Hackback: Permitting Retaliatory Hacking by Non-State Actors as Proportionate Countermeasures to Transboundary Cyberharm

Cyberespionage has received even greater attention in the wake of reports of persistent and brazen cyberexploitation of U.S. and Canadian firms by the Chinese military. But the recent disclosures about NSA surveillance programs have made clear that a national program of cyberdefense of private firms\u27 intellectual property is politically infeasible. Following the lead of companies like Google, private corporations may increasingly resort to the use of self-defense, hacking back against cross-border incursions on the Internet. Most scholarship, however, has surprisingly viewed such actions as outside the ambit of international law. This Note provides a novel account of how international law should govern cross-border hacks by private actors, and especially hackbacks. It proposes that significant harm to a state\u27s intellectual property should be viewed as transboundary cyberharm and can be analyzed under traditional international legal principles, including the due diligence obligation to prevent significant harm to another state\u27s territorial sovereignty. Viewing cyber espionage within this framework, international law may presently permit states to allow private actors to resort to self-defense as proportionate countermeasures. By doing so, this Note offers a prescription for how states might regulate private actors to prevent unnecessary harm or vigilantism while preserving the right of self-defense

Untersuchungen über die therapeutische Wirkung von fatalem Mesenchym bei akuter Strahlenkrankheit von Mäusen

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SigsPack, a package for cancer mutational signatures

BACKGROUND: Mutational signatures are specific patterns of somatic mutations introduced into the genome by oncogenic processes. Several mutational signatures have been identified and quantified from multiple cancer studies, and some of them have been linked to known oncogenic processes. Identification of the processes contributing to mutations observed in a sample is potentially informative to understand the cancer etiology. RESULTS: We present here SigsPack, a Bioconductor package to estimate a sample's exposure to mutational processes described by a set of mutational signatures. The package also provides functions to estimate stability of these exposures, using bootstrapping. The performance of exposure and exposure stability estimations have been validated using synthetic and real data. Finally, the package provides tools to normalize the mutation frequencies with respect to the tri-nucleotide contents of the regions probed in the experiment. The importance of this effect is illustrated in an example. CONCLUSION: SigsPack provides a complete set of tools for individual sample exposure estimation, and for mutation catalogue & mutational signatures normalization

Identification and ranking of recurrent neo-epitopes in cancer

BACKGROUND: Immune escape is one of the hallmarks of cancer and several new treatment approaches attempt to modulate and restore the immune system’s capability to target cancer cells. At the heart of the immune recognition process lies antigen presentation from somatic mutations. These neo-epitopes are emerging as attractive targets for cancer immunotherapy and new strategies for rapid identification of relevant candidates have become a priority. METHOS: We carefully screen TCGA data sets for recurrent somatic amino acid exchanges and apply MHC class I binding predictions. RESULTS: We propose a method for in silico selection and prioritization of candidates which have a high potential for neo-antigen generation and are likely to appear in multiple patients. While the percentage of patients carrying a specific neo-epitope and HLA-type combination is relatively small, the sheer number of new patients leads to surprisingly high reoccurence numbers. We identify 769 epitopes which are expected to occur in 77629 patients per year. CONCLUSION: While our candidate list will definitely contain false positives, the results provide an objective order for wet-lab testing of reusable neo-epitopes. Thus recurrent neo-epitopes may be suitable to supplement existing personalized T cell treatment approaches with precision treatment options

Identification and ranking of recurrent neo-epitopes in cancer

Neo-epitopes are emerging as attractive targets for cancer immunotherapy and new strategies for rapid identification of relevant candidates have become a priority. We propose a method for in silico selection of candidates which have a high potential for neo-antigen generation and are likely to appear in multiple patients. This is achieved by carefully screening 33 TCGA data sets for recurrent somatic amino acid exchanges and, for the 1,055 resulting recurrent variants, applying MHC class I binding prediction algorithms. A preliminary confirmation of epitope binding and recognition by CD8 T cells has been carried out for a couple of candidates in humanized mice. Recurrent neo-epitopes may be suitable to supplement existing personalized T cell treatment approaches with precision treatment options

YAP and β-catenin co-operate to drive oncogenesis in basal breast cancer

Targeting cancer stem cells (CSCs) can serve as an effective approach toward limiting resistance to therapies and the development of metastases in many forms of cancer. While basal breast cancers encompass cells with CSC features, rational therapies remain poorly established. Here, we show that receptor tyrosine kinase Met signalling promotes the activity of the Hippo component YAP in basal breast cancer. Further analysis revealed enhanced YAP activity within the CSC population. Using both genetic and pharmaceutical approaches, we show that interfering with YAP activity delays basal cancer formation, prevents luminal to basal trans-differentiation and reduces CSC survival. Gene expression analysis of YAP knock-out mammary glands revealed a strong decrease in β-catenin target genes in basal breast cancer, suggesting that YAP is required for nuclear β-catenin activity. Mechanistically, we find that nuclear YAP interacts and overlaps with β-catenin and TEAD4 at common gene regulatory elements. Analysis of proteomic data from primary breast cancer patients identified a significant upregulation of the YAP activity signature in basal compared to other breast cancers, suggesting that YAP activity is limited to basal types. Our findings demonstrate that in basal breast cancers, β-catenin activity is dependent on YAP signalling and controls the CSC program. These findings suggest that targeting the YAP/TEAD4/β-catenin complex offers a potential therapeutic strategy for eradicating CSCs in basal (triple-negative) breast cancers