Characterization and quantitative trait loci (QTL) analysis for wheat stem sawfly (Hymenoptera: Cephidae) resistance in winter wheat

2020 Fall.Includes bibliographical references.The wheat stem sawfly (Cephus cinctus) (WSS) has quickly become a major pest of Colorado wheat production over the past ten years. Prior resistant cultivars have relied on the expression of a solid-stemmed trait (Qss.msub-3BL) to decrease damage from sawfly infestations, however environmental factors (sun, rain, etc.) may result in inconsistent pith expression. The limitations of solid-stemmed varieties have aided in the recent identification of novel quantitative trait loci (QTL) for reducing WSS infestation and stem cutting by host-plant preference. In this light, crosses between 'Denali'/'Hatcher' and 'Avery'/'CO11D1397' were completed in the greenhouse during Fall 2014 and Spring 2015 to create two doubled haploid (DH) populations for discovery of QTL associated with non solid-stemmed resistance. Each population was grown under naturally occurring sawfly pressure at two different northeastern Colorado locations during the 2018-19 field season, however only the Avery/CO11D1397 population was selected for planting in the 2019-20 field season due to resource limitations. Entries were evaluated for plant height, heading date, physiological maturity, cutting score, and kernel weight. Next generation sequencing data were generated through genotyping-by-sequencing and resulted in 776 single-nucleotide polymorphisms (SNP) markers in the final genetic map for Avery/CO11D1397. Quantitative trait loci analysis identified a total of 11 QTL, seven major-effect and four minor-effect, in the Avery/CO11D1397 DH population for reduced WSS cutting in multiple environments. Two QTL were associated on the same chromosomal arms as photoperiod genes Ppd-D1 (Qwss.csu-2DS) and Ppd-B1 (Qwss.csu-2BS). The Qwss.csu-1BL was also associated on the long arm of chromosome 1B with the earliness per se gene Eps-B1. Qwss.csu-7DS and Qwss.csu-5BS were the only two major-effect QTL identified that were not associated with major developmental genes, and thus could be associated with antixenosis. Results from this study suggest that a relationship between lower cutting score and a later flowering date exists for genotypes within the Avery/CO11D1397 DH population. Introgression of Qwss.csu-7DS and Qwss.csu-5BS into cultivars with stem-solidness may help in developing new wheat varieties with durable WSS resistance

The Immune Microenvironment of Microsatellite Instable Endometrial Cancer

Limited treatment options are available for patients with advanced and recurrent endometrial cancer (EC) should standard chemotherapy fail. Recent studies in other tumor types have shown that tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy treatments compared to microsatellite stable (MSS) tumors. Patients with MSI-H EC may also benefit from these therapies; however, the tumor immune microenvironment in MSI-H EC has not yet been well described. In order to evaluate the immune microenvironment of MSI-H EC, multiple approaches were used, including analysis of large publically available datasets and detailed characterization of patient tumor samples. Uterine cancer data from The Cancer Genome Atlas (TCGA) was used to study immune-related gene expression in MSI-H EC compared to MSS EC at both the individual gene and pathway level. Fluorescent multiplexing immunohistochemistry (IHC) was used to evaluate differences in immune cell populations using tumor specimens from these two groups followed by automated multispectral imaging and analysis to visualize and quantify staining in the tumor epithelial and stromal compartments. Nonparametric Mann-Whitney test was used to determine statistical significance (p value Overall, MSI-H EC demonstrated increased immune activation compared to MSS EC. Using TCGA data, MSI-H (n=118) EC showed overall activation of the granzyme B signaling pathway compared to MSS (n=160) EC (p +cells (114.9 cells/mm2 vs 75.8 cells/mm2; p2 vs 28.0 cells/mm2; p+ cells (291.6 cells/mm2 vs 240.5 cells/mm2; p+ and activated cytotoxic T cells was also increased in the tumor epithelial compartment of MSI-H compared to MSS ECs. There was no difference in the other markers evaluated. In conclusion, the immune microenvironment differs in MSI-H ECs with increased tumor immunogenicity compared to MSS tumors. Elevated PD-L1 expression also suggests immune response inhibition in these tumors, and patients with this subset of tumors are likely candidates for immune checkpoint blocking agents

Survival Disparities in Non-Small Cell Lung Cancer Patients Receiving Radiation Treatment: An Investigation of Race and Gender

Multiple studies evaluating non-small cell lung cancer disparities reveal male gender and African American race as independent predictors for poorer outcome. This study aims to evaluate the prognostic factors affecting survival of non-small cell lung cancer patients receiving radiation treatment at the University of Washington and to investigate whether race and gender disparities persist at the level of access to radiation treatment. Race, age, stage at presentation, radiation treatment length, and length of time from initial diagnosis to death or last follow-up were recorded and analyzed in a retrospective review of 372 patients receiving radiation treatment from 1994 - 2008. Of a final 372 patients, 306 were Caucasian, 32 African American, 34 Asian American and 134 female, 238 male patients. Cox regression models showed male gender [hazard ratio (HR, 1.34) p-value 0.027] and stage at presentation [stage III: HR, 1.93, p-value .001, stage IV: HR, 2.46, P value \u3c 0.001] were predictors for shorter survival. In these analyses, race had no significant effect on length of survival. These results suggest disparate origins of race and gender inequity in non-small cell lung cancer outcome, highlighting that race differences in lung cancer survival disappear at the level patients have access to radiation treatment. This supports the notion that gender survival differences are likely the result of biologic differences, while racial survival disparities are an issue of healthcare access- however, additional studies are needed to conclusively discern the etiology of these disparities

PD-L1 Expression in Endometrial Carcinoma Cells and Intratumoral Immune Cells Differences Across Histologic and TCGA-based Molecular Subgroups

Programmed death-ligand 1 (PD-L1) is a biomarker that may predict the response to anti-programmed death 1/PD-L1 immunotherapy. We evaluated the expression of PD-L1 in carcinoma cells (Ca) and immune cells (ICs) across histopathologic and The Cancer Genome Atlas (TCGA) molecular subgroups of endometrial carcinoma (EC). Our study included 842 patients with EC. Direct sequencing of polymerase epsilon (POLE) exonuclease domain hot spots and conventional immunohistochemistry (MLH1, PMS2, MSH2, MSH6, p53) were conducted to identify TCGA classification-based molecular subgroups of EC: POLE-mutated, mismatch repair deficient, no specific molecular profile, and p53 aberrant. Multiplex immunohistochemistry was performed to evaluate PD-L1 expression in Ca and tumor-infiltrating ICs. PD-L1 expression in Ca and in ICs was detected in 8.6% and 27.7% of the cases, respectively. A combined positive score (CPS) was >= 1% in 19.4% of the samples. PD-L1 positivity in Ca and ICs, and CPS correlated with tumor T-cell density (P= 1% (P=0.037) positivity compared with early disease. In conclusion, PD-L1 expression profiles differ between molecular subclasses, histologic subtypes, and disease stage of EC. Prospective studies are needed to explore the predictive value of various PD-L1 scoring systems within the subgroups of EC. CPS presents methodological advantages over cell type-specific scoring systems.Peer reviewe