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ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (EGFR/ALK/ROS1). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally. Lung cancer is the most common cause of cancer death in Australia and worldwide. This disease often happens due to alterations in specific genes that allow cancer cells to develop and spread. Scientists have designed targeted drugs that are better at attacking cancer cells that have specific 'actionable' gene alterations and have less effect on other cells in the body. The result is often more benefit from treatment and fewer side effects than other standard treatments (chemotherapy or immunotherapy). The targeted drugs are well established as the best initial treatments for some gene alterations, but more research is needed to know if this is true for some of the less common or recently identified gene alterations, and where the targeted drugs are very new. Comprehensive genomic profiling is a new way of testing lung cancer cells for all the gene alterations (the well-known ones as well as the rare ones) in a single test. It is expected that this test will find many more of these gene alterations, which will allow more people to have safer and more effective targeted treatments leading to potentially better outcomes, and will allow some people to join clinical trials testing newer targeted treatments. The ASPiRATION study will help work out whether comprehensive genomic profiling is better than the current way of testing for gene alterations in Australia, and if it is feasible to use in all people diagnosed with advanced lung cancer in Australia. Clinical Trial Registration: ACTRN12621000221853 (ANZCTR) ASPiRATION is an Australian national prospective observational study assessing feasibility, clinical and economic value of comprehensive genomic profiling in newly diagnosed metastatic lung cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Until recently the outcome for women with advanced endometrial carcinoma has been poor. New immune therapies have resulted in much better outcomes for some, but not all, women with advanced disease. Determining which women are likely to respond is important, both to identify potential responders and prevent overtreatment of women who are not likely to respond. In this study we looked to see if there were any other markers that could be used to better predict those tumors that would be more likely to respond to the immune therapy known as durvalumab versus those tumors more likely to be resistant. Using statistical methods to evaluate each of the components examined we determined the cut-off point with the best performance. We found that the presence of tumor associated inflammatory cells had the strongest association with response. We also found that an algorithm derived from our best performing cut-off points identified women not likely to respond to treatment. While the presence of inflammatory cells was not significant when mismatch repair status was considered, our novel algorithm was. This is a small study and the findings do require validation in a larger group of women. Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed. [ABSTRACT FROM AUTHOR]

We have previously reported that P2Y2 purinoceptors and muscarinic M3 receptors trigger Ca2+ responses in HT-29 cells that differ in their timecourse, the Ca2+ response to P2Y2 receptor activation being marked by a more rapid decline of intracellular Ca2+ concentration ([Ca2+]i) after the peak response and that this rapid decline of [Ca2+]i was slowed in cells expressing heterologous β-adrenergic receptor kinase (βARK). In the present study, we demonstrate that, during P2Y2 receptor activation, βARK expression increases the rate of Gd3+-sensitive Mn2+ influx, a measure of the rate of store-operated Ca2+ entry from the extracellular space, during P2Y2 activation and that this effect of βARK is mimicked by exogenous α-subunits of Gq, G11 and Gi2. The effect of βARK on the rate of Mn2+ influx is thus attributable to its ability to scavenge G protein βγ-subunits released during activation of P2Y2 receptor. We further find that the effect of βARK on the rate of Mn2+ influx during P2Y2 receptor activation can be overcome by arachidonic acid. In addition, the UTP-induced Mn2+ influx rate was significantly increased by inhibitors of phospholipase A2 (PLA2) and an siRNA directed against PLA2β, but not by an siRNA directed against PLA2α or by inhibitors of arachidonic acid metabolism. These findings provide evidence for the existence of a P2Y2 receptor-activated signalling system that acts in parallel with depletion of intracellular Ca2+ stores to inhibit Ca2+ influx across the cell membrane. This signalling process is mediated via Gβγ and involves PLA2β and arachidonic acid. [Copyright &y& Elsevier]

Summary Plasma membrane-spanning G-protein-linked receptors transduce approximately 60% of all extracellular stimuli in higher animals. Many G-protein-linked receptor pathways are yet to be elucidated, with the receptor, G-protein or effector system as yet unidentified. In addition, many fundamental issues pertaining to G-protein signalling remain unresolved, such as the factors governing the specificity of G-protein receptor coupling and the control of signal amplitude in response to G-protein activation. In order to address some of these issues, the use of replication-deficient adenoviruses as gene transfer vectors for investigations of G-protein signalling has been developed, facilitating dissection of G-protein-linked signal transduction pathways in an extensive range of cultured cells, as well as in vivo. The present review focuses on the versatility and utility of adenoviruses for the investigation of signalling by heterotrimeric G-proteins and explores some of the recent advances in adenoviral technology as they relate to the study of signal transduction. [ABSTRACT FROM AUTHOR]