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  1. Abstract

    Genomic profiles of cancer cells provide valuable information on genetic alterations in cancer. Several recent studies employed these data to predict the response of cancer cell lines to drug treatment. Nonetheless, due to the multifactorial phenotypes and intricate mechanisms of cancer, the accurate prediction of the effect of pharmacotherapy on a specific cell line based on the genetic information alone is problematic. Emphasizing on the system-level complexity of cancer, we devised a procedure to integrate multiple heterogeneous data, including biological networks, genomics, inhibitor profiling, and gene-disease associations, into a unified graph structure. In order to construct compact, yet information-rich cancer-specific networks, we developed a novel graph reduction algorithm. Driven by not only the topological information, but also the biological knowledge, the graph reduction increases the feature-only entropy while preserving the valuable graph-feature information. Subsequent comparative benchmarking simulations employing a tissue level cross-validation protocol demonstrate that the accuracy of a graph-based predictor of the drug efficacy is 0.68, which is notably higher than those measured for more traditional, matrix-based techniques on the same data. Overall, the non-Euclidean representation of the cancer-specific data improves the performance of machine learning to predict the response of cancer to pharmacotherapy. The generated data aremore »freely available to the academic community at

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  2. With the growing effort to reduce power consumption in machines, fault tolerance becomes more of a concern. This holds particularly for large-scale computing, where execution failures due to soft faults waste excessive time and resources. These large-scale applications are normally parallel in nature and rely on control structures tailored specifically for parallel computing, such as locks and barriers. While there are many studies on resilient software, to our knowledge none of them focus on protecting these parallel control structures. In this work, we present a method of ensuring the correct operation of both locks and barriers in parallel applications. Our method tracks the memory locations used within parallel sections and detects a violation of the control structures. Upon detecting any violation, the violating thread is rolled back to the beginning of the structure and reattempts it, similar to rollback mechanisms in transactional memory systems. We test the method on representative samples of the BigDataBench kernels and find it exhibits a mean error reduction of 93.6% for basic mutex locks and barriers with a mean 6.55% execution time overhead at 64 threads. Additionally, we provide a comparison to transactional memory methods and demonstrate up to a mean 57.5% execution time overheadmore »reduction.« less
  3. Abstract Traditional techniques to identify macromolecular targets for drugs utilize solely the information on a query drug and a putative target. Nonetheless, the mechanisms of action of many drugs depend not only on their binding affinity toward a single protein, but also on the signal transduction through cascades of molecular interactions leading to certain phenotypes. Although using protein-protein interaction networks and drug-perturbed gene expression profiles can facilitate system-level investigations of drug-target interactions, utilizing such large and heterogeneous data poses notable challenges. To improve the state-of-the-art in drug target identification, we developed GraphDTI, a robust machine learning framework integrating the molecular-level information on drugs, proteins, and binding sites with the system-level information on gene expression and protein-protein interactions. In order to properly evaluate the performance of GraphDTI, we compiled a high-quality benchmarking dataset and devised a new cluster-based cross-validation protocol. Encouragingly, GraphDTI not only yields an AUC of 0.996 against the validation dataset, but it also generalizes well to unseen data with an AUC of 0.939, significantly outperforming other predictors. Finally, selected examples of identified drugtarget interactions are validated against the biomedical literature. Numerous applications of GraphDTI include the investigation of drug polypharmacological effects, side effects through offtarget binding, and repositioningmore »opportunities.« less