Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed hosts. In healthy...Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed hosts. In healthy individuals the intestinal microbiota have a symbiotic relationship with the host organism and possess important and unique functions, including a metabolic function （i.e. digestion of dietary compounds and xenobiotics, fermentation of undigestible carbohydrates with production of short chain fatty acids）, a mucosal barrier function （i.e. by inhibiting pathogen invasion and strengthening epithelial barrier integrity）, and an immune modula- tory function （i.e. mucosal immune system priming and maintenance of intestinal epithelium homeostasis）. A fine balance regulates the mechanism that allows co- existence of mammals with their commensal bacteria. In IBD this mechanism of immune tolerance is impaired because of several potential causative factors. The gut microbiota composition and activity of IBD patients are abnormal, with a decreased prevalence of dominant members of the human commensal microbiota （i.e. Clostridium IXa and IV groups, Bacteroides, bifldobacteria） and a concomitant increase in detrimental bacteria （i.e. sulphate-reducing bacteria, Escherichia coll. The observed dysbiosis is concomitant with defectiveinnate immunity and bacterial killing （i.e. reduced mucosal defensins and IgA, malfunctioning phagocytosis） and overaggressive adaptive immune response （due to ineffective regulatory T cells and antigen presenting cells）, which are considered the basis of IBD pathogen- esis. However, we still do not know how the interplay between these parameters causes the disease. Studies looking at gut microbial composition, epithelial integrity and mucosal immune markers in genotyped IBD populations are therefore warranted to shed light on this obscure pathogenesis.展开更多
Aim:Primary tumors can be divided into oncogene-addicted(e.g.,lung)and non-oncogene addicted(e.g.,breast).Only the former group has an Achilles-heel single gene for successful target therapy,whereas the latter has mut...Aim:Primary tumors can be divided into oncogene-addicted(e.g.,lung)and non-oncogene addicted(e.g.,breast).Only the former group has an Achilles-heel single gene for successful target therapy,whereas the latter has mutations of multiple causative genes.Currently,tissue biopsy used for genetic surveys do not give a complete picture of the molecular profile and clonal evolution,but only provide static information over time.Methods:A series of 133 patients with 16 different solid tumors were enrolled.Blood samples were collected and cell-free DNA(cfDNA)was extracted.cfDNA libraries were analyzed using AVENIO circulating tumor DNA(ctDNA)Expanded Kit and Illumina NextSeq 550 for sequencing was used.In order to evaluate the clinical evolution over time,a second cfDNA analysis was performed after a mean interval of 2 months.Results:Through the cfDNA liquid biopsy,we found 89 pathogenic variants in 54 genes.Breast,lung,and prostate cancers showed the largest number of mutated genes.TP53,PIK3CA,FGFR3,KRAS,and ERBB2 were the most frequently mutated genes among 16 different tumors.Gene distribution didn’t show any type of prevalence.In particular,every patient with disease progression seems to have a“private”combination of gene pair mutations,with TP53 as the most frequently mutated gene.Conclusion:We showed that the clonal evolution of tumors includes a private combination of genes,regardless of tumor type.In the future,the cancer treatment can be the targeted therapy against specific tumor mutation(s).The present approach seems promising to both identify key cancer genes and follow clonal evolution over time.展开更多
文摘Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed hosts. In healthy individuals the intestinal microbiota have a symbiotic relationship with the host organism and possess important and unique functions, including a metabolic function （i.e. digestion of dietary compounds and xenobiotics, fermentation of undigestible carbohydrates with production of short chain fatty acids）, a mucosal barrier function （i.e. by inhibiting pathogen invasion and strengthening epithelial barrier integrity）, and an immune modula- tory function （i.e. mucosal immune system priming and maintenance of intestinal epithelium homeostasis）. A fine balance regulates the mechanism that allows co- existence of mammals with their commensal bacteria. In IBD this mechanism of immune tolerance is impaired because of several potential causative factors. The gut microbiota composition and activity of IBD patients are abnormal, with a decreased prevalence of dominant members of the human commensal microbiota （i.e. Clostridium IXa and IV groups, Bacteroides, bifldobacteria） and a concomitant increase in detrimental bacteria （i.e. sulphate-reducing bacteria, Escherichia coll. The observed dysbiosis is concomitant with defectiveinnate immunity and bacterial killing （i.e. reduced mucosal defensins and IgA, malfunctioning phagocytosis） and overaggressive adaptive immune response （due to ineffective regulatory T cells and antigen presenting cells）, which are considered the basis of IBD pathogen- esis. However, we still do not know how the interplay between these parameters causes the disease. Studies looking at gut microbial composition, epithelial integrity and mucosal immune markers in genotyped IBD populations are therefore warranted to shed light on this obscure pathogenesis.
文摘Aim:Primary tumors can be divided into oncogene-addicted(e.g.,lung)and non-oncogene addicted(e.g.,breast).Only the former group has an Achilles-heel single gene for successful target therapy,whereas the latter has mutations of multiple causative genes.Currently,tissue biopsy used for genetic surveys do not give a complete picture of the molecular profile and clonal evolution,but only provide static information over time.Methods:A series of 133 patients with 16 different solid tumors were enrolled.Blood samples were collected and cell-free DNA(cfDNA)was extracted.cfDNA libraries were analyzed using AVENIO circulating tumor DNA(ctDNA)Expanded Kit and Illumina NextSeq 550 for sequencing was used.In order to evaluate the clinical evolution over time,a second cfDNA analysis was performed after a mean interval of 2 months.Results:Through the cfDNA liquid biopsy,we found 89 pathogenic variants in 54 genes.Breast,lung,and prostate cancers showed the largest number of mutated genes.TP53,PIK3CA,FGFR3,KRAS,and ERBB2 were the most frequently mutated genes among 16 different tumors.Gene distribution didn’t show any type of prevalence.In particular,every patient with disease progression seems to have a“private”combination of gene pair mutations,with TP53 as the most frequently mutated gene.Conclusion:We showed that the clonal evolution of tumors includes a private combination of genes,regardless of tumor type.In the future,the cancer treatment can be the targeted therapy against specific tumor mutation(s).The present approach seems promising to both identify key cancer genes and follow clonal evolution over time.
