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Transcriptomic features of T cell-barren tumors are conserved across diverse tumor types
No full textFrontiers in Immunology, Volume 11, 13 February 2020, Article number 57.Background: Understanding how tumors subvert immune destruction is essential to the development of cancer immunotherapies. New evidence suggests that tumors limit anti-tumor immunity by exploiting transcriptional programs that regulate intratumoral trafficking and accumulation of effector cells. Here, we investigated the gene expression profiles that distinguish immunologically “cold” and “hot” tumors across diverse tumor types. Methods: RNAseq profiles of tumors (n = 8,920) representing 23 solid tumor types were analyzed using immune gene signatures that quantify CD8+ T cell abundance. Genes and pathways associated with a low CD8+ T cell infiltration profile (CD8-Low) were identified by correlation, differential expression, and statistical ranking methods. Gene subsets were evaluated in immunotherapy treatment cohorts and functionally characterized in cell lines and mouse tumor models. Results: Among different cancer types, we observed highly significant overlap of genes enriched in CD8-Low tumors, which included known immunomodulatory genes (e.g., BMP7, CMTM4, KDM5B, RCOR2) and exhibited significant associations with Wnt signaling, neurogenesis, cell-cell junctions, lipid biosynthesis, epidermal development, and cancer-testis antigens. Analysis of mutually exclusive gene clusters demonstrated that different transcriptional programs may converge on the T cell-cold phenotype as well as predict for response and survival of patients to Nivo treatment. Furthermore, we confirmed that a top-ranking candidate belonging to the TGF-β superfamily, BMP7, negatively regulates CD8+ T cell abundance in immunocompetent murine tumor models, with and without anti-PD-L1 treatment. Conclusions: This study presents the first evidence that solid tumors of diverse anatomical origin acquire conserved transcriptional alterations that may be operative in the T cell-cold state. Our findings demonstrate the potential clinical utility of CD8-Low tumor-associated genes for predicting patient immunotherapy outcomes and point to novel mechanisms with potential for broad therapeutic exploitation
Incorporating uncertainty into USDA commodity price forecasts
No full textAmerican Journal of Agricultural Economics, Volume 102, Issue 2, 1 March 2020, Pages 696-712.From 1977 through April 2019, USDA published monthly season-average price (SAP) forecasts for key agricultural commodities in the form of intervals meant to indicate forecasters' uncertainty but without attaching a confidence level. In May 2019, USDA eliminated the intervals and began publishing a single point estimate—a value that has a very low probability of being realized. We demonstrate how a density forecasting format can improve the usefulness of USDA price forecasts and explain how such a methodology can be implemented. We simulate 21 years of out-of-sample density-based SAP forecasts using historical data, with forward-looking, backward-looking, and composite methods, and we evaluate them based on commonly-accepted criteria. Each of these approaches would offer USDA the ability to portray richer and more accurate price forecasts than its old intervals or its current single point estimates. Backward-looking methods require little data and provide significant improvements. For commodities with active derivatives markets, option-implied volatilities (IVs) can be used to generate forward-looking and composite models that reflect (and adjust dynamically to) market sentiment about uncertainty—a feature that is not possible using backward-looking data alone. At certain forecast steps, a composite method that combines forward- and backward-looking information provides useful information regarding farm-level prices beyond that contained in IVs
Programmed genome rearrangements in Oxytricha produce transcriptionally active extrachromosomal circular DNA
No full textNucleic acids research, Volume 47, Issue 18, 10 October 2019, Pages 9741-9760.Extrachromosomal circular DNA (eccDNA) is both a driver of eukaryotic genome instability and a product of programmed genome rearrangements, but its extent had not been surveyed in Oxytricha, a ciliate with elaborate DNA elimination and translocation during development. Here, we captured rearrangement-specific circular DNA molecules across the genome to gain insight into its processes of programmed genome rearrangement. We recovered thousands of circularly excised Tc1/mariner-type transposable elements and high confidence non-repetitive germline-limited loci. We verified their bona fide circular topology using circular DNA deep-sequencing, 2D gel electrophoresis and inverse polymerase chain reaction. In contrast to the precise circular excision of transposable elements, we report widespread heterogeneity in the circular excision of non-repetitive germline-limited loci. We also demonstrate that circular DNAs are transcribed in Oxytricha, producing rearrangement-specific long non-coding RNAs. The programmed formation of thousands of eccDNA molecules makes Oxytricha a model system for studying nucleic acid topology. It also suggests involvement of eccDNA in programmed genome rearrangement
Temporarily closed stores at Hechinger Mall
No full textTemporarily closed sign at Hechinger Mall on Benning Road NE
Protecting children against torture in detention: global solutions for a global problem
No full textThis edited volume brings together contributions by more than 30 international children’s rights experts in response to former UN's thematic report on torture of children deprived of liberty
Newlywed couple wearing face masks
No full textNewlywed couple wearing face masks sits on front steps outside of their house in Bloomingdale
Exterior view of Amazing Love Health Services
No full textExterior view of Amazing Love Health Services on 15th Street NE. A sign hangs on one door and another door is propped open