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  • 1
    Language: English
    In: International Journal of Molecular Sciences, 01 March 2018, Vol.19(3), p.767
    Description: The major obstacle in the clinical use of the antitumor drug cisplatin is inherent and acquired resistance. Typically, cisplatin resistance is not restricted to a single mechanism demanding for a systems pharmacology approach to understand a whole cell’s reaction to the drug. In this study, the cellular transcriptome of untreated and cisplatin-treated A549 non-small cell lung cancer cells and their cisplatin-resistant sub-line A549rCDDP2000 was screened with a whole genome array for relevant gene candidates. By combining statistical methods with available gene annotations and without a previously defined hypothesis HRas, MAPK14 (p38), CCL2, DOK1 and PTK2B were identified as genes possibly relevant for cisplatin resistance. These and related genes were further validated on transcriptome (qRT-PCR) and proteome (Western blot) level to select candidates contributing to resistance. HRas, p38, CCL2, DOK1, PTK2B and JNK3 were integrated into a model of resistance-associated signalling alterations describing differential gene and protein expression between cisplatin-sensitive and -resistant cells in reaction to cisplatin exposure.
    Keywords: Cisplatin Resistance ; Cellular Signalling ; Hras ; P38 ; Ccl2 ; Dok1 ; Ptk2b ; Jnk3 ; Biology
    E-ISSN: 1422-0067
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  • 2
    Language: English
    In: Cell Reports, 05 June 2018, Vol.23(10), pp.3042-3055
    Description: Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications. Jenks et al. demonstrate that enhanced ciliogenesis can facilitate resistance to a number of kinase inhibitors. Both acquired and resistant cells show increases in cilia numbers and length and increased Hedgehog signaling. Targeting ciliogenesis or ciliary signaling overcomes kinase inhibitor resistance.
    Keywords: Cilia ; Kinase Inhibitor ; Resistance ; Hedgehog Pathway ; Fgfr ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 3
    Language: English
    In: International Journal for Parasitology, March 2018, Vol.48(3-4), pp.197-201
    Description: parasites are a major cause of diarrhoea that pose a particular threat to children in developing areas and immunocompromised individuals. Curative therapies and vaccines are lacking, mainly due to lack of a long-term culturing system of this parasite. Here, we show that COLO-680N cells infected with two different strains produce sufficient infectious oocysts to infect subsequent cultures, showing a substantial fold increase in production, depending on the experiment, over the most optimistic HCT-8 models. Oocyst identity was confirmed using a variety of microscopic- and molecular-based methods. This culturing system will accelerate research on and the development of anti- drugs.
    Keywords: Cryptosporidium ; Cell Culture ; Colo-680n ; Lipidomics ; Proteomics ; Atomic Force Microscopy ; Immunofluorescence Microscopy ; Electron Microscopy ; Biology ; Zoology
    ISSN: 0020-7519
    E-ISSN: 1879-0135
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