The maternal tract plays a critical role in the success of early embryonic development providing an optimal environment for establishment and maintenance of pregnancy. Preparation of this environment requires an intimate dialogue between the embryo and her mother. To advance our understanding of the process by which a foreign blastocyst is accepted by the maternal endometrium and better address the clinical challenges of infertility and pregnancy failure, it is imperative to decipher this complex molecular dialogue. The objective of the present work is to define the local response(s) of the maternal tract towards the embryo during the earliest stages of pregnancy.
Early developing pig embryos mediate their own environment in the maternal tract.
Specimen part, Disease
View SamplesThe objective of the present study is to investigate if females have the ability to recognise X or Y chromosome bearing spermatozoa and present a different response to different spermatozoa.
The battle of the sexes starts in the oviduct: modulation of oviductal transcriptome by X and Y-bearing spermatozoa.
Specimen part
View SamplesGlioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy due to its aggressive behaviour. Cancer stem cells have been described to be the only cell population with tumorogenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells may be beneficial. We have established different cultures of glioblastoma stem cells (GSCs) derived from surgical specimens and found that, after induction of differentiation, NFB was activated, which allows intermediate tumor precursor cells to remain cycling. We also showed that blockade of NFB signaling in differentiating GSCs by different genetic strategies or treatment with small molecule inhibitors, promoted replication arrest, progression to a mature phenotype, mainly neuronal cells, and senescence. This effect was partly mediated by downregulation of the NFB target gene cyclin D1. Furthermore, intravenous treatment of immunodeficient mice bearing human GSC-derived tumors with a novel small-molecule inhibitor of the NFB pathway induced senescence of tumor cells but no ultraestructural alterations of the brain parenchymal cells were detected. These findings reveal that activation of NFB may keep differentiating GSCs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed at promoting premature senescence in GSCs undergoing differentiation.
Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo.
Specimen part, Disease
View SamplesRescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Using the NCI anticancer drug screen data, we identified two compounds from the thiosemicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53R175 mutant. Mechanistic studies reveal that NSC319726 restores WT structure and function to the p53R175 mutant. This compound kills p53R172H knock-in mice with extensive apoptosis and inhibits xenograft tumor growth in a 175-allele specific mutant p53 dependent manner. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53R175 mutant reactivator and as a lead compound for p53 targeted drug development.
Allele-specific p53 mutant reactivation.
Specimen part, Cell line, Treatment
View SamplesChemotherapy resistance presents a major hurdle for cancer treatment. We proposed to identify the molecular changes through which breast cancer cells evolve resistance to conventional treatment, here cisplatin, so targeted therapy can be developed. Candidate approach RNAi screening was combined with cisplatin treatment in order to identify molecular pathways conferring survival advantages. The screening identified ATP7A, a copper transport ATPase responsible for the intercellular movement and sequestering of cisplatin, as a therapeutic target. Copper chelation with tetrathiomolybdate (TM) targets ATP7A. TM in combination with cisplatin sensitized drug-resistant breast cancer cells. Allograft and xenograft models in aythymic mice treated with TM/cisplatin combination therapy inhibited tumor growth and increased survival compared with monotreated mice. Examination of the molecular effects of TM on cisplatin efficacy in drug-resistant tumors revealed reduced levels of APT7A, reduced cisplatin sequestering by ATP7A and increased nuclear availability of cisplatin. Further, we showed that TM treatment combined with cisplatin reduced the half-life of ATP7A in human breast cancer cell lines. This finding offered the potential to combat drug platinum-resistant tumors and sensitize patients to conventional breast cancer treatments by identifying and targeting resistant tumors unique molecular adaptations.
Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin.
Cell line, Time
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miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice.
Specimen part, Treatment
View SamplesMiR-30e represses the osteogenic program in mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs) by targeting IGF2, and drives their differentiation into adipogenic or smooth muscle lineage, respectively.
miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice.
Specimen part, Treatment
View SamplesMiR-30e represses the osteogenic program in mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs) by targeting IGF2, and drives their differentiation into adipogenic or smooth muscle lineage, respectively.
miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice.
Specimen part, Treatment
View SamplesMiR-30e represses the osteogenic program in mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs) by targeting IGF2, and drives their differentiation into adipogenic or smooth muscle lineage, respectively.
miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice.
Specimen part, Treatment
View SamplesIn addition to its well-know function in chromosome segregation, increasing evidence implicates cohesin in the control of gene expression. It has been previously reported that inactivation of the cohesin loader Mis4 in G1-arrested cells leads to the dissociation of cohesin from chromatin. We exploited this experimental situation to ask whether this loss of cohesin would affect gene expression on a genome-wide scale.
Role for cohesin in the formation of a heterochromatic domain at fission yeast subtelomeres.
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