Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motives we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified co-regulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B cell and T cell infiltration. We calculated metagenes as surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation associated genes. In multivariate Cox regression analysis the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort (Hazard Ratio (HR) 2.20, 95% confidence interval (CI) 1.40-3.46). The B cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR 0.66, 95% CI 0.46 - 0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high grade tumors (n=286, HR 0.78, 95% CI 0.62-0.98), and a second validation cohort enriched for younger patients (n=302, HR 0.83, 95% CI 0.7-0.97). Thus, we could demonstrate in three cohorts of untreated node-negative breast cancer patients, that the humoral immune system plays a pivotal role for metastasis-free survival of carcinomas of the breast.
The humoral immune system has a key prognostic impact in node-negative breast cancer.
Disease stage
View SamplesRheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced inter-patient heterogeneity. To characterize RA at the molecular level and to uncover key pathomechanisms, we performed whole-genome gene expression analyses. Synovial tissues from rheumatoid arthritis patients were compared to those from osteoarthritis patients and to normal donors.
Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis.
Sex, Age
View SamplesAnalysis of biopsy hippocampal tissue of patients with pharmacoresistant temporal lobe epilepsy (TLE) undergoing neurosurgical removal of the epileptogenic focus for seizure control. Chronic TLE goes along with focal hyperexcitability. Results provide insight into molecular mechanisms that may play a role in seizure propensity
Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus.
Specimen part
View SamplesProgressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an inherited neurodegenerative disease with myoclonus, seizures and ataxia, caused by the mutations in cystatin B (CSTB) gene. In an approach towards understanding the molecular basis of pathogenic events in EPM1 we have utilized the cystatin B deficient mice (Cstb-/-), a model for the disease. We have characterized the gene expression changes from the cerebellum of Cstb-/- mouse at postnatal day 7 (P7) and P30 as well as in cultured cerebellar granule cells using a pathway-based approach. A marked upregulation of immune response genes was seen at P30, reflecting the ongoing neuropathology, however, the observed alterations in complement cascade genes could also imply defects in synaptic plasticity. Differentially expressed genes in pre-symptomatic Cstb-/- animals at P7 were connected to synaptic function and plasticity and in cultured cerebellar granule cells to cellular biogenesis, cytoskeleton and intracellular transport. Especially GABAergic pathways were affected.
Gene expression alterations in the cerebellum and granule neurons of Cstb(-/-) mouse are associated with early synaptic changes and inflammation.
Sex, Specimen part
View SamplesA key question in developmental biology is how cells exchange positional information for proper patterning during organ development. In plant roots the radial tissue organization is highly conserved with a central vascular cylinder in which two water conducting cell types, protoxylem and metaxylem, are patterned centripetally. We show that this patterning occurs through crosstalk between the vascular cylinder and the surrounding endodermis mediated by cell-to-cell movement of a transcription factor in one direction and microRNAs in the other. SHORT ROOT, produced in the vascular cylinder, moves into the endodermis to activate SCARECROW. Together these transcription factors activate MIR165a and 166b. Endodermally produced miR165/6 then acts to degrade its target mRNAs encoding class III homeodomain-leucine zipper transcription factors in the endodermis and stele periphery. The resulting differential distribution of target mRNA in the vascular cylinder determines xylem cell types in a dosage dependent manner.
Cell signalling by microRNA165/6 directs gene dose-dependent root cell fate.
Age, Specimen part
View SamplesWe profiled transcripts from sorted phloem cells of wild-type and apl mutants to identify the genes regulated by APL in phloem.
Plant development. Arabidopsis NAC45/86 direct sieve element morphogenesis culminating in enucleation.
Specimen part
View SamplesPDX tumors at various passages post first implantation in nude mice
High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response.
No sample metadata fields
View SamplesEwing sarcoma family of tumors (ESFT) are aggressive bone and soft tissue tumors of unknown cellular origin. Most ESFT express EWS-FLI1, a chimeric protein which functions as a growth-promoting oncogene in ESFT but is toxic to most normal cells. A major difficulty in understanding EWS-FLI1 function has been the lack of an adequate model in which to study EWS-FLI1-induced transformation. Although the cell of origin of ESFT remains elusive, both mesenchymal (MSC) and neural crest (NCSC) have been implicated. We recently developed the tools to generate NCSC from human embryonic stem cells (hNCSC). In the current study we used this model to test the hypothesis that neural crest-derived stem cells are the cells of origin of ESFT and to evaluate the consequences of EWS-FLI1 expression on human neural crest biology.
Modeling initiation of Ewing sarcoma in human neural crest cells.
Specimen part
View SamplesGene expression was studied from the blood derived RNAs of the Finnish family members as well as from 10 controls using GeneChip Human Genome U133 Plus2 (Affymetrix). Eight out of 10 family members in the expression analysis are heterozygous for the NPAT c.2437-2438delAG, three of which are NLPHL cases.
Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma.
Specimen part, Disease, Disease stage, Subject
View SamplesWhen misexpressed in late Drosophila prepupae, the transcription factor Senseless (Sens) blocks death of the larval salivary glands that normally occurs in the early pupa. The aim of the experiment was to identify genes responding to Sens that might mediate the effect of the protein on cell death and other biological processes. The yeast transcription factor GAL4, expressed from a heat-inducible transgene (P{GAL4-Hsp70.PB}89-2-1), was used to drive expression of Sens from a UAS-sens transgene. After crossing the GAL4 and UAS lines, expression of GAL4 was induced by a 30-min heat shock treatment (37 C) of the progeny at 9 hours after puparium formation. Salivary glands were dissected at 14 hours after puparium formation and RNA isolated for microarray analysis with Affymetrix GeneChips. Control samples were obtained from animals treated the same way carrying one copy of the GAL4 transgene (progeny of a cross between flies of the P{GAL4-Hsp70.PB}89-2-1 and w1118 strains) and w1118 animals. The microarray data identified several genes associated with programmed cell death, including caspase genes, which respond to Sens. In addition, the data show that many Drosophila genes respond to the yeast transcription factor GAL4 in a UAS-independent manner. To identify target genes of Sens that are of biological relevance, gene expression patterns in the presence of Sens were compared to gene expression patterns in both the presence and the absence of GAL4. This comparison revealed that Sens seems to preferentially downregulate targets that are upregulated by GAL4, suggesting that these genes may not necessarily constitute true transcriptional targets of Sens.
A genomic response to the yeast transcription factor GAL4 in Drosophila.
No sample metadata fields
View Samples