To describe normal cardiac and brain development during late first and early second trimester in human fetuses using microarray and pathways analysis and the creation of a corresponding normal database. RNA from recovered tissues was used for transcriptome analysis with Affymetrix 1.0 ST microarray chip. From the amassed data we investigated differences in cardiac and brain development within the 10-18 GA period dividing the sample by GA in three groups: 10-12 (H1), 13-15(H2) and 16-18(H3) weeks. A fold change of 2 or above adjusted for a false discovery rate of 5% was used as initial cut-off to determine differential gene expression for individual genes. Test for enrichment to identify functional groups were carried out using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Array analysis correctly identified the cardiac specific genes, and transcripts reported to be differentially expressed were confirmed by qRT-PCR.
Metabolic gene profile in early human fetal heart development.
Specimen part
View SamplesA phase I trial of a SRC kinase Inhibitor, dasatinib, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Background: We conducted a phase I study of dasatinib, an oral SRC tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer (EOC). Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Based on the 3+3 design, cohorts of 3-6 pts received paclitaxel 175 mg/m2 and carboplatin AUC 6 every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. Results: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 yrs (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 pts in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia. Other toxicities in all cycles included neutropenia (95% grade 3-4), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 45% (complete responses, 3/18(17%); partial responses, 5/18(28%)) and 56% (10/18) had stable disease. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose is 150 mg daily of dasatinib in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity in advanced EOC.
A phase I trial of dasatinib, an SRC-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.
Subject
View SamplesLearn about the transcriptome profiling of zona glomerulosa (ZG), zona fasciculata (ZF) and aldosterone-producing adenomas (APA) in human adrenals
DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion.
Specimen part, Disease
View SamplesResistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma. Overall design: We examine 1) gene expression of MM cells in response to PI and 2)alternative splicing in response to PI and comparator chemotherapeutic compound. We further investigate splice factor mechanism in MM cells, by examining alternative splicing in MM with overexpression of wild type and mutant splice factor, SRSF1
Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma.
Cell line, Subject, Compound, Time
View SamplesAnalysis of aldosterone-producing adenoma (APA) samples from patients with primary hyperaldosteronism. These APAs have a somatic mutation in either KCNJ5, CACNA1D, or ATP1A1. Results provide insight into the different mechanisms each mutation may cause leading to elevated aldosterone production in APA.
Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension.
Specimen part, Disease, Disease stage
View SamplesThis SuperSeries is composed of the SubSeries listed below.
MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
Specimen part, Cell line
View SamplesDownregulation of EZH2 Leads to Cellular Senescence with Features of SASP Overall design: Cells were infected with a lentivirus vector expressing shRNA against EZH2 and harvested at 4 and 8 days after infection. Total RNA was harvested from cells using Trizol reagent (Invitrogen) and further purified using the Purelink RNA Mini kit (Invitrogen) with DNase I digestion. RNA library preparation with polyA selection and Illumina HiSeq 2x150bp sequencing was performed by GeneWiz Inc. Paired-end reads were quality trimmed using Trim galore v0.4.0 and subsequently aligned to the human reference genome, hg19, using HISAT2 v2.1.0. Reads mapping to annotated genes were quantified using featureCounts (Liao et al., 2014). Differential gene expression was determined using DESeq2 v1.12.4 (Love et al., 2014) and significance was defined as FDR-corrected p-values of <0.05. The log2 fold change for each gene was used to rank the list of genes for GSEAPreranked analysis (Subramanian et al., 2005). FPKM values were calculated using DESeq2 and Z-scores were generated from FPKMs
Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage- and Histone Methylation-Dependent Pathways.
Subject, Time
View SamplesAn experimental lung metastasis assay was used to derive an invasive subline of U87 that is metastatic in mice.
MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
Specimen part, Cell line
View SamplesMicroRNA-10b may target numerous genes in gliomagenesis. The target genes of miR-10b may differ according to the cellular context.
MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme.
Specimen part, Cell line
View SamplesA doxycyline-inducible INS-1 insulinoma cell line expressing proinsulin (C96Y)-GFP was engineered. Addition of doxycyline causes the production of the proinsulin (C96Y)-GFP, which is retained in the endoplasmic reticulum. This study analyzes the gene expression changes that occur after doxycyline-induced expression of proinsulin (C96Y)-GFP for 24h, 48h and 5 days. Expression changes were compared between control un-induced cells and cells treated with doxycyline. Three replicates (experiments) were performed for each time point.
Endoplasmic reticulum stress response in an INS-1 pancreatic beta-cell line with inducible expression of a folding-deficient proinsulin.
Cell line
View Samples