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Background 68Gallium-labelled prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-11 PET) is a valuable staging tool, but its utility in characterising primary prostate cancer remains unclear. The maximum standardised uptake value (SUVmax) is a quantification measure of highest radiotracer uptake within PET-avid lesions. Objective To assess the utility of SUVmax in detecting clinically significant prostate cancer (csPCa) on biopsy alone and in combination with multiparametric magnetic resonance imaging (mpMRI). Design, setting, and participants This was a retrospective analysis of 200 men who underwent 68Ga-PSMA-11 PET/CT, mpMRI, and transperineal template prostate biopsy between 2016 and 2018. Outcome measurements and statistical analysis The primary and secondary outcomes were detection of grade group (GG) 3–5 and GG 2–5 prostate cancer, respectively. We used the Mann-Whitney U test to compare SUVmax by GG, and calculated sensitivity and specificity for csPCa detection via 68Ga-PSMA-11 PET/CT, mpMRI, and both. Multivariable logistic regression analyses were used to identify predictors of csPCa on biopsy. Results and limitations The median SUVmax was greater for GG 3–5 tumours (6.40, interquartile range [IQR] 4.47–11.0) than for benign and GG 1–2 tumours (3.14, IQR 2.55–3.91; p Conclusions Greater SUVmax on 68Ga-PSMA-11 PET/CT is associated with detection of GG 3–5 cancer on biopsy. The combination of PI-RADS score and SUVmax provides higher sensitivity and NPV than either alone. 68Ga-PSMA-11 PET/CT may be useful alongside mpMRI in improving risk stratification for localised disease. Patient summary The amount of a radioactive tracer taken up in the prostate during a type of scan called PET (positron emission tomography) can predict whether aggressive prostate cancer is likely to be found on biopsy. This may complement the more usual type of scan, MRI (magnetic resonance imaging), used to detect prostate cancer.

Purpose Accurate risk stratification remains a barrier for the safety of active surveillance in patients with intermediate-risk prostate cancer. [68Ga]Ga-PSMA-11 Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography (68Ga-PSMA PET/CT) and the maximum Standardized Uptake Value (SUVmax) may improve risk stratification within this population. Materials and methods We reviewed men with ISUP Grade Group 2-3 disease on transperineal template biopsy undergoing 68Ga-PSMA PET/CT from November 2015 to January 2021. Primary outcome was the presence of high percentage Gleason pattern 4 (GP4) disease per-segment at surgery, at three thresholds: >/ / / Results Of 220 men who underwent biopsy, 135 men underwent surgery. SUVmax was higher in high GP4 groups: 5.51 (IQR 4.19-8.49) vs 3.31 (2.64-4.41) >/ / / 50% (OR=1.39 [95%CI 1.18-1.65], p 20% (OR=1.24 [1.04-1.47], p=0.015) GP4 disease per-segment, and of pathologic upgrading (OR=1.22 [1.01-1.48], p=0.036). SUVmax threshold 4.5 predicted >20% GP4 with 58% specificity, 85% sensitivity, positive predictive value (PPV) 75% and negative predictive value (NPV) 72%. Threshold 5.4 predicted pathologic upgrading with 91% specificity and NPV 94%. Conclusions SUVmax on 68Ga-PSMA PET/CT is associated with GP4. SUVmax may improve risk stratification for men with intermediate-risk prostate cancer.

PURPOSE Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.

OBJECTIVES: To assess the concordance between biopsy and radical prostatectomy (RP) specimens using the 2005 Gleason score (GS) and the International Society of Urological Pathology (ISUP) 2014/World Health Organization 2016 modified system, accounting for the introduction of transperineal biopsy and pre-biopsy multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: Between 2002 and 2019, we identified 2431 patients with paired biopsy and RP histopathology from a prospectively recorded and maintained prostate cancer database. Biopsy specimens were graded according to the 2005 GS or ISUP 2014 modified system, according to the year of diagnosis. Multivariable logistic regression analysis was conducted to retrospectively assess the impact of prostate-specific antigen (PSA), PSA density, age, pre-biopsy mpMRI, and biopsy method, on the rate of upgraded disease. The kappa coefficient was used to establish the degree of change in concordance between groups. RESULTS: Overall, 24% of patients had upgraded disease and 8% of patients had downgraded disease when using the modified ISUP 2014 criteria. Agreement in the updated ISUP 2014 cohort was 68%, compared with 55% in the 2005 GS group, which was validated by a kappa coefficient that was good (k = 0.5 ± 0.4) and poor (k = 0.3 ± 0.1), respectively. In multivariable models, a change in grading system independently improved overall disease concordance (P = 0.02), and there were no other co-segregated patient or pathological factors such as PSA, total number of cores, maximum cancer length, biopsy route or the use of mpMRI that impacted this finding. CONCLUSION: The 2014 ISUP modifed system improves overall concordance between biopsy and surgical specimens, and thus allows more accurate prognostication and management in high-grade disease, independent of more extensive prostate sampling and the use of mpMRI.

BACKGROUND: Focal treatment for prostate cancer (PCa) is a hybrid approach combining ablative treatment of the involved prostate gland and continued active surveillance (AS) of the unaffected gland. Low dose-rate (LDR) brachytherapy can be used as a lesion-targeted focal therapy, however, further studies are required to support its use. The aim of this study is to evaluate the dosimetry, toxicity and oncological outcomes of men receiving lesion-targeted focal LDR brachytherapy for low to intermediate risk PCa. METHODS: This is a retrospective cohort study of 26 men with unifocal, low to intermediate grade PCa diagnosed on a combination of multiparametric-magnetic resonance imaging (mp-MRI) and targeted plus template transperineal (TP) biopsy, who received focal LDR brachytherapy at a single institution. Brachytherapy involved a single monotherapy implant using iodine-125 seeds to deliver a prescribed dose of 145 Gy to the index lesion. RESULTS: The mean focal planning target volume (F-PTV) as a percentage of the prostate volume was 24.5%. The percentage of the focal gross tumour volume (F-GTV) receiving 100% of the prescription dose was 100% for 12 patients and ≥98% for 18 patients. The median follow-up for toxicity and biochemical control outcomes was 23.1 [interquartile range (IQR) 19.1–31.3] and 24.2 (IQR 17.9–30.0) months, respectively. Grade 2 urinary and erectile toxicities were reported by 29.2% and 45.8% of patients, respectively, with resolution of urinary symptoms to baseline by last follow-up. There were no grade ≥3 urinary or erectile toxicities or grade ≥2 rectal toxicity. All 21 patients who underwent a repeat mp-MRI and TP biopsy at 12–24 months post-treatment were negative for clinically significant disease and 25 (96.2%) patients were free from biochemical failure (FFBF). CONCLUSIONS: Focal LDR brachytherapy is associated with a favourable toxicity profile and a high rate of control of significant PCa at 12–18 months post-treatment. We have commenced the LIBERATE prospective registry in focal LDR brachytherapy based on the highly encouraging outcomes of this initial experience.

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012–2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer., The prognosis of castration-resistant prostate cancers remains dismal, but accurate preclinical models can lead to effective therapies. Here the Melbourne Urological Research Alliance establish prostate cancer patient-derived xenografts, use the tumors for organoids and single-cell RNA-seq, and show the efficacy of PARP inhibitor combination treatments.

Background Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival. Methods Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8). Results A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p Conclusions The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.

OBJECTIVE: To compare the accuracy of 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) with multiparametric MRI (mpMRI) in detecting and localising primary prostate cancer when compared with radical prostatectomy (RP) specimen pathology. PATIENTS AND METHODS: Retrospective review of men who underwent 68 Ga-PSMA PET/CT and mpMRI for primary prostate cancer before RP across four centres between 2015 and 2018. Patients undergoing imaging for recurrent disease or before non-surgical treatment were excluded. We defined pathological index tumour as the lesion with highest International Society of Urological Pathology Grade Group (GG) on RP specimen pathology. Our primary outcomes were rates of accurate detection and localisation of RP specimen pathology index tumour using 68 Ga-PSMA PET/CT or mpMRI. We defined tumour detection as imaging lesion corresponding with RP specimen tumour on any imaging plane, and localisation as imaging lesion matching RP specimen index tumour in all sagittal, axial, and coronal planes. Secondary outcomes included localisation of clinically significant and transition zone (TZ) index tumours. We defined clinically significant disease as GG 3-5. We used descriptive statistics and the Mann-Whitney U-test to define and compare demographic and pathological characteristics between detected, missed and localised tumours using either imaging modality. We used the McNemar test to compare detection and localisation rates using 68 Ga-PSMA PET/CT and mpMRI. RESULTS: In all, 205 men were included in our analysis, including 133 with clinically significant disease. There was no significant difference between 68 Ga-PSMA PET/CT and mpMRI in the detection of any tumour (94% vs 95%, P > 0.9). There was also no significant difference between localisation of all index tumours (91% vs 89%, P = 0.47), clinically significant index tumours (96% vs 91%, P = 0.15) or TZ tumours (85% vs 80%, P > 0.9) using 68 Ga-PSMA PET/CT and mpMRI. Limitations include retrospective study design and non-central review of imaging and pathology. CONCLUSION: We found no significant difference in the detection or localisation of primary prostate cancer between 68 Ga-PSMA PET/CT and mpMRI. Further prospective studies are required to evaluate a combined PET/MRI model in minimising tumours missed by either modality.

We present a new method for the determination of the surface properties of airless bodies from measurements of the emitted infrared flux. Our approach uses machine learning techniques to train, validate, and test a neural network representation of the thermophysical behavior of the atmosphereless body given shape model, illumination and observational geometry of the remote sensors. The networks are trained on a dataset of thermal simulations of the emitted infrared flux for different values of surface rock abundance, roughness, and values of the thermal inertia of the regolith and of the rock components. These surrogate models are then employed to retrieve the surface thermal properties by Markov Chain Monte Carlo Bayesian inversion of observed infrared fluxes. We apply the method to the inversion of simulated infrared fluxes of asteroid (101195) Bennu -- according to a geometry of observations similar to those planned for NASA's OSIRIS-REx mission -- and infrared observations of asteroid (25143) Itokawa. In both cases, the surface properties of the asteroid -- such as surface roughness, thermal inertia of the regolith and rock component, and relative rock abundance -- are retrieved; the contribution from the regolith and rock components are well separated. For the case of Itokawa, we retrieve a rock abundance of about 85% for pebbles larger than the diurnal skin depth, which is about 2 cm. The thermal inertia of the rock is found to be lower than the expected value for LL chondrites, indicating that the rocks on Itokawa could be fractured. The average thermal inertia of the surface is around 750 $J s^{-1/2} K^{-1} m^{-2}$ and the measurement of thermal inertia of the regolith corresponds to an average regolith particle diameter of about 10 mm, consistently with in situ measurements as well as results from previous studies., Comment: 20 pages, 8 figures, 6 tables. Accepted for publication in Icarus

Background Primary Seminal Vesicle (SV) tumours are a rare entity, with most SV masses representing invasion of the SV by malignancy originating in an adjacent organ, most often the prostate. Previously reported primary SV epithelial tumours have included adenocarcinoma and cystadenoma, with limited prior reports of inracystic papillary structures. Case presentation A 35-year-old male presented with azoospermia, intermittent macroscopic haematuria, and mild right iliac fossa and groin pain. A papillary appearing seminal vesicle mass was found on imaging and seminal vesicoscopy. The mass was robotically excised with diagnosis of benign cystic papillary adenoma made. Conclusion In this manuscript we describe a rare case of a benign cystic papillary adenoma of the seminal vesicle, a unique histological entity differentiated from cystadenoma of the Seminal Vesicle by its papillary component.

The latency associated with bone metastasis emergence in castrate‐resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single‐cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor‐intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor‐intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor‐intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long‐term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor‐intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone‐metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune‐based therapies in solid cancers., Tumor‐intrinsic type I IFN is lost upon outgrowth of dormant prostate cancer cells in bone, driving metastasis. Therapeutic reversal of tumor‐intrinsic IFN loss enhances tumor cell visibility and the effectiveness of systemic immunomodulatory agents against bone‐metastasis.

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

Anterior cruciate ligament (ACL) injuries are common among athletes. Despite a successful return to sport (RTS) for most of the injured athletes, a significant proportion do not return to competitive levels, and thus RTS post ACL reconstruction still represents a challenge for clinicians. Wearable sensors, owing to their small size and low cost, can represent an opportunity for the management of athletes on-the-field after RTS by providing guidance to associated clinicians. In particular, this study aims to investigate the ability of a set of inertial sensors worn on the lower-limbs by rugby players involved in a change-of-direction (COD) activity to differentiate between healthy and post-ACL groups via the use of machine learning. Twelve male participants (six healthy and six post-ACL athletes who were deemed to have successfully returned to competitive rugby and tested in the 5&ndash, 10 year period following the injury) were recruited for the study. Time- and frequency-domain features were extracted from the raw inertial data collected. Several machine learning models were tested, such as k-nearest neighbors, na&iuml, ve Bayes, support vector machine, gradient boosting tree, multi-layer perceptron, and stacking. Feature selection was implemented in the learning model, and leave-one-subject-out cross-validation (LOSO-CV) was adopted to estimate training and test errors. Results obtained show that it is possible to correctly discriminate between healthy and post-ACL injury subjects with an accuracy of 73.07% (multi-layer perceptron) and sensitivity of 81.8% (gradient boosting). The results of this study demonstrate the feasibility of using body-worn motion sensors and machine learning approaches for the identification of post-ACL gait patterns in athletes performing sport tasks on-the-field even a number of years after the injury occurred.

INTRODUCTION AND OBJECTIVE:Androgen receptor (AR) signalling is important in prostate cancer progression, and therapies that specifically target this pathway are the mainstay of treatment for advan...

Background Prostate cancer changes the phenotype of cells within the stromal microenvironment, including fibroblasts, which in turn promote tumour progression. Functional changes in prostate cancer-associated fibroblasts (CAFs) coincide with alterations in DNA methylation levels at loci-specific regulatory regions. Yet, it is not clear how these methylation changes compare across CAFs from different patients. Therefore, we examined the consistency and prognostic significance of genome-wide DNA methylation profiles between CAFs from patients with different grades of primary prostate cancer. Results We used Infinium MethylationEPIC BeadChips to evaluate genome-wide DNA methylation profiles from 18 matched CAFs and non-malignant prostate tissue fibroblasts (NPFs) from men with moderate to high grade prostate cancer, as well as five unmatched benign prostate tissue fibroblasts (BPFs) from men with benign prostatic hyperplasia. We identified two sets of differentially methylated regions (DMRs) in patient CAFs. One set of DMRs reproducibly differed between CAFs and fibroblasts from non-malignant tissue (NPFs and BPFs). Indeed, more than 1200 DMRs consistently changed in CAFs from every patient, regardless of tumour grade. The second set of DMRs varied between CAFs according to the severity of the tumour. Notably, hypomethylation of the EDARADD promoter occurred specifically in CAFs from high-grade tumours and correlated with increased transcript abundance and increased EDARADD staining in patient tissue. Across multiple cohorts, tumours with low EDARADD DNA methylation and high EDARADD mRNA expression were consistently associated with adverse clinical features and shorter recurrence free survival. Conclusions We identified a large set of DMRs that are commonly shared across CAFs regardless of tumour grade and outcome, demonstrating highly consistent epigenome changes in the prostate tumour microenvironment. Additionally, we found that CAFs from aggressive prostate cancers have discrete methylation differences compared to CAFs from moderate risk prostate cancer. Together, our data demonstrates that the methylome of the tumour microenvironment reflects both the presence and the severity of the prostate cancer and, therefore, may provide diagnostic and prognostic potential.

Background The intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC. Objective To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC. Design, setting, and participants Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system. Intervention The following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258). Outcome measurements and statistical analysis Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments. Results and limitations Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258. Conclusions This study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation. Patient summary Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.

Prostate cancer displays a wide spectrum of clinical behaviour from biological indolence to rapidly lethal disease, but we remain unable to accurately predict an individual tumor's future clinical course at an early curable stage. Beyond basic dimensions and volume calculations, tumor morphometry is an area that has received little attention, as it requires the analysis of the prostate gland and tumor foci in three-dimensions. Previous efforts to generate three-dimensional prostate models have required specialised graphics units and focused on the spatial distribution of tumors for optimisation of biopsy strategies rather than to generate novel morphometric variables such as tumor surface area. Here, we aimed to develop a method of creating three-dimensional models of a prostate's pathological state post radical prostatectomy that allowed the derivation of surface areas and volumes of both prostate and tumors, to assess the method's accuracy to known clinical data, and to perform initial investigation into the utility of morphometric variables in prostate cancer prognostication. Serial histology slides from 21 prostatectomy specimens covering a range of tumor sizes and pathologies were digitised. Computer generated three-dimensional models of tumor and prostate space filling models were reconstructed from these scanned images using Rhinoceros 4.0 spatial reconstruction software. Analysis of three-dimensional modelled prostate volume correlated only moderately with weak concordance to that from the clinical data (r=0.552, θ=0.405), but tumor volume correlated well with strong concordance (r=0.949, θ=0.876). We divided the cohort of 21 patients into those with features of aggressive tumor versus those without and found that larger tumor surface area (32.7 vs 3.4cc, p=0.008) and a lower tumor surface area to volume ratio (4.7 vs 15.4, p=0.008) were associated with aggressive tumor biology.

Operational oceanography can be described as the provision of routine oceanographic information needed for decision-making purposes. It is dependent upon sustained research and development through the end-to-end framework of an operational service, from observation collection to delivery mechanisms. The core components of operational oceanographic systems are a multi-platform observation network, a data management system, a data assimilative prediction system, and a dissemination/accessibility system. These are interdependent, necessitating communication and exchange between them, and together provide the mechanism through which a clear picture of ocean conditions, in the past, present, and future, can be seen. Ocean observations play a critical role in all aspects of operational oceanography, not only for assimilation but as part of the research cycle, and for verification and validation of products. Data assimilative prediction systems are advancing at a fast pace, in tandem with improved science and the growth in computing power. To make best use of the system capability these advances would be matched by equivalent advances in operational observation coverage. This synergy between the prediction and observation systems underpins the quality of products available to stakeholders, and justifies the need for sustained ocean observations. In this white paper, the components of an operational oceanographic system are described, highlighting the critical role of ocean observations, and how the operational systems will evolve over the next decade to improve the characterization of ocean conditions, including at finer spatial and temporal scales.

Complications of bleeding, liver abscess and movement have been associated with previous duodeno-jejunal bypass liner (DJBL) applications in the past. A new anchoring system and design of a DJBL is presented as a pilot study. A newly designed DJBL device was inserted in 2 pigs and observed over 2 months. The newly designed device was anchored and monitored for 1 month in 1 of 2 pigs, the other being passed early. Effectiveness and safety have been shown. The results of this pilot study warrant further investigation of the modified DJBL setup, which may help solve standing issues associated with the clinical use of a DJB liner.

Background Serially transplantable patient-derived xenografts (PDXs) are invaluable preclinical models for studying tumor biology and evaluating therapeutic agents. As these models are challenging to establish from prostate cancer specimens, the ability to preserve them through cryopreservation has several advantages for ongoing research. Despite this, there is still uncertainty about the ability to cryopreserve PDXs of prostate cancer. This study compared three different cryopreservation protocols to identify a method that can be used to reproducibly cryopreserve a diverse cohort of prostate cancer PDX models. Methods One serially transplantable prostate cancer PDX from the Melbourne Urological Research Alliance cohort was used to compare three cryopreservation protocols: slow freezing in fetal calf serum (FCS) with 10% dimethyl sulfoxide (DMSO), FCS with 10% DMSO supplemented with the Rho-associated kinase (ROCK) inhibitor Y-27632 and vitrification. The efficiency of the slow freezing protocols was then assessed in 17 additional prostate cancer PDXs. Following cryopreservation, PDXs were re-established in host mice that were either intact and supplemented with testosterone or castrated. Graft take rate, tumor growth, histological features, and transcriptome profiles before and after cryopreservation were compared. Results Slow freezing maintained the viability and histological features of prostate cancer PDXs, and the addition of a ROCK inhibitor increased their growth following cryopreservation. Using the slow freezing method, we re-established 100% of PDXs grown in either testosterone-supplemented or castrated host mice. Importantly, the long-term tumor growth rate and transcriptome profile were maintained following cryopreservation. Conclusion This study has identified a protocol to reliably cryopreserve and re-establish a diverse cohort of serially transplantable PDXs of prostate cancer. This study has the potential to significantly improve the practicality of maintaining PDX models. Cryopreservation may also increase the accessibility of these important resources and provide new opportunities for preclinical studies on a broader spectrum of prostate tumors.

OBJECTIVE To evaluate the significance of routinely reported 'equivocal' lymphovascular invasion (LVI) in prostatectomy specimens of patients with clinically localized prostate cancer. MATERIALS AND METHODS Prospectively collected data from men who underwent prostatectomy for clinically localized prostate cancer were retrospectively reviewed. Rates of adverse pathological features and biochemical recurrence (BCR) were compared between tumours positive, negative or 'equivocal' for LVI. Multivariable Cox regression analysis was performed to identify independent predictors of BCR. RESULTS Of 1 310 consecutive cases, LVI was present definitively in 82 (6.3%) and equivocally in 43 (3.3%) cases. Similar to definitive LVI, equivocal LVI was significantly associated with other adverse pathological features, including advanced stage, higher Gleason grade and positive surgical margins. BCR occurred more frequently in patients with tumours that were equivocal (61%) or positive for LVI (71%) than in patients with negative results (14.7%). In addition, patients with both definitive and equivocal LVI had a significantly shorter BCR-free survival time compared with those with negative LVI. Multivariable Cox regression analysis indicated that the presence of either definitive or equivocal LVI were independent predictors of disease recurrence (hazard ratio [HR] 3.32, 95% confidence interval [CI] 2.3-4.8; P

338 Background: Androgen receptor (AR) signalling is important in prostate cancer progression, and therapies that specifically target this pathway are the mainstay of treatment for advanced disease. Treatment however is non-curative, and resistance develops inevitably with time. Although the mechanisms that drive castration resistant disease have been intensively analysed, how tumours survive and persist during the initial pathway inhibition is unclear. Methods: To track this process in detail we performed a Phase II neo-adjuvant study of a novel combination of AR targeting therapies (degarelix & abiraterone & bicalutamide) for 6 months prior to prostatectomy in men with high risk, localised disease. To determine what was driving tumour persistence in poorly responding patients, we comprehensively characterised pre- and post-treatment samples using both whole genome and RNA-sequencing, validating pertinent findings by qRT-PCR, IHC and FISH. Results: Despite universal ‘biochemical responses’, objective responses to treatment as measured by residual tumours volumes were highly variable. This state which we term ‘castration-persistence’, is molecularly distinct from ‘castration-resistance’, and is characterised by global transcriptional reprogramming leading to a transitional EMT state. Whole genome sequencing confirms tumour persistence is not associated with the emergence of a ‘driver’ lesion, rather treatment response is associated with regression of a ‘treatment sensitive’ subclonal population, defined by deletion of the EMT master regulator SNAI2. The extent of treatment response observed was determined by the prevalence of cells with loss of SNAI2 in pre-treatment biopsies. Conclusions: Cell plasticity with transition to a mesenchymal phenotype defines prostate cancer cell survival to acute AR signalling inhibition. Tumour response is determined by the proportion of cells present harbouring defects in this program.

Patients with defects in the mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer, whilst germline MMR defects in either MLH1 or PMS2, exhibit no such increase. Prostatic carcinogenesis is driven by androgen signalling. Here we show that androgen-receptor activation can disrupt the MSH2 gene in prostate cancer model systems. We screened tumors from two contrasting risk cohorts of prostate cancer patients to confirm loss of MSH2 protein expression and surprisingly found a small but significant fraction of high risk cases exhibited reduced expression of MSH2. Stratifying a large independent TCGA prostate cancer cohort for MSH2 expression levels revealed that patients whose tumors exhibited either complete loss or aberrant levels of MSH2 had equally significant worse survival outcomes and accelerated clinical progression. In contrast, colorectal cancer patients with aberrant MSH2 levels had improved clinical survival. We show that reduced expression of MSH2 can also occur through androgen-induced miRNA regulatory mechanisms. Aberrant MSH2 expression in prostate tumors does not induce enhanced immune cell mobilisation seen in colorectal tumors suggesting that the prostate is an immune privileged site that is less likely to benefit from immunotherapies.

BACKGROUND Fresh patient specimens of castrate-resistant prostate cancer (CRPC) are invaluable for studying tumor heterogeneity and responses to current treatments. They can be used for primary patient-derived xenografts (PDXs) or serially transplantable PDXs, but only a small proportion of samples grow successfully. To improve the efficiency and quality of PDXs, we investigated the factors that determine the initial engraftment of patient tissues derived from TURP specimens. METHODS Fresh tissue was collected from castrate patients who required a TURP for urinary symptoms. Tissue was grafted under the renal capsule of immune-compromised mice for up to 14 weeks. The abundance of cancer in ungrafted and grafted specimens was compared using histopathology. Mice were castrated or implanted with testosterone pellets to determine the androgen-responsiveness of CRPC PDXs from TURP tissue. RESULTS Primary PDXs were successfully established from 7 of 10 patients that underwent grafting. Of the 112 grafts generated from these 10 patients, 21% contained cancer at harvest. Grafts were most successful when the original patient specimens contained high amounts of viable cancer, defined as samples with (i) at least 50% cancer cells, (ii) no physical damage, and (iii) detectable Ki67 expression. PDX grafts survived in castrated hosts and proliferated in response to testosterone, confirming that they were castrate resistant but androgen-responsive. CONCLUSIONS Primary PDXs of CRPC can be established from TURP specimens with modest success. The take rate can be increased if the original tissues contain sufficient numbers of actively proliferating cancer cells. Selecting specimens with abundant viable cancer will maximize the rate of engraftment and increase the efficiency of establishing PDXs that can be serially transplanted. Prostate 75:1475–1483, 2015. © 2015 Wiley Periodicals, Inc.

Objective To determine the relevance of intraductal carcinoma of the prostate (IDC-P) in advanced prostate cancer by first examining whether IDC-P was originally present in patients who later developed advanced prostate cancer and then using patient-derived xenografts (PDXs) to investigate the response of IDC-P to androgen deprivation therapy (ADT). Materials and methods We conducted a retrospective pathology review of IDC-P in primary prostate biopsy or surgery specimens from 38 men who subsequently developed advanced prostate cancer. Overall survival was calculated using the Kaplan-Meier method. To demonstrate the response of IDC-P to ADT, we established PDXs from seven patients with familial and/or high-risk sporadic prostate cancer. After castration and testosterone restoration of host mice, we measured the volume and proliferation of IDC-P within PDX grafts. Results We found that IDC-P was a prominent feature in the primary prostate specimens, present in 63% of specimens and often co-existing with poorly differentiated adenocarcinoma. Overall survival was similar in patients with or without IDC-P. In the PDXs from all seven patients, IDC-P was identified and present at a similar volume to adenocarcinoma. Residual IDC-P lesions persisted after host castration and, similar to castrate-tolerant adenocarcinoma, testosterone restoration led to tumour regeneration. Conclusion The study showed that IDC-P is prevalent in aggressive prostate cancer and contains cells that can withstand androgen deprivation. Thus, IDC-P appears functionally relevant in advanced prostate cancer. The presence of IDC-P may be a trigger to develop innovative clinical management plans.

Personalised oncology through mutational profiling of cancers requires the procurement of fresh frozen tumour samples for genomics applications. While primary cancers are often surgically excised and therefore yield such tissue, metastases in the setting of a known cancer diagnosis are not routinely sampled prior to systemic therapy. Our study aimed to determine the suitability of extracted nucleic acids for genomics applications using distant metastatic prostate cancer samples obtained via percutaneous or surgical biopsy. Patients with metastatic prostate cancer were recruited for image-guided biopsy of metastases. Patients undergoing surgical procedures for the complications of metastases were also recruited. Tissue samples were flash frozen and cryosectioned for histological examination. DNA and RNA were simultaneously extracted and genomic DNA hybridised onto SNP arrays for genome-wide copy number analysis. 37 samples of metastatic tissue from seven patients with prostate cancer were obtained. Five of these underwent image-guided biopsies whilst two had therapeutic surgical procedures performed. 22 biopsy samples were obtained across the image-guided biopsy patients with 80 % of samples being successfully processed for downstream analysis. Nucleic acid yield from these samples were satisfactory for genomics applications. Copy number analysis revealed a median estimated tumour purity of 53 % and all samples showed chromosomal abnormalities suggestive of malignancy. The procurement of osseous metastatic prostate cancer from live patients, including the use of image-guided biopsy, is safe and feasible. Sufficient tissue can be obtained in a manner such that extracted nucleic acids are suitable for genomics research.

Keratoacanthoma formation after skin grafting is rare. We report the third case in the literature of multiple keratoacanthomas developed at both split-thickness skin graft donor and recipient sites. We provide possible explanations for this poorly understood phenomenon and highlight its implications on treatment options.

On April 20, 1999, Eric Harris and Dylan Klebold murdered 12 students and one teacher at Columbine High School in Littleton, Colorado, in what was then the deadliest school shooting in American history. Despite causing a national panic and serving as a flash point for larger narratives on bullying, gun control, and media violence, both boys have gained active online fans. These fandoms dedicated to the Columbine shooters are widely referred to as dark examples of Internet communities, while the fans are also frequently denigrated as unstable and violent outcasts. Such dark online fandoms are yet to permeate mainstream culture or to challenge the preexisting perception of these communities as breeding grounds for the next wave of school shooters. While studies have covered the types of fans and their myriad interests, the field remains focused on more conventional examples of fan communities. In an effort to challenge and expand the object of focus when we study fandom, this qualitative study examines Columbine fans and their activity in order to understand the dominant motives they appear to have for engaging with and around such controversial figures and then concludes by exploring how this community might help us reflect more broadly on our concept of fandom. Redeeming these fans as part of diverse and complex communities of social relevance can demonstrate how even a dark fandom such as that of these Columbine shooters provides valuable cultural insights and benefits the field of fan studies.

Endometrial cancer is the most common gynaecological malignancy in the developed world. The majority of cases can be divided into two broad categories based on clinico-pathological and molecular characteristics; Type I oestrogen-dependent with endometrioid morphology and Type II non-oestrogen-dependent with serous papillary or clear cell morphology. As has been described for other malignancies, such as colorectal carcinoma, the transition from normal endometrium to carcinoma is thought to involve a stepwise accumulation of alterations in cellular regulatory pathways leading to dysfunctional cell growth. This article reviews the current knowledge of the molecular changes commonly associated with endometrial cancer and presents possible progression models.

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 applications. High- g simulation results predicted safe operation above 100,000× g and preliminary experimental tests were successfully performed to 40,000× g . Sensitivities ranging between 50 and 343 nV/g were measured for differing accelerometer sensing elements. Non-linear behavior was observed over the shock range relative to the commercial benchmark accelerometer. These initial results offer promise for the use of 6H-SiC accelerometers in extreme impact sensing.

The renewable energy is a promising field, which shows a lot of potential for future energy solutions. The design of the blade shows a lot effects on the efficiency of the wind turbine, and the design parameters governs the performance characteristics. This paper addresses a number of innovative blade designs that was developed by alterations made to the existing conventional straight blade. These blades were extensively studied using computational fluid dynamics (CFD) software, and showed promising results, which was the motive behind this study. We are designing an experiment to study small scale wind turbines, which will enable us to gather data that will explain some differences in power and torque output. These steps will help us to come to a better understanding of some aerodynamic aspects that will impact the performance of each individual blade design. The comparing criteria for this study was the torque generation at the axes of rotation, which can be translated to several parameters, such as energy output, using some theoretical basis equations.Copyright © 2014 by ASME

Advances in genomic platforms have led to the need for well-characterized, high quality biospecimens for research. Bladder cancer, despite being a major epidemiological concern, has been under-represented in genomic programs due to unique challenges in collection of clinical informatics and tissues. Currently no targeted therapy exists for management of the disease. We report our experiences and lessons learnt in establishing an integrated model of bladder cancer that uses a dedicated bladder cancer team and relational databases. It streamlines both clinical activity and serial harvesting of biospecimens to obtain tissue that is consistently suitable for high-throughput genomic research. Fresh tissue, blood, and urine samples were prospectively collected and stored. RNA and DNA were extracted simultaneously, quality control was performed, and whole transcriptome sequencing also performed using the illumina series of platforms. Over a 15-month period, urine was banked for 209 patients, plasma and whole blood for 185 patients, and tissue for 71 patients. The collections included normal mucosa from patients with and without bladder cancer and cancer tissue across the entire histopathogical spectrum of bladder cancer from low-grade noninvasive cancers to metastatic lymph nodes. We used a relational database to link clinical information to tumor inventory and provide access to richly annotated specimens and matched clinical informatics. We found that tumor tissue was successfully banked more often in patients who had macroscopic papillary disease compared to those without. We also show that the median RNA integrity number (RIN) scores are significantly higher in patients whose tissues were banked using cold-cup biopsies compared to those banked using electrocautery. Transcriptome sequencing of all samples banked using cold-cup biopsies passed bioinformatics quality assessment and had a mean Q30 quality score well over the illumina quality control benchmark. Such an infrastructure will allow genomic profiling of bladder cancer to help us understand the "global picture" in bladder cancer pathogenesis.

significantly higher in AA (Median 6.72 versus 6.35, p 1⁄4 0.04). No differences in age or stage of disease were detected between groups (p > 0.05). In Caucasians, MIC 1 expression was positively associated with PSA (p 0.0001), while Gleason score was positively associated with PSA (p < 0.05) and age (p < 0.05). Log transformed PSA and MIC 1 were used for valid inferences. Thus, higher levels of MIC 1 expression and higher Gleason scores were associated with older patients when limiting our sample to Caucasians. In AA, however, both older and younger patients had highly expressed MIC 1 and high Gleason scores. CONCLUSIONS: Although a detailed sample analysis is required, these observations indicate that addition of MIC 1 may help to improve the diagnostic capability of an aggressive stage of prostate cancer at least in African American men.

Struvite calculi form in an alkaline environment created by urease producing uropathogens. We developed a viable upper tract urinary acidification model by performing gastric patch pyeloplasty in the rabbit. This model produces urinary acidification sufficient for the treatment and prevention of struvite renal calculi. We evaluated the physiological, metabolic and surgical outcomes.gastric segment was harvested based on branches of the left gastro-epiploic artery. The flap was folded along the transverse axis and the adjacent edges were closed. The mouth of this reconfigured pouch provided optimal dimensions for anastomosis with the diminutive renal pelvis. Half of the rabbits were treated with internal stenting and H-2 blockade. Urinary pH was assessed by weekly cage collection and direct collection from the cannulated ureters. Urine culture was done, and serum gastrin and electrolytes were assessed at regular intervals. The rabbits were sacrificed at 3 to 26 weeks. Histological examination was routinely performed.A total of 15 rabbits were available for complete assessment. Sustained urinary acidification was produced in 7 animals (47%) with a mean pH decrease of 2.27. In another 2 rabbits (13%) the urine was initially acidic but subsequently became alkaline due to ureteral obstruction. Electrolytes and gastrin were unchanged in these rabbits and urine culture was positive in 2. Histological testing revealed nonspecific inflammatory changes of the renal pelvis. Anastomotic complications were the most common surgical complication and the most common cause of failed acidification. The cohort treated without stents and H-2 blockade was at significantly greater risk for anastomotic leakage.Gastric patch pyeloplasty may significantly increase urinary acidity in the rabbit model without altering the serum electrolyte balance or gastrin level. The procedure utilizes common techniques of reconstructive urology and may be possible with laparoscopy. Further study is required to assess the in vivo effect of this procedure for treating and preventing upper tract struvite calculi.