Correction: Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C

Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and its incidence is increasing worldwide. Recently, several types of cells have been considered as the origin of ICC, namely cholangiocytes, liver progenitor cells, and hepatocytes. Here, we have established a novel mouse model of ICC by liver-specific Kras activation and Pten deletion. An activating mutation of Kras in combination with deletion of Pten was introduced in embryonic hepatic bipotential progenitor cells (so-called hepatoblasts) and mature hepatocytes using the Cre-loxP system. As a result, liver-specific Kras activation and homozygous Pten deletion cooperated to induce ICCs exclusively. In contrast, Kras activation in combination with heterozygous Pten deletion induced both ICCs and HCCs, whereas Kras activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre-loxP demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific Kras activation in combination with homozygous Pten deletion should be useful for the investigation of therapeutic strategies for human ICC.

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Mutation Analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese Patients with Myeloproliferative Neoplasms

BioMed Research International ◽

10.1155/2014/485645 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Min Wang ◽

Na He ◽

Tian Tian ◽

Lu Liu ◽

Shuang Yu ◽

...

Keyword(s):

Mouse Model ◽

Tyrosine Kinase ◽

Genome Sequence ◽

Mutation Analysis ◽

Myeloproliferative Neoplasms ◽

Jak2v617f Mutation ◽

Chinese Patients ◽

Whole Genome Sequence ◽

Whole Genome ◽

Activating Mutation

Since the discovery of JAK2V617F tyrosine kinase-activating mutation, several genes have been found mutated in myeloproliferative neoplasms (MPNs). FLT3-ITD, NPM1, and DNMT3A mutations frequently occurred in AML patients and have been found conferred with myeloproliferative neoplasms in mouse model. Therefore, we sought to search for mutations in JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in 129 cases including 120 classic MPN cases and 9 MDS/MPN cases. JAK2V617F mutation was found in 60% of the 120 classic MPNs. However, none of the patients displayed FLT3-ITD and NPM1 mutations; only 2 patients harbored DNMT3A R882 mutation. Further studies including whole-genome sequence will be conducted to investigate the possible involvement of these genes in MPN.

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Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity

Journal of Experimental Medicine ◽

10.1084/jem.20180660 ◽

2019 ◽

Vol 216 (6) ◽

pp. 1359-1376 ◽

Cited By ~ 6

Author(s):

Benjamin D. Medina ◽

Mengyuan Liu ◽

Gerardo A. Vitiello ◽

Adrian M. Seifert ◽

Shan Zeng ◽

...

Keyword(s):

T Cells ◽

Mouse Model ◽

Cd8 T Cells ◽

Antitumor Immunity ◽

Γδ T Cells ◽

Imatinib Treatment ◽

Kinase Inhibition ◽

Gm Csf ◽

T Cell Infiltration ◽

Activating Mutation

Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b− dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b− DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1β. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.

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Physiological expression of the PI3K-activating mutation Pik3caH1047R combines with Apc loss to promote development of invasive intestinal adenocarcinomas in mice

Biochemical Journal ◽

10.1042/bj20131412 ◽

2014 ◽

Vol 458 (2) ◽

pp. 251-258 ◽

Cited By ~ 16

Author(s):

Lauren M. Hare ◽

Toby J. Phesse ◽

Paul M. Waring ◽

Karen G. Montgomery ◽

Kathryn M. Kinross ◽

...

Keyword(s):

Mouse Model ◽

Pi3k Pathway ◽

Apc Gene ◽

Intestinal Tumorigenesis ◽

Human Cancers ◽

Activating Mutation

We used a novel mouse model to investigate the role of a common PI3K pathway mutation observed in human cancers and demonstrated that when combined with loss of the Apc gene, intestinal tumorigenesis is enhanced compared with Apc loss alone.

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Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C

Journal of Experimental Medicine ◽

10.1084/jem.20210479 ◽

2021 ◽

Vol 218 (11) ◽

Author(s):

Vishwas Mishra ◽

Avipsa Bose ◽

Shashi Kiran ◽

Sanghita Banerjee ◽

Idrees A. Shah ◽

...

Keyword(s):

Mouse Model ◽

Fluid Secretion ◽

Sodium Content ◽

Mutant Mice ◽

Chronic Inflammatory Bowel Disease ◽

Small Intestinal Transit ◽

Fecal Microbiome ◽

Activating Mutations ◽

Heat Stable ◽

Activating Mutation

Activating mutations in receptor guanylyl cyclase C (GC-C), the target of gastrointestinal peptide hormones guanylin and uroguanylin, and bacterial heat-stable enterotoxins cause early-onset diarrhea and chronic inflammatory bowel disease (IBD). GC-C regulates ion and fluid secretion in the gut via cGMP production and activation of cGMP-dependent protein kinase II. We characterize a novel mouse model harboring an activating mutation in Gucy2c equivalent to that seen in an affected Norwegian family. Mutant mice demonstrated elevated intestinal cGMP levels and enhanced fecal water and sodium content. Basal and linaclotide-mediated small intestinal transit was higher in mutant mice, and they were more susceptible to DSS-induced colitis. Fecal microbiome and gene expression analyses of colonic tissue revealed dysbiosis, up-regulation of IFN-stimulated genes, and misregulation of genes associated with human IBD and animal models of colitis. This novel mouse model thus provides molecular insights into the multiple roles of intestinal epithelial cell cGMP, which culminate in dysbiosis and the induction of inflammation in the gut.

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Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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