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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

Prostate cancer is the most commonly diagnosed solid-organ cancer amongst males worldwide. Metastatic castrate-resistant prostate cancer (mCRPC) is a rapidly fatal end-sequelae of prostate cancer. Therapeutic options for men with mCRPC are limited and are not curative in nature. The recent development of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of treatment-resistant haematological malignancies, and several studies are underway investigating the utility of this technology in the treatment of solid tumours. In this review, we evaluate the current treatment options for men with mCRPC as well as the current landscape of preclinical and clinical trials of CAR-T cell therapy against prostate cancer. We also appraise the various prostate cancer-specific tumour-associated antigens that may be targeted by CAR-T cell technology. Finally, we examine the potential translational barriers of CAR-T cell therapy in solid tumours. Despite preclinical success, preliminary clinical trials in men with prostate cancer have had limited efficacy. Therefore, further clinically translatable preclinical models are required to enhance the understanding of the role of this investigational therapeutic in men with mCRPC. In the era of precision medicine, tailored immunotherapy administered to men in a tumour-agnostic approach provides hope to a group of men who otherwise have few treatment options available.

The impact of lifestyle interventions on diabetes and mental health conditions have been documented among people with diabetes. However, the mental health benefits of lifestyle interventions designed for diabetes prevention have not been systematically investigated among people at high risk of diabetes, particularly in low- and middle-income countries. We examined the effects of a 12-month peer support lifestyle intervention designed for diabetes prevention on depression and anxiety symptomology in the sample population of the Kerala Diabetes Prevention Program. Mixed-effects linear regression models were used to examine the effect of the intervention on depression and anxiety scores at 12 and 24 months in the total sample of 1007 adults at risk for diabetes and among those with mild-severe depressive or anxiety symptoms at baseline (n = 326 for depression; n = 203 for anxiety). Among all participants, the intervention group had a significantly higher reduction of depressive symptoms as compared to the control group at 12 months (mean diff score = -0.51; 95% CI: -0.95, -0.07; P = 0.02). This effect was not sustained at 24 months. There were no significant intervention effects for anxiety. Among those with mild-severe symptoms at baseline, the intervention group had a significantly higher reduction of depressive symptoms (mean diff score = -1.55; 95% CI -2.50, -0.6; P = 0.001) and anxiety symptoms (mean diff score = -1.64; 95% CI -2.76, -0.52; P = 0.004) at 12 months. The effect was sustained at 24 months for depression, but not anxiety. Lifestyle interventions designed for prevention of diabetes might improve depressive and anxiety symptoms in the short-term, particularly among those with mild-severe symptoms.

BACKGROUND: Cross-cultural evidence on the factorial structure and invariance of the PHQ-9 and the GAD-7 is lacking for South Asia. Recommendations on the use of unit-weighted scores of these scales (the sum of items' scores) are not well-founded. This study aims to address these contextual and methodological gaps using data from a rural Indian population. METHODS: The study surveyed 1,209 participants of the Kerala Diabetes Prevention Program aged 30-60 years (n at risk of diabetes = 1,007 and n with diabetes = 202). 1,007 participants were surveyed over 2 years using the PHQ-9 and the GAD-7. Bifactor-(S - 1) modeling and multigroup confirmatory factor analysis were used. RESULTS: Factor analysis supported the existence of a somatic and cognitive/affective subcomponent for both scales, but less explicitly for the GAD-7. Hierarchical omega values were 0.72 for the PHQ-9 and 0.76 for the GAD-7. Both scales showed full scalar invariance and full or partial residual invariance across age, gender, education, status of diabetes and over time. Effect sizes between categories measured by unit-weighted scores versus latent means followed a similar trend but were systematically higher for the latent means. For both disorders, female gender and lower education were associated with higher symptom severity scores, which corresponds with regional and global trends. CONCLUSIONS: For both scales, psychometric properties were comparable to studies in western settings. Distinct clinical profiles (somatic-cognitive) were supported for depression, and to a lesser extent for anxiety. Unit-weighted scores of the full scales should be used with caution, while scoring subscales is not recommended. The stability of these scales supports their use and allows for meaningful comparison across tested subgroups. CLINICAL TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12611000262909http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336603&isReview=true.

Deep learning is a subdiscipline of artificial intelligence that uses a machine learning technique called artificial neural networks to extract patterns and make predictions from large data sets. The increasing adoption of deep learning across healthcare domains together with the availability of highly characterised cancer datasets has accelerated research into the utility of deep learning in the analysis of the complex biology of cancer. While early results are promising, this is a rapidly evolving field with new knowledge emerging in both cancer biology and deep learning. In this review, we provide an overview of emerging deep learning techniques and how they are being applied to oncology. We focus on the deep learning applications for omics data types, including genomic, methylation and transcriptomic data, as well as histopathology-based genomic inference, and provide perspectives on how the different data types can be integrated to develop decision support tools. We provide specific examples of how deep learning may be applied in cancer diagnosis, prognosis and treatment management. We also assess the current limitations and challenges for the application of deep learning in precision oncology, including the lack of phenotypically rich data and the need for more explainable deep learning models. Finally, we conclude with a discussion of how current obstacles can be overcome to enable future clinical utilisation of deep learning.

This study aims to describe the prevalence of depression and anxiety among a population sample of people at high risk for type 2 diabetes in Kerala, India, and examine the relationship between depressive symptoms, anxiety, and incident Type 2 Diabetes Mellitus (T2DM) over a two-year period. We used data from the Kerala Diabetes Prevention Program, a cluster-randomized controlled trial for diabetes prevention among 1007 high-risk individuals. The prevalence of depression and anxiety were estimated using the 9-item Patient Health Questionnaire and the Generalized Anxiety Disorder 7-item scale, respectively. We calculated proportions for depression and anxiety and performed generalized estimating equations (GEE) to examine the relationship between baseline mental health status and incident T2DM. The prevalence of depression and anxiety at baseline were 7.5% and 5.5%, respectively. Compared with those reporting none/low symptoms, the odds ratio for incident diabetes was 1.07 (95% CI 0.54-2.12) for participants with moderate to severe depression and 0.73 (95% CI 0.23-2.28) for participants with moderate to severe anxiety, after adjusting for potential confounders. Our findings suggest that the prevalence of depression and anxiety were higher than those previously reported in the general population in India. However, among this sample of community-based adults at high risk of developing T2DM, the presence of moderate to severe depression and/or anxiety symptoms was not significantly associated with the risk of developing T2DM. Trial registration: Australia and New Zealand Clinical Trials Registry ACTRN12611000262909. Registered 10 March 2011.

Extracellular matrix remodeling has emerged as an important factor in many cancers. Proteoglycans, including versican (VCAN), are regulated via cleavage by the proteolytic actions of A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 motif (ADAMTS) family members. Alterations in the balance between Proteoglycans and ADAMTS enzymes have been proposed to contribute to cancer progression. Here, we analyzed the expression of ADAMTS-15 in human prostate cancer, and investigated the effects of enforced expression in prostate cancer cell lines. ADAMTS-15 was found to be expressed in human prostate cancer biopsies with evidence of co-localization with VCAN and its bioactive cleavage fragment versikine. Enforced expression of ADAMTS-15, but not a catalytically-inactive version, decreased cell proliferation and migration of the ‘castrate-resistant’ PC3 prostate cancer cell line in vitro, with survival increased. Analysis of ‘androgen-responsive’ LNCaP prostate cancer cells in vivo in NOD/SCID mice revealed that ADAMTS-15 expression caused slower growing tumors, which resulted in increased survival. This was not observed in castrated mice or with cells expressing catalytically-inactive ADAMTS-15. Collectively, this research identifies the enzymatic function of ADAMTS-15 as having a tumor suppressor role in prostate cancer, possibly in concert with androgens, and that VCAN represents a likely key substrate, highlighting potential new options for the clinic.

Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.

BACKGROUND: Breast cancers acquire aggressive capabilities via epithelial to mesenchymal transition (EMT), in which various integrins/integrin-linked kinase signalling are upregulated. METHODS: We investigated this in two patient-derived xenografts (PDXs) developed from breast-to-bone metastases, and its functional significance in a breast cancer cell line system. ED03 and EDW01 PDXs were grown subcutaneously in immunocompromised SCID mice through 11 passages and 7 passages, respectively. Tumour tissue was assessed using immunohistochemistry (IHC) for oestrogen receptor (ER)-alpha, E-cadherin, vimentin, Twist1, beta-catenin, P120-RasGAP, CD44, CD24 and Ki67, and RT-qPCR of EMT-related factors (CDH1, VIM, CD44, CD24), integrins beta 1 (ITGB1), alpha 2 (ITGA2) and ILK. Integrin and ILK expression in epidermal growth factor (EGF)-induced EMT of the PMC42-ET breast cancer cell line was assessed by RT-qPCR and Western blotting, as were the effects of their transient knockdown via small interfering RNA +/- EGF. Cell migration, changes in cell morphology and adhesion of siRNA-transfected PMC42-ET cells to various extracellular matrix (ECM) substrates was assessed. RESULTS: The ED03 (ER+/PR-/HER2-/lobular) and EDW01 (ER+/PR-/HER2-/ductal) PDXs were both classified as molecular subtype luminal A. ED03 xenografts exhibited mutated E-cadherin with minimal expression, but remained vimentin-negative across all passages. In EDW01, the hypoxic indicator gene CAIX and Twist1 were co-ordinately upregulated at passages 4-5, corresponding with a decrease in E-cadherin. At passages 6-7, VIM was upregulated along with ITGB1 and ITGA2, consistent with an increasing EMT. The ED03 PDX displayed minimal change over passages in mice, for all genes examined. ILK, ITGB1 and ITGA2 mRNAs were also increased in the EGF-induced EMT of PMC42-ET cells (in which CDH1 was downregulated) although siRNA against these targets revealed that this induction was not necessary for the observed EMT. However, t

Reciprocal interactions between prostate epithelial cells and their adjacent stromal microenvironment not only are essential for tissue homeostasis but also play a key role in tumor development and progression. Malignant transformation is associated with the formation of a reactive stroma where cancer-associated fibroblasts (CAFs) induce matrix remodeling and thereby provide atypical biochemical and biomechanical signals to epithelial cells. Previous work has been focused on the cellular and molecular phenotype as well as on matrix stiffness and remodeling, providing potential targets for cancer therapeutics. So far, biomechanical changes in CAFs and adjacent epithelial cells of the prostate have not been explored. Here, we compared the mechanical properties of primary prostatic CAFs and patient-matched non-malignant prostate tissue fibroblasts (NPFs) using atomic force microscopy (AFM) and real-time deformability cytometry (RT-FDC). It was found that CAFs exhibit an increased apparent Young's modulus, coinciding with an altered architecture of the cytoskeleton compared with NPFs. In contrast, co-cultures of benign prostate epithelial (BPH-1) cells with CAFs resulted in a decreased stiffness of the epithelial cells, as well as an elongated morphological phenotype, when compared with co-cultures with NPFs. Moreover, the presence of CAFs increased proliferation and invasion of epithelial cells, features typically associated with tumor progression. Altogether, this study provides novel insights into the mechanical interactions between epithelial cells with the malignant prostate microenvironment, which could potentially be explored for new diagnostic approaches.

OBJECTIVE: The majority of cancers are diagnosed following a decision to access medical help for symptoms. People from ethnic minority backgrounds have longer patient intervals following identification of cancer symptoms. This study quantified ethnic differences in barriers to symptomatic presentation including culturally specific barriers. Correlates of barriers (eg, migration status, health literacy, and fatalism) were also explored. METHODS: A cross-sectional survey of 720 White British, Caribbean, African, Indian, Pakistani, and Bangladeshi women aged 30 to 60 (n = 120/group) was carried out in England. Barrier items were taken from the widely used cancer awareness measure; additional culturally specific barriers to symptomatic presentation were included following qualitative work (11 barriers in total). Migration status, health literacy, and fatalism were included as correlates to help-seeking barriers. RESULTS: Ethnic minority women reported a higher number of barriers (P < .001, 2.6-3.8 more than White British women). Emotional barriers were particularly prominent. Women from ethnic minority groups were more likely to report "praying about a symptom" (P < .001, except Bangladeshi women) and "using traditional remedies" (P < .001, except Caribbean women). Among ethnic minority women, adult migration to the United Kingdom, low health literacy, and high fatalistic beliefs increased likelihood of reporting barriers to symptomatic presentation. For example, women who migrated as adults were more likely to be embarrassed (OR = 1.83; CI, 1.06-3.15), worry what the GP might find (OR = 1.91; CI, 1.12-3.26), and be low on body vigilance (OR = 4.44; CI, 2.72-7.23). CONCLUSIONS: Campaigns addressing barriers to symptomatic presentation among ethnic minority women should be designed to reach low health literacy populations and include messages challenging fatalistic views. These would be valuable for reducing ethnic inequalities in cancer outcomes.

The propensity of cancer cells to transition between epithelial and mesenchymal phenotypic states via the epithelial-mesenchymal transition (EMT) program can regulate metastatic processes, cancer progression, and treatment resistance. Transcriptional investigations using reversible models of EMT, revealed the mesenchymal-to-epithelial reverting transition (MErT) to be enriched in clinical samples of metastatic castrate resistant prostate cancer (mCRPC). From this enrichment, a metastasis-derived gene signature was identified that predicted more rapid cancer relapse and reduced survival across multiple human carcinoma types. Additionally, the transcriptional profile of MErT is not a simple mirror image of EMT as tumour cells retain a transcriptional "memory" following a reversible EMT. This memory was also enriched in mCRPC samples. Cumulatively, our studies reveal the transcriptional profile of epithelial-mesenchymal plasticity and highlight the unique transcriptional properties of MErT. Furthermore, our findings provide evidence to support the association of epithelial plasticity with poor clinical outcomes in multiple human carcinoma types.