Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Phase transitions in ammonium perchlorate to 26 GPA and 700 K in a diamond anvil cell

Ammonium perchlorate (AP) showed previously unreported phase behavior when studied in a diamond anvil cell (DAC) at high temperature (to 693 K) and high pressure (to {approximately}26 GPa). Liquid droplets, observed above the known 513 K orthorhombic-to-cubic phase transition, are interpreted as the onset to melting. The melting point decreased with increasing pressure. Mid-infrared FTIR spectra of the residue showed only AP. The AP melt may contribute to shock insensitivity of AP-based propellants. Gas formation was seen at higher temperatures. A phase diagram was constructed using the appearance of liquid and gas as solid-liquid and liquid-gas transitions. Preliminary pressurized differential scanning calorimetry data showed a weak pressure dependence (to {approximately}6.9 MPa) for the orthorhombic-to-cubic phase transition

Influence d'une préhydratation sans confinement sur les performances hydrauliques des GSB

National audienceIt is recommended to confine geosynthetic clay liners (GCLs) used in sealing works in progress during their implementation. In the case of a use in sealing of underground works (shaft walling, superior slab for example) GCLs can be hydrated after their installation and before confining because of risk of construction site or of unfavourable weather conditions. The objective of the study presented is to estimate the impact of such a prehydration towards the later hydraulic performances of the GCL, in particular when its containment is realized at this water content state, for several GCL which discriminate themselves mainly by their bonding type allowing to contain the bentonite. The results indicate a maintaining of their hydraulic performance for some GCLs prehydrated without containment cover. But this observation is not valid for all the GCLs.Il est recommandé de confiner les géosynthétiques bentonitiques (GSB) utilisés en étanchéité d'ouvrages à l'avancement lors de leur mise en oeuvre. Dans le cas d'une utilisation en étanchéité d'ouvrages souterrains, les GSB peuvent se trouver hydratés après leur pose et avant confinement du fait d'aléas de chantier ou de conditions météo défavorables. L'objectif de l'étude présentée est d'évaluer l'incidence d'une telle préhydratation vis-à-vis des performances hydrauliques ultérieures du géosynthétique bentonitique, et notamment lorsque son confinement est réalisé dans cet état hydrique, pour plusieurs GSB qui se distinguent principalement par leur mode de liaisonnement permettant de contenir la bentonite. Les premiers résultats indiquent un maintien des performances hydrauliques pour certains GSB préhydratés sans confinement. Ce constat n'est pas généralisable à tous les GSB

Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1

AbstractBackground: On the basis of experiments suggesting that Notch and Delta have a role in axonal development in Drosophila neurons, we studied the ability of components of the Notch signaling pathway to modulate neurite formation in mammalian neuroblastoma cells in vitro.Results: We observed that N2a neuroblastoma cells expressing an activated form of Notch, Notch1IC, produced shorter neurites compared with controls, whereas N2a cell lines expressing a dominant-negative Notch1 or a dominant-negative Delta1 construct extended longer neurites with a greater number of primary neurites. We then compared the effects on neurites of contacting Delta1 on another cell and of overexpression of Delta1 in the neurite-extending cell itself. We found that N2a cells co-cultured with Delta1-expressing quail cells produced fewer and shorter neuritic processes. On the other hand, high levels of Delta1 expressed in the N2a cells themselves stimulated neurite extension, increased numbers of primary neurites and induced expression of Jagged1 and Notch1.Conclusions:These studies show that Notch signals can antagonize neurite outgrowth and that repressing endogenous Notch signals enhances neurite outgrowth in neuroblastoma cells. Notch signals therefore act as regulators of neuritic extension in neuroblastoma cells. The response of neuritic processes to Delta1 expressed in the neurite was opposite to that to Delta1 contacted on another cell, however. These results suggest a model in which developing neurons determine their extent of process outgrowth on the basis of the opposing influences on Notch signals of ligands contacted on another cell and ligands expressed in the same cell

Re-using implicit knowledge in short-term information profiles for context-sensitive tasks

Abstract. Typically, case-based recommender systems recommend single items to the on-line customer. In this paper we introduce the idea of recommending a user-defined collection of items where the user has implicitly encoded the relationships between the items. Automated collaborative filtering (ACF), a socalled ‘contentless ’ technique, has been widely used as a recommendation strategy for music items. However, its reliance on a global model of the user’s interests makes it unsuited to catering for the user’s local interests. We consider the context-sensitive task of building a compilation, a user-defined collection of music tracks. In our analysis, a collection is a case that captures a specific shortterm information/music need. In an offline evaluation, we demonstrate how a case-completion strategy that uses short-term representations is significantly more effective than the ACF technique. We then consider the problem of recommending a compilation according to the user’s most recent listening preferences. Using a novel on-line evaluation where two algorithms compete for the user’s attention, we demonstrate how a knowledge-light case-based reasoning strategy successfully addresses this problem.