Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identifi...Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identification of a potent DHODH inhibitor by proteomic profiling.Cell-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer cells.Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic acid.Moreover,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid.These results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell growth.Thus,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.展开更多
BACKGROUND Bile duct cancer constitutes gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICA),and extrahepatic cholangiocarcinoma(ECA).These three entities show morphological and immunohistochemical resemblance...BACKGROUND Bile duct cancer constitutes gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICA),and extrahepatic cholangiocarcinoma(ECA).These three entities show morphological and immunohistochemical resemblance so that it is difficult to differentiate between primary ICA and liver metastasis of GBC,which sometimes becomes a point of discussion in clinical practice.Although these cancers demonstrate significant differences in their mutational landscape,several reports demonstrated shared genomic alteration in paired primary and metastatic site aids in distinguishing metastatic recurrence from second primary cancers.CASE SUMMARY We present a 73-year-old female patient who underwent curative resection for GBC harboring epidermal growth factor receptor 2(ERBB2)activating mutation on next-generation sequencing(NGS)-based genomic testing.One year later,a hepatic lesion was observed on follow-up imaging and she underwent surgical resection for a pathological diagnosis.The histological findings of the hepatic lesion were similar to those of the primary lesion.Additionally,using NGS panel testing,the hepatic lesion was found to have ERBB2 activating mutation,which is the identical mutation detected in the sequencing result of the primary site.ERBB2 activating mutation occurs more frequently in GBC than ICA and ECA.Therefore,in the present case,we think this molecular finding potentiated the diagnosis of the liver mass toward a metastatic recurrence.Additionally,this patient underwent HER2-targeted treatment with lapatinib in combination with capecitabin and obtained clinical benefit.CONCLUSION This case illustrated NGS panel usefulness in distinguishing GBC recurrence from second primary cancer and HER2-targeted agent efficacy on ERBB2 mutated GBC.展开更多
OBJECTIVE Cytokine-induced killer （CIK） cells are T-cells that display effective anti-tumor activity. In this stud, we investigated the anti-tumor activity of CIK cells in vitro, and conducted a preliminary investig...OBJECTIVE Cytokine-induced killer （CIK） cells are T-cells that display effective anti-tumor activity. In this stud, we investigated the anti-tumor activity of CIK cells in vitro, and conducted a preliminary investigation using autologous CIK cells to treat glioma patients through local administration. METHODS The CIK cells were derived from peripheral blood monocytes （PBMCs） of the glioma patients. The anti-tumor activity of the CIK cells against human T98-G glioma cell was tested in vitro. In addition, the autologous CIK cells were locally administrated into the tumor cavity in the malignant glioma patients through an Ommaya reservoir which was pre-inserted during tumor resection. The 4 x 108 CIK cells in a 5 ml suspension were injected once a week 2 times per cycle. Five hundreds KU of IL-2 was injected every other day. RESULTS （i） With incubation, the CIK cells showed dual staining of CD3^＋CD56^＋ with a positive rate of 3.45% on day 10 and 55.2% on day 30. In vitro anti-tumor activity （against T98-G cells） of the CIK cells reached the highest level after 18 days of incubation with different effector/target （E：T） ratios. （ii） Six patients received autologous CIK cell treatment （10 cycles）. Two patients showed no recurrence and are still alive （24 and 10 months）, while 4 cases had a recurrence 3 of which have died. The mean survival time from the first CIK cell treatment to the end of follow-up was 12.5 months. The main side-effects of the local CIK cell treatment was brain edema, which was controlled by mannitol in most of the cases. However for one patient injection of CIK cells and IL-2 had to be discontinued. CONCLUSION In vitro CIK cells are effective anti-glioma T-cells. Local therapy with CIK cells has potential anti-glioma efficacy and tolerable side-effects.展开更多
Objective:To study the risk factors of hemorrhagic transformation in patients with acute cerebral infarction and to analyze the risk factors.Methods: A total of 96 patients with acute cerebral infarction after the thr...Objective:To study the risk factors of hemorrhagic transformation in patients with acute cerebral infarction and to analyze the risk factors.Methods: A total of 96 patients with acute cerebral infarction after the thrombolysis in our hospital from June 2016 to December 2017 were selected as the research object. And they were divided into bleeding group 48 cases and hemorrhage transformation group 48 cases according to whether with hemorrhage occurs transformation. Then the lipid metabolism, atrial fibrillation, history of smoking and drinking, history of hypertension and diabetes, blood pressure, treatment time after onset and infarction area of two groups were compared, and the relationship between those factors and the disease were analyzed by the multi-factor Logistic regression analysis.Results: The atrial fibrillation, history of smoking and drinking of two groups had significant differences;The hospital fasting plasma glucose and LDL-C level of two groups had significant differences;the treatment time after onset and infarction area of two groups had significant differences;The multi-factor Logistic regression analysis showed that atrial fibrillation, blood glucose on admission, LDL-C and large area of infarction are the factors affecting the risk of bleeding in patients with acute cerebral infarction transformation.Conclusion:Atrial fibrillation, blood glucose on admission, LDL-C, treatment time after onset and large area of infarction belongs to the patients with acute cerebral infarction after the thrombolysis transformation of bleeding risk factors.展开更多
Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from ...Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.展开更多
基金supported by AMED Grants(Nos.JP16cm0106112 and JP16cm0106002)JSPS KAKENHI Grants(Nos.JP17H06412,18H05503,JP19K05744,JP20K05857,JP20H05620,JP21H04720,JP22H04922,and JP22K05363).
文摘Dihydroorotate dehydrogenase(DHODH)is a central enzyme of the de novo pyrimidine biosynthesis pathway and is a promising drug target for the treatment of cancer and autoimmune diseases.This study presents the identification of a potent DHODH inhibitor by proteomic profiling.Cell-based screening revealed that NPD723,which is reduced to H-006 in cells,strongly induces myeloid differentiation and inhibits cell growth in HL-60 cells.H-006 also suppressed the growth of various cancer cells.Proteomic profiling of NPD723-treated cells in ChemProteoBase showed that NPD723 was clustered with DHODH inhibitors.H-006 potently inhibited human DHODH activity in vitro,whereas NPD723 was approximately 400 times less active than H-006.H-006-induced cell death was rescued by the addition of the DHODH product orotic acid.Moreover,metabolome analysis revealed that H-006 treatment promotes marked accumulation of the DHODH substrate dihydroorotic acid.These results suggest that NPD723 is reduced in cells to its active metabolite H-006,which then targets DHODH and suppresses cancer cell growth.Thus,H-006-related drugs represent a potentially powerful treatment for cancer and other diseases.
文摘BACKGROUND Bile duct cancer constitutes gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICA),and extrahepatic cholangiocarcinoma(ECA).These three entities show morphological and immunohistochemical resemblance so that it is difficult to differentiate between primary ICA and liver metastasis of GBC,which sometimes becomes a point of discussion in clinical practice.Although these cancers demonstrate significant differences in their mutational landscape,several reports demonstrated shared genomic alteration in paired primary and metastatic site aids in distinguishing metastatic recurrence from second primary cancers.CASE SUMMARY We present a 73-year-old female patient who underwent curative resection for GBC harboring epidermal growth factor receptor 2(ERBB2)activating mutation on next-generation sequencing(NGS)-based genomic testing.One year later,a hepatic lesion was observed on follow-up imaging and she underwent surgical resection for a pathological diagnosis.The histological findings of the hepatic lesion were similar to those of the primary lesion.Additionally,using NGS panel testing,the hepatic lesion was found to have ERBB2 activating mutation,which is the identical mutation detected in the sequencing result of the primary site.ERBB2 activating mutation occurs more frequently in GBC than ICA and ECA.Therefore,in the present case,we think this molecular finding potentiated the diagnosis of the liver mass toward a metastatic recurrence.Additionally,this patient underwent HER2-targeted treatment with lapatinib in combination with capecitabin and obtained clinical benefit.CONCLUSION This case illustrated NGS panel usefulness in distinguishing GBC recurrence from second primary cancer and HER2-targeted agent efficacy on ERBB2 mutated GBC.
文摘OBJECTIVE Cytokine-induced killer （CIK） cells are T-cells that display effective anti-tumor activity. In this stud, we investigated the anti-tumor activity of CIK cells in vitro, and conducted a preliminary investigation using autologous CIK cells to treat glioma patients through local administration. METHODS The CIK cells were derived from peripheral blood monocytes （PBMCs） of the glioma patients. The anti-tumor activity of the CIK cells against human T98-G glioma cell was tested in vitro. In addition, the autologous CIK cells were locally administrated into the tumor cavity in the malignant glioma patients through an Ommaya reservoir which was pre-inserted during tumor resection. The 4 x 108 CIK cells in a 5 ml suspension were injected once a week 2 times per cycle. Five hundreds KU of IL-2 was injected every other day. RESULTS （i） With incubation, the CIK cells showed dual staining of CD3^＋CD56^＋ with a positive rate of 3.45% on day 10 and 55.2% on day 30. In vitro anti-tumor activity （against T98-G cells） of the CIK cells reached the highest level after 18 days of incubation with different effector/target （E：T） ratios. （ii） Six patients received autologous CIK cell treatment （10 cycles）. Two patients showed no recurrence and are still alive （24 and 10 months）, while 4 cases had a recurrence 3 of which have died. The mean survival time from the first CIK cell treatment to the end of follow-up was 12.5 months. The main side-effects of the local CIK cell treatment was brain edema, which was controlled by mannitol in most of the cases. However for one patient injection of CIK cells and IL-2 had to be discontinued. CONCLUSION In vitro CIK cells are effective anti-glioma T-cells. Local therapy with CIK cells has potential anti-glioma efficacy and tolerable side-effects.
文摘Objective:To study the risk factors of hemorrhagic transformation in patients with acute cerebral infarction and to analyze the risk factors.Methods: A total of 96 patients with acute cerebral infarction after the thrombolysis in our hospital from June 2016 to December 2017 were selected as the research object. And they were divided into bleeding group 48 cases and hemorrhage transformation group 48 cases according to whether with hemorrhage occurs transformation. Then the lipid metabolism, atrial fibrillation, history of smoking and drinking, history of hypertension and diabetes, blood pressure, treatment time after onset and infarction area of two groups were compared, and the relationship between those factors and the disease were analyzed by the multi-factor Logistic regression analysis.Results: The atrial fibrillation, history of smoking and drinking of two groups had significant differences;The hospital fasting plasma glucose and LDL-C level of two groups had significant differences;the treatment time after onset and infarction area of two groups had significant differences;The multi-factor Logistic regression analysis showed that atrial fibrillation, blood glucose on admission, LDL-C and large area of infarction are the factors affecting the risk of bleeding in patients with acute cerebral infarction transformation.Conclusion:Atrial fibrillation, blood glucose on admission, LDL-C, treatment time after onset and large area of infarction belongs to the patients with acute cerebral infarction after the thrombolysis transformation of bleeding risk factors.
基金Our research group was funded by Taiho Pharmaceutical Co.,Ltd.(Tokyo,Japan),UNITECH Co.,Ltd.(Chiba,Japan),IDEA Consultants Inc.(Tokyo,Japan),Kinshu-kai Medical Corporation(Osaka,Japan).
文摘Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.
