The fatty acid synthase inhibitor triclosan : repurposing an anti-microbial agent for targeting prostate cancer

Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.

Antimicrobial stewardship activities : a survey of Queensland hospitals

Objective: In 2011, the Australian Commission on Safety and Quality in Health Care (ACSQHC) recommended that all hospitals in Australia must have an Antimicrobial Stewardship (AMS) program by 2013. Nevertheless, little is known about current AMS activities. This study aimed to determine the AMS activities currently undertaken, and to identify gaps, barriers to implementation and opportunities for improvement in Queensland hospitals. Methods: The AMS activities of 26 facilities from 15 hospital and health services in Queensland were surveyed during June 2012 to address strategies for effective AMS: implementing clinical guidelines, formulary restriction, reviewing antimicrobial prescribing, auditing antimicrobial use and selective reporting of susceptibility results. Results: The response rate was 62%. Nineteen percent had an AMS team (a dedicated multidisciplinary team consisting of a medically trained staff member and a pharmacist). All facilities had access to an electronic version of Therapeutic Guidelines: Antibiotic, with a further 50% developing local guidelines for antimicrobials. One-third of facilities had additional restrictions. Eighty-eight percent had advice for restricted antimicrobials from in-house infectious disease physicians or clinical microbiologists. Antimicrobials were monitored with feedback given to prescribers at point of care by 76% of facilities. Deficiencies reported as barriers to establishing AMS programs included: pharmacy resources, financial support by hospital management, and training and education in antimicrobial use. Conclusions: Several areas for improvement were identified: reviewing antimicrobial prescribing with feedback to the prescriber, auditing, and training and education in antimicrobial use. There also appears to be a lack of resources to support AMS programs in some facilities. What is known about the topic? The ACSQHC has recommended that all hospitals implement an AMS program by 2013 as a requirement of Standard 3 (Preventing and Controlling Healthcare-Associated Infections) of the National Safety and Quality Health Service Standards. The intent of AMS is to ensure appropriate prescribing of antimicrobials as part of the broader systems within a health service organisation to prevent and manage healthcare-associated infections, and improve patient safety and quality of care. This criterion also aligns closely with Standard 4: Medication Safety. Despite this recommendation, little is known about what AMS activities are undertaken in these facilities and what additional resources would be required in order to meet these national standards. What does the paper add? This is the first survey that has been conducted of public hospital and health services in Queensland, a large decentralised state in Australia. This paper describes what AMS activities are currently being undertaken, identifies practice gaps, barriers to implementation and opportunities for improvement in Queensland hospitals. What are the implications for practitioners? Several areas for improvement such as reviewing antimicrobial prescribing with feedback to the prescriber, auditing, and training and education in antimicrobial use have been identified. In addition, there appears to be a lack of resources to support AMS programs in some facilities.

Multi-agent systems for modeling high penetration photovoltaic system impacts in distribution networks

This paper reviews the use of multi-agent systems to model the impacts of high levels of photovoltaic (PV) system penetration in distribution networks and presents some preliminary data obtained from the Perth Solar City high penetration PV trial. The Perth Solar City trial consists of a low voltage distribution feeder supplying 75 customers where 29 consumers have roof top photovoltaic systems. Data is collected from smart meters at each consumer premises, from data loggers at the transformer low voltage (LV) side and from a nearby distribution network SCADA measurement point on the high voltage side (HV) side of the transformer. The data will be used to progressively develop MAS models.

Promiscuity, pheromones and pathogenicity : why all Enterococci are not created equal

Enterococcus faecalis is a Gram-positive, coccus shaped, lactic acid bacterium, with demonstrated ubiquity across multiple anatomical sites. Enterococcus faecalis isolates have been isolated from clinical samples as the etiological agent in patients with overt infections, and from body sites previously thought to be sterile but absent of signs and symptoms of infection. E. faecalis is implicated in both human health and disease, recognized as a commensal, a probiotic and an opportunistic multiply resistant pathogen. E. faecalis has emerged as a key pathogen in nosocomial infections. E. faecalis is well equipped to avert recognition by host cell immune mediators. Antigenic cell wall components including lipotechoic acids are concealed from immune detection by capsular polysaccharides produced by some strains. Thereby preventing complement activation, the pro-inflammatory response, opsonisation and phagocytosis. E. faecalis also produces a suite of enzymes including gelatinase and cytolysin, which aid in both virulence and host immune evasion. The ability of enterococci to form biofilms in vivo further increases virulence, whilst simultaneously preventing detection by host cells. E. faecalis exhibits high levels of both intrinsic and acquired antimicrobial resistance. The mobility of the E. faecalis genome is a significant contributor to antimicrobial resistance, with this species also transferring resistance to other Gram-positive bacteria. Whilst E. faecalis is of increasing concern in nosocomial infections, its role as a member of the endogenous microbiota cannot be underestimated. As a commensal and probiotic, E. faecalis plays an integral role in modulating the immune response, and in providing endogenous antimicrobial activity to enhance exclusion or inhibition of opportunistic pathogens in certain anatomical niches. In this chapter we will review possible mediators of enterococcal transition from commensal microbe to opportunistic pathogen, considering isolates obtained from patients diagnosed with pathogenic infections and those obtained from asymptomatic patients.

Analysis of passenger group behaviour and its impact on passenger flow using an agent-based model

Group interaction within crowds is a common phenomenon and has great influence on pedestrian behaviour. This paper investigates the impact of passenger group dynamics using an agent-based simulation method for the outbound passenger process at airports. Unlike most passenger-flow models that treat passengers as individual agents, the proposed model additionally incorporates their group dynamics as well. The simulation compares passenger behaviour at airport processes and discretionary services under different group formations. Results from experiments (both qualitative and quantitative) show that incorporating group attributes, in particular, the interactions with fellow travellers and wavers can have significant influence on passengers activity preference as well as the performance and utilisation of services in airport terminals. The model also provides a convenient way to investigate the effectiveness of airport space design and service allocations, which can contribute to positive passenger experiences. The model was created using AnyLogic software and its parameters were initialised using recent research data published in the literature.

Dynamic agent composition for large-scale agent-based models

PURPOSE: This paper describes dynamic agent composition, used to support the development of flexible and extensible large-scale agent-based models (ABMs). This approach was motivated by a need to extend and modify, with ease, an ABM with an underlying networked structure as more information becomes available. Flexibility was also sought after so that simulations are set up with ease, without the need to program. METHODS: The dynamic agent composition approach consists in having agents, whose implementation has been broken into atomic units, come together at runtime to form the complex system representation on which simulations are run. These components capture information at a fine level of detail and provide a vast range of combinations and options for a modeller to create ABMs. RESULTS: A description of the dynamic agent composition is given in this paper, as well as details about its implementation within MODAM (MODular Agent-based Model), a software framework which is applied to the planning of the electricity distribution network. Illustrations of the implementation of the dynamic agent composition are consequently given for that domain throughout the paper. It is however expected that this approach will be beneficial to other problem domains, especially those with a networked structure, such as water or gas networks. CONCLUSIONS: Dynamic agent composition has many advantages over the way agent-based models are traditionally built for the users, the developers, as well as for agent-based modelling as a scientific approach. Developers can extend the model without the need to access or modify previously written code; they can develop groups of entities independently and add them to those already defined to extend the model. Users can mix-and-match already implemented components to form large-scales ABMs, allowing them to quickly setup simulations and easily compare scenarios without the need to program. The dynamic agent composition provides a natural simulation space over which ABMs of networked structures are represented, facilitating their implementation; and verification and validation of models is facilitated by quickly setting up alternative simulations.

An agent-based approach to immune modelling

This study focuses on trying to understand why the range of experience with respect to HIV infection is so diverse, especially as regards to the latency period. The challenge is to determine what assumptions can be made about the nature of the experience of antigenic invasion and diversity that can be modelled, tested and argued plausibly. To investigate this, an agent-based approach is used to extract high-level behaviour which cannot be described analytically from the set of interaction rules at the cellular level. A prototype model encompasses local variation in baseline properties contributing to the individual disease experience and is included in a network which mimics the chain of lymphatic nodes. Dealing with massively multi-agent systems requires major computational efforts. However, parallelisation methods are a natural consequence and advantage of the multi-agent approach. These are implemented using the MPI library.

Considerations for a social and geographical framework for agent-based epidemics

Understanding the dynamics of disease spread is of crucial importance, in contexts such as estimating load on medical services to risk assessment and intervention policies against large-scale epidemic outbreaks. However, most of the information is available after the spread itself, and preemptive assessment is far from trivial. Here, we investigate the use of agent-based simulations to model such outbreaks in a stylised urban environment. For most diseases, infection of a new individual may occur from casual contact in crowds as well as from repeated interactions with social partners such as work colleagues or family members. Our model therefore accounts for these two phenomena.Presented in this paper is the initial framework for such a model, detailing implementation of geographical features and generation of social structures. Preliminary results are a promising step towards large-scale simulations and evaluation of potential intervention policies.

Model refinement through high-performance computing: an agent-based HIV example

Background Recent advances in Immunology highlighted the importance of local properties on the overall progression of HIV infection. In particular, the gastrointestinal tract is seen as a key area during early infection, and the massive cell depletion associated with it may influence subsequent disease progression. This motivated the development of a large-scale agent-based model. Results Lymph nodes are explicitly implemented, and considerations on parallel computing permit large simulations and the inclusion of local features. The results obtained show that GI tract inclusion in the model leads to an accelerated disease progression, during both the early stages and the long-term evolution, compared to a theoretical, uniform model. Conclusions These results confirm the potential of treatment policies currently under investigation, which focus on this region. They also highlight the potential of this modelling framework, incorporating both agent-based and network-based components, in the context of complex systems where scaling-up alone does not result in models providing additional insights.

Agent-based modelling of viral infection

The three phases of the macroscopic evolution of the HIV infection are well known, but it is still difficult to understand how the cellular-level interactions come together to create this characteristic pattern and, in particular, why there are such differences in individual responses. An 'agent-based' approach is chosen as a means of inferring high-level behaviour from a small set of interaction rules at the cellular level. Here the emphasis is on cell mobility and viral mutations.

A parallel approach to social network generation and agent-based epidemic simulation

Understanding the dynamics of disease spread is essential in contexts such as estimating load on medical services, as well as risk assessment and interven- tion policies against large-scale epidemic outbreaks. However, most of the information is available after the outbreak itself, and preemptive assessment is far from trivial. Here, we report on an agent-based model developed to investigate such epidemic events in a stylised urban environment. For most diseases, infection of a new individual may occur from casual contact in crowds as well as from repeated interactions with social partners such as work colleagues or family members. Our model therefore accounts for these two phenomena. Given the scale of the system, efficient parallel computing is required. In this presentation, we focus on aspects related to paralllelisation for large networks generation and massively multi-agent simulations.

Decentralised Communication in Autonomous Agent Swarms

Communication and information diffusion are typically difficult in situations where centralised structures may become unavailable. In this context, decentralised communication based on epidemic broadcast becomes essential. It can be seen as an opportunity-based flooding for message broadcasting within a swarm of autonomous agents, where each entity tries to share the information it possesses with its neighbours. As an example of applications for such a system, we present simulation results where agents have to coordinate to map an unknown area.

Agent-based modelling and simulation of airplane boarding processes

Passenger flow simulations are an important tool for designing and managing airports. This thesis examines the different boarding strategies for the Boeing 777 and Airbus 380 aircraft in order to investigate their current performance and to determine minimum boarding times. The most optimal strategies have been discovered and new strategies that are more efficient are proposed. The methods presented offer reduced aircraft boarding times which plays an important role for reducing the overall aircraft Turn Time for an airline.

An Australian native plant: A novel antimicrobial for the treatment of MRSA

Chronic wounds, often associated with venous and arterial ulcers, diabetes and pressure sores, is an area of great concern. In Australia, the cost of treating chronic wounds is conservatively estimated at $285 million/annum for the treatment of pressure ulcers and $654 million annually for the treatment and management of leg ulcers. Current figures indicate that more than seven million people suffer from chronic wounds worldwide with Australians accounting for approximately 600,000 of this number. Bacterial infection of the wound site is a major issue as contamination of a chronic wound with methicillin-resistant Staphylococcus aureus (MRSA) significantly delays wound healing. Further, once systemic, current antibiotic therapies capable of treating the infection are limited. Aboriginal bush medicine has been used for thousands of years for the treatment of wounds and sores. Hence, we selected a native Australian plant to evaluate its bactericidal activity against MRSA.

Magnetic nanoparticles boosting the osmotic efficiency of a polymeric FO draw agent: Effect of polymer conformation

Poly sodium acrylate (PSA)-coated Magnetic Nanoparticles (PSA-MNPs) were synthesized as smart osmotic draw agent (SMDA) for water desalination by forward osmosis (FO) process. The PSA-coated MNPs demonstrated significantly higher osmotic pressure (~ 30 fold) as well as high FO water flux (~ 2–3 fold) when compared to their polymer (polyelectrolyte) counterpart, even at a very low concentration of ~ 0.13 wt.% in the draw solution. The PSA polymer chain conformation – coiled to extended – demonstrates a significant impact on the availability of the polymer hydrophilic groups in solution which is the driving force to attain higher osmotic pressure and water flux. When an optimum concentration of the polymer was anchored to a NP surface, the polymer chains assume an extended open conformation making the functional hydrophilic groups available to attract water molecules. This in turn boosts the osmotic pressure and FO water flux of the PSA-MNP draw agents. The low concentration of the PSA-MNP osmotic agent and the associated high water flux enhances the cost-effectiveness of our proposed SMDA system. In addition, easier magnetic separation and regeneration of the SMDA also improves its usability making it efficient, cost-effective and environment-friendly.