Type I IFNs are implicated in the pathophysiology of systemic sclerosis (SSc). Recently, a Phase I open-label trial was conducted with an anti-IFNAR1 receptor antibody (anifrolumab) in adult SSc patients. In this study, we aim to assess the downstream effects of anifrolumab and elucidate the role of type I IFN in SSc. Serum proteins and extracellular matrix (ECM) markers were measured in relation to IFN pathway activation status and SSc disease activity. Our results demonstrated a robust overexpression of multiple serum proteins in SSc patients, particularly those with an elevated baseline type I IFN gene signature. Anifrolumab administration was associated with significant downregulation of T cellassociated proteins and upregulation of type III collagen degradation marker. Whole-blood and skin microarray results also indicated the inhibition of T cell receptor and ECMrelated transcripts by anifrolumab. In summary, our study demonstrates suppressive effects of anifrolumab on T cell activation and collagen accumulation through which tissue fibrosis may be reduced in SSc patients. The relationship between these peripheral markers and the clinical response to anifrolumab may be examined in larger double-blind, placebo-controlled trials.
Suppression of T Cell Activation and Collagen Accumulation by an Anti-IFNAR1 mAb, Anifrolumab, in Adult Patients with Systemic Sclerosis.
Specimen part, Disease, Disease stage, Time
View SamplesEpithelial-mesenchymal transition (EMT) has been linked to cancer progression and metastatic propensity. The 4T1 tumor is a clinically relevant model of spontaneous breast cancer metastasis. Here we characterize 4T1-derived cell lines for EMT, in vitro invasiveness and in vivo metastatic ability. Contrary to expectations, the 67NR cells, which form primary tumors but fail to metastasize, express vimentin and N-cadherin, but not E-cadherin. 4T1 cells, however, express E-cadherin, are highly migratory and invasive, and metastasize to multiple sites. The 66cl4 metastatic cells display mixed epithelial and mesenchymal markers, but are less migratory and invasive than 67NR cells. These findings demonstrate that the metastatic ability of breast cancer cells does not correlate with genotypic and phenotypic properties of EMT per se, and suggest that other processes may govern metastatic capability. Gene expression analysis also has not identified differences in EMT markers, but has identified several candidate genes that may influence metastatic ability.
Epithelial-mesenchymal transition (EMT) is not sufficient for spontaneous murine breast cancer metastasis.
Sex, Specimen part
View SamplesTranscriptomic analysis of ICM and TE from in vivo-derived equine blastocysts using Illumina sequencing technology Overall design: RNA was extracted from individual equine blastocyst ICM and TE (Arcturus Picopure), cDNA was synthesized and amplified (Nugen Ovation V2) and indexed libraries were created for sequencing (TruSeq DNA V1)
RNA-seq transcriptome profiling of equine inner cell mass and trophectoderm.
Specimen part, Subject
View SamplesIn this study we conducted transcriptomics analyses of: (i) liver samples from patients suffering from acetaminophen-induced acute liver failure (n=3) and from healthy livers (n=2) and (ii) hepatic cell systems exposed to acetaminophen, including their respective vehicle controls. The investigated in vitro systems are: HepaRG cells, HepG2 cells and a novel human skinpostnatal stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC).
Gene expression data from acetaminophen-induced toxicity in human hepatic <i>in vitro</i> systems and clinical liver samples.
Specimen part, Disease stage, Cell line
View SamplesMost cancer deaths are caused by metastases, which are the end-results of circulating tumor cells (CTC) that detach from the cancer primary and succeed to survive in distant organs. The aim of the present study was to develop a gene signature of CTC and to assess its prognostic relevance after surgery for pancreatic ductaladenocarcinoma (PDAC).
Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery.
Sex, Age, Disease stage
View SamplesDuring development of the central nervous system (CNS), cycling uncommitted progenitor cells give rise to a variety of distinct neuronal and glial cell types. As these different cell types are born, they progress from newly specified cells to fully differentiated neurons and glia. In order to define the developmental processes of individual cell types, single cell expression profiling was carried out on developing ganglion and amacrine cells of the murine retina. Individual cells from multiple developmental stages were isolated and profiled on Affymetrix oligonucleotide arrays. These experiments have yielded an expanded view of the processes underway in developing retinal ganglion and amacrine cells, as well as several hundred new marker genes for these cell types. In addition, this study has allowed for the definition of some of the molecular heterogeneity both between developing ganglion and amacrine cells and among subclasses of each cell type.
Molecular heterogeneity of developing retinal ganglion and amacrine cells revealed through single cell gene expression profiling.
Specimen part
View SamplesAlthough liganded nuclear receptors have been established to regulate RNA polymerase II (Pol II)-dependent transcription units, their role in regulating Pol III-transcribed DNA repeats remains largely unknown. Here we report that ~2-3% of the ~100,000-200,000 total human DR2 Alu repeats located in proximity to activated Pol II transcription units are activated by the retinoic acid receptor (RAR) in human embryonic stem cells to generate Pol III-dependent RNAs. These transcripts are processed, initially in a DICER-dependent fashion, into small RNAs (~28-65 nt) referred to as repeat-induced RNAs that cause the degradation of a subset of crucial stem-cell mRNAs, including Nanog mRNA, which modulate exit from the proliferative stem-cell state. This regulation requires AGO3-dependent accumulation of processed DR2 Alu transcripts and the subsequent recruitment of AGO3-associated decapping complexes to the target mRNA. In this way, the RAR-dependent and Pol III-dependent DR2 Alu transcriptional events in stem cells functionally complement the Pol II-dependent neuronal transcriptional program. Overall design: RNA-sequencing of polyA selected RNA molecules in NTera2/D1 cells and Global Run On (GRO) assay followed by high throughput sequencing (GRO-seq).
DICER- and AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation.
Specimen part, Treatment, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Transcriptional code and disease map for adult retinal cell types.
Specimen part
View SamplesBrain circuits are assembled from a large variety of morphologically and functionally diverse cell types. It is not known how the intermingled cell types of individual brain regions differ in their expressed genomes. Here we describe an atlas of cell type transcriptomes of the adult retina. We found that each adult cell type expresses a specific set of genes, including a unique set of transcription factors, forming a barcode for cell identity. Cell type transcriptomes carry enough information to categorize cells into corresponding morphological classes and types. Surprisingly, several barcode genes are eye disease-associated genes that we demonstrate to be specifically expressed not only in photoreceptors but also in particular retinal circuit elements such as inhibitory neurons as well as in retinal microglia. Our data suggest that distinct cell types of individual brain regions are characterized by marked differences in their expressed genomes.
Transcriptional code and disease map for adult retinal cell types.
Specimen part
View SamplesFocal nodular hyperplasias (FNHs) are benign liver lesions considered to be a hyperplastic response to increased blood flow in otherwise normal liver. In contrast, FNH-like nodules occur in cirrhotic liver but share similar histopathological features. To better understand the pathophysiology of FNH, we performed a transcriptomic analysis. Methods: Affymetrix and cDNA microarrays were used to compare gene expression in eight FNHs with that in tissue from six normal livers. Selected genes were validated with quantitative RT-PCR in 70 benign liver tumors including adenomas and cirrhotic and FNH-like lesions. Results: Among the deregulated genes in FNHs, 19 were physiologically zonated in the normal liver lobule. All six periveinous genes were up-regulated in FNH, whereas 13 genes normally expressed in the periportal area were down-regulated. Immunohistochemistry revealed that glutamine synthetase was markedly overexpressed, forming anastomosed areas usually centered on visible veins. -catenin mRNA was slightly but significantly overexpressed, as were several known -catenin target genes. Moreover, activated hypophosphorylated -catenin protein accumulated in FNH in the absence of activating mutations. These results suggest zonated activation of the -catenin pathway specifically in FNH, whereas the other benign hepatocellular tumors, including FNH-like lesions, demonstrated an entirely different pattern of -catenin expression. Conclusions: In FNH, increased expression of the -catenin pathway was restricted to enlarged periveinous areas, which may explain the slight polyclonal over-proliferation of hepatocytes at the origin of the lesion. FNH-like nodules may have a different pathogenetic origin.
The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules.
Sex, Specimen part, Disease
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