Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas

Mortality in breast cancer is linked to metastasis and recurrence yet there is no acceptable biological model for cancer relapse. We hypothesise that there might exist primary tumour cells capable of escaping surgery by migration and resisting radiotherapy and chemotherapy to cause cancer recurrence. We investigated this possibility in invasive ductal carcinoma (IDC) tissue and observed the presence of solitary primary tumour cells (SPCs) in the dense collagen stroma that encapsulates intratumoural cells (ICs). In IDC tissue sections, collagen was detected with either Masson's Trichrome or by second harmonics imaging. Cytokeratin-19 (CK-19) and vimentin (VIM) antibodies were, respectively, used to identify epithelial-derived tumour cells and to indicate epithelial to mesenchymal transition (EMT). Confocal/multiphoton microscopy showed that ICs from acini were mainly CK-19 +ve and were encapsulated by dense stromal collagen. Within the stroma, SPCs were detected by their staining for both CK-19 and VIM (confirming EMT). ICs and SPCs were subsequently isolated by laser capture microdissection followed by multiplex tandem-PCR studies. SPCs were found to be enriched for pro-migratory and anti-proliferative genes relative to ICs. In vitro experiments using collagen matrices at 20 mg/cm 3, similar in density to tumour matrices, demonstrated that SPC-like cells were highly migratory but dormant, phenotypes that recapitulated the genotypes of SPCs in clinical tissue. These data suggest that SPCs located at the breast cancer perimeter are invasive and dormant such that they may exceed surgical margins and resist local and adjuvant therapies. This study has important connotations for a role of SPCs in local recurrence.

The effectiveness of information-sharing interventions as a means to reduce anxiety in families waiting for surgical patients undergoing an elective surgical procedure : a systematic review protocol

Review question/objective What are the most effective information sharing strategies used to reduce anxiety in families of patients undergoing elective surgery? This review seeks to synthesize the best available evidence in relation to the most effective information-sharing intervention to reduce anxiety for families waiting for patients undergoing an elective surgical procedure. The specific objectives are to review the effectiveness of evidence of interventions designed to reduce the anxiety of families waiting whilst their loved one undergoes a surgical intervention. A variety of interventions exist and include surgical nurse liaison services, intraoperative reporting either by face-to-face or telephone delivery, informational cards, visual information screens, and intraoperative paging devices for families. Inclusion criteria Types of participants All studies of family members over 18 years of age waiting for patients undergoing an elective surgical procedure will be included, including those waiting for both adult and paediatric patients. Studies of families waiting for other patient populations, eg emergency surgery, chemotherapy or intensive care patients will be excluded. Types of intervention(s)/phenomena of interest All information-sharing Interventions for families of patients undergoing an elective surgical procedure will be included, including but not limited to: surgical nurse liaison services, in-person intraoperative reporting, visual information screens, paging devices, informational cards and telephone delivery of intraoperative progress reports. Interventions that take place during the intraoperative phase of care only will be included in the review. Preadmission information sharing interventions will be excluded. Types of outcomes The outcomes of interest include: Primary outcome: the level of anxiety amongst family members or close relatives whilst waiting for patients undergoing surgery, as measured by a validated instrument (such as the S-Anxiety portion of the State-Trait Anxiety Inventory).4 Secondary outcomes: family satisfaction and other measurements that may be considered indicators of stress and anxiety, such as mean arterial pressure (MAP) and heart rate.

The role of biological extracellular matrix scaffolds in vascularized three-dimensional tissue growth in vivo

An in vivo murine vascularized chamber model has been shown to generate spontaneous angiogenesis and new tissue formation. This experiment aimed to assess the effects of common biological scaffolds on tissue growth in this model. Either laminin-1, type I collagen, fibrin glue, hyaluronan, or sea sponge was inserted into silicone chambers containing the epigastric artery and vein, one end was sealed with adipose tissue and the other with bone wax, then incubated subcutaneously. After 2, 4, or 6 weeks, tissue from chambers containing collagen I, fibrin glue, hyaluronan, or no added scaffold (control) had small amounts of vascularized connective tissue. Chambers containing sea sponge had moderate connective tissue growth together with a mild "foreign body" inflammatory response. Chambers containing laminin-1, at a concentration 10-fold lower than its concentration in Matrigel™, resulted in a moderate adipogenic response. In summary, (1) biological hydrogels are resorbed and gradually replaced by vascularized connective tissue; (2) sponge-like matrices with large pores support connective tissue growth within the pores and become encapsulated with granulation tissue; (3) laminin-containing scaffolds facilitate adipogenesis. It is concluded that the nature and chemical composition of the scaffold exerts a significant influence on the amount and type of tissue generated in this in vivo chamber model.

Second-harmonic generation from biological tissues : effect of excitation wavelength

We report on the measurement of second-harmonic signals from hyperplastic parenchyma and stroma in malignant human prostate tissue under femtosecond pulsed illumination in the wavelength range from 730 to 870 nm. In particular, the relationship of the second-harmonic generation to the excitation wavelength is measured. The result in these two regions behaves considerably differently and thus provides a possible indicator for identifying tissue components and malignancy.

Two-photon fluorescence spectroscopy for identification of healthy and malignant biological tissues

Two-photon fluorescence spectroscopy has been performed on rat skeletal muscles to investigate the effect of fixation processes on the micro-environments of the endogenous fluorophors in rat skeletal muscles. The two-photon fluorescence spectra measured for different fixation periods show a differential among those samples that were fixed in water, formalin and methanol, respectively. The results imply that two-photon fluorescence spectroscopy can be a potential technique for identification of healthy and malignant biological tissues.

Spatial prediction on a river network

This article develops methods for spatially predicting daily change of dissolved oxygen (Dochange) at both sampled locations (134 freshwater sites in 2002 and 2003) and other locations of interest throughout a river network in South East Queensland, Australia. In order to deal with the relative sparseness of the monitoring locations in comparison to the number of locations where one might want to make predictions, we make a classification of the river and stream locations. We then implement optimal spatial prediction (ordinary and constrained kriging) from geostatistics. Because of their directed-tree structure, rivers and streams offer special challenges. A complete approach to spatial prediction on a river network is given, with special attention paid to environmental exceedances. The methodology is used to produce a map of Dochange predictions for 2003. Dochange is one of the variables measured as part of the Ecosystem Health Monitoring Program conducted within the Moreton Bay Waterways and Catchments Partnership.

Study Protocol - Alcohol Management Plans (AMPs) in remote indigenous communities in Queensland: their impacts on injury, violence, health and social indicators and their cost-effectiveness

Background In 2002/03 the Queensland Government responded to high rates of alcohol-related harm in discrete Indigenous communities by implementing alcohol management plans (AMPs), designed to include supply and harm reduction and treatment measures. Tighter alcohol supply and carriage restrictions followed in 2008 following indications of reductions in violence and injury. Despite the plans being in place for over a decade, no comprehensive independent review has assessed to what level the designed aims were achieved and what effect the plans have had on Indigenous community residents and service providers. This study will describe the long-term impacts on important health, economic and social outcomes of Queensland’s AMPs. Methods/Design The project has two main studies, 1) outcome evaluation using de-identified epidemiological data on injury, violence and other health and social indicators for across Queensland, including de-identified databases compiled from relevant routinely-available administrative data sets, and 2) a process evaluation to map the nature, timing and content of intervention components targeting alcohol. Process evaluation will also be used to assess the fidelity with which the designed intervention components have been implemented, their uptake and community responses to them and their perceived impacts on alcohol supply and consumption, injury, violence and community health. Interviews and focus groups with Indigenous residents and service providers will be used. The study will be conducted in all 24 of Queensland’s Indigenous communities affected by alcohol management plans. Discussion This evaluation will report on the impacts of the original aims for AMPs, what impact they have had on Indigenous residents and service providers. A central outcome will be the establishment of relevant databases describing the parameters of the changes seen. This will permit comprehensive and rigorous surveillance systems to be put in place and provided to communities empowering them with the best credible evidence to judge future policy and program requirements for themselves. The project will inform impending alcohol policy and program adjustments in Queensland and other Australian jurisdictions. The project has been approved by the James Cook University Human Research Ethics Committee (approval number H4967 & H5241).

Biological performance of a polycaprolactone-based scaffold plus recombinant human morphogenetic protein-2 (rhBMP-2) in an ovine thoracic interbody fusion model

PURPOSE. We develop a sheep thoracic spine interbody fusion model to study the suitability of polycaprolactone-based scaffold and recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute within the thoracic spine. The surgical approach is a mini- open thoracotomy with relevance to minimally invasive deformity correction surgery for adolescent idiopathic scoliosis. To date there are no studies examining the use of this biodegradable implant in combination with biologics in a sheep thoracic spine model. METHODS. In the present study, six sheep underwent a 3-level (T6/7, T8/9 and T10/11) discectomy with randomly allocated implantation of a different graft substitute at each of the three levels; (i) calcium phosphate (CaP) coated polycaprolactone-based scaffold plus 0.54μg rhBMP-2, (ii) CaP coated PCL- based scaffold alone or (iii) autograft (mulched rib head). Fusion was assessed at six months post-surgery. RESULTS. Computed Tomographic scanning demonstrated higher fusion grades in the rhBMP-2 plus PCL- based scaffold group in comparison to either PCL-based scaffold alone or autograft. These results were supported by histological evaluations of the respective groups. Biomechanical testing revealed significantly higher stiffness for the rhBMP-2 plus PCL- based scaffold group in all loading directions in comparison to the other two groups. CONCLUSION. The results of this study demonstrate that rhBMP-2 plus PCL- based scaffold is a viable bone graft substitute, providing an optimal environment for thoracic interbody spinal fusion in a large animal model.

Precise relative clock synchronization for distributed control using TSC registers

Precise clock synchronization is essential in emerging time-critical distributed control systems operating over computer networks where the clock synchronization requirements are mostly focused on relative clock synchronization and high synchronization precision. Existing clock synchronization techniques such as the Network Time Protocol (NTP) and the IEEE 1588 standard can be difficult to apply to such systems because of the highly precise hardware clocks required, due to network congestion caused by a high frequency of synchronization message transmissions, and high overheads. In response, we present a Time Stamp Counter based precise Relative Clock Synchronization Protocol (TSC-RCSP) for distributed control applications operating over local-area networks (LANs). In our protocol a software clock based on the TSC register, counting CPU cycles, is adopted in the time clients and server. TSC-based clocks offer clients a precise, stable and low-cost clock synchronization solution. Experimental results show that clock precision in the order of 10~microseconds can be achieved in small-scale LAN systems. Such clock precision is much higher than that of a processor's Time-Of-Day clock, and is easily sufficient for most distributed real-time control applications over LANs.

Optimal Bayesian experimental design for models with intractable likelihoods using indirect inference applied to biological process models

This paper addresses the problem of determining optimal designs for biological process models with intractable likelihoods, with the goal of parameter inference. The Bayesian approach is to choose a design that maximises the mean of a utility, and the utility is a function of the posterior distribution. Therefore, its estimation requires likelihood evaluations. However, many problems in experimental design involve models with intractable likelihoods, that is, likelihoods that are neither analytic nor can be computed in a reasonable amount of time. We propose a novel solution using indirect inference (II), a well established method in the literature, and the Markov chain Monte Carlo (MCMC) algorithm of Müller et al. (2004). Indirect inference employs an auxiliary model with a tractable likelihood in conjunction with the generative model, the assumed true model of interest, which has an intractable likelihood. Our approach is to estimate a map between the parameters of the generative and auxiliary models, using simulations from the generative model. An II posterior distribution is formed to expedite utility estimation. We also present a modification to the utility that allows the Müller algorithm to sample from a substantially sharpened utility surface, with little computational effort. Unlike competing methods, the II approach can handle complex design problems for models with intractable likelihoods on a continuous design space, with possible extension to many observations. The methodology is demonstrated using two stochastic models; a simple tractable death process used to validate the approach, and a motivating stochastic model for the population evolution of macroparasites.

Critical dependence of blood-borne biomarker concentrations on the half-lives of their carrier proteins

Until recently, the low-abundance (LA) range of the serum proteome was an unexplored reservoir of diagnostic information. Today it is increasingly appreciated that a diagnostic goldmine of LA biomarkers resides in the blood stream in complexed association with more abundant higher molecular weight carrier proteins such as albumin and immunoglobulins. As we now look to the possibility of harvesting these LA biomarkers more efficiently through engineered nano-scale particles, mathematical approaches are needed in order to reveal the mechanisms by which blood carrier proteins act as molecular 'mops' for LA diagnostic cargo, and the functional relationships between bound LA biomarker concentrations and other variables of interest such as biomarker intravasation and clearance rates and protein half-lives in the bloodstream. Here we show, by simple mathematical modeling, how the relative abundance of large carrier proteins and their longer half-lives in the bloodstream work together to amplify the total blood concentration of these tiny biomarkers. The analysis further suggests that alterations in the production of biomarkers lead to gradual rather than immediate changes in biomarker levels in the blood circulation. The model analysis also points to the characteristics of artificial nano-particles that would render them more efficient harvesters of tumor biomarkers in the circulation, opening up possibilities for the early detection of curable disease, rather than simply better detection of advanced disease.

On governance structures for the cloud computing services and assessing their effectiveness

This research suggests information technology (IT) governance structures to manage the cloud computing services. The interest in acquiring IT resources as a utility from the cloud computing environment is gaining momentum. The cloud computing services present organizations with opportunities to manage their IT expenditure on an ongoing basis, and access to modern IT resources to innovate and manage their continuity. However, the cloud computing services are no silver bullet. Organizations would need to have appropriate governance structures and policies in place to manage the cloud computing services. The subsequent decisions from these governance structures will ensure the effective management of the cloud computing services. This management will facilitate a better fit of the cloud computing services into organizations’ existing processes to achieve the business (process-level) and the financial (firm-level) objectives. Using a triangulation approach, we suggest four governance structures for managing the cloud computing services. These structures are a chief cloud officer, a cloud management committee, a cloud service facilitation centre, and a cloud relationship centre. We also propose that these governance structures would relate directly to organizations cloud computing services-related business objectives, and indirectly to cloud computing services-related financial objectives. Perceptive field survey data from actual and prospective cloud computing service adopters suggest that the suggested governance structures would contribute directly to cloud computing-related business objectives and indirectly to cloud computing-related financial objectives.

The cost-effectiveness of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer

Objective To summarise how costs and health benefits will change with the adoption of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer. Design Cost-effectiveness modelling using the information from a randomised controlled trial. Participants Two hypothetical modelled cohorts of 1000 individuals undergoing total laparoscopic hysterectomy and total abdominal hysterectomy. Outcome measures Surgery costs; hospital bed days used; total healthcare costs; quality-adjusted life years; and net monetary benefits. Results For 1000 individuals receiving total laparoscopic hysterectomy surgery, the costs were $509 575 higher, 3548 hospital fewer bed days were used and total health services costs were reduced by $3 746 221. There were 39.13 more quality-adjusted life years for a 5 year period following surgery. Conclusions The adoption of total laparoscopic hysterectomy is almost certainly a good decision for health services policy makers. There is 100% probability that it will be cost saving to health services, a 86.8% probability that it will increase health benefits and a 99.5% chance that it returns net monetary benefits greater than zero.