A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood

Background: The lack of an accurate blood biomarker in neuroendocrine tumor (NET) disease has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy—liquid biopsy—to facilitate real-time management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD). Patients and methods: A systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified ten original scientific papers that met the inclusion criteria. These were assessed by qualitative analysis and thereafter meta-analysis. Data were pooled and a median [95% confidence interval (CI)] diagnostic odds ratio (DOR), positive likelihood ratio (+LR), and negative likelihood ratio (−LR) were calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and area under the curve (AUC) data. Results: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. The meta-analysis identified the diagnostic accuracy of the NETest to be 95%–96% with a mean DOR of 5 853, +LR of 195, and −LR of 0.06. The NETest was 84.5%–85.5% accurate in differentiating stable disease from progressive disease. As a marker of natural history, the accuracy was 91.5%–97.8%. As an interventional/response biomarker, the accuracy was 93.7%–97.4%. The pooled AUC for the NETest was 0.954 ± 0.005, with a z-statistic of 175.06 (P < 0.001). Conclusions: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of this as a biomarker provides information relevant to NET management consistent with observations regarding utility of liquid biopsies in other oncological disciplines. © 2019 European Society for Medical Oncolog

A role of myosin Vb and Rab11-FIP2 in the aquaporin-2 shuttle

Arginine-vasopressin (AVP) regulates water reabsorption in renal collecting duct principal cells. Its binding to Gs-coupled vasopressin V2 receptors increases cyclic AMP (cAMP) and subsequently elicits the redistribution of the water channel aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane (AQP2 shuttle), thereby facilitating water reabsorption from primary urine. The AQP2 shuttle is a paradigm for cAMP-dependent exocytic processes. Using sections of rat kidney, the AQP2-expressing cell line CD8, and primary principal cells, we studied the role of the motor protein myosin Vb, its vesicular receptor Rab11, and the myosin Vb- and Rab11-binding protein Rab11-FIP2 in the AQP2 shuttle. Myosin Vb colocalized with AQP2 intracellularly in resting and at the plasma membrane in AVP-treated cells. Rab11 was found on AQP2-bearing vesicles. A dominant-negative myosin Vb tail construct and Rab11-FIP2 lacking the C2 domain (Rab11-FIP2-DeltaC2), which disrupt recycling, caused condensation of AQP2 in a Rab11-positive compartment and abolished the AQP2 shuttle. This effect was dependent on binding of myosin Vb tail and Rab11-FIP2-DeltaC2 to Rab11. In summary, we identified myosin Vb as a motor protein involved in AQP2 recycling and show that myosin Vb- and Rab11-FIP2-dependent recycling of AQP2 is an integral part of the AQP2 shuttle

IL-33 triggers early eosinophil-dependent events leading to metaplasia in a chronic model of gastritis-prone mice

IL-33/IL-1F11 is an important mediator for the development of Th2-driven inflammatory disorders and has also been implicated in the pathogenesis of GI-related cancers, including gastric carcinoma. We therefore sought to mechanistically determine IL-33's potential role as a critical factor linking chronic inflammation and gastric carcinogenesis using gastritis-prone SAMP1/YitFc (SAMP) mice METHODS: SAMP and (parental control) AKR mice were assessed for baseline gastritis and progression to metaplasia. Expression/localization of IL-33 and its receptor, ST2/IL-1R4, were characterized in corpus tissues, and both activation and neutralization studies were performed targeting the IL-33/ST2 axis. Dissection of immune pathways leading to metaplasia were evaluated, including eosinophil depletion studies using anti-IL-5/anti-CCR3 treatment RESULTS: Progressive gastritis and ultimately, intestinalized spasmolytic polypeptide-expressing metaplasia (SPEM) was detected in SAMP stomachs, which was absent in AKR, but could be moderately-induced with exogenous, recombinant (r)IL-33. Robust peripheral (bone-marrow, BM) expansion of eosinophils and local recruitment of both eosinophils and IL-33-expressing M2 macrophages into corpus tissues were evident in SAMP. Interestingly, IL-33 blockade did not affect BM-derived expansion and local infiltration of eosinophils, but markedly decreased M2 macrophages and SPEM features, while eosinophil depletion caused a significant reduction in both local IL-33-producing M2 macrophages and SPEM in SAMP CONCLUSIONS: IL-33 promotes metaplasia and the sequelae of eosinophil-dependent downstream infiltration of IL-33-producing M2 macrophages leading to intestinalized SPEM in SAMP, suggesting that IL-33 represents a critical link between chronic gastritis and intestinalizing metaplasia that may serve as a potential therapeutic target for pre-neoplastic conditions of the GI tract