Loss of pten and activation of kras synergistically induce formation of intraductal papillary mucinous neoplasia from pancreatic ductal cells in mice

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasias (IPMNs) are precancerous cystic lesions that can develop into pancreatic ductal adenocarcinomas (PDACs). These large macroscopic lesions are frequently detected during medical imaging, but it is unclear how they form or progress to PDAC. We aimed to identify cells that form IPMNs and mutations that promote IPMN development and progression. METHODS: We generated mice with disruption of Pten specifically in ductal cells (Sox9CreER(T2);Pten(flox/flox);R26R(YFP) or Pten(ΔDuct/ΔDuct) mice) and used Pten(ΔDuct/+) and Pten(+/+) mice as controls. We also generated Kras(G12D);Pten(ΔDuct/ΔDuct) and Kras(G12D);Pten(ΔDuct/+) mice. Pancreata were collected when mice were 28 weeks to 14.5 months old and analyzed by histology, immunohistochemistry, and electron microscopy. We performed multiplexed droplet digital polymerase chain reaction to detect spontaneous Kras mutations in Pten(ΔDuct/ΔDuct) mice and study the effects of Ras pathway activation on initiation and progression of IPMNs. We obtained 2 pancreatic sections from a patient with an invasive pancreatobiliary IPMN and analyzed the regions with and without the invasive IPMN (control tissue) by immunohistochemistry. RESULTS: Mice with ductal cell-specific disruption of Pten but not control mice developed sporadic, macroscopic, intraductal papillary lesions with histologic and molecular features of human IPMNs. Pten(ΔDuct/ΔDuct) mice developed IPMNs of several subtypes. In Pten(ΔDuct/ΔDuct) mice, 31.5% of IPMNs became invasive; invasion was associated with spontaneous mutations in Kras. Kras(G12D);Pten(ΔDuct/ΔDuct) mice all developed invasive IPMNs within 1 month. In Kras(G12D);Pten(ΔDuct/+) mice, 70% developed IPMN, predominately of the pancreatobiliary subtype, and 63.3% developed PDAC. In all models, IPMNs and PDAC expressed the duct-specific lineage tracing marker yellow fluorescent protein. In immunohistochemical analyses, we found that the invasive human pancreatobiliary IPMN tissue had lower levels of PTEN and increased levels of phosphorylated (activated) ERK compared with healthy pancreatic tissue. CONCLUSIONS: In analyses of mice with ductal cell-specific disruption of Pten, with or without activated Kras, we found evidence for a ductal cell origin of IPMNs. We also showed that PTEN loss and activated Kras have synergistic effects in promoting development of IPMN and progression to PDAC

Nonlinear Control for Proximity Operations Based on Differential Algebra

A new algorithm based on differential algebra (DA) is proposed to obtain a high order Taylor expansion of State-Dependent Riccati Equation (SDRE) solution. The main advantage of this approach is that the sub-optimal solution of a class of non-linear optimal control problem, characterized by a quadratic cost function and an input-affine plant model, is obtained by a mere evaluation of a polynomial expression, reducing the computational effort due to well-known algorithm for the SDRE solution. Relative position tracking and attitude synchronization problem involving in docking maneuvering operations between two Earth satellites is investigated. Particularly, two possible docking scenarios are simulated by using a specific platform designed by DLR (Deutsches Zentrum für Luft- und Raumfahrt) Institute of Space Systems to emulate the satellite motion on ground. The experiments show the effectiveness of proposed DA-based algorithm and the potential computational benefit when it runs on a real hardware