In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumours

Purpose: Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors. Experimental Design: Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors. Results:In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm3. In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA. Conclusions: Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.

Osteopontin expression correlates with melanoma invasion

Melanoma is one of the most aggressive cancers affecting humans. Although early melanomas are curable with surgical excision, metastatic melanomas are associated with high mortality. The mechanism of melanoma development, progression, and metastasis is largely unknown. In order to uncover genes unique to melanoma cells, we used high-density DNA microarrays to examine the gene expression profiles of metastatic melanoma nodules using benign nevi as controls. Over 190 genes were significantly overexpressed in metastatic melanomas compared with normal nevi by at least 2-fold. One of the most abundantly expressed genes in metastatic melanoma nodules is osteopontin (OPN). Immunohistochemistry staining on tissue microarrays and individual skin biopsies representing different stages of melanoma progression revealed that OPN expression is first acquired at the step of melanoma tissue invasion. In addition, blocking of OPN expression by RNA interference reduced melanoma cell numbers in vitro. Our observations suggest that OPN may be acquired early in melanoma development and progression, and may enhance tumor cell growth in invasive melanoma.

Shoot growth dynamics and photosynthetic response to increased nitrogen availability in the alpine willow salix-glauca

Plants subjected to increases in the supply of resource(s) limiting growth may allocate more of those resources to existing leaves, increasing photosynthetic capacity, and/or to production of more leaves, increasing whole-plant photosynthesis. The responses of three populations of the alpine willow, Salix glauca, growing along an alpine topographic sequence representing a gradient in soil moisture and organic matter, and thus potential N supply, to N amendments, were measured over two growing seasons, to elucidate patterns of leaf versus shoot photosynthetic responses. Leaf-(foliar N, photosynthesis rates, photosynthetic N-use efficiency) and shoot-(leaf area per shoot, number of leaves per shoot, stem weight, N resorption efficiency) level measurements were made to examine the spatial and temporal variation in these potential responses to increased N availability. The predominant response of the willows to N fertilization was at the shoot-level, by production of greater leaf area per shoot. Greater leaf area occurred due to production of larger leaves in both years of the experiment and to production of more leaves during the second year of fertilization treatment. Significant leaf-level photosynthetic response occurred only during the first year of treatment, and only in the dry meadow population. Variation in photosynthesis rates was related more to variation in stomatal conductance than to foliar N concentration. Stomatal conductance in turn was significantly related to N fertilization. Differences among the populations in photosynthesis, foliar N, leaf production, and responses to N fertilization indicate N availability may be lowest in the dry meadow population, and highest in the ridge population. This result is contrary to the hypothesis that a gradient of plant available N corresponds with a snowpack/topographic gradient.

An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects

The treatment of challenging fractures and large osseous defects presents a formidable problem for orthopaedic surgeons. Tissue engineering/regenerative medicine approaches seek to solve this problem by delivering osteogenic signals within scaffolding biomaterials. In this study, we introduce a hybrid growth factor delivery system that consists of an electrospun nanofiber mesh tube for guiding bone regeneration combined with peptide-modified alginate hydrogel injected inside the tube for sustained growth factor release. We tested the ability of this system to deliver recombinant bone morphogenetic protein-2 (rhBMP-2) for the repair of critically-sized segmental bone defects in a rat model. Longitudinal [mu]-CT analysis and torsional testing provided quantitative assessment of bone regeneration. Our results indicate that the hybrid delivery system resulted in consistent bony bridging of the challenging bone defects. However, in the absence of rhBMP-2, the use of nanofiber mesh tube and alginate did not result in substantial bone formation. Perforations in the nanofiber mesh accelerated the rhBMP-2 mediated bone repair, and resulted in functional restoration of the regenerated bone. [mu]-CT based angiography indicated that perforations did not significantly affect the revascularization of defects, suggesting that some other interaction with the tissue surrounding the defect such as improved infiltration of osteoprogenitor cells contributed to the observed differences in repair. Overall, our results indicate that the hybrid alginate/nanofiber mesh system is a promising growth factor delivery strategy for the repair of challenging bone injuries.

Urban growth monitoring techniques for sustainable development

This paper discusses the role of advance techniques for monitoring urban growth and change for sustainable development of urban environment. It also presents results of a case study involving satellite data for land use/land cover classification of Lucknow city using IRS-1C multi-spectral features. Two classification algorithms have been used in the study. Experiments were conducted to see the level of improvement in digital classification of urban environment using Artificial Neural Network (ANN) technique.

Thomas Young's contribution to visual optics : the Bakerian lecture "On the mechanism of the eye"

Thomas Young (1773-1829) carried out major pioneering work in many different subjects. In 1800 he gave the Bakerian Lecture of the Royal Society on the topic of the “mechanism of the eye”: this was published in the following year (Young, 1801). Young used his own design of optometer to measure refraction and accommodation, and discovered his own astigmatism. He considered the different possible origins of accommodation and confirmed that it was due to change in shape of the lens rather than to change in shape of the cornea or an increase in axial length. However, the paper also dealt with many other aspects of visual and ophthalmic optics, such as biometric parameters, peripheral refraction, longitudinal chromatic aberration, depth-of-focus and instrument myopia. These aspects of the paper have previously received little attention. We now give detailed consideration to these and other less-familiar features of Young’s work and conclude that his studies remain relevant to many of the topics which currently engage visual scientists.

Integrated sustainable urban infrastructure management: the Brisbane urban growth model

Sustainable urban development and the liveability of a city are increasingly important issues in the context of land use planning and infrastructure management. In recent years, the promotion of sustainable urban development in Australia and overseas is facing various physical, socio-economic and environmental challenges. These challenges and problems arise from the lack of capability of local governments to accommodate the needs of the population and economy in a relatively short timeframe. The planning of economic growth and development is often dealt with separately and not included in the conventional land use planning process. There is also a sharp rise in the responsibilities and roles of local government for infrastructure planning and management. This increase in responsibilities means that local elected officials and urban planners have less time to prepare background information and make decisions. The Brisbane Urban Growth Model has proven initially successful in providing a dynamic platform to ensure timely and coordinated delivery of urban infrastructure. Most importantly, this model is the first step for local governments in moving toward a systematic approach to pursuing sustainable and effective urban infrastructure management.

The role of sulphates and organic vapours in growth of newly formed particles in a eucalypt forest

The influence of biogenic particle formation on climate is a well recognised phenomenon. To understand the mechanisms underlying the biogenic particle formation, determining the chemical composition of the new particles and therefore the species that drive the particle production is of utmost importance. Due to the very small amount of mass involved, indirect approaches are frequently used to infer the composition. We present here the results of such an indirect approach by simultaneously measuring volatile and hygroscopic properties of newly formed particles in a forest environment. It is shown that the particles are composed of both sulphates and organics, with the amount of sulphate component strongly depending on the available gas-phase sulphuric acid, and the organic components having the same volatility and hygroscopicity as photooxidation products of a monoterpene such as α-pinene. Our findings agree with a two-step process through nucleation and cluster formation followed by simultaneous growth by condensation of sulphates and organics that take the particles to climatically relevant sizes.

Brisbane urban growth model : an integrated infrastructure management framework for Brisbane, Australia

In recent years, local government infrastructure management practices have evolved from conventional land use planning to more wide ranging and integrated urban growth and infrastructure management approaches. The roles and responsibilities of local government are no longer simply to manage daily operational functions of a city and provide basic infrastructure. Local governments are now required to undertake economic planning, manage urban growth; be involved in major infrastructure planning; and even engage in achieving sustainable development objectives. The Brisbane Urban Growth model has proven initially successful to ensure timely and coordinated delivery of urban infrastructure. This model may be the first step for many local governments to move toward an integrated, sustainable and effective infrastructure management.

A two-compartment mechanochemical model of the roles of transforming growth factor-beta and tissue tension in dermal wound healing

The repair of dermal tissue is a complex process of interconnected phenomena, where cellular, chemical and mechanical aspects all play a role, both in an autocrine and in a paracrine fashion. Recent experimental results have shown that transforming growth factor-beta (TGF-beta) and tissue mechanics play roles in regulating cell proliferation, differentiation and the production of extracellular materials. We have developed a 1D mathematical model that considers the interaction between the cellular, chemical and mechanical phenomena, allowing the combination of TGF-beta and tissue stress to inform the activation of fibroblasts to myofibroblasts. Additionally, our model incorporates the observed feature of residual stress by considering the changing zero-stress state in the formulation for effective strain. Using this model, we predict that the continued presence of TGF-beta in dermal wounds will produce contractures due to the persistence of myofibroblasts; in contrast, early elimination of TGF-beta significantly reduces the myofibroblast numbers resulting in an increase in wound size. Similar results were obtained by varying the rate at which fibroblasts differentiate to myofibroblasts and by changing the myofibroblast apoptotic rate. Taken together, the implication is that elevated levels of myofibroblasts is the key factor behind wounds healing with excessive contraction, suggesting that clinical strategies which aim to reduce the myofibroblast density may reduce the appearance of contractures.

The role of the internet on international market growth of Australian firms : an exploratory study

The Internet has been shown to positively influence the internationalisation activities of firms through enhanced information, knowledge and network development. Although there has been evidence of a positive impact of the Internet on internationalisation process components, it is vague as to whether the Internet has an impact on firm international market growth. This paper examines the role of the Internet in the outward internationalisation of a cross-national sample of 224 firms from Australia. The results show evidence that a there is a link between Internet usage, Internet intensity and the international market growth of the firm. The findings indicate that firms are using Internet technologies beyond simple e-mail and websites in their international marketing. For example, Internet directories and Internet market spaces are assisting international market expansion of the firm. Firms are integrating the Internet into international marketing processes such as advertising, marketing, market research and international market management as well as in data transference between company and supplier and company and customer. Further, there is evidence in this study of the statistical relationships between the use of website, e-mail and online sales with the international market growth of the firm.

Internet usage, internet marketing intensity and international marketing growth

This paper examines the role of the Internet in international marketing growth. Evidence of a positive relationship between e-mail, website usage, online marketing and advertising with international market growth was found, in terms of increased sales from new customers in new countries, new customers in existing countries, and existing customers.