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Prostate cancer is primarily hormone-dependent, and medical treatments have focused on inhibiting androgen biosynthesis or signaling through various approaches. Despite significant advances with the introduction of androgen receptor signalling inhibitors (ARSIs), patients continue to progress to castration-resistant prostate cancer (CRPC), highlighting the need for targeted therapies that extend beyond hormonal blockade. Chimeric Antigen Receptor (CAR) T cells and other engineered immune cells represent a new generation of adoptive cellular therapies. While these therapies have significantly enhanced outcomes for patients with hematological malignancies, ongoing research is exploring the broader use of CAR T therapy in solid tumors, including advanced prostate cancer. In general, CAR T cell therapies are less effective against solid cancers with the immunosuppressive tumor microenvironment hindering T cell infiltration, activation and cytotoxicity following antigen recognition. In addition, inherent tumor heterogeneity exists in patients with advanced prostate cancer that may prevent durable therapeutic responses using single-target agents. These barriers must be overcome to inform clinical trial design and improve treatment efficacy. In this review, we discuss the innovative and rationally designed strategies under investigation to improve the clinical translation of cellular immunotherapy in prostate cancer and maximise therapeutic outcomes for these patients.

BACKGROUND: There are relatively few widely used models of prostate cancer compared to other common malignancies. This impedes translational prostate cancer research because the range of models does not reflect the diversity of disease seen in clinical practice. In response to this challenge, research laboratories around the world have been developing new patient-derived models of prostate cancer, including xenografts, organoids, and tumor explants. METHODS: In May 2023, we held a workshop at the Monash University Prato Campus for researchers with expertise in establishing and using a variety of patient-derived models of prostate cancer. This review summarizes our collective ideas on how patient-derived models are currently being used, the common challenges, and future opportunities for maximizing their usefulness in prostate cancer research. RESULTS: An increasing number of patient-derived models for prostate cancer are being developed. Despite their individual limitations and varying success rates, these models are valuable resources for exploring new concepts in prostate cancer biology and for preclinical testing of potential treatments. Here we focus on the need for larger collections of models that represent the changing treatment landscape of prostate cancer, robust readouts for preclinical testing, improved in vitro culture conditions, and integration of the tumor microenvironment. Additional priorities include ensuring model reproducibility, standardization, and replication, and streamlining the exchange of models and data sets among research groups. CONCLUSIONS: There are several opportunities to maximize the impact of patient-derived models on prostate cancer research. We must develop large, diverse and accessible cohorts of models and more sophisticated methods for emulating the intricacy of patient tumors. In this way, we can use the samples that are generously donated by patients to advance the outcomes of patients in the future.

Patient-derived xenografts (PDXs) are generated by engrafting human tumours into mice. Serially transplantable PDXs are used to study tumour biology and test therapeutics, linking the laboratory to the clinic. Although few prostate cancer PDXs are available in large repositories, over 330 prostate cancer PDXs have been established, spanning broad clinical stages, genotypes and phenotypes. Nevertheless, more PDXs are needed to reflect patient diversity, and to study new treatments and emerging mechanisms of resistance. We can maximize the use of PDXs by exchanging models and datasets, and by depositing PDXs into biorepositories, but we must address the impediments to accessing PDXs, such as institutional, ethical and legal agreements. Through collaboration, researchers will gain greater access to PDXs representing diverse features of prostate cancer.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

UNLABELLED: Cancer cells undergo metabolic reprogramming to meet increased bioenergetic demands. Studies in cells and mice have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer; however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric (14C) and stable (13C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDX). Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared with benign PDXs. De novo lipogenesis (DNL) and storage of free fatty acids into phospholipids and triacylglycerols were increased in malignant PDXs. There was no difference in substrate utilization between localized and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. Mechanistically, glucose utilization was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the tricarboxylic acid cycle through transaminase reactions before being utilized via oxidative or reductive pathways. Blocking fatty acid uptake or fatty acid oxidation with pharmacologic inhibitors was sufficient to reduce cell viability in PDX-derived organoids, whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy. These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilize all metabolic substrates, albeit with marked heterogeneity across tumors. We also confirm that fatty acid uptake and oxidation are targetable metabolic dependencies in human prostate cancer. IMPLICATIONS: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacologic targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localized and metastatic tumors.

Prostate cancer invokes major shifts in gene transcription and metabolic signaling to mediate alterations in nutrient acquisition and metabolic substrate selection when compared to normal tissues. Exploiting such metabolic reprogramming is proposed to enable the development of targeted therapies for prostate cancer, yet there are several challenges to overcome before this becomes a reality. Herein, we outline the role of several nutrients known to contribute to prostate tumorigenesis, including fatty acids, glucose, lactate and glutamine, and discuss the major factors contributing to variability in prostate cancer metabolism, including cellular heterogeneity, genetic drivers and mutations, as well as complexity in the tumor microenvironment. The review draws from original studies employing immortalized prostate cancer cells, as well as more complex experimental models, including animals and humans, that more accurately reflect the complexity of the in vivo tumor microenvironment. In synthesizing this information, we consider the feasibility and potential limitations of implementing metabolic therapies for prostate cancer management.

OBJECTIVES: To perform a systematic review and meta-analysis of the literature to understand the variation in the reporting of neuroendocrine staining and determine the influence of reporting neuroendocrine staining at diagnosis on patient outcomes. METHODS: Medical databases were searched to identify studies in which adenocarcinoma specimens were stained with any of the following four neuroendocrine markers: chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin and CD56. The prevalence of neuroendocrine staining and correlation of the prevalence of neuroendocrine staining to patient outcomes were analysed using a random-effects model. All statistical tests were two-sided. RESULTS: Sixty-two studies spanning 7616 patients were analysed. The pooled prevalence for the most common marker, CgA (41%), was similar to that of NSE (39%) and higher than that of synaptophysin (31%). The prevalence of CgA staining was significantly influenced by reporting criteria, where objective thresholds reduced the variation in prevalence to 26%. No correlation was found between CgA prevalence and tumour grade. Patients positive for CgA staining using objective criteria had more rapid biochemical progression (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.49 to 2.65) and poorer prostate cancer-specific survival (HR 7.03, 95% CI 2.55 to 19.39) compared to negative patients, even among those with low-risk cancers. CONCLUSION: Discrepancies in the reported prevalence of neuroendocrine cells in adenocarcinoma are driven by the inconsistent scoring criteria. This study unequivocally demonstrates that when neuroendocrine cell staining is assessed with objective criteria it identifies patients with poor clinical outcomes. Future studies are needed to determine the exact quantifiable thresholds for use in reporting neuroendocrine cell staining to identify patients at higher risk of progression.

UNLABELLED: Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies. SIGNIFICANCE: Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strateg

Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4-5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D'Amico intermediate or high risk, comparable to our previously published BRCA2 an

Androgen and androgen receptor (AR) targeted therapies are the main treatment for most prostate cancer (PC) patients. Although AR signaling inhibitors are effective, tumors can evade this treatment by transforming to an AR-negative PC via lineage plasticity. OCT1 is a transcription factor interacting with the AR to enhance signaling pathways involved in PC progression, but its role in the emergence of the AR-negative PC is unknown. We performed chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells to identify genes that are regulated by OCT1. Interestingly, a group of genes associated with neural precursor cell proliferation was significantly enriched. Then, we focused on neural genes STNB1 and PFN2 as OCT1-targets among them. Immunohistochemistry revealed that both STNB1 and PFN2 are highly expressed in human AR-negative PC tissues. Knockdown of SNTB1 and PFN2 by siRNAs significantly inhibited migration of AR-negative PC cells. Notably, knockdown of PFN2 showed a marked inhibitory effect on tumor growth in vivo. Thus, we identified OCT1-target genes in AR-negative PC using a patient-derived model, clinicopathologial analysis and an animal model.

Integrating a multi-effect distillation (MED) process with a concentrated solar power (CSP) plant can enable a sustainable solution to meet our global society's increasing energy and freshwater demands. This integration makes possible the ‘free’ reuse of waste heat from an advanced power block, albeit at slightly reduced thermal efficiency. As such, this study can be considered a pioneering analysis of the potential of integrating a cascaded MED system with a supercritical CO2 (sCO2) cycle, which provides two main innovations: (a) a highly efficient sCO2 cycle is proposed to mitigate the energy efficiency penalty of the more traditional (Rankine Cycle) in CSP-Desalination (CSP-D) coupling, and (b) a cascaded MED system is proposed to recover much more of the rejected waste heat than a single MED configuration. These two innovations were explored in detail by employing an in-house thermo-economic numerical model, which was validated using literature data. It was found that 4-MED systems maximized the distillate production, with 57% waste heat energy recovery compared to 26% energy recovery using a single-MED system. Encouraged by this positive performance boost, an economic feasibility analysis was conducted by considering the installation site (i.e., pipeline distance from the coastline and the direct normal irradiance (DNI) resource) and the potential revenue from a power purchasing agreement (PPA) and a water purchasing agreement (WPA). It was found that the desalination process has a negligible effect on the payback due to the limited water production (i.e., ∼1 million m3/yr) compared to the high electricity generation (i.e., ∼190 GWh/yr). Thus, reducing the power block's investment cost and installing the plant in high PPA markets (i.e., above 20 UScents/kWh) represent the two most significant factors for improving the plant's feasibility. It was also found that a 0.6 kWh/m2day of additional DNI is required to offset each 100 km of pumping energy consumption (fo

Gold nanoparticles (GNP) aided hyperthermia has demonstrated promising results in the treatment of cancer. However, most existing investigations focus only on the extinction spectra of GNP solutions, few reported the actual heat generation capability of these solutions to estimate their real potential in in-situ hyperthermia treatment. In this study, the impact of GNP clustering on the optical properties and heating capability of GNP aggregates in acidic solutions have been investi-gated. It was found that localized heat generation could be significantly enhanced (to up to 60.0 ℃) when acidic solutions were illuminated by a near infrared light source at 1.7 W/cm2. In addition, infrared thermography imaging can only detect the surface temperature during thermal treatment, leaving the localized temperature distribution inside the tissues unknown. To overcome this limita-tion, in this study, the absorbed energy during NIR irradiation in GNP solutions was obtained com-putationally by coupling the P1 approximation with the DDA calculation to predict the localized temperature change in the solutions. It was demonstrated that due to the accumulation and dissi-pation of heat, some local areas showed higher temperature increase with the hot spots being con-nected and merged over time.

Distillation systems can achieve much higher energy efficiency by utilizing multiple effects to internally recycle latent heat. Flat sheet membrane distillation systems (i.e., the Memsys MDS range of products) have taken advantage of this, but hollow fiber vacuum membrane distillation systems have not yet been systematically designed to incorporate the multi-effect concept. To advance this concept, a hollow fiber-based multi-effect VMD (HF V-MEMD) was designed and manufactured to internally recover the latent heat of the permeate vapor between effects using hollow helical baffles. A mathematical model was developed to investigate the effect of the operating and design conditions on the permeate flux, the gained output ratio (GOR), and the specific total energy consumption (STEC). It was found that a GOR of 1.5–3.5 can be achieved across a range of operating conditions. Additionally, for an optimal module design (e.g., 500 m2/m3 packing density, 0.5 m module length, and a 0.2–0.3 m shell diameter), the results indicate that a 4-effect design can improve the STEC by more than 60% compared to a single-effect design. Overall, this study concludes that the proposed energy-efficient HF V-MEMD design is most suitable for compact, portable systems to alleviate water scarcity in rural arid-regions.

Ultra-low pressure gravity-driven membrane (GDM) systems have the potential to be significantly less costly and complex than conventional membranes for water treatment applications. To build upon this inherent advantage, this study assesses the reuse of recycled membranes in GDM systems for producing drinking water. Two reverse osmosis spiral-wound modules were recycled into nanofiltration (NF)-like and ultrafiltration (UF)-like membranes via controlled exposure to free chlorine. To operate the recycled membranes, two housing devices, based on a simple fitting and an advanced end-caps design, were developed. The recycled membrane systems were tested under a range of conditions (submerged vs. external system configuration and continuous vs. intermittent filtration mode). Synthetic river water feed solutions were used in the tests where performance, fouling, and clogging were measured. NF-like recycled membranes resulted in poor salt rejection and low permeability (~1.7 L m−2 h−1 bar−1), but also in high rejection (>81%) of dissolved organic carbon. UF-like recycled membranes maintained their capacity to reject biopolymers (BP) (>74%) and featured up to 18-fold higher permeate rate than NF-like recycled membranes. The optimized operating conditions were found when the recycled membranes were housed in the end-caps device and operated intermittently (relaxation time plus forward flushing). Flushing reduced the fouling accumulation inside the membrane (only 12% and 40% of BP accumulation was observed in the NF-like and UF-like, respectively). However, the end-caps-based device was estimated to be more expensive during the economic analysis. To address this techno-economic trade-off, a decision-making tree was developed to select the appropriate configuration based upon the implementation context. Overall, this study concludes that these designs can serve as robust, low-cost (water production cost <1 USD ct. yr. L−1), and light-weight GDM alternatives. This study is bene

Although vacuum membrane distillation (VMD) has a high distillate flux, its potential is limited by its high specific heat consumption (SHC). Flat sheet VMD systems recover the brine energy by employing a cascade system to improve the SHC. Hollow fiber VMD systems, however, have not yet been optimized for energy recovery. To overcome this knowledge gap, four multi-stage configurations (with and without brine energy recovery) were investigated via experimentation and through numerical simulations. The results show that having permeate flux promoting conditions, such as high feed temperature or lower vacuum pressure, improves the SHC for VMD configurations without brine recirculation, but have little impact for configurations with brine energy recovery. A Pareto multi-objective optimization showed that the optimized first-stage heating MS-VMD without brine recirculation has the highest SHC (908 kWh/m3) but one of the lowest LCOW (2.37 USD/m3). In contrast, the configuration with the first-stage heating with brine recirculation provided the lowest SHC (585–629 kWh/m3) and an acceptable LCOW (2.27–8.30 USD/m3). This study reveals that the development of MS-VMD represents a promising direction for thermal desalination technologies, particularly for high saline water applications.

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.

Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.

New treatments are required for advanced prostate cancer; however, there are fewer preclinical models of prostate cancer than other common tumor types to test candidate therapeutics. One opportunity to increase the scope of preclinical studies is to grow tissue from patient-derived xenografts (PDXs) as organoid cultures. Here we report a scalable pipeline for automated seeding, treatment and an analysis of the drug responses of prostate cancer organoids. We established organoid cultures from 5 PDXs with diverse phenotypes of prostate cancer, including castrate-sensitive and castrate-resistant disease, as well as adenocarcinoma and neuroendocrine pathology. We robotically embedded organoids in Matrigel in 384-well plates and monitored growth via brightfield microscopy before treatment with poly ADP-ribose polymerase inhibitors or a compound library. Independent readouts including metabolic activity and live-cell imaging-based features provided robust measures of organoid growth and complementary ways of assessing drug efficacy. Single organoid analyses enabled in-depth assessment of morphological differences between patients and within organoid populations and revealed that larger organoids had more striking changes in morphology and composition after drug treatment. By increasing the scale and scope of organoid experiments, this automated assay complements other patient-derived models and will expedite preclinical testing of new treatments for prostate cancer.

Chimeric antigen receptor T (CAR T) cell therapy is an adoptive immunotherapy that has led to new treatments for lymphoma, leukemia, and other blood cancers; however, its efficacy for prostate cancer remains unproven. Here we report pre-clinical evidence of the efficacy of CAR T cell therapy against the Lewis Y antigen (LeY) using patient-derived models of prostate cancer. To assess the expression of LeY on prostate tumours, we performed immunohistochemistry on a cohort of 41 patient-derived xenografts (PDXs). Cytoplasmic and membrane expression were separately assessed and quantified, for each patient. Overall, 61% (25/41) of PDXs were positive for membrane LeY expression, of which 18 PDXs had greater than 50% membrane-positive cells, and considered most suitable to detection and stable binding by anti-LeY CAR T’s. To determine the in vitro sensitivity to CAR T cytotoxicity, we selected 4 PDXs with high and 2 PDXs with low LeY expression using 3 androgen receptor (AR)-positive adenocarcinomas and 3 AR-negative tumors expressing neuroendocrine markers. Next we established organoids for in vitro co-culture assays where organoids were co-incubated with an equal number of anti-LeY+ CAR T cells or Empty vector control CAR T cells (Ev CAR T). Using time-lapse microscopy we reported destruction of organoids by LeY+ CAR T cells as indicated by their morphological collapse and uptake of propidium iodide from the culture medium; control Ev CAR T cells produced no cytotoxicity. Over the 48h assay, the level of target cell death of the LeY+ organoids was correlated to the intensity LeY surface expression. Target cell death mediated by the CAR T cells required perforin and granzyme B, as potent and highly specific small molecule inhibitors of perforin (SN34960) and granzyme B (C20) applied alone or in combination greatly decreased PI uptake, indicating organoid survival. Neither inhibitor adversely affected CAR T cell viability as measured by PI and Annexin V staining.

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.

Membrane distillation represents a promising solution for high salinity water desalination (e.g. shale gas produced waste wastewater), but so far it has achieved limited commercial success relative to other thermally driven desalination technologies. This study aims to advance membrane distillation technology by systematically investigating three innovative features which can potentially help improve overall performance: a 3D-printed helical baffle, a superhydrophobic membrane coating, and an intermittent operation mode. Our experimental and numerical results reveal that the 3D-printed helical baffle can enhance the permeate flux by 6–46% (depending on flow rate) and increase the average membrane shear by ~60%, with negligible additional pumping power. The impact of a super-hydrophobic coated membrane was evaluated for a synthetic wastewater (35 g/L of NaCl and 0.1 mM of sodium dodecyl sulfate) which mimicked low surface tension shale gas wastewater. It was found that the modified membrane's flux and salt rejection were maintained ~25% longer than a conventional uncoated polypropylene (PP). Lastly it was found intermittent operation consisting of 5 h of operation followed by 1 h of regeneration doubled module durability compared to continuous operation for the equivalent volume of permeate production. Based on these results, it was estimated that the synergy between these three enhancements would provide >6% more permeate flux and >100% durability, as compared to the baseline. Thus, these results demonstrate that by improving heat and mass transport while also enhancing the hydrophobicity of underlying membranes, it may be possible to make MD systems a viable option for industrial wastewater treatment.

The outdoor deployment of solar nanofluids in practical solar photothermal conversion devices for prolonged periods of time has been an ongoing challenge. This is due to their exposure to intense solar radiation, elevated temperatures, thermal and solar cycling, and other rough operation conditions that compromise their dispersion and chemical stability. This work is an attempt to address this challenge in light of state-of-the-art advances in understanding, characterizing, and mitigating issues pertaining to the stability of solar nanofluids. We first defined the concept of nanofluids, along with their types and applications, merits and limitations, and preparation techniques. This was followed by presenting the basic physical principles that govern the interparticle interactions, clustering and deposition kinetics, and theories of colloidal stability for nanoparticles in aqueous environments. Building on a sound understanding of these necessary fundamentals, the destabilization factors and instability effects on solar nanofluids were systematically identified. A critical evaluation of the most recent stability characterization techniques and stabilization strategies for solar nanofluids was then provided. A coverage of selected state-of-the-art works in the literature that target the enhanced stability of solar nanofluids in different photothermal conversion processes based on the direct volumetric absorption of solar radiation was presented and comparatively evaluated. Finally, recommendations were drawn regarding current knowledge gaps and future research directions in order to overcome the stability limitations hindering the deployment of solar nanofluids in practical solar photothermal conversion applications.

© 2019 Elsevier Ltd Water vapor is vital both as an energy carrier and as an intermediary state for removing impurities from water. In nature, transpiration occurs when water is transported (against gravity) from the roots to the underside of leaves where it evaporates. Using this process, one large tree can pump and purify 400 L of water each day. Based on trunk cross-sectional area, this corresponds to a water flux range of ∼100–1000 kg/m2day, but based on evaporation area it only corresponds to a rate of ∼0.1 kg/m2day. Compared to industrial mechanisms of producing water vapor (i.e. typical thermal-driven systems have a flux of ∼4000 kg/m2day), natural wood has a relatively low flux. In an effort to boost the flux of sustainable, natural wood, we investigated wood surface modifications, laser carbonization and deposition of gold nanolayers, which achieved an instantaneous evaporation rate of ∼4 kg/m2h—under 3 kW/m2 light intensity, exceeding all previous studies of synthetic materials (including 3.8 kg/m2h reported by Zhou et al. in a 2016 Nature Photonics article) for solar steam generation applications. The cost analysis of different natural and synthetic material-based techniques for solar steam generation indicated that the carbonization and laser treatments are very cost-effective and even the gold coating was comparable to previously reported synthetic materials. Based on these results, we suggest that natural, surface-modified poplar wood could represent a viable alternative to synthetic materials for liquid/vapor separation.

The concentrated solar power industry requires high-temperature receivers to push towards advanced power cycles. However, as the outlet temperature of a receiver increases, radiation losses (which are ∝T4) become dominant. In addition, at high temperatures, not many liquid working fluids are suitable. To address these issues, this research proposes an innovative, robust design of a gas-phase cavity receiver which utilises semi-transparent spheres as a volumetric absorption medium. The motivation behind this design is to break the long-standing outlet temperature versus efficiency trade-off by maximising the “volumetric effect” (i.e. obtaining a higher outlet fluid temperature than the receiver's surface temperature). A range of designs were compared (i.e. packed beds of semi-transparent and high-transparency quartz spheres against an opaque bed of ceramic spheres). This study is important because it determines how the volumetric effect modifies the overall receiver efficiency via a holistic metric (proposed herein) which accounts for the optical, thermal, and pumping power efficiencies. Through a detailed ray-tracing analysis and a comprehensive thermal circuit model, this study reveals that a semi-transparent quartz packed bed receiver can have an overall receiver efficiency of around 80% at outlet temperatures above 700 °C. Most significantly, the best proposed design achieved a high value for the elusive volumetric effect (e.g. a maximum index value of 1.45). Based upon these results, the authors can conclude that these packed bed designs represent a promising new pathway towards reliable and cost-effective high-temperature and high-efficiency receivers which can be implemented into advanced, high-temperature power cycles.

© 2019 Elsevier Ltd Concentrated solar power (CSP) plants provide the means to generate dispatchable, renewable electricity in high direct normal incidence (DNI) locations around the world. Due to the strong inverse correlation between DNI resources and freshwater resources, most of the best potential CSP sites also lack sufficient freshwater resources. Thus, an attractive natural symbiotic pathway exists for developing CSP plants integrated with desalination (D) technology, particularly for sites in proximity to large bodies of salty water (e.g., seawater or saline groundwater). As such, this review critically explores the potential for five CSP-D designs proposed in the literature. Overall, this critical review compares and contrasts the major integration designs on the basis of common merits and limitations. A key finding of this review is that the choice of the most feasible CSP desalination integration is not a straightforward process. It was found that the details surrounding where energy extraction takes place from the CSP cycle can make a significant impact on the feasibility of the plant. In general, waste heat coupling and electrical-driven reverse osmosis integration were found to provide the best technical and economical results. However, no clear-cut ‘winning’ design could be concluded from this review. In fact, the water and energy losses of the condenser were found to significantly shift the results between the two designs. As such, we hope that this review will help guide researchers and engineers towards CSP-D development which has the highest chance of commercial uptake.

High throughput particle/cell concentration is crucial for a wide variety of biomedical, clinical, and environmental applications. In this work, we have proposed a passive spiral microfluidic concentrator with a complex cross-sectional shape, i.e., a combination of rectangle and trapezoid, for high separation efficiency and a confinement ratio less than 0.07. Particle focusing in our microfluidic system was observed in a single, tight focusing line, in which higher particle concentration is possible, as compared with simple rectangular or trapezoidal cross-sections with similar flow area. The sharper focusing stems from the confinement of Dean vortices in the trapezoidal region of the complex cross-section. To quantify this effect, we introduce a new parameter, complex focusing number or CFN, which is indicative of the enhancement of inertial focusing of particles in these channels. Three spiral microchannels with various widths of 400 μ m, 500 μ m, and 600 μ m, with the corresponding CFNs of 4.3, 4.5, and 6, respectively, were used. The device with the total width of 600 μ m was shown to have a separation efficiency of ~98%, and by recirculating, the output concentration of the sample was 500 times higher than the initial input. Finally, the investigation of results showed that the magnitude of CFN relies entirely on the microchannel geometry, and it is independent of the overall width of the channel cross-section. We envision that this concept of particle focusing through complex cross-sections will prove useful in paving the way towards more efficient inertial microfluidic devices.

The industrial sector consumes ∼32% of the world's final energy demand, most in the form of heat which is derived primarily from fossil fuels. Two fundamentally different technologies exist for harvesting sunlight to offset fossil fuel use - solar thermal (ST) and photovoltaic (PV) collectors. The former convert sunlight into heat while the later convert sunlight directly into electricity (although electricity can be converted into heat via heat pumps and/or resistance heating). If/when factories transition towards utilizing their rooftops for solar harvesting, an essential question will be: which solar technology, or a mix of technologies, should be chosen for factory rooftops? This paper investigates this (as yet unanswered) question by assessing the global greenhouse gas emission (GHGe) mitigation potential of PV and ST collectors in a side-by-side mix (e.g. a percentage where 0% is solely PV and 100% is solely ST available roof area coverage) to supply medium temperature heat (150 °C-400 °C) for industrial processes. It was found that in most locations globally, a mix of both technologies optimizes the solar output. Globally, installing the optimum PV:ST mix can save up to 141.8 or 205.8 kt CO2e over installing solely PV or solely ST collectors, respectively. Another interesting finding of this study was that GHGe mitigation potential stems largely from where the solar collectors were manufactured (i.e. the embodied emissions from using local primary energy to fabricate the collectors). Thus, this study reveals that project managers, policymakers, corporate sustainability directors, etc could achieve maximum global GHGe mitigation through simply considering a mix of solar collector technologies and the best practices for manufacturing them.

For solar thermal systems, nanofluids have been proposed as working fluids due to their enhanced optical and thermal properties. However, nanoparticles may agglomerate over time, heating and thermal cycles. Even though pristine nanofluids have proven to enhance performance in low-temperature applications, it is still unclear if nanofluids can meet the reliability requirements of solar thermal applications. For this aim, the present study conducted experiments with several formulations of oil-based CuO nanofluids in terms of their maximum operational temperatures and their stabilities upon cyclic heating. In the samples tested, the maximum temperature ranged from 80 to 150 °C, and the number of heating cycles ranged from 5 to 45, with heating times between 5 to 60 min. The results showed that heating temperature, heating cycles, and heating time all exacerbated agglomeration of samples. Following these experiments, orthogonal experiments were designed to improve the preparation process and the resultant thermal-impulse stability. Thermal properties of these samples were characterized, and thermal performance in an "on-sun" linear Fresnel solar collector was measured. All tests revealed that thermal performance of a solar collecting system could be enhanced with nanofluids, but thermal stability still needs to be further improved for industrial applications.

Patient-derived xenografts (PDXs) are tools of the trade for many researchers from all disciplines and medical specialties. Most endocrinologists, and especially those working in oncology, commonly use PDXs for preclinical drug testing and development, and over the last decade large collections of PDXs have emerged across all tumor streams. In this review, we examine how the field has evolved to include PDXs as versatile resources for research discoveries, providing evidence for guidelines and changes in clinical practice.

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 canc

BACKGROUND: There is convincing evidence that men with advanced prostate cancer experience improved quality of life as a result of exercise therapy, although there is limited preclinical, and no clinical, data to directly support the notion that exercise training improves prostate cancer prognosis or outcome. The aim of this study was to investigate the effect of regular exercise training on the early stages of prostate cancer progression, as well as assessing whether alterations to prostate cancer metabolism are induced by exercise. METHODS: Mice with prostate-specific deletion of Pten (Pten-/- ) remained sedentary or underwent 6 weeks of endurance exercise training or high-intensity exercise training involving treadmill running. At the conclusion of the training period, the prostate lobes were excised. A portion of fresh tissue was used to assess glucose, glutamine, and fatty acid metabolism by radiometric techniques and a second portion was fixed for histopathology. RESULTS: Despite the implementation of an effective exercise regime, as confirmed by improvements in running capacity, neither prostate mass, cell proliferation or the incidence of high-grade prostate intraepithelial hyperplasia or noninvasive carcinoma in situ were significantly different between groups. Similarly, neither glucose uptake, oxidation and de novo lipogenesis, glutamine oxidation, or fatty acid uptake, oxidation and storage into various lipids were significantly different in prostate tissue obtained from untrained and exercise trained mice. CONCLUSIONS: These results show that 6 weeks of moderate or high-intensity exercise training does not alter substrate metabolism in the prostate or slow the progression of Pten-null prostate cancer. These results question whether exercise is a useful therapy to prevent or delay prostate cancer progression.

Inertial microfluidics represents a powerful new tool for accurately positioning cells and microparticles within fluids for a variety of biomedical, clinical, and industrial applications. In spite of enormous advancements in the science and design of these devices, particularly in curved microfluidic channels, contradictory experimental results have confounded researchers and limited progress. Thus, at present, a complete theory which describes the underlying physics is lacking. We propose that this bottleneck is due to one simple mistaken assumption - the locations of inflection points of the Dean velocity profile in curved microchannels are not fixed, but can actually shift with the flow rate. Herein, we propose that the dynamic distance (δ) between the real equilibrium positions and their nearest inflection points can clearly explain several (previously) unexplained phenomena in inertial microfluidic systems. More interestingly, we found that this parameter, δ, is a function of several geometric and operational parameters, all of which are investigated (in detail) here with a series of experiments and simulations of different spiral microchannels. This key piece of understanding is expected to open the door for researchers to develop new and more effective inertial microfluidic designs.

Single-layer, anti-reflective coatings prepared via the sol-gel method can be scaled to large-area applications (e.g. solar collectors). In the specific case of evacuated tube solar thermal collectors, there are often three glass-air or glass-vacuum interfaces which can cause reflection. Thus, in the absence of any anti-reflective technology (i.e. most commercial products), a steep 15% or 22% reflective loss (e.g. transmission ∼0.92N, where N = 2 or 3) occurs in evacuated tube solar collectors. Porous MgF2-based materials have been shown to provide low refractive index as a single layer, but they have not yet been applied to solar thermal collector technology - which requires elevated temperature stability and spectrum transmission. Importantly, these should be low cost at the m2 scale. Further, since solar technologies are considered 'green', the materials used in their manufacturing should be carefully considered. In this study, we have employed trifluoroacetic acid (instead of hydrofluoric acid) as the fluorine source to produce single-layer porous MgF2 coatings. These coatings were designed and modeled with OpenFilters, fabricated with dip-coating, and characterized with ellipsometetry, x-ray diffraction, Raman spectroscopy, and focused ion beam/transmission electron microscopy to validate the OpenFilters model. For high transmission substrates, the dip coated films produced in this study can reach a solar-weighted reflectance of 2.3%. Additionally, to test if these films are suitable for solar thermal collectors, durability tests were conducted, which revealed acceptable heat resistance. However, without a water-resistant outer layer, the films did not pass an ASTM D870-09 water immersion test. Overall, this study presents a low-cost approach to developing anti-reflective coatings which are suitable for large-area solar thermal applications.

Solar technologies are considered as clean harvesters of utilizable energy, but they do have embodied environmental impacts associated with their manufacture, transportation, and installation. Although these embodied impacts have been extensively analyzed in the literature for individual components/collectors, no single study has looked comparatively at the embodied impacts of solar photovoltaics versus solar thermal collectors globally. To address this gap, this study investigates local manufacturing/assembly of solar collectors and presents the embodied emissions results as global maps (i.e. for 635 locations). It was found that the embodied emissions of a monocrystalline PV collector can vary between 318–952 kg CO2e/m2ap, and the embodied emissions of a linear Fresnel collector embodied emissions can vary between 169 – 1437 kg CO2e/m2ap. Intriguingly, it was found that moving the manufacturing base for solar technologies to a lower emission location (or improving manufacturing practices) can provide a meaningful shift in the global emissions picture.

It has been more than two decades since the discovery of nanofluids-mixtures of common liquids and solid nanoparticles less than 100 nm in size. As a type of colloidal suspension, nanofluids are typically employed as heat transfer fluids due to their favorable thermal and fluid properties. There have been numerous numerical studies of nanofluids in recent years (more than 1000 in both 2016 and 2017, based on Scopus statistics). Due to the small size and large numbers of nanoparticles that interact with the surrounding fluid in nanofluid flows, it has been a major challenge to capture both the macro-scale and the nano-scale effects of these systems without incurring extraordinarily high computational costs. To help understand the state of the art in modeling nanofluids and to discuss the challenges that remain in this field, the present article reviews the latest developments in modeling of nanofluid flows and heat transfer with an emphasis on 3D simulations. In part I, a brief overview of nanofluids (fabrication, applications, and their achievable thermo-physical properties) will be presented first. Next, various forces that exist in particulate flows such as drag, lift (Magnus and Saffman), Brownian, thermophoretic, van der Waals, and electrostatic double layer forces and their significance in nanofluid flows are discussed. Afterwards, the main models used to calculate the thermophysical properties of nanofluids are reviewed. This will be followed with the description of the main physical models presented for nanofluid flows and heat transfer, from single-phase to Eulerian and Lagrangian two-phase models. In part II, various computational fluid dynamics (CFD) techniques will be presented. Next, the latest studies on 3D simulation of nanofluid flow in various regimes and configurations are reviewed. The present review is expected to be helpful for researchers working on numerical simulation of nanofluids and also for scholars who work on experimental aspects of nano

© 2019 IEEE. Spectrum splitting for hybrid photovoltaic/thermal (PV/T) collectors presents an opportunity to deliver higher combined efficiencies than either technology alone. Nanofluids offer an inexpensive alternative to spectrum splitting mirrors, and serve both as an optical filter and a heat transfer mechanism. This paper introduces experimental testing of spectrum splitting nanofluids for three cells: c-Si, GaAs, and Ge solar cells. The nanofluids were composed of combinations of core-shell silver-silica (Ag-SiO 2 ) nanoplates as visible light absorbers and silica-coated gold and gold-copper nanorods as infrared absorbers. These nanoparticles were suspended in various concentrations in either a water or oil base fluid according to the spectral response of the solar cell. Indoor test results are presented for all three cell types. The Ag-SiO 2 aqueous fluid, paired with a c-Si PV cell, delivered the highest combined efficiency, which indicates that this PV-nanofluid combination is a strong candidate for a low cost, high-efficiency spectrum splitting technology.

Modeling and simulation of nanofluid flows is crucial for applications ranging from the cooling of electronic devices to solar water heating systems, particularly when compared to the high expense of experimental studies. Accurate simulation of a thermal-fluid system requires a deep understanding of the underlying physical phenomena occurring in the system. In the case of a complex nanofluid-based system, suitable simplifying approximations must be chosen to strike a balance between the nano-scale and macro-scale phenomena. Based on these choices, the computational approach – or set of approaches – to solve the mathematical model can be identified, implemented and validated. In Part I of this review (Mahian et al., 2019), we presented the details of various approaches that are used for modeling nanofluid flows, which can be classified into single-phase and two-phase approaches. Now, in Part II, the main computational methods for solving the transport equations associated with nanofluid flow are briefly summarized, including the finite difference, finite volume, finite element, lattice Boltzmann methods, and Lagrangian methods (such as dissipative particle dynamics and molecular dynamics). Next, the latest studies on 3D simulation of nanofluid flow in various regimes and configurations are reviewed. The numerical studies in the literature mostly focus on various forms of heat exchangers, such as solar collectors (flat plate and parabolic solar collectors), microchannels, car radiators, and blast furnace stave coolers along with a few other important nanofluid flow applications. Attention is given to the difference between 2D and 3D simulations, the effect of using different computational approaches on the flow and thermal performance predictions, and the influence of the selected physical model on the computational results. Finally, the knowledge gaps in this field are discussed in detail, along with some suggestions for the next steps in this field. The present revi