We have witnessed the rise and fall of antiangiogenic therapy in breast cancer (BC). Nevertheless, clinical remissions were observed in patients and we were interested in studying the activity of antiangiogenic drugs in BC. Inefficacy of sunitinib was observed in mouse models of metastatic BC, where evidence of enhanced metastasis was reported, and lack of efficacy of sunitinib-docetaxel combination was recently reported in a phase III clinical trial. Our aim was to understand the mechanisms and predictors of response to sunitinib in BC in a cohort of patients with untreated locally advanced or operable BC treated with an upfront window of single agent sunitinib, followed by the combination of sunitinib and docetaxel.
No associated publication
Age, Disease, Disease stage, Treatment, Subject, Time
View SamplesThe SnRK1 protein kinase, the plant ortholog of mammalian AMPK and yeast Snf1, is activated by the energy depletion caused by adverse environmental conditions. Upon activation, SnRK1 triggers extensive transcriptional changes to restore homeostasis and promote stress tolerance and survival partly through the inhibition of anabolism and the activation of catabolism. Despite the identification of a few bZIP transcription factors as downstream effectors, the mechanisms underlying gene regulation, and in particular gene repression by SnRK1, remain mostly unknown. microRNAs (miRNAs) are 20-24nt RNAs that regulate gene expression post-transcriptionally by driving the cleavage and/or translation attenuation of complementary mRNA targets. In addition to the well-established role of miRNAs as regulators of plant development, mounting evidence implicates miRNAs in the response to environmental stress. Given the involvement of miRNAs in stress responses and the fact that some of the SnRK1-regulated genes are miRNA targets, we postulated that miRNAs drive part of the transcriptional reprogramming triggered by SnRK1 activation. To test this we have performed comparative analyses of the transcriptional response to energy deprivation between WT and dcl1-9, a mutant deficient in miRNA biogenesis.
miRNAs mediate SnRK1-dependent energy signaling in Arabidopsis.
Specimen part, Treatment
View SamplesPlant reproduction depends on the concerted activation of many genes to assure the correct communication between pollen and pistil. Here we queried the whole transcriptome of Arabidopsis thaliana in order to identify genes with specific reproductive functions.
Whole genome analysis of gene expression reveals coordinated activation of signaling and metabolic pathways during pollen-pistil interactions in Arabidopsis.
Specimen part
View SamplesThe A238L gene has been selectively expressed in mouse T lymphocytes using tissue specific promoter, enhancer and locus control region sequences for CD2. The resulting two independently derived transgenic mice expressed the transgene and developed a metastatic, angiogenic and transplantable CD4+CD8+ CD69- lymphoma. The absence of CD69 from the tumour cells suggests that they were derived from T-cells at a stage prior to positive selection. In contrast, transgenic mice similarly expressing a mutant A238L, mutA238L, solely inhibiting transcription mediated by NFkappaB, were indistinguishable from wild type mice. Expression of Rag 1, Rag2, TCRbeta V8.2, CD25, FoxP3, Bcl3, Bcl2 l14, Myc, IL-2, NFAT1, Itk, by purified CD4+CD8+ CD69- thymocytes from A238L transgenic mice was consistent with the phenotype. Similarly evaluated expression profiles of CD4+CD8+ CD69- thymocytes from the mutant A238L transgenic mice were comparable to those of wild type mice.
No associated publication
Sex, Specimen part
View SamplesDespite their different origin and function, both pollen tubes and root hairs share the same sort of apical growth mechanism, i.e., the spatially focused cell expansion at the very apex. Ion fluxes, membrane trafficking, the actin cytoskeleton and their interconnection via signaling networks have been identified as fundamental processes underlying this kind of growth. Several molecules involved in apical growth have been identified, but the genetic basis is far from being fully characterized. We have used Affymetrix Arabidopsis ATH1 GeneChips to obtain the expression profiles of isolated Arabidopsis root hairs. A comparison with the expression profile of flow-sorted pollen grains reveals an overlap in the expression of 4989 genes, which corresponds to 42% of the root hair transcriptome and 76% of the pollen transcriptome, respectively. Our comparison with transcriptional profiles of vegetative tissues by principal component analysis and hierarchical clustering shows a clear separation of these samples comprised of cell types with diffuse growth from the two cell types with apical growth. 277 genes are enriched and 49 selectively expressed, respectively, in root hairs and pollen. From this set of genes emerges an apical growth signature containing novel candidate genes for apical growth determination.
Transcriptional profiling of Arabidopsis root hairs and pollen defines an apical cell growth signature.
Specimen part
View SamplesWe have previously shown that low doses of ionizing radiation (LDIR) induce angiogenesis. In the present study we investigated their action in experimentally induced hindlimb ischemia. We demonstrated that 0.3 Gy, administered for four consecutive days, significantly improves blood perfusion in the murine ischemic limb by stimulating angiogenesis and arteriogenesis. This is achieved through durable and simultaneous up-regulation of a repertoire of pro-angiogenic factors and their receptors in endothelial cells, as evident in cells isolated from the irradiated gastrocnemius muscles. Moreover, we demonstrated that this mechanism is mediated via VEGFR signaling, since VEGFR inhibition abrogated the LDIR-mediated gene up-regulation and impeded the increase in vessel density. Importantly, the vasculature in an irradiated non-ischemic bed is not affected and no adverse effects associated to the use of LDIR were seen. These findings disclose an innovative, non-invasive strategy to induce therapeutic angiogenesis in a murine model of severe hindlimb ischemia, emerging as a novel approach in the treatment of Critical Limb Ischemia patients.
No associated publication
Specimen part
View SamplesTo unravel the molecular mechanism by which HOXB4 promotes the expansion of early hematopoietic progenitors within differentiating ES cells, we analzed the gene expression profiles of embryoid bodies (EBs) in which transcription of HOXB4 had been induced or not induced. A substantial number of the identified HOXB4 target genes are involved in signaling pathways important for controlling self-renewal, maintenance and differentiation of stem cells. Furthermore, we demonstrate that HOXB4 activity and FGF-signaling are intertwined. HOXB4-mediated expansion of ES cell-derived early progenitors was enhanced by specific and complete inhibition of FGF-receptors. In contrast, the expanding activity of HOXB4 on hematopoietic progenitors in day4-6 embryoid bodies was blunted in the presence of basic FGF (FGF2) indicating a dominant negative effect of FGF-signaling on the earliest hematopoietic cells. Taken together, we show that modulation of FGF signaling is an essential feature of HOXB4 activity in the context of embryonic hematopoiesis.
HOXB4's road map to stem cell expansion.
No sample metadata fields
View SamplesAnalysis of Drosophila melanogaster early embryos (pre-zygotic genome activation) following the germ line-specific depletion of the dMLL3/4 histone methyltransferase (also known as Trr). These results provide insight into the molecular mechanisms responsible for the assembly of the zygotic genome at fertilization.
The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization.
Specimen part
View SamplesA toxicogenomic analysis from liver of different pharmacological active coumarins (mammea A/BA+A/BB 3:1 and soulatrolide ) was performed on mice treated (20mg/kg/daily) for a whole week to evaluate if such compounds possess or could develop a hazardous profile on liver.
Toxicogenomic analysis of pharmacological active coumarins isolated from Calophyllum brasiliense.
Sex, Specimen part, Treatment
View SamplesSubstantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease. However, ventral tegmental area (VTA), a region adjacent to SNpc, is less affected in PD. Until now, molecular mechanisms behind VTA aging have not been fully investigated using high throughput techniques.
Age-mediated transcriptomic changes in adult mouse substantia nigra.
Specimen part
View Samples