PLK1 and PARP positively correlate in Middle Eastern breast cancer and their combined inhibition overcomes PARP inhibitor resistance in triple negative breast cancer

BackgroundDespite advancements in treatment approaches, patients diagnosed with aggressive breast cancer (BC) subtypes typically face an unfavorable prognosis. Globally, these cancers continue to pose a significant threat to women's health, leading to substantial morbidity and mortality. Consequently, there has been a significant struggle to identify viable molecular targets for therapeutic intervention in these patients. Polo-like Kinase-1 (PLK1) represents one of these molecular targets currently undergoing rigorous scrutiny for the treatment of such tumors. Yet, its role in the pathogenesis of BC in Middle Eastern ethnicity remains unexplored.MethodsWe investigated the expression of PLK1 protein in a cohort of more than 1500 Middle Eastern ethnicity BC cases by immunohistochemistry. Association with clinicopathological parameters and prognosis were performed. In vitro studies were conducted using the PLK1 inhibitor volasertib and the PARP inhibitor olaparib, either alone or in combination, in PTC cell lines. ResultsOverexpression of PLK1 was detected in 27.4% of all BC cases, and this was notably correlated with aggressive clinicopathological markers. PLK1 was enriched in the triple-negative breast cancer (TNBC) subtype and exhibited poor overall survival (p = 0.0347). Notably, there was a positive correlation between PLK1 and PARP overexpression, with co-expression of PLK1 and PARP observed in 15.7% of cases and was associated with significantly poorer overall survival (OS) compared to the overexpression of either protein alone (p = 0.0050). In vitro, we studied the effect of PLK1 and PARP inhibitors either single or combined treatments in two BRCA mutated, and one BRCA proficient TNBC cell lines. We showed that combined inhibition significantly reduced cell survival and persuaded apoptosis in TNBC cell lines. Moreover, our findings indicate that inhibition of PLK1 can reinstate sensitivity in PARP inhibitor (PARPi) resistant TNBC cell lines. ConclusionOur results shed light on the role of PLK1 in the pathogenesis and prognosis of Middle Eastern BC and support the potential clinical development of combined inhibition of PLK1 and PARP, a strategy that could potentially broaden the use of PLK1 and PARP inhibitors beyond BC cases lacking BRCA

Testing homogeneity of effect sizes in pooling 2x2 contingency tables from multiple studies: a comparison of methods

Meta-analysis is a statistical methodology that combines the outcomes of several independent studies. Either a fixed-effects or a random-effects model is used to combine the results of the independent studies. The choice depends on whether the outcomes can be considered homogeneous or not. Several methods have been developed to test the homogeneity of effect sizes. Although many of them have been compared already, they have not been studied in more realistic practical settings where individuals all have their own risk of an event and a complete overview is lacking. In this article, we investigate the performance of 10 statistical methods to test homogeneity of a binary exposure on a binary clinical outcome, using an extensive simulation study and a real life meta-analysis. We evaluated the Type I error and the statistical power. The fixed-effects regression model for treatment and study interaction was found to be a slightly liberal test, while the Q-statistic and the Bliss statistic can be considered conservative tests. The random-effects regression model, the Peto statistic and the I2 perform rather poorly compared to the other methods. All chi-square tests that are based on the calculation of a specific odds ratio and the fixed-effects logistic regression analysis perform best. Among these chi-square tests, we recommend the Breslow–Day test, but only for convenience purposes, since it is available in most statistical software packages and the other tests are not

Copas’ method is sensitive to different mechanisms of publication bias

Copas’ method corrects a pooled estimate from an aggregated data meta-analysis for publication bias. Its performance has been studied for one particular mechanism of publication bias. We show through simulations that Copas’ method is not robust against other realistic mechanisms. This questions the usefulness of Copas’ method, since publication bias mechanisms are typically unknown in practice

Tests for publication bias are unreliable in case of heteroscedasticity

Regression based methods for the detection of publication bias in meta-analysis have been extensively evaluated in literature. When dealing with continuous outcomes, specific hidden factors (e.g., heteroscedasticity) may interfere with the test statistics. In this paper we investigate the influence of residual heteroscedasticity on the performance of four tests for publication bias: the Egger test, the Begg-Mazumdar test and two tests based on weighted regression. In the presence of heteroscedasticity, the Egger test and the weighted regression tests highly inflate the Type I error rate, while the Begg-Mazumdar test deflates the Type I error rate. Although all three tests already have low statistical power, heteroscedasticity typically reduces it further. Our results in combination with earlier discussions on publication bias tests lead us to conclude that application of these tests on continuous treatment effects is not warranted

Combined Statistical Analyses for Long-Term Stability Data with Multiple Storage Conditions:A Simulation Study

Shelf-life estimation usually requires that at least three registration batches are tested for stability at multiple storage conditions. The shelf-life estimates are often obtained by linear regression analysis per storage condition, an approach implicitly suggested by ICH guideline Q1E. A linear regression analysis combining all data from multiple storage conditions was recently proposed in the literature when variances are homogeneous across storage conditions. The combined analysis is expected to perform better than the separate analysis per storage condition, since pooling data would lead to an improved estimate of the variation and higher numbers of degrees of freedom, but this is not evident for shelf-life estimation. Indeed, the two approaches treat the observed initial batch results, the intercepts in the model, and poolability of batches differently, which may eliminate or reduce the expected advantage of the combined approach with respect to the separate approach. Therefore, a simulation study was performed to compare the distribution of simulated shelf-life estimates on several characteristics between the two approaches and to quantify the difference in shelf-life estimates. In general, the combined statistical analysis does estimate the true shelf life more consistently and precisely than the analysis per storage condition, but it did not outperform the separate analysis in all circumstances

Evaluation of a virtual pet visit system with live video streaming of patient images over the Internet in a companion animal intensive care unit in the Netherlands

Objective To evaluate the impact of a virtual pet visit system (“TelePet” System, TPS) on owners and staff of a companion animal ICU. Design Longitudinal interventional study (2010–2013). Setting Companion animal ICU at a university veterinary medical teaching hospital. Study Populations Pet owners, ICU technicians. Interventions The introduction of the TPS, with live video streaming of patient images over the Internet, in a companion animal ICU. Measurements and Main Results Pet owners experienced TPS as a valuable extra service. Most TPS users (72.4%) experienced less anxiety and felt less need (40.4% of TPS users) to visit their hospitalized pet in person. Most users (83.5%) shared TPS access with their family. The introduction of the TPS did not improve overall owner satisfaction, except for the score on “quality of medical treatment.” Seven of 26 indicators of owner satisfaction were awarded higher scores by TPS users than by TPS nonusers in the survey after the introduction of the system. However, the lack of randomization of owners might have influenced findings. The enthusiasm of the ICU technicians for the system was tempered by the negative feedback from a small number of owners. Nevertheless they recognized the value of the system for owners. The system was user friendly and ICU staff and TPS users experienced few technical problems. Conclusions As veterinary healthcare is moving toward a more client-centered approach, a virtual pet visit system, such as TPS, is a relatively simple application that may improve the well-being of most owners during the hospitalization of their pet

Evaluation of a virtual pet visit system with live video streaming of patient images over the Internet in a companion animal intensive care unit in the Netherlands

Objective To evaluate the impact of a virtual pet visit system (“TelePet” System, TPS) on owners and staff of a companion animal ICU. Design Longitudinal interventional study (2010–2013). Setting Companion animal ICU at a university veterinary medical teaching hospital. Study Populations Pet owners, ICU technicians. Interventions The introduction of the TPS, with live video streaming of patient images over the Internet, in a companion animal ICU. Measurements and Main Results Pet owners experienced TPS as a valuable extra service. Most TPS users (72.4%) experienced less anxiety and felt less need (40.4% of TPS users) to visit their hospitalized pet in person. Most users (83.5%) shared TPS access with their family. The introduction of the TPS did not improve overall owner satisfaction, except for the score on “quality of medical treatment.” Seven of 26 indicators of owner satisfaction were awarded higher scores by TPS users than by TPS nonusers in the survey after the introduction of the system. However, the lack of randomization of owners might have influenced findings. The enthusiasm of the ICU technicians for the system was tempered by the negative feedback from a small number of owners. Nevertheless they recognized the value of the system for owners. The system was user friendly and ICU staff and TPS users experienced few technical problems. Conclusions As veterinary healthcare is moving toward a more client-centered approach, a virtual pet visit system, such as TPS, is a relatively simple application that may improve the well-being of most owners during the hospitalization of their pet