To identify key biological pathways that define susceptibility factors for pulmonary infection during obesity, diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice were exposed to 0.5 g/L inhaled lipopolysaccharide (LPS) for 1 hr/d for 4 days over a period of 2 weeks.
Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin.
Specimen part
View SamplesUsing a macrophage cell line, we demonstrate the ability of amorphous silica particles to stimulate inflammatory protein secretion and induce cytotoxicity. Whole genome microarray analysis of early gene expression changes induced by 10nm and 500nm particles showed that the magnitude of change for the majority of genes correlated more tightly with particle surface area than either particle mass or number. Gene expression changes that were size-specific were also identified, however the overall biological processes represented by all gene expression changes were nearly identical, irrespective of particle diameter. Our results suggest that on an equivalent nominal surface area basis, common biological modes of action are expected for nano- and supranano-sized silica particles.
Macrophage responses to silica nanoparticles are highly conserved across particle sizes.
No sample metadata fields
View SamplesMesenchymal stem cells (MSCs) are an essential component of the bone marrow (BM) microenvironment and have shown to support cancer evolution in multiple myeloma (MM). Despite the increasing evidence that MM MSCs differ from their healthy counterparts, little knowledge exists as to whether MSCs independently influence disease outcome. The aim of the present study was to determine the importance of MSCs in disease progression and outcome in MM.
The Pattern of Mesenchymal Stem Cell Expression Is an Independent Marker of Outcome in Multiple Myeloma.
Specimen part, Disease, Subject
View SamplesThis series represents bone marrow aspirates from smoldering multiple myeloma patients
Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis.
No sample metadata fields
View SamplesDrug resistance is a major obstacle in cancer therapy. The molecular mechanisms of drug resistance still remain largely elusive. Microarray analyses on paired primary myeloma samples at baseline and after therapy or at relapse showed that NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced TNM stage. Our studies indicate that over-expressing NEK2 in cancer cells resulted in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. We found that NEK2 over-expression activates cell cycle progression and cell division through the stimulation of cell cycling genes CDC2/CCNB1 and PBK. Interestingly, NEK2-overexpression also activated the Wnt/-catenin signaling pathway. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy.
NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.
Specimen part, Subject
View SamplesTo identify the CAR-, PXR- and PPAR-specific genome-wide expression changes, hepatocyte cultures from six individual donors were treated with the prototypical ligands for
Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARα in primary human hepatocytes.
Sex, Age
View SamplesStatins are widely used cholesterol-lowering drugs that inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis. In some cases, however, these drugs may cause a number of toxic side effects in hepatocytes and skeletal muscle tissue. Currently, the specific molecular mechanisms that cause these adverse effects are not sufficiently understood. In this work, genome-wide RNA expression changes in primary human hepatocytes of six individuals were measured at five time points upon atorvastatin treatment. A novel systems-level analysis workflow was applied to reconstruct regulatory mechanisms based on these drug-response data and available knowledge about transcription factor binding specificities, protein-protein interactions and protein-drug interactions. Several previously unknown transcription factors, regulatory cofactors and signaling molecules were found to be involved in atorvastatin-responsive gene expression. Some novel relationships, e.g., the regulatory influence of nuclear receptor NR2C2 on CYP3A4, were successfully validated in wet-lab experiments.
Inferring statin-induced gene regulatory relationships in primary human hepatocytes.
Specimen part, Treatment, Subject
View SamplesPurpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types. Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or down-regulation by small interfering RNA. Results: Over-expression of the PI3K isoforms p110 and p110 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110 with RNA interference (RNAi) or selective pharmacological inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, while targeting p110 was less effective. Inhibition of p110 also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mammalian target of rapamycin (mTOR) pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). A DNA microarray analysis revealed that p110 inhibition profoundly affected the balance of pro- and anti-apoptotic Bcl-2 family proteins. Finally, p110 inhibition led to impaired SCLC tumor formation and vascularization in vivo. Conclusion: Together our data demonstrate the key involvement of the PI3K isoform p110 in multiple tumor-promoting processes in SCLC.
Targeting the phosphoinositide 3-kinase p110-α isoform impairs cell proliferation, survival, and tumor growth in small cell lung cancer.
Cell line, Treatment
View SamplesGene expression analysis identified a MLL translocation-specific signature of differentially expressed genes discriminating ALL and AML with and without MLL rearrangements.
MLL rearrangements in pediatric acute lymphoblastic and myeloblastic leukemias: MLL specific and lineage specific signatures.
No sample metadata fields
View SamplesWe used microarrays to study the changes in the transcriptional profile upon Snail knockdown in murine lung adenocarcinomas
Snail mediates repression of the Dlk1-Dio3 locus in lung tumor-infiltrating immune cells.
Age, Specimen part
View Samples