The Role Of Multidisciplinary In The Diagnosis And Therapy Of Gastric Cancer

Gastric cancer is a common malignant tumors with high morbidity and mortality in China.How to improve the diagnosis rate of early gastric cancer and find new strategies for the treatment of advanced gastric cancer are the key topics of current medical research.With the development of science,the cross integration of medicine and other related disciplines has become a trend.The first part of this research combines the medical imaging with artificial intelligence technology,choosing Helicobacter pylori infection as the explorative model,in order to extend the artificial intelligence technology to early gastric cancer recognition in the future.Patients who received upper endoscopy and gastric biopsies at Hospital(January 2015-June 2015)were retrospectively searched.A novel Computer-Aided Decision Support System that incorporates Convolutional Neural Network(CNN)model(ResNet-50)based on endoscopic gastric images was developed to evaluate for H.pylori infection.Diagnostic accuracy was evaluated in an independent validation cohort.Of 1,959 patients,1,507(77%)including 11,729 gastric images were assigned to the derivation cohort,and 452(23%)including 3,755 images were assigned to the validation cohort.Area under the curve for multiple gastric images(8.3±3.3)per patient was 0.97(95%CI 0.96-0.99)with sensitivity,specificity,and accuracy of 91.6%(95%CI 88.0%-94.4%),98.6%(95%CI 95.0%-99.8%),and 93.8%(95%CI 91.2%95.8%),respectively,using an optimal cutoff value of 0.4.In this pilot study,CNN using multiple archived gastric images achieved high diagnostic accuracy for the evaluation of H.pylori infection.The second part of this research combines medical engineering and oncology therapeutics to explore new strategies for targeted therapy of advanced gastric cancer.Studies have demonstrated that about 30%of human tumors have RAS proto-oncogene amplification or activating mutations.Targeting the RAS protein and its downstream signaling molecules has become a hot spot in the research of anti-tumor drugs.However,adaptive resistance to MAPK/MEK inhibitors is a major challenge in targeted therapy.In this study,we found that KRAS mutant gastric cancer cell lines are sensitive to MEK inhibitors,but SHP2 activation and reactivation of the MAPK signaling pathway lead to adaptive resistance to MEK inhibitors.The combination of MEK inhibitor and SHP099 had a synergistic anti-tumor effect and resulted in potent and durable suppression of pERK.Mechanistically,SHP2 activation disrupts its ability to bind with KSR1,then KSR1 shift and anchor to the cell membrane,promoting MAPK signal propagation.KSR1 knockdown increases the sensitivity of KRAS mutant gastric cancer cell lines to MEK inhibitors,while KSR1 activation weakens the synergistic anti-tumor effect of SHP099 and MEK inhibitors.This study is the first to explore the molecular mechanism of SHP2 regulating KSR1 activation,which is helpful to understand the pattern of combination of kinase and phosphatase targeting,and provides new ideas for precise therapy of gastric cancer and the development of small inhibitors.