PURPOSE
Gene expression profiling reveals novel biomarkers in nonsmall cell lung cancer.
Specimen part, Disease
View SamplesBackground. The development of reliable gene expression profiling technology is having an increasing impact on our understanding of breast cancer biology.
Gene expression signatures in breast cancer distinguish phenotype characteristics, histologic subtypes, and tumor invasiveness.
Disease stage
View SamplesRheumatoid arthritis is an autoimmune disease in which joint inflammation lead to progressive cartilage and bone destruction. Matrix metalloproteinases (MMP) implicated in homeostasis of extracellular matrix (ECM) play a central role in cartilage degradation. The aim of this study was to investigate the role of MMP-8 (collagenase-2) suppression in the K/BxN serum-transfer arthritis model.
Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model.
Specimen part
View SamplesMultiple Myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC50s from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand-breaks (DSB), evidenced by an increase in phospho-Histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53-wild type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSB and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumours also demonstrated Histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA-damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumour plasma cells to DSB, and strongly supports the use of this compound in MM patients.
Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.
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View SamplesTumor growth and metastasis is controlled by paracrine signaling between cells of the tumor microenvironment and malignant cells. Cancer-associated fibroblasts (CAFs), are functionally important components of the tumor microenvironment. Although some steps involved in the cross-talk between these cells are known, there is still a lot that is not clear. Thus, the addition of, the consideration of microenvironment in the development of the disease, to the clinical and pathological procedures (currently admitted as the consistent value cancer treatments) could lay the foundations for the development of new treatment strategies to control the disease.
Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature.
Specimen part
View SamplesThe abscence of TBR2 gene in human leads to microcephaly. This condition is mimicked by the specific ablation of the murine gene in developing cerebral cortex. Herein we compared gene expression in control and Tbr2 cKO in E14.5 cerebral cortices. This approach represents a useful tool to identify the molecular mechanisms at the basis of the phenotype.
The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways.
Specimen part
View SamplesTranscriptional dysregulation in Huntingtons disease (HD) is an early event that affects the expression of genes involved in survival and neuronal functions throughout the progression of the pathology. In the last years, extensive research has focused on epigenetic and chromatin-modifying factors as a causative explanation for such dysregulation, offering attractive targets for pharmacological therapies. In this work we examined the gene expression profiles in cortex, striatum, hippocampus and cerebellum of juvenile R6/1 and N171-82Q mice, two models of fast progressive HD, to retrieve the early transcriptional signatures associated with this pathology.These profiles showed significant coincidences with the transcriptional changes in the conditional knockout for the lysine acetyltransferase CBP in postmitotic forebrain neurons.
Early alteration of epigenetic-related transcription in Huntington's disease mouse models.
Sex, Age, Specimen part
View SamplesWe compared the expression of genes related to inflammatory cytotoxic functions between MSI and MSS (HLA class I negative and positive) gastrointestinal adenocarcinomas (GIACs), seeking evidence of differences in inflammatory mediators and cytotoxic T-cell responses. Twenty-two GIACs were divided into three study groups as a function of HLA class I expression and MSI phenotype. Comparison between eight high-level MSI (MSI-H) and 8 MSS/HLA+ (control) cancers identified 2170 differentially expressed genes (p< 0.05) after microarray analysis on the Affymetrix HG-U133-Plus-PM plate. We grouped genes in Gene Ontology functional categories: apoptotic programme (119 genes, p=5.110-7), leukocyte activation (32 genes, p=0.01), T cell activation (20 genes, p= 0.01), and cytokine production (19 genes, p= 0.04). Real-time RT-PCR and immunohistochemical evaluation were used to confirm some microarray data, finding that increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators were associated with greater infiltration by CD8+ T lymphocytes in the MSI-H group (p<0.001). Finally, tumours with immunohistochemical HLA class I negative pattern were not grouped together but rather in accordance with features of the gene expression profile of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-ABC negative CRCs. In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and differentiate MSI from MSS cancers. The two types of tumours, MSI/HLA- and MSS/HLA-, showed marked differences in the composition and intensity of infiltrating leukocytes, suggesting that their immune escape strategies involve distinct pathways.
No associated publication
Specimen part
View SamplesTranscriptional dysregulation is an important early feature of polyglutamine diseases. One of its proposed causes is defective neuronal histone acetylation, but important aspects of this hypothesis, such as the precise genomic topography of acetylation deficits
Genomic landscape of transcriptional and epigenetic dysregulation in early onset polyglutamine disease.
Sex, Age, Specimen part
View SamplesWe compare here the neurodegenerative processes observed in the hippocampus of bitransgenic mice with chronically altered levels of cAMP-response element-binding protein (CREB) function. The combination of genome-wide transcriptional profiling of degenerating hippocampal tissue with microscopy analyses reveals that the sustained inhibition of CREB function in A-CREB mice is associated with dark neuron degeneration, whereas its strong chronic activation in VP16-CREB mice primarily causes excitotoxic cell death and inflammation. Furthermore, the meta-analysis with gene expression profiles available in public databases identifies relevant common markers to other neurodegenerative processes and highlights the importance of the immune response in neurodegeneration. Overall, these analyses define the ultrastructural and transcriptional signatures associated with these two forms of hippocampal neurodegeneration, confirm the importance of fine-tuned regulation of CREBdependent gene expression for CA1 neuron survival and function, and provide novel insight into the function of CREB in the etiology of neurodegenerative processes.
No associated publication
Age
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