Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate.

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472, p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies.

The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

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.

Relationship between strength characteristics and unweighted and weighted vertical jump height.

PURPOSE: To investigate the relationship between maximum strength and differences in jump height during weighted and unweighted (body weight) static (SJ) and countermovement jumps (CMJ). METHODS: Sixty-three collegiate athletes (mean +/- SD; age= 19.9 +/- 1.3 y; body mass = 72.9 +/- 19.6 kg; height = 172.8 +/- 7.7 cm) performed two trials of the SJ and CMJ with 0 kg and 20 kg on a force plate; and two trials of mid-thigh isometric clean pulls in a custom rack over a force plate (1000-Hz sampling). Jump height (JH) was calculated from flight time. Force-time curve analyses determined the following: isometric peak force (IPF), isometric force (IF) at 50, 90, and 250 ms, and isometric rates of force development (IRFD). Absolute and allometric scaled forces, [absolute force/(body mass(0.67))], were used in correlations. RESULTS: IPF, IRFD, F50(a), F50, F90, and F250 showed moderate/strong correlations with SJ and CMJ height percent decrease from 0 to 20 kg. IPF(a) and F250(a) showed weak/moderate correlations with percent height decrease. Comparing strongest (n = 6) to weakest (n = 6): t tests revealed that stronger athletes (IPF(a)) performed superior to weaker athletes. CONCLUSION: Data indicate the ability to produce higher peak and instantaneous forces and IRFD is related to JH and to smaller differences between weighted and unweighted jump heights. Stronger athletes jump higher and show smaller decrements in JH with load. A weighted jump may be a practical method of assessing relative strength levels.