Explore the vast range of titles available.

Prediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I-associated peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, -B, -C and -G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles and distinct motifs associated with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I-associated ligands with 1.5-fold improvement in positive predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were observed experimentally in 11 patient-derived tumor cell lines. Prediction of HLA class I epitopes is improved in accuracy and breath with peptidomes from 95 mono-allelic cell lines.

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

This paper provides an experimentally validated, probabilistic model of file behavior when consumed by a set of pre-existing parsers. File behavior is measured by way of a standardized set of Boolean \"messages\" produced as the files are read. By thresholding the posterior probability that a file exhibiting a particular set of messages is from a particular dialect, our model yields a practical classification algorithm for two dialects. We demonstrate that this thresholding algorithm for two dialects can be bootstrapped from a training set consisting primarily of one dialect. Both the (parametric) theoretical and the (non-parametric) empirical distributions of file behaviors for one dialect yield good classification performance, and outperform classification based on simply counting messages. Our theoretical framework relies on statistical independence of messages within each dialect. Violations of this assumption are detectable and allow a format analyst to identify \"boundaries\" between dialects. A format analyst can therefore greatly reduce the number of files they need to consider when crafting new criteria for dialect detection, since they need only consider the files that exhibit ambiguous message patterns.

While using formal methods offers advantages over unit testing, their steep learning curve can be daunting to developers and can be a major impediment to widespread adoption. To support integration into an industrial software engineering workflow, a tool must provide useful information and must be usable with relatively minimal user effort. In this paper, we discuss our experiences associated with identifying and applying formal methods tools on an electronic warfare (EW) system with stringent safety requirements and present perspectives on formal methods tools from EW software engineers who are proficient in development yet lack formal methods training. In addition to a difference in mindset between formal methods and unit testing approaches, some formal methods tools use terminology or annotations that differ from their target programming language, creating another barrier to adoption. Input/output contracts, objects in memory affected by a function, and loop invariants can be difficult to grasp and use. In addition to usability, our findings include a comparison of vulnerabilities detected by different tools. Finally, we present suggestions for improving formal methods usability including better documentation of capabilities, decreased manual effort, and improved handling of library code.

This paper proposes an unsupervised classification method that partitions a set of files into non-overlapping dialects based upon their behaviors, determined by messages produced by a collection of programs that consume them. The pattern of messages can be used as the signature of a particular kind of behavior, with the understanding that some messages are likely to co-occur, while others are not. Patterns of messages can be used to classify files into dialects. A dialect is defined by a subset of messages, called the required messages. Once files are conditioned upon dialect and its required messages, the remaining messages are statistically independent. With this definition of dialect in hand, we present a greedy algorithm that deduces candidate dialects from a dataset consisting of a matrix of file-message data, demonstrate its performance on several file formats, and prove conditions under which it is optimal. We show that an analyst needs to consider fewer dialects than distinct message patterns, which reduces their cognitive load when studying a complex format.

Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses 1 , 2 and can function as bona fide antigens that facilitate tumour rejection 3 . Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma 4 – 6 , is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load 1 , 7 and an immunologically ‘cold’ tumour microenvironment 8 . We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone—a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma—generated circulating polyfunctional neoantigen-specific CD4 + and CD8 + T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma. Neoantigen-targeting vaccines are a feasible therapy for tumours with a low mutation burden and immunologically ‘cold’ tumour microenvironment, as neoantigen-specific T cells from the peripheral blood migrate into intracranial glioblastoma, thereby altering the immune milieu of the glioblastoma.