Loss of p120ctn results in dysplasia and invasive cancer in the mouse esophagus and squamous forestomach.
Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene.
Specimen part
View SamplesThe goal of this study is to investigate if interferon signaling regulates immune checkpoint blockade in mouse melanoma model. Overall design: Transcription profiling for B16, B16 after chronic interferon treatment, B16 derived checkpoint blockade resistant strain 499 and various knockout from 499, coupled with ATA-seq data.
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.
Specimen part, Treatment, Subject
View SamplesResponse to immune checkpoint inhibitors may be improved through combinations with each other and other therapies, raising questions about non-redundancy and resistance. We report results from parallel studies of melanoma patients and mice treated with anti-CTLA4 and radiation (RT). Although combined treatment improved responses, resistance was common. Computational analyses of immune and transcriptomic profiles (provided here) revealed that resistance in mice was due to upregulation of tumor PD-L1 that drives T cell exhaustion. Accordingly, optimal response requires RT, anti-CTLA4, and anti-PD-L1. Anti-CTLA4 inhibits Tregs, RT diversifies and shapes the TCR repertoire, and anti-PD-L1 reinvigorates exhausted T cells. Together, all three therapies promote the expansion of clonotypes with distinct TCR traits. Similar to mice, patients with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response through distinct mechanisms.
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer.
No sample metadata fields
View SamplesThe normal growth and function of mammary epithelial cells depend on interactions with the supportive stroma. Alterations in this communication can lead to the progression or expansion of malignant growth. The human mammary gland contains two distinctive types of fibroblasts within the stroma. The epithelial cells are surrounded by loosely connected intralobular fibroblasts, which are subsequently surrounded by the more compacted interlobular fibroblasts. The different proximity of these fibroblasts to the epithelial cells suggests distinctive functions for these two subtypes. In this report, we compared the gene expression profiles between the two stromal subtypes.
Interlobular and intralobular mammary stroma: genotype may not reflect phenotype.
No sample metadata fields
View SamplesSeven novel and potent Raf small molecule kinase inhibitors were evaluated in 7-day oral repeat-dose rat toxicity studies. All compounds tested induced hyperplasia in multiple tissues. Microarrays were used to investigate transciptional changes associated by treatment with a single compound to gain insight into the cellular changes that may contribute to the tissue hyperplasia.
Raf inhibition causes extensive multiple tissue hyperplasia and urinary bladder neoplasia in the rat.
Sex, Specimen part, Treatment
View SamplesThe tumor suppressor gene RASSF1A (Ras association domain family protein 1A) coding for a microtubule stabilizing protein is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologues of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic because Hippo pathway components are rarely mutated. Rassf1a homozygous knockout mice developed liver tumors. However, heterozygous deletion of Sav1 or co-deletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A binding partners by mass spectrometry identified the Hippo kinases MST1, MST2 and the oncogenic IkB kinase TBK1 as the most significantly enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a-/- livers was more deregulated than that of Sav1+/- livers and the transcriptome of Rassf1a-/-, Sav1+/- livers was similar to that of Rassf1a-/- mice. We found that the levels of Tbk1 protein were substantially upregulated in livers lacking Rassf1a, and at the transcript level, factors regulating Tbk1 stability, including Usp2 and Dtx4, were also dysregulated. Furthermore, transcripts of several beta tubulin isoforms were increased in the Rassf1a-deficient liver genotypes presumably reflecting a role of Rassf1a as a tubulin-binding and microtubule-stabilizing protein. Our data suggest a multifactorial role of Rassf1a in suppression of liver carcinogenesis.
Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1.
No sample metadata fields
View SamplesGene expression profile in circulating leukocytes identifies patients with coronary artery disease
Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease.
Sex, Age, Specimen part, Race
View SamplesIn contrast to the considerable in vitro and in vivo data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferases (UGT) activity. The objective of this study was to determine the effects of TBI alone and along with treatment with either erythropoietin (EPO) or anakinra on gene expression of hepatic inflammatory proteins and drug metabolizing enzymes and transporters in a cortical contusion impact (CCI) injury animal model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h and 7 days post-CCI.
Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model.
Sex, Specimen part, Treatment, Time
View SamplesmiR-142 gene is specifically and abundantly expressed in hematopoietic cells. Mice that lack this miRNA gene develop immunodeficiency and display altered hematopoeisis.
Altered lymphopoiesis and immunodeficiency in miR-142 null mice.
Specimen part
View SamplesBlood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples, to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocytes and pDC specific, miR-150; lymphoid cells specific, miR-652 and miR-223; both myeloid cells specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA-mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA-mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p < 9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.
Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression.
Specimen part
View Samples