubule-actin crosslinking factor 1, which may indicate a novel interaction between SHBG and these proteins, but ultimately failed to detect a membrane receptor potentially responsible for the putative RSHBG-mediated signaling. This PhD project has reported the proteolytic processing of SHBG by two members of the kallikrein family, KLK4 and KLK14. The effect of SHBG proteolysis by KLK4 and KLK14 on RSHBG-mediated signaling activation was unable to be determined as the reported signal transduction pathway was not activated after treatment with SHBG, in combination with either DHT or estradiol. However, the digestion of SHBG by these two proteases positively regulated androgen bioavailability to prostate cancer cells in vitro. The increased uptake of androgens is deleterious in prostate cancer due to the promotion of proliferation, metastasis, invasion and the inhibition of apoptosis. The increased bioavailability of androgens, from SHBG proteolysis by KLK4 and KLK14, may therefore promote both carcinogenesis and progression of prostate cancer. Finally, this information may contribute to the development of therapeutic treatment strategies for prostate cancer by inhibiting the proteolysis of SHBG, by KLK4 and KLK14, to prevent the increased uptake of androgens by hormone-dependent cancerous tissues.

The stimulation of healing within a rat calvarial defect by mPCL–TCP/collagen scaffolds loaded with rhBMP-2

Bone morphogenetic proteins (BMPs) have been widely investigated for their clinical use in bone repair and it is known that a suitable carrier matrix to deliver them is essential for optimal bone regeneration within a specific defect site. Fused deposited modeling (FDM) allows for the fabrication of medical grade poly 3-caprolactone/tricalcium phosphate (mPCL–TCP) scaffolds with high reproducibility and tailor designed dimensions. Here we loaded FDM fabricated mPCL–TCP/collagen scaffolds with 5 mg recombinant human (rh)BMP-2 and evaluated bone healing within a rat calvarial critical-sized defect. Using a comprehensive approach, this study assessed the newly regenerated bone employing microcomputed tomography (mCT), histology/histomorphometry, and mechanical assessments. By 15 weeks, mPCL–TCP/collagen/rhBMP-2 defects exhibited complete healing of the calvarium whereas the non- BMP-2-loaded scaffolds showed significant less bone ingrowth, as confirmed by mCT. Histomorphometry revealed significantly increased bone healing amongst the rhBMP-2 groups compared to non-treated scaffolds at 4 and 15 weeks, although the % BV/TV did not indicate complete mineralisation of the entire defect site. Hence, our study confirms that it is important to combine microCt and histomorphometry to be able to study bone regeneration comprehensively in 3D. A significant up-regulation of the osteogenic proteins, type I collagen and osteocalcin, was evident at both time points in rhBMP-2 groups. Although mineral apposition rates at 15 weeks were statistically equivalent amongst treatment groups, microcompression and push-out strengths indicated superior bone quality at 15 weeks for defects treated with mPCL–TCP/collagen/rhBMP-2. Consistently over all modalities, the progression of healing was from empty defect < mPCL–TCP/collagen < mPCL–TCP/collagen/rhBMP-2, providing substantiating data to support the hypothesis that the release of rhBMP-2 from FDM-created mPCL–TCP/collagen scaffolds is a clinically relevant approach to repair and regenerate critically-sized craniofacial bone defects. Crown Copyright 2008 Published by Elsevier Ltd. All rights reserved.

Automating human thought processes for a UAV forced landing

This paper describes the current status of a program to develop an automated forced landing system for a fixed-wing Unmanned Aerial Vehicle (UAV). This automated system seeks to emulate human pilot thought processes when planning for and conducting an engine-off emergency landing. Firstly, a path planning algorithm that extends Dubins curves to 3D space is presented. This planning element is then combined with a nonlinear guidance and control logic, and simulated test results demonstrate the robustness of this approach to strong winds during a glided descent. The average path deviation errors incurred are comparable to or even better than that of manned, powered aircraft. Secondly, a study into suitable multi-criteria decision making approaches and the problems that confront the decision-maker is presented. From this study, it is believed that decision processes that utilize human expert knowledge and fuzzy logic reasoning are most suited to the problem at hand, and further investigations will be conducted to identify the particular technique/s to be implemented in simulations and field tests. The automated UAV forced landing approach presented in this paper is promising, and will allow the progression of this technology from the development and simulation stages through to a prototype system

Early objective detection of lymphoedema

The aetiology of secondary lymphoedema seems to be multifactorial, with acquired abnormalities as well as pre-existing conditions being contributory factors. Many characteristics bear inconsistent relationships to lymphoedema risk, and the few that are consistently associated with an increased risk of developing the condition, do not alone distinguish the at-risk population. Further, our current prevention and management recommendations are not backed by strong evidence. Consequently, there remains much to be learned about who gets it, how can it be prevented and how can we best treat it. Nonetheless, it is clear that lymphoedema is associated with adverse side effects, which have a profound impact on daily life, and that preliminary evidence suggests that early detection may lead to more effective treatment and lack of treatment may lead to progression. These represent important reasons as to why lymphoedema deserves clinical attention. However, several pragmatic issues must be considered when discussing whether a routine objective measure of lymphoedema could be integrated among the standard clinical care of those undertaking treatment for cancers known to be associated with the development of lymphoedema.