Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2 signaling pathway, and the molecular mechanisms related to treatment response were sought. To search for response predictors, genomic and transcriptomic profiling, PIK3CA mutations and PTEN status were associated to the drug responses and several genes involved in the response of the compounds were identified.
No associated publication
Sex, Cell lineView Samples
Osteosarcomas are the most common primary malignant tumours of bone, and almost all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. The cell lines showed complex patterns of DNA copy number changes, where copy number gains were significantly associated with gene-rich regions of the genome and losses with gene-poor areas. Integration of the datasets showed that the mRNA levels were regulated by either alterations in DNA copy number or DNA methylation. Using a recurrence threshold of 6/19 (> 30 %) cell lines, 348 genes were identified as having alterations of two data types (gain or hypo-methylation/over-expression, loss or hyper-methylation/under-expression). These genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2-deoxycytidine treatment for all four genes tested. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for some genes. Integrative analysis of genome-wide genetic and epigenetic alterations identified mechanistic dependencies and relationships between DNA copy number and DNA methylation in terms of regulating mRNA expression levels in osteosarcomas, contributing to better understanding of osteosarcoma biology.
Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma.
Sex, Specimen part, Cell lineView Samples
The Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenase AlkB from E. coli is a demethylase which repairs alkyl lesions in DNA, as well as RNA, through a direct reversal mechanism. Humans possess nine AlkB homologues (ALKBH1-8 and FTO). ALKBH2 and ALKBH3 display demethylase activities corresponding to that of AlkB, and both ALKBH8 and FTO are RNA modification enzymes. The biochemical functions of the rest of the homologues are still unknown. To increase our knowledge on the functions of ALKBH4 and ALKBH7 we have here performed yeast two-hybrid screens to identify interaction partners of the two proteins. While no high-confidence hits were detected in the case of ALKBH7, several proteins associated with chromatin and/or involved in transcription were found to interact with ALKBH4. For all interaction partners, the regions mediating binding to ALKBH4 comprised domains previously reported to be involved in interaction with DNA or chromatin. Furthermore, some of these partners showed nuclear co-localization with ALKBH4. However, the global gene expression pattern was only marginally altered upon ALKBH4 over-expression, and larger effects were observed in the case of ALKBH7. Although the molecular function of both proteins remains to be revealed, our findings suggest a role for ALKBH4 in regulation of gene expression or chromatin state and support the previous association of ALKBH7 with spermatogenesis.
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Specimen part, Cell lineView Samples
Gene expression changes as a response to PEGylated interferon-a2b treatment of one sensitive and two resistant osteosarcoma xenografts established in nude mice
Characterization of Treatment Response to Recombinant Interferon-alpha2b in Osteosarcoma Xenografts
Specimen part, Disease, Disease stage, Subject, CompoundView Samples
Patients diagnosed with glioblastomas continue to have a dismal prognosis, highlighting the need for a better characterization of these tumors in order to identify more efficient therapies. In this study, we generated genome-wide expression data from normal brain and glioma samples, representing major glioma subtypes, using exon-level microarrays (n=70). A multi-component approach was used to characterize molecular pathways and tumor infiltrate, with particular focus on the poor prognosis primary glioblastomas (pGBM). Two independent, publically available datasets were used for validation of survival data. Grade II glioma and secondary GBM were enriched in cytotoxic lymphocytes, while pGBM exhibited a heterogeneous cell-related immune infiltrate with high infiltration of monocytic cells. Infiltration by cells of monocytic origin predicted poorer prognosis, regardless of the tumor subtype. High TSPYL2 expression was found to be associated with a poor prognosis in pGBM and to correlate with genes involved in tumor invasion. The multi-component transcriptome phenotypes of pGBM introduced in this study add insights into the main pathways associated with aggressiveness, and identified infiltration by cells of monocytic origin as a universal prognostic marker for all glioma subtypes.
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Sex, Age, DiseaseView Samples
Glucose intolerance and diabetes mellitus are classical parts of endogenous Cushings syndrome (CS), and insulin resistance is a feature of cortisol excess. CS patients display characteristics including hyperglycemia, abdominal obesity, reduced high-density lipoprotein cholesterol levels and elevated triglycerides, and arterial hypertension. Hypercortisolism is a well known cause of bone loss, and patients with CS frequently display low bone mass and fragility fractures. Cortisol excess inhibits bone formation, increases bone resorption, impairs calcium absorption from the gut, and affects the secretion of several hormones, cytokines, and growth factors with potential influence on bone metabolism. Bone biopsies from nine CS patients, before and mean 3 months after surgery, were screened for expressional candidate genes using Affymetrix human Gene Plus 2.0 Arrays. Analyses were performed to identify genes in glucocorticoid-induced osteoporosis and genes in glucose metabolism and energy homeostasis.
The glucocorticoid-induced leucine zipper gene (GILZ) expression decreases after successful treatment of patients with endogenous Cushing's syndrome and may play a role in glucocorticoid-induced osteoporosis.
Sex, Age, Specimen partView Samples
The epithelial marker E-cadherin plays a crucial role in epithelial mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumor size, invasion, and poor response to somatostatin analog (SA) treatment, but the potential mechanisms of EMT progression in these adenomas are lacking. Adenomas from sixteen acromegalic patients, eight with high (tertile 3)and eight with low (tertile 1) expression of E-cadherin where four adenomas treated with SA in each group, were screened for expressional candidate genes using Affymetrix human Gene Plus 2.0 Arrays. Analyses were performed to identify EMT-related transcripts.
No associated publication
Sex, Age, TreatmentView Samples