Query: baoan ji

title: Cancer associated stromal fibroblasts promote pancreatic tumor progression.
abstract: Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC CM) on in vitro proliferation, migration, invasion, soft agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co injecting them with cancer cells and analyzing growth and metastasis. HPSC CM dose dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC CM. HPSC CM activated the mitogen activated protein kinase and Akt pathways in tumor cells. Co injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC derived factors may lead to novel stroma targeted therapies for pancreatic cancer.

title: Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice.
abstract: Intra acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.

title: Inhibition of miR 155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model
abstract: Acute pancreatitis (AP) is a common digestive disease characterized by inflammation of the pancreas. MiR 155 plays a role in promoting inflammation and inhibiting the activation of anti inflammatory pathways. Impaired autophagy could promote zymogen activation, abnormal acinar cell secretion, cell death, and the inflammatory response to aggravate AP. The aim of this study was to ascertain the effect of silencing miR 155 on AP through its effects on inflammation and impaired autophagy in vivo. In this study, AAV(adeno associated virus) mediated miR 155 and miR 155 sponge were injected through the tail vein of mice. After 3 weeks, AP was induced by intraperitoneal (IP) injections of cerulein. Pancreatic and pulmonary tissues were analyzed after 24 h. Silencing of miR 155 ameliorated pancreas and lung damage in three AP models of mice by preventing accumulation of autophagosomes that are unable to fuse with lysosomes and decreasing pancreatic inflammation by targeting TAB2. 3 MA could reduce the aberrant accumulation of autophagosomes, which alleviates the pancreas damage that was aggravated by increasing miR 155 levels. These findings demonstrate that the inhibition of miR 155 holds promise for limiting pancreatitis.

title: Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H.
abstract: Currently, an effective targeted therapy for pancreatitis is still lacking. Hereditary pancreatitis (HP) is a heritable, autosomal dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full length human PRSS1R122Hgene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice as well as enzymatically inactivated Dead PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anti coagulation therapy, synergistically prevented the progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

title: Transgenic Expression of PRSS1R122H Sensitizes Mice to Pancreatitis.
abstract: Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice.  We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1R122H) specifically in pancreatic acinar cells under control of a full length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide (LPS) to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real time PCR, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured.  Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1R122H. Pancreata from mice that express PRSS1 or PRSS1R122H had increased levels of HSP70 and NRF2 and reduced levels of chymotrypsin C (CTRC) compared with control mice. Increased expression of PRSS1 or PRSS1R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of LPS exacerbated inflammation in mice that express PRSS1R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1R122H developed more severe pancreatitis after ethanol feeding or a high fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice.  Expression of a transgene encoding PRSS1R122H in mice promoted inflammation and increase the severity of pancreatitis, compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by LPS, ethanol, or a high fat diet.

title: Induction of Pancreatic Inflammation Accelerates Pancreatic Tumorigenesis in Mice.
abstract: Pancreatitis is a major risk factor for the development of pancreatic cancer. In genetically engineered mouse models, induction of pancreatic inflammation dramatically accelerates oncogenic KRas induced fibrosis, precancerous PanIN formation, and tumorigenesis. Here we describe simple methods of secretagogue induced experimental acute and chronic pancreatitis, the most commonly used pancreatitis models, and their applications in pancreatic cancer research. Additionally, the preparation of primary pancreatic acinar cells is introduced. Primary acinar cells can be used to study the early events of pancreatic inflammation and pancreatic acinar to ductal (ADM) metaplasia.

title: Transgenic expression of human PRSS2 exacerbates pancreatitis in mice
abstract: We read with great interest the study by Hegyi et al 1 which reported that a commonly occurring haplotype spanning the PRSS1 PRSS2 locus (encoding human cationic and anionic trypsinogens) is associated with chronic pancreatitis. While PRSS1 is the major focus in many studies,2 3 PRSS2 is also a major trypsinogen isoform synthesised in human pancreas. In normal human, the PRSS1/PRSS2 ratio is approximately 2:1.4 Chronic alcoholism increases the risk of pancreatitis. Strikingly, in these patients, total trypsinogen secretion was increased with selective upregulation of PRSS2, reversing the PRSS1/PRSS2 ratio.5 In vitro studies have shown human PRSS2 more sensitive to autocatalytic degradation and with lower autoactivation than PRSS1.6 In test tube assays under conditions of intracellular pathological trypsinogen activation, mixtures of PRSS1 and PRSS2 with increasing ratios of PRSS2 had markedly decreased rates of trypsinogen activation and yields of active  These observations led to a hypothesis that upregulation of PRSS2 may play a protective role against

title: Transgenic expression of cyclooxygenase 2 in pancreatic acinar cells induces chronic pancreatitis.
abstract: Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase 2 (COX 2) a rate limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX 2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX 2 in fibrogenesis and the development of chronic pancreatitis, COX 2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX 2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX 2 was specifically expressed in pancreatic acinar cells. COX 2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar to ductal metaplasia. Quantitative RT PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX 2 transgenic mice. Expression of COX 2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW NOTEWORTHY COX 2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX 2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX 2 inhibition may be an effective preventive and therapeutic strategy.

title: 791 A Novel Humanized Animal Model of Hereditary Pancreatitis and Its Effective Therapy

title: Sa1341 Pancreatic Acinar Carcinoma Has Distinct Mutation Patterns Than Pdac and Neuroendocrine Tumor