INTRODUCTION: Irritable bowel syndrome (IBS) is a common and debilitating disorder estimated to affect approximately 11% of the world's population. Typically, IBS is a diagnosis of exclusion after patients undergo a costly and invasive colonoscopy to exclude organic disease. Clinician's and researchers have identified a need for a new cost-effective, accurate, and noninvasive diagnostic test for IBS. METHODS: Using a diagnostic case-control study, we explored the use of bowel sounds to characterize IBS with a view to diagnostic use. We recruited participants with an existing clinical diagnosis of IBS or healthy (asymptomatic) digestive systems. We recorded bowel sounds for 2 hours after fasting and then for 40 minutes after a standard meal. RESULTS: We here report our results including our accuracy in characterizing IBS-related bowel sounds and differentiation between participants with IBS and healthy participants. Leave-one-out cross-validation of our model developed using the first 31 IBS and 37 healthy participants gave 90% sensitivity and 92% specificity for IBS diagnosis. Independent testing using the next 15 IBS and 15 healthy participants demonstrated 87% sensitivity and 87% specificity for IBS diagnosis. CONCLUSIONS: These preliminary results provide proof of concept for the use of bowel sound analysis to identify IBS. A prospective study is needed to confirm these findings. TRANSLATIONAL IMPACT: Our belt and model offer hope of a new approach for IBS diagnosis in primary practice. Combined with screening tests for organic disease, it would offer greater confidence to patients and could reduce the burden of unnecessary colonoscopies for health care systems and patients.

Tissue-resident memory T (TRM) cells have emerged as key players in the immune control of melanoma. These specialized cells are identified by expression of tissue retention markers such as CD69, CD103 and CD49a with downregulation of egress molecules such as Sphingosine-1-Phosphate Receptor-1 (S1PR1) and the lymphoid homing receptor, CD62L. TRM have been shown to be integral in controlling infections such as herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV) and influenza. More recently, robust pre-clinical models have also demonstrated TRM are able to maintain melanoma in a dormant state without progression to macroscopic disease reminiscent of their ability to control viral infections. The discovery of the role these cells play in anti-melanoma immunity has coincided with the advent of immune checkpoint inhibitor (ICI) therapy which has revolutionized the treatment of cancers. ICIs that target programmed death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) have led to substantial improvements in outcomes for patients with metastatic melanoma and have been rapidly employed to reduce recurrences in the resected stage III setting. While ICIs mediate anti-tumor activity via CD8+ T cells, the specific subsets that facilitate this response is unclear. TRM invariably exhibit high expression of immune checkpoints such as PD-1, CTLA-4 and lymphocyte activating gene-3 (LAG-3) which strongly implicates this CD8+ T cell subset as a crucial mediator of ICI activity. In this review, we present pre-clinical and translational studies that highlight the critical role of TRM in both immune control of primary melanoma and as a key CD8+ T cell subset that mediates anti-tumor activity of ICIs for the treatment of melanoma.

Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.

No abstract