Analysis of extracellular matrix network dynamics in cancer using the MatriNet database

Abstract The extracellular matrix (ECM) is a three-dimensional network of proteins of diverse nature, whose interactions are essential to provide tissues with the correct mechanical and biochemical cues they need for proper development and homeostasis. Changes in the quantity of extracellular matrix (ECM) components and their balance within the tumor microenvironment (TME) accompany and fuel all steps of tumor development, growth and metastasis, and a deeper and more systematic understanding of these processes is fundamental for the development of future therapeutic approaches. The wealth of “big data” from numerous sources has enabled gigantic steps forward in the comprehension of the oncogenic process, also impacting on our understanding of ECM changes in the TME. Most of the available studies, however, have not considered the network nature of ECM and the possibility that changes in the quantity of components might be regulated (co-occur) in cancer and significantly “rebound” on the whole network through its connections, fundamentally altering the matrix interactome. To facilitate the exploration of these network-scale effects we have implemented MatriNet (www.matrinet.org), a database enabling the study of structural changes in ECM network architectures as a function of their protein-protein interaction strengths across 20 different tumor types. The use of MatriNet is intuitive and offers new insights into tumor-specific as well as pan-cancer features of ECM networks, facilitating the identification of similarities and differences between cancers as well as the visualization of single-tumor events and the prioritization of ECM targets for further experimental investigations

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

© The Author(s), under exclusive licence to Springer Nature Limited 2019In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.info:eu-repo/semantics/publishedVersio

Search for Diphoton Events with Large Missing Transverse Energy in 7 TeV Proton-Proton Collisions with the ATLAS Detector

A search for diphoton events with large missing transverse energy is presented. The data were collected with the ATLAS detector in proton-proton collisions at √s=7  [square root of s=7] TeV at the CERN Large Hadron Collider and correspond to an integrated luminosity of 3.1  pb-1 [pb superscript -1]. No excess of such events is observed above the standard model background prediction. In the context of a specific model with one universal extra dimension with compactification radius R and gravity-induced decays, values of 1/R<729  GeV are excluded at 95% C. L., providing the most sensitive limit on this model to date.United States. Dept. of EnergyNational Science Foundation (U.S.