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08 June 2022, Volume 49 Issue 6 Previous Issue    Next Issue

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Mechanism study on regulation of glioblastoma cell proliferation and apoptosis by sciadopitysin combined with CX-4945 through Notch1 pathway Lian Haiwei, Yang Shuorui, Liu Renzhong 2022, 49 (6):  321-326.  doi: 10.3760/cma.j.cn371439-20220118-00061 Abstract ( 519 )   HTML ( 37 )   PDF (1291KB) ( 206 )   Save ObjectiveTo investigate the effects and mechanism of sciadopitysin combined with CK2 inhibitor CX-4945 on proliferation and apoptosis of glioblastoma U87 cells. Methods Glioblastoma U87 cells were cultured in vitro, and treated with 0.01, 0.10, 1.00, 10.00, 100.00 μmol/L of sciadopitysin respectively. U87 cells were treated with 1.25, 2.50, 5.00, 10.00, 20.00 μmol/L of CX-4945. U87 cells were divided into control group （without any treatment）, sciadopitysin group （100.00 μmol/L of sciadopitysin）, CX-4945 group （5.00 μmol/L of CX-4945）, sciadopitysin combined with CX-4945 group （100.00 μmol/L of sciadopitysin plus 5.00 μmol/L of CX-4945）. MTT method was used to detect cell viability, Caspase3/7 activity assay and Annexin Ⅴ/ PI double staining were used to detect cell apoptosis, and Western blotting was used to detect the expressions of Notch1 pathway related proteins ICN1, HES1 and DLL3. Results The cell viabilities of U87 cells treated with 0, 0.01, 0.10, 1.00, 10.00, 100.00 μmol/L of sciadopitysin were （100.00±6.30）%, （112.02±7.63）%, （140.84±6.73）%, （113.92±7.92）%, （102.60±7.12）% and （73.16±2.74）% respectively, and there was a statistically significant difference （F=55.21, P<0.001）. There were statistically significant differences in the cell viabilities of U87 cells between 0 μmol/L and 0.01, 0.10, 1.00, 100.00 μmol/L of sciadopitysin treatment （P=0.009; P<0.001; P=0.003; P<0.001）. The cell viability of U87 cells was inhibited by 100.00 μmol/L of sciadopitysin, while sciadopitysin at other low concentrations manifested as enhancement or no obvious effect. The cell viabilities of U87 cells treated with 0, 1.25, 2.50, 5.00, 10.00, 20.00 μmol/L of CX-4945 were （100.00±5.53）%, （108.70±10.24）%, （93.14±2.82）%, （81.46±4.92）%, （56.92±3.99）% and （31.24±2.67）% respectively, and there was a statistically significant difference （F=135.18, P<0.001）. There were statistically significant differences in the cell viabilities of U87 cells between 0 μmol/L and 1.25, 5.00, 10.00, 20.00 μmol/L of CX-4945 treatment （P=0.022; P<0.001; P<0.001; P<0.001）. Low concentration （1.25 μmol/L） of CX-4945 enhanced the cell viability of U87 cells, however higher concentrations （5.00, 10.00, 20.00 μmol/L） of CX-4945 shown inhibitory effect. The cell viabilities of U87 cells in the control group, sciadopitysin group, CX-4945 group and sciadopitysin combined with CX-4945 group were （100.00±5.53）%, （71.96±2.10）%, （77.66±4.12）% and （42.56±4.22）% respectively, and there was a statistically significant difference （F=160.56, P<0.001）. There were statistically significant differences between the control group and each treatment groups （all P<0.001）. There were statistically significant differences between the sciadopitysin combined with CX-4945 group and sciadopitysin group, CX-4945 group （both P<0.001）. The Caspase3/7 activities of U87 cells in the above four groups were 2.34±0.47, 4.02±0.22, 3.67±0.32 and 5.85±0.28 respectively, and there was a statistically significant difference （F=55.80, P<0.001）. The apoptosis rates of each groups were （0.40±0.10）%, （17.37±0.57）%, （3.00±0.66）% and （33.47±0.87）% respectively, and there was a statistically significant difference （F=1 822.18, P<0.001）. Further pairwise comparison showed that there were statistically significant differences in Caspase3/7 activities and apoptosis rates between the control group and each treatment groups （P<0.001, P=0.001, P<0.001; P<0.001, P=0.001, P<0.001）. There were statistically significant differences in Caspase3/7 activities and apoptosis rates between the sciadopitysin combined with CX-4945 group and sciadopitysin group, CX-4945 group （all P<0.001）. The protein expression levels of Notch 1 pathway related proteins ICN1 （0.55±0.07 vs. 1.01±0.09）, HES1 （0.66±0.08 vs. 1.00±0.06） and DLL3 （0.74±0.04 vs. 1.01±0.09） in U87 cells decreased significantly after treatment with 100.00 μmol/L of sciadopitysin （t=5.94, P=0.004; t=5.15, P=0.007; t=4.00, P=0.016）. Conclusion Sciadopitysin can synergize with CK2 inhibitor CX-4945 to inhibit the proliferation and promote apoptosis of glioblastoma U87 cells by inhibiting Notch1 signaling pathway. Figures and Tables | References | Related Articles | Metrics

Establishment of an efficacy prediction model for gefitinib in non-small cell lung cancer patients based on ABCB1 and ABCG2 gene polymorphisms Zhang Yan, Pan Lei, Liu Shuting 2022, 49 (6):  327-333.  doi: 10.3760/cma.j.cn371439-20210901-00062 Abstract ( 258 )   HTML ( 31 )   PDF (980KB) ( 178 )   Save ObjectiveTo explore the relationship between ABCB1 or ABCG2 gene polymorphisms and therapeutic effects of gefitinib in non-small cell lung cancer （NSCLC） patients, and establish a prediction model of efficacy. Methods A total of 176 NSCLC patients with epidermal growth factor receptor （EGFR）-sensitive mutation treated with gefitinib admitted to Department of Pulmonary Disease of Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine of Hebei Province from December 2018 to December 2020 were employed as subjects,and all patients were detected ABCB1 and ABCG2 gene polymorphisms. Patients were divided into remission group and non-remission group according to curative effect after 3 months of gefitinib treatment. The clinical data, ABCB1 and ABCG2 gene polymorphisms, levels of serum carcinoembryonic antigen （CEA） and carbohydrate antigen 125 （CA125） were compared between the two groups. The related factors of failure to remission after treatment were analyzed by multivariate logistic regression analysis.combined with ABCB1 and ABCG2 gene polymorphisms, the prediction model for gefitinib efficacy was constructed and the nomogram was drawn. Results During the follow-up period, 5 patients were lost to follow-up and 7 patients withdrew from the trial due to intolerable adverse effects, finally 108 patients were employed as remission group, and 56 patients were employed as non-remission group. The numbers of GG, GT and TT at ABCB1 rs2032582 in the remission group were 49, 50 and 9, and those in the non-remission group were 12, 35 and 9, with a statistically significant difference （χ2=9.56, P=0.008）. The numbers of GG, GA and AA at ABCG2 rs2231137 in the remission group were 13, 72 and 23, and those in the non-remission group were 11, 42 and 3, with a statistically significant difference （χ2=7.74, P=0.021）. Before treatment, the levels of serum CEA in the remission group and the non-remission group were （34.28±5.11） ng/ml and （37.88±7.05） ng/ml, with a statistically significant difference （t=3.74, P<0.001）. The levels of CA125 of the two groups were （27.24±6.50） U/ml and （33.31±6.09） U/ml, with a statistically significant difference （t=-5.79, P<0.001）. Multivariate logistic regression analysis showed that TT at rs2032582 of ABCB1 gene （OR=12.99, 95%CI： 3.17-53.23, P<0.001）, GG at rs2231137 of ABCG2 gene （OR=7.75, 95%CI： 1.36-44.07, P=0.021） and GA（OR=6.94, 95%CI： 1.47-32.84, P=0.015）, CA125 （OR=1.18, 95%CI： 1.10-1.28, P<0.001） were independent risk factors of failure to remission in NSCLC patients with EGFR sensitive mutation after treatment. The consistency index （C-index） of nomogram for predicting failure to remission was 0.92 （95%CI： 0.86-0.94）. Conclusion ABCB1 rs2032582 and ABCG2 rs2231137 polymorphisms are related to therapeutic effects of gefitinib in the NSCLC patients, the nomogram based on the two genes combined with serum CA125 can predict efficacy of gefitinib. Figures and Tables | References | Related Articles | Metrics

Comparison of safety and efficacy between chemoradiotherapy and chemotherapy after R0 resection in pN+ esophageal squamous cell carcinoma patients Xia Lingling, Chen Yongshun, Li Bin, Ning Tingting, Zhang Caiyutian 2022, 49 (6):  334-339.  doi: 10.3760/cma.j.cn371439-20220325-00063 Abstract ( 349 )   HTML ( 19 )   PDF (985KB) ( 167 )   Save ObjectiveTo investigate the safety and efficacy of chemoradiotherapy compared with chemotherapy after R0 excision in pN+ esophageal squamous cell carcinoma （ESCC） patients. Methods A retrospective analysis was performed on the pathological data of 99 pN+ ESCC patients who underwent radical esophagectomy with R0 resection in Renmin Hospital of Wuhan University from January 2017 to December 2020. According to postoperative adjuvant treatment methods, the patients were divided into chemo-radiotherapy group （n=41） and chemotherapy group （n=58）. The main outcome measures were disease-free survival （DFS）, overall survival （OS） and the incidences of treatment-related adverse events. Kaplan-Meier method was used to draw the survival curve accompanied with log-rank test. Cox regression model was used to analyze the prognostic factors. Results The median DFS and OS of 99 patients were 20.0 months and 28.0 months respectively. The 1- and 3-year DFS rates were 60.8% and 34.5% respectively. The 1- and 3-year OS rates were 83.5% and 40.2% respectively. The median DFS was 39.0 months in the chemoradiotherapy group and 10.0 months in the chemotherapy group, and the 1- and 3-year DFS rates were 79.4% vs. 48.3% and 57.3% vs. 24.5% respectively, with a statistically significant difference （χ2=12.27, P<0.001）. The median OS in the chemoradiotherapy group was not reached, and 21.0 months in the chemotherapy group, and the 1- and 3-year OS rates of the chemoradiotherapy group and chemotherapy group were 92.1% vs. 75.9% and 60.8% vs. 27.3%, with a statistically significant difference （χ2=11.12, P=0.001）. Univariate analysis showed that pN stage （HR=0.58, 95%CI： 0.34-0.97, P=0.038）, nerve invasion （HR=1.88, 95%CI： 1.11-3.20, P=0.020） and adjuvant therapy （HR=0.37, 95%CI： 0.21-0.67, P<0.001） were independent influencing factors of DFS in pN+ ESCC patients. Adjuvant therapy （HR=0.33, 95%CI： 0.17-0.66, P=0.001） was an independent factor influencing OS in pN+ ESCC patients. Multivariate analysis showed that pN stage （HR=0.54, 95%CI： 0.30-0.97, P=0.038） and adjuvant therapy （HR=0.38, 95%CI： 0.21-0.69, P=0.001） were independent prognostic factors of DFS. Adjuvant therapy （HR=0.34, 95%CI： 0.17-0.69, P=0.003） was an independent prognostic factor for OS. During adjuvant therapy, there were statistically significant differences in the incidences of leukopenia [65.85% （27/41） vs. 31.03% （18/58）, χ2=11.75, P=0.001], thrombocytopenia [29.27% （12/41） vs. 10.34% （6/58）, χ2=5.78, P=0.016], radioactive esophagitis [21.95% （9/41） vs. 0 （0/58）, χ2=11.48, P=0.001], and radioactive pneumonia [21.95% （9/41） vs. 0 （0/58）, χ2=11.48, P=0.001] between the two groups. Conclusion Compared with chemotherapy, chemoradiotherapy can significantly improve DFS and OS of pN+ ESCC patients with R0 resection after radical surgery, and the adverse reactions can be tolerated. pN stage and adjuvant therapy are independent prognostic factors for DFS, and adjuvant therapy is an independent prognostic factor for OS. Figures and Tables | References | Related Articles | Metrics

Clinical efficacy and adverse reactions of SBRT combined with mFOLFOXIRI and cetuximab in liver metastases after colorectal cancer surgery Guo Yanyong, Liu Sen, Gao Yuan 2022, 49 (6):  340-344.  doi: 10.3760/cma.j.cn371439-20220111-00064 Abstract ( 317 )   HTML ( 20 )   PDF (800KB) ( 131 )   Save Objective To investigate the efficacy of stereotactic body radiotherapy （SBRT） combined with modified FOLFOXIRI （mFOLFOXIRI, irinotecan, oxaliplatin, leucovorin and fluorouracil） and cetuximab in the treatment of postoperative liver metastases in patients with KRAS, BRAF and NRAS gene wild-type colorectal cancer, and to evaluate treatment-related adverse reactions. Methods A total of 86 patients with postoperative liver metastases from colorectal cancer diagnosed in Shandong Daizhuang Hospital from January 2018 to January 2021 were selected, all of whom were KRAS, BRAF and NRAS gene wild-type. All patients were divided into control group and study group according to the random number table method, with 43 cases in each group. The patients in the control group were treated with mFOLFOXIRI and cetuximab, 14 days a cycle, for a total of 12 cycles. The patients in the study group were treated with SBRT for liver metastases on the basis of the control group. Two patients in the control group were withdrawn from the study due to intolerance of myelosuppression （grade 4）, and patients in the study group were withdrawn from the study due to intolerance of 1 case of myelosuppression, 1 case of gastrointestinal reaction and 1 case of abnormal liver function （all grade 4）. The efficacy, median progression-free survival （PFS）, median overall survival （OS） and adverse reactions were compared between the two groups after treatment. Results After 12 cycles of treatment, the objective response rate （ORR） and disease control rate （DCR） of the study group were 55.00% （22/40） and 80.00% （32/40） respectively, which were higher than 31.71% （13/41） and 58.54% （24/41） of the control group, with statistically significant differences （χ2=4.48, P=0.034; χ2=4.37, P=0.037）. After treatment, 14 patients （35.00%） in the study group were resectable, which was higher than 6 patients （14.63%） in the control group, with a statistically significant difference （χ2=4.52, P=0.034）. The median PFS and median OS of the study group were 9.2 months and 19.5 months respectively, which were longer than 6.5 months and 15.2 months of the control group, with statistically significant differences （χ2=8.83, P=0.015; χ2=7.52, P=0.027）. There were no significant differences in incidences of leukopenia [55.00% （22/40） vs. 46.34% （19/41）, χ2=0.61, P=0.436], anemia [45.00% （18/40） vs. 39.02% （16/41）, χ2=0.30, P=0.585], thrombocytopenia [37.50% （15/40） vs. 31.71% （13/41）, χ2=0.30, P=0.584], nausea and vomiting [55.00% （22/40） vs. 48.78% （20/41）, χ2=0.31, P=0.575], constipation and diarrhea [20.00% （8/40） vs. 17.07% （7/41）, χ2=0.12, P=0.734], liver function damage [35.00% （14/40） vs. 29.27% （12/41）, χ2=0.31, P=0.581], peripheral sensory neuropathy [30.00% （12/40） vs. 26.83% （11/41） ）, χ2=0.10, P=0.752], acute cholinergic syndrome [12.50% （5/40） vs. 14.63% （6/41）, χ2=0.08, P=0.779] and fatigue [52.50% （21/40） vs. 43.90% （18/41）, χ2=0.60, P=0.439]. Conclusion SBRT combined with mFOLFOXIRI and cetuximab is more effective than drug therapy alone in patients with liver metastases after colorectal cancer surgery, which can effectively prolong the survival period, and the adverse reactions are tolerable. Figures and Tables | References | Related Articles | Metrics

Reviews

Research progress in influences of epigenetic modifications on PD-L1 expression in tumors Wang Yue, Hu Qun, Hou Yingwei 2022, 49 (6):  345-348.  doi: 10.3760/cma.j.cn371439-20220323-00065 Abstract ( 276 )   HTML ( 26 )   PDF (752KB) ( 204 )   Save Tumor cells expression of programmed death ligand-1 （PD-L1） is a major mechanism of immune escape and a predictor of therapeutic efficacy of immune checkpoint inhibitors. The expression of PD-L1 is regulated by a variety of mechanisms, among which epigenetic modifications such as DNA methylation, histone modification and non-coding RNA can promote the occurrence, development and drug resistance of tumors by regulating the expression of PD-L1. To clarify its regulation mechanism can bring new ideas for clinical immunotherapy of tumors. References | Related Articles | Metrics

Mechanism of action of lactic acid in tumor microenvironment and related treatment Zhang Zishu, Wu Xinlin 2022, 49 (6):  349-352.  doi: 10.3760/cma.j.cn371439-20220330-00066 Abstract ( 793 )   HTML ( 244 )   PDF (716KB) ( 346 )   Save Lactic acid, a widespread metabolite in the tumor microenvironment, is mainly produced by tumor cells that undergo aerobic glycolysis. Lactic acid is closely related to the occurrence and development of tumor. It not only serves as a substrate to supply energy to tumor cells, but also acts as a signaling molecule to activate multiple pathways to promote invasive and metastasis, angiogenesis and immune escape of tumor cells. In-depth research on the mechanism of action of lactic acid in the occurrence and development of tumor and related therapeutic progress will help to find drug targets for treatment of tumor and improve prognosis of patients. References | Related Articles | Metrics

Research progress of avermectins in anti-tumor Wang Liwei, Liang Hongsheng, Du Songlin, Chen Zhihao, Wang Qing, Gao Aili 2022, 49 (6):  353-356.  doi: 10.3760/cma.j.cn371439-20220321-00067 Abstract ( 250 )   HTML ( 16 )   PDF (745KB) ( 381 )   Save Avermectins can affect biological processes of multiple tumor, including tumor cell proliferation and metastasis, cell cycle arrest, induction of apoptosis and autophagy, regulation of tumor microenvironment and tumor stem cells. Avermectins can be administered alone or combined with chemotherapeutic drugs to reverse multidrug resistance. To further explore the anti-tumor mechanism of avermectins will provide reliable experimental and theoretical guidance for future clinical application. References | Related Articles | Metrics

Research progress of oxidative stress in the sensitivity of chemoradiotherapy for gliomas Xiao Nan, Sun Pengfei 2022, 49 (6):  357-361.  doi: 10.3760/cma.j.cn371439-20220309-00068 Abstract ( 272 )   HTML ( 20 )   PDF (732KB) ( 205 )   Save Following oxidative stress, reactive oxygen species are produced and accumulate in glioma cells in large quantities, and to avoid the occurrence of cellular dysfunction, glioma cells can respond adaptively in the biological processes of DNA damage repair, lipid peroxidation and protein modification to produce radiotherapy resistance. The expression of nuclear factor erythroid 2-related factor 2, solute carrier family 7 member 11, glutathione and microRNA, as key regulatory molecules, can regulate reactive oxygen species levels, alter glioma oxidative stress status, and affect radiochemotherapy sensitivity. Further study on the relationship between oxidative stress and sensitivity to radiotherapy and chemotherapy of glioma can provide theoretical basis for precise treatment of glioma. References | Related Articles | Metrics

Research progress on the mechanism of CDK4/6 inhibitors promoting antitumor immunity by regulating the immune microenvironment of triple negative breast cancer Wu Jiayi, Chen Keyu, Shao Xiying, Wang Xiaojia 2022, 49 (6):  362-365.  doi: 10.3760/cma.j.cn371439-20211215-00069 Abstract ( 273 )   HTML ( 24 )   PDF (741KB) ( 203 )   Save Triple negative breast cancer is a subtype of breast cancer with poor prognosis and lack of effective treatment. Cyclin dependent kinase（CDK）4/6 inhibitors promote antitumor immunity by influencing the triple negative breast cancer immune microenvironment, such as increasing the tumor cell surface pragrammed death-ligand 1 protein expression, enhancing T cell activation and antigen presentation, changing the proportion of T cell subgroup and inducing lymphocyte infiltration. The change of immune microenvironment is related to tumor progression, but its mechanism is extremely complex. Exploring the mechanism of CDK4/6 inhibitor affecting immune microenvironment and its biomarkers can provide a new direction for the diagnosis and treatment of triple negative breast cancer. References | Related Articles | Metrics

Advances in neoadjuvant immunotherapy for lung cancer Cai Gangxiang, Li Jing, Xu Bin 2022, 49 (6):  366-370.  doi: 10.3760/cma.j.cn371439-20220323-00070 Abstract ( 284 )   HTML ( 15 )   PDF (730KB) ( 200 )   Save Neoadjuvant immunotherapy can reduce the risk of postoperative recurrence or distant metastasis in patients with resectable lung cancer, prolong the survival of patients, and has better efficacy compared to neoadjuvant chemotherapy. Existing clinical trials with a small sample size indicate that neoadjuvant immunotherapy combined with chemotherapy has a higher rate of major pathologic response compared to single-agent immunotherapy, but it is also accompanied by a higher incidence of treatment-related adverse events and a longer treatment cycle, which may lead to delayed surgery or increased risk of intraoperative complications. The selection of therapeutic regimens, surgical timing, efficacy evaluation, and other issues have not been determined. Several phase Ⅲ clinical studies of a single drug and combined regimen of neoadjuvant immunotherapy are ongoing, and the efficacy of neoadjuvant immunotherapy is expected to be further verified through follow-up data. References | Related Articles | Metrics

Application of tumor biomarkers in the diagnosis and prognosis of hepatocellular carcinoma Liu Xiaoting, Liu Yang, Zhang Huanqin, Xing Jinliang, Quan Zhibo 2022, 49 (6):  371-375.  doi: 10.3760/cma.j.cn371439-20220309-00071 Abstract ( 243 )   HTML ( 13 )   PDF (731KB) ( 199 )   Save Tumor biomarkers have multiple characteristics, including noninvasive, repeatable analysis and real-time monitoring, and they have important application value in early diagnosis and prognosis monitoring of hepatocellular carcinoma （HCC）. In recent years, the researches on tumor markers of HCC have developed rapidly. There are not only traditional serological tumor markers, such as alpha fetoprotein, des-gamma carboxy prothrombin, Golgi protein 73, glypican-3, etc., but also new emerging "liquid biopsy" tumor markers, such as circulating tumor cells, circulating tumor DNA etc. Further study on the correlation between tumor biomarkers and HCC can provide reference for the treatment and prognosis evaluation of HCC. References | Related Articles | Metrics