Search

Simple Summary: Prostate cancer is the most common cancer in men and a major cause of cancer-related deaths around the world. Prostate cancer that has spread to other parts of the body (advanced prostate cancer) is often treated with a drug called enzalutamide, which is a type of hormone therapy. Enzalutamide works by blocking the effect of the testosterone hormone on prostate cancer cells to stop them from growing. While this can be effective for several years, unfortunately, many patients being treated with enzalutamide eventually go on to become resistant to treatment, and the therapy stops working. Here, we show that prostate cancer cells that have become resistant to enzalutamide have increased levels of a type of sugar (known as sialic acid) on their surfaces. We set out to test whether stripping sialic acid from the surface of prostate cancer cells could help keep enzalutamide working for longer. Excitingly, our experiments show that treating prostate cancer cells with a drug to block sialic acid can partially reverse enzalutamide resistance. These findings suggest that drugs targeting sialic acid could be used in combination with enzalutamide therapy to disarm drug resistance and provide urgently needed new treatment options for men with prostate cancer. Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation androgen receptor antagonist that is used to treat castrate-resistant prostate cancer. Among patients who initially respond to enzalutamide, virtually all acquire secondary resistance, and an improved understanding of the mechanisms involved is urgently needed. Aberrant glycosylation, and, in particular, alterations to sialylated glycans, have been reported as mediators of therapy resistance in cancer, but a link between tumour-associated glycans and resistance to therapy in prostate cancer has not yet been investigated. Here, using cell line models, we show that prostate cancer cells with acquired resistance to enzalutamide therapy have an upregulation of the sialyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) and increased levels of α2,6-sialylated N-glycans. Furthermore, using the sialyltransferase inhibitor P-SiaFNEtoc, we discover that acquired resistance to enzalutamide can be partially reversed by combining enzalutamide therapy with sialic acid blockade. Our findings identify a potential role for ST6GAL1-mediated aberrant sialylation in acquired resistance to enzalutamide therapy for prostate cancer and suggest that sialic acid blockade in combination with enzalutamide may represent a novel therapeutic approach in patients with advanced disease. Our study also highlights the potential to bridge the fields of cancer biology and glycobiology to develop novel combination therapies for prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: Understanding doctors' health beliefs is essential for developing effective and competent healthcare practices that benefit doctors and their patients. This study aimed to qualitatively explore doctors' perceptions of on-shift health-protective behaviours and their perceived effects on competence., Methods: The research applied theoretically driven Expanded Health Belief Model (EHBM) enquiry methods to explore beliefs and experiences through an occupational context survey, 14 individual depth interviews, and two focus groups. Semantic and deductive themes associated with EHBM domains were examined, and an inductive thematic analysis of the interviews was conducted., Results: Doctors' beliefs were strongly imbued by their perceived identity within the systemic context; they expressed impaired self-efficacy in reacting to their health needs on shift, and several disclosed harm to themselves and patients. Dominant themes included the psychosocial effects of the systemic culture and the influence of the situational occupational context in impacting health-protective behavioural action. The context and implications of experiences during the COVID-19 pandemic are discussed., Conclusions: This study presents key belief-oriented factors influencing doctors' health-protective behaviour at work and its implications for competent practice. Further doctor-led guidance on focus points for evidence-based theoretically driven health improvement solutions is provided regarding operational practice, formulating policies, developing interventions and further research.

Cylindromas are cutaneous tumors first described in the medical literature over 150 years ago. They are now known to occur on an inherited basis as a result of mutations in the tumor-suppressor gene CYLD. The discovery of this gene has provided novel insights into this rare skin tumor syndrome. As well as enabling genetic counseling of affected patients, the knowledge of CYLD function has led to steps toward development of novel therapeutics, with CYLD-regulated signaling pathways as the target for this approach., (Copyright © 2016 Elsevier Inc. All rights reserved.)