Gastrointestinal stromal tumors (GIST) are the most common mesenchymal-derived tumors of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) are the cornerstone of GIST therapy, but mutations in resistance genes pose many problems for treatment, especially the heterogeneity of KIT resistance mutations. In recent years, with the release of a number of GIST related drug research and experimental results, the great potential of targeted therapy, immunotherapy and combination therapy to treat GIST in different directions has been revealed, providing more therapeutic directions for GIST. This article will review the experimental research and future direction in recent years.

Humans ; Hypertension, Pulmonary/surgery* ; Learning Curve ; Angioplasty, Balloon ; Pulmonary Embolism/therapy* ; Chronic Disease ; Pulmonary Artery/surgery*

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC = 66 nmol/L) and VEGFR2 autophosphorylation in cells (ECs ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy and exhibited good PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.

Objective To investigate the related factors of central regional lymph node metastasis (CLNM) in patients with papillary thyroid microcarcinoma (PTMC).Methods The clinical and pathological fea tures of 550 cases of PTMC with clinical lymph node negative (cN0) were retrospectively analyzed.x2 test and multivariate logistic regression analysis were used to analyze the related factors of CLNM.ROC curve was used to analyze tumor diameter and CLNM of PTMC.Results The CLNM rate was 35.6％.Univariate analysis showed that patients aging less than 45 y(x2=13.983,P＜0.001),with tumor diameter≥7 mm (x2=14.263,P＜0.001),with capsule invasion (x2=7.316,P=0.006),multifocality (x2=14.321,P＜0.05) and bilateral tumors (x2=9.265,P=0.002) were more likely to have CLNM.Multivariate Logistic regression analysis showed that age ＜45 y,tumor diameter ≥7 mm,invasion of capsule and multifocal are all independent risk factors of CLNM for patients with PTMC.The optimal cutoff value of CLNM by diameter was 8 mm.Conclusion The CLNM of PTMC is related to many factors.When the age of the patient is less than 45 y,the diameter of the tumor is more than 7 mm,the invasion of the capsule and the multifocal lesion,the central lymph node dissection should be performed.

Objective To explore the FOXP3-related mechanism underlying head and neck squamous cell carcinoma.Methods We used cbioportal to identify the co-expressed genes of FOXP3 in 279 samples from head and neck squamous cell carcinoma in TCGA database.We used String database to establish the co-expression network of FOXP3.The function of co-expression network was identified through DAVID database.We used miRTarBase and StarBase database to screen the microRNA,lncRNA and circRNA that regulate FOXP3.Finally,Cytoscape software was used to establish FOXP3-related ceRNA network.Results We found 950 FOXP3 related co-expressed gene.(Spearman score over 0.5) These genes were enriched in immune response including T cell,leukocyte and lymphocyte activation.CeRNA network revealed that 2 microRNAs (i.e.,miR-31-5p and miR-210-3p),42 lncRNAs (e.g.,XIST,TUG1,JRK and LINC00473) and 31 circRNAs (e.g.,ZNF223 _hsa_ circ_ 000898 and ISY1 _hsa _circ _001090) could regulate FOXP3.Conclusion We established FOXP3-related ceRNA network and identified 42 lncRNAs and 31 circRNAs that regulate FOXP3.The data generated from this study could provide a new cut point in research and treatment of head and neck squamous cell carcinoma.

Objective To find out the expression relation between TP53 and NOTCH1,and to explore their effects in head and neck squamous cell carcinoma.Methods Obtained the differentially expressed genes data of head and neck squamous cell carcinoma from 279 samples in TCGA database.Analyzed the co-expression relation between TP53 and NOTCH1 through Pearson and Spearman method.Cbioportal was used to analyze their co-expressed genes.Establish the co-expression network of TP53 and NOTCH1 with String database.The pathway and function of co-expression network was identified through KEGG and DAVID database respectively.Results Among the 279 samples,TP53 and NOTCH1 was co-expressed in head and neck squamous cell carcinoma.(Pearson score =0.45;Spearman score =0.41) There were 182 interaction pairs of TP53 and NOTCH1 related co-expressed gene according to the String database.(Pearson and Spearman score ＞ 0.3)These genes were enriched in some pathways such as T cell receptor signaling pathway,cell cycle,cell adhesion molecules and so on.These genes were enriched in some tumor related function including immune response,regulation of transposition,regulation of apoptotic process,cell cycle,regulation of GTPase activity and so on.Conclusion TP53 and NOTCH1 was co-expressed.Through establishing co-expressed network of TP53 and NOTCH1 and bioinformatics analysis,their function and signaling pathway were explored.The data generated from this study could provide a new reference in mechanism research of head and neck squamous cell carcinoma.

Objective Screening the functional gene modules that can play important roles in hypopharyngeal cancer and the potential anti-cancer drugs.Methods GEO database and MeV software were employed to screen the differentially expressed genes in hypopharyngeal cancer.Using STRING database,the protein-protein interaction network was identified.MCODE plugin of Cytoscape was used to identify the functional gene modules in the network.Based on DAVID database,the functions of modules were identified.DrugBank was used to screen the potential drugs that regulate the target genes of modules.Results 1 222 differentially expressed genes including 219 interaction pairs were i-dentified in whole genome profiling(P <0.05 ).Seven functional modules were identified in the network.The results of function analysis showed the module genes were enriched in cancer development related-function ‘regulation of angiogenesis’,‘cell adhesion’,‘DNA meta-bolic process’.A total of 50 potential drugs that regulating the 5 modules were screened.Conclusion Five functional modules that regulate the progress of hypopharyngeal cancer were identified,and maybe they can promote hypopharyngeal cancer through some functions such as regulation of angiogenesis 18 up-regulated protein kinases were identified.Their kinase inhibitors may potential have a role in anti-cancer, which provides a new target point for molecular therapy of nasopharyngeal cancer.

Objective To evaluate the effect of fluid load on the prognosis of severe hand , foot and mouth disease in children. Methods The patients with severe hand foot and mouth disease in the emergency department of PICU in our hospital were enrolled as the research object. We would collect demographic characteristics , labora-tory tests and clinical data: age, gender, focus, basic disease, and simplified acute severity score (SAPS)Ⅱ and record the cumulative amount of fluid balance at 24, 48, 72 hours after admission. Results There was a signifi-cant difference on fluid balance at 48 and 72 hours between the survival group and the death group , the death group appeared the positive liquid balance , and there were significant differences in PICU retention time , mechani-cal ventilation rate, MODF involved organs, mortality and other prognostic indicators between the negative fluid balance group and the positive fluid balance group. Conclusion Fluid balance is an important treatment for severe hand foot and mouth disease, and positive liquid balance is related to mortality and other adverse prognosis.

Heart Diseases ; Humans ; Ryanodine Receptor Calcium Release Channel