Standardized versus research-based PAM50 intrinsic subtyping of breast cancer

To date, there is only one standardized assay for identification of the so-called intrinsic molecular subtypes of breast cancer (i.e., Luminal A, Luminal B, HER2-enriched, and Basal-like) described by Perou et al. This assay uses the nCounter technology, has been CE Marked, and is commercially available worldwide. Over the years, however, several research-based methods for subtype identification have been reported. However, none of them is standardized and, in most cases, proper controls or data to suggest that the method is accurate and precise compared to the standardized and clinically validated nCounter-based PAM50 assay are missing. This is worrisome, since important conclusions regarding the prognostic or predictive value of the PAM50 subtypes are being drawn from “homebrew” research-based PAM50 versions often run on different technologies

Acceleration of the universe, vacuum metamorphosis, and the large-time asymptotic form of the heat kernel

We investigate the possibility that the late acceleration observed in the rate of expansion of the universe is due to vacuum quantum effects arising in curved spacetime. The theoretical basis of the vacuum cold dark matter (VCDM), or vacuum metamorphosis, cosmological model of Parker and Raval is revisited and improved. We show, by means of a manifestly nonperturbative approach, how the infrared behavior of the propagator (related to the large-time asymptotic form of the heat kernel) of a free scalar field in curved spacetime causes the vacuum expectation value of its energy-momentum tensor to exhibit a resonance effect when the scalar curvature R of the spacetime reaches a particular value related to the mass of the field. we show that the back reaction caused by this resonance drives the universe through a transition to an accelerating expansion phase, very much in the same way as originally proposed by Parker and Raval. Our analysis includes higher derivatives that were neglected in the earlier analysis, and takes into account the possible runaway solutions that can follow from these higher-derivative terms. We find that the runaway solutions do not occur if the universe was described by the usual classical FRW solution prior to the growth of vacuum energy-density and negative pressure (i.e., vacuum metamorphosis) that causes the transition to an accelerating expansion of the universe in this theory.Comment: 33 pages, 3 figures. Submitted to Physical Review D15 (Dec 23, 2003). v2: 1 reference added. No other change

Investigation of stratiform sulphide mineralisation at Meall Mor, South Knapdale, Argyll

A co-ordinated geochemical-geophysical-geological investigation of copper mineralisation in the Meal1 ?46r area, South Knapdale, Argyll was carried 0th in 1976 and followed by a drilling programme of 3 shallow holes in early 1977. The mineralisation occursin a zone of weak stratiform sulphide mineralisation (the pyrite zone) with a strike length of 1Okm in the Upper &ins Quartz&e of the Middle Dalradian. The geochemical drainage survey showed the existence of a strongly anomalous distribution of Cu and Sb in the Abhainn Srathain draining south from . Meal1 M&- and detailed soil sampling over the pyrite zone outlined a broad area enriched in copper. Deeper soil sampling confirmed the anomalously high copper values and a coincident IP anomaly was found stretching from Meal1 M& south to the old mine workings on Abhainn Srathain, and is probably caused by a local enrichment of pyrite and chalcopyrite within the pyrite zone. Three boreholes were drilled; two on coincident geochemical and geophysical anomalies, and the third beneath the old mines at Abhainn Srathain. Copper values in the first two holes range up to 0.24% Cu over 4.27m, but up to 1.06% Cu over 2.67m in the third and this enrichment may be related to a later remobilisation of the disseminated chalcopyrite. The results of subsequent drilling at two other sites are given in Appendix III

The Established and Evolving Role of Nailfold Capillaroscopy in Connective-Tissue Disease

Nailfold capillaroscopy (NFC) is a low-cost, non-invasive, rapid, highly specific and reproducible investigation well established in the diagnosis of systemic sclerosis and related conditions. This chapter will detail the relevant underlying scientific principles that underpin the investigation, the methods for performing NFC, the range of abnormalities that can be present and the currently available classification criteria before moving on to discuss the various established and emerging applications as relevant to the connective tissue diseases. In addition to its role in the diagnosis of SSc, highlighted by its inclusion in the most recent ACR/EULAR consensus classification criteria, NFC has been shown to predict disease activity, many organ-specific complications such as digital ulcers, pulmonary hypertension and interstitial lung disease, and even mortality. It is emerging as a useful investigation in other CTDs characterised by microvasculopathy, such as in the idiopathic inflammatory myopathies and mixed connective tissue disease, as well as being studied as a serial investigation in patients to act as a potential biomarker and measure of treatment efficacy. NFC can contribute to the earlier identification of patients with CTDs with clinically important complications and if applied accurately, therefore, can help improve outcomes in these often challenging diseases

Improved indel detection in DNA and RNA via realignment with ABRA2

Motivation: Genomic variant detection from next-generation sequencing has become established as an extremely important component of research and clinical diagnoses in both cancer and Mendelian disorders. Insertions and deletions (indels) are a common source of variation and can frequently impact functionality, thus making their detection vitally important. While substantial effort has gone into detecting indels from DNA, there is still opportunity for improvement. Further, detection of indels from RNA-Seq data has largely been an afterthought and offers another critical area for variant detection. Results: We present here ABRA2, a redesign of the original ABRA implementation that offers support for realignment of both RNA and DNA short reads. The process results in improved accuracy and scalability including support for human whole genomes. Results demonstrate substantial improvement in indel detection for a variety of data types, including those that were not previously supported by ABRA. Further, ABRA2 results in broad improvements to variant calling accuracy across a wide range of post-processing workflows including whole genomes, targeted exomes and transcriptome sequencing

Combined EEG-fMRI and tractography to visualise propagation of epileptic activity

In a patient with refractory temporal lobe epilepsy, EEG-fMRI showed activation in association with left anterior temporal interictal discharges, in the left temporal, parietal and occipital lobes. Dynamic causal modelling suggested propagation of neural activity from the temporal focus to the area of occipital activation. Tractography showed connections from the site of temporal lobe activation to the site of occipital activation. This demonstrates the principle of combining EEG-fMRI and tractography to delineate the pathways of propagation of epileptic activity

Tn-Seq Analysis Identifies Genes Important for Yersinia pestis Adherence during Primary Pneumonic Plague

Following inhalation, Yersinia pestis rapidly colonizes the lung to establish infection during primary pneumonic plague. Although several adhesins have been identified in Yersinia spp., the factors mediating early Y. pestis adherence in the lung remain unknown. To identify genes important for Y. pestis adherence during primary pneumonic plague, we used transposon insertion sequencing (Tn-seq). Wild-type and capsule mutant (Δcaf1) Y. pestis transposon mutant libraries were serially passaged in vivo to enrich for nonadherent mutants in the lung using a mouse model of primary pneumonic plague. Sequencing of the passaged libraries revealed six mutants that were significantly enriched in both the wild-type and Δcaf1 Y. pestis backgrounds. The enriched mutants had insertions in genes that encode transcriptional regulators, chaperones, an endoribonuclease, and YPO3903, a hypothetical protein. Using single-strain infections and a transcriptional analysis, we identified a significant role for YPO3903 in Y. pestis adherence in the lung and showed that YPO3903 regulated transcript levels of psaA, which encodes a fimbria previously implicated in Y. pestis adherence in vitro. Deletion of psaA had a minor effect on Y. pes-tis adherence in the lung, suggesting that YPO3903 regulates other adhesins in addition to psaA. By enriching for mutations in genes that regulate the expression or assembly of multiple genes or proteins, we obtained screen results indicating that there may be not just one dominant adhesin but rather several factors that contribute to early Y. pestis adherence during primary pneumonic plague

Meta-analysis of airway epithelium gene expression in asthma

Differential gene expression in the airway epithelium of patients with asthma versus controls has been reported in several studies. However, there is no consensus on which genes are reproducibly affected in asthma. We sought to identify a consensus list of differentially expressed genes (DEGs) using a meta-analysis approach. We identified eight studies with data that met defined inclusion criteria. These studies comprised 355 cases and 193 controls and involved sampling either bronchial or nasal epithelium. We conducted study-level analyses, followed by a meta-analysis. Likewise, we applied a meta-analysis framework to the results of study-level pathway enrichment. We identified 1273 DEGs, 431 of which had not been identified in previous studies. 450 DEGs exhibited large effect sizes and were robust to study population differences in age, sex, race/ethnicity, medication use, smoking status and exacerbations. The magnitude of differential expression of these 450 genes was highly similar in bronchial and nasal airway epithelia. Meta-analysis of pathway enrichment revealed a number of consistently dysregulated biological pathways, including putative transcriptional and post-transcriptional regulators. In total, we identified a set of genes that is consistently dysregulated in asthma, that links to known and novel biological pathways, and that will inform asthma subtype identification

Genetic determinants of the molecular portraits of epithelial cancers

The ability to characterize and predict tumor phenotypes is crucial to precision medicine. In this study, we present an integrative computational approach using a genome-wide association analysis and an Elastic Net prediction method to analyze the relationship between DNA copy number alterations and an archive of gene expression signatures. Across breast cancers, we are able to quantitatively predict many gene signatures levels within individual tumors with high accuracy based upon DNA copy number features alone, including proliferation status and Estrogen-signaling pathway activity. We can also predict many other key phenotypes, including intrinsic molecular subtypes, estrogen receptor status, and TP53 mutation. This approach is also applied to TCGA Pan-Cancer, which identify repeatedly predictable signatures across tumor types including immune features in lung squamous and basal-like breast cancers. These Elastic Net DNA predictors could also be called from DNA-based gene panels, thus facilitating their use as biomarkers to guide therapeutic decision making

Epstein-Barr Virus-Positive Cancers Show Altered B-Cell Clonality

Epstein-Barr virus (EBV) is convincingly associated with gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. To test the hypothesis that there are additional cancer types with high prevalence of EBV, we determined EBV viral expression in all the Cancer Genome Atlas Project (TCGA) mRNA sequencing (mRNA-seq) samples (n 10,396) from 32 different tumor types. We found that EBV was present in gastric adenocarcinoma and lymphoma, as expected, and was also present in 5% of samples in 10 additional tumor types. For most samples, EBV transcript levels were low, which suggests that EBV was likely present due to infected infiltrating B cells. In order to determine if there was a difference in the B-cell populations, we assembled B-cell receptors for each sample and found B-cell receptor abundance (P 1.4 1020) and diversity (P 8.3 1027) were significantly higher in EBV-positive samples. Moreover, diversity was independent of B-cell abundance, suggesting that the presence of EBV was associated with an increased and altered B-cell population. IMPORTANCE Around 20% of human cancers are associated with viruses. Epstein-Barr virus (EBV) contributes to gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. We assessed the prevalence of EBV in RNA-seq from 32 tumor types in the Cancer Genome Atlas Project (TCGA) and found EBV to be present in 5% of samples in 12 tumor types. EBV infects epithelial cells and B cells and in B cells causes proliferation. We hypothesized that the low expression of EBV in most of the tumor types was due to infiltration of B cells into the tumor. The increase in B-cell abundance and diversity in subjects where EBV was detected in the tumors strengthens this hypothesis. Overall, we found that EBV was associated with an increased and altered immune response. This result is not evidence of causality, but a potential novel biomarker for tumor immune status