deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution

BACKGROUND: Analysis of somatic mutations provides insight into the mutational processes that have shaped the cancer genome, but such analysis currently requires large cohorts. We develop deconstructSigs, which allows the identification of mutational signatures within a single tumor sample. RESULTS: Application of deconstructSigs identifies samples with DNA repair deficiencies and reveals distinct and dynamic mutational processes molding the cancer genome in esophageal adenocarcinoma compared to squamous cell carcinomas. CONCLUSIONS: deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine

The effect of magnesium on the local structure and initial dissolution rate of simplified UK Magnox waste glasses

A series of simplified glasses were prepared to mimic the United Kingdom’'s Magnox radioactive waste glasses and determine the separate effect of the presence of Mg on the glass structure and the initial dissolution rate. These glasses had an alkaline earth (Ca/Mg) content of 6.5 mol% and relative ratios of Si, B and Na similar to 25 wt% waste loaded Magnox waste glass simulant. Each simplified glass had similar macroscopic properties, differing only in Ca/Mg ratio. 25Mg magic angle spinning nuclear magnetic resonance (MASNMR) spectra of the simplified Mg endmember (MgEM) glass (with no Ca) and the full-component simulant glass were similar, consistent with the similar Mg local environments in both glasses. 11B MASNMR spectra of the series of simplified glasses showed a systematic increase in the amount of three-coordinated boron ([3]B) with increasing amounts of Mg. A clear change in the charge balancing of four-coordinated boron ([4]B) by Mg compared with Ca is observed. However, 11B NMR measurements of the leached material showed that the additional [3]B was not preferentially leached from the Mg containing samples. Despite the structural changes in the glass induced by Ca/Mg substitution, initial dissolution rates (r0) remained invariant, within error, with Ca/Mg ratio. This indicates that the poorer aqueous durability of Mg-containing Magnox waste glass measured experimentally in long-term leaching experiments, compared with SON68 glass containing Ca, is not caused by a primary structural effect in the glass.R. Guo acknowledges the EPSRC and the University of Cambridge for an International Doctoral Scholarship. A portion of this work was funded by Radioactive Waste Management Limited (C.T. Brigden, S.W. Swanton and I. Farnan). The UK 850 MHz solid-state NMR Facility used in this research was funded by EPSRC and BBSRC (contract reference PR140003), as well as the University of Warwick including via part funding through Birmingham Science City Advanced Materials Projects 1 and 2 supported by Advantage West Midlands (AWM) and the European Regional Development Fund (ERDF). Collaborative assistance from the 850 MHz Facility Manager (Dinu Iuga, University of Warwick) is acknowledged

APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

The APOBEC mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted

De Soto’s First Headquarters in Florida

Knowing that Hernando de Soto, his expedition, and the places he visited will probably be matters of discussion for years and years, I have not recently ventured any further contributions regarding them. However, challenge of one of my conclusions, the probable site of the Indian town of Ucita where De Soto established his first North American headquarters, has recently been made in a scientifically motivated paper (“The Terra Ceia Site, Manatee County, Florida.” No. 3 of the Publications of the Florida Anthropological Society, by Ripley P. Bullen), and this calls for some comments

Principles of Stakes Fairness in Sport

Fairness in sport is not just about assigning the top prizes to the worthiest competitors. It is also about the way the prize structure itself is organised. For many sporting competitions, although it may be acceptable for winners to receive more than losers, it can seem unfair for winners to take everything and for losers to get nothing. Yet this insight leaves unanswered some difficult questions about what stakes fairness requires and which principles of stakes fairness are appropriate for particular competitions. In this article I specify a range of different principles of stakes fairness (ten in total) that could regulate sporting competitions. I also put forward a theoretical method for pairing up appropriate principles of stakes fairness with given sporting competitions. Specifically, I argue that the underlying rationales for holding sporting competitions can provide useful guides for identifying appropriate principles of stakes fairness. I then seek to clarify and work through some of the implications of this method for a sample of real world controversies over sporting prize structures. I also attempt to refine the method in response to two possible objections from indeterminacy and relativism. Finally, I compare and contrast my conclusions with more general philosophical debates about justice

De Soto and Terra Cei

In connection with my work as chairman of the De Soto Expedition Commission between 1935 and 1938 I made a study of the documentary and geographical evidence regarding the location of the point where De Soto landed on the Florida coast in 1539 and the position of his first headquarters. While I was assisted to some extent by other members of the Commission, the conclusions reached were more particularly mine and I assume all responsibility for them. They were originally stated in a paper printed in “The Florida Historical Quarterly” (vol. XVI, no. 3; Jan. 1938) and were incorporated later in the “Final Report of the United States De Soto Expedition Commission” (Washington, 1939). The point where the greater part of the Spanish army was landed was believed to be Shaws Point, and the native town where he established his headquarters apparently at the Indian site on Terra Ceia Island