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SRP090472
Homo sapiens
122 Downloadable Samples
Description
Millions of patients suffer from lymphedema worldwide. Supporting the contractility of lymphatic collectors is an attractive target for pharmacological therapy of lymphedema. However, lymphatics have mostly been studied in animals, while the cellular and molecular characteristics of human lymphatic collectors are largely unknown. We studied epifascial lymphatic collectors of the thigh, which were isolated for autologous transplantations. Our immunohistological studies identify additional markers for LECs (vimentin, CCBE-1). We show and confirm differences between initial and collecting lymphatics concerning the markers ESAM1, D2-40 and LYVE-1. Our transmission electron microscopic studies reveal two types of smooth muscle cells (SMCs) in the media of the collectors with dark and light cytoplasm. We observed vasa vasorum in the media of the largest collectors, as well as interstitial Cajal-like cells, which are highly ramified cells with long processes, caveolae, and lacking a basal lamina. They are in close contact with SMCs, which possess multiple caveolae at the contact sites. Immunohistologically we identified such cells with antibodies against vimentin and PDGFRa, but not CD34 and cKIT. With Next Generation Sequencing we searched for highly expressed genes in the media of lymphatic collectors, and found therapeutic targets, suitable for acceleration of lymphatic contractility, such as neuropeptide Y receptors 1, and 5; tachykinin receptors 1, and 2; purinergic receptors P2RX1, and 6, P2RY12, 13, and 14; 5-hydroxytryptamine receptors HTR2B, and 3C; and adrenoceptors a2A,B,C. Our studies represent the first comprehensive characterization of human epifascial lymphatic collectors, as a prerequisite for diagnosis and therapy. Overall design: The transcriptome of 6 different normal human lymphatic collectors (Lyko1, Lyko 4-12, Lyko 5, Lyko12, Lyko13, Lyko26) from the dermis of the thigh of women between 44 and 61 years of age was compared to cultures of human dermal lymphatic endothelial cells (LEC1, LEC2, HD-LEC9A) and a mixture of 3 different human dermal blood endothelial cells (HD-BEC-CA) to identify potential drug targets in the media of the collectors.
Publication Title
Morphological and Molecular Characterization of Human Dermal Lymphatic Collectors.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 15 Downloadable Samples
Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Human dendritic cells (DC) are suppressed by tumor-derived alpha fetoprotein (AFP), but less so by cord blood-derived normal AFP.
Publication Title
Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 19 Downloadable Samples
- Illumina HiSeq 2000
Description
Objectives: The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies, but the pathogenesis, including the role of mutant collagen VI in the matrix is poorly understood. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD patients from controls. Methods: We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD patients (8 dominant negative and 5 null) and 6 controls. Sequence reads were analyzed using the TopHat/Cufflinks pipeline. Results: Differentially expressed transcripts between COL6-RD patient and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples Overall design: Expression profiles of dermal fibroblasts from 13 COL6-RD patients with dominant negative (8) or null (5) mutations compared to 6 control fibroblasts.
Publication Title
Transcriptome profiling identifies regulators of pathogenesis in collagen VI related muscular dystrophy.
Sample Metadata Fields
Specimen part, Subject
View Samples- Danio rerio
- 16 Downloadable Samples
- IlluminaHiSeq2500
Description
The RNA-binding protein FUS is implicated in transcription, alternative splicing of neuronal genes and DNA repair. Mutations in FUS have been linked to human neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis). We genetically disrupted fus in zebrafish (Danio rerio) using the CRISPR-Cas9 system. The fus knockout animals are fertile and did not show any distinctive phenotype. Mutation of fus induces mild changes in gene expression on the transcriptome and proteome level in the adult brain. We observed a significant influence of genetic background on gene expression and 3’UTR usage, which could mask the effects of loss of Fus. Unlike published fus morphants, maternal zygotic fus mutants do not show motoneuronal degeneration and exhibit normal locomotor activity. Overall design: We performed paired-end sequencing (100bp reads) of the polyA+ transcriptome from brains of five individuals with Fus-/- genotype and four with Fus wild type genotype. Note on RNA-Seq replicates: after performing first RNA sequencing on four replicates of Fus-/- and WT (labeled with the prefix "Sample_imb_ketting_2014_13_") we received a notice from Illumina stating a problem with the library preparation kit lot that was used to prepare the libraries. Due to that, we performed RNA sequencing a second time, using the same input RNA, except for the Fus knockout replicate #3, because there was not enough input RNA left. Instead, a different Fus knockout replicate (#1) was sequenced. However, we compared the mapped reads from sequencing run 1 and sequencing run 2 using plotCorrelaction from DeepTools, and the samples are highly correlated (at least 0.97 and 0.95, Spearman and Pearson correlation respectively). Therefore, we considered first ("Sample_imb_ketting_2014_13_") and second sequencing runs as technical replicates.
Publication Title
Characterization of genetic loss-of-function of Fus in zebrafish.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Hepatocellular carcinoma (HCC) is a fatal malignancy with a dismal prognosis. The recent advances in genomics and transcriptomics have led to large volumes of molecular data for HCC, providing an unprecedented opportunity to translate these data into more effective therapeutics. By creating HCC gene expression signatures and comparing with drug response signatures from multiple datasets, we identified four antihelminthics (from over 1000 FDA-approved drugs) that can reverse the HCC disease gene expression. Among these four, niclosamide was the top hit, which we further evaluated in clinically relevant HCC cell lines and patient-derived xenografts (PDX). Given the poor water-solubility and limited systemic bioavailability of niclosamide, we also evaluated its ethanolamine salt (NEN), which has improved solubility and bioavailability. Both niclosamide and NEN significantly inhibited HCC cell proliferation in vitro, which was associated with down-regulation of key proteins involved in the AKT-mTOR, Wnt, Stat3, and EGFR/Ras/Raf signaling pathways. NEN additionally decreased the growth of three PDX models after oral administration (1,5000 ppm in food) for 4-6 weeks. Expression profiling demonstrated that niclosamide and NEN induced highly similar gene expression changes in HepG2 cells and in PDX models, and that both compounds significantly reversed HCC gene expression in vitro and in vivo . Our results suggest that NEN may be a preferred drug candidate for the treatment of HCC.
Publication Title
Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 119 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
CONTEXT Slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms are thought to contribute, but the most promising targets for timely intervention have not been identified. OBJECTIVE In the current study we seek to determine the driving force behind progressive histological damage of renal allografts, without the interference of donor pathology, delayed graft function and acute graft rejection. DESIGN We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. PATIENTS Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection. RESULTS In this highly cross-validated study, we demonstrate the significant association of established, ongoing and future chronic histological damage with regulation of adaptive immune gene expression (T-cell and B-cell transcript sets) and innate immune response gene expression (dendritic cell, NK-cell, mast cell and granulocyte transcripts). We demonstrate the ability of gene expression analysis to perform as a quantitative marker for ongoing inflammation with a wide dynamic range: from subtle subhistological inflammation prior to development of chronic damage, over moderate subclinical inflammation associated with chronic histological damage, to marked inflammation of Banff-grade acute T-cell mediated rejection. CONCLUSION Progressive chronic histological damage after kidney transplantation is associated with significant regulation of both innate and adaptive immune responses, months before the histological lesions appear. This study therefore corroborates the hypothesis that quantitative inflammation below the diagnostic threshold of classic T-cell or antibody-mediated rejection is associated with early subclinical stages of progressive renal allograft damage.
Publication Title
Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes.
Sample Metadata Fields
Specimen part, Time
View Samples- Homo sapiens
- 102 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
The metastatic form of Melanoma has a reported ten-year survival rate of approximately 15%. Clinical trials have shown modest success in a subset of patients. Particularly, combinational therapy using checkpoint blockade has shown the most success, but many patients do not respond. The patients that do respond to treatments often have a pre-existing antitumor immunity.
Publication Title
Dysregulated NF-κB-Dependent ICOSL Expression in Human Dendritic Cell Vaccines Impairs T-cell Responses in Patients with Melanoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 38 Downloadable Samples
- Affymetrix Murine 11K SubA Array (mu11ksuba)
Description
Identification of common mechanisms underlying organ development and primary tumor formation should yield new insights into tumor biology and facilitate the generation of relevant cancer models. We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)human cerebellar tumorsonto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60). Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. Furthermore, metastatic MBs were highly associated with mouse P5 cerebella, suggesting that a clinically distinct subset of tumors is identifiable by molecular similarity to a precise developmental stage. Genewise, down- and up-regulated MB genes segregate to late and early stages of development, respectively. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. Our findings indicate both a recapitulation of tissue-specific developmental programs in diverse solid tumors and the utility of tumor characterization on the developmental time axis for identifying novel aspects of clinical and biological behavior.
Publication Title
Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 36 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
HutchinsonGilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein. Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular
Publication Title
Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis.
Sample Metadata Fields
Cell line
View Samples- Saccharomyces cerevisiae x saccharomyces kudriavzevii, Saccharomyces cerevisiae
- 9 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
The aim of this project was to evaluate the ploidy of a S. cerevisiae *S. kudriavzevii hybrid in comparison to the lab strain S288C. Other wine yeast have been icluded in the project for the global analysis.
Publication Title
Ecological success of a group of Saccharomyces cerevisiae/Saccharomyces kudriavzevii hybrids in the northern european wine-making environment.
Sample Metadata Fields
No sample metadata fields
View Samples