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Jun 2017 • 3D Image Acquisition and Display: Technology, Perception and Applications …, 2017

ChromaBlur: Rendering Chromatic Eye Aberration Improves Accommodation and Realism in HMDs

Martin S Banks, Steven A Cholewiak, Gordon D Love, Pratul Srinivasan, Ren Ng

We developed a rendering method that takes into account the eye’s chromatic aberration. Accommodation is driven much more accurately with this method than with conventional methods. Perceived realism is also improved.

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May 2017 • Science signaling

Genome-wide identification and characterization of Notch transcription complex–binding sequence-paired sites in leukemia cells

Eric Severson, Kelly L Arnett, Hongfang Wang, Chongzhi Zang, Len Taing, Hudan Liu, Warren S Pear, X Shirley Liu, Stephen C Blacklow, Jon C Aster

Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer–binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and have been linked to the Notch responsiveness of a few genes. To assess the overall contribution of SPSs to Notch-dependent gene regulation, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay and applied insights from these in vitro studies to Notch-“addicted” T cell acute lymphoblastic leukemia (T-ALL) cells. We found that SPSs contributed to the regulation of about a third of direct Notch target genes. Although originally described in promoters, SPSs are present mainly in long-range enhancers, including an enhancer containing a newly described SPS that regulates HES5 expression. Our …

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May 2017

Integrative analysis and refined design of CRISPR knockout screens

Chen-Hao Chen

Genome-wide CRISPR-Cas9 screen has been widely used to interrogate gene functions. However, the analysis remains challenging and rules to design better libraries beg further refinement. Here we present MAGeCK-NEST, which integrates protein-protein interaction (PPI) and improves the inference accuracy when fewer guide-RNAs (sgRNAs) are available. MAGeCK-NEST also adopts a maximum-likelihood approach to remove sgRNA outliers, which are characterized with higher G-nucleotide counts, especially in regions distal from the PAM motif. Noticing that various replication cycles affect knockout effects, we further normalized MAGeCK-NEST output considering cell replication cycles. Normalized CRISPR-Cas9 screens using different libraries can thus be integrated as a ‘reference’, from which condition-specific hits could be derived. Moreover, we found that choosing non-targeting sgRNAs as negative controls lead to strong bias, which can be mitigated by sgRNAs targeting “safe harbor”, a region of the genome that is considered to be both transcriptionally active and its disruption does not lead to discernable phenotypic effects. Custom-designed screens confirmed our findings, and further revealed that 19nt sgRNAs consistently gave the best signal-to-noise separation. These methods and characterizations enabled development of an improved genome-wide CRISPR screen library and application in dissecting the mechanism of methyltransferase EZH2 inhibitors. Pharmacological inhibition of EZH2 preferentially suppresses the growth of lymphoma cells with activating mutations in EZH2 that augment PRC2-dependent silencing …

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Feb 2017 • Cancer Causes & Control 28 (2), 167-176, 2017

Proceedings of the third international molecular pathological epidemiology (MPE) meeting

Peter T Campbell, Timothy R Rebbeck, Reiko Nishihara, Andrew H Beck, Colin B Begg, Alexei A Bogdanov, Yin Cao, Helen G Coleman, Gordon J Freeman, Yujing J Heng, Curtis Huttenhower, Rafael A Irizarry, N Sertac Kip, Franziska Michor, Daniel Nevo, Ulrike Peters, Amanda I Phipps, Elizabeth M Poole, Zhi Rong Qian, John Quackenbush, Harlan Robins, Peter K Rogan, Martha L Slattery, Stephanie A Smith-Warner, Mingyang Song, Tyler J VanderWeele, Daniel Xia, Emily C Zabor, Xuehong Zhang, Molin Wang, Shuji Ogino

Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods, and resources from epidemiology, pathology, biostatistics, bioinformatics, and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: (1) the development of new statistical methods to address etiologic heterogeneity; (2) the enhancement of causal inference; (3) the identification of previously unknown exposure-subtype disease associations; and (4) better …

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Jan 2017 • bioRxiv

ClusterEnG: An interactive educational web resource for clustering big data

Mohith Manjunath, Yi Zhang, Steve H Yeo, Omar Sobh, Nathan Russell, Christian Followell, Colleen Bushell, Umberto Ravaioli, Jun S Song

Summary Clustering is one of the most common techniques used in data analysis to discover hidden structures by grouping together data points that are similar in some measure into clusters. Although there are many programs available for performing clustering, a single web resource that provides both state-of-the-art clustering methods and interactive visualizations is lacking. ClusterEnG (acronym for Clustering Engine for Genomics) provides an interface for clustering big data and interactive visualizations including 3D views, cluster selection and zoom features. ClusterEnG also aims at educating the user about the similarities and differences between various clustering algorithms and provides clustering tutorials that demonstrate potential pitfalls of each algorithm. The web resource will be particularly useful to scientists who are not conversant with computing but want to understand the structure of their data in an intuitive manner.Availability ClusterEnG is part of a bigger project called KnowEnG (Knowledge Engine for Genomics) and is available at http://education.knoweng.org/clustereng.Contact songi@illinois.edu

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2017 • Cancer Res

TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells

T Li, J Fan, B Wang, N Traugh, Q Chen, S Liu, B Li, XS Liu

Recent clinical successes of cancer immunotherapy necessitate the investigation of the interaction between malignant cells and the host immune system. However, elucidation of complex tumor–immune interactions presents major computational and experimental challenges. Here, we present Tumor Immune Estimation Resource (TIMER; cistrome.shinyapps.io/timer) to comprehensively investigate molecular characterization of tumor–immune interactions. Levels of six tumor-infiltrating immune subsets are precalculated for 10,897 tumors from 32 cancer types. TIMER provides 6 major analytic modules that allow users to interactively explore the associations between immune infiltrates and a wide spectrum of factors, including gene expression, clinical outcomes, somatic mutations, and somatic copy number alterations. TIMER provides a user-friendly web interface for dynamic analysis and visualization of these …

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2017 • Proc Natl Acad Sci U.S.A.

Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-l- clear cell renal carcinoma

W Gao, W Li, T Xiao, XS Liu, WG Jr Kaelin

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we …

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2017 • Cancer Res

Cistrome Cancer: a web resource for integrative gene regulation modeling in cancer

S Mei, R Meyer, CA, Zheng, Q Qin, Q Wu, P Jiang, B Li, X Shi, B Wang, J Fan, M Brown, C Zang, XS Liu

Cancer results from a breakdown of normal gene expression control, so the study of gene regulation is critical to cancer research. To gain insight into the transcriptional and epigenetic factors regulating abnormal gene expression patterns in cancers, we developed the Cistrome Cancer web resource (http://cistrome.org/CistromeCancer/). We conducted the systematic integration and modeling of over 10,000 tumor molecular profiles from The Cancer Genome Atlas (TCGA) with over 23,000 ChIP-seq and chromatin accessibility profiles from our Cistrome collection. The results include reconstruction of functional enhancer profiles, “super-enhancer” target genes, as well as predictions of active transcription factors and their target genes for each TCGA cancer type. Cistrome Cancer reveals novel insights from integrative analyses combining chromatin profiles with tumor molecular profiles and will be a useful resource to …

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2017 • PLOS ONE

The common oncogenomic program of NOTCH1 and NOTCH3 signaling in T-cell acute lymphoblastic leukemia

SH Choi, E Severson, WS Pear, XS Liu, JC Aster, SC Blacklow

Notch is a major oncogenic driver in T cell acute lymphoblastic leukemia (T-ALL), in part because it binds to an enhancer that increases expression of MYC. Here, we exploit the capacity of activated NOTCH1 and NOTCH3 to induce T-ALL, despite substantial divergence in their intracellular regions, as a means to elucidate a broad, common Notch-dependent oncogenomic program through systematic comparison of the transcriptomes and Notch-bound genomic regulatory elements of NOTCH1- and NOTCH3-dependent T-ALL cells. ChIP-seq studies show a high concordance of functional NOTCH1 and NOTCH3 genomic binding sites that are enriched in binding motifs for RBPJ, the transcription factor that recruits activated Notch to DNA. The interchangeability of NOTCH1 and NOTCH3 was confirmed by rescue of NOTCH1-dependent T-ALL cells with activated NOTCH3 and vice versa. Despite remarkable overall similarity, there are nuanced differences in chromatin landscapes near critical common Notch target genes, most notably at a Notch-dependent enhancer that regulates MYC, which correlates with responsiveness to Notch pathway inhibitors. Overall, a common oncogenomic program driven by binding of either Notch is sufficient to maintain T-ALL cell growth, whereas cell-context specific differences appear to influence the response of T-ALL cells to Notch inhibition.

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2017 • Cell Death Dis

G9A promotes tumor cell growth and invasion by silencing CASP1 in non-small-cell lung cancer cells

T Huang, P Zhang, W Li, T Zhao, Z Zhang, S Chen, Y Yang, Y Feng, F Li, XS Liu, I Zhang, G Jiang, F Zhang

Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide. Although epigenetic deregulation is known to be important for tumor progression, the molecular mechanisms in NSCLC remain unclear. Here, we found that G9A (known as EHMT2), a histone methyltransferase responsible for mono-or di-methylation of histone 3 (H3) lysine 9 (K9), is significantly upregulated in NSCLC. Knocking down G9A or pharmacological inhibition of its activity suppressed tumor cell growth, colony formation, invasion and migration. Furthermore, G9A exerts these functions by repressing CASP1 expression. Knocking down CASP1 in G9A-deficient cell restored capacities of tumor cell invasion and migration. Mechanistically, G9A silences the CASP1 promoter activity by increasing H3K9me2 around its promoter. Finally, high expression of G9A or low expression of CASP1 is correlated with poor …

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2017 • Blood

Topological analysis reveals a PD-L1 associated microenvironmental niche for Reed-Sternberg cells in Hodgkins Lymphoma

CD Carey, D Gusenleitner, M Lipschitz, MGM Roemer, EC Stack, E Gjini, X Hu, R Redd, GJ Freeman, D Neuberg, FS Hodi, XS Liu, MA Shipp, SJ Rodig

Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+ and PD-1+ cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+ TAMs, which physically colocalize with PD-L1+ HRS cells in a microenvironmental niche. PD-L1+ TAMs are enriched …

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2017 • Proc Natl Acad Sci U S A

Transcriptional landscape of the human cell cycle

Y Liu, S Chen, S Wang, F Soares, M Fischer, F Meng, Z Du, C Lin, C Meyer, JA DeCaprio, M Brown, XS Liu, HH He

Steady-state gene expression across the cell cycle has been studied extensively. However, transcriptional gene regulation and the dynamics of histone modification at different cell-cycle stages are largely unknown. By applying a combination of global nuclear run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and histone-modification Chip sequencing (ChIP-seq), we depicted a comprehensive transcriptional landscape at the G0/G1, G1/S, and M phases of breast cancer MCF-7 cells. Importantly, GRO-seq and RNA-seq analysis identified different cell-cycle–regulated genes, suggesting a lag between transcription and steady-state expression during the cell cycle. Interestingly, we identified genes actively transcribed at early M phase that are longer in length and have low expression and are accompanied by a global increase in active histone 3 lysine 4 methylation (H3K4me2) and histone 3 lysine 27 …

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2017 • PNAS

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing

T Fei, Y Chen, T Xiao, W Li, L Cato, P Zhang, MB Cotter, M Bowden, RT Lis, S.G. Zhao, Q Wu, FY Feng, M Loda, HH He, XS Liu, M Brown

Alternative RNA splicing plays an important role in cancer. To determine which factors involved in RNA processing are essential in prostate cancer, we performed a genome-wide CRISPR/Cas9 knockout screen to identify the genes that are required for prostate cancer growth. Functional annotation defined a set of essential spliceosome and RNA binding protein (RBP) genes, including most notably heterogeneous nuclear ribonucleoprotein L (HNRNPL). We defined the HNRNPL-bound RNA landscape by RNA immunoprecipitation coupled with next-generation sequencing and linked these RBP–RNA interactions to changes in RNA processing. HNRNPL directly regulates the alternative splicing of a set of RNAs, including those encoding the androgen receptor, the key lineage-specific prostate cancer oncogene. HNRNPL also regulates circular RNA formation via back splicing. Importantly, both HNRNPL and its …

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2017

Modeling Accommodation Control of the Human Eye: Chromatic Aberration and Color Opponency

Agostino Gibaldi, Steven A Cholewiak, Marty S Banks

Accommodation is the process by which the eye lens changes optical power to maintain a clear retinal image as the distance to the fixated object varies. Although luminance blur has long been considered the driving feature for accommodation, it is by definition unsigned (ie, there is no difference between the defocus of an object closer or farther than the focus distance). Nonetheless, the visual system initially accommodates in the correct direction, implying that it exploits a cue with sign information. Here, we present a model of accommodation control based on such a cue: Longitudinal Chromatic Aberration (LCA). The model relies on color-opponent units, much like those observed among retinal ganglion cells, to make the computation required to use LCA to drive accommodation.

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2017 • Cell

Applications of Immunogenomics to Cancer

XS Liu, ER Mardis

Cancer immunogenomics originally was framed by research supporting the hypothesis that cancer mutations generated novel peptides seen as “non-self” by the immune system. The search for these “neoantigens” has been facilitated by the combination of new sequencing technologies, specialized computational analyses, and HLA binding predictions that evaluate somatic alterations in a cancer genome and interpret their ability to produce an immune-stimulatory peptide. The resulting information can characterize a tumor’s neoantigen load, its cadre of infiltrating immune cell types, the T or B cell receptor repertoire, and direct the design of a personalized therapeutic.

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2017 • Genome Biol

Revisit linear regression-based deconvolution methods for tumor gene expression data

B Li, JS Liu, XS Liu

We have recently published a statistical deconvolution method to study infiltrating immune cells using tumor RNA-seq data [1]. One of the goals in that work was to understand how proportions of different cell types covary across different cancer tissues. To this end, we estimated the abundance of six cell types over 9000 tumor samples across 23 cancer types, and then assessed the correlations of these estimated proportions across the different samples within a cancer type. In particular we compared our method (TIMER) with CIBERSORT [2], a previously published deconvolution approach, for their ability to assess such correlations. To our surprise, we found many non-biological negative correlations between CIBERSORT estimates, and we believed that this artifact was, to a large extent, due to the incorporation of highly similar features in the linear model, or statistical collinearity. Newman et al., the authors of …

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2017 • Nat Genet

Ultrasensitive detection of TCR hypervariable-region sequences in solid-tissue RNA-seq data

B Li, T Li, B Wang, R Dou, J Zhang, JS Liu, XS Liu

Figure 1 Evaluation of the performance of TRUST in single-end mode.(a) Venn diagrams showing the number of CDR3 sequences called using TCR–seq and TRUST, and their overlap.(b) TRUST-reported CDR3 sequences are enriched for clonotypes with high abundance. At each quantile, the y axis shows the fraction of TRUST-reported CDR3 sequences with a clonal frequency greater than or equal to that for the quantile.(c) Accuracy of variable and joining gene estimations by TRUST.(d) Recall and precision estimations based on in silico simulations at different read depths.(e) Recall and precision estimations at different read length settings. Each box includes data between the 25th and 75th percentiles, with the horizontal line representing the median. The upper whisker is min (max (x), Q3+ 1.5× IQR) and the lower whisker is max (min (x), Q1–1.5× IQR), where x is the data, Q3 is the 75th percentile, Q1 is the …

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2017 • PLOS ONE

CRISPR-FOCUS: a web server for designing focused CRISPR screening experiments

Q Cao, J Ma, C-H Chen, H Xu, Z Chen, W Li, XS Liu

The recently developed CRISPR screen technology, based on the CRISPR/Cas9 genome editing system, enables genome-wide interrogation of gene functions in an efficient and cost-effective manner. Although many computational algorithms and web servers have been developed to design single-guide RNAs (sgRNAs) with high specificity and efficiency, algorithms specifically designed for conducting CRISPR screens are still lacking. Here we present CRISPR-FOCUS, a web-based platform to search and prioritize sgRNAs for CRISPR screen experiments. With official gene symbols or RefSeq IDs as the only mandatory input, CRISPR-FOCUS filters and prioritizes sgRNAs based on multiple criteria, including efficiency, specificity, sequence conservation, isoform structure, as well as genomic variations including Single Nucleotide Polymorphisms and cancer somatic mutations. CRISPR-FOCUS also provides pre-defined positive and negative control sgRNAs, as well as other necessary sequences in the construct (e.g., U6 promoters to drive sgRNA transcription and RNA scaffolds of the CRISPR/Cas9). These features allow users to synthesize oligonucleotides directly based on the output of CRISPR-FOCUS. Overall, CRISPR-FOCUS provides a rational and high-throughput approach for sgRNA library design that enables users to efficiently conduct a focused screen experiment targeting up to thousands of genes. (CRISPR-FOCUS is freely available at http://cistrome.org/crispr-focus/)

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2017 • Nucleic Acids Res

Exploring genetic assoications with ceRNA regulation in the human genome

MJ Li, J Zhang, Q Liang, C Xuan, J Wu, P Jiang, W Li, Y Zhu, P Wang, D Fernandez, Y Shen, Y Chen, JA Kocher, Y Yu, PC Sham, J Wang, JS Liu, XS Liu

Competing endogenous RNAs (ceRNAs) are RNA molecules that sequester shared microRNAs (miRNAs) thereby affecting the expression of other targets of the miRNAs. Whether genetic variants in ceRNA can affect its biological function and disease development is still an open question. Here we identified a large number of genetic variants that are associated with ceRNA's function using Geuvaids RNA-seq data for 462 individuals from the 1000 Genomes Project. We call these loci competing endogenous RNA expression quantitative trait loci or ‘cerQTL’, and found that a large number of them were unexplored in conventional eQTL mapping. We identified many cerQTLs that have undergone recent positive selection in different human populations, and showed that single nucleotide polymorphisms in gene 3΄UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in …

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2017 • Environ Health Perspect

Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells

D Chen, L Fang, S Mei, H Li, X Xu, TL Des marais, K Lu, XS Liu, C Jin

Background:Formaldehyde (FA) is an environmental and occupational chemical carcinogen. Recent studies have shown that exogenous FA causes only a modest increase in DNA adduct formation compared with the amount of adducts formed by endogenous FA, raising the possibility that epigenetic mechanisms may contribute to FA-mediated carcinogenicity.Objectives:We investigated the effects of FA exposure on histone modifications and chromatin assembly. We also examined the role of defective chromatin assembly in FA-mediated transcription and cell transformation.Methods:Cellular fractionation and Western blot analysis were used to measure the levels of histone modifications in human bronchial epithelial BEAS-2B cells and human nasal RPMI2650 cells in the presence of FA. Chromatin immunoprecipitation (ChIP) and micrococcal nuclease (MNase) digest assays were performed to examine the …

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Dec 2016 • Genome biology

Comprehensive analyses of tumor immunity: implications for cancer immunotherapy

Bo Li, Eric Severson, Jean-Christophe Pignon, Haoquan Zhao, Taiwen Li, Jesse Novak, Peng Jiang, Hui Shen, Jon C Aster, Scott Rodig, Sabina Signoretti, Jun S Liu, X Shirley Liu

Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor–immune interactions in cancers. We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggests that MAGEA3 is a potential immune target in melanoma, but not in non-small cell lung cancer, and implicates SPAG5 as an alternative cancer vaccine target in multiple cancers. We find that melanomas expressing high levels of CTLA4 separate into two distinct groups with respect to CD8 T-cell infiltration, which might influence clinical responses to anti-CTLA4 agents. We observe similar dichotomy of TIM3 expression with respect to CD8 T cells in kidney cancer and validate it experimentally. The abundance of immune infiltration, together with our downstream analyses and findings, are accessible through TIMER, a public resource at http://cistrome.org/TIMER . We develop a computational approach to study tumor-infiltrating immune cells and their interactions with cancer cells. Our resource of immune-infiltrate levels, clinical associations, as well as predicted therapeutic markers may …

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