Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

PTEN is a candidate tumour suppressor gene and frequently mutated in multiple cancers, however, not in pancreatic cancer. Recently, it has been demonstrated that PTEN expression is regulated by TGF-β1. Using TGF-β1 transgenic mice (n=7) and wildtype littermates (n=6), as well as pancreatic tissues obtained from organ donors (n=10) and patients with pancreatic cancer (n=10), we assessed the expression of PTEN by means of immunohistochemistry and semiquantitative PCR analysis. In addition, PANC-1 cells were treated with TGF-β1 in vitro and the levels of PTEN mRNA were determined in these cells. In human pancreatic cancers PTEN mRNA levels were significantly decreased (P<0.05). In addition, in the pancreas of TGF-β1 transgenic mice the expression of PTEN was significantly reduced (P<0.01), as compared to wildtype littermates and incubation of PANC-1 cells with TGF-β1 decreased PTEN mRNA levels after 24 h. Inasmuch as TGF-β1 decreases PTEN expression in human pancreatic cancer cells and human pancreatic cancers overexpress TGF-β1, the reduced expression of PTEN in pancreatic cancer may be mediated by TGF-β1 overexpression. Thus, although PTEN is not mutated in pancreatic cancers, the reduction of its expression may give pancreatic cancer cells an additional growth advantage

Activated K-ras and INK4a/Arf Deficiency Cooperate During the Development of Pancreatic Cancer by Activation of Notch and NF-κB Signaling Pathways

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, suggesting that novel strategies for the prevention and treatment of PDAC are urgently needed. K-ras mutations are observed in >90% of pancreatic cancer, suggesting its role in the initiation and early developmental stages of PDAC. In order to gain mechanistic insight as to the role of mutated K-ras, several mouse models have been developed by targeting a conditionally mutated K-ras(G12D) for recapitulating PDAC. A significant co-operativity has been shown in tumor development and metastasis in a compound mouse model with activated K-ras and Ink4a/Arf deficiency. However, the molecular mechanism(s) by which K-ras and Ink4a/Arf deficiency contribute to PDAC has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS:To assess the molecular mechanism(s) that are involved in the development of PDAC in the compound transgenic mice with activated K-ras and Ink4a/Arf deficiency, we used multiple methods, such as Real-time RT-PCR, western blotting assay, immunohistochemistry, MTT assay, invasion, EMSA and ELISA. We found that the deletion of Ink4a/Arf in K-ras(G12D) expressing mice leads to PDAC, which is in part mediated through the activation of Notch and NF-κB signaling pathways. Moreover, we found down-regulation of miR-200 family, which could also play important roles in tumor development and progression of PDAC in the compound transgenic mice. CONCLUSIONS/SIGNIFICANCE:Our results suggest that the activation of Notch and NF-κB together with the loss of miR-200 family is mechanistically linked with the development and progression of PDAC in the compound K-ras(G12D) and Ink4a/Arf deficient transgenic mice

Manganese Provision in Parenteral Nutrition: An Update

Manganese (Mn) is an essential micronutrient required for the activity of metalloenzymes. It is an essential component of parenteral nutrition (PN), but requirements are low. Mn status is difficult to assess, with the commonest method being measurement of its concentration in whole blood. This method has limitations, including artifactually high concentrations resulting from contamination of specimen tubes. Mn toxicity is a well-recognized complication of PN, the risk of which increases if there is cholestasis or if the patient has received high doses. It usually presents with parkinsonian-like symptoms but may be detected presymptomatically as hypermanganesemia or as increased signal intensity of the basal ganglia upon T1-weighted magnetic resonance imaging. Caution is necessary when providing Mn for patients on long-term PN (>1 month). It is advisable to withhold supplementation if hypermanganesemia or cholestasis develops. Deficiency of Mn is rare in patients treated with PN. PN regimens are contaminated with Mn in amounts likely to meet requirements. Consequently, it is debated whether PN should be routinely supplemented with Mn. The currently recommended dose of Mn in adults treated with PN is 55 μg/d, but the doses provided by most currently available multi–trace element products exceed this. In response to calls for new products to be developed, 2 new multi–trace element products are currently available in Europe that provide Mn doses of 55 μg/d. Once these products are in general use, it is likely that the incidence of Mn toxicity will decrease