Introduction: Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context. Our studies shed light on the mechanistic differences that are responsible for NOTCH1's opposing roles in lung adenocarcinoma and lung squamous cell carcinoma. Methods:We integrated transcriptional patient-derived datasets with gene co-expression analyses to elucidate mechanisms behind NOTCH1 function in subsets of NSCLC. Differential co-expression was examined using hierarchical clustering and principal component analysis. Enrichment analysis was used to examine pathways associated with the underlying transcriptional networks. These pathways were validated in vitro and in vivo. Endogenously epitope-tagged NOTCH1 was used to identify novel interacting proteins.Results: NOTCH1 co-expressed genes in lung adenocarcinoma and squamous carcinoma were distinct and associated with either angiogenesis and immune system pathways or cell cycle control and mitosis pathways, respectively. Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown showed growth differences and opposing effects on these pathways. Differential NOTCH1 interacting proteins were identified as potential mediators of these differences.Conclusions: Recognition of the opposing role of NOTCH1 in lung cancer, downstream pathways, and interacting proteins in each context may help direct the development of rational NOTCH1 pathway-dependent targeted therapies for specific tumor subsets of NSCLC.
The microstructure of a series of experimental high chromium, high carbon cast irons was examined by optical and electron microscopy to determine the mechanisms that impart their resistance to wear by impact of reduced iron pellets at 550°C. The samples were cast following an experimental design in which the amount of different carbide forming elements was varied. The microstructure of these alloys was found to consist of a primary network of M 7 C 3 carbides surrounded by an austenitic matrix and eutectic carbides. It was found that the size distribution of the proeutectic primary carbide exerts an in uence on wear, but no correlation was found between the hardness of the different constituents and wear. The experimental results indicate that the alloys cast with the greatest amounts of molybdenum showed the lowest resistance to wear. Scanning electron microscopy of a low wear resistant sample showed evidence of the localisation of molybdenum in proeutectic carbides.MST/5170
Chunky graphite is a particular form of graphite degeneracy that appears in the centre of large iron castings, with a well-defined transition from the outer unaffected area and the inner affected one. All previous works that looked for macrosegration to explain the phenomenon concluded that there are no significant composition differences between the inner and outer parts of such castings. This was challenged again because the analytical methods generally used for chemical analysis are not efficient for low-level elements. Accordingly, an ICP-MS procedure has been developed and validated to replace the usual ICP-OES method. Together with the usual methods for analysis of C, S and Si, this ICP-MS procedure has been applied to characterize chemical heterogeneities in a large block with chunky graphite in its centre, and to a standard part for comparison. It could be concluded that no macrosegregation has built up during the solidification process of the block investigated, i.e. that chunky graphite appearance is not related to any composition changes at the scale of the cast parts, in particular of elements known to affect graphite shape such as Ce, Mg, Sb, S, · · · .KEY WORDS: nodular cast-iron; chunky graphite; chemical analysis; segregation; heavy section. measuring trace elements in small samples being about 0.1 g in weight is thus presented. Measurements of silicon, carbon and sulfur contents were performed with 0.5 g samples following the standard procedures that will be also shortly described for consistency. In the present work, these procedures have been applied to materials coming from the outer part (without CHG) and inner part (with CHG) of a heavy-section block. For purpose of comparison, measurements were also performed on material taken out from a light-section part that was cast with a melt of similar composition. This light-section part showed no CHG and presented a much larger nodule count. Experimental DetailsThe chemical analyses have been performed with three methods: -gravimetric method for silicon; -combustion with a LECO CS-200 facility for carbon and sulfur; -induction coupled plasma-mass spectroscopy (ICP-MS) with an Agilent 7500 CE apparatus for all other elements considered in this study. The first and third methods apply to solutions obtained by dissolving the material in acids having ACS analytical grade, i.e. containing less than 5 ppm metal atoms. These three methods are successively detailed below with more detail for ICP-MS; they all give results per weight percents that are recalculated, either automatically or manually, from the initial masses of material involved for analysis which were weighed on calibrated balances with the following requirements: -silicon analysis: 0.5Ϯ0.005 g; -carbon and sulfur analysis: 0.5Ϯ0.005 g; -trace elements: 0.1Ϯ0.0005 g. Measurement of SiliconSilicon is analysed along a procedure based on the E350 ASTM standard. The method consists in first dissolving the sample in a mixture of HNO 3 (68 mass%) and HCl (38 mass%). Silicic acid H 4 SiO 4 forms i...
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