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Comparing with natural imaging datasets used in transfer learning, the effects of med- ical pre-training datasets are underexplored. In this study, we carry out transfer learning pre-training dataset effect analysis in breast cancer imaging by evaluating three popular deep neural networks and one patch-based convolutional neural network on three target datasets under different fine-tuning configurations. Through a series of comparisons, we conclude that the pre-training dataset, DDSM, is effective on two other mammogram datasets. However, it is ineffective on an ultrasound dataset. What is more, fine-tuning may mask the inefficacy of a pre-training dataset. In addition, the efficacy/inefficacy of DDSM on the target datasets is corroborated by a representational analysis. At last, we show that hybrid transfer learning cannot mitigate the masking effect of fine-tuning. 

Current Hi-C analysis approaches focus on uniquely mapped reads and little research has been carried out to include multi-mapping reads, which leads to a lack of biological signals from DNA repetitive regions. We propose a heuristic strategy to assign multi-mapping reads to loci according to the distance to their closest restriction enzyme cutting sites. We demonstrate that the heuristic strategy can rescue multi-mapping reads thus enhance the quality of Hi-C data. Compared with mHi-C, it not only improves replicate reproducibility in the same cell type, but also maintains the difference between replicates of different cell types. Moreover, the strategy identifies much more common statistically significant chromatin interactions between Hi-C experiments of different restriction enzymes and has a huge advantage on computing resources. Therefore, the heuristic strategy can be used to enhance Hi-C data by utilizing multi-mapping reads. 

Abstract Beyond the most common oncogenes activated by mutation (mut-drivers), there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and posttranslational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function. The list of putative mut-drivers includes established drivers and others with poorly understood roles in cancer. This ML model is available as a web application. As a case study, we focused the approach on nonreceptor tyrosine kinases (NRTK) and found a recurrent mutation in activated CDC42 kinase-1 (ACK1) that disrupts the Mig6 homology region (MHR) and ubiquitin-association (UBA) domains on the ACK1 C-terminus. By studying these domains in cultured cells, we found that disruption of the MHR domain helps activate the kinase while disruption of the UBA increases kinase stability by blocking its lysosomal degradation. This ACK1 mutation is analogous to lymphoma-associated mutations in its sister kinase, TNK1, which also disrupt a C-terminal inhibitory motif and UBA domain. This study establishes a mut-driver discovery tool for the research community and identifies a mechanism of ACK1 hyperactivation shared among ACK family kinases. Implications:This research identifies a potentially targetable activating mutation in ACK1 and other possible oncogenic mutations, including PTM-disrupting mutations, for further study.