Most FDA approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient specific and cell-context specific heterogeneity of metformin response, using cancer cell lines fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages.
Patient- and Cell Type-Specific Heterogeneity of Metformin Response.
Specimen part, Cell line
View SamplesMyelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell diseases characterized by dysplasia of one or more hematologic lineages and a high-risk of developing acute myeloid leukemia (AML). MDS patients have recurrent bacterial infections and abnormal expression of CD56 by monocytes. We investigated MDS patients’ bone marrow CD56+/CD56- monocytes and their in vitro derived dendritic cell (DCs) populations in comparison to cells obtained from disease-free subjects. We found that monocytes from MDS patients, irrespective of CD56 expression, have reduced phagocytosis activity and low expression of genes involved in triggering immune responses, regulation of immune and inflammatory response signaling pathways, and in the response to lipopolysaccharide. Dendritic cells (DCs) derived in vitro from MDS monocytes failed to develop dendritic projections and had reduced expression of HLA-DR and CD86 suggesting that antigen processing and T cell activation capabilities are impaired. In conclusion, we identified in both CD56+ and CD56- monocytes from MDS-patients several abnormalities that may be related to the increased susceptibility to infections observed in these patients.
Bone Marrow Monocytes and Derived Dendritic Cells from Myelodysplastic Patients Have Functional Abnormalities Associated with Defective Response to Bacterial Infection.
Specimen part, Disease
View SamplesBackground: Plants, involved in highly complex and well-coordinated system, have evolved a considerable degree of developmental plasticity, thus minimize the damages caused by stresses. MicroRNAs (miRNAs) have recently emerged as key regulators in gene regulation, developmental processes and stress tolerance in plants. Results: In this study, systematic discovery of soybean miRNAs associated with stress response (mock, drought, salinity and alkalinity) has been identified and analyzed in combination with deep sequencing technology and in-depth bioinformatics analysis. We found that a total of 133 conserved miRNAs corresponding to 95 miRNA families have expressed in soybean under four diverse treatments. In addition, 71, 50 and 45 miRNAs are either uniquely or differently expressed under drought, salinity and alkalinity respectively, suggesting that many miRNAs are inducible and are differentially expressed in response to certain stress. Conclusion: Our study has important implications for further identification of gene regulation under abiotic stresses and also significantly contributes a complete profile of miRNAs in Glycine max.
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Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Sex, Specimen part, Treatment
View SamplesMouse bone marrow-derived macrophages (BMDM) grown in macrophage colony-stimulating factor (CSF-1) have been used widely in studies of macrophage biology and the response to toll-like receptor agonists. We investigated whether similar cells could be derived from the domestic pig. Cultivation of pig bone marrow cells for 5-7 days in presence of rhCSF-1 generated a pure population of BMDM that expressed the usual macrophage markers (CD14, CD16, CD163, CD172a), are potent phagocytic cells and produced tumor necrosis factor (TNF) in response to lipopolysaccharide (LPS). Bone marrow cells could be stored frozen and thawed, providing a renewable resource.
Pig bone marrow-derived macrophages resemble human macrophages in their response to bacterial lipopolysaccharide.
Sex, Specimen part, Time
View SamplesSystemic administration of -adrenoceptor (-AR) agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of -AR signaling has been highlighted by the inability of 13-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic acute administration of the 2-AR agonist formoterol. Skeletal muscle gene expression (from murine tibialis anterior) was profiled at both 1 and 4 hours following systemic administration of the 2-AR agonist formoterol, using 46K Illumina(R) Sentrix BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress.
Expression profiling of skeletal muscle following acute and chronic beta2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm.
Treatment
View SamplesProtein arginine methyltransferase-6 (PRMT6) regulates steroid-dependent transcription and alternative splicing, and is implicated in endocrine system development and function, cell death, cell cycle, gene expression and cancer. Despite its role in these processes, little is known about its function and cellular targets in breast cancer. To identify novel gene targets regulated by PRMT6 in breast cancer cells, we used a combination of small interfering RNA (siRNA) and exon-specific microarray profiling in vitro, coupled to in vivo validation in normal breast and primary human breast tumours. This approach, which allows the examination of genome-wide changes in individual exon usage and total transcript levels, demonstrated PRMT6 knockdown significantly affected: (i) the transcription of 159 genes, and (ii) alternate splicing of 449 genes. Importantly, the levels of PRMT6 itself were significantly decreased in breast cancer, relative to normal breast tissue. The PRMT6 dependent transcriptional and alternative splicing targets identified in vitro, were validated in human breast tumours. Notably, expression of PRMT6 and the corresponding gene signature, correlated with decreased probability of relapse-free or distant metastasis free survival in ER+ breast cancer. These results suggest that dysregulation of PRMT6 dependent transcription and alternative splicing may be involved in breast cancer pathophysiology and the molecular consequences identifying a unique and informative biomarker profile.
Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes.
Cell line, Treatment
View SamplesThese microarrays were performed for use in a genome-wide scan for LPS-regulated genes in mouse macrophages, in order to construct a list of LPS-regulated genes for detailed interrogation on custom microarrays (see GSE19490 for custom array analysis).
Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Specimen part
View SamplesThese microarrays were performed for use in a genome-wide scan for LPS-regulated genes in human monocyte-derived macrophages, in order to construct a list of LPS-regulated genes for detailed interrogation on custom microarrays (see GSE19482 for custom array analysis).
Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Specimen part
View SamplesAlthough the role of macrophage colony stimulating factor (M-CSF/CSF-1) in homeostasis and disease processes has been studied extensively in mice, little is known of the impact of this cytokine on differentiated human macrophages. Here we show that, in contrast to its effects on mouse bone marrow-derived macrophages (BMM), CSF-1 did not induce expression of urokinase plasminogen activator mRNA, repress expression of apolipoprotein E mRNA, or prime LPS-induced TNF secretion in human monocyte-derived macrophages (HMDM) from several independent donors. Using expression profiling, we show that CSF-1 dynamically regulated the expression of several genes that encode chemokines and chemokine receptors (e.g. CXCL10/IP-10, CXCL2, CCL7, SDF2L1, CXCR4) in HMDM. CSF-1 also upregulated the expression of several genes encoding enzymes of the cholesterol biosynthetic pathway (HMGCR, MVD, IDI1, FDPS, SQLE, CYP51A1, EBP, NSDHL, DHCR7 and DHCR24), while expression of ABCG1, encoding a cholesterol efflux transporter, was repressed. Although the CSF-1/CSF-1R system has been proposed as a target for the treatment of inflammatory and metastatic disease based on studies in rodents, this is the first systematic analysis of the effects of CSF-1 on mature human macrophages. Our data demonstrates that CSF-1 represents a further link between inflammation and cardiovascular disease, inflammtion and immunity.
Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages.
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