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BACKGROUND: Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS). METHODS: In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival. RESULTS: Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT. CONCLUSION: This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.

Figure S1. HLA Class I (A) and II (B) expression body map including anatomical substructures. Figure S2. Immunological characterization of brain samples. Figure S3. Locus specific expression of classical HLA class I (A) and class II (B) genes across all examined tissues. Figure S4. Expression body map of the non-classical HLA Class I genes. (A) HLA-E transcripts are ubiquitously expressed in all tissues. Figure S5. Expression of constitutive proteasome versus immunoproteasome normalized with TPM. Figure S6. Correlation analysis of CIITA and HLA expression. Figure S7. Expression of constitutive proteasome, Immunoproteasome and its inducing cytokines. Figure S8. Expression of TAP1, TAP2 and PSMB9. (PPTX 5223Â kb)

Alternative pre-messenger RNA splicing influences development, physiology and disease, but its regulation in humans is not well understood, partially because of the limited scale at which the expression of specific splicing events has been measured. We generated the first genome-scale expression compendium of human alternative splicing events using custom whole-transcript microarrays monitoring expression of 24,426 alternative splicing events in 48 diverse human samples. Over 11,700 genes and 9,500 splicing events were differentially expressed, providing a rich resource for studying splicing regulation. An unbiased, systematic screen of 21,760 4-mer to 7-mer words for cis-regulatory motifs identified 143 RNA 'words' enriched near regulated cassette exons, including six clusters of motifs represented by UCUCU, UGCAUG, UGCU, UGUGU, UUUU and AGGG, which map to trans-acting regulators PTB, Fox, Muscleblind, CELF/CUG-BP, TIA-1 and hnRNP F/H, respectively. Each cluster showed a distinct pattern of genomic location and tissue specificity. For example, UCUCU occurs 110 to 35 nucleotides preceding cassette exons upregulated in brain and striated muscle but depleted in other tissues. UCUCU and UGCAUG seem to have similar function but independent action, occurring 5' and 3', respectively, of 33% of the cassette exons upregulated in skeletal muscle but co-occurring for only 2%.

Winterthur Museum, Garden & Library is committed to lifelong learning in the humanities and to the sustainable preservation of the collections that support this mission. To this end, Winterthur requests a $350,000 NEH SCHC implementation grant as part of an $873,338 project to enhance the preservation of the collections and reduce collection-related energy costs. Installation of a new HVAC control system will effectively manage energy and the preservation environment in Winterthur’s three major collection buildings–the Museum, Galleries, and Research Building. These buildings house one of America’s outstanding collections of decorative arts and research material related to material culture as well as extensive programming, exhibitions, conservation and scientific research facilities, and two graduate programs critical to training cultural heritage professionals.

Virus identification. HBV is expressed in the liver carcinoma cell line PLC/PRF/5. (PPTX 180 kb)

We systematically examined seismic data from deep earthquakes in the western and northwestern Pacific, Tonga/Fiji, and South America for signs of sharp gradients in seismic properties that could represent either a mineralogical phase change or the boundary between geochemical reservoirs in the Earth’s lower mantle.

We inverted 4864 ScS-S and 1671 Sdiff-SKS residual travel times for shear wave speed anomalies at the base of the Earth’s mantle. We applied ellipticity corrections, accounted for mantle structure outside of the basal layer using mantle tomography models, and used finite size sensitivity kernels. The basal layer thickness was set to 290 km; however, the data allow thicknesses between 200 and 500 km. The residuals were inverted using a spherical harmonic basis set of degree 30 for a model that both is smooth and has a small Euclidean norm, which limited spectral leakage of higher-order structures into low-order wavelengths. Hotspots dominantly overlay slow wave speed regions. Nonsightings of ultralow-velocity zones (ULVZs) most frequently appear in fast regions, suggesting that slow regions at the base of the mantle are associated with ULVZs. However, ULVZ sightings appear in both slow and fast regions. Recently active subduction zones do not correlate with velocity anomalies; however, the locations of subduction zones active prior to 90 Ma correlate extremely well with fast anomalies, implying that slabs descend as fast as 2 cm yr⁻¹ through the lower mantle. The correlation continues through the historical subduction record to 180 Ma, suggesting that slabs remain in the deep mantle at least 90 Myr. Fast anomalies reach +2%, while slow anomalies extend to -5%. If we assume that the anomalies are thermal and anharmonic in origin and apply a wave speed/thermal anomaly conversion, the temperature deviations would be over -500°K (cold) in fastest regions and over +1000°K (hot) in the slowest regions, which would initiate plumes much hotter than those observed at the surface. Alternative explanations for the large anomalies are widespread partial melt or compositional differences in the lowermost mantle.

The Earth's core-mantle boundary (CMB) marks the boundary between the hot, molten iron core and the silicate mantle and is a thermal, chemical, and flow boundary. Previous observations of very slow compressional wavespeeds suggest that thin ultra-low-velocity zones (ULVZs), possibly composed of a mixture of molten iron and silicates, exist at the base of the mantle. A molten or partially molten layer would cause a large shear wavespeed decrease; however this velocity drop has not been observed. Here, we use core reflected ScP phases to investigate the shear properties of ULVZs. These phases reveal at least two distinct regions: one region under Central America which is distinctly average (PREM and iasp91-like) and a second region under the entire Gulf of Alaska that produces large ScP reflections with amplitudes of up to 30 times larger than calculated with average Earth models. The large amplitudes suggest a combination of focusing by CMB topography, high shear wavespeeds at the bottom of the mantle, and low attenuation (high Q) along the ScP path; high shear wavespeeds and low attenuation are opposite from what would be expected from a shear wave ULVZ. A ULVZ in compressional wavespeeds (ultra-low Vp) has previously been observed in this region; however, in addition to the large amplitudes, the short-period ScP waveforms show no complexity that can be related to a ULVZ. Thus, either there is not a ULVZ under the Gulf of Alaska or, if it does exist, it is restricted to compressional wavespeed changes, precluding interpretation as partial melt but rather suggesting a chemical origin.

We inverted 4864 ScS-S and 1671 S(diff)-SKS residual travel times for shear wave speed anomalies at the base of the Earth's mantle. We applied ellipticity corrections, accounted for mantle structure outside of the basal layer using mantle tomography models, and employed finite size sensitivity kernels. The basal layer thickness was set to 290 km; however, the data allow thicknesses between 200 and 500 km. The residuals were inverted using a spherical harmonic basis set of degree 30 for a model that both is smooth and has a small Euclidean norm, which limited spectral leakage of higher-order structures into low-order wavelengths. Hotspots dominantly overlay slow wave speed regions. Nonsightings of ultralow-velocity zones (ULVZs) most frequently appear in fast regions, suggesting that slow regions at the base of the mantle are associated with ULVZs. However, ULVZ sightings appear in both slow and fast regions. Recently active subduction zones do not correlate with velocity anomalies; however, the locations of subduction zones active prior to 90 Ma correlate extremely well with fast anomalies, implying that slabs descend as fast as 2 cm /yr through the lower mantle. The correlation continues through the historical subduction record to 180 Ma, suggesting that slabs remain in the deep mantle at least 90 Myr. Fast anomalies reach +2 percent, while slow anomalies extend to -5 percent. If we assume that the anomalies are thermal and anharmonic in origin and apply a wave speed/thermal anomaly conversion, the temperature deviations would be over -500 K (cold) in fastest regions and over +1000 K (hot) in the slowest regions, which would initiate plumes much hotter than those observed at the surface. (Author)

A combination of microarray data with extensive genome annotations resulted in a set of 28,456 experimentally supported transcripts, providing the first experiment-driven annotation of the human genome., Background Computational and microarray-based experimental approaches were used to generate a comprehensive transcript index for the human genome. Oligonucleotide probes designed from approximately 50,000 known and predicted transcript sequences from the human genome were used to survey transcription from a diverse set of 60 tissues and cell lines using ink-jet microarrays. Further, expression activity over at least six conditions was more generally assessed using genomic tiling arrays consisting of probes tiled through a repeat-masked version of the genomic sequence making up chromosomes 20 and 22. Results The combination of microarray data with extensive genome annotations resulted in a set of 28,456 experimentally supported transcripts. This set of high-confidence transcripts represents the first experimentally driven annotation of the human genome. In addition, the results from genomic tiling suggest that a large amount of transcription exists outside of annotated regions of the genome and serves as an example of how this activity could be measured on a genome-wide scale. Conclusions These data represent one of the most comprehensive assessments of transcriptional activity in the human genome and provide an atlas of human gene expression over a unique set of gene predictions. Before the annotation of the human genome is considered complete, however, the previously unannotated transcriptional activity throughout the genome must be fully characterized.

Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and recent developments in MS-based peptide analysis technologies now support the generation of the required data. Importantly, the availability of diverse immunopeptidomic datasets has resulted in an increasing need to standardize, store and exchange this type of data to enable better collaborations among researchers, to advance the field more efficiently and to establish quality measures required for the meaningful comparison of datasets. Here we present the SysteMHC Atlas (https://systemhcatlas.org), a public database that aims at collecting, organizing, sharing, visualizing and exploring immunopeptidomic data generated by MS. The Atlas includes raw mass spectrometer output files collected from several laboratories around the globe, a catalog of context-specific datasets of MHC class I and class II peptides, standardized MHC allele-specific peptide spectral libraries consisting of consensus spectra calculated from repeat measurements of the same peptide sequence, and links to other proteomics and immunology databases. The SysteMHC Atlas project was created and will be further expanded using a uniform and open computational pipeline that controls the quality of peptide identifications and peptide annotations. Thus, the SysteMHC Atlas disseminates quality controlled immunopeptidomic information to the public domain and serves as a community resource toward the generation of a high-quality comprehensive map of the human immunopeptidome and the support of consistent measurement of immunopeptidomic sample cohorts. ISSN:1362-4962 ISSN:0301-5610

Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and recent developments in MS-based peptide analysis technologies now support the generation of the required data. Importantly, the availability of diverse immunopeptidomic datasets has resulted in an increasing need to standardize, store and exchange this type of data to enable better collaborations among researchers, to advance the field more efficiently and to establish quality measures required for the meaningful comparison of datasets. Here we present the SysteMHC Atlas (https://systemhcatlas.org), a public database that aims at collecting, organizing, sharing, visualizing and exploring immunopeptidomic data generated by MS. The Atlas includes raw mass spectrometer output files collected from several laboratories around the globe, a catalog of context-specific datasets of MHC class I and class II peptides, standardized MHC allele-specific peptide spectral libraries consisting of consensus spectra calculated from repeat measurements of the same peptide sequence, and links to other proteomics and immunology databases. The SysteMHC Atlas project was created and will be further expanded using a uniform and open computational pipeline that controls the quality of peptide identifications and peptide annotations. Thus, the SysteMHC Atlas disseminates quality controlled immunopeptidomic information to the public domain and serves as a community resource toward the generation of a high-quality comprehensive map of the human immunopeptidome and the support of consistent measurement of immunopeptidomic sample cohorts., Nucleic Acids Research, 46 (D1), ISSN:1362-4962, ISSN:0301-5610