Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME.
Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation.
Specimen part
View SamplesRNA-sequencing was performed on human CD19- CD138+ bone marrow plasma cells. Overall design: 4 biological replicates of human CD19- CD138+ bone marrow plasma cells and 1 replicate each of naïve, IgM memory, IgG memory, and plasmablasts from peripheral blood.
Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells.
Specimen part, Subject
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 SamplesWe used microarray to detect pathway differences in the various brain regions in a monogenic in mucopolysaccharidosis type VII ( MPS VII ), a mouse model of a lysosomal storage disease
Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology.
Specimen part
View SamplesWe used microarray to detect pathway differences in the hippocampus in mucopolysaccharidosis type VII ( MPS VII ), a mouse model of a lysosomal storage disease
Integrated analysis of proteome and transcriptome changes in the mucopolysaccharidosis type VII mouse hippocampus.
Sex, Age, Specimen part
View SamplesTwo-year rodent bioassays play a central role in evaluating both the carcinogenic potential of a chemical and generating quantitative information on the dose-response behavior for chemical risk assessments. The bioassays involved are expensive and time-consuming, requiring nearly lifetime exposures (two years) in mice and rats and costing $2 to $4 million per chemical. Since there are approximately 80,000 chemicals registered for commercial use in the United States and 2,000 more are added each year, applying animal bioassays to all chemicals of concern is clearly impossible. To efficiently and economically identify carcinogens prior to widespread use and human exposure, alternatives to the two-year rodent bioassay must be developed. In this study, animals were exposed for 13 weeks to two chemicals that were positive for lung tumors in the two-year rodent bioassay, two chemicals that were negative for tumors, and two vehicle controls. Gene expression analysis was performed on the lungs of the animals to assess the potential for identifying gene expression biomarkers that can predict tumor formation in a two-year bioassay following a 13 week exposure.
A comparison of transcriptomic and metabonomic technologies for identifying biomarkers predictive of two-year rodent cancer bioassays.
Sex, Age, Subject
View SamplesTwo-year rodent bioassays play a central role in evaluating both the carcinogenic potential of a chemical and generating quantitative information on the dose-response behavior for chemical risk assessments. The bioassays involved are expensive and time-consuming, requiring nearly lifetime exposures (two years) in mice and rats and costing $2 to $4 million per chemical. Since there are approximately 80,000 chemicals registered for commercial use in the United States and 2,000 more are added each year, applying animal bioassays to all chemicals of concern is clearly impossible. To efficiently and economically identify carcinogens prior to widespread use and human exposure, alternatives to the two-year rodent bioassay must be developed. In this study, animals were exposed for 13 weeks to two chemicals that were positive for liver tumors in the two-year rodent bioassay, two chemicals that were negative for liver tumors, and two vehicle controls. Gene expression analysis was performed on the livers of the animals to assess the potential for identifying gene expression biomarkers that can predict tumor formation in a two-year bioassay following a 13 week exposure.
A comparison of transcriptomic and metabonomic technologies for identifying biomarkers predictive of two-year rodent cancer bioassays.
Sex, Age, Subject
View SamplesLiver undergoes both size increase and differentiation during postnatal period, which in mice is approximately first 30 days. The mechanisms of simultaneous postnatal liver cell proliferation and maturation are not clear. In these experiments, role of yes associated protein (Yap), the downstream effector of Hippo Kinase signaling pathway was investigated.
Yes-associated protein is involved in proliferation and differentiation during postnatal liver development.
Specimen part
View SamplesWe examined the impact of Abca1 deficiency and APOE isoform expression on the response to TBI using 3-months-old, human APOE3+/+ (E3/Abca1+/+) and APOE4+/+ (E4/Abca1+/+) targeted replacement mice, and APOE3+/+ and APOE4+/+ mice with only one functional copy of the Abca1 gene (E3/Abca1+/-; E4/Abca1+/-). TBI-treated mice received a craniotomy followed by a controlled cortical impact (CCI) brain injury in the left hemisphere; sham-treated mice received the same surgical procedure without the impact. We performed RNA-seq using samples from cortices and hippocampi collected at 14 days post-injury, followed by genome-wide differential gene expression analysis. Overall design: We used 3-months-old, human APOE3+/+ (E3/Abca1+/+) and APOE4+/+ (E4/Abca1+/+) targeted replacement mice, and APOE3+/+ and APOE4+/+ mice with only one functional copy of the Abca1 gene (E3/Abca1+/-; E4/Abca1+/-). Groups consisted of 6-8 animals of both genders. TBI-treated mice received a craniotomy followed by a controlled cortical impact (CCI) brain injury in the left hemisphere; sham-treated mice received the same surgical procedure without the impact. We performed RNA-seq using samples from cortices and hippocampi collected at 14 days post-injury from 58 samples, followed by genome-wide differential gene expression analysis.
ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms.
Sex, Treatment, Subject
View SamplesAlthough HSF1 is known to play an important role in regulating the cellular response to proteotoxic stressors, little is known about the structure and function of the HSF1 signaling network under both stressed and unstressed conditions. In this study, we used a combination of chromatin immunoprecipitation (ChIP) microarray analysis and time course gene expression microarray analysis with and without siRNA-mediated inhibition of HSF1 comprehensively identify genes directly and indirectly regulated by HSF1 and examine the structure of the extended HSF1 signaling network. Correlation between promoter binding and gene expression was not significant for all genes bound by HSF1 suggesting that HSF1 binding per se is not sufficient for expression. However, the correlation with promoter binding was significant for genes identified as HSF1-regulated following siRNA knockdown allowing the identification of direct transcriptional targets of HSF1. Among promoters bound by HSF1 following heat shock, a gene ontology (GO) analysis showed significant enrichment only in categories related to protein folding. In contrast, analysis of the extended HSF1 signaling network showed enrichment in a variety of categories related to protein folding, anti-apoptosis, RNA splicing, ubiquitination and others, highlighting a complex transcriptional program directly and indirectly regulated by HSF1.
Genome-wide analysis of human HSF1 signaling reveals a transcriptional program linked to cellular adaptation and survival.
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