Research Progress of Adverse Events Related to PD-1/PD-L1 Inhibitors Based Combination Therapy / 中国肺癌杂志

The development of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of cancer patients, but a large population of patients are still ineffective to ICIs treatment or develop aquired drug resistance. In order to improve the clinical benefits, a number of studies on ICIs based combination therapy have been actively explored, and have achieved satisfactory results. With the application of ICIs based combination therapy in clinical practice, increasing attention has been paid to the safety of combination therapy and the management of treatment-related adverse events. In this review, the characteristics of adverse events related to ICIs based combination therapies, especially programmed cell death protein 1/protein ligand 1 (PD-1/PD-L1) inhibitors are discussed, in order to provide profound thoughts for toxicity evaluation and individualized treatment decision in future clinical practice.
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microRNA-1183 Promotes the Proliferation and Metastasis by Suppressing the Expression of CBL-B in Gastric Cancer Cells / 中国医科大学学报

Objective To investigate the effect of microRNA-1183 on proliferation and metastasis on gastric cancer cells and to explore the role of microRNA-1183 and CBL-B signaling pathways in this process. Methods MGC803 cells were transfected with a microRNA-1183 mimic. Real-time PCR detected the expression of microRNA-1183 in gastric cancer cell line MGC803. MTT detected the proliferative effect of microRNA-1183 on MGC803 gastric cancer cells. A Transwell assay detected the effect of microRNA-1183 on the metastasis of MGC803 gastric cancer cells. A dual luciferase reporter assay detected the binding ability between microRNA-1183 and CBL-B. The expression of the protein was tested by Western blotting. Results MTT assay results showed that microRNA-1183 promoted the proliferation of MGC803 cells. Transwell assay results revealed that microRNA-1183 promoted the metastasis of MGC803 cells. The results of BLAST contrast analysis show that CBL-B is one of the target genes of microRNA-1183. Western blotting analysis showed that the mimic microRNA-1183 inhibited the expression of CBL-B. A dual luciferase reporter assay showed that CBL-B was the target gene of microRNA-1183. A CBL-B knockdown promoted the proliferation and metastasis of MGC803 cells. microRNA-1183 promoted the proliferation and metastasis of MGC803 cells by inhibiting the expression of CBL-B. Conclusion microRNA-1183 can inhibit the proliferation and metastasis of gastric cancer cell lines by inhibiting the expression of CBL-B.

Anti-tumor therapy of thalidomide / 国际肿瘤学杂志

Studies have found that thalidomide has anti-tumor activity due to its inhibitory effect on angiogenesis and immunomodulation,which has been effectively used in targeted therapy resistant non-small cell lung cancer,castration-resistant prostate cancer,colorectal cancer,advanced hepatocarcinoma and advanced gastric cancer.Many clinical studies have also found that it has certain practical value in the aspects of improvement of cancer cachexia and chemotherapy-induced nausea and vomiting.

Role of Akt and SRC Pathways in Exosome-mediated Migration of Homologous Lung Adenocarninoma Cells / 中国医科大学学报

Objective To investigate the effect of Exosomes derived from lung cancer cells on the migration of secretory cells and homologous tumor cells and to explore the role of PI3K/Akt and SRC signaling pathways in this process.Methods Exosomes were isolated from the supematant post density gradient centrifugation of A549,lung cancer cells.Morphology of the Exosomes was studied using transmission electron microscopy.Protein expression was analyzed using Western blotting.Cell migration was analyzed by a transwell assay.Results The double-membrane-bound Exosomes appeared as discal-shaped structures,30-100 nm in diameter.Western blotting showed that CD9 was abundant in the Exosomes.The Exosomes promoted the migration of A549 cells and their homologous tumor cells,HCC827 in a dose-dependent manner,accompanied by the activation of Akt and SRC.Conclusion The Exosomes derived from A549 (lung cancer) cells promote the migration of the secreting cells and the homologous tumor cells.The mechanism may be correlated with the activation of Akt and SRC.

Role of Akt and SRC Pathways in Exosome?mediated Proliferation of Homologous Lung Adenocarninoma Cells / 中国医科大学学报

Objective To explore the effect of Exosomes isolated from the A549 lung cancer cells on the proliferation of these cells and their ho?mologous tumor cells,HCC827,and the role of the PI3K/Akt and SRC signaling pathways in this process. Methods Exosomes were isolated from the supernatant after density gradient centrifugation of A549 cells. The Exosomes morphology was observed by transmission electron microscopy. The expression of the Exosome?specific proteins was analyzed using Western blotting. Cell proliferation was investigated using the MTT assay. Re?sults The A549?derived Exosomes were 30?100 nm in diameter and had a bilayer membrane.Western blotting showed that CD9 was detected in these Exosomes. The isolated Exosomes promoted the proliferation of the A549 and the HCC827 cells in a dose?and time?dependent manner,ac?companied by the activation of Akt and SRC. Conclusion Exosomes isolated from A549 cells promote the proliferation of the secreting cells and the homologous tumor cells in a dose?and time?dependent manner. The mechanism may be related to the activation of Akt and SRC.

Analysis of Clinical Significance of AKT3 Expression in Gastric Cancer Utilizing TCGA Datasets / 中国医科大学学报

Objective To investigate the prognostic value of AKT3 expression in gastric cancer. Methods AKT3 expression data in The Cancer Genome Atlas(TCGA)datasets and its clinical information were downloaded. Statistically assessed was performed for relationship with clinicopatho?logical factors and prognosis. Gene set enrichment analysis(GSEA)was used to predict the gene sets modulated by AKT3. Results The expres?sion of AKT3 was associated with T stage(P=0.001),TNM stage(P=0.049)and differentiation(P<0.001).High level of AKT3 expression indi?cates poor prognosis(P=0.001). AKT3 could regulate gene sets involving cell adhesion molecule,cytoskeleton regulation,focal adhesion and TGF?βsignaling pathway. Conclusion AKT3 could be used as a potential prognostic marker and a therapeutic target in gastric cancer.

Association of UGT1A1*6 Polymorphisms with Irinotecan-induced Toxicities:A Meta-analysis / 中国医科大学学报

Objective To conduct a meta?analysis of literatures to explore the relationship of UGT1A1*6 gene polymorphism and irinotecan toxici?ty,so as to guide clinical treatment. Methods Papers were searched by PubMed database and manual search. The inclusion and exclusion criteria of studies were formulated and the methodologies quality was assessed,data were extracted and the statistical analysis was made using STATA12.0 software. Results A total of 12 articles were included according to the inclusion and exclusion criteria. Patients with mutated UGT1A1*6 showed an increased risk for neutropenia compared to wild UGT1A1*6(OR=2.37,95%CI 1.58?3.55,P=0.001). Both homozygous and heterozygous muta?tion showed an increased risk for neutropenia compared to wild type and the homozygous mutation(OR=5.09,95%CI 2.74?9.45,P<0.001) showed an even higher risk for neutropenia compared to the heterozygous mutation(OR=2.07,95%CI 1.37?3.13,P=0.001). For severe diarrhea, mutated UGT1A1*6 showed an increased risk compared to wild type(OR=1.48,95%CI 0.86?2.55,P=0.153),though without statistical signifi?cance. The homozygous mutation performed a significantly increased risk(OR=3.51,95%CI 1.33?9.25,P=0.011)and the heterozygous mutation also showed increased risk,however,the difference between them was not statistically significant. Conclusion UGT1A1*6polymorphisms can pre?dict irinotecan toxicity,especially for incidence of neutropenia.

Clinical Analysis of Treatment and Prognosis of Patients with Pain Caused by Malignant Bone Metastasis / 中国医科大学学报

Objective To analyze the clinical features,therapeutic effect and prognosis in patients with bone pain induced by malignant bone me?tastasis as well as the rationality of analgesic application,so as to improve the level of diagnosis and treatment for metastatic bone pain. Methods Totally 123 patients with pain due to malignant bone metastasis received antitumor therapy and analgesic therapy based on standardized three?step guidelines. Their clinical characteristics were retrospectively analyzed. Results The total pain relief rate was 85.4%and the pain was significantly relieved(P<0.05). The DUI value of each narcotic agent was close to 1 and the application of narcotic agents tended to be rational. The Kaplan?Meier survival analysis showed that patients with moderate pain had longer survival time than those with severe pain(P=0.015). The survival rate of patients with significant pain relief after treatment was higher than those unrelieved(P=0.021). The survival rate of patients without visceral me?tastasis was higher than those with visceral metastasis(P=0.000). The COX multivariate analysis indicated that the pain intensity and visceral me?tastasis were independent risk factors influencing patient prognosis. Conclusion Standard treatment can improve symptoms in most patients with bone metastasis and prolong survival time. Opioids have satisfactory analgesic effect for moderate to severe pain and the adverse reactions can be tol?erated.

Type 2 diabetes mellitus is a prognostic predictor in patients with resectable pancreatic ductal adenocarcinoma / 中国肿瘤临床

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal human cancers. Cur-rent studies on the relationship between complicated type 2 diabetes mellitus (T2DM) and PDAC prognosis have demonstrated inconsis-tent results. The present study aimed to determine the relationship between complicated T2DM and the clinicopathological characteris-tics of PDAC, and evaluate whether complicated T2DM is a significant predictor for overall survival in patients with resectable PDAC. Methods: In this study, clinicopathological characteristics were observed in 136 patients who underwent surgery for PDAC at the Shengjing Hospital of China Medical University between January 2009 and February 2011. The relationship between complicated T2DM and overall survival of PDAC patients was analyzed using univariate and multivariate analyses. Results:The median age of pa-tients was 60 years (range: 35-80 years). Among the 136 patients, 76(55.9%) were male. The prevalence of complicated T2DM was 27.9%in 136 PDAC cases. Preexisting T2DM was not associated with any of the clinicopathological characteristics (all P>0.05). Uni-variate analysis showed that complicated T2DM (P=0.045), maximum diameter (P=0.011), histological differentiation (P=0.013), pT stage (P=0.034), vessel invasion (P=0.032), and pTNM stage (P=0.030) were significantly associated with the overall survival of PDAC patients. The median overall survival time was 14.2 months for T2DM patients, and 18.8 months for non-T2DM patients. In mul-tivariate analysis, complicated T2DM [hazard ratio (HR), 1.873;95%confidence interval (CI), 1.187-2.954;P=0.007], poorly differenti-ated tumor (HR, 2.647;95%CI, 1.413-4.957;P=0.002), and maximum diameter≥4.0 cm (HR, 1.699;95%CI, 1.094-2.640;P=0.018) were the independent predictors associated with poor overall survival. Conclusion:Complicated T2DM was associated with poor prog-nosis. It could be used as a prognostic predictor in patients with resectable PDAC. If confirmed, these findings may provide a novel ap-proach for individualized adjuvant therapy.

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Arsenic trioxide (ATO) is a strong inducer of apoptosis in malignant hematological cells. Inducible phosphatidyl inositol 3 kinase (PI3K)-Akt activation promotes resistance to ATO. In the present study, we evaluated whether E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in the action of ATO. The effect of ATO on cell viability was measured by the Trypan blue exclusion assay or by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was determined by flow cytometry and protein expression was assayed by Western blotting. ATO decreased the viability of HL60 cells and induced cellular apoptosis, which was accompanied by transient activation of Akt. The PI3K/Akt inhibitor, LY294002, significantly increased ATO-induced apoptosis (P < 0.05). In addition, ATO up-regulated the expression of Cbl-b proteins. Furthermore, ATO inhibited cell viability with an IC50 of 18.54 μM at 24 h in rat basophilic leukemia-2H3 cells. ATO induced cellular apoptosis with transient activation of Akt and Cbl-b was also up-regulated. Rat basophilic leukemia-2H3 cells transfected with a dominant negative (DN) Cbl-b mutation showed overexpression of Cbl-b (DN) and enhanced Akt activation. Compared with cells transfected with vector, ATO-induced apoptosis was decreased and G2/M phase cells were increased at the same concentration (P < 0.05). The PI3K/Akt inhibitor, LY294002, re-sensitized Cbl-b (DN) overexpressing cells to ATO and reversed G2/M arrest (P < 0.05). Taken together, these results suggest that Cbl-b potentiates the apoptotic action of ATO by inhibition of the PI3K/Akt pathway.

Relationship between the Sensitivity of Gastric Cancer Cells to Arsenic Trioxide and the Increase of Reactive Oxygen Species Level / 中国医科大学学报

Objective To investigate the relationship between the sensitivity of gastric cancer cells to arsenic trioxide（As2O3）and the level of reactive oxygen species（ROS）production.Methods The viability of gastric cancer cell lines MGC803,BGC823 and SGC7901 treated with As2O3 was determined by MTT assay.ROS levels of the gastric cancer cells before and after the treatment of As2O3 were detected by flow cytometry.Results Cell growth was significantly inhibited by As2O3 in time-and dose-dependent manner in three gastric cancer cell lines.The IC50（72 h）of As2O3 for MGC803,BGC823 and SGC7901 was about 2.8,3.1 and 10.2 μmol/L,respectively.IC50（72 h）of MGC803 and BGC823 was lower than that of SGC7901（P 0.01）,gastric cancer cell line SGC7901 was less sensitive than the others.The inherent ROS level of MGC803,BGC823 and SGC7901 was 20.3±2.0,64.2±3.3 and 57.7±2.0.After treatment with As2O3 5 μmol/L for 24 h,the peak level of ROS in MGC803 and BGC823 cells increased to 100.8±3.8 and 103.5±2.3,compared with inherent ROS level,the difference had statistical significance（P 0.001,P 0.01）,but the inherent ROS level in SGC7901 cells was 56.5±2.4（P 0.05）.Conclusion The sensitivity of gastric cancer cells to arsenic trioxide is associated with the increase of reactive oxygen species level.

Oxaliplatin Enhances TRAIL-induced Apoptosis in Gastric Cancer Cells by Inhibiting PI3K/Akt Pathway / 中国医科大学学报

Objective To investigate the role of phosphoinositide 3-kinases （PI3K）/Akt signaling pathway in TRAIL-induced cell apoptosis, and the effect of oxaliplatin on TRAIL-induced apoptosis in gastric cancer BGC823 cells. Methods Cell proliferation was roeasured using MTT assay. Cell apoptosis was determined by flow eytoroetry. The expression of Akt and phospbor-Akt were determined by Western blotting. Results 100 ng/mL TRAIL caused little cell apoptosis in BGC823 cells. TRAIL activated P13K/Akt pathway. Pretreated with PI3K in- hibitor LY294002 （25 μmol/L）for 1 h followed by exposure to TRAIL for 16 h,the cell apoptosis was obviously higher （12.7%±3,1% vs 3.5%±1.1% ,P 〈 0.05） than that without the treatment of LY294002. Treatment with 38 μg/mL oxaliplatin blocked the activation of P13K/ Akt signaling, and enhanced the sensitivity of cells to TRAIl,, the rate of cell apoptosis increased to 35.5%±4.5% （P 〈 0.05 ）. Conclusion Oxaliplatin enhanced the sensitivity of gastric cancer BGC823 cells to TRAIL by inhibiting TRAIL-induced the activation of PI3K/Akt pathway.

The Role of NF-kappa B Signaling Pathway in TNF-α-induced Gastric Cancer Cell Apoptosis / 中国医科大学学报

Objective To investigate the role of nuclear factor kappa-B（NF-κB）signaling pathway in tumor necrosis factor α（TNF-α）-induced apoptosis in gastric cancer cells.Methods Human gastric cancer cell line SGC7901 was treated with TNF-α for 24 hours.MTT assay,flowcytometry and Western blot was used to detect the cell viability and apoptosis.Transient transfection was performed by using Lipofectamine 2000 reagent.The cells of experimental group and control group were respectively transfected with mutant IκB cDNA and vectors.Results Under the treatment of 100,1 000 or 10 000 U/ml TNF-α,the cell viability of SGC7901 cells was（99.2±0.6）%,（92.0±2.7）% and（97.9±2.2）%,respectively.Further study showed that TNF-α engagement led to rapid activation of NF-κB signaling pathway.Blockage of TNF-α-induced NF-κB activation by transient transfection with a mutant IκB enhanced the sensitivity of cells towards TNF-α-induced apoptosis.Conclusion In human gastric cancer cells,activation of NF-κB signaling pathway by TNF-α might be responsible for the resistance to TNF-α-induced apoptosis.Blockage of NF-κB significantly enhanced the apoptosis induced by TNF-α.

The expression and clinical significance of FGFR2, and c-Cbl in gastric carcinoma / 中国癌症杂志

Background and purpose: FGFR2 is a receptor tyrosine kinase and c-Cbl is a new RING finger type of ubiquitin ligase in the ubiquitin-proteasomes path. The purpose of this study was to evaluate the expression and significance of FGFR2 and c-Cbl in gastric carcinoma. Methods: The expression of FGFR2 and c-Cbl were detected by immunohistochemical method of SP. Results: The positive expression rates of FGFR2 and c-Cbl were 77.4%,71.0% in gastric carcinoma, respectively, both were higher than those normal tissue (P<0.05);The expression of FGFR2 and c-Cbl were positively correlated with depth of invasion and TNM staging, and there was a positive relationship between the expressions of FGFR2 and c-Cbl. Conclusion. The expressions of FGFR2 and c-Cbi were associated with some clinicopathologic features in gastric carcinoma, indicating that their expression may be the prognostic factors for gastric carcinoma.

WT1 downregulation during K562 cell differentiation and apoptosis induced by bufalin / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the change of WT1 gene expression during human leukemic K562 cell differentiation and apoptosis induced by bufalin.</p><p><b>METHODS</b>Cell viability was determined by trypan blue exclusion, cell differentiation and apoptosis by nitro blue tetrazolium (NBT) reduction test, morphology and flow cytometry, expression of WT1 protein by Western blot analysis, and expression of WT1 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR).</p><p><b>RESULTS</b>(1) The cell proliferation was inhibited by bufalin and the IC(50) at 24, 48, 72 h were 0.026, 0.032 and 0.006 micro mol/L, respectively. (2) Bufalin induced K562 cell differentiation towards macrophage/monocyte within concentration from 0.01 to 0.05 micro mol/L and apoptosis at higher than 0.026 micro mol/L. (3) The expression of WT1 protein and mRNA were downregulated by bufalin in the initial stage of differentiation and apoptosis induced by bufalin.</p><p><b>CONCLUSION</b>K562 cell differentiation and apoptosis induced by bufalin might relate to the downregulation of WT1 expression.</p>