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Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia

Genes & Diseases 2024年第1期11卷 413-429页

作者： Dongsheng Zhang Wenjuan Tang Haitao Niu William Tse Hai-Bin Ruan Helmut Dolznig thomas knosel Friedrich Karl-Heinz Madeleine Themanns Jiang Wang Mingquan Song Lee Denson Lukas Kenner Richard Moriggl Yi Zheng Xiaonan Han Division of Hematology and Oncology Division of Cancer BiologyDepartment of MedicineMetroHealth Medical Center(MHMC)Case Western Reserve University(CWRU)School of MedicineClevelandOH 44109USA Cancer Genomics and Epigenomics Program Case Comprehensive Cancer CenterCase Western Reserve University(CWRU)ClevelandOH 44106USA Division of Gastroenterology Hepatology and NutritionCincinnati Children’s Hospital Medical Center(CCHMC)CincinnatiOH 45229USA Children’s Hospital of Fudan University Shanghai 201102China School of Medicine Jinan UniversityGuangzhouGuangdong 510632China Laboratory Animal Science(ILAS) Chinese Academy of Medical Science(CAMS)and Peking Union Medical College(PUMC)Beijing 100006China Department of Integrative Biology and Physiology University of Minnesota Medical SchoolMinneapolisMI 55455USA Institute of Medical Genetics Medical University of ViennaVienna 1040Austria Institute of Pathology Ludwig-Maximilians-University MunichMunich 80539Germany Institute of Biochemistry II University Hospital JenaJena 07743Germany Laboratory Animal Pathology University of Veterinary Medicine ViennaVienna 1210Austria Department of Pathology University of CincinnatiCincinnatiOH 45221USA Department of Gastroenterology The Affiliated Hospital of Qingdao UniversityQingdaoShandong 266005China Department of Pathology Medical University of ViennaVienna 1040Austria Ludwig Boltzmann Institute for Cancer Research Vienna 1090Austria Medical University of Vienna Vienna 1040Austria Institute of Animal Breeding and Genetics University of Veterinary Medicine ViennaVienna 1210Austria Division of Experimental Hematology CCHMCCincinnatiOH 45229USA

CDC42 controls intestinal epithelial(IEC)stem cell(IESC)*** aberrant CDC42 initiates intestinal inflammation or neoplasia is *** utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and *** specimens were collected to determine the levels of CDC42 in IBD or colorectal ***42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi1-CreERT2 mice to generate Cdc42 deficient ***,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC *** studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD *** Cdc42 depletion significantly reduced Lgr5+IEsCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt *** Cdc42 depletion markedly enhanced irra-diation-or chemical-induced *** or inhibition of Cdc42 reduced colonic Lgr5+IESC *** conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal *** monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.

关键词： Cell divisioncycle 42(CDC42) Colitis Colorectal cancer(CRC) Inflammatory bowel diseases(IBD) Intestinal epithelial cell(IEC) Intestinal epithelial stem cell(IESC) Irradiation

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Radioembolization for neuroendocrine liver metastases is safe and effective prior to major hepatic resection

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Hepatobiliary Surgery and Nutrition 2020年第3期9卷 312-321页

作者： Florian Bosch Harun Ilhan Vanessa Pfahler Michael thomas thomas knosel Valentin Eibl Sebastian Pratschke Peter Bartenstein Max Seidensticker Christoph J.Auernhammer Christine Spitzweg Markus O.Guba Jens Werner Martin K.Angele Department of General Visceraland Transplant SurgeryLudwig-Maximilians-University MunichMunichGermany Interdisciplinary Center of Neuroendocrine Tumors of the Gastro Entero Pancreatic System Ludwig-Maximilians-University MunichMunichGermany Department of Nuclear Medicine University HospitalLudwig-Maximilians-University MunichMunichGermany Department of Radiology Ludwig-Maximilians-University MunichMunichGermany Institute of Pathology Ludwig-Maximilians-University MunichMunichGermany Department of Internal Medicine 4 Ludwig-Maximilians-University MunichMunichGermany

Background:Radioembolization(RE)is well established in the treatment of neuroendocrine liver *** surgery is rarely performed after RE,although liver resection is the gold standard in the treatment of localized neuroendocrine liver ***,aim of the present study was to evaluate the safety and feasibility of liver resection after RE in a homogenous ***:From a prospective surgical(n=494)and nuclear medical(n=138)database patients with NELM who underwent liver resection and/or RE were *** 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 *** surgical specimens were analyzed for necrosis,fibrosis,inflammation,and ***: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 *** for RE were oncological(6/8)or carcinoid syndrome associated reasons(2/8).Mean overall survival was 25.1 months after RE and subsequent *** necrosis in radioembolized lesions was 29.4%without evidence of fibrosis and inflammation in hepatic ***:This is the first study analyzing the multimodal therapeutic approach of liver resection following whole liver *** treatment algorithm is safe,does not lead to an increased morbidity and is associated with a favorable oncological ***,patient selection remains a key issue.

关键词： Radioembolization(RE) neuroendocrine tumor liver surgery

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