Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

The global prevalence and association between the risk of myocarditis and mRNA-based COVID-19 vaccination: A network meta-analysis version 1; peer review: awaiting peer review

Background: Cases of myocarditis development have been reported after administration of messenger ribonucleic acid (mRNA)-based coronavirus disease (COVID-19) vaccines. However, the reports vary among the studies, and the types of mRNA vaccines with potential to cause myocarditis remain unidentified. The objective was to assess the cumulative prevalence of myocarditis and determine the association between myocarditis and mRNA-based COVID-19 vaccination. Methods: We performed a network meta-analysis by searching articles in PubMed, Scopus, and Web of Science. Information on the prevalence of myocarditis after the mRNA-based COVID-19 vaccination was collected from each study. Analysis was performed by calculating the pooled prevalence rate, and the association was determined using the Z-test. Data networking was performed using the Bayesian method. Results: A total of 18 papers was included in our analysis. We found that the cumulative prevalence of myocarditis was 1.7, 1.9, 1.2, and 1.1 per 100,000 population after vaccination with different types of mRNA-based COVID-19 vaccines, namely all mRNA COVID-19 vaccines, BNT162b1, mRNA-1273, and the combination of BNT162b1 and mRNA-1273, respectively. Moreover, the results revealed that BNT162b1 vaccination increased the risk of myocarditis by 1.64- and 1.71-folds compared to mRNA-1273 and the combination of BNT162b2 and mRNA-1273, respectively. Similar risks of developing myocarditis were observed after mRNA-1273 and the combination of BNT162b1 and mRNA-1273 vaccination. Conclusions: Our findings suggest the cumulative prevalence of myocarditis after mRNA-based COVID-19 vaccination with maximum prevalence was observed after BNT162b2 administration. BNT162b2 was associated with a higher risk of developing myocarditis than the other mRNA-based COVID-19 vaccines

Forest conflicts and the informal nature of realizing indigenous land rights in Indonesia

Despite a widening legal scope for indigenous rights, the invocation of indigeneity to claim land rights rarely empowers marginalized communities. This article develops an explanation for why this formal recognition of community rights actually has little substantive impact on local struggles over land in Indonesia. Employing almost two years of fieldwork on how rural communities employ indigeneity-based land claims in South Sulawesi, it argues that claims for land rights on the basis of indigeneity are settled not simply on the basis of law, but also on that of the relative bargaining positions and the character of informal linkages between communities, their mediators and local authorities. Indigenous status therefore must be understood as a privilege most likely to be obtained by those groups with relatively strong connections to influential state actors. In contrast, communities that are in conflict with local state actors tend be excluded from obtaining the status of indigeneity and hence the state is likely to deny them their land rights claims.Effective Protection of Fundamental Rights in a pluralist worl