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1. chinaXiv:201803.00958 [pdf]

PIK3CA and AKT2 mutations of gastric cancer in China

wenxiang cheng
Subjects: Biology >> Genetics

Mutations in PI3K and/or AKT have been reported in a variety of cancers. This indicates that the two pathways interact to cause cancer. We have therefore investigated their roles in gastric cancer (GC) in China. In our study, exons 9, 18 and 20 of PIK3CA gene and exons 6~14 of AKT2 gene were screened in 10 GC cell lines and 100 advanced primary GC together with matched normal tissues. Denaturing high performance liquid chromatography (DHPLC) and DNA sequencing were used to analyze the mutations in the two genes. Two point mutations in the PIK3CA gene were identified in 4 of 10 GC cell lines and in 4 of 100 GC primary tumors. Two polymorphisms in AKT2 were detected in 19 of 100 GC primary tumors. One point mutation in AKT2 was detected in 1 of 10 GC cell lines and 3 of 100 GC primary tumors, and no hot spot variation was detected. Our results indicate that PIK3CA and AKT2 mutations are found in GC, although not a common event, therefore they might still play an important role in mediating kinase activities towards gastric carcinogenesis.

submitted time 2018-03-16 Hits2416Downloads1211 Comment 0

2. chinaXiv:201703.01011 [pdf]

Identification of EGFR kinase domain mutations among lung cancer patients in China: implication for targeted cancer therapy

Qin, BM; Chen, X; Zhu, JD; Pei, DQ
Subjects: Biology >> Biomedical Laboratory Science

Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.

submitted time 2017-03-30 Hits1897Downloads673 Comment 0

3. chinaXiv:201605.01518 [pdf]

Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells

Cao, Wei; Zhang, Ran; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Huang, Laiqiang; Cao, Wei; Liu, Ying; Zhang, Ran; Wang, Teng; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Huang, Laiqiang; Cao, Wei; Liu, Ying; Zhang, Ran; Wang, Teng
Subjects: Biology >> Biophysics

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia, on Gefitinib-resistant NSCLC cell lines in vitro and in vivo. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGF beta signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo. Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.

submitted time 2016-05-12 Hits1742Downloads885 Comment 0

4. chinaXiv:201605.01321 [pdf]

Peptidyl-prolyl isomerization targets rice Aux/IAAs for proteasomal degradation during auxin signalling

Jing, Hongwei; Yang, Xiaolu; Zhang, Jian; Zheng, Huakun; Nian, Jinqiang; Feng, Jian; Li, Jiayang; Zuo, Jianru; Jing, Hongwei; Yang, Xiaolu; Zhang, Jian; Zheng, Huakun; Nian, Jinqiang; Feng, Jian; Li, Jiayang; Zuo, Jianru; Jing, Hongwei; Yang, Xiaolu; Zheng, Huakun; Liu, Xuehui
Subjects: Biology >> Biophysics

In plants, auxin signalling is initiated by the auxin-promoted interaction between the auxin receptor TIR1, an E3 ubiquitin ligase, and the Aux/IAA transcriptional repressors, which are subsequently degraded by the proteasome. Gain-of-function mutations in the highly conserved domain II of Aux/IAAs abolish the TIR1-Aux/IAA interaction and thus cause an auxin-resistant phenotype. Here we show that peptidyl-prolyl isomerization of rice OsIAA11 catalysed by LATERAL ROOTLESS2 (LRT2), a cyclophilin-type peptidyl-prolyl cis/trans isomerase, directly regulates the stability of OsIAA11. NMR spectroscopy reveals that LRT2 efficiently catalyses the cis/trans isomerization of OsIAA11. The lrt2 mutation reduces OsTIR1-OsIAA11 interaction and consequently causes the accumulation of a higher level of OsIAA11 protein. Moreover, knockdown of the OsIAA11 expression partially rescues the lrt2 mutant phenotype in lateral root development. Together, these results illustrate cyclophilin-catalysed peptidyl-prolyl isomerization promotes Aux/IAA degradation, as a mechanism regulating auxin signalling.

submitted time 2016-05-11 Hits789Downloads416 Comment 0

5. chinaXiv:201605.01245 [pdf]

Serial in Vivo Imaging Using a Fluorescence Probe Allows Identification of Tumor Early Response to Cetuximab Immunotherapy

Ma, Teng; Liu, Hao; Sun, Xianlei; Gao, Liquan; Shi, Jiyun; Zhao, Huiyun; Jia, Bing; Wan, Fan; Liu, Zhaofei; Ma, Teng; Liu, Hao; Sun, Xianlei; Gao, Liquan; Jia, Bing; Wan, Fan; Liu, Zhaofei; Shi, Jiyun; Zhao, Huiyun
Subjects: Biology >> Biophysics

Cetuximab is an antiepidermal growth factor receptor (EGFR) monoclonal antibody that has received the approval of the Food and Drug Administration (FDA) for cancer treatment. However, most clinical studies indicate that cetuximab can only elicit positive effects on a subset of cancer patients. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging of tumor vascular endothelial growth factor (VEGF) expression could be a biomarker for tumor early response to cetuximab therapy in preclinical wild-type and mutant tumor models of the KRAS gene. The treatment efficacy of cetuximab was determined in both HT-29 (wild-type KRAS) and HTC-116 (mutant KRAS) human colon cancer models. A VEGF-specific optical imaging probe (Dye755-Ran) was synthesized by conjugating ranibizumab (an anti-VEGF antibody Fab fragment) with a NIRF dye. Serial optical scans with Dye755-Ran were performed in HT-29 and HTC-116 xenograft models. By using longitudinal NIRF imaging, we were able to detect early tumor response on day 3 and day 5 after initiation of cetuximab treatment in the cetuximab-responsive HT-29 tumor model. Enzyme-linked immunosorbent assay (ELISA) confirmed that cetuximab treatment inhibited human VEGF expression in the KRAS wild-type HT-29 tumor but not in the KRAS mutant HCT-116 tumor. We have demonstrated that the antitumor effect of cetuximab can be noninvasively monitored by serial fluorescence imaging using Dye755-Ran. VEGF expression detected by optical imaging could serve as a sensitive biomarker for tumor early response to drugs that directly or indirectly act on VEGF.

submitted time 2016-05-11 Hits1424Downloads745 Comment 0

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