PLoS Genet

Tumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this interdependency in an in vivo setting and assess the viability of Brg1 as a potential therapeutic target. Using a range of transgenic approaches, we deleted Brg1 in the context of Wnt-activated murine small intestinal epithelium. Pan-epithelial loss of Brg1 using VillinCreERT2 and AhCreERT transgenes attenuated expression of Wnt target genes, including a subset of stem cell-specific genes and suppressed Wnt-driven tumourigenesis improving animal survival. A similar increase in survival was observed when Wnt activation and Brg1 loss were restricted to the Lgr5 expressing intestinal stem cell population. We propose a mechanism whereby Brg1 function is required for aberrant Wnt signalling and ultimately for the maintenance of the tumour initiating cell compartment, such that loss of Brg1 in an Apc-deficient context suppresses adenoma formation. Our results highlight potential therapeutic value of targeting Brg1 and serve as a proof of concept that targeting the cells of origin of cancer may be of therapeutic relevance

Performance of a plastic scintillator developed using styrene monomer polymerization

This paper presents a newly developed plastic scintillator produced in collaboration with Turkiye Energy, Nuclear and Mineral Research Agency (TENMAK). The scintillator is manufactured using thermal polymerization of commercially available styrene monomer. The absorption spectrum of the scintillator exhibited two absorption bands at 225 nm and 340 nm, with an absorption edge observed at 410 nm. The wavelength of the emitted light was measured in the range of 400-800 nm, with a maximum intensity at 427 nm. Monoenergetic electrons from the 137Cs source were used to evaluate the characteristics of the new scintillator, particularly its light yield. As the light readout the MAPD-3NM type silicon photomultiplier array (4 x 4) with an active area of 15 x 15 mm2, assembled using single MAPDs with an active area of 3.7 x 3.7 mm2, was used. The light yield of the scintillator was determined to be 6134 photons/MeV. In addition, the efficiency of the scintillator for gamma rays with an energy of 662 keV was found to be approximately 1.8 %. A CmBe neutron source was employed to evaluate its fast neutron detection performance. However, neutron/gamma discrimination using pulse shape discrimination (charge integration) method was not observed. The results demonstrate the potential of a newly produced plastic scintillator for various applications, particularly in radiation monitoring and detection systems.Comment: 7 pages, 7 figure

The importance of constraint relief caused by rubber cavitation in the toughening of epoxy

Many rubber-toughened epoxies are thought to derive the bulk of their toughness through the processes of rubber cavitation and plastic shear-yielding in the epoxy matrix. Constraint relief has been considered to be a key mechanism which allows extra plastic shear deformation to occur. The present work attempts to provide direct experimental evidence of the constraint relief effect by combining testing geometries that vary the degree of constraint with microscopic observations. The results show that the success of a rubber as a toughening agent for epoxies is closely related to its ability to cavitate. Evidence for local constraint relief is presented. Upon cavitation of the rubber, the stress state in a specimen with initial constraint is found to change to a plane stress state. The constraint relief circumvents or delays the crack initiation in the matrix, which allows more plastic deformation to occur.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44723/1/10853_2005_Article_BF01352202.pd

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Transcriptome and H3K27 tri-methylation profiling of Ezh2-deficient lung epithelium

The adaptation of the lungs to air breathing at birth requires the fine orchestration of different processes to control lung morphogenesis and progenitor cell differentiation. However, there is little understanding of the role that epigenetic modifiers play in the control of lung development. We found that the histone methyl transferase Ezh2 plays a critical role in lung lineage specification and survival at birth. We performed a genome-wide transcriptome study combined with a genome-wide analysis of the distribution of H3K27 tri-methylation marks to interrogate the role of Ezh2 in lung epithelial cells. Lung cells isolated from Ezh2-deficient and control mice at embryonic day E16.5 were sorted into epithelial and mesenchymal populations based on EpCAM expression. This enabled us to dissect the transcriptional and epigenetic changes induced by the loss of Ezh2 specifically in the lung epithelium. Here we provide a detailed description of the analysis of the RNA-seq and ChIP-seq data, including quality control, read mapping, differential expression and differential binding analyses, as well as visualisation methods used to present the data. These data can be accessed from the Gene Expression Omnibus database (super-series accession number GSE57393)

Miniaturized read-out interface “Spectrig MAPD” dedicated for silicon photomultipliers

The new pocket size read-out interface device dedicated for silicon photomultipliers (SiPM) has been designed and developed. While it was designed as a miniaturized and low power device it still provides a wide spectrum of functionality necessary for measurements and testing of SiPMs and SiPM based detectors. Full signal processing has been integrated within the device involving variable gain amplification, filtration and digitization. Signal acquisition can be performed with sampling frequency 400 MSa/s at 12 bit resolution or 600 MSa/s at 8 bit resolution while achieving full waveform capture & download rate about 20 000 events per second. The read-out interface is fully powered from the USB bus allowing operation without need of additional power line connection. An integrated bias source can be set in range from 0V to +200V with 12 bit precision. The read-out interface is primarily dedicated for spectroscopy purposes. There are two input signal channels with different optimization regarding the signal gain to cover a low energy range corresponding to single photo-electron detector response as well as to cover a high energy range corresponding to a detector response operated with scintillator registering gamma radiation in order of MeVs. Both input channels are equipped with fine gain adjustment in range from -9 dB to 26 dB with 1 dB step in addition to the fixed gain of each signal channel. The FPGA based design of the read-out interface allowed implementation of advanced triggering functionality like a data driven trigger, external trigger, gating of trigger to extend readout interface capability even further in a way of complex experiments. A set of functional tests and experiments with SiPM called micropixel avalanche photodiode (MAPD) and MAPD based detectors have been performed to characterize real properties of the read-out interface