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发布于:2018-5-18 01:51:16  访问:1 次 回复:0 篇
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Ibrutinib Finally Got You Straight Down? We've Got The Right Formula
genego.com/cgi/data_manager.cgi) to group the selected 512 probes. Selected genes were statistically compared to the entire set of genes spotted onto the array to look for under- and over-represented functional categories. Supporting Information Table 1 shows the 10 biological processes selected with a p-value < 0.05. To validate the microarray data, a selection of 16 genes belonging http://www.selleckchem.com/products/pci-32765.html to four different biological processes including ��Apoptosis and survival�� (BOX 1), ��stress response�� (BOX 2), ��signal transduction�� (BOX 3) and ��transcription-CREB pathway�� (BOX 4) were analyzed by RT-PCR (Supporting Information Fig. 3). To correct for batch effects, analyses were performed on independent pools of RNA purified from the same exponentially growing cells. Results obtained by qRT-PCR (empty columns) reflected those obtained by microarray (full columns) in both qualitative and quantitative terms. This suggests that most array probe sets are likely to accurately measure single transcript levels within a complex mixture of transcripts. Trabectedin has recently been shown to possess a significant antitumor activity in MLS with an objective response rate of ?50%, median progression-free survival of almost 1.5 years and 2-years progression free survival exceeding 30%. However, even after prolonged responses, drug resistance occurs, patients thus requiring alternative treatments.9, 10 To investigate the mechanism of trabectedin click here resistance in MLS, we exposed the sensitive 402-91 cell line to stepwise increases in trabectedin concentrations to generate the resistant cell line, 402-91/ET which is ?10 times less sensitive to the drug. Resistance was irreversible over more than 2 years. The 402-91/ET cell line maintains the typical translocation t(12;16)(q13;p11) that results in the expression of the FUS-CHOP fusion gene, which represents the hallmark and the principal pathogenic lesion of MLS.44�C46 To our knowledge this Alpelisib is the first trabectedin-resistant MLS cell line that has been obtained and characterized. From our present studies, we can exclude that the mechanism of trabectedin resistance was due to a low intracellular drug retention. Not only the expression levels of the multidrug resistant transporters, but also the intracellular drug concentrations were closely similar in the two cell lines. Furthermore, the reduced sensitivity to trabectedin was not related to the higher GSH or cysteine level found in the 402-91/ET cell line. Previous data from this24, 25, 47 and other laboratories26�C28 have indicated that NER deficiency confers resistance to trabectedin. Takebayashi et al.26 characterized a cell line, HCT-116/ER5, which was selected for resistance to trabectedin. This cell line did not express functional XPG because of a point mutation in the XPG gene which resulted in a premature termination codon.
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