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Background Beckwith-Wiedemann Syndrome (BWS) is characterised by overgrowth and tumour predisposition. While multiple epigenetic and genetic mechanisms cause BWS, the majority are caused by methylation defects in imprinting control regions on chromosome 11p15.5. Disease-causing methylation defects are often mosaic within affected individuals. Phenotypic variability among individuals with chromosome 11p15.5 defects and tissue mosaicism led to the definition of the Beckwith-Wiedemann Spectrum (BWSp). Molecular diagnosis of BWSp requires use of multiple sensitive diagnostic techniques to reliably detect low-level aberrations. Methods Multimodal BWS diagnostic testing was performed on samples from 1057 individuals. Testing included use of a sensitive qRT-PCR-based quantitation method enabling identification of low-level mosaic disease, identification of CNVs within 11p15.5 via array comparative genomic hybridisation or qRT-PCR, and Sanger sequencing of CDKN1C. Results A molecular diagnosis was confirmed for 27.4% of individuals tested, of whom 43.4% had mosaic disease. The presence of a single cardinal feature was associated with a molecular diagnosis of BWSp in 20% of cases. Additionally, significant differences in the prevalence of mosaic disease among BWS molecular subtypes were identified. Finally, the diagnostic yield obtained by testing solid tissue samples from individuals with negative blood testing results shows improved molecular diagnosis. Conclusion This study highlights the prevalence of mosaic disease among individuals with BWSp and the increases in diagnostic yield obtained via testing both blood and solid tissue samples from affected individuals. Additionally, the results establish the presence of a molecular diagnosis in individuals with very subtle features of BWSp. [ABSTRACT FROM AUTHOR]

The progressive restriction of cell fate during lineage differentiation is a poorly understood phenomenon despite its ubiquity in multicellular organisms. We recently used a cell fusion assay to define a mode of epigenetic silencing that we termed 'occlusion', wherein affected genes are silenced by cis-acting chromatin mechanisms irrespective of whether trans-acting transcriptional activators are present. We hypothesized that occlusion of lineage-inappropriate genes could contribute to cell fate restriction. Here, we test this hypothesis by introducing bacterial artificial chromosomes (BACs), which are devoid of chromatin modifications necessary for occlusion, into mouse fibroblasts. We found that BAC transgenes corresponding to occluded endogenous genes are expressed in most cases, whereas BAC transgenes corresponding to silent but non-occluded endogenous genes are not expressed. This indicates that the cellular milieu in trans supports the expression of most occluded genes in fibroblasts, and that the silent state of these genes is solely the consequence of occlusion in cis. For the BAC corresponding to the occluded myogenic master regulator Myf5, expression of the Myf5 transgene on the BAC triggered fibroblasts to acquire a muscle-like phenotype. These results provide compelling evidence for a critical role of gene occlusion in cell fate restriction. [ABSTRACT FROM AUTHOR]

Individualization of cancer management requires prognostic markers and therapy-predictive markers. Prognostic markers assess risk of disease progression independent of therapy, whereas therapy- predictive markers identify patients whose disease is sensitive or resistant to treatment. We show that an experimentally derived IFN-related DNA damage resistance signature (IRDS) is associated with resistance to chemotherapy and/or radiation across different cancer cell lines. The IRDS genes STAT1, ISG15, and IFIT1 all mediate experimental resistance. Clinical analyses reveal that IRDS(+) and IRDS(-) states exist among common human cancers. In breast cancer, a seven-gene-pair classifier predicts for efficacy of adjuvant chemotherapy and for local-regional control after radiation. By providing information on treatment sensitivity or resistance, the IRDS improves outcome prediction when combined with standard markers, risk groups, or other genomic classifiers [ABSTRACT FROM AUTHOR]

This study investigates the effect of financial leverage, or relatively greater use of debt capital, on industry profitability. Recently at least two cross-section studies have yielded the surprising result that systematically higher rates of return are earned by firms with relatively low leverage. Measuring leverage inversely as the ratio of equity to assets, one would expect the rate of return on equity and this ratio to vary in opposite directions, lower values of equity/assets and the associated riskier bond intensive capital structures implying higher equilibrium profit rates, ceteris paribus. But so far the evidence has gone the other way. Fred D. Arditti calculated expected profit rates for firms as a geometric average of past rates of return and regressed this variable on the ratio of debt to equity. Examination of the leverage variable for the major firms in the sample of industries indicates that firms in the same industry tend to have similar amounts of leverage. This observation suggests that industry conditions play a role in determining the leverage ratios firms select. Since a firm's leverage choice carries with it a financial risk choice, this decision may be influenced by demand and cost risks in its industry.

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Personal protective equipment (PPE) frequently is used to reduce the risk of spreading adventitial diseases in rodent colonies. The PPE worn often reflects the historic practices of the research institution rather than published performance data. Standard PPE for a rodent facility typically consists of a disposable hair bonnet, gown, face mask, shoe covers, and gloves, which are donned on facility entry and removed on exiting. This study evaluated the effect of a reduced PPE protocol on disease spread within an endemically infected mouse colony. In the reduced protocol, only the parts of the wearer that came in direct contact with the mice or their environment were covered with PPE. To test the reduced PPE protocol, proven naïve mice were housed in a facility endemically infected with murine norovirus and mouse hepatitis virus for 12 wk. During that time, routine husbandry operations were conducted by using either the standard or reduced PPE protocols. All study mice remained free of virus antibody when reduced PPE was implemented. These results indicate that reduced PPE is adequate for disease containment when correct techniques for handling microisolation caging are used. Reducing the amount of PPE used in an animal facility affords considerable cost savings yet limits the risk of disease spread.

Both diffusible factors acting in trans and chromatin components acting in cis are implicated in gene regulation, but the extent to which either process causally determines a cell's transcriptional identity is unclear. We recently used cell fusion to define a class of silent genes termed "cis-silenced" (or "occluded") genes, which remain silent even in the presence of trans-acting transcriptional activators. We further showed that occlusion of lineage-inappropriate genes plays a critical role in maintaining the transcriptional identities of somatic cells. Here, we present, for the first time, a comprehensive map of occluded genes in somatic cells. Specifically, we mapped occluded genes in mouse fibroblasts via fusion to a dozen different rat cell types followed by whole-transcriptome profiling. We found that occluded genes are highly prevalent and stable in somatic cells, representing a sizeable fraction of silent genes. Occluded genes are also highly enriched for important developmental regulators of alternative lineages, consistent with the role of occlusion in safeguarding cell identities. Alongside this map, we also present whole-genome maps of DNA methylation and eight other chromatin marks. These maps uncover a complex relationship between chromatin state and occlusion. Furthermore, we found that DNA methylation functions as the memory of occlusion in a subset of occluded genes, while histone deacetylation contributes to the implementation but not memory of occlusion. Our data suggest that the identities of individual cell types are defined largely by the occlusion status of their genomes. The comprehensive reference maps reported here provide the foundation for future studies aimed at understanding the role of occlusion in development and disease.