CDC42 controls intestinal epithelial(IEC)stem cell(IESC)division.How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear.We utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,a...CDC42 controls intestinal epithelial(IEC)stem cell(IESC)division.How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear.We utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia.Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer.Cdc42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient mice.Irradiation,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC repair.Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD colon.Colonic Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt dysplasia.Colonic Cdc42 depletion markedly enhanced irra-diation-or chemical-induced colitis.Depletion or inhibition of Cdc42 reduced colonic Lgr5+IESC regeneration.In conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal inflammation.Constitutive monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.展开更多
Background:Radioembolization(RE)is well established in the treatment of neuroendocrine liver metastases.However surgery is rarely performed after RE,although liver resection is the gold standard in the treatment of lo...Background:Radioembolization(RE)is well established in the treatment of neuroendocrine liver metastases.However surgery is rarely performed after RE,although liver resection is the gold standard in the treatment of localized neuroendocrine liver metastases.Therefore,aim of the present study was to evaluate the safety and feasibility of liver resection after RE in a homogenous cohort.Methods:From a prospective surgical(n=494)and nuclear medical(n=138)database patients with NELM who underwent liver resection and/or RE were evaluated.Between September 2011 and December 2017 eight patients could be identified who underwent liver resection after RE(mean therapeutic activity of 1,746 Mbq).Overall and progression free survival were evaluated as well as epidemiological and perioperative factors.The surgical specimens were analyzed for necrosis,fibrosis,inflammation,and steatosis.Results:The mean hepatic tumor load of patients,who had liver surgery after RE,was 31.4%with a mean Ki-67 proliferation index of 5.9%.The majority of these patients(7/8)received whole liver RE prior to liver resection,which did not increase morbidity and mortality compared to a surgical collective.Indications for RE were oncological(6/8)or carcinoid syndrome associated reasons(2/8).Mean overall survival was 25.1 months after RE and subsequent surgery.Tumor necrosis in radioembolized lesions was 29.4%without evidence of fibrosis and inflammation in hepatic tissue.Conclusions:This is the first study analyzing the multimodal therapeutic approach of liver resection following whole liver RE.This treatment algorithm is safe,does not lead to an increased morbidity and is associated with a favorable oncological outcome.Nonetheless,patient selection remains a key issue.展开更多
基金supported by NIDDK RO1,USA(No.R01DK123299)(X.H.)MHMC/CWRU start-up(X.H.).R.M.was supported by a private cancer metabolism grant donation from Liechtenstein and the Austrian Science Fund(FWF)(No.SFB F4707 and SFB-F06105).
文摘CDC42 controls intestinal epithelial(IEC)stem cell(IESC)division.How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear.We utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia.Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer.Cdc42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient mice.Irradiation,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC repair.Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD colon.Colonic Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt dysplasia.Colonic Cdc42 depletion markedly enhanced irra-diation-or chemical-induced colitis.Depletion or inhibition of Cdc42 reduced colonic Lgr5+IESC regeneration.In conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal inflammation.Constitutive monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.
文摘Background:Radioembolization(RE)is well established in the treatment of neuroendocrine liver metastases.However surgery is rarely performed after RE,although liver resection is the gold standard in the treatment of localized neuroendocrine liver metastases.Therefore,aim of the present study was to evaluate the safety and feasibility of liver resection after RE in a homogenous cohort.Methods:From a prospective surgical(n=494)and nuclear medical(n=138)database patients with NELM who underwent liver resection and/or RE were evaluated.Between September 2011 and December 2017 eight patients could be identified who underwent liver resection after RE(mean therapeutic activity of 1,746 Mbq).Overall and progression free survival were evaluated as well as epidemiological and perioperative factors.The surgical specimens were analyzed for necrosis,fibrosis,inflammation,and steatosis.Results:The mean hepatic tumor load of patients,who had liver surgery after RE,was 31.4%with a mean Ki-67 proliferation index of 5.9%.The majority of these patients(7/8)received whole liver RE prior to liver resection,which did not increase morbidity and mortality compared to a surgical collective.Indications for RE were oncological(6/8)or carcinoid syndrome associated reasons(2/8).Mean overall survival was 25.1 months after RE and subsequent surgery.Tumor necrosis in radioembolized lesions was 29.4%without evidence of fibrosis and inflammation in hepatic tissue.Conclusions:This is the first study analyzing the multimodal therapeutic approach of liver resection following whole liver RE.This treatment algorithm is safe,does not lead to an increased morbidity and is associated with a favorable oncological outcome.Nonetheless,patient selection remains a key issue.
