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Summary Aims To assess if performing frozen sections of tissue biopsies from fresh radical prostatectomy specimens, prior to tissue banking, could improve the identification of the banked samples compared to standard fresh tumour banking procedures. Methods Tissue biopsies banked from 332 fresh prostatectomy specimens were assessed for accuracy of diagnosis, comparing two separate methods of tumour identification: one in which tumour was identified in the gross specimen by visual inspection ( n = 155) and one in which rapid frozen sectioning was applied ( n = 177). The associations with correct tumour annotation and clinicopathological variables, including age, pre-operative prostate specific antigen (PSA) levels, pathological Gleason score, pathological T stage, tumour volume and surgical margins, were examined using univariable and multivariable binary logistic regression models. Results For the gross visual inspection cohort the rate of correctly identifying and banking specimens containing prostate cancer was 69%. For the cohort assessed with rapid frozen sections, 94% of banked specimens actually had cancer. On multivariable analysis, we found that only frozen sectioning and tumour volume variables were independent predictors of correctly banked tumour specimens whilst all other routinely reported pathological variables had no influence on the success rates of fresh prostate tumour banking. Conclusion The success rate for correctly banking fresh prostate tumour specimens is directly related to the tumour volume. Frozen section scrutiny of prostate samples is recommended to prevent misclassification of the banked material.

Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention.

We designed and fully evaluated the performance of a nomogram to identify patients with prostate cancer who may be suitable for active surveillance.We developed a nomogram to predict the probability of minimal prostate cancer (total tumor volume less than 0.5 cc, organ confined disease and no Gleason pattern 4 or 5) using preoperative data on 2,525 Australian patients who underwent radical prostatectomy. Accuracy and error rates at multiple probability cutoffs were compared with those of contemporary Epstein criteria and the Prostate Cancer Research International: Active Surveillance trial inclusion criteria when applied to these patients. High risk disease was defined as 1 or more adverse characteristics (including positive surgical margins, seminal vesicle invasion, extracapsular extension, 50% or greater Gleason pattern 4/5 and/or tumor volume 4.0 cc or greater) at radical prostatectomy.Minimal cancer was confirmed in 152 men (6.0%) at prostatectomy. The bootstrap corrected predictive accuracy of our nomogram was 93.3% vs 89.1% and 91.0% for Prostate Cancer Research International: Active Surveillance and Epstein criteria, respectively. For men with a nomogram derived minimal cancer probability of 0% to 4.9%, 5.0% to 19.9%, 20.0% to 34.9%, 35.0% to 49.9% and 50.0% to 71.0% the rate of high risk disease was 70.8%, 37.8%, 22.4%, 9.0% and 3.8%, respectively. In contrast, the rate of high risk disease for men who met Prostate Cancer Research International: Active Surveillance and Epstein criteria were 17.1% and 13.9%, respectively.A detailed breakdown of the expected rates of false-positive results and high risk disease associated with the nomogram derived probability of minimal cancer would provide more complete information to clinicians and patients on which to base therapeutic clinical decisions for presumed early stage prostate cancer.

Heightened concerns about the treatment of individuals during interviews and interrogations have stimulated efforts to develop “non-intrusive” technologies for rapidly assessing the credibility of statements by individuals in a variety of sensitive environments. Methods or processes that have the potential to precisely focus investigative resources will advance operational excellence and improve investigative capabilities. Facial expressions have the ability to communicate emotion and regulate interpersonal behavior. Over the past 30 years, scientists have developed human-observer based methods that can be used to classify and correlate facial expressions with human emotion. However, these methods have proven to be labor intensive, qualitative, and difficult to standardize. The Facial Action Coding System (FACS) developed by Paul Ekman and Wallace V. Friesen is the most widely used and validated method for measuring and describing facial behaviors. The Automated Facial Expression Recognition System (AFERS) automates the manual practice of FACS, leveraging the research and technology behind the CMU/PITT Automated Facial Image Analysis System (AFA) system developed by Dr. Jeffery Cohn and his colleagues at the Robotics Institute of Carnegie Mellon University. This portable, near real-time system will detect the seven universal expressions of emotion (figure 1), providing investigators with indicators of the presence of deception during the interview process. In addition, the system will include features such as full video support, snapshot generation, and case management utilities, enabling users to re-evaluate interviews in detail at a later date.

A 67-year-old male presenting with persistent cough was found to have a large anterior mediastinal tumour (top). He underwent mediastinotomy and resection of a thymic tumour, which was subsequently diagnosed as a benign thymoma (bottom left). Six months post-thymectomy he presented with symptomatic anaemia, with full blood examination revealing severe thrombocytopenia in addition to the anaemia: haemoglobin 66 g/l, white cell count 5AE2 · 10/l, platelet count 8 · 10/l, and neutrophils 1AE5 · 10/l. There had been no recent exposure to drugs or chemicals known to cause marrow aplasia and serology for parvovirus and hepatitis B and C were negative. Bone marrow trephine biopsy showed a markedly hypocellular marrow (cellularity c. 10%) with few haemopoietic elements present, consistent with evolving aplastic anaemia (bottom right); there was no clonal T-cell population or evidence of paroxysmal nocturnal haemoglobinuria detected by flow cytometry. A computed tomography scan showed no evidence of recurrent thymoma. The patient was treated with anti-thymocyte globulin and ciclosporin; the most recent blood tests showed a near complete response at 10 weeks. Aplastic anaemia is a rare complication of thymoma occurring concurrently in c. 1% of cases. Aplastic anaemia following thymectomy is exceedingly rare with only five other cases identified by us in the literature. Thymoma-related aplastic anaemia often fails to respond to thymectomy requiring immunosuppressive therapy for count recovery. Autoreactive T-cell clones generated by the thymoma are postulated to be the cause of aplastic anaemia and other autoimmune manifestations. The occurrence of aplastic anaemia as a late autoimmune complication following resection of thymoma indicates that autoreactive T-cell clones may persist post-thymectomy leading to late rather than concurrent autoimmune haematological manifestations.

An important aspect of reserves estimates is to quantify the contribution of uncertainties in underlying parameters such as structure, Sand extent, Fault Seal, Aquifer support, etc. If field production history is available, it can be incorporated to generate reliable measures of uncertainties for these parameters and identify the most likely field models. History Matching (HM) can be solved successfully using the Design of Experiment (DOE) method to define modeled scenarios. In the past decade DOE methodology has been used to compute estimated reserves while minimizing the simulation effort. This paper describes its extension to History Matching. The process of HM using DOE is a four stage process. The first step is to identify an uncertainty frame-work listing the uncertain parameters (X) and history matching parameters (Y). The second stage is to generate a design (the specified model combinations of the reservoir parameters) capable of estimating the effect and interactions of all parameters. Thirdly, the specified models are made and simulated and the response surface y(x) calculated, relating reservoir simulator input x and each output y. The last step is to predict the history matching parameter values for all possible model scenarios and measure goodness of history match for each model. The History Match can be quantified by the D-Score, a measure of the difference between the realized and predicted value of the history matching parameter standardized across modeling error. The D-score based probabilistic measures are flexible and allow the user to incorporate prior information. The above methodology for History Match will be presented for a field, which has over 11 years of oil production and 7 years of water-cut. We will demonstrate that History Matching using DOE is reliable, fast, efficient, and can quantify the probability of scenario occurrence.

193 Background: Genomic heterogeneity has been observed in a number of tumor types including prostate cancer. However, how subclonal tumor diversity changes during metastasis and progression to lethality remains unexplored. Large scale genomic analyses have reported the most prevalent somatic aberrations associated with the dominant clone of the tumor without permitting an analysis of subclonal complexity or how this complexity impinges on metastatic potential or resistance to treatment. Methods: To understand and track the evolution of lethal prostate cancer from initial therapy to end stage metastases, we performed longitudinal and multiregional sampling of tumors from 7 patients with lethal prostate cancer. We performed whole-genome sequencing, RNA sequencing, and SNP profiling. Computational approaches were used to reconstruct the genetic relationships and evolution of the tumors. These evolutionary tree reconstructions allowed us to observe the dynamics of chromoplexy and mutational processes along specific branches of tumor evolution. To refine the genetic landscape and spatial connections between subclones, we employed deep, targeted re-sequencing of variant loci in the original sequenced samples, in additional FFPE sites sampled from the organ confined tumors, and from blood. Results: We show that while all primary and metastatic prostate tumors share a single ancestral clone, metastases arise from subclones present at minor frequencies in the primary tumor. We reveal that individual metastases comprise mixtures of subclones indicative of intra-metastatic heterogeneity. We provide evidence for cross-metastatic site seeding and dynamic remolding of subclonal mixtures in response to therapy suggesting a distinct metastatic hierarchy. Ultra-deep sequencing of end-stage blood reveals the presence of diverse subclones with metastatic potential derived from various stages in the evolution of the tumor. Conclusions: Our results demonstrate unexpected complexity in the origins of both primary and metastatic prostate cancer, with distinct implications for treatment of advanced disease.

71 Background: Androgen receptor splice variants (ARvs) are upregulated in response to castration, and can activate transcription in the absence of ligand. Recent evidence indicates that CTC ARv7 expression is an accurate predictor of absence of response to abiraterone and enzalutamide, providing strong clinical support for ARv7 upregulation as potential overarching mechanism of castration resistance. There is however limited data regarding the expression of ARv7 in clinically localized prostate cancer (CaP), and it is unknown if expression in the primary tumor is similarly predictive. We were therefore interested to determine the expression of ARv7 in high-risk disease, and correlate this with response to an abiraterone-containing castrating regimen. Methods: We performed an open label non-randomized Phase II neoadjuvant study of ‘supercastration’ in men with high-risk clinically localized CaP using an optimal 2-stage design (ACTRN12612000772842). Treatment consisted of degarelix 240/80mg q 1/12, abiraterone 1000mg OD, bicalutamide 50mg OD and prednisolone 5mg OD for 24 weeks. The primary endpoints were safety/tolerability and pT0 response rate. ARv7 expression was determined by immunohistochemistry and qRT-PCR in both pre- and post treatment tumor specimens, and correlated with pathological response. Fresh specimens from resistant tumors are currently being profiled by RNA-seq. Results: 17 patients were recruited to the study. The combination treatment was well tolerated, with hot flushes and fatigue being the most commonly reported side effects, and all patients completed six months of treatment. Six patients with asymptomatic elevation of liver transaminases required Abiraterone dose reductions, and there were no unexpected toxicities. 16 patients proceeded to prostatectomy, and a pT0 response observed in one patient, with minimal residual disease present in a further three patients. ARv7 expression was uniformly present in all pre-treatment specimens, and neither level nor localization of expression predicted tumor response. Conclusions: ARv7 expression in primary CaP does not predict response to abiraterone-based castration. Clinical trial information: ACTRN12612000772842.

It is my proposal that unused building shells of the past serve as cocoons for the future, providing the precedence from which grows "a building within a building". The tension created between old and new encourages a didactic relationship between building and city, cognizant of the past while looking towards the future. Master of Architecture

We report the utilization of key design parameters to simulate, batch-fabricate and evaluate first-generation single crystal 6H-SiC piezoresistive accelerometers for extreme impact, high electromagnetic fields (EM) and high temperature applications. The results from finite element analysis (FEA) of the selected design models were compared to evaluated prototypes. While FEA results predicted safe operation above 100,000-g's, preliminary experimental tests were performed up to 40,000-g's. Sensitivities ranging between 50 and 343 nV/g were measured. Non-linear behavior was observed over the shock range relative to the commercial accelerometer used as a benchmark. These initial results offer promise for the use of 6H-SiC accelerometers for extreme impact sensing in strong EM fields and temperature up to 600/spl deg/C that are beyond the capability of silicon.

This paper describes a gas re-injection project designed with the dual objectives of emissions reduction and enhanced oil recovery in an Australian offshore oil field. While gas injection for enhancing oil recovery is common oilfield practice, there are fewer projects that look exclusively at greenhouse gas (GHG) control (either by sequestration or emission reduction), although there is increasing environmental awareness in the industry on the benefits of doing so. The predominant contribution to total GHG CO2 -e emissions is from flaring. Significant reductions in flaring have been achieved since completion of commissioning of injection. Flare CO2 emissions at the beginning of 2000 (February-March) reduced from approximately 163,000 tonnes per month to an average of approximately 26,000 tonnes per month over the remainder of 2000, and to 9,800 tonnes per month, over the first half of 2001. GHG efficiency, evident in the ratio of GHGs emitted per tonne of hydrocarbon produced, reduced from approximately 0.4 tonnes CO2 -e per tonne of total hydrocarbon produced before injection to 0.08 after injection over the remainder of 2000, and to 0.06 over the first half of 2001. Miscible displacement is expected to add around 6 million barrels to ultimate recovery from the Corallina reservoir. The use of stored gas as a fuel is expected to achieve significant reductions in operational expenditure later in field life.Copyright © 2002 by ASME

67 Background: Structural rearrangements in cancers genomes have the potential to disrupt normal gene function and result in a selective growth advantage, either by inactivating tumour suppressors or creating novel gene fusions with oncogenic gain-of-function. Specific fusion genes identified to date are found in particular tumor types rather than being present in all cancers suggesting there are tissue-specific mechanisms underlying these events. The most well-known fusion event in prostate cancer is TMPRSS2-ERG. Recent studies have suggested that androgen receptor may play a role in the formation of TMPRSS2-ERG fusions, bringing the two loci in close proximity in the nucleus and facilitating DNA strand break and repair along with AR associated enzymes. Methods: To explore this mechanism more comprehensively, we performed whole-genome sequencing of 14 prostate cancers from seven patients as well as paired whole blood controls. Results: Across the cancer genomes we identified approximately 4,500 high confidence DNA breakpoints and found that a large proportion of these breakpoints were in close proximity to curated androgen receptor binding sites. Furthermore, when we examined breakpoints in 11 other cancers from the TCGA and ICGC projects, we identified a similar association with androgen (and estrogen) receptor binding sites specifically in hormone-dependent tumour types, suggesting a role for steroid hormone receptors in the formation of cancer driving structural rearrangements. In addition, in at least one patient, the formation of a novel gene fusion contributed directly to the lethal evolution of his tumour. Conclusions: These data suggest that the androgen receptor drives genome wide breakpoints and novel fusion events in prostate cancer.

This paper presents a study of a gas re-injection project, designed with the dual objectives of emissions reduction and enhanced oil recovery in an Australian offshore oil field. A significant reduction in greenhouse gas emissions has been achieved since the project commenced late in 1999, with some 1.3 million tonnes of CO2 emissions avoided in year 2000 alone. Miscible displacement is expected to add around 6 million barrels to ultimate recovery from the Corallina reservoir, and use of stored gas as fuel is expected to achieve significant reductions in operational expenditure later in field life. Gas injection for the purposes of enhancing oil recovery has been common oilfield practice for several decades. Many technical papers have been written on this subject, from both theoretical and practical points of view. Projects that focus exclusively on greenhouse gas control (either by sequestration or emission reduction) are less common, although the level of research is rapidly increasing as environmental awareness spreads throughout the industry. The Laminaria / Corallina gas re-injection project is designed to achieve both objectives.

The study examined whether intravenous (i.v.) leptin increased Fos-production in spinally projecting neurons in the hypothalamic paraventricular nucleus (PVN). We combined (i) rhodamine tagged microspheres injected into the upper thoracic spinal cord and (ii) Fos (marker of neuronal activation) immunohistochemistry. Effects of recombinant murine leptin were compared to vehicle (containing lipopolysaccharide a contaminant present in the leptin solution). Following leptin, 10% of the spinally projecting neurons contained Fos. However, vehicle elicited similar effects and there was no significant difference between the groups.

We investigated whether a monosynaptic connection from the nucleus tractus solitarius (NTS) or the depressor ventrolateral medulla (VLM) to the pressor region of the rostral VLM (RVLM) constituted part of the reflex pathway activated by cardiopulmonary baroreceptors. Volume expansion in the conscious rabbit, which elicits renal nerve inhibition predominantly via cardiac mechanoreceptors, was used as the stimulus. The protein Fos was used as a marker of neuronal activation. The retrogradely transported tracer rhodamine-tagged microspheres, previously injected into the pressor region of the RVLM, identified medullary neurons that projected to that region. Volume expansion significantly increased the number of Fos-positive cell nuclei in the NTS and in the depressor VLM. Neurons that projected to the RVLM were found throughout the depressor region of the VLM and in the NTS but were not activated by volume expansion. Thus, although the central reflex pathways activated by volume expansion include the NTS and the depressor region of the VLM, we could not find evidence for a monosynaptic connection between those regions and the RVLM.

Vertical benchmarks are complex system designs represented at multiple levels of abstraction. More effective than component-based CAD benchmarks, vertical benchmarks enable quantitative comparison of CAD techniques within or across design flows. This work describes the notion of vertical benchmarks and presents our benchmark, which is based on a commercial DSP, by comparing two alternative design flows.

With today's traffic conditions there is an ever-increasing need to provide motorists with travel information and to be able to accurately locate individual vehicles when dealing with incidents. It is often quite difficult for motorists to pinpoint their location when a breakdown or accident occurs. This is particularly apparent on motorways when motorists use their mobile telephones instead of the emergency telephones. The police motorway controllers and motoring organisations then have the additional task of trying to locate motorists instead of relying upon automatic identification by the motorway emergency telephone system. Equally, the public find it difficult to accurately describe their location even on familiar routes, particularly in the heat of the moment. With the advent of satellite navigation, mobile telephones and advanced computing it is now possible to pinpoint motorists and provide telematics services to assist them. The subject of this paper is an integrated system that has been developed by the Automobile Association to provide these services. The system described is currently being deployed and offers an operational service to users.

In recent years, loss of cell polarity and tissue architecture has been defined as a hallmark of epithelial cancer yet the molecular mechanisms underlying this predisposition are not fully understood. Two distinct polarity programs are required for the correct assembly and function of all mammalian epithelial tissues; apical-basal polarity and non-canonical Wnt/planar cell polarity (1). The Scribble complex functions to establish and maintain both aspects of epithelial polarity and has been shown to mediate cell adhesion, migration and asymmetric cell division (2). In human colorectal, breast, and cervical cancers, expression of the Scribble complex member SCRIB is often mislocalised and deregulated, suggesting that polarity regulators plays a role in maintaining homeostasis of epithelial tissues (1,3). Scrib null mice are neonatal lethal owing to a neural tube closure defect. To determine the tumor suppressive role of Scrib within epithelial tissues, we have employed tissue specific Cre-LoxP technology to deplete Scrib specifically within the prostate, mammary or lung. Scrib depletion in these epithelial tissues results in tumor initiation, supporting previous work in Drosophila (1). We and others have previously shown that SCRIB loss stimulates Ras/MAPK signaling in vitro, suggesting that SCRIB negatively regulates the Ras/MAPK cascade to suppress tumorigenesis (4,5). We now show elevated p-ERK1/2 expression is a common feature of Scrib deficient tumors in vivo. Accordingly, administration of the MEK inhibitor PD0325901 in Scrib+/− mice partially rescued the hyperplastic prostate phenotype. Together, these studies establish that depletion of the polarity regulator Scrib can initiate murine tumorigenesis in several epithelial tissues in a process involving deregulation of the Ras/MAPK cascade. Interestingly, tissue specific activation of oncogenic K-ras in combination with Scrib depletion accelerated tumor progression in both the prostate and lung. Thus, K-ras activation and Scrib deficiency synergise to facilitate tumor growth, demonstrating that Scrib depletion can contribute to tumor progression in the presence of an additional oncogenic mutation. The clinical relevance of this research is highlighted by our observation that SCRIB deregulation strongly correlated with PSA recurrence free survival in human prostate cancer (3). Together, our findings suggest that the polarity network may hold prognostic value or provide a novel route for therapeutic intervention. (1) Humbert PO et al (2008) Oncogene 27(55):6888-6907 (2) Kallay LM et al (2006) J Cell Biochem 99: 647-64 (3) Pearson HB et al (2011) J Clin Invest 121(11):4257-4267 (4) Dow LE et al (2008) Oncogene 27(46):5988-6001 (5) Nagasaka K et al (2010) Oncogene 29(38):5311-5321 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3291. doi:1538-7445.AM2012-3291