Using complementary forms of high dimensional profiling we define differences in CD45+ cells from syngeneic mouse tumors that either grow progressively or eventually reject following immune checkpoint therapy (ICT). Unbiased assessment of gene expression of tumor infiltrating cells by single cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages distinguishable by the combinatorial presence or absence of CD206, CX3CR1, CD1d and iNOS, markers of different macrophage activation states that change over time during ICT in a manner partially dependent on IFN?. Both the CyTOF data and additional analysis of scRNAseq data support the hypothesis that macrophage polarization/activation results from effects on circulatory monocytes/early macrophages entering tumors rather than on pre-polarized mature intratumoral macrophages. Thus, ICT induces transcriptional and functional remodeling of both myeloid and lymphoid compartments. Overall design: Droplet-based 3' end massively parallel single-cell RNA sequencing was performed by encapsulating sorted live CD45+ tumor infiltrating cells into droplets and libraries were prepared using Chromium Single Cell 3' Reagent Kits v1 according to manufacturer's protocol (10x Genomics). The generated scRNAseq libraries were sequenced using an Illumina HiSeq2500.
High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy.
Specimen part, Cell line, Subject
View SamplesChronic loss of Lasp1 alters the expression of other genes associated with cell motility/attachment, and/or other cellular functions. Results provide new information showing that loss of Lasp1 leads to up- and down-regulation of genes involved in cell motility/attachment/growth.
Lasp1 gene disruption is linked to enhanced cell migration and tumor formation.
No sample metadata fields
View SamplesInbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit a marked difference in their susceptibility to atherosclerosis and the arterial wall has proven to be a source of the difference in atherosclerosis susceptibility. Genome-wide gene expression analysis was conducted in aortic walls of the two strains. Total RNA was extracted from aortas of 6-week-old female B6 and C3H apoE-deficient (apoE-/-) mice fed a chow or Western diet. 1514 genes in chow fed mice and 590 genes in Western fed mice were found to be differentially expressed between the two strains. RNA was extracted from aorta using a Trizol protocol. Total RNA was pooled in an equal amount from 4 mice for each group. Standard Affymetrix procedures were performed using 8ug of total RNA.
Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility.
No sample metadata fields
View SamplesTo define molecular markers of tyrosine kinase inhibitor-induced cardiotoxicity, we measured transcriptome changes in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with one of four tyrosine kinase inhibitors (Erlotinib, Lapatinib, Sorafenib, or Sunitinib) displaying a range of mild to severe cardiotoxicity or a vehicle-only control (DMSO). Gene expression changes were assessed at the cell population level using total RNA-seq, which measured levels of both mRNAs and non-coding RNAs. hiPSC-CMs used in this study were the Cor.4U cells purchased from Ncardia. Overall design: hiPSC-CMs were treated with each TKI (Erlotinib, Lapatinib, Sorafenib or Sunitinib) at three doses (1, 3 and 10 µM) for 24 hours and the intermediate dose (3 µM) for an additional three time points (6h, 72h and 168h). hiPSC-CMs were also treated with the DMSO vehicle-only control at four time points (6h, 24h, 72h and 168h). Each treatment condition had three biological replicates, collected from three independent experiments using three different lots of hiPSC-CMs. Total RNA was collected from all these samples.
Adaptation of Human iPSC-Derived Cardiomyocytes to Tyrosine Kinase Inhibitors Reduces Acute Cardiotoxicity via Metabolic Reprogramming.
Sex, Specimen part, Subject, Compound, Time
View SamplesCigarette smoking is associated with reduced risk of developing Parkinsons disease (PD). To identify genes that interact with nicotine/smoking, we performed hypothesis-free genome-wide experiments in a paraquat-induced Drosophila model and in a case-control study of PD. We demonstrated that nicotine extends life-span in paraquat-treated Drosophila (P=4E-30). Brain tissue from flies treated with combinations of paraquat and nicotine revealed elevated expression of CG14691 with paraquat which was restored with nicotine co-treatment (P(interaction)=2E-11, P(FDR-adjusted)=4E-7). Independently, variants in the 5 region of SV2C, a human ortholog of CG14691, gave the strongest signal for interaction with smoking (P(interaction)=9E-8). The effect of smoking on PD risk varied six-fold by SV2C genotype (P(heterogeneity)=4E-10). Moreover, SV2C variants identified here were associated with SVC2 gene-expression in the HapMap data. Present results suggest synaptic vesicle protein SV2C plays a role in PD pathogenesis, and that the SV2C genotype may be useful for clinical trials of nicotine for treating PD.
A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease.
Sex, Specimen part
View SamplesMechanical overload in the heart induces pathological remodeling that typcially leads to heart failure. We sought to build an in vitro model of heart failure by applying cyclic stretch to engineered isotropic (iso) and anisotropic (aniso) NRVM tissues.
Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip.
Specimen part
View SamplesChronic alcohol consumption can lead to alchohol-related brain damage (ARBD). Despite the well known acute effects of alcohol the mechanism responsible for chronic brain damage is largely unknown. Pathologically the major change is the loss of white matter while neuronal loss is mild and restricted to a few areas such as the prefrontal cortex. In order to improve our understanding of ARBD pathogenesis we used microarrays to explore the white matter transcriptome of alcoholics and controls.
Comorbidities, confounders, and the white matter transcriptome in chronic alcoholism.
Specimen part, Disease, Disease stage
View SamplesThe goal of this experiment was to explore the extent of KIN10 (At3g01090) transcriptional regulation and identify its early target genes in Arabidopsis mesophyll protoplasts. Results suggest that KIN10 targets a remarkably broad array of genes that orchestrate transcription networks, promote catabolism and autophagy, and suppress anabolism and ribosome biogenesis. The transient expression condition ruled out secondary or long-term effects of metabolism and growth, and circumvented experimental limitations caused by redundancy and embryonic lethality observed in mammals and plants.
A central integrator of transcription networks in plant stress and energy signalling.
No sample metadata fields
View SamplesThe goal of this experiment was to investigate the early transcript changes (6h) induced by hypoxia treatment in mesophyll protoplasts. A single pair (control & hypoxia) of GeneChips was used to confirm that hypoxia treatment altered the expression of an overlapping set of genes controlled by KIN10 (At3g01090) in Arabidopsis mesophyll protoplasts.
A central integrator of transcription networks in plant stress and energy signalling.
No sample metadata fields
View SamplesThe goal of this experiment was to explore the molecular network of glucose-TOR signaling in Arabidopsis seedling autotrophic transition stage. We used the whole-genome microarrays to detail the global program of gene expression mediated by glucose and TOR.
Glucose-TOR signalling reprograms the transcriptome and activates meristems.
Age, Specimen part, Treatment
View Samples