Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter...Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel isminimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca2+ channels are not expressed in epithelial cells, selective T-type Ca2+ channel blockers may be useful in the treatment of certain types of cancers.展开更多
Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epit...Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.展开更多
Background:Whether the extra-hepatic bile duct(EHBD)should be routinely resected for gallbladder carcinoma(GBC)remains controversial.The current study aimed to determine the clinical impact of combined EHBD resection ...Background:Whether the extra-hepatic bile duct(EHBD)should be routinely resected for gallbladder carcinoma(GBC)remains controversial.The current study aimed to determine the clinical impact of combined EHBD resection during curative surgery for advanced GBC.Methods:In total,213 patients who underwent curative surgery for T2,T3 or T4 GBC were enrolled.The clinicopathological features were compared between the patients treated with EHBD resection and those without EHBD resection.Meanwhile,univariable and multivariable Cox-proportional hazards regression models were used to identify risk factors for overall survival(OS).Results:Among the 213 patients identified,87(40.8%)underwent combined EHBD resection.Compared with patients without EHBD resection,patients with EHBD resection suffered more post-operative complications(33.3%vs.21.4%,P=0.046).However,the median OS of the EHBD resection group was longer than that of the non-EHBD resection group(25 vs.11 months,P=0.008).Subgroup analyses were also performed according to tumor(T)category and lymph-node metastasis.The median OS was significantly longer in the EHBD resection group than in the non-EHBD resection group for patients with T3 lesion(15 vs.7 months,P=0.002),T4 lesion(11 vs.6 months,P=0.021)or lymph-node metastasis(12 vs.7 months,P<0.001).No survival benefit of EHBD resection was observed in GBC patients with T2 lesion or without lymph-node metastasis.T category,lymph-node metastasis,margin status,pre-operative CA19-9 level and EHBD resection were identified as independent prognostic factors for OS of patients with advanced GBC(all P values<0.05).Conclusions EHBD resection can independently affect the OS in advanced GBC.For GBC patients with T3 lesion,T4 lesion and lymph-node metastasis,combined EHBD resection is justified and may improve OS.展开更多
文摘Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel isminimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca2+ channels are not expressed in epithelial cells, selective T-type Ca2+ channel blockers may be useful in the treatment of certain types of cancers.
基金the Deutsche Forschungsgemeinschaft (Emmy Noether Programm, SFB 610)the Wilhelm Sander Stiftung, and the Bundesministerium fuer Wissenschaft und Forschung (Start-up fonds Kompetenznetz Hepatitis)
文摘Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host’s human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV- specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.
基金supported by the grant from the Science&Technology Support Project of Sichuan Province(No.2018JY0019).
文摘Background:Whether the extra-hepatic bile duct(EHBD)should be routinely resected for gallbladder carcinoma(GBC)remains controversial.The current study aimed to determine the clinical impact of combined EHBD resection during curative surgery for advanced GBC.Methods:In total,213 patients who underwent curative surgery for T2,T3 or T4 GBC were enrolled.The clinicopathological features were compared between the patients treated with EHBD resection and those without EHBD resection.Meanwhile,univariable and multivariable Cox-proportional hazards regression models were used to identify risk factors for overall survival(OS).Results:Among the 213 patients identified,87(40.8%)underwent combined EHBD resection.Compared with patients without EHBD resection,patients with EHBD resection suffered more post-operative complications(33.3%vs.21.4%,P=0.046).However,the median OS of the EHBD resection group was longer than that of the non-EHBD resection group(25 vs.11 months,P=0.008).Subgroup analyses were also performed according to tumor(T)category and lymph-node metastasis.The median OS was significantly longer in the EHBD resection group than in the non-EHBD resection group for patients with T3 lesion(15 vs.7 months,P=0.002),T4 lesion(11 vs.6 months,P=0.021)or lymph-node metastasis(12 vs.7 months,P<0.001).No survival benefit of EHBD resection was observed in GBC patients with T2 lesion or without lymph-node metastasis.T category,lymph-node metastasis,margin status,pre-operative CA19-9 level and EHBD resection were identified as independent prognostic factors for OS of patients with advanced GBC(all P values<0.05).Conclusions EHBD resection can independently affect the OS in advanced GBC.For GBC patients with T3 lesion,T4 lesion and lymph-node metastasis,combined EHBD resection is justified and may improve OS.
