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10.1371/journal.pone.0120851 http://scihub22266oqcxt.onion/10.1371/journal.pone.0120851 C4372593!4372593 !25803032     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25803032 &cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\25803032 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       PLoS+One 2015 ; 10 (3 ): e0120851 Nephropedia Template TP {{tp|p=25803032 |t=2015. Smad4 loss synergizes with TGF? overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis |pdf=|usr=}}{{25803032 }} gab.com Text Smad4 loss synergizes with TGF overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis JO: PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=25803032 #FOAvip AIMS: While overexpression of TGF? has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGF? develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-? signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGF? and TGF-? signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. METHODS: The MT-TGF? mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGF?;p48-Cre (STP). After TGF? overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGF?, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (?-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. RESULTS: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGF? mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. CONCLUSION: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer. Twit Text FOAVip Smad4 loss synergizes with TGF overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis ????PLoS One http://www.kidney.de/pget.php?&tw=1&pmid=25803032 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25803032 #FOAvip English Wikipedia <ref>{{Cite pmid|25803032 }}</ref> Smad4 loss synergizes with TGF? overexpression in promoting pancreatic metaplasia, PanIN development, and fibrosis #MMPMID25803032 Garcia-Carracedo D ; Yu CC ; Akhavan N ; Fine SA ; Schönleben F ; Maehara N ; Karg DC ; Xie C ; Qiu W ; Fine RL ; Remotti HE ; Su GH PLoS One 2015[]; 10 (3 ): e0120851 PMID25803032 show ga AIMS: While overexpression of TGF? has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGF? develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-? signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGF? and TGF-? signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. METHODS: The MT-TGF? mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGF?;p48-Cre (STP). After TGF? overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGF?, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (?-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. RESULTS: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGF? mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. CONCLUSION: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer. |*Gene Knockout Techniques [MESH] |Acinar Cells/pathology [MESH] |Animals [MESH] |Biomarkers/metabolism [MESH] |Carcinogenesis/genetics [MESH] |Disease Progression [MESH] |Epithelial Cells/pathology [MESH] |Fibrosis [MESH] |Gene Expression [MESH] |Humans [MESH] |Metaplasia/genetics/pathology [MESH] |Mice [MESH] |Mice, Transgenic [MESH] |Pancreas/*pathology [MESH] |Pancreatic Diseases/*genetics/*pathology [MESH] |Pancreatic Ducts/pathology [MESH] |Pancreatitis/metabolism [MESH] |Signal Transduction [MESH] |Smad4 Protein/*deficiency/*genetics/metabolism [MESH]Smad4 loss synergizes with TGF? overexpression in promoting pancreatic(epmc).pdf DeepDyve Pubget Overpricing