Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. In the present study, we aimed to identify resistance mechanisms to the small-molecule tyrosine kinase inhibitor nintedanib in the Py2T murine breast cancer transplantation model. To identify differences in gene expression between short- and long-term nintedanib and untreaded FAC-sorted tumor and endothelial cells, we performed gene expression profiling by using affymetrix microarrays.
Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.
Specimen part, Treatment
View SamplesEvidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic, and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small cell lung cancer patients. We observed that, PD-1T T cells show a markedly different transcriptional and metabolic profile as compared to PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes are impaired in classical effector cytokine production, they produce CXCL13 that mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1 bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides novel potential avenues for therapeutic intervention. Overall design: Intratumoral CD8+ T cells from 11 non-small cell lung cancer patients that were sub-sorted into PD1-high (PD-1T), PD1-intermediate (PD-1N) and PD1-negative (PD-1-) cells, were sequenced using Illumina HiSeq4000. In addition, peripheral blood effector memory T cells from 4 healthy donors were sequenced using Illumina HiSeq4000.
A transcriptionally and functionally distinct PD-1<sup>+</sup> CD8<sup>+</sup> T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.
Specimen part, Subject
View SamplesWe undertook a survey of gene expression changes in primary microglial cultures with and without neurovirulent (FrCasE) and non-neurovirulent (Fr57E) virus infection to identify physiological changes that could be relevant to the induction of spongiform neurodegeneration. These gene expression analyses were performed using Affymetrix 430A mouse GeneChips (5 chips for each of the three experimental conditions, representing over 14,000 murine genes and ESTs. RNA from 5 separate microglial culture preparations were analyzed for Control (mock infected), Fr57E-, and FrCasE-infected microglia. Present/absent calls were based on MicroArray Suite 5.0 from Affymetrix. Affymetrix CEL files were analyzed using dChip software after normalization of the data between all 15 arrays. Statistical analyses were performed using ANOVA.
Gene expression profiling of microglia infected by a highly neurovirulent murine leukemia virus: implications for neuropathogenesis.
Specimen part
View SamplesExpression analysis of 36 pancreatic ductal adenocarcinoma tumors and matching normal pancreatic tissue samples from pancreatic cancer patients of the Clinical Institute Fundeni (ICF) using Affymetrix U133 Plus 2.0 whole-genome chips.
Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia.
Subject
View SamplesMacrophage inflammatory protein 1alpha/CCL3 protein is a known pro-inflammatory cytokine that can mediate chemotaxis of monocytes and promote cell degranulation. Ccl3 gene expression is elevated in the CNS and visceral tissue of many lysosomal storage disorders. The deletion of Ccl3 in a mouse model of Sandhoff disease was reported to result in reduced monocyte-associated pathology in the brain, delayed neurodegeneration, and prolonged health. However, deletion of Ccl3 in a mouse model of Niemann-Pick C disease was dentrimental or neutral instead of beneficial. Prevention of neuronal loss was instead mediated by providing NPC1 to neurons.
Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Screening and validation of lncRNAs and circRNAs as miRNA sponges.
Cell line
View SamplesIntensive research in past two decades has uncovered the presence and importance of noncoding RNAs (ncRNAs), which includes microRNAs (miRs) and long ncRNAs (lncRNAs). These two classes of ncRNAs interact to a certain extent, as some lncRNAs bind to miRs to sequester them. Such lncRNAs are collectively called 'competing endogenous RNAs' or 'miRNA sponges'. In this study, we screened for lncRNAs that may act as miRNA sponges using the publicly available data sets and databases. To uncover the roles of miRNA sponges, loss-of-function experiments were conducted, which revealed the biological roles as miRNA sponges. LINC00324 is important for the cell survival by binding to miR-615-5p leading to the de-repression of its target BTG2 LOC400043 controls several biological functions via sequestering miR-28-3p and miR-96-5p, thereby changing the expressions of transcriptional regulators. Finally, we also screened for circular RNAs (circRNAs) that may function as miRNA sponges. The results were negative at least for the selected circRNAs in this study. In conclusion, miRNA sponges can be identified by applying a series of bioinformatics techniques and validated with biological experiments.
Screening and validation of lncRNAs and circRNAs as miRNA sponges.
Cell line
View SamplesNC1153 was shown to inhibit JAK3 tyrosine kinase. Lymphocytes survival depends on the integrity of STAT5, the primary downstream target of JAK3.
Uncoupling JAK3 activation induces apoptosis in human lymphoid cancer cells via regulating critical survival pathways.
Cell line
View SamplesIn most metazoan nuclei, heterochromatin is located at the nuclear periphery in contact with the nuclear lamina, which provides mechanical stability to the nucleus. We show that in cultured cells, chromatin de-compaction by the nucleosome binding protein HMGN5 decreases the sturdiness, elasticity, and rigidity of the nucleus. Mice overexpressing HMGN5, either globally or only in the heart, are normal at birth but develop hypertrophic heart with large cardiomyoctyes, deformed nuclei and disrupted lamina, and die of cardiac malfunction. Chromatin de-compaction is seen in cardiomyocytes of newborn mice but misshaped nuclei with disrupted lamina are seen only in adult cardiomyocytes, suggesting that loss of heterochromatin diminishes the ability of the nucleus to withstand the mechanical forces of the contracting heart. Thus, heterochromatin enhances the ability of the nuclear lamina to maintain the sturdiness and shape of the eukaryotic nucleus; a structural role for chromatin that is distinct from its genetic functions.
Chromatin decompaction by the nucleosomal binding protein HMGN5 impairs nuclear sturdiness.
Specimen part
View SamplesIn order to provide functional data of kidney-specific long intergenic non-coding RNAs (lincRNA), loss-of-function study was conducted.
Logic programming to infer complex RNA expression patterns from RNA-seq data.
Cell line
View Samples