Adoptive T-cell Therapy (ACT) involves using tumor-infiltrating lymphocytes (TIL) isolated from metastatic melanoma and expanding them ex vivo prior to infusion into lympho-depleted patients. This is one of the most promising approaches to treat metastatic melanoma, with the rates of clinical response between 48-50% based on studies done at NCI, M.D. Anderson Cancer Center (Houston, TX), and Sheba Medical Center (Tel Aviv, Israel). In the Phase II ACT Trial at M.D. Anderson Cancer Center , our group has uncovered an association between positive clinical response and the amount of CD8+ tumor-infiltrating lymphocytes expressing B and T Lymphocyte Attenuator (BTLA), a reported inhibitory receptor on T-cells.
BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties.
Sex, Age, Specimen part, Subject
View SamplesKidneys were snap frozen from 2 month old wild type, Col4a3-/-, or Col4a3-/-OPN-/- mice. RNA was isolated using Mirvana Paris kit.
Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits.
Specimen part
View SamplesActivation of the immune system is a way for host tissue to defend itself against tumor growth. Hence, treatment strategies that are based on immunomodulation are on the rise. Conventional cytostatic drugs such as the anthracycline doxorubicin can also activate immune cell functions of macrophages and natural killer cells. In addition, cytotoxicity of doxorubicin can be enhanced by combining this drug with the cytokine IFN-alpha. Although doxorubicin is one of the most applied cytostatics, the molecular mechanisms of its immunomodulation ability are not investigated thoroughly. In microarray analyses of HeLa cells, a set of 19 genes related to interferon signaling was significantly overrepresented among genes regulated by doxorubicin exposure including STAT-1, -2, IRF9, NMI, and caspase 1. Regulation of these genes by doxorubicin was verified with Real-Time PCR and immunoblotting. An enhanced secretion of IFN-alpha was observed when HeLa cells were exposed to doxorubicin as compared to untreated cells. IFN-alpha neutralizing antibodies and inhibitors of JAK-STAT signaling (ATA and AG490) significantly abolished doxorubicin-stimulated expression of interferon signaling-related genes. Furthermore, inhibition of JAK-STAT signaling significantly reduced doxorubicin induced caspase 3 activation and desensitized HeLa cells to doxorubicin cytotoxicity. In conclusion, we demonstrate that doxorubicin induces interferon-responsive genes via IFN-alpha-JAK-STAT1 signaling and that this pathway is relevant for doxorubicins cytotoxicity in HeLa cells. As immunomodulation is a promising strategy in anticancer treatment, this novel mode of action of doxorubicin may help to further improve the use of this drug among different types of anticancer treatment strategies.
Regulation of interferon-inducible proteins by doxorubicin via interferon γ-Janus tyrosine kinase-signal transducer and activator of transcription signaling in tumor cells.
Cell line, Treatment
View SamplesEffect of LUBEL catalytic dead mutation in immune response Overall design: Mutation was introduced in the LUBEL catalytic region by CRISPR/Cas9 techonology in Drosophila melanogaster and their transcriptome was compared in control (sample 23930 to 23941) and e.coli pricked samples (sample 28984 to 28995).
Linear ubiquitination by LUBEL has a role in Drosophila heat stress response.
Sex, Specimen part, Subject
View SamplesEffect of LUBEL catalytic dead mutation upon Heastshock Overall design: Mutation was introduced in CG11321 catalytic region by CRISPR/Cas9 techonology in Drosophila melanogaster and transcriptome was compared in untreated and heatshocked samples
Linear ubiquitination by LUBEL has a role in Drosophila heat stress response.
Treatment, Subject
View SamplesAlthough human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) have emerged as a novel platform for heart regeneration, disease modeling, and drug screening, their immaturity significantly hinders their application. A hallmark of postnatal cardiomyocyte maturation is the metabolic substrate switch from glucose to fatty acids. We hypothesized that fatty acid supplementation would enhance hPSC-CM maturation. Fatty acid treatment induces cardiomyocyte hypertrophy and significantly increases cardiomyocyte force production. The improvement in force generation is accompanied by enhanced calcium transient peak height and kinetics, and by increased action potential upstroke velocity. Fatty acids enhance mitochondrial respiratory reserve capacity. RNA sequencing showed fatty acid treatment upregulates genes involved in fatty acid ß-oxidation and downregulates genes in lipid synthesis. Signal pathway analyses reveal that fatty acid treatment results in phosphorylation of multiple intracellular kinases. Thus, fatty acids increase human cardiomyocyte hypertrophy, force generation, calcium dynamics, action potential upstroke velocity, and oxidative capacity. This enhanced maturation should facilitate hPSC-CMs usage for cell therapy, disease modeling, and drug/toxicity screens. Overall design: We did RNA-seq of hPSC-CM culture in control and fatty acid media, with two biological replicates per condition
Fatty Acids Enhance the Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Transcription factor <i>TFCP2L1</i> patterns cells in the mouse kidney collecting ducts.
Specimen part
View SamplesGene expression analysis of mouse kidney after conditional inactivation of transcription factor Tfcp2l1
Transcription factor <i>TFCP2L1</i> patterns cells in the mouse kidney collecting ducts.
Specimen part
View SamplesIn a transcriptome study of psoriatic (PP) vs. normal (NN) skin, we found a co-expressed gene module (N5) enriched 11.5-fold for lipid biosynthetic genes. We also observed fewer visible hairs in PP skin, compared to uninvolved (PN) or NN skin (p<0.0001). To ask whether these findings might be due to abnormalities of the pilosebaceous unit, we carried out 3D morphometric analysis of paired PP and PN biopsies. Sebaceous glands (SG) were markedly atrophic in PP vs. PN skin (91% average reduction in volume, p=0.031). Module N5 genes were strongly downregulated in PP vs. NN skin (fold-change [FC] < 0.25, 44.4-fold), and strongly up-regulated in sebaceous hyperplasia (SH, FC > 4, 54.1-fold). The intersection of PP-downregulated and SH-upregulated gene lists generated a gene expression signature consisting solely of module N5 genes, whose expression in PP vs. NN skin was inversely correlated with the signature of IL17-stimuated keratinocytes. Despite loss of visible hairs, morphometry identified elongated follicles in PP vs. PN skin (average 1.7 vs. 1.2 Jm, p=0.020). These results document SG atrophy in non-scalp psoriasis, identify a cytokine-regulated set of SG signature genes, and suggest that loss of visible hair in PP skin may result from abnormal SG function.
Sebaceous Gland Atrophy in Psoriasis: An Explanation for Psoriatic Alopecia?
Specimen part, Disease, Disease stage
View SamplesBackground: We got interested whether genes of airway basal cells are enriched in COPD.
BAL Cell Gene Expression Is Indicative of Outcome and Airway Basal Cell Involvement in Idiopathic Pulmonary Fibrosis.
Specimen part, Disease
View Samples