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Volume 26,Issue 4,2019 Table of Contents
2019, 26(4):365-373.
DOI: 10.3872/j.issn.1007-385X.2019.04.001
Abstract:
[Abstract] Chimeric antigen receptor T-cell (CAR-T) targeting CD19 has made significant progress in the treatment of B cell malignancies.FDA has approved two CD19 CAR-T therapeutic products. With the development in the clinical and mechanism research of immunotherapy (CAR-T, bispecific T-cell engager [BiTE]), dual affinity re-targeting [DART], and genetically modified T cell receptor-T cell [TCR-T]), its potential risks and side effects have been more widely recognized, especially cytokine release syndrome (CRS).CRS is currently the most common complication after CAR-T treatment and can be life-threatening in severe cases. Moreover, the pathophysiological process of CRS is complex, involving a variety of immune cells and non-immune cells, and can affect whole body organs. Elucidating the mechanisms of CRS development is of great significance to improve the safety of CAR-T therapy. In recent years, researchers have conducted study in animal models to illustrate the mechanisms of CRS more deeply. This review discusses the development, pathophysiological mechanisms, animal models, clinical features, and graded treatments of CRS, aiming to provide an in-depth understanding of the mechanism of CRS and improve the safety of CAR-T therapy.
[Abstract] Chimeric antigen receptor T-cell (CAR-T) targeting CD19 has made significant progress in the treatment of B cell malignancies.FDA has approved two CD19 CAR-T therapeutic products. With the development in the clinical and mechanism research of immunotherapy (CAR-T, bispecific T-cell engager [BiTE]), dual affinity re-targeting [DART], and genetically modified T cell receptor-T cell [TCR-T]), its potential risks and side effects have been more widely recognized, especially cytokine release syndrome (CRS).CRS is currently the most common complication after CAR-T treatment and can be life-threatening in severe cases. Moreover, the pathophysiological process of CRS is complex, involving a variety of immune cells and non-immune cells, and can affect whole body organs. Elucidating the mechanisms of CRS development is of great significance to improve the safety of CAR-T therapy. In recent years, researchers have conducted study in animal models to illustrate the mechanisms of CRS more deeply. This review discusses the development, pathophysiological mechanisms, animal models, clinical features, and graded treatments of CRS, aiming to provide an in-depth understanding of the mechanism of CRS and improve the safety of CAR-T therapy.
2019, 26(4):374-380.
DOI: 10.3872/j.issn.1007-385X.2019.04.002
Abstract:
[Abstract] Objective: To prepare human peripheral blood T lymphocytes with TIM3 (T cell immunologlobulin and mucin-3) gene knockout by using CRISPR-Cas9 gene editing technique and plasmid electrotransfection system, and to discuss whether the knockout of TIM3 gene could enhance the immune response and anti-tumor efficacy of T cells. Methods: Double plasmids hTIM3 sgRNA/Cas9 were transfected into human peripheral blood T lymphocytes of EBV positive gastric cancer patients by using electrotransfection system.The transfection efficiency was examined 24 h later by flow cytometry and fluorescence microscope. The proliferation activity of the T cells after gene knockout was observed during in vitro culture, and the knockout efficiency and phenotypes of the modified T cells were evaluated by flow cytometry. Furthermore, tumor antigen peptide was used to activate T cells, and the level of modified T cells secreting cytokines and its cytotoxicity against gastric cancer AGS-EBV cells were evaluated. Results: Electrotransfection system could successfully transfect hTIM3 sgRNA/Cas9 double plasmids into human peripheral blood T lymphocytes with an average transfection efficiency of (41.5±3.6)%, and the gene knockout efficiency fluctuated between 40.0% and 50.0% (all P<0.01). The proliferation of the modified T cells was not significantly changed in the TIM3 gene knockout group even after the prolonged co-culturing with tumor antigenicpeptide; and for the activated molecules, only HLA-DR exhibited significant elevation as compared with control group (P<0.05).Remarkably, T cells with TIM3 gene knockout showed significantly elevated secretion of TNF-α and IFN-γ (P<0.01 or P<0.05), as well as obviously enhanced in vitro cytotoxicity against gastric cancer AGS-EBV cells (P<0.05). Conclusion: It’s simple and feasible of CRISPR-Cas9 gene editing technique and plasmid electrotransfection system to prepare T lymphocytes with engineered TIM3 gene knockout. The expression level of TIM3 was down-regulated in in vitro culture. More importantly, the modified T cells performed superior immune response and cytotoxicity, which may provide a new idea for gene engineering cell immunotherapy.
[Abstract] Objective: To prepare human peripheral blood T lymphocytes with TIM3 (T cell immunologlobulin and mucin-3) gene knockout by using CRISPR-Cas9 gene editing technique and plasmid electrotransfection system, and to discuss whether the knockout of TIM3 gene could enhance the immune response and anti-tumor efficacy of T cells. Methods: Double plasmids hTIM3 sgRNA/Cas9 were transfected into human peripheral blood T lymphocytes of EBV positive gastric cancer patients by using electrotransfection system.The transfection efficiency was examined 24 h later by flow cytometry and fluorescence microscope. The proliferation activity of the T cells after gene knockout was observed during in vitro culture, and the knockout efficiency and phenotypes of the modified T cells were evaluated by flow cytometry. Furthermore, tumor antigen peptide was used to activate T cells, and the level of modified T cells secreting cytokines and its cytotoxicity against gastric cancer AGS-EBV cells were evaluated. Results: Electrotransfection system could successfully transfect hTIM3 sgRNA/Cas9 double plasmids into human peripheral blood T lymphocytes with an average transfection efficiency of (41.5±3.6)%, and the gene knockout efficiency fluctuated between 40.0% and 50.0% (all P<0.01). The proliferation of the modified T cells was not significantly changed in the TIM3 gene knockout group even after the prolonged co-culturing with tumor antigenicpeptide; and for the activated molecules, only HLA-DR exhibited significant elevation as compared with control group (P<0.05).Remarkably, T cells with TIM3 gene knockout showed significantly elevated secretion of TNF-α and IFN-γ (P<0.01 or P<0.05), as well as obviously enhanced in vitro cytotoxicity against gastric cancer AGS-EBV cells (P<0.05). Conclusion: It’s simple and feasible of CRISPR-Cas9 gene editing technique and plasmid electrotransfection system to prepare T lymphocytes with engineered TIM3 gene knockout. The expression level of TIM3 was down-regulated in in vitro culture. More importantly, the modified T cells performed superior immune response and cytotoxicity, which may provide a new idea for gene engineering cell immunotherapy.
3 Chidamide enhances inhibitory effect on colon cancer cells by modulating tumorassociated macrophage
2019, 26(4):381-388.
DOI: 10.3872/j.issn.1007-385X.2019.04.003
Abstract:
[Abstract] Objective: To investigate the effect of tumor-associated macrophage (TAM) on the anti-tumor function of chidamide and to explore the mechanism. Methods: Mouse macrophage cell lines Ana1 and Raw264.7 were cultured in vitro and induced into TAM with tumor supernatant. HDAC enzyme activity was detected after TAM treated with chidamide. The mRNA expressions of cytokines, such as IL-6, IL-12,TNF and IL-1β, in TAM were detected by qPCR. The protein expression of NF-κB and STAT3 in TAM treated with chidamide were detected by Wb. The mixture of TAM and colon cancer CT26 cells was inoculated into nude mice to construct the subcutaneous xenograft model; and the efficacy of chidamide (3.87 mg/kg) on the growth of CT26 xenograft tumors was observed. The protein expressions of PCNA, F4/80, Arg1 and iNos were detected by immunohistochemistry. Results: Chidamide inhibited the proliferation of CT26 cells. In the in vivo experiment, the inhibition rate of chidamide alone on CT26 xenograft was about 18.7%; however,the inhibition rate was up to 57.2% with the presence of TAM. Chidamide could inhibit the activity of HDAC enzyme in TAM,and further increase the Histone acetylation level. Chidamide could affect the expression of nuclear transcription factor NF- κB,inhibit the expressions of Arg1, IL-6 and IL-12, but up-regulate the expressions of iNOS, TNF and IL-1β in TAM. Conclusion:Chidamide can enhance its inhibitory effect on colon cancer CT26 cells via regulating the expression of cytokines and inhibiting the activity of HDAC in TAM.
[Abstract] Objective: To investigate the effect of tumor-associated macrophage (TAM) on the anti-tumor function of chidamide and to explore the mechanism. Methods: Mouse macrophage cell lines Ana1 and Raw264.7 were cultured in vitro and induced into TAM with tumor supernatant. HDAC enzyme activity was detected after TAM treated with chidamide. The mRNA expressions of cytokines, such as IL-6, IL-12,TNF and IL-1β, in TAM were detected by qPCR. The protein expression of NF-κB and STAT3 in TAM treated with chidamide were detected by Wb. The mixture of TAM and colon cancer CT26 cells was inoculated into nude mice to construct the subcutaneous xenograft model; and the efficacy of chidamide (3.87 mg/kg) on the growth of CT26 xenograft tumors was observed. The protein expressions of PCNA, F4/80, Arg1 and iNos were detected by immunohistochemistry. Results: Chidamide inhibited the proliferation of CT26 cells. In the in vivo experiment, the inhibition rate of chidamide alone on CT26 xenograft was about 18.7%; however,the inhibition rate was up to 57.2% with the presence of TAM. Chidamide could inhibit the activity of HDAC enzyme in TAM,and further increase the Histone acetylation level. Chidamide could affect the expression of nuclear transcription factor NF- κB,inhibit the expressions of Arg1, IL-6 and IL-12, but up-regulate the expressions of iNOS, TNF and IL-1β in TAM. Conclusion:Chidamide can enhance its inhibitory effect on colon cancer CT26 cells via regulating the expression of cytokines and inhibiting the activity of HDAC in TAM.
2019, 26(4):389-395.
DOI: 10.3872/j.issn.1007-385X.2019.04.004
Abstract:
[Abstract] Objective: To investigate the function of anti-PD-1 (scFv)/IL-15/ IL-15Rα - sushi fusion protein (PD-S15) to specifically bind to PD-1 in vitro and to explore its effect on NK/T cell proliferation. Methods: The human anti-PD-1 (scFv) gene sequence and human IL-15/IL-15Rα-sushi fusion gene sequence were synthesized chemically. The recombinant expression plasmid pUC57-PD-S15 was constructed by enzyme digestion and ligation of the two target genes, and then transiently transfected into HEK293T cells by lipofectamineTM 2000. The supernatants of cell culture medium were acquired, and the expression of PD-S15 fusion protein in cell culture supernatants was detected by Wb assay. PBMCs and TILs were cultured in mediums with different proportion of PD-S15/X-VIVOTM15,respectively. Then, the capacity of PD-S15 fusion protein to bind to PD-1 in vitro and its effect on the proliferation of PBMCs and the proportion of CD3+CD8+, CD3+CD4+ and CD3-CD56+ subsets were detected by flow cytometry. The effect of PD-S15 fusion protein on the proliferation of TILs was detected by cytometry. Results: The successful construction of pUC57-PD-S15 eukaryotic expression plasmid was confirmed by double enzyme digestion and sequencing, and then successfully transfected into HEK293T cells. The relative molecular weight of the target protein was approximately 55 000, and was in line with expectations. PD-S15 fusion protein could specifically combine with PD-1 in vitro (P<0.05) and stimulate NK/T cell proliferation (P<0.05). Compared with classical TILs culture method,the efficiency of activation and amplification of T cells in vitro by PD-S15 culture method was better (P<0.01). Conclusion: PD-S15 fusion protein can specifically target PD-1 and rapidly expand NK/T cells in vitro, which lays a foundation for the selective expansion of CD8+PD-1+ antigen-specific T lymphocytes from tumor tissues and even peripheral blood.
[Abstract] Objective: To investigate the function of anti-PD-1 (scFv)/IL-15/ IL-15Rα - sushi fusion protein (PD-S15) to specifically bind to PD-1 in vitro and to explore its effect on NK/T cell proliferation. Methods: The human anti-PD-1 (scFv) gene sequence and human IL-15/IL-15Rα-sushi fusion gene sequence were synthesized chemically. The recombinant expression plasmid pUC57-PD-S15 was constructed by enzyme digestion and ligation of the two target genes, and then transiently transfected into HEK293T cells by lipofectamineTM 2000. The supernatants of cell culture medium were acquired, and the expression of PD-S15 fusion protein in cell culture supernatants was detected by Wb assay. PBMCs and TILs were cultured in mediums with different proportion of PD-S15/X-VIVOTM15,respectively. Then, the capacity of PD-S15 fusion protein to bind to PD-1 in vitro and its effect on the proliferation of PBMCs and the proportion of CD3+CD8+, CD3+CD4+ and CD3-CD56+ subsets were detected by flow cytometry. The effect of PD-S15 fusion protein on the proliferation of TILs was detected by cytometry. Results: The successful construction of pUC57-PD-S15 eukaryotic expression plasmid was confirmed by double enzyme digestion and sequencing, and then successfully transfected into HEK293T cells. The relative molecular weight of the target protein was approximately 55 000, and was in line with expectations. PD-S15 fusion protein could specifically combine with PD-1 in vitro (P<0.05) and stimulate NK/T cell proliferation (P<0.05). Compared with classical TILs culture method,the efficiency of activation and amplification of T cells in vitro by PD-S15 culture method was better (P<0.01). Conclusion: PD-S15 fusion protein can specifically target PD-1 and rapidly expand NK/T cells in vitro, which lays a foundation for the selective expansion of CD8+PD-1+ antigen-specific T lymphocytes from tumor tissues and even peripheral blood.
2019, 26(4):396-401.
DOI: 10.3872/j.issn.1007-385X.2019.04.005
Abstract:
[Abstract] Objective: To investigate the effect and mechanism of AMP-activated protein kinase α (AMPKα) over-expression on proliferation,migration, invasion and epithelial mesenchymal transition (EMT) of bladder cancer T24 cells. Methods: A bladder cancer T24 cells over-expressing AMPKα was established and divided into T24 group, pc-DNA group and pc-AMPKα group according to different plasmid transfection. Western blotting was used to verify the over-expression of AMPKα and detect the expressions of EMT-related proteins and EMT pathway-related molecules. Hoechst staining was used to detect apoptosis of transfected T24 cells. CCK8 assay was used to detect cell proliferation. Cell scratch test was used to detect cell migration. Transwell assay was used to detect cell invasion.Results: The bladder cancer cell line T24 over-expressing AMPKα was successfully constructed. Compared with the T24 group and the pc-DNA group, the level of E-cadherin in the pc-AMPKα group was significantly increased (P<0.01) while the levels of Vimentin and N-cadherin were significantly decreased (all P<0.01), and the activities of P38 and STAT3 which related to EMT pathway were significantly inhibited (all P<0.01); cell proliferation, migration and invasion were significantly decreased while cell apoptosis was obviously enhanced (all P<0.01). Conclusion: Over-expression of AMPKα can inhibit the activity of EMT pathway-related molecules, which leads to obvious apoptosis, limited proliferation, reduced invasion and migration of bladder cancer T24 cells, and accompanied by the reversal of EMT.
[Abstract] Objective: To investigate the effect and mechanism of AMP-activated protein kinase α (AMPKα) over-expression on proliferation,migration, invasion and epithelial mesenchymal transition (EMT) of bladder cancer T24 cells. Methods: A bladder cancer T24 cells over-expressing AMPKα was established and divided into T24 group, pc-DNA group and pc-AMPKα group according to different plasmid transfection. Western blotting was used to verify the over-expression of AMPKα and detect the expressions of EMT-related proteins and EMT pathway-related molecules. Hoechst staining was used to detect apoptosis of transfected T24 cells. CCK8 assay was used to detect cell proliferation. Cell scratch test was used to detect cell migration. Transwell assay was used to detect cell invasion.Results: The bladder cancer cell line T24 over-expressing AMPKα was successfully constructed. Compared with the T24 group and the pc-DNA group, the level of E-cadherin in the pc-AMPKα group was significantly increased (P<0.01) while the levels of Vimentin and N-cadherin were significantly decreased (all P<0.01), and the activities of P38 and STAT3 which related to EMT pathway were significantly inhibited (all P<0.01); cell proliferation, migration and invasion were significantly decreased while cell apoptosis was obviously enhanced (all P<0.01). Conclusion: Over-expression of AMPKα can inhibit the activity of EMT pathway-related molecules, which leads to obvious apoptosis, limited proliferation, reduced invasion and migration of bladder cancer T24 cells, and accompanied by the reversal of EMT.
6 Expression and clinical significance of melanoma antigen genes MAGE-A1 and MAGE-A3 in glioma tissues
2019, 26(4):402-408.
DOI: 10.3872/j.issn.1007-385X.2019.04.006
Abstract:
[Abstract] Objective: To detect the expressions of melanoma antigen genes MAGE-A1 and MAGE-A3 in glioma tissues and to explore their clinical significance. Methods: Seventy-eight surgically resected glioma specimens and 15 normal brain tissue samples from donors suffered traffic accidence were collected at the Department of Neurosurgery, the Fourth Hospital of Hebei Medical University between January 2006 and January 2010, and the mRNA expressions of MAGE-A1 and MAGE-A3 in collected tissues were detected with RT-PCR; their associations with the overall survival of patients were also analyzed.The promoter methylation status of the two genes was observed with methylation specific PCR, and the relationship between the gene expressions and promoter methylation status was analyzed. The expressions of MAGE-A1 and MAGE-A3 genes in U251 and U87 glioma cell lines were detected by RT-PCR before and after the treatment with DNA methyltransferase inhibitor 5-aza-CdR and/ or histone deacetylase inhibitor trichostatin A (TSA). Results:The positive expression rates of MAGE-A1 and MAGE-A3 genes in glioma tissues were 65.34% and 38.46%, respectively;however, the two genes were not detected in 15 cases of normal brain tissues.The 5-year overall survival of patients in MAGEA1 positive expression group was shorter than that of negative expression group (P<0.05). There was significant correlation between the mRNA expressions of two genes and their promoter methylation status (all P<0.01). There was no mRNA expressions of MAGEA1 and MAGE-A3 in U87 cells untreated with 5-Aza-CdR and TSA, but a small amount of MAGE-A1 mRNA and MAGE-A3 mRNA were detected in U251 cells. TSA alone could not activate the expression of MAGE-A1 and MAGE-A3 genes. 5-Aza-CdR alone or in combination with TSA could activate the expression of both genes, and the combined effect was better than that of single administration.Conclusion: There are different degrees of MAGE-A1 and-A3 expression in glioma tissues, and the expression of MAGE-A1 is a negative prognostic factor for glioma patients. DNA promoter methylation and histone acetylation are important mechanisms of the activation of MAGE-A1 and MAGE-A3 expression.
[Abstract] Objective: To detect the expressions of melanoma antigen genes MAGE-A1 and MAGE-A3 in glioma tissues and to explore their clinical significance. Methods: Seventy-eight surgically resected glioma specimens and 15 normal brain tissue samples from donors suffered traffic accidence were collected at the Department of Neurosurgery, the Fourth Hospital of Hebei Medical University between January 2006 and January 2010, and the mRNA expressions of MAGE-A1 and MAGE-A3 in collected tissues were detected with RT-PCR; their associations with the overall survival of patients were also analyzed.The promoter methylation status of the two genes was observed with methylation specific PCR, and the relationship between the gene expressions and promoter methylation status was analyzed. The expressions of MAGE-A1 and MAGE-A3 genes in U251 and U87 glioma cell lines were detected by RT-PCR before and after the treatment with DNA methyltransferase inhibitor 5-aza-CdR and/ or histone deacetylase inhibitor trichostatin A (TSA). Results:The positive expression rates of MAGE-A1 and MAGE-A3 genes in glioma tissues were 65.34% and 38.46%, respectively;however, the two genes were not detected in 15 cases of normal brain tissues.The 5-year overall survival of patients in MAGEA1 positive expression group was shorter than that of negative expression group (P<0.05). There was significant correlation between the mRNA expressions of two genes and their promoter methylation status (all P<0.01). There was no mRNA expressions of MAGEA1 and MAGE-A3 in U87 cells untreated with 5-Aza-CdR and TSA, but a small amount of MAGE-A1 mRNA and MAGE-A3 mRNA were detected in U251 cells. TSA alone could not activate the expression of MAGE-A1 and MAGE-A3 genes. 5-Aza-CdR alone or in combination with TSA could activate the expression of both genes, and the combined effect was better than that of single administration.Conclusion: There are different degrees of MAGE-A1 and-A3 expression in glioma tissues, and the expression of MAGE-A1 is a negative prognostic factor for glioma patients. DNA promoter methylation and histone acetylation are important mechanisms of the activation of MAGE-A1 and MAGE-A3 expression.
2019, 26(4):409-416.
DOI: 10.3872/j.issn.1007-385X.2019.04.007
Abstract:
[Abstract] Objective: To investigate the mechanism of lncRNA HCG18/miR-17-5p/HMGA2 axis regulating the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells. Methods: Sixty-two pairs of NSCLC tissues and corresponding para-cancerous tissues collected at Central Hospital of Chengde City from June 2017 to June 2018 were used for this study; in addition, NSCLC cell lines (A549, NCI-H1299, H1650, NCI-H460) and human lung epithelial BEAS-B cells were also collected. mRNA expression levels of HCG18, miR-17-5p and high-mobility group AT-hook 2 (HMGA2) in NSCLC tissues and cell lines were measured by quantitative Real-time polymerase chain reaction (qPCR). Si-HCG18, miR-17-5p, miR-17-5p+HCG18 or pcDNA3.1-HMGA2 were transfected into A549 cells and NCI-H460 cells; CCK-8 assay was used to detect the proliferation of transfected cells, Transwell assay was used to detect the migration and invasion ability of cells, and Wb was used to analyze the expressions of HMGA2 and EMT associated proteins (E-cadherin, N-cadherin and vimentin). The target relationships between HCG18 and miR-17-5p, or between miR-17-5p and HMGA2 were confirmed by dual luciferase reporter gene assay. Mice A549 cell xenograft model with HCG18 knockdown was constructed, and the growth of transplanted tumor was observed. Results: lncRNA HCG18 was highly expressed in NSCLC tissues and cells (all P<0.01); HCG18 level was significantly increased in patients at late stage or with lymphnode metastasis; and high HCG18 level was correlated with poor prognosis and low survival rates of NSCLC patients (all P<0.01). Knockdown of HCG18 significantly inhibited NSCLC cell proliferation, migration and invasion (all P<0.01), up-regulated E-cadherin expression but suppressed N-cadherin and vimentin expression (all P<0.01), and the volume of xenograft was obviously decreased (P<0.05). Dual luciferase reporter gene assay confirmed the relationship between HCG18 and miR-17-5p as well as miR-17-5p and HMGA2. miR-17-5p transfection significantly inhibited NSCLC cell proliferation, migration and invasion (all P<0.01), and up-regulated E-cadherin expression, reversely suppressed N-cadherin and vimentin expression (all P<0.01); however, miR-17-5p + HCG18 transfection reversed the effect of miR-17-5p on NSCLCcells. Conclusion:HCG18 promotes the proliferation and migration ofNSCLCcells through regulating miR-17-5p/HMGA2 axis.
[Abstract] Objective: To investigate the mechanism of lncRNA HCG18/miR-17-5p/HMGA2 axis regulating the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells. Methods: Sixty-two pairs of NSCLC tissues and corresponding para-cancerous tissues collected at Central Hospital of Chengde City from June 2017 to June 2018 were used for this study; in addition, NSCLC cell lines (A549, NCI-H1299, H1650, NCI-H460) and human lung epithelial BEAS-B cells were also collected. mRNA expression levels of HCG18, miR-17-5p and high-mobility group AT-hook 2 (HMGA2) in NSCLC tissues and cell lines were measured by quantitative Real-time polymerase chain reaction (qPCR). Si-HCG18, miR-17-5p, miR-17-5p+HCG18 or pcDNA3.1-HMGA2 were transfected into A549 cells and NCI-H460 cells; CCK-8 assay was used to detect the proliferation of transfected cells, Transwell assay was used to detect the migration and invasion ability of cells, and Wb was used to analyze the expressions of HMGA2 and EMT associated proteins (E-cadherin, N-cadherin and vimentin). The target relationships between HCG18 and miR-17-5p, or between miR-17-5p and HMGA2 were confirmed by dual luciferase reporter gene assay. Mice A549 cell xenograft model with HCG18 knockdown was constructed, and the growth of transplanted tumor was observed. Results: lncRNA HCG18 was highly expressed in NSCLC tissues and cells (all P<0.01); HCG18 level was significantly increased in patients at late stage or with lymphnode metastasis; and high HCG18 level was correlated with poor prognosis and low survival rates of NSCLC patients (all P<0.01). Knockdown of HCG18 significantly inhibited NSCLC cell proliferation, migration and invasion (all P<0.01), up-regulated E-cadherin expression but suppressed N-cadherin and vimentin expression (all P<0.01), and the volume of xenograft was obviously decreased (P<0.05). Dual luciferase reporter gene assay confirmed the relationship between HCG18 and miR-17-5p as well as miR-17-5p and HMGA2. miR-17-5p transfection significantly inhibited NSCLC cell proliferation, migration and invasion (all P<0.01), and up-regulated E-cadherin expression, reversely suppressed N-cadherin and vimentin expression (all P<0.01); however, miR-17-5p + HCG18 transfection reversed the effect of miR-17-5p on NSCLCcells. Conclusion:HCG18 promotes the proliferation and migration ofNSCLCcells through regulating miR-17-5p/HMGA2 axis.
2019, 26(4):417-425.
DOI: 10.3872/j.issn.1007-385X.2019.04.008
Abstract:
[Abstract] Objective: To investigate the effect of astragalus polysaccharides (APS) on proliferation, invasion, apoptosis and drugresistance of cisplatin-resistant colorectal cancer (CRC) HT-29/DDP cells through regulating miR-20a/TGFBR2 axis, and to explore the possible mechanism. Methods: Human CRC HT-29 cells and HT-29/DDP cells were used as non-drug resistant and resistant cell models,respectively; HT-29/DDP cells were randomly divided into four groups, including untreated (HT-29/DDP) group, APS treatment group, miR-20a mimics + APS group, and si-TGFBR2 + APS group. qPCR and Western blotting were applied to detect the expressions of miR-20a and TGFBR2 in HT-29/DDP cells treated with different concentrations of APS (0, 0.5, 1.0, 1.5 and 2.0 mg/ml). Subsequently,dual luciferase reporter gene assay was used to verify whether TGFBR2 was a target gene of miR-20a. In addition, CCK-8, Transwell and Annexin V-FITC/PI double staining were applied to examine the effect of APS on proliferation, invasion and apoptosis of HT-29/DDP cells. Furthermore, subcutaneous HT-29/DDP cell xenograft model was established on nude mice, and the effect of APS on the growth of transplanted tumor was observed. Results: APS significantly inhibited the proliferation of HT-29/DDP cells in a dose-dependent manner (P<0.01). Meanwhile, the expression of miR-20a was down-regulated in HT-29/DDP cells treated with APS, while the expression of TGFBR2 was significantly up-regulated (all P<0.01). Additionally, dual luciferase reporter gene assay result showed that TGFBR2 was a direct target of miR-20a in HT-29/DDP cells and its expression was suppressed. Furthermore, APS could enhance the drug sensitivity of HT-29 /DDP cells through downregulating the inhibitory effect of miR-20a on TGFBR2 expression, thereby suppressed proliferation and invasion, and induced apoptosis of HT-29/DDP cells in vitro and in vivo. It was also found that this effect was related with the suppression of PCNA and Bcl-2 proteins and promotion of Bax and Caspase-3 proteins. Conclusion: APS reverses the resistance of HT-29/DDP cells to cisplatin by down-regulating the inhibitory effect of miR-20a on TGFBR2 expression.
[Abstract] Objective: To investigate the effect of astragalus polysaccharides (APS) on proliferation, invasion, apoptosis and drugresistance of cisplatin-resistant colorectal cancer (CRC) HT-29/DDP cells through regulating miR-20a/TGFBR2 axis, and to explore the possible mechanism. Methods: Human CRC HT-29 cells and HT-29/DDP cells were used as non-drug resistant and resistant cell models,respectively; HT-29/DDP cells were randomly divided into four groups, including untreated (HT-29/DDP) group, APS treatment group, miR-20a mimics + APS group, and si-TGFBR2 + APS group. qPCR and Western blotting were applied to detect the expressions of miR-20a and TGFBR2 in HT-29/DDP cells treated with different concentrations of APS (0, 0.5, 1.0, 1.5 and 2.0 mg/ml). Subsequently,dual luciferase reporter gene assay was used to verify whether TGFBR2 was a target gene of miR-20a. In addition, CCK-8, Transwell and Annexin V-FITC/PI double staining were applied to examine the effect of APS on proliferation, invasion and apoptosis of HT-29/DDP cells. Furthermore, subcutaneous HT-29/DDP cell xenograft model was established on nude mice, and the effect of APS on the growth of transplanted tumor was observed. Results: APS significantly inhibited the proliferation of HT-29/DDP cells in a dose-dependent manner (P<0.01). Meanwhile, the expression of miR-20a was down-regulated in HT-29/DDP cells treated with APS, while the expression of TGFBR2 was significantly up-regulated (all P<0.01). Additionally, dual luciferase reporter gene assay result showed that TGFBR2 was a direct target of miR-20a in HT-29/DDP cells and its expression was suppressed. Furthermore, APS could enhance the drug sensitivity of HT-29 /DDP cells through downregulating the inhibitory effect of miR-20a on TGFBR2 expression, thereby suppressed proliferation and invasion, and induced apoptosis of HT-29/DDP cells in vitro and in vivo. It was also found that this effect was related with the suppression of PCNA and Bcl-2 proteins and promotion of Bax and Caspase-3 proteins. Conclusion: APS reverses the resistance of HT-29/DDP cells to cisplatin by down-regulating the inhibitory effect of miR-20a on TGFBR2 expression.
2019, 26(4):426-430.
DOI: 10.3872/j.issn.1007-385X.2019.04.009
Abstract:
[Abstract] Objective: To investigate the short-term efficacy and toxicity of bevacizumab combined with DP or rh-endostatin（recombinant human vascular endostatin injection）combined with DP in locally advanced EGFR wild-type non-small cell lung cancer (NSCLC). Methods: Seventy-two patients with treatment of locally advanced EGFR wild-type NSCLC admitted to the Department of Respiratory Medicine of Zhongshan Hospital Affiliated to Guangdong Medical University from January 2014 to January 2017 were divided into bevacizumab group (34 cases) and rh-endostatin group (38 cases) according to the random number method. The former group was treated with bevacizumab combined with docetaxel and cisplatin, while the latter was treated with rh-endostatin combined with docetaxel and cisplatin. According to RECISIT 1.1 standard, the changes of lesion size before and after treatment in two groups were evaluated. Serum levels of vascular endothelial growth factor (VEGF), carcinoembryonic antigen (CEA), cytokeratin 21-1 fragment (CYFRA21-1), squamous cell carcinoma antigen (SCC) were measured. The adverse reactions during treatment were also evaluated.Results: In bevacizumab group, patients with CR, PR, SD, PD, DCR and ORR were 2 cases, 12 cases, 15 cases, 5 cases, 41.18%and 85.29%, respectively. In rh-endostatin group, patients with CR, PR, SD, PD, DCR, ORR were 2 cases, 16 cases, 14 cases, 6 cases,47.37% and 84.21%, respectively. The DCR in rh-endostatin group was significantly higher than that in bevacizumab group (P<0.05).The serum levels of VEGF and CEA in rh-endostatin group decreased more obvious than those in bevacizumab group (all P<0.05). The incidence of gastrointestinal reaction, skin reaction and cardiac toxicity in rh-endostatin group was higher than that in bevacizumab group, while the incidence of bleeding in bevacizumab group was higher than that in rh-endostatin group (all P<0.05). Conclusion: In patients with locally advanced EGFR wild-type NSCLC, rh-endostatin combined with DP regimen is better than bevacizumab combined with DP regimen. In clinical practice, corresponding treatment regimen can be selected according to different characteristics of patients,so as to minimize the toxic reaction during treatment and avoid clinical risk.
[Abstract] Objective: To investigate the short-term efficacy and toxicity of bevacizumab combined with DP or rh-endostatin（recombinant human vascular endostatin injection）combined with DP in locally advanced EGFR wild-type non-small cell lung cancer (NSCLC). Methods: Seventy-two patients with treatment of locally advanced EGFR wild-type NSCLC admitted to the Department of Respiratory Medicine of Zhongshan Hospital Affiliated to Guangdong Medical University from January 2014 to January 2017 were divided into bevacizumab group (34 cases) and rh-endostatin group (38 cases) according to the random number method. The former group was treated with bevacizumab combined with docetaxel and cisplatin, while the latter was treated with rh-endostatin combined with docetaxel and cisplatin. According to RECISIT 1.1 standard, the changes of lesion size before and after treatment in two groups were evaluated. Serum levels of vascular endothelial growth factor (VEGF), carcinoembryonic antigen (CEA), cytokeratin 21-1 fragment (CYFRA21-1), squamous cell carcinoma antigen (SCC) were measured. The adverse reactions during treatment were also evaluated.Results: In bevacizumab group, patients with CR, PR, SD, PD, DCR and ORR were 2 cases, 12 cases, 15 cases, 5 cases, 41.18%and 85.29%, respectively. In rh-endostatin group, patients with CR, PR, SD, PD, DCR, ORR were 2 cases, 16 cases, 14 cases, 6 cases,47.37% and 84.21%, respectively. The DCR in rh-endostatin group was significantly higher than that in bevacizumab group (P<0.05).The serum levels of VEGF and CEA in rh-endostatin group decreased more obvious than those in bevacizumab group (all P<0.05). The incidence of gastrointestinal reaction, skin reaction and cardiac toxicity in rh-endostatin group was higher than that in bevacizumab group, while the incidence of bleeding in bevacizumab group was higher than that in rh-endostatin group (all P<0.05). Conclusion: In patients with locally advanced EGFR wild-type NSCLC, rh-endostatin combined with DP regimen is better than bevacizumab combined with DP regimen. In clinical practice, corresponding treatment regimen can be selected according to different characteristics of patients,so as to minimize the toxic reaction during treatment and avoid clinical risk.
2019, 26(4):431-439.
DOI: 10.3872/j.issn.1007-385X.2019.04.010
Abstract:
[Abstract] Objective: To identify the differentially expressed genes (DEGs) between hepatocellular carcinoma (HCC) tissues and normal liver tissues by bioinformatic methods, and to explore the intrinsic mechanism of these candidate genes involving in the occurrence and development of HCC from transcriptome level as well as the clinical significance of their associations with the prognosis of HCC patients. Methods: Gene expression profiles of GSE45267, GSE64041, GSE84402 and TCGA were downloaded from GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas), respectively. R software and Bioconductor packages were used to identify the DEGs between HCC tissues and para-cancer tissues, and then Gene Ontology (GO) Enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Protein-Protein Interaction (PPI) network analysis and survival analysis were performed.Results: Forty-six up-regulated genes and 154 down-regulated genes were screened out,and GO enrichment analysis showed that these DEGs were mainly related to cell division, proliferation, cycle regulation, oxidation-reduction process and certain metabolic pathways. KEGG pathway analysis revealed that DEGs were mainly involved in tryptophan metabolism, retinol metabolism and other metabolic pathways as well as p53 pathway. Over-expression of a panel of up-regulated genes (CCNA2, CDK1, DLGAP5, KIF20A,KPNA2 and MELK) was shown to be significantly negatively correlated with the prognosis of HCC patients in the TCGA dataset(all P<0.01). Conclusion: A set of up-regulated hub genes that are negatively correlated with prognosis will provide potential guiding value for the clinical research on the diagnosis and treatment of HCC.
[Abstract] Objective: To identify the differentially expressed genes (DEGs) between hepatocellular carcinoma (HCC) tissues and normal liver tissues by bioinformatic methods, and to explore the intrinsic mechanism of these candidate genes involving in the occurrence and development of HCC from transcriptome level as well as the clinical significance of their associations with the prognosis of HCC patients. Methods: Gene expression profiles of GSE45267, GSE64041, GSE84402 and TCGA were downloaded from GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas), respectively. R software and Bioconductor packages were used to identify the DEGs between HCC tissues and para-cancer tissues, and then Gene Ontology (GO) Enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Protein-Protein Interaction (PPI) network analysis and survival analysis were performed.Results: Forty-six up-regulated genes and 154 down-regulated genes were screened out,and GO enrichment analysis showed that these DEGs were mainly related to cell division, proliferation, cycle regulation, oxidation-reduction process and certain metabolic pathways. KEGG pathway analysis revealed that DEGs were mainly involved in tryptophan metabolism, retinol metabolism and other metabolic pathways as well as p53 pathway. Over-expression of a panel of up-regulated genes (CCNA2, CDK1, DLGAP5, KIF20A,KPNA2 and MELK) was shown to be significantly negatively correlated with the prognosis of HCC patients in the TCGA dataset(all P<0.01). Conclusion: A set of up-regulated hub genes that are negatively correlated with prognosis will provide potential guiding value for the clinical research on the diagnosis and treatment of HCC.
11 Detection of gene mutation in pancreatic mucinous cystadenocarcinoma and its clinical significance
2019, 26(4):440-444.
DOI: 10.3872/j.issn.1007-385X.2019.04.011
Abstract:
[Abstract] Objective：To detect the distribution of gene mutations in pancreatic mucinous cystadenocarcinoma (PMCC) by highthroughput sequencing and to explore its clinical significance. Methods: Four cases of paraffin-embedded cancer tissues and paracancerous tissues from PMCC patients, who underwent surgical resection from January 2012 to December 2016, received NGS (next generation sequencing) examination using Illumina Hiseq 2500 platform. The characteristics of gene mutation in PMCC patients were analyzed with sequencing results and clinicopathological data. Results: Seven significantly mutated genes (SMGs) were detected in all four PMCC samples, namely KRAS, AHNAK2, MUC16, MUC17, MUC19, MUC3A and MUC4. Twenty-four SMGs were detected in 3 of the 4 samples, namely ADAMTS9, ALDH3B1, CARD14, CSMD3, MKI67, OR1N2, PKHD1, PLCE1, RTL1, SIGLEC12,CCDC168, CEP295, CUBN, DST, HRNR, LAMA5, OR10G4, OR2T4, PLEKHG4B, RP1L1, SLC15A5, SVEP1, TAS1R1 and TNRC18.KRAS-driven gene mutations were detected in all 4 samples, including K12 hot spot mutation in 3 cases and D33E non-hot spot mutation in 1 case. Conclusion: The high mutation of KRAS and MUC family in PMCC may be a potential target and biomarker for precise treatment of PMCC.
[Abstract] Objective：To detect the distribution of gene mutations in pancreatic mucinous cystadenocarcinoma (PMCC) by highthroughput sequencing and to explore its clinical significance. Methods: Four cases of paraffin-embedded cancer tissues and paracancerous tissues from PMCC patients, who underwent surgical resection from January 2012 to December 2016, received NGS (next generation sequencing) examination using Illumina Hiseq 2500 platform. The characteristics of gene mutation in PMCC patients were analyzed with sequencing results and clinicopathological data. Results: Seven significantly mutated genes (SMGs) were detected in all four PMCC samples, namely KRAS, AHNAK2, MUC16, MUC17, MUC19, MUC3A and MUC4. Twenty-four SMGs were detected in 3 of the 4 samples, namely ADAMTS9, ALDH3B1, CARD14, CSMD3, MKI67, OR1N2, PKHD1, PLCE1, RTL1, SIGLEC12,CCDC168, CEP295, CUBN, DST, HRNR, LAMA5, OR10G4, OR2T4, PLEKHG4B, RP1L1, SLC15A5, SVEP1, TAS1R1 and TNRC18.KRAS-driven gene mutations were detected in all 4 samples, including K12 hot spot mutation in 3 cases and D33E non-hot spot mutation in 1 case. Conclusion: The high mutation of KRAS and MUC family in PMCC may be a potential target and biomarker for precise treatment of PMCC.
2019, 26(4):445-453.
DOI: 10.3872/j.issn.1007-385X.2019.04.012
Abstract:
[Abstract] Objective: To determine the potential diagnostic value of miRNA-29 (miR-29) for malignant tumor. Methods: A systematic search of literature regarding miR-29 was performed in three English databases (PubMed, Web of Science, and Embase) and two Chinese databases (Chinese National Knowledge Infrastructure [CNKI] and WanFang). The retrieval was ended until September 15,2018. Search terms included miRNA-29 (miR-29), tumor, cancer, serum, plasma, diagnosis, etc. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was carried out to evaluate the quality of the selected articles. STATA12.0 was used to calculate the combined sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR). Subgroup analysis and Meta-regression analysis were carried out to explore the origin of heterogeneity. Results: Twenty eligible articles were selected from 1 172 literatures related to tumors and miR-29. The combined sensitivity was 0.76 (95%CI: 0.68-0.83), combined specificity was 0.83 (95%CI: 0.74-0.89), combined PLR was 4.5 (95%CI: 2.7-7.4), combined NLR was 0.28 (95%CI: 0.20-0.41), DOR was 16 (95%CI: 7-35), and the AUC was 0.86 (95%CI: 0.83-0.89). The combined specificity of plasma samples was higher than that of serum samples, and the difference was statistically significant (P<0.01). There was a higher diagnostic value of miR-29 for breast cancer and pancreatic cancer (DOR=101.52, 11.22), but lower diagnostic value for colorectal cancer and non-small cell lung cancer (DOR=5.05, 6.57); miR-29b showed a high diagnostic value for cancer (DOR=60.91). The publication bias was not obvious in this study (P>0.05). Conclusion: This systematic review and Meta-analysis suggests that miR-29 family is a potential biomarker in the diagnosis of cancers with great sensitivity and specificity.
[Abstract] Objective: To determine the potential diagnostic value of miRNA-29 (miR-29) for malignant tumor. Methods: A systematic search of literature regarding miR-29 was performed in three English databases (PubMed, Web of Science, and Embase) and two Chinese databases (Chinese National Knowledge Infrastructure [CNKI] and WanFang). The retrieval was ended until September 15,2018. Search terms included miRNA-29 (miR-29), tumor, cancer, serum, plasma, diagnosis, etc. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was carried out to evaluate the quality of the selected articles. STATA12.0 was used to calculate the combined sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR). Subgroup analysis and Meta-regression analysis were carried out to explore the origin of heterogeneity. Results: Twenty eligible articles were selected from 1 172 literatures related to tumors and miR-29. The combined sensitivity was 0.76 (95%CI: 0.68-0.83), combined specificity was 0.83 (95%CI: 0.74-0.89), combined PLR was 4.5 (95%CI: 2.7-7.4), combined NLR was 0.28 (95%CI: 0.20-0.41), DOR was 16 (95%CI: 7-35), and the AUC was 0.86 (95%CI: 0.83-0.89). The combined specificity of plasma samples was higher than that of serum samples, and the difference was statistically significant (P<0.01). There was a higher diagnostic value of miR-29 for breast cancer and pancreatic cancer (DOR=101.52, 11.22), but lower diagnostic value for colorectal cancer and non-small cell lung cancer (DOR=5.05, 6.57); miR-29b showed a high diagnostic value for cancer (DOR=60.91). The publication bias was not obvious in this study (P>0.05). Conclusion: This systematic review and Meta-analysis suggests that miR-29 family is a potential biomarker in the diagnosis of cancers with great sensitivity and specificity.
2019, 26(4):454-462.
DOI: 10.3872/j.issn.1007-385X.2019.04.013
Abstract:
[摘要] 肿瘤免疫逃逸是肿瘤发生发展的十大特征之一，针对免疫逃逸环节的免疫疗法近年来取得了显著的成功。免疫疗法涉及多个因素和环节，与肿瘤细胞自身和肿瘤微环境的改变均有相关且机制复杂，目前在临床实践过程中仍面临着不小的挑战。本文从3 个方面介绍了肿瘤免疫逃逸的机制，包括肿瘤自身的改变、肿瘤诱导微环境的改变以及肿瘤微环境促进肿瘤的发展。同时针对这些机制，将目前的治疗策略进行了梳理，包括免疫检查点抑制剂、CAR-T疗法以及免疫细胞疗法等的困境与进展，旨在为肿瘤免疫治疗的下一步发展理清思路。
[摘要] 肿瘤免疫逃逸是肿瘤发生发展的十大特征之一，针对免疫逃逸环节的免疫疗法近年来取得了显著的成功。免疫疗法涉及多个因素和环节，与肿瘤细胞自身和肿瘤微环境的改变均有相关且机制复杂，目前在临床实践过程中仍面临着不小的挑战。本文从3 个方面介绍了肿瘤免疫逃逸的机制，包括肿瘤自身的改变、肿瘤诱导微环境的改变以及肿瘤微环境促进肿瘤的发展。同时针对这些机制，将目前的治疗策略进行了梳理，包括免疫检查点抑制剂、CAR-T疗法以及免疫细胞疗法等的困境与进展，旨在为肿瘤免疫治疗的下一步发展理清思路。
2019, 26(4):463-467.
DOI: 10.3872/j.issn.1007-385X.2019.04.014
Abstract:
[摘要] CMTM家族作为一个新的基因家族，在免疫、生殖等系统以及多种肿瘤的发病机制中起到重要作用。CMTM家族中，CMTM1 可影响细胞增殖，导致肿瘤发生；与非小细胞肺癌（NSCLC）患者的化疗耐药和预后有关。CMTM2 通过AP-1、CREB通路一定程度上影响HIV-1 转录，同时在男性生殖系统中起重要作用。CMTM3 等位基因失活或甲基化使其丧失对细胞增殖的负性调控能力，是胃癌独立的预后指标。CMTM4 调控细胞周期影响肿瘤细胞增殖，通过对PD-L1 的协同保护参与免疫逃逸。CMTM5 在许多肿瘤中沉默表达，参与肿瘤发生发展相关的信号通路。CMTM6 协同PD-L1 参与免疫逃逸，是潜在的免疫治疗靶点。CMTM7 在NSCLC中通过Rab5 控制EGFR-AKT信号影响肿瘤发展，且与胃癌发展相关。CMTM8 通过MARVEL区域影响EGFR和相关信号通路，调控细胞增殖、分化和凋亡等。上述重要发现，为研究肿瘤的发生发展及肿瘤基因治疗提供了新思路。
[摘要] CMTM家族作为一个新的基因家族，在免疫、生殖等系统以及多种肿瘤的发病机制中起到重要作用。CMTM家族中，CMTM1 可影响细胞增殖，导致肿瘤发生；与非小细胞肺癌（NSCLC）患者的化疗耐药和预后有关。CMTM2 通过AP-1、CREB通路一定程度上影响HIV-1 转录，同时在男性生殖系统中起重要作用。CMTM3 等位基因失活或甲基化使其丧失对细胞增殖的负性调控能力，是胃癌独立的预后指标。CMTM4 调控细胞周期影响肿瘤细胞增殖，通过对PD-L1 的协同保护参与免疫逃逸。CMTM5 在许多肿瘤中沉默表达，参与肿瘤发生发展相关的信号通路。CMTM6 协同PD-L1 参与免疫逃逸，是潜在的免疫治疗靶点。CMTM7 在NSCLC中通过Rab5 控制EGFR-AKT信号影响肿瘤发展，且与胃癌发展相关。CMTM8 通过MARVEL区域影响EGFR和相关信号通路，调控细胞增殖、分化和凋亡等。上述重要发现，为研究肿瘤的发生发展及肿瘤基因治疗提供了新思路。
2019, 26(4):468-473.
DOI: 10.3872/j.issn.1007-385X.2019.04.015
Abstract:
[摘要] T-Vec（talimogene laherparepvec）是由Ⅰ型单纯疱疹病毒（HSV-1）改造而来的一种溶瘤病毒，能够选择性地在恶性肿瘤细胞中复制而不伤及其他正常细胞。T-Vec 在治疗晚期黑色素瘤患者的Ⅲ期临床试验中显示出良好的安全性和肿瘤治疗效果，已于2015 年经美国FDA批准用于治疗晚期黑色素瘤。为了提高T-Vec 的疗效，扩大其应用范围，T-Vec 联合其他抗肿瘤疗法以及应用于其他肿瘤的临床试验仍在陆续开展。近期，T-Vec 联合免疫检查点抑制剂在治疗晚期黑色素瘤的临床试验中取得新进展，临床数据显示T-Vec 联合疗法具有更强的抗肿瘤活性。此外，T-Vec 在治疗头颈癌、胰腺癌、肝癌等肿瘤的临床研究中也取得了一定进展。本文对近年来T-Vec治疗肿瘤的临床试验的相关研究进展做一综述。
[摘要] T-Vec（talimogene laherparepvec）是由Ⅰ型单纯疱疹病毒（HSV-1）改造而来的一种溶瘤病毒，能够选择性地在恶性肿瘤细胞中复制而不伤及其他正常细胞。T-Vec 在治疗晚期黑色素瘤患者的Ⅲ期临床试验中显示出良好的安全性和肿瘤治疗效果，已于2015 年经美国FDA批准用于治疗晚期黑色素瘤。为了提高T-Vec 的疗效，扩大其应用范围，T-Vec 联合其他抗肿瘤疗法以及应用于其他肿瘤的临床试验仍在陆续开展。近期，T-Vec 联合免疫检查点抑制剂在治疗晚期黑色素瘤的临床试验中取得新进展，临床数据显示T-Vec 联合疗法具有更强的抗肿瘤活性。此外，T-Vec 在治疗头颈癌、胰腺癌、肝癌等肿瘤的临床研究中也取得了一定进展。本文对近年来T-Vec治疗肿瘤的临床试验的相关研究进展做一综述。
2019, 26(4):474-478.
DOI: 10.3872/j.issn.1007-385X.2019.04.016
Abstract:
[摘要] 细胞周期蛋白依赖性激酶12（CDK12）属于丝氨酸/苏氨酸蛋白激酶家族，其主要功能是调节转录和转录后过程，从而调控多种细胞的功能。早期研究认为CDK12 是一种转录型CDK，它与cyclin K形成复合物，通过磷酸化RNA聚合酶Ⅱ介导基因转录。最近的研究表明，CDK12 还参与DNA复制，影响发育。CDK12 被证明能特异性地上调DNA损伤、应激和热激反应中相关基因的表达，目前已在食管癌、胃癌、乳腺癌、子宫内膜癌、卵巢癌、膀胱癌、结直肠癌和胰腺癌中被检测到CDK12 基因发生改变，占被检测病例的5%~15%。越来越多的研究显示，检测CDK12 能够预测肿瘤的治疗反应，包括聚ADP核糖聚合酶（PARP）抑制和PD-1 抑制治疗。CDK12 抑制是抑制肿瘤生长的有效策略，特定的遗传或细胞背景能够使CDK12 抑制的敏感性增强，包括PARP 和CHK1 抑制、MYC依赖和EWS/FLI 重排。多种不同化学结构和作用范围的CDK12 抑制剂已经被用于临床前研究，CDK12有望成为肿瘤治疗的新靶点。
[摘要] 细胞周期蛋白依赖性激酶12（CDK12）属于丝氨酸/苏氨酸蛋白激酶家族，其主要功能是调节转录和转录后过程，从而调控多种细胞的功能。早期研究认为CDK12 是一种转录型CDK，它与cyclin K形成复合物，通过磷酸化RNA聚合酶Ⅱ介导基因转录。最近的研究表明，CDK12 还参与DNA复制，影响发育。CDK12 被证明能特异性地上调DNA损伤、应激和热激反应中相关基因的表达，目前已在食管癌、胃癌、乳腺癌、子宫内膜癌、卵巢癌、膀胱癌、结直肠癌和胰腺癌中被检测到CDK12 基因发生改变，占被检测病例的5%~15%。越来越多的研究显示，检测CDK12 能够预测肿瘤的治疗反应，包括聚ADP核糖聚合酶（PARP）抑制和PD-1 抑制治疗。CDK12 抑制是抑制肿瘤生长的有效策略，特定的遗传或细胞背景能够使CDK12 抑制的敏感性增强，包括PARP 和CHK1 抑制、MYC依赖和EWS/FLI 重排。多种不同化学结构和作用范围的CDK12 抑制剂已经被用于临床前研究，CDK12有望成为肿瘤治疗的新靶点。
17 Apatinib combined with chemotherapy for breast carcinosarcoma：a case report and literature review
2019, 26(4):479-481.
DOI: 10.3872/j.issn.1007-385X.2019.04.017
Abstract:
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- 《中国肿瘤生物治疗杂志》
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Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.