An analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy

A plethora of individual candidate biomarkers for predicting PSA relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with PSA relapse. In the current study, these biomarkers were re-analysed for PSA relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n=324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with PSA relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; P=0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; P=0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, P<0.001). Our findings indicate that PSA relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.Alison Y. Zhang, Karen Chiam ... Tina Bianco‐Miotto, Carmela Ricciardelli … Wayne Tilley, Lisa M. Butler ... et al

&alpha;-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors.

OBJECTIVE: Central melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine if peripheral &alpha;-melanocyte stimulating hormone (&alpha;-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting &alpha;-MSH. METHODS: We established glucose-stimulated &alpha;-MSH secretion using humans, non-human primates, and mouse models. Continuous &alpha;-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of &alpha;-MSH in glucose regulation. Complementary ex&nbsp;vivo and in&nbsp;vitro techniques were employed to delineate the direct action of &alpha;-MSH via the melanocortin 5 receptor (MC5R)-PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and &alpha;-MSH was adopted to restore glucose tolerance in obese mice. RESULTS: Here we demonstrate that pituitary secretion of &alpha;-MSH is increased by glucose. Peripheral &alpha;-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of &alpha;-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores &alpha;-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice. CONCLUSION: These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary &alpha;-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity