Abstract
We present a numerical code to simulate maps of Galactic emission in intensity and polarization at microwave frequencies, aiding in the design of cosmic microwave background experiments. ...This python code builds on existing efforts to simulate the sky by providing an easy-to-use interface and is based on publicly available data from the WMAP (Wilkinson Microwave Anisotropy Probe) and Planck satellite missions. We simulate synchrotron, thermal dust, free–free and anomalous microwave emission over the whole sky, in addition to the cosmic microwave background, and include a set of alternative prescriptions for the frequency dependence of each component, for example, polarized dust with multiple temperatures and a decorrelation of the signals with frequency, which introduce complexity that is consistent with current data. We also present a new prescription for adding small-scale realizations of these components at resolutions greater than current all-sky measurements. The usefulness of the code is demonstrated by forecasting the impact of varying foreground complexity on the recovered tensor-to-scalar ratio for the LiteBIRD satellite. The code is available at: https://github.com/bthorne93/PySM_public.
Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes ...are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.
The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.
The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.
BACKGROUNDThe KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently ...bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed, they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance.METHODSHere, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep-RNA and whole-exome sequencing comparing pretreatment, posttreatment, and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition.RESULTSIn addition to decreased KRAS G12C-mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell-intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation, and tumor angiogenesis, and several lines of evidence of immunologic evasion.CONCLUSIONTogether, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling, and diverse remodeling of the tumor microenvironment.FUNDINGRichard and Fran Duley, Jimmy and Kay Mann, the NIH, and the North Carolina Biotechnology Center.
Breast cancer metastasis remains a clinical challenge, even within a single patient across multiple sites of the disease. Genome-wide comparisons of both the DNA and gene expression of primary tumors ...and metastases in multiple patients could help elucidate the underlying mechanisms that cause breast cancer metastasis. To address this issue, we performed DNA exome and RNA sequencing of matched primary tumors and multiple metastases from 16 patients, totaling 83 distinct specimens. We identified tumor-specific drivers by integrating known protein-protein network information with RNA expression and somatic DNA alterations and found that genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases.
ABSTRACT
The intrinsic photometric properties of inner and outer stellar bars within 17 double-barred galaxies are thoroughly studied through a photometric analysis consisting of (i) two-dimensional ...(2D) multicomponent photometric decompositions, and (ii) three-dimensional (3D) statistical deprojections for measuring the thickening of bars, thus retrieving their 3D shape. The results are compared with previous measurements obtained with the widely used analysis of integrated light. Large-scale bars in single- and double-barred systems show similar sizes, and inner bars may be longer than outer bars in different galaxies. We find two distinct groups of inner bars attending to their in-plane length and ellipticity, resulting in a bimodal behaviour for the inner/outer bar length ratio. Such bimodality is related neither to the properties of the host galaxy nor the dominant bulge, and it does not show a counterpart in the dimension off the disc plane. The group of long inner bars lays at the lower end of the outer bar length versus ellipticity correlation, whereas the short inner bars are out of that relation. We suggest that this behaviour could be due to either a different nature of the inner discs from which the inner bars are dynamically formed or a different assembly stage for the inner bars. This last possibility would imply that the dynamical assembly of inner bars is a slow process taking several Gyr to happen. We have also explored whether all large-scale bars are prone to develop an inner bar at some stage of their lives, possibility we cannot fully confirm or discard.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and ...prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease.
We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval CI 1.7-10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group.
Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets. Please see later in the article for the Editors' Summary.
Background and Aims
Epstein-Barr virus (EBV) is present in the malignant epithelial cells of 10% of all gastric adenocarcinomas; however, localization of the virus in normal gastrointestinal mucosa ...is largely unexplored. In the present study, we measured EBV DNA and localized viral gene products in gastritis specimens (
n
= 89), normal gastric and colonic mucosa (
n
= 14), Crohn’s disease (
n
= 9), and ulcerative colitis (
n
= 11) tissues.
Methods
A battery of sensitive and specific quantitative polymerase chain reactions targeted six disparate regions of the EBV genome:
BamH1
W, EBNA1, LMP1, LMP2, BZLF1,
and
EBER1
. EBV infection was localized by
EBV
-
encoded RNA
(
EBER
) in situ hybridization and by immunohistochemical stains for viral latent proteins LMP1 and LMP2 and for viral lytic proteins BMRF1 and BZLF1. B lymphocytes were identified using CD20 immunostains.
Results
EBV DNA was essentially undetectable in normal gastric mucosa but was present in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn’s disease, and 64% of ulcerative colitis samples. Levels of EBV DNA exceeded what would be expected based on the numbers of B lymphocytes in inflamed tissues, suggesting that EBV is preferentially localized to inflammatory gastrointestinal lesions. Histochemical staining revealed
EBER
expression in lymphoid cells of some PCR-positive lesions. The viral lytic viral proteins, BMRF1 and BZLF1, were expressed in lymphoid cells of two ulcerative colitis tissues, both of which had relatively high viral loads by quantitative PCR.
Conclusion
EBV-infected lymphocytes are frequently present in inflamed gastric and colonic mucosa. Active viral replication in some lesions raises the possibility of virus-related perpetuation of gastrointestinal inflammation.
Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with ...additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium.
Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression.
Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%).
Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.
Soil-applied liquid termiticides are the most common control measure for subterranean termites. Characteristics unique to insecticidal chemistries such as repellency, toxicity, and time between ...contact and mortality, influence the interaction of termites with treated soil and overall treatment success. Two different treated-tunnel bioassays were used to evaluate the behavioral impacts and mortality of termites from treatment with chlorantraniliprole (the active ingredient in Altriset® termiticide) to existing, mature tunnels. Termites that were provided constant access to a 10-cm-long mature tunnel within soil treated with 5 or 50 ppm chlorantraniliprole were not repelled by the treatment and began exhibiting slower, uncoordinated movement, and cessation of tunneling and feeding in as little as 1 h after access. Termites provided access for 7, 14, or 21 d to previously constructed tunnels recently treated with 50 ppm chlorantraniliprole exhibited complete or near complete mortality by 28 d. The second bioassay design resembled a more typical field situation with a 40-cm-long mature tunnel and termites allowed access for a maximum of 5 min. Termites collected after just 5 min of access to the previously constructed tunnels recently treated with 50 ppm chlorantraniliprole exhibited similar symptomology within an hour followed by complete mortality at 18 d after exposure. These test designs simulate what occurs in the soil around an infested structure at the time of treatment. Results from these evaluations suggest that termites readily crawl through chlorantraniliprole-treated mature tunnels, rapidly lose ability to feed, and acquire a lethal dose from brief exposures.
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