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Pancreatic cancer is not caused by a specific series of genetic alterations that occur sequentially but by one, or few, catastrophic events that result in simultaneous oncogenic genetic rearrangements, giving rise to highly aggressive tumours. Pancreatic cancer genome evolution Pancreatic cancer is a highly aggressive tumour type. With a view to examining the evolution of rapid tumour progression in this cancer, this paper presents an analysis of more than a hundred tumour-enriched whole-genome sequences from primary and metastatic pancreas cancers obtained from collaborating hospitals in Canada and the United States of America. Challenging a traditional model of progressive evolution based on ordered mutations in several genes, the authors find support for a role of complex rearrangements and chromothripsis in pancreatic cancer progression, which suggests that the genomic instability that marks this cancer may be explained by a punctuated equilibrium model. Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development 1 . The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations 2 , 3 , 4 , 5 ( KRAS , followed by CDKN2A , then TP53 and SMAD4 ); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage 2 , 5 , 6 , 7 , 8 , 9 , indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage 10 . However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection 11 , suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory 12 . In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

Divers who wish to prolong their time underwater while carrying less equipment often use devices called rebreathers, which recycle the gas expired after each breath instead of discarding it as bubbles. However, rebreathers’ need to replace oxygen used by breathing creates a failure mechanism that can and frequently does lead to hypoxia, loss of consciousness, and death. The purpose of this study was to determine whether a pulse oximeter could provide a useful amount of warning time to a diver with a rebreather after failure of the oxygen addition mechanism. Twenty-eight volunteer human subjects breathed on a mixed-gas rebreather in which the oxygen addition system had been disabled. The subjects were immersed in water in four separate environmental scenarios, including cold and warm water, and monitored using pulse oximeters placed at multiple locations. Pulse oximeters placed on the forehead and clipped on the nasal ala provided a mean of 32 s (±10 s SD) of warning time to divers with falling oxygen levels, prior to risk of loss of consciousness. These devices, if configured for underwater use, could provide a practical and inexpensive alarm system to warn of impending loss of consciousness in a manner that is redundant to the rebreather.

Abstract In this study, three individual descriptions of anxiety as experienced in social situations were analyzed so that a general structure representing social anxiety could potentially be obtained. The descriptions analyzed produced results that not only overlapped with already existing literature from various perspectives on the topic, but also highlighted certain key factors that have largely been unaccounted for by prior studies. By utilizing the Descriptive Phenomenological Method in Psychology (Giorgi, 2009), these factors were brought to light in more depth and clarity than if the same phenomenon were studied using a third person approach. Specifically, six constituents of social anxiety were revealed; including factors related to inter-subjectivity, the relationship between fear and anxiety, and the relationship between desire and self-lack.

What kind of event could destabilize, simultaneously, planetary trajectories and existential subjectivities? We argue that an encounter with an alien logic has the power to irrevocably dislodge common sense thinking from conventional spaces that have been molded into representational thought. To invoke such an experience, we draw on specific narrative elements in Ted Chiang’s “Story of Your Life” as well as its cinematic adaptation, Arrival, to elucidate how subjectivity can become reconstructed, existentially, through language and time in very precise, yet nonlinear ways. Categorically speaking, this essay designates the highly interactive, embodied procedures involved in the production of subjectivity under a rubric of three: apocalypse, a solution to the non-zero-sum game and a planetary event of post-anthropocentric ramifications; language, a new use of symbols in affective and transformational communicativity; and temporality, a remembering of the future and a vision of self-destiny.

SeqControl uses 15 quality metrics of high-throughput sequencing experiments to predict how much sequencing is needed to reach a desired depth of coverage. As high-throughput sequencing continues to increase in speed and throughput, routine clinical and industrial application draws closer. These 'production' settings will require enhanced quality monitoring and quality control to optimize output and reduce costs. We developed SeqControl, a framework for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, basewise coverage and basewise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references, we derived multivariate models that predict sequencing quality and depth. SeqControl robustly predicted how much sequencing was required to reach a given coverage depth (area under the curve (AUC) = 0.993), accurately classified clinically relevant formalin-fixed, paraffin-embedded samples, and made predictions from as little as one-eighth of a sequencing lane (AUC = 0.967). These techniques can be immediately incorporated into existing sequencing pipelines to monitor data quality in real time. SeqControl is available at http://labs.oicr.on.ca/Boutros-lab/software/SeqControl/ .

Background A comprehensive assessment of the epigenetic dynamics in cancer cells is the key to understanding the molecular mechanisms underlying cancer and to improving cancer diagnostics, prognostics and treatment. By combining genome-wide ChIP-seq epigenomics and microarray transcriptomics, we studied the effects of oxygen deprivation and subsequent reoxygenation on histone 3 trimethylation of lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in a breast cancer cell line, serving as a model for abnormal oxygenation in solid tumors. A priori, epigenetic markings and gene expression levels not only are expected to vary greatly between hypoxic and normoxic conditions, but also display a large degree of heterogeneity across the cell population. Where traditionally ChIP-seq data are often treated as dichotomous data, the model and experiment here necessitate a quantitative, data-driven analysis of both datasets. Results We first identified genomic regions with sustained epigenetic markings, which provided a sample-specific reference enabling quantitative ChIP-seq data analysis. Sustained H3K27me3 marking was located around centromeres and intergenic regions, while sustained H3K4me3 marking is associated with genes involved in RNA binding, translation and protein transport and localization. Dynamic marking with both H3K4me3 and H3K27me3 (hypoxia-induced bivalency) was found in CpG-rich regions at loci encoding factors that control developmental processes, congruent with observations in embryonic stem cells. Conclusions In silico -identified epigenetically sustained and dynamic genomic regions were confirmed through ChIP-PCR in vitro, and obtained results are corroborated by published data and current insights regarding epigenetic regulation.

Nature 538, 378–382 (2016); doi:10.1038/nature19823 In this Letter, owing to a typesetter error the ‘received date’ was incorrectly shown as ‘8 August 2015’ instead of ‘27 November 2015’ in both the print and PDF versions; this has been corrected online.