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  • 1
    Publication Date: 2014-06-10
    Description: Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells, was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2-GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boumahdi, Soufiane -- Driessens, Gregory -- Lapouge, Gaelle -- Rorive, Sandrine -- Nassar, Dany -- Le Mercier, Marie -- Delatte, Benjamin -- Caauwe, Amelie -- Lenglez, Sandrine -- Nkusi, Erwin -- Brohee, Sylvain -- Salmon, Isabelle -- Dubois, Christine -- del Marmol, Veronique -- Fuks, Francois -- Beck, Benjamin -- Blanpain, Cedric -- England -- Nature. 2014 Jul 10;511(7508):246-50. doi: 10.1038/nature13305. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; 1] Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2]. ; 1] Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium [2] DIAPATH-Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; Laboratory of Cancer Epigenetics, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; Machine Learning Group, Computer Science Department, Faculte des Sciences, Universite Libre de Bruxelles, Brussels B-1050, Belgium. ; Department of Dermatology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; 1] Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium [2] WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Carcinoma, Squamous Cell/genetics/pathology ; Cell Adhesion/genetics ; Cell Proliferation ; Cell Transformation, Neoplastic/*genetics/metabolism ; Disease Models, Animal ; Gene Deletion ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Gene Regulatory Networks/genetics ; Mice ; Mice, Inbred Strains ; Neoplastic Stem Cells/*metabolism ; SOXB1 Transcription Factors/genetics/*metabolism ; *Skin Neoplasms/genetics/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-08-13
    Description: Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Keymeulen, Alexandra -- Lee, May Yin -- Ousset, Marielle -- Brohee, Sylvain -- Rorive, Sandrine -- Giraddi, Rajshekhar R -- Wuidart, Aline -- Bouvencourt, Gaelle -- Dubois, Christine -- Salmon, Isabelle -- Sotiriou, Christos -- Phillips, Wayne A -- Blanpain, Cedric -- England -- Nature. 2015 Sep 3;525(7567):119-23. doi: 10.1038/nature14665. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; Institut Jules Bordet, Universite Libre de Bruxelles, Brussels B-1000, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; DIAPATH - Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne 3002, Australia. ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3002, Australia. ; WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266985" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/metabolism/*pathology ; Cell Differentiation/genetics ; Cell Division ; Cell Lineage ; Cell Transformation, Neoplastic ; Female ; Genes, p53/genetics ; Humans ; Mammary Neoplasms, Animal/*genetics/metabolism/*pathology ; Mice ; Mutation/genetics ; Neoplasm Invasiveness/genetics ; Phenotype ; Phosphatidylinositol 3-Kinases/*genetics/metabolism ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-06-27
    Description: Daptomycin is a last-resort membrane-targeting lipopeptide approved for the treatment of drug-resistant staphylococcal infections, such as bacteremia and implant-related infections. Although cases of resistance to this antibiotic are rare, increasing numbers of clinical, in vitro , and animal studies report treatment failure, notably against Staphylococcus aureus . The aim of this study was to identify the features of daptomycin and its target bacteria that lead to daptomycin treatment failure. We show that daptomycin bactericidal activity against S. aureus varies significantly with the growth state and strain, according to the membrane fatty acid composition. Daptomycin efficacy as an antibiotic relies on its ability to oligomerize within membranes and form pores that subsequently lead to cell death. Our findings ascertain that daptomycin interacts with tolerant bacteria and reaches its membrane target, regardless of its bactericidal activity. However, the final step of pore formation does not occur in cells that are daptomycin tolerant, strongly suggesting that it is incapable of oligomerization. Importantly, membrane fatty acid contents correlated with poor daptomycin bactericidal activity, which could be manipulated by fatty acid addition. In conclusion, daptomycin failure to treat S. aureus is not due to a lack of antibiotic-target interaction, but is driven by its capacity to form pores, which depends on membrane composition. Manipulation of membrane fluidity to restore S. aureus daptomycin bactericidal activity in vivo could open the way to novel antibiotic treatment strategies.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 4
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 0168-583X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Biochimie 69 (1987), S. 1257-1260 
    ISSN: 0300-9084
    Keywords: cell cycle ; concanavalin A ; concanavaline A ; cycle cellulaire ; lymphocytes ; lymphocytes ; metabolism ; metabolisme ; phosphate ; phosphate ; phosphatidyl choline ; phosphatidyl choline
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0012-1606
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Leukotrienes (LT), and in particular LTB4, are potent inflammatory mediators and immunomodulators. In its interactions with leukocytes, LTB4 can activate numerous functions of neutrophils and modulate the activities of various lymphocyte subsets. LTB4 can also augment macrophage and monocyte cytotoxic activities and enhance their production of hydrogen peroxide and the monokines interleukin 1 and tumor necrosis factor. These observations allow a more detailed understanding of the effects of LTB4 on cellular immune and inflammatory functions.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We have produced epitaxial Si1−x−yGexCy/Si heterostructures by rapid thermal chemical vapor deposition using methylsilane SiCH6). These layers were grown in the SiH4/GeH4/SiCH6/H2 system between 550 and 600 °C at 1.5 Torr. Suitable process conditions were found that allow very efficient substitutional carbon incorporation. No carbon cross contamination was observed. Crystal quality, chemical composition, and lattice strain were deduced from Nomarski microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, secondary ion mass spectrometry, and x-ray diffraction. Defect-free alloy layers with compositions of up to 20 at.% Ge and 2.2 at. % C were produced. The lattice parameter was tailored so that the strain in these layers gradually moved from compressive to tensile. A tensile strain of up to 0.35% was achieved. © 1995 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1238
    Keywords: Key words Ether ; Acute respiratory distress syndrome ; Nitric oxide ; Corticosteroid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To the best of our knowledge, no case of ether-induced acute respiratory distress syndrome (ARDS) has been published as yet. A 36-year-old female developed pneumonitis which showed all the characteristics of a chemical-associated ARDS due to intravenous self-administration of ether: the hemodynamic investigation demonstrated a normal blood flow pattern with low left-heart filling pressure while the anteroposterior roentgenogram evidenced disseminated bilateral lung edema. Advanced symptomatic respiratory support including inhaled nitric oxide and steroidal anti-inflammatory use was the treatment of choice.
    Type of Medium: Electronic Resource
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