Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Deformation analysis of a metropolis from C- to X-band PSI: proof-of-concept with Cosmo-Skymed over Rome, Italy

Stability of monuments and subsidence of residential quarters in Rome (Italy) are depicted based on geospatial analysis of more than 310,000 Persistent Scatterers (PS) obtained from Stanford Method for Persistent Scatterers (StaMPS) processing of 32 COSMO-SkyMed 3m-resolution HH StripMap ascending mode scenes acquired between 21 March 2011 and 10 June 2013. COSMO-SkyMed PS densities and associated displacement velocities are compared with almost 20 years of historical C-band ERS- 1/2, ENVISAT and RADARSAT-1/2 imagery. Accounting for differences in image processing algorithms and satellite acquisition geometries, we assess the feasibility of ground motion monitoring in big cities and metropolitan areas by coupling newly acquired and legacy SAR in full time series. Limitations and operational benefits of the transition from medium resolution C-band to high resolution X-band PS data are discussed, alongside the potential impact on the management of expanding urban environments

Polymorphism, genetic exchange and intragenic recombination of the aureolysin gene among Staphylococcus aureus strains

<p>Abstract</p> <p>Background</p> <p><it>Staphylococcus aureus </it>expresses several proteases, which are thought to contribute to the virulence of this bacterium. Here we focus on aureolysin, the major thermolysin-like metalloprotease. Despite the importance of aureolysin in the physiology and pathogenesis of <it>S. aureus</it>, relatively little information was so far available concerning the <it>aur </it>gene diversity and mobility within and between the major subdivisions of the <it>S. aureus </it>population. Therefore, an epidemiologically and genetically diverse collection of <it>S. aureus </it>strains was used to determine the range of aureolysin (<it>aur</it>) gene polymorphism.</p> <p>Results</p> <p>Sequence analyses support the conclusion that the <it>aur </it>gene occurs in two distinct types of related sequences. The <it>aur </it>gene was much more polymorphic but, at the same time, showed higher purifying selection than genes utilized for multilocus sequence typing (MLST). Gene trees constructed from <it>aur </it>and concatenated MLST genes revealed several putative assortative recombination events (<it>i.e</it>. entire <it>aur </it>gene exchanges) between divergent lineages of <it>S. aureus</it>. Evidence for intragenic recombination events (<it>i.e</it>. exchanges of internal <it>aur </it>segments) across <it>aur </it>genes was also found. The biochemical properties and substrate specificity of the two types of aureolysin purified to homogeneity were studied, revealing minor differences in their affinity to low molecular weight synthetic substrates.</p> <p>Conclusion</p> <p>Although numerous nucleotide differences were identified between the <it>aur </it>alleles studied, our findings showed that a strong purifying selection is acting on the <it>aur </it>gene. Moreover, our study distinguishes between homologous exchanges of the entire <it>aur </it>gene (assortative recombination) between divergent <it>S. aureus </it>lineages and recombination events within <it>aur </it>genes.</p

Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models

WCK 771, the arginine salt of S-(−)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC(50)) and the MIC(90) of WCK 771 were 0.03 and 0.03 μg/ml, respectively, and for 198 methicillin-resistant strains the MIC(50) and the MIC(90) were 0.5 and 1.0 μg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 μg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains

The Impact of Teams on Output, Quality, and Downtime: An Empirical Analysis Using Individual Panel Data

The authors use the econometric case study method to investigate the direct impact of offline teams on productivity in a non-unionized subsidiary of a multinational firm from January 1999 through November 2001. They analyze daily data on rejection, production, and downtime rates for both team and non-team-member operators. They hypothesize that team membership without complementary involvement practices is initially sufficient to enhance productivity and quality control. Further, the use of teams leads initially to more downtime, but this cost will diminish over time. Findings indicate that membership in offline teams initially increases individual productivity by about 3% and lowers rejection rates by about 27%. These improvements dissipate, however, typically at a rate of 10 to 16% per 100 days in a team. For these benefits to be sustained, team membership must be complemented with measures that provide extrinsic rewards. The authors also find that the performance-enhancing effects of team membership are generally greater and longer-lasting for more educated members. JEL classification: F23, J24, L60, M11, M12, M5

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies