Modeling prostate cancer: a perspective on transgenic mouse models

Despite considerable success in treatment of early stage localized prostate cancer (PC), acute inadequacy of late stage PC treatment and its inherent heterogeneity poses a formidable challenge. Clearly, an improved understanding of PC genesis and progression along with the development of new targeted therapies are warranted. Animal models, especially, transgenic immunocompetent mouse models, have proven to be the best ally in this respect. A series of models have been developed by modulation of expression of genes implicated in cancer-genesis and progression; mainly, modulation of expression of oncogenes, steroid hormone receptors, growth factors and their receptors, cell cycle and apoptosis regulators, and tumor suppressor genes have been used. Such models have contributed significantly to our understanding of the molecular and pathological aspects of PC initiation and progression. In particular, the transgenic mouse models based on multiple genetic alterations can more accurately address the inherent complexity of PC, not only in revealing the mechanisms of tumorigenesis and progression but also for clinically relevant evaluation of new therapies. Further, with advances in conditional knockout technologies, otherwise embryonically lethal gene changes can be incorporated leading to the development of new generation transgenics, thus adding significantly to our existing knowledge base. Different models and their relevance to PC research are discussed.

Cholesterol enhances phospholipid-dependent activated protein C anticoagulant activity

The influence of cholesterol on activated protein C (APC) anticoagulant activity in plasma and on factor Va inactivation was investigated. Anticoagulant and procoagulant activities of phosphatidylcholine/phosphatidylserine (PC/PS) vesicles containing cholesterol were assessed in the presence and absence of APC using factor Xa-1-stage clotting and factor Va inactivation assays. Cholesterol at approximate physiological membrane levels (30%) in PC/PS (60%/10% w/w) vesicles prolonged the factor Xa-1-stage clotting time dose-dependently in the presence of APC but not in the absence of APC. APC-mediated cleavage of purified recombinant factor Va variants that were modified at specific APC cleavage sites (Q306/Q679-factor Va; Q506/Q679-factor Va) was studied to define the effects of cholesterol on APC cleavage at R506 and R306. When compared to control PC/PS vesicles, cholesterol in PC/PS vesicles enhanced factor Va inactivation and the rate of APC cleavage at both R506 and R306. Cholesterol also enhanced APC cleavage rates at R306 in the presence of the APC cofactor, protein S. In summary, APC anticoagulant activity in plasma and factor Va inactivation as a result of cleavages at R506 and R306 by APC is markedly enhanced by cholesterol in phospholipid vesicles. These results suggest that cholesterol in a membrane surface may selectively enhance APC activities. © 2005 International Society on Thrombosis and Haemostasis.

Thermal performance optimization of building aspect ratio and south window size in five cities having different climatic characteristics of Turkey

The aim of the study is to establish optimum building aspect ratios and south window sizes of residential buildings from thermal performance point of view. The effects of 6 different building aspect ratios and eight different south window sizes for each building aspect ratio are analyzed for apartments located at intermediate floors of buildings, by the aid of the computer based thermal analysis program SUNCODE-PC in five cities of Turkey: Erzurum, Ankara, Diyarbakir, Izmir, and Antalya. The results are evaluated in terms of annual energy consumption and the optimum values are driven. Comparison of optimum values and the total energy consumption rates is made among the analyzed cities.

A hardware-based multi-disciplinary design optimization method for aeronautical applications

There are many applications in aeronautics where there exist strong couplings between disciplines. One practical example is within the context of Unmanned Aerial Vehicle(UAV) automation where there exists strong coupling between operation constraints, aerodynamics, vehicle dynamics, mission and path planning. UAV path planning can be done either online or offline. The current state of path planning optimisation online UAVs with high performance computation is not at the same level as its ground-based offline optimizer's counterpart, this is mainly due to the volume, power and weight limitations on the UAV; some small UAVs do not have the computational power needed for some optimisation and path planning task. In this paper, we describe an optimisation method which can be applied to Multi-disciplinary Design Optimisation problems and UAV path planning problems. Hardware-based design optimisation techniques are used. The power and physical limitations of UAV, which may not be a problem in PC-based solutions, can be approached by utilizing a Field Programmable Gate Array (FPGA) as an algorithm accelerator. The inevitable latency produced by the iterative process of an Evolutionary Algorithm (EA) is concealed by exploiting the parallelism component within the dataflow paradigm of the EA on an FPGA architecture. Results compare software PC-based solutions and the hardware-based solutions for benchmark mathematical problems as well as a simple real world engineering problem. Results also indicate the practicality of the method which can be used for more complex single and multi objective coupled problems in aeronautical applications.

Broadening of transgenic adenocarcinoma of the mouse prostate (TRAMP) model to represent late stage androgen depletion independent cancer

BACKGROUND The transgenic adenocarcinoma of the mouse prostate (TRAMP) model closely mimics PC-progression as it occurs in humans. However, the timing of disease incidence and progression (especially late stage) makes it logistically difficult to conduct experiments synchronously and economically. The development and characterization of androgen depletion independent (ADI) TRAMP sublines are reported. METHODS Sublines were derived from androgen-sensitive TRAMP-C1 and TRAMP-C2 cell lines by androgen deprivation in vitro and in vivo. Epithelial origin (cytokeratin) and expression of late stage biomarkers (E-cadherin and KAI-1) were evaluated using immunohistochemistry. Androgen receptor (AR) status was assessed through quantitative real time PCR, Western blotting, and immunohistochemistry. Coexpression of AR and E-cadherin was also evaluated. Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays. Proliferation/survival of sublines in response to androgen was assessed by WST-1 assay. In vivo growth of subcutaneous tumors was assessed in castrated and sham-castrated C57BL/6 mice. RESULTS The sublines were epithelial and displayed ADI in vitro and in vivo. Compared to the parental lines, these showed (1) significantly faster growth rates in vitro and in vivo independent of androgen depletion, (2) greater tumorigenic, and invasive potential in vitro. All showed substantial downregulation in expression levels of tumor suppressor, E-cadherin, and metastatis suppressor, KAI-1. Interestingly, the percentage of cells expressing AR with downregulated E-cadherin was higher in ADI cells, suggesting a possible interaction between the two pathways. CONCLUSIONS The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness.

An FPGA-based approach to multi-objective evolutionary algorithm for multi-disciplinary design optimisation

This paper investigates the field programmable gate array (FPGA) approach for multi-objective and multi-disciplinary design optimisation (MDO) problems. One class of optimisation method that has been well-studied and established for large and complex problems, such as those inherited in MDO, is multi-objective evolutionary algorithms (MOEAs). The MOEA, nondominated sorting genetic algorithm II (NSGA-II), is hardware implemented on an FPGA chip. The NSGA-II on FPGA application to multi-objective test problem suites has verified the designed implementation effectiveness. Results show that NSGA-II on FPGA is three orders of magnitude better than the PC based counterpart.

The rise of co-creative consumers : user experience sharing behaviour in online communities

This thesis examines consumer initiated value co-creation behaviour in the context of convergent mobile online services using a Service-Dominant logic (SD logic) theoretical framework. It focuses on non-reciprocal marketing phenomena such as open innovation and user generated content whereby new viable business models are derived and consumer roles and community become essential to the success of business. Attention to customers. roles and personalised experiences in value co-creation has been recognised in the literature (e.g., Prahalad & Ramaswamy, 2000; Prahalad, 2004; Prahalad & Ramaswamy, 2004). Similarly, in a subsequent iteration of their 2004 version of the foundations of SD logic, Vargo and Lusch (2006) replaced the concept of value co-production with value co-creation and suggested that a value co-creation mindset is essential to underpin the firm-customer value creation relationship. Much of this focus, however, has been limited to firm initiated value co-creation (e.g., B2B or B2C), while consumer initiated value creation, particularly consumer-to-consumer (C2C) has received little attention in the SD logic literature. While it is recognised that not every consumer wishes to make the effort to engage extensively in co-creation processes (MacDonald & Uncles, 2009), some consumers may not be satisfied with a standard product, instead they engage in the effort required for personalisation that potentially leads to greater value for themselves, and which may benefit not only the firm, but other consumers as well. Literature suggests that there are consumers who do, and as a result initiate such behaviour and expend effort to engage in co-creation activity (e.g., Gruen, Osmonbekov and Czaplewski, 2006; 2007 MacDonald & Uncles, 2009). In terms of consumers. engagement in value proposition (co-production) and value actualisation (co-creation), SD logic (Vargo & Lusch, 2004, 2008) provides a new lens that enables marketing scholars to transcend existing marketing theory and facilitates marketing practitioners to initiate service centric and value co-creation oriented marketing practices. Although the active role of the consumer is acknowledged in the SD logic oriented literature, we know little about how and why consumers participate in a value co-creation process (Payne, Storbacka, & Frow, 2008). Literature suggests that researchers should focus on areas such as C2C interaction (Gummesson 2007; Nicholls 2010) and consumer experience sharing and co-creation (Belk 2009; Prahalad & Ramaswamy 2004). In particular, this thesis seeks to better understand consumer initiated value co-creation, which is aligned with the notion that consumers can be resource integrators (Baron & Harris, 2008) and more. The reason for this focus is that consumers today are more empowered in both online and offline contexts (Füller, Mühlbacher, Matzler, & Jawecki, 2009; Sweeney, 2007). Active consumers take initiatives to engage and co-create solutions with other active actors in the market for their betterment of life (Ballantyne & Varey, 2006; Grönroos & Ravald, 2009). In terms of the organisation of the thesis, this thesis first takes a „zoom-out. (Vargo & Lusch, 2011) approach and develops the Experience Co-Creation (ECo) framework that is aligned with balanced centricity (Gummesson, 2008) and Actor-to-Actor worldview (Vargo & Lusch, 2011). This ECo framework is based on an extended „SD logic friendly lexicon. (Lusch & Vargo, 2006): value initiation and value initiator, value-in-experience, betterment centricity and betterment outcomes, and experience co-creation contexts derived from five gaps identified from the SD logic literature review. The framework is also designed to accommodate broader marketing phenomena (i.e., both reciprocal and non-reciprocal marketing phenomena). After zooming out and establishing the ECo framework, the thesis takes a zoom-in approach and places attention back on the value co-creation process. Owing to the scope of the current research, this thesis focuses specifically on non-reciprocal value co-creation phenomena initiated by consumers in online communities. Two emergent concepts: User Experience Sharing (UES) and Co-Creative Consumers are proposed grounded in the ECo framework. Together, these two theorised concepts shed light on the following two propositions: (1) User Experience Sharing derives value-in-experience as consumers make initiative efforts to participate in value co-creation, and (2) Co-Creative Consumers are value initiators who perform UES. Three research questions were identified underpinning the scope of this research: RQ1: What factors influence consumers to exhibit User Experience Sharing behaviour? RQ2: Why do Co-Creative Consumers participate in User Experience Sharing as part of value co-creation behaviour? RQ3: What are the characteristics of Co-Creative Consumers? To answer these research questions, two theoretical models were developed: the User Experience Sharing Behaviour Model (UESBM) grounded in the Theory of Planned Behaviour framework, and the Co-Creative Consumer Motivation Model (CCMM) grounded in the Motivation, Opportunity, Ability framework. The models use SD logic consistent constructs and draw upon multiple streams of literature including consumer education, consumer psychology and consumer behaviour, and organisational psychology and organisational behaviour. These constructs include User Experience Sharing with Other Consumers (UESC), User Experience Sharing with Firms (UESF), Enjoyment in Helping Others (EIHO), Consumer Empowerment (EMP), Consumer Competence (COMP), and Intention to Engage in User Experience Sharing (INT), Attitudes toward User Experience Sharing (ATT) and Subjective Norm (SN) in the UESBM, and User Experience Sharing (UES), Consumer Citizenship (CIT), Relating Needs of Self (RELS) and Relating Needs of Others (RELO), Newness (NEW), Mavenism (MAV), Use Innovativeness (UI), Personal Initiative (PIN) and Communality (COMU) in the CCMM. Many of these constructs are relatively new to marketing and require further empirical evidence for support. Two studies were conducted to underpin the corresponding research questions. Study One was conducted to calibrate and re-specify the proposed models. Study Two was a replica study to confirm the proposed models. In Study One, data were collected from a PC DIY online community. In Study Two, a majority of data were collected from Apple product online communities. The data were examined using structural equation modelling and cluster analysis. Considering the nature of the forums, the Study One data is considered to reflect some characteristics of Prosumers and the Study Two data is considered to reflect some characteristics of Innovators. The results drawn from two independent samples (N = 326 and N = 294) provide empirical support for the overall structure theorised in the research models. The results in both models show that Enjoyment in Helping Others and Consumer Competence in the UESBM, and Consumer Citizenship and Relating Needs in CCMM have significant impacts on UES. The consistent results appeared in both Study One and Study Two. The results also support the conceptualisation of Co-Creative Consumers and indicate Co-Creative Consumers are individuals who are able to relate the needs of themselves and others and feel a responsibility to share their valuable personal experiences. In general, the results shed light on "How and why consumers voluntarily participate in the value co-creation process?. The findings provide evidence to conceptualise User Experience Sharing behaviour as well as the Co-Creative Consumer using the lens of SD logic. This research is a pioneering study that incorporates and empirically tests SD logic consistent constructs to examine a particular area of the logic – that is consumer initiated value co-creation behaviour. This thesis also informs practitioners about how to facilitate and understand factors that engage with either firm or consumer initiated online communities.

The expression, regulation and function of kallikrein 4 in prostate cancer

Prostate cancer is a significant health problem faced by aging men. Currently, diagnostic strategies for the detection of prostate cancer are either unreliable, yielding high numbers of false positive results, or too invasive to be used widely as screening tests. Furthermore, the current therapeutic strategies for the treatment of the disease carry considerable side effects. Although organ confined prostate cancer can be curable, most detectable clinical symptoms occur in advanced disease when primary tumour cells have metastasised to distant sites - usually lymph nodes and bone. Many growth factors and steroids assist the continued growth and maintenance of prostatic tumour cells. Of these mitogens, androgens are important in the development of the normal prostate but are also required to sustain the growth of prostate cancer cells in the early stage of the disease. Not only are androgens required in the early stage of disease, but also many other growth factors and hormones interact to cause uncontrolled proliferation of malignant cells. The early, androgen sensitive phase of disease is followed by an androgen insensitive phase, whereby androgens are no longer required to stimulate the growth of the tumour cells. Growth factors such as transforming growth factor  and  (TGF/), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factors (IGFs), Vitamin D and thyroid hormone have been suggested to be important at this stage of disease. Interestingly, some of the kallikrein family of genes, including prostate specific antigen (PSA), the current serum diagnostic marker for prostate cancer, are regulated by androgens and many of the aforementioned growth factors. The kallikrein gene family is a group of serine proteases that are involved in a diverse range of physiological processes: regulation of local blood flow, angiogenesis, tissue invasion and mitogenesis. The earliest members of the kallikrein gene family (KLK1-KLK3) have been strongly associated with general disease states, such as hypertension, inflammation, pancreatitis and renal disease, but are also linked to various cancers. Recently, this family was extended to include 15 genes (KLK1-15). Several newer members of the kallikrein family have been implicated in the carcinogenesis and tumour metastasis of hormone-dependent cancers such as prostate, breast, endometrial and ovarian cancer. The aims of this project were to investigate the expression of the newly identified kallikrein, KLK4, in benign and malignant prostate tissues, and prostate cancer cell lines. This thesis has demonstrated the elevated expression of KLK4 mRNA transcripts in malignant prostate tissue compared to benign prostates. Additionally, expression of the full length KLK4 transcript was detected in the androgen dependent prostate cancer cell line, LNCaP. Based on the above finding, the LNCaP cell line was chosen to assess the potential regulation of full length KLK4 by androgen, thyroid hormone and epidermal growth factor. KLK4 mRNA and protein was found to be up-regulated by androgen and a combination of androgen and thyroid hormone. Thyroid hormone alone produced no significant change in KLK4 mRNA or protein over the control. Epidermal growth factor treatment also resulted in elevated expression levels of KLK4 mRNA and protein. To assess the potential functional role(s) of KLK4/hK4 in processes associated with tumour progression, full length KLK4 was transfected into PC-3 cells - a prostate cancer cell line originally derived from a secondary bone lesion. The KLK4/hK4 over-expressing cells were assessed for their proliferation, migration, invasion and attachment properties. The KLK4 over-expressing clones exhibited a marked change in morphology, indicative of a more aggressive phenotype. The KLK4 clones were irregularly shaped with compromised adhesion to the growth surface. In contrast, the control cell lines (parent PC-3 and empty vector clones) retained a rounded morphology with obvious cell to cell adhesion, as well as significant adhesion to their growth surface. The KLK4 clones exhibited significantly greater attachment to Collagen I and IV than native PC-3s and empty vector controls. Over a 12 hour period, in comparison to the control cells, the KLK4 clones displayed an increase in migration towards PC-3 native conditioned media, a 3 fold increase towards conditioned media from an osteoblastic cell line (Saos-2) and no change in migration towards conditioned media from neonatal foreskin fibroblast cells or 20% foetal bovine serum. Furthermore, the increase in migration exhibited by the KLK4 clones was partially blocked by the serine protease inhibitor, aprotinin. The data presented in this thesis suggests that KLK4/hK4 is important in prostate carcinogenesis due to its over-expression in malignant prostate tissues, its regulation by hormones and growth factors associated with prostate disease and the functional consequences of over-expression of KLK4/hK4 in the PC-3 cell line. These results indicate that KLK4/hK4 may play an important role in tumour invasion and bone metastasis via increased attachment to the bone matrix protein, Collagen I, and enhanced migration due to soluble factors produced by osteoblast cells. This suggestion is further supported by the morphological changes displayed by the KLK4 over-expressing cells. Overall, this data suggests that KLK4/hK4 should be further studied to more fully investigate the potential value of KLK4/hK4 as a diagnostic/prognostic biomarker or in therapeutic applications.

Speeding by young novice drivers : what can personal characteristics and psychosocial theory add to our understanding?

Purpose: Young novice drivers continue to be overrepresented in fatalities and injuries arising from crashes even with the introduction of countermeasures such as graduated driver licensing (GDL). Enhancing countermeasures requires a better understanding of the variables influencing risky driving. One of the most common risky behaviours performed by drivers of all ages is speeding, which is particularly risky for young novice drivers who, due to their driving inexperience, have difficulty in identifying and responding appropriately to road hazards. Psychosocial theory can improve our understanding of contributors to speeding, thereby informing countermeasure development and evaluation. This paper reports an application of Akers’ social learning theory (SLT), augmented by Gerrard and Gibbons’ prototype/willingness model (PWM), in addition to personal characteristics of age, gender, car ownership, and psychological traits/states of anxiety, depression, sensation seeking propensity and reward sensitivity, to examine the influences on self-reported speeding of young novice drivers with a Provisional (intermediate) licence in Queensland, Australia. Method: Young drivers (n = 378) recruited in 2010 for longitudinal research completed two surveys containing the Behaviour of Young Novice Drivers Scale, and reported their attitudes and behaviours as pre-Licence/Learner (Survey 1) and Provisional (Survey 2) drivers and their sociodemographic characteristics. Results: An Akers’ measurement model was created. Hierarchical multiple regressions revealed that (1) personal characteristics (PC) explained 20.3%; (2) the combination of PC and SLT explained 41.1%; and (3) the combination of PC, SLT and PWM explained 53.7% of variance in self-reported speeding. Whilst there appeared to be considerable shared variance, the significant predictors in the final model included gender, car ownership, reward sensitivity, depression, personal attitudes, and Learner speeding. Conclusions: These results highlight the capacity for psychosocial theory to improve our understanding of speeding by young novice drivers, revealing relationships between previous behaviour, attitudes, psychosocial characteristics and speeding. The findings suggest multi-faceted countermeasures should target the risky behaviour of Learners, and Learner supervisors should be encouraged to monitor their Learners’ driving speed. Novice drivers should be discouraged from developing risky attitudes towards speeding.

Development of a 3D culture system to study the skeletal metastasis of prostate cancer

In the cancer research field, most in vitro studies still rely on two-dimensional (2D) cultures. However, the trend is rapidly shifting towards using a three-dimensional (3D) culture system. This is because 3D models better recapitulate the microenvironment of cells, and therefore, yield cellular and molecular responses that more accurately describe the pathophysiology of cancer. By adopting technology platforms established by the tissue engineering discipline, it is now possible to grow cancer cells in extracellular matrix (ECM)-like environments and dictate the biophysical and biochemical properties of the matrix. In addition, 3D models can be modified to recapitulate different stages of cancer progression for instance from the initial development of tumor to metastasis. Inevitably, to recapitulate a heterotypic condition, comprising more than one cell type, it requires a more complex 3D model. To date, 3D models that are available for studying the prostate cancer (CaP)-bone interactions are still lacking. Therefore, the aim of this study is to establish a co-culture model that allows investigation of direct and indirect CaP-bone interactions. Prior to that, 3D polyethylene glycol (PEG)-based hydrogel cultures for CaP cells were first developed and growth conditions were optimised. Characterization of the 3D hydrogel cultures show that LNCaP cells form a multicellular mass that resembles avascular tumor. In comparison to 2D cultures, besides the difference in cell morphology, the response of LNCaP cells to the androgen analogue (R1881) stimulation is different compared to the cells in 2D cultures. This discrepancy between 2D and 3D cultures is likely associated with the cell-cell contact, density and ligand-receptor interactions. Following the 3D monoculture study, a 3D direct co-culture model of CaP cells and the human tissue engineered bone (hTEBC) construct was developed. Interactions between the CaP cells and human osteoblasts (hOBs) resulted in elevation of Matrix Metalloproteinase 9 (MMP9) for PC-3 cells and Prostate Specific Antigen (PSA) for LNCaP cells. To further investigate the paracrine interaction of CaP cells and (hOBs), a 3D indirect co-culture model was developed, where LNCaP cells embedded within PEG hydrogels were co-cultured with hTEBC. It was found that the cellular changes observed reflect the early event of CaP colonizing the bone site. In the absence of androgens, interestingly, up-regulation of PSA and other kallikreins is also detected in the co-culture compared to the LNCaP monoculture. This non androgenic stimulation could be triggered by the soluble factors secreted by the hOB such as Interleukin-6. There are also decrease in alkaline phosphatase (ALP) activity and down-regulation of genes of the hOB when co-cultured with LNCaP cells that have not been previously described. These genes include transforming growth factor β1 (TGFβ1), osteocalcin and Vimentin. However, no changes to epithelial markers (e.g E-cadherin, Cytokeratin 8) were observed in both cell types from the co-culture. Some of these intriguing changes observed in the co-cultures that had not been previously described have enriched the basic knowledge of the CaP cell-bone interaction. From this study, we have shown evidence of the feasibility and versatility of our established 3D models. These models can be adapted to test various hypotheses for studies pertaining to underlying mechanisms of bone metastasis and could provide a vehicle for anticancer drug screening purposes in the future.

Chemopreventive effect of PSP through targeting of prostate cancer stem cell-like population

Recent evidence suggested that prostate cancer stem/progenitor cells (CSC) are responsible for cancer initiation as well as disease progression. Unfortunately, conventional therapies are only effective in targeting the more differentiated cancer cells and spare the CSCs. Here, we report that PSP, an active component extracted from the mushroom Turkey tail (also known as Coriolus versicolor), is effective in targeting prostate CSCs. We found that treatment of the prostate cancer cell line PC-3 with PSP led to the down-regulation of CSC markers (CD133 and CD44) in a time and dose-dependent manner. Meanwhile, PSP treatment not only suppressed the ability of PC-3 cells to form prostaspheres under non-adherent culture conditions, but also inhibited their tumorigenicity in vivo, further proving that PSP can suppress prostate CSC properties. To investigate if the anti-CSC effect of PSP may lead to prostate cancer chemoprevention, transgenic mice (TgMAP) that spontaneously develop prostate tumors were orally fed with PSP for 20 weeks. Whereas 100% of the mice that fed with water only developed prostate tumors at the end of experiment, no tumors could be found in any of the mice fed with PSP, suggesting that PSP treatment can completely inhibit prostate tumor formation. Our results not only demonstrated the intriguing anti-CSC effect of PSP, but also revealed, for the first time, the surprising chemopreventive property of oral PSP consumption against prostate cancer.

Dynamics of rod and cone photoreceptor interactions under mesopic light levels

Visual adaptation regulates contrast sensitivity during dynamically changing light conditions (Crawford, 1947; Hecht, Haig & Chase, 1937). These adaptation dynamics are unknown under dim (mesopic) light levels when the rod (R) and long (L), medium (M) and short (S) wavelength cone photoreceptor classes contribute to vision via interactions in shared non-opponent Magnocellular (MC), chromatically opponent Parvocellular (PC) and Koniocellular (KC) visual pathways (Dacey, 2000). This study investigated the time-course of adaptation and post-receptoral pathways mediating receptor specific rod and cone interactions under mesopic illumination. A four-primary photostimulator (Pokorny, Smithson & Quinlan, 2004) was used to independently control the activity of the four photoreceptor classes and their post-receptoral visual athways in human observers. In the first experiment, the contrast sensitivity and time-course of visual adaptation under mesopic illumination were measured for receptoral (L, S, R) and post-receptoral (LMS, LMSR, L-M) stimuli. An incremental (Rapid-ON) sawtooth conditioning pulse biased detection to ON-cells within the visual pathways and sensitivity was assayed relative to pulse onset using a briefly presented incremental probe that did not alter adaptation. Cone.Cone interactions with luminance stimuli (L cone, LMS, LMSR) reduced sensitivity by 15% and the time course of recovery was 25± 5ms-1 (μ ± SEM). PC mediated (+L-M) chromatic stimuli sensitivity loss was less (8%) than for luminance and recovery was slower (μ = 2.95 ± 0.05 ms-1), with KC mediated (S cone) chromatic stimuli showing a high sensitivity loss (38%) and the slowest recovery time (1.6 ± 0.2 ms-1). Rod-Rod interactions increased sensitivity by 20% and the time course of recovery was 0.7 ± 0.2 ms-1 (μ ± SD). Compared to these interaction types, Rod-Cone interactions reduced sensitivity to a lesser degree (5%) and showed the fastest recovery (μ = 43 ± 7 ms-1). In the second experiment, rod contribution to the magnocellular, parvocellular and koniocellular post-receptoral pathways under mesopic illumination was determined as a function of incremental stimulus duration and waveform (rectangular; sawtooth) using a rod colour match procedure (Cao, Pokorny & Smith, 2005; Cao, Pokorny, Smith & Zele, 2008a). For a 30% rod increment, a cone match required a decrease in [L/(L+M)] and an increase in [L+M] and [S/(L+M)], giving a greenish-blue and brighter appearance for probe durations of 75 ms or longer. Probe durations less than 75 ms showed an increase in [L+M] and no change in chromaticity [L/(L+M) or S/(L+M)], uggesting mediation by the MC pathway only for short duration rod stimuli. s We advance previous studies by determining the time-course and nature of photoreceptor specific retinal interactions in the three post-receptoral pathways under mesopic illumination. In the first experiment, the time-course of adaptation for ON cell processing was determined, revealing opponent cell facilitation in chromatic PC and KC pathways. The Rod-Rod and Rod-Cone data identify previously unknown interaction types that act to maintain contrast sensitivity during dynamically changing light conditions and improve the speed of light adaptation under mesopic light levels. The second experiment determined the degree of rod contribution to the inferred post-eceptoral pathways as a function of the temporal properties of the rod signal. r The understanding of the mechanisms underlying interactions between photoreceptors under mesopic illumination has implications for the study of retinal disease. Visual function has been shown to be reduced in persons with age-related maculopathy (ARM) risk genotypes prior to clinical signs of the disease (Feigl, Cao, Morris & Zele, 2011) and disturbances in rod-mediated adaptation have been shown in early phases of ARM (Dimitrov, Guymer, Zele, Anderson & Vingrys, 2008; Feigl, Brown, Lovie-Kitchin & Swann, 2005). Also, the understanding of retinal networks controlling vision enables the development of international lighting standards to optimise visual performance nder dim light levels (e.g. work-place environments, transportation).

Orthopedic bone plates : evolution in structure implementation technique and biomaterial

With many important developments over the last century, nowadays orthopedic bone plate now excels over other types of internal fixators in bone fracture fixation. The developments involve the design, material and implementation techniques of the plates. This paper aims to review the evolution in implementation technique and biomaterial of the orthopedic bone plates. Plates were initially used to fix the underlying bones firmly. Accordingly, Compression plate (CP), Dynamic compression plate (DCP), Limited contact dynamic compression plate (LC-DCP) and Point contact fixator (PC-Fix) were developed. Later, the implementation approach was changed to locking, and the Less Invasive Stabilization System (LISS) plate was introduced as a result. Finally, a combination of both of these approaches has been used by introducing the Locking Compression Plate (LCP). Currently, precontoured LCPs are mainly used for bone fracture fixation. In parallel with structure and implementation techniques, numerous advances have occurred in biomaterials of the plates. Titanium and stainless steel alloys are now the most common biomaterials in production of orthopedic bone plates. However, regarding the biocompatibility, bioactivity and biodegradability characteristics of Mg alloys, Ta alloys, SMAs, carbon fiber composites and bioceramics, these materials are considered as potentially suitable for plates. However, due to poor mechanical properties, they have very limited applications. Therefore, further studies are required in future to solve these problems and make them feasible for heavy-duty bone plates.

Targeting aurora kinases : a novel approach to curb the growth and chemoresistance of androgen refractory prostate cancer

Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC.

Expression of PTRF in PC3 cells modulates cholesterol dynamics and the actin cytoskeleton impacting secretion pathways

Expression of caveolin-1 is up-regulated in prostate cancer metastasis and is associated with aggressive recurrence of the disease. Intriguingly, caveolin-1 is also secreted from prostate cancer cell lines and has been identified in secreted prostasomes. Caveolin-1 is the major structural component of the plasma membrane invaginations called caveolae. Co-expression of the coat protein Polymerase I and transcript release factor (PTRF) is required for caveolae formation. We recently found that expression of caveolin-1 in the aggressive prostate cancer cell line PC-3 is not accompanied by PTRF, leading to noncaveolar caveolin-1 lipid rafts. Moreover, ectopic expression of PTRF in PC-3 cells sequesters caveolin-1 into caveolae. Here we quantitatively analyzed the effect of PTRF expression on the PC-3 proteome using stable isotope labeling by amino acids in culture and subcellular proteomics. We show that PTRF reduced the secretion of a subset of proteins including secreted proteases, cytokines, and growth regulatory proteins, partly via a reduction in prostasome secretion. To determine the cellular mechanism accounting for the observed reduction in secreted proteins we analyzed total membrane and the detergent-resistant membrane fractions. Our data show that PTRF expression selectively impaired the recruitment of actin cytoskeletal proteins to the detergent-resistant membrane, which correlated with altered cholesterol distribution in PC-3 cells expressing PTRF. Consistent with this, modulating cellular cholesterol altered the actin cytoskeleton and protein secretion in PC-3 cells. Intriguingly, several proteins that function in ER to Golgi trafficking were reduced by PTRF expression. Taken together, these results suggest that the noncaveolar caveolin-1 found in prostate cancer cells generates a lipid raft microenvironment that accentuates secretion pathways, possibly at the step of ER sorting/exit. Importantly, these effects could be modulated by PTRF expression.