Mice selected for high and low acute inflammation were tested for pristane induced arthritis, showing to be susceptible and resistant, respectively.
Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation.
Sex, Age, Specimen part
View SamplesGraft-versus-host disease (GvHD) is still one of the major complications following allogeneic stem cell transplantation (SCT) triggered by alloreactive donor T cells. Whereas murine data have clearly shown the beneficial effects of regulatory T cells (Tregs) on the development of GvHD, data from the human system are rare mainly due to low cell numbers of circulating or organ-infiltrating Tregs in lymphopenic patients. Here, we present a comparative analysis of Tregs from patients with and without acute/ chronic GvHD designed as a dynamical approach studying the whole genome profile over the first 6 months after SCT. For this purpose, blood samples were collected monthly for FACS-based isolation of CD4+CD25highCD127low/- Tregs. The Treg transcriptome showed a high stability in the first half year representing the most sensitive time window for tolerance induction. However, the comparison of the Treg transcriptome from patients with and without GvHD uncovered regulated gene transcripts that point to a reduced suppressive function of Tregs with diminished migration capacity to the target organs likely contributing to the development of GvHD. These findings highlight the critical role of human Tregs in the pathophysiology of GvHD and identify novel targets for the manipulation of Tregs to optimize cellular immune intervention strategies.
Human regulatory T cells in allogeneic stem cell transplantation.
Specimen part, Disease, Disease stage, Time
View SamplesPurpose: Severe late normal tissue damage limits radiotherapy treatment regimens. This study aims to validate -H2AX foci decay ratios and induced expression levels of DNA double strand break (DSB) repair genes, found in a retrospective study, as possible predictors for late radiation toxicity. Methods and Materials: Prospectively, decay ratios (initial/residual -H2AX foci numbers) and genome-wide expression profiles were examined in ex vivo irradiated lymphocytes of 198 prostate cancer patients. All patients were followed 2 years after radiotherapy, clinical characteristics were assembled and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. Results: No clinical factors were correlated with late radiation toxicity. Analysis of -H2AX foci uncovered a negative correlation between the foci decay ratio and toxicity grade. Significantly smaller decay ratios were found in grade3 compared to grade 0 patients (p=0.02), indicating less efficient DNA-DSB repair in radio-sensitive patients. Moreover, utilizing a foci decay ratio threshold determined in our previous retrospective study correctly classified 23 of the 28 grade3 patients (sensitivity, 82%) and 9 of the 14 grade 0 patients (specificity, 64%). Grade of toxicity also correlated with a reduced induction of the homologous recombination (HR) repair gene-set. The difference in average fold induction of the HR gene-set was most pronounced between grade 0 and grade3 patients (p=0.008). Conclusions: Reduced responsiveness of HR repair genes to irradiation and inefficient DSB repair correlate with an increased risk of late radiation toxicity. Using a decay ratio classifier, we could correctly classify 82% of the patients with grade3 toxicity. Additional studies are required to further optimize and validate the foci decay assay and to assess its predictive value for late radiation toxicity in patients prostate cancer
Prostate Cancer Patients with Late Radiation Toxicity Exhibit Reduced Expression of Genes Involved in DNA Double-Strand Break Repair and Homologous Recombination.
Specimen part, Subject
View SamplesMouse Bcell, upon ectopic expression of the transcription factor Cebpa for 18h, can be reprogrammed to iPS with extremely high efficiency. To understand the molecular control of this phenomena we performed multiple high throughtput functionnal genomic analysis. Overall design: Transcriptomic by RNAseqencing (polyA+, non stranded) in Bcell, Bcell+Cebpa18h, Bcell+Cebpa18h+OKSM1d, Bcell+Cebpa18h+OKSM2d, ES cells
C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4.
No sample metadata fields
View SamplesIn this study gene expression of human blood classical monocytes (CD14++CD16-), CD16 positive monocytes (consisting of non-classical CD14+16++ and intermediate CD14++CD16+ monocytes) and CD1c+ CD19- dendritic cells from healthy subjects were investigated.
Transcript profiling of CD16-positive monocytes reveals a unique molecular fingerprint.
Specimen part
View SamplesThe retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1G) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1G/G MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1G/G MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1G/G cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1G/G MEFs is responsive to p16 expression, indicating that the G-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1G/G mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified.
A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice.
Specimen part
View SamplesColorectal cancer (CRC) is a heterogeneous disease classified into four consensus molecular subtype (CMSs) with distinct biological and clinical features. This study aims to understand the value of patient-derived xenografts (PDXs) in relation to these CMSs. A total of 42 primary tumors, recurrences and metastases were used to develop PDXs. Detailed genetic analyses were performed on PDXs and corresponding patient tumors to determine relationship and PDX heterogeneity. Out of 42 tumors 22 (52%) showed successfully PDX engraftment, which was biased towards metastases and CMS1 and CMS4 tumors. Importantly, gene expression analysis revealed a clinical relevant association between an engraftment gene signature and prognosis for stage II patients. Moreover, this gene signature revealed an association between Src pathway activation and positive engraftment. Src pathway activity co-aligned with CMS4 and the levels of fibronectin in tumors and was confirmed by pSrc immunohistochemistry. From this analysis we further deduced that decreased cell cycle activity is a prognostic factor for successful engraftment and related to patient prognosis. However, this is not a general phenomenon, but subtype specific as decreased cell cycle activity was highly prognostic for recurrence-free survival within CMS2 but not in CMS1 and CMS4, while it showed an inverse correlation in CMS3. These data illustrate that CRC PDX establishment is biased toward CMS1 and CMS4, which impacts translation of results derived from pre-clinical studies using PDXs. Moreover, our analysis reveals subtype-specific features, pSrc in CMS4 and low Ki67 in CMS2, which provide novel avenues for therapy and diagnosis.
Capturing colorectal cancer inter-tumor heterogeneity in patient-derived xenograft (PDX) models.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesStudy was carried out to examine how E2 and TNFa together influence gene expression in breast cancer cells compared to either factor alone.
Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer.
No sample metadata fields
View SamplesWe scored adrenocortical carcinomas and adenomas for abnormal beta-catenin staining, and sequenced the beta-catenin gene in some samples. We compared adrenocortincal carcinomas with and without abnormal beta-catenin staining and found many significant expression differences and significant results from enrichment testing. A similar comparison in the adenomas gave relatively few differences, and they did not correlate to differences found for the carcinomas. Abnormal beta-catenin staining was associated with mitotic rate and poorer patient survival in the carcinomas. In a second independent data set (given in a supplement) we again found beta-catenin associated with poor survival. The array data given is the same as GEO series GSE10927, with additional characteristics about beta-catenin, and new patient followup data. The analysis shown in a supplementary Excel file is also new.
Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin.
Sex, Age
View SamplesNatural SIV infection of sooty mangabeys (SMs) does not progress to disease despite chronic virus replication. In contrast to pathogenic SIV infection of rhesus macaques (RMs), chronic SIV infection of SMs is characterized by low immune activation. To elucidate the mechanisms underlying this phenotype, we longitudinally assessed host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs is consistently associated with a robust innate immune response, including widespread up-regulation of interferon-stimulated genes (ISGs). Our findings indicate that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low immuneactivation of chronically SIV-infected SMs.
Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys.
Sex, Specimen part
View Samples