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Search Results: 1 - 10 of 10723 matches for " Matthew Smalley "
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Highway to heaven: mammary gland development and differentiation
Lorenzo Melchor, Matthew J Smalley
Breast Cancer Research , 2008, DOI: 10.1186/bcr2147
Abstract: In the mammary epithelium, recent successes in identifying stem and progenitor cells and lineage-specific transcription factors have raised the possibility of a much deeper understanding of what controls lineage commitment and cell fate. We have some way to go before we can approach the current level of understanding of haematopoietic lineage commitment. Nevertheless, every new report adds another piece to the puzzle and two recent publications have done just that.Pietersen and co-workers have described the expression of Bmi1 in mammary cells and its crucial role in mouse mammary gland biology [1]. Bmi1 is a member of the polycomb group of proteins and a regulator of stem/progenitor cell function in other systems [2,3]. However, Pietersen and co-workers found that Bmi1 was expressed in all mammary epithelial cells and reported the profound inhibition of mammary gland development in a Bmi1 knockout mouse model, as well as a reduction of the mammary stem cell activity and premature lobuloalveolar differentiation. Interestingly, the co-deletion of Ink4a/Arf (repressors of the cell cycle down-regulated by Bmi1) partially rescued normal mammary gland development, whereas pregnancy did so completely. Thus, Bmi1 regulates stem and progenitor cell proliferation not only through the inhibition of Ink4a/Arf, but also through the inhibition of other genes related to differentiation processes that are significantly up-regulated by pregnancy.While Bmi1 is a gene ubiquitously expressed in mammary cells, other genes are differentially expressed between cell populations and are important for lineage commitment and cell-fate. Raouf and co-workers [4] have recently compared the gene expression profiles of four human mammary cell populations isolated using cell-surface marker expression. Genes from the NOTCH signalling pathway, known to regulate cell fate decisions in other systems [5-7], were described as differentially expressed between two cell populations with different colony for
CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells
Katherine E Sleeman, Howard Kendrick, Alan Ashworth, Clare M Isacke, Matthew J Smalley
Breast Cancer Research , 2005, DOI: 10.1186/bcr1371
Abstract: Mouse mammary glands were dissociated and stained with CD24. Cells were sorted into separate populations based on CD24 expression and assessed for luminal epithelial and myoepithelial/basal markers by direct fluorescent microscopy and real time PCR. The stem/progenitor potential of these cell populations was assessed in vivo by cleared mammary fat pad transplantation.Three populations of CD24 expressing cells were identified: CD24Negative, CD24Low and CD24High. Staining of these cells with cytokeratin markers revealed that these populations correspond to non-epithelial, myoepithelial/basal and luminal epithelial cells, respectively. Cell identities were confirmed by quantitative PCR. Cleared mammary fat pad transplantation of these cell populations revealed that extensive mammary fat pad repopulation capacity segregates with the CD24Low cells, whilst CD24High cells have limited repopulation capacity.Differential staining of mammary epithelial cells for CD24 can be used to simultaneously isolate pure populations of non-epithelial, myoepithelial/basal and luminal epithelial cells. Furthermore, mammary fat pad repopulation capacity is enriched in the CD24Low population. As separation is achieved using a single marker, it will be possible to incorporate additional markers to further subdivide these populations. This will considerably facilitate the further analysis of mammary epithelial subpopulations, whilst ensuring high purity, which is key for understanding mammary epithelial stem cells in normal tissue biology and carcinogenesis.There is increasing evidence that normal tissue stem cells are the cells of origin of many cancers, and the identification of such cells is, therefore, key to understanding the aetiology of carcinogenesis [1-4]. Stem cell identification strategies rely on the prospective isolation of candidate cell populations using cell surface markers, followed by in vivo functional assays in mouse models [5-7]. The accurate definition and characterisatio
The future of mammary stem cell biology: the power of in vivo transplants
Geoffrey J Lindeman, Jane E Visvader, Matthew J Smalley, Connie J Eaves
Breast Cancer Research , 2008, DOI: 10.1186/bcr1986
Abstract: Smith and Medina [1] suggest that a conflict may exist in the consistency of CD49f, CD29 and CD24 as positive mouse MaSC markers. However, we find the results reported thus far to be in full agreement with one another. The CD49fhi/CD24med population described by Stingl and coworkers [6] is identical to the CD29hi/CD24+ population described by Shackleton and colleagues [4] and to the CD49fhi/CD24lo/Sca-1-population reported by Sleeman and coworkers [5]. Specifically, there is considerable overlap (> 85%) between the fraction of CD24+ cells that are CD49fhi and CD29hi, suggesting that α6 and β1 integrin (CD49f and CD29, respectively) are co-expressed in the basal stem cell-enriched population (unpublished data). Although the MaSC-enriched population is CD24+, the level of expression is clearly lower than in cells with luminal features, including luminal progenitors [5,6]. Different levels of fluorescence are obtained with different anti-CD24 reagents and staining protocols, and this has led to differential reporting of MaSCs as CD24+, CD24mod, or CD24lo [8]. The resultant confusion is unfortunate and underscores the need for improved standardization in phenotyping procedures and nomenclature.There is also consistency in the reported phenotypes of luminal progenitors and their more mature progeny. The latter are widely recognized to be CD24+/hi/CD29lo/CD61-/prominin-1+/Sca-1+, whereas the luminal progenitors are CD24+/hi/CD29lo/CD61+/prominin-1-. The CD24hi/prominin-1-/Sca-1- population described by Sleeman and coworkers [8] contains within it the CD29lo/CD24+/CD61+population isolated by Asselin-Labat and coworkers [9] (Smalley MJ, unpublished data). This accounts for our similar observations of oestrogen receptor-α expression being largely confined to the more mature CD24+/hi/CD61-/prominin-1+/Sca-1+ luminal cells (although a potentially important finding is that a small fraction of luminal progenitor cells also express ER-α) [8-10].Smith and Medina [1] rightly highli
It's all in the details: methods in breast development and cancer
Mohamed Bentires-Alj, Robert B Clarke, Jos Jonkers, Matthew Smalley, Torsten Stein
Breast Cancer Research , 2009, DOI: 10.1186/bcr2346
Abstract: There are several meetings devoted to breast cancer research, some of which include talks on normal breast development. In contrast, there is no meeting specifically dedicated to discussing methods used in breast development and cancer. A new group, the European Network for Breast Development and Cancer (ENBDC), has initiated an annual meeting specifically devoted to presenting and discussing methods in the mammary gland field. The first meeting was organised in Weggis, Switzerland last April. First-year graduate students as well as novices in the field of breast development and cancer were encouraged to attend. This inaugural meeting encompassed discussions on breast cancer histopathology, tumour-initiating cells, animal models and normal breast stem cells.The first session included David Robertson from the Breakthrough Breast Cancer Research Centre in London and Dr Kim Jensen from Cambridge University. Robertson presented the latest developments in multi-colour fluorescent imaging using formalin-fixed paraffin-embedded (FFPE) sections. FFPE archives around the world add up to a large database of tumour samples, but standard staining using chromogenic substrates has several limitations, especially the inability to target multiple proteins simultaneously and the limited intracellular resolution. Immunofluorescence potentially provides increased resolution and allows a multi-colour approach. However, FFPE material often displays a high level of auto-fluorescence. Using an optimised protocol and confocal laser microscopy, Robertson was able to dramatically reduce this background fluorescence, allowing the use of four-colour fluorescence for cellular and intracellular co-localisation studies on FFPE tissue microarrays [1]. His latest protocols will be published on the ENBDC website [2].Kim Jensen from Fiona Watt's laboratory also presented work on studying multiple genes in small samples. He has developed a technique for full genome microarray analysis on RNA amounts e
Methods in Mammary Gland Development and Cancer: the second ENDBC meeting - intravital imaging, genomics, modeling and metastasis
John Stingl, Matthew J Smalley, Marina A Glukhova, Mohamed Bentires-Alj
Breast Cancer Research , 2010, DOI: 10.1186/bcr2630
Abstract: The European Network for Breast Development and Cancer (ENBDC) organized its second meeting to foster interactions and the sharing of protocols between groups working on breast development and cancer. Graduate students, postdocs and research associates were encouraged to attend. The meeting included discussions on genomics, bioinformatics, intravital microscopy, disseminated tumor cells, ex vivo culture and in vivo models for studying breast cancer.Nuno Barbosa-Morais (Cancer Research UK, Cambridge Research Institute) discussed the importance of the correct annotation of microarray probes and of being sure that a probe truly maps to the gene of interest. Further problems to consider are probes that map to intron-exon boundaries, the presence of SNPs, and alternative splicing, which, as is becoming apparent, occurs on a far wider scale than previously appreciated. Splicing may lead to difficulties when summarizing data from multiple probes apparently mapping to the same gene but which in fact detect different splice variants. Overall, it is clear that whatever array platform is being used, application of the latest, most reliable annotation is important. In a test of annotation reliability, it was found that Refseq annotations are a more reliable guide to probe identity than GenBank/UniGene.Britta Weigelt (Cancer Research UK, London Research Institute) spoke on the design of gene expression microarray studies, which fall into three types. The first, class comparison, is a supervised analysis to define molecular differences between predefined groups. The second, class prediction, is a supervised analysis where, after identifying the transcriptional differences between predefined groups, a genomic classifier (signature) is defined to classify new samples. It has become clear that class prediction signatures mainly identify tumors with high proliferation, although they do perform well in identifying poor prognosis tumors of the estrogen receptor-positive type. The third
Lost In Thought: Authenticity in Rap and Literature – A Swedish Case Study
Nichola Smalley
Opticon1826 , 2012, DOI: 10.5334/opt.ag
Abstract: This article explores the notion of authenticity as expressed in literature and in rap. In order to do this, I have chosen two texts that were produced in similar time periods and take as their subject similar conditions and locations. I show how authenticity can be both recreated and destabilised, with the help of two Swedish texts: a rap, and a short story. The two texts in question are The Latin Kings’ ‘Borta i tankar’ (‘Lost in Thought’), and Alejandro Leiva Wenger’s ‘Borta i tankar’ (‘Lost in Thought’). Both texts engage with social conditions in Sweden at the turn of the millennium. The two texts are connected by more than just their name, with the most obvious intersection being the themes they both address. The lyrics of Dogge Doggelito (The Latin Kings’ frontman) depict the struggle of a young man seeking to make something of himself in difficult circumstances. Similarly, Leiva Wenger relates the story of a young man attempting to come to terms with his own abilities, tolerances and opportunities, and the expectations of those around him. However, as I will argue, there are aspects of both texts that make their relationship to authenticity more complex.
Asteroseismology with SuperWASP
Barry Smalley
Physics , 2013, DOI: 10.1017/S174392131301404X
Abstract: The highly successful SuperWASP planetary transit finding programme has surveyed a large fraction of both the northern and southern skies. There now exists in the its archive over 420 billion photometric measurements for more than 31 million stars. SuperWASP provides good quality photometry with a precision exceeding 1% per observation in the approximate magnitude range 9 < V < 12. The archive enables long-baseline, high-cadence studies of stellar variability to be undertaken. An overview of the SuperWASP project is presented, along with results which demonstrate the survey's asteroseismic capabilities.
Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells
Kara L Britt, Howard Kendrick, Joseph L Regan, Gemma Molyneux, Fiona-Ann Magnay, Alan Ashworth, Matthew J Smalley
Breast Cancer Research , 2009, DOI: 10.1186/bcr2245
Abstract: Mice were put through a full-term pregnancy at 9 weeks of age, when the mammary epithelium is mature. The total mammary epithelium was purified from parous 7-week post-lactation and age-matched virgin mice and analysed by flow cytometry and limiting dilution cleared fat pad transplants.There were no significant differences in the proportions of different mammary epithelial cell populations or numbers of CD24+/Low Sca-1- CD49fHigh cells (stem cell enriched basal mammary epithelial compartment). There was no significant difference in stem/progenitor cell frequency based on limiting dilution transplants between the parous and age-matched virgin epithelium.Although differences between parous and virgin mammary epithelium at later time points post lactation or following multiple pregnancies cannot be ruled out, there are no differences in stem/progenitor cell numbers between mammary epithelium isolated from parous animals which were mated at 9 weeks old and virgin animals. However, a recent report has suggested that animals that were mated at 5 weeks old have a twofold reduction in stem/progenitor cell numbers. This is of interest given the association between early, but not late, pregnancy and breast cancer risk reduction in humans. However, a mechanistic connection between stem cell numbers and breast cancer risk remains to be established.It is well established that pregnancy has a profound effect on breast cancer risk [1] (reviewed in [2]). Breast cancer risk is significantly increased immediately after parturition and this elevated risk can last for a period of 5 to 10 years in humans [3,4]. Once this elevated risk period is past, however, breast cancer risk drops in women who have had an early first full-term pregnancy to below the levels of nulliparous women of a similar age. The eventual risk decrease is more profound the earlier the age at which the first full-term pregnancy occurs [1,3,5]; a woman who has a first full-term pregnancy under the age of 20 can reduc
Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate
Howard Kendrick, Joseph L Regan, Fiona-Ann Magnay, Anita Grigoriadis, Costas Mitsopoulos, Marketa Zvelebil, Matthew J Smalley
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-591
Abstract: A whole transcriptome analysis of basal/myoepithelial cells, luminal estrogen receptor negative cells and luminal estrogen receptor positive cells isolated from the virgin mouse mammary epithelium identified 861, 326 and 488 genes as highly differentially expressed in the three cell types, respectively. Network analysis of the transcriptomic data identified a subpopulation of luminal estrogen receptor negative cells with a novel potential role as non-professional immune cells. Analysis of the data for potential paracrine interacting factors showed that the basal/myoepithelial cells, remarkably, expressed over twice as many ligands and cell surface receptors as the other two populations combined. A number of transcriptional regulators were also identified that were differentially expressed between the cell lineages. One of these, Sox6, was specifically expressed in luminal estrogen receptor negative cells and functional assays confirmed that it maintained mammary epithelial cells in a differentiated luminal cell lineage.The mouse mammary epithelium is composed of three main cell types with distinct gene expression patterns. These suggest the existence of a novel functional cell type within the gland, that the basal/myoepithelial cells are key regulators of paracrine signalling and that there is a complex network of differentially expressed transcription factors controlling mammary epithelial cell fate. These data will form the basis for understanding not only cell fate determination and cellular homeostasis in the normal mammary epithelium but also the contribution of different mammary epithelial cell types to the etiology and molecular pathology of breast disease.The function of complex tissues, such as the mammary epithelium, is a product of the interactions between their constituent cell types. In such tissues, disease states like cancer are essentially a failure of this cellular homeostasis and are characterised by insensitivity of cells to external regulatory fa
Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment
Olivia Wansbury, Alan Mackay, Naoko Kogata, Costas Mitsopoulos, Howard Kendrick, Kathryn Davidson, Christiana Ruhrberg, Jorge S Reis-Filho, Matthew J Smalley, Marketa Zvelebil, Beatrice A Howard
Breast Cancer Research , 2011, DOI: 10.1186/bcr2928
Abstract: Here, we define the transcriptome of the mammary primordium and the two distinct cellular compartments that comprise it, the mammary primordial bud epithelium and mammary mesenchyme. Pathway and network analysis was performed and comparisons of embryonic mammary gene expression profiles to those of both postnatal mouse and human mammary epithelial cell sub-populations and stroma were made.Several of the genes we have detected in our embryonic mammary cell signatures were previously shown to regulate mammary cell fate and development, but we also identified a large number of novel candidates. Additionally, we determined genes that were expressed by both embryonic and postnatal mammary cells, which represent candidate regulators of mammary cell fate, differentiation and progenitor cell function that could signal from mammary lineage inception during embryogenesis through postnatal development. Comparison of embryonic mammary cell signatures with those of human breast cells identified potential regulators of mammary progenitor cell functions conserved across species.These results provide new insights into genetic regulatory mechanisms of mammary development, particularly identification of novel potential regulators of mammary fate and mesenchymal-epithelial cross-talk. Since cancers may represent diseases of mesenchymal-epithelial communications, we anticipate these results will provide foundations for further studies into the fundamental links between developmental, stem cell and breast cancer biology.The mammary lineage is first established during organogenesis of the mammary primordium that forms during embryogenesis. Mammary primordia, comprised of mammary epithelial and associated mesenchymal tissues, develop as a result of inductive crosstalk between the surface epithelium and underlying mesenchyme [1]. During mouse embryogenesis, a multilayered epithelial mammary placode is evident at embryonic day (E) 11.0, which reaches the bud stage by E12.0. When E13.0 mamma
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