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

Virus expression detection reveals RNA-sequencing contamination in TCGA

Background: Contamination of reagents and cross contamination across samples is a long-recognized issue in molecular biology laboratories. While often innocuous, contamination can lead to inaccurate results. Cantalupo et al., for example, found HeLa-derived human papillomavirus 18 (H-HPV18) in several of The Cancer Genome Atlas (TCGA) RNA-sequencing samples. This work motivated us to assess a greater number of samples and determine the origin of possible contaminations using viral sequences. To detect viruses with high specificity, we developed the publicly available workflow, VirDetect, that detects virus and laboratory vector sequences in RNA-seq samples. We applied VirDetect to 9143 RNA-seq samples sequenced at one TCGA sequencing center (28/33 cancer types) over 5 years. Results: We confirmed that H-HPV18 was present in many samples and determined that viral transcripts from H-HPV18 significantly co-occurred with those from xenotropic mouse leukemia virus-related virus (XMRV). Using laboratory metadata and viral transcription, we determined that the likely contaminant was a pool of cell lines known as the "common reference", which was sequenced alongside TCGA RNA-seq samples as a control to monitor quality across technology transitions (i.e. microarray to GAII to HiSeq), and to link RNA-seq to previous generation microarrays that standardly used the "common reference". One of the cell lines in the pool was a laboratory isolate of MCF-7, which we discovered was infected with XMRV; another constituent of the pool was likely HeLa cells. Conclusions: Altogether, this indicates a multi-step contamination process. First, MCF-7 was infected with an XMRV. Second, this infected cell line was added to a pool of cell lines, which contained HeLa. Finally, RNA from this pool of cell lines contaminated several TCGA tumor samples most-likely during library construction. Thus, these human tumors with H-HPV or XMRV reads were likely not infected with H-HPV 18 or XMRV

Prognostic value of B cells in cutaneous melanoma

Background: Measures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and predictive value in skin cutaneous melanoma (SKCM). Less is known about the significance of tumor-infiltrating B cells in SKCM. Our goal was to understand the prognostic and predictive value of B cell phenotypic subsets in SKCM using RNA sequencing. Methods: We used our previously published algorithm, V'DJer, to assemble B cell receptor (BCR) repertoires and estimate diversity from short-read RNA sequencing (RNA-seq). We applied machine learning-based cellular phenotype classifiers to measure relative similarity of bulk tumor sample gene expression profiles and different B cell phenotypes. We assessed these aspects of B cell biology in 473 SKCM from the Cancer Genome Atlas Project (TCGA) as well as in RNA-seq data corresponding to tumor samples procured from patients who received CTLA-4 and PD-1 inhibitors for metastatic SKCM. Results: We found that the BCR repertoire was associated with different clinical factors, such as tumor tissue site and sex. However, increased clonality of the BCR repertoire was favorably prognostic in SKCM and was prognostic even after first conditioning on various clinical factors. Mutation burden was not correlated with any BCR measurement, and no specific mutation had an altered BCR repertoire. Lack of an assembled BCR in pre-treatment tumor tissues was associated with a lack of anti-tumor response to a CTLA-4 inhibitor in metastatic SKCM. Conclusions: These findings suggest an important prognostic and predictive role for B cell characteristics in SKCM. This has implications for melanoma immunobiology and potential development of immunogenomics features to predict survival and response to immunotherapy

Ponderomotive entangling of atomic motions

We propose the use of ponderomotive forces to entangle the motions of different atoms. Two situations are analyzed: one where the atoms belong to the same optical cavity and interact with the same radiation field mode; the other where each atom is placed in own optical cavity and the output field of one cavity enters the other.Comment: Revtex file, five pages, two eps figure

Back reaction in the formation of a straight cosmic string

A simple model for the formation of a straight cosmic string, wiggly or unperturbed is considered. The gravitational field of such string is computed in the linear approximation. The vacuum expectation value of the stress tensor of a massless scalar quantum field coupled to the string gravitational field is computed to the one loop order. Finally, the back-reaction effect on the gravitational field of the string is obtained by solving perturbatively the semiclassical Einstein's equations.Comment: 29 pages, LaTeX, no figures. A postcript version can be obtained from anonymous ftp at ftp://ftp.ifae.es/preprint.f

B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors

Localized D-dimensional global k-defects

We explicitly demonstrate the existence of static global defect solutions of arbitrary dimensionality whose energy does not diverge at spatial infinity, by considering maximally symmetric solutions described by an action with non-standard kinetic terms in a D+1 dimensional Minkowski space-time. We analytically determine the defect profile both at small and large distances from the defect centre. We verify the stability of such solutions and discuss possible implications of our findings, in particular for dark matter and charge fractionalization in graphene.Comment: 6 pages, published versio

On-disk coronal rain

Small and elongated, cool and dense blob-like structures are being reported with high resolution telescopes in physically different regions throughout the solar atmosphere. Their detection and the understanding of their formation, morphology and thermodynamical characteristics can provide important information on their hosting environment, especially concerning the magnetic field, whose understanding constitutes a major problem in solar physics. An example of such blobs is coronal rain, a phenomenon of thermal non- equilibrium observed in active region loops, which consists of cool and dense chromospheric blobs falling along loop-like paths from coronal heights. So far, only off-limb coronal rain has been observed and few reports on the phenomenon exist. In the present work, several datasets of on-disk H{\alpha} observations with the CRisp Imaging SpectroPolarimeter (CRISP) at the Swedish 1-m Solar Telescope (SST) are analyzed. A special family of on-disk blobs is selected for each dataset and a statistical analysis is carried out on their dynamics, morphology and temperatures. All characteristics present distributions which are very similar to reported coronal rain statistics. We discuss possible interpretations considering other similar blob-like structures reported so far and show that a coronal rain interpretation is the most likely one. Their chromospheric nature and the projection effects (which eliminate all direct possibility of height estimation) on one side, and their small sizes, fast dynamics, and especially, their faint character (offering low contrast with the background intensity) on the other side, are found as the main causes for the absence until now of the detection of this on-disk coronal rain counterpart.Comment: 18 pages, 10 figures. Accepted for Solar Physic

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4- induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification