Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair

Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments.

Strategy in developing cell based therapy for large bone

Regeneration of osseous defects by tissue-engineering approach provides a novel means of treatment utilizing cell biology, materials science, and molecular biology. The concept of in vitro cultured osteoblasts having an ability to induce new bone formation has been demonstrated in the critical size defects using small animal models. The bone derived cells can be incorporated into bioengineered scaffolds and synthesize bone matrix, which on implantation can induce new bone formation. In search of optimal cell delivery materials, the extracellular matrix as cell carriers for the repair and regeneration of tissues is receiving increased attention. We have investigated extracellular matrix formed by osteoblasts in vitro as a scaffold for osteoblasts transplantation and found a mineralized matrix, formed by human osteoblasts in vitro, can initiate bone formation by activating endogenous mesenchymal cells. To repair the large bone defects, osteogenic or stem cells need to be prefabricated in a large three dimensional scaffold usually made of synthetic biomaterials, which have inadequate interaction with cells and lead to in vivo foreign body reactions. The interstitial extracellular matrix has been applied to modify biomaterials surface and identified vitronectin, which binds the heparin domain and RGD (Arg-Gly-Asp) sequence can modulate cell spreading, migration and matrix formation on biomaterials. We also synthesized a tri-block copolymer, methoxy-terminated poly(ethylene glycol)(MPEG)-polyL-lactide(PLLA)-polylysine(PLL) for human osteoblasts delivery. We identified osteogenic activity can be regulated by the molecular weight and composition of the triblock copolymers. Due to the sequential loss of lineage differentiation potential during the culture of bone marrow stromal cells that hinderers their potential clinical application, we have developed a clonal culture system and established several stem cell clones with fast growing and multi-differentiation properties. Using proteomics and subtractive immunization, several differential proteins have been identified and verified their potential application in stem cell characterization and tissue regeneration

Triangular Linguistic Fuzzy based performance measurement model for supply chain to assess leanness attributes

Increasing global competitiveness worldwide has forced manufacturing organizations to produce high-quality products more quickly and at a competitive cost. In order to reach these goals, they need good quality components from suppliers at optimum price and lead time. This actually forced all the companies to adapt different improvement practices such as lean manufacturing, Just in Time (JIT) and effective supply chain management. Applying new improvement techniques and tools cause higher establishment costs and more Information Delay (ID). On the contrary, these new techniques may reduce the risk of stock outs and affect supply chain flexibility to give a better overall performance. But industry people are unable to measure the overall affects of those improvement techniques with a standard evaluation model .So an effective overall supply chain performance evaluation model is essential for suppliers as well as manufacturers to assess their companies under different supply chain strategies. However, literature on lean supply chain performance evaluation is comparatively limited. Moreover, most of the models assumed random values for performance variables. The purpose of this paper is to propose an effective supply chain performance evaluation model using triangular linguistic fuzzy numbers and to recommend optimum ranges for performance variables for lean implementation. The model initially considers all the supply chain performance criteria (input, output and flexibility), converts the values to triangular linguistic fuzzy numbers and evaluates overall supply chain performance under different situations. Results show that with the proposed performance measurement model, improvement area for each variable can be accurately identified.

Beyond the positivist mirror : towards a project management 'Gnosis'

This paper aims to clarify the foundations of the discipline of project management (PM). Historically, PM has evolved from a conceptual approach based on a positivist paradigm. The author questions the appropriateness of such foundations for the kind of project management which claims to deal with complex problems. To answer this question, a brief history of project management emphasizes key concepts useful to the discussion. Comprehensive definitions of knowledge, competencies, performance and knowledge management are reviewed to provide a better understanding of the project environment in terms of its present positivist epistemological position. This paper explores the tensions and paradoxes encountered in PM practice, when set within the boundaries of a normative approach; it also highlights the polysemic nature of PM, for which an extended framework is proposed. Dialectic, qualitative and interpretative aspects of PM are presented alongside its quantitative body of Knowledge. The author finally introduces an innovative overview of project management, set in the greater context of the learning organization. Implications and applications of this perspective are discussed and lead to the presentation of the MAP metamethod, a systemic practical approach.

Intrinsic kinetics of titania photocatalysis : simplified models for their investigation

Even though titanium dioxide photocatalysis has been promoted as a leading green technology for water purification, many issues have hindered its application on a large commercial scale. For the materials scientist the main issues have centred the synthesis of more efficient materials and the investigation of degradation mechanisms; whereas for the engineers the main issues have been the development of appropriate models and the evaluation of intrinsic kinetics parameters that allow the scale up or re-design of efficient large-scale photocatalytic reactors. In order to obtain intrinsic kinetics parameters the reaction must be analysed and modelled considering the influence of the radiation field, pollutant concentrations and fluid dynamics. In this way, the obtained kinetic parameters are independent of the reactor size and configuration and can be subsequently used for scale-up purposes or for the development of entirely new reactor designs. This work investigates the intrinsic kinetics of phenol degradation over titania film due to the practicality of a fixed film configuration over a slurry. A flat plate reactor was designed in order to be able to control reaction parameters that include the UV irradiance, flow rates, pollutant concentration and temperature. Particular attention was paid to the investigation of the radiation field over the reactive surface and to the issue of mass transfer limited reactions. The ability of different emission models to describe the radiation field was investigated and compared to actinometric measurements. The RAD-LSI model was found to give the best predictions over the conditions tested. Mass transfer issues often limit fixed film reactors. The influence of this phenomenon was investigated with specifically planned sets of benzoic acid experiments and with the adoption of the stagnant film model. The phenol mass transfer coefficient in the system was calculated to be km,phenol=8.5815x10-7Re0.65(ms-1). The data obtained from a wide range of experimental conditions, together with an appropriate model of the system, has enabled determination of intrinsic kinetic parameters. The experiments were performed in four different irradiation levels (70.7, 57.9, 37.1 and 20.4 W m-2) and combined with three different initial phenol concentrations (20, 40 and 80 ppm) to give a wide range of final pollutant conversions (from 22% to 85%). The simple model adopted was able to fit the wide range of conditions with only four kinetic parameters; two reaction rate constants (one for phenol and one for the family of intermediates) and their corresponding adsorption constants. The intrinsic kinetic parameters values were defined as kph = 0.5226 mmol m-1 s-1 W-1, kI = 0.120 mmol m-1 s-1 W-1, Kph = 8.5 x 10-4 m3 mmol-1 and KI = 2.2 x 10-3 m3 mmol-1. The flat plate reactor allowed the investigation of the reaction under two different light configurations; liquid and substrate side illumination. The latter of particular interest for real world applications where light absorption due to turbidity and pollutants contained in the water stream to be treated could represent a significant issue. The two light configurations allowed the investigation of the effects of film thickness and the determination of the catalyst optimal thickness. The experimental investigation confirmed the predictions of a porous medium model developed to investigate the influence of diffusion, advection and photocatalytic phenomena inside the porous titania film, with the optimal thickness value individuated at 5 ìm. The model used the intrinsic kinetic parameters obtained from the flat plate reactor to predict the influence of thickness and transport phenomena on the final observed phenol conversion without using any correction factor; the excellent match between predictions and experimental results provided further proof of the quality of the parameters obtained with the proposed method.

Optimal planning of electric-vehicle charging stations in distribution systems

With the progressive exhaustion of fossil energy and the enhanced awareness of environmental protection, more attention is being paid to electric vehicles (EVs). Inappropriate siting and sizing of EV charging stations could have negative effects on the development of EVs, the layout of the city traffic network, and the convenience of EVs' drivers, and lead to an increase in network losses and a degradation in voltage profiles at some nodes. Given this background, the optimal sites of EV charging stations are first identified by a two-step screening method with environmental factors and service radius of EV charging stations considered. Then, a mathematical model for the optimal sizing of EV charging stations is developed with the minimization of total cost associated with EV charging stations to be planned as the objective function and solved by a modified primal-dual interior point algorithm (MPDIPA). Finally, simulation results of the IEEE 123-node test feeder have demonstrated that the developed model and method cannot only attain the reasonable planning scheme of EV charging stations, but also reduce the network loss and improve the voltage profile.

Preparing nanocomposite fibrous scaffolds of P3HB/nHA for bone tissue engineering

Nanocomposites are recently known to be among the most successful materials in biomedical applications. In this work we sought to fabricate fibrous scaffolds which can mimic the extra cellular matrix of cartilaginous connective tissue not only to a structural extent but with a mechanical and biological analogy. Poly(3-hydroxybutyrate) (P3HB) matrices were reinforced with 5, 10 and 15 %wt hydroxyapatite (HA) nanoparticles and electrospun into nanocomposite fibrous scaffolds. Mechanical properties of each case were compared with that of a P3HB scaffold produced in the same processing condition. Spectroscopic and morphological observations were used for detecting the interaction quality between the constituents. Nanoparticles rested deep within the fibers of 1 μm in diameter. Chemical interactions of hydrogen bonds linked the constituents through the interface. Maximum elastic modulus and mechanical strength was obtained with the presence of 5%wt hydroxyapatite nanoparticles. Above 10%wt, nanoparticles tended to agglomerate and caused the entity to lose its mechanical performance; however, viscoelasticity interfered at this concentration and lead to a delayed failure. In other words, higher elongation at break and a massive work of rupture was observed at 10%wt.

Characterisation of atmospheric deposited particles during a dust storm in urban areas of Eastern Australia

The characteristics of dust particles deposited during the 2009 dust storm in the Gold Coast and Brisbane regions of Australia are discussed in this paper. The study outcomes provide important knowledge in relation to the potential impacts of dust storm related pollution on ecosystem health in the context that the frequency of dust storms is predicted to increase due to anthropogenic desert surface modifications and climate change impacts. The investigated dust storm contributed a large fraction of fine particles to the environment with an increased amount of total suspended solids, compared to dry deposition under ambient conditions. Although the dust storm passed over forested areas, the organic carbon content in the dust was relatively low. The primary metals present in the dust storm deposition were aluminium, iron and manganese, which are common soil minerals in Australia. The dust storm deposition did not contain significant loads of nickel, cadmium, copper and lead, which are commonly present in the urban environment. Furthermore, the comparison between the ambient and dust storm chromium and zinc loads suggested that these metals were contributed to the dust storm by local anthropogenic sources. The potential ecosystem health impacts of the 2009 dust storm include, increased fine solids deposition on ground surfaces resulting in an enhanced capacity to adsorb toxic pollutants as well as increased aluminium, iron and manganese loads. In contrast, the ecosystem health impacts related to organic carbon and other metals from dust storm atmospheric deposition are not considered to be significant.

The effect of exercise training on sleep quality in heart failure

Background: Heart failure is a serious condition estimated to affect 1.5-2.0% of the Australian population with a point prevalence of approximately 1% in people aged 50-59 years, 10% in people aged 65 years or more and over 50% in people aged 85 years or over (National Heart Foundation of Australian and the Cardiac Society of Australia and New Zealand, 2006). Sleep disturbances are a common complaint of persons with heart failure. Disturbances of sleep can worsen heart failure symptoms, impair independence, reduce quality of life and lead to increased health care utilisation in patients with heart failure. Previous studies have identified exercise as a possible treatment for poor sleep in patients without cardiac disease however there is limited evidence of the effect of this form of treatment in heart failure. Aim: The primary objective of this study was to examine the effect of a supervised, hospital-based exercise training programme on subjective sleep quality in heart failure patients. Secondary objectives were to examine the association between changes in sleep quality and changes in depression, exercise performance and body mass index. Methods: The sample for the study was recruited from metropolitan and regional heart failure services across Brisbane, Queensland. Patients with a recent heart failure related hospital admission who met study inclusion criteria were recruited. Participants were screened by specialist heart failure exercise staff at each site to ensure exercise safety prior to study enrolment. Demographic data, medical history, medications, Pittsburgh Sleep Quality Index score, Geriatric Depression Score, exercise performance (six minute walk test), weight and height were collected at Baseline. Pittsburgh Sleep Quality Index score, Geriatric Depression Score, exercise performance and weight were repeated at 3 months. One hundred and six patients admitted to hospital with heart failure were randomly allocated to a 3-month disease-based management programme of education and self-management support including standard exercise advice (Control) or to the same disease management programme as the Control group with the addition of a tailored physical activity program (Intervention). The intervention consisted of 1 hour of aerobic and resistance exercise twice a week. Programs were designed and supervised by an exercise specialist. The main outcome measure was achievement of a clinically significant change (.3 points) in global Pittsburgh Sleep Quality score. Results: Intervention group participants reported significantly greater clinical improvement in global sleep quality than Control (p=0.016). These patients also exhibited significant improvements in component sleep disturbance (p=0.004), component sleep quality (p=0.015) and global sleep quality (p=0.032) after 3 months of supervised exercise intervention. Improvements in sleep quality correlated with improvements in depression (p<0.001) and six minute walk distance (p=0.04). When study results were examined categorically, with subjects classified as either "poor" or "good" sleepers, subjects in the Control group were significantly more likely to report "poor" sleep at 3 months (p=0.039) while Intervention participants were likely to report "good" sleep at this time (p=0.08). Conclusion: Three months of supervised, hospital based, aerobic and resistance exercise training improved subjective sleep quality in patients with heart failure. This is the first randomised controlled trial to examine the role of aerobic and resistance exercise training in the improvement of sleep quality for patients with this disease. While this study establishes exercise as a therapy for poor sleep quality, further research is needed to investigate the effect of exercise training on objective parameters of sleep in this population.

Refined plastic hinge analysis of steel frame structures comprising non-compact sections : II : verification

Application of "advanced analysis" methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A refined plastic hinge method suitable for practical advanced analysis of steel frame structures comprising non-compact sections is presented in a companion paper. The method implicitly accounts for the effects of gradual cross-sectional yielding, longitudinal spread of plasticity, initial geometric imperfections, residual stresses, and local buckling. The accuracy and precision of the method for the analysis of steel frames comprising non-compact sections is established in this paper by comparison with a comprehensive range of analytical benchmark frame solutions. The refined plastic hinge method is shown to be more accurate and precise than the conventional individual member design methods based on elastic analysis and specification equations.

Analytical benchmark solutions for steel frame structures subject to local buckling effects

Application of "advanced analysis" methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A research project has been conducted with the aim of developing concentrated plasticity methods suitable for practical advanced analysis of steel frame structures comprising non-compact sections. This paper contains a comprehensive set of analytical benchmark solutions for steel frames comprising non-compact sections, which can be used to verify the accuracy of simplified concentrated plasticity methods of advanced analysis. The analytical benchmark solutions were obtained using a distributed plasticity shell finite element model that explicitly accounts for the effects of gradual cross-sectional yielding, longitudinal spread of plasticity, initial geometric imperfections, residual stresses, and local buckling. A brief description and verification of the shell finite element model is provided in this paper.

Study of a geo-multicast framework for efficient message dissemination at unmanned level crossings

Collisions among trains and cars at road/rail level crossings (LXs) can have severe consequences such as high level of fatalities, injuries and significant financial losses. As communication and positioning technologies have significantly advanced, implementing vehicular ad hoc networks (VANETs) in the vicinity of unmanned LXs, generally LXs without barriers, is seen as an efficient and effective approach to mitigate or even eliminate collisions without imposing huge infrastructure costs. VANETs necessitate unique communication strategies, in which routing protocols take a prominent part in their scalability and overall performance, through finding optimised routes quickly and with low bandwidth overheads. This article studies a novel geo-multicast framework that incorporates a set of models for communication, message flow and geo-determination of endangered vehicles with a reliable receiver-based geo-multicast protocol to support cooperative level crossings (CLXs), which provide collision warnings to the endangered motorists facing road/rail LXs without barriers. This framework is designed and studied as part of a $5.5 m Government and industry funded project, entitled 'Intelligent-Transport-Systems to improve safety at road/rail crossings'. Combined simulation and experimental studies of the proposed geo-multicast framework have demonstrated promising outcomes as cooperative awareness messages provide actionable critical information to endangered drivers who are identified by CLXs.

Distributed plasticity analysis of steel frame structures comprising non-compact sections

Application of 'advanced analysis' methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A research project has been conducted with the aim of developing concentrated plasticity methods suitable for practical advanced analysis of steel frame structures comprising non-compact sections. A primary objective was to produce a comprehensive range of new distributed plasticity analytical benchmark solutions for verification of the concentrated plasticity methods. A distributed plasticity model was developed using shell finite elements to explicitly account for the effects of gradual yielding and spread of plasticity, initial geometric imperfections, residual stresses and local buckling deformations. The model was verified by comparison with large-scale steel frame test results and a variety of existing analytical benchmark solutions. This paper presents a description of the distributed plasticity model and details of the verification study.

Pseudo plastic zone analysis of steel frame structures comprising non-compact sections

Application of `advanced analysis' methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A concentrated plasticity method suitable for practical advanced analysis of steel frame structures comprising non-compact sections is presented in this paper. The pseudo plastic zone method implicitly accounts for the effects of gradual cross-sectional yielding, longitudinal spread of plasticity, initial geometric imperfections, residual stresses, and local buckling. The accuracy and precision of the method for the analysis of steel frames comprising non-compact sections is established by comparison with a comprehensive range of analytical benchmark frame solutions. The pseudo plastic zone method is shown to be more accurate and precise than the conventional individual member design methods based on elastic analysis and specification equations.

Large-scale testing of steel frame structures comprising non-compact sections

Application of 'advanced analysis' methods suitable for non-linear analysis and design of steel frame structures permits direct and accurate determination of ultimate system strengths, without resort to simplified elastic methods of analysis and semi-empirical specification equations. However, the application of advanced analysis methods has previously been restricted to steel frames comprising only compact sections that are not influenced by the effects of local buckling. A research project has been conducted with the aim of developing concentrated plasticity methods suitable for practical advanced analysis of steel frame structures comprising non-compact sections. A series of large-scale tests were performed in order to provide experimental results for verification of the new analytical models. Each of the test frames comprised non-compact sections, and exhibited significant local buckling behaviour prior to failure. This paper presents details of the test program including the test specimens, set-up and instrumentation, procedure, and results.