Efficacy of the New Double-Layer Stent for Unresectable Distal Malignant Biliary Obstruction: A Single-Center Retrospective Study

Background and Aims. For distal malignant biliary obstruction in cases with short life expectancy, occlusion of plastic stents (PSs) does not usually occur before death, and the application of such a procedure is considered adequate from the viewpoint of cost-effectiveness. Methods and Setting. A new commercially available DLS with side holes, a conventional DLS, and, uncovered self-expanding metal stents (SEMSs) were retrospectively evaluated in patients with jaundice due to unresectable distal malignant biliary obstruction. Results. A total of 64 patients received endoscopic biliary stenting (23 patients with the new DLS, 24 patients with conventional DLS, and 17 patients with uncovered SEMS) from December 2002 to August 2009. Median patency time was found to be 198 days for the new DLS group and 99 days for the conventional DLS group, revealing a significant difference between devices. There was, however, no significant difference in median patency time between the new DLS and the uncovered SEMS (198 days versus 344 days). Conclusion. The new DLS is efficient and safe and may be considered the first choice for unresectable distal malignant obstruction in cases with short life expectancy

Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2: Higher Affinity than That with MD-2 or CD14

Toll-like receptors (TLRs) are innate recognition molecules for microbial products, but their direct interactions with corresponding ligands remain unclarified. LPS, a membrane constituent of gram-negative bacteria, is the best-studied TLR ligand and is recognized by TLR4 and MD-2, a molecule associated with the extracellular domain of TLR4. Although TLR4-MD-2 recognizes LPS, little is known about the physical interaction between LPS and TLR4-MD-2. Here, we demonstrate cell surface LPS–TLR4-MD-2 complexes. CD14 greatly enhances the formation of LPS–TLR4-MD-2 complexes, but is not coprecipitated with LPS–TLR4-MD-2 complexes, suggesting a role for CD14 in LPS loading onto TLR4-MD-2 but not in the interaction itself between LPS and TLR4-MD-2. A tentative dissociation constant (Kd) for LPS–TLR4-MD-2 complexes was ∼3 nM, which is ∼10–20 times lower than the reported Kd for LPS–MD-2 or LPS–CD14. The presence of detergent disrupts LPS interaction with CD14 but not with TLR4-MD-2. E5531, a lipid A antagonist developed for therapeutic intervention of endotoxin shock, blocks LPS interaction with TLR4-MD-2 at a concentration 100 times lower than that required for blocking LPS interaction with CD14. These results reveal direct LPS interaction with cell surface TLR4-MD-2 that is distinct from that with MD-2 or CD14

Oncolytic virus-mediated p53 overexpression promotes immunogenic cell death and efficacy of PD-1 blockade in pancreatic cancer

Immune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) antibody, provide improved clinical outcome in certain cancers. However, pancreatic ductal adeno-carcinoma (PDAC) is refractory to PD-1 blockade therapy due to poor immune response. Oncolytic virotherapy is a novel approach for inducing immunogenic cell death (ICD). We demonstrated the therapeutic potential of p53-expressing telo-merase-specific oncolytic adenovirus OBP-702 to induce ICD and anti-tumor immune responses in human PDAC cells with different p53 status (Capan-2, PK-59, PK-45H, Capan-1, MIA PaCa-2, BxPC-3) and murine PDAC cells (PAN02). OBP-702 significantly enhanced ICD with secretion of extracel-lular adenosine triphosphate and high-mobility group box pro-tein B1 by inducing p53-mediated apoptosis and autophagy. OBP-702 significantly promoted the tumor infiltration of CD8+ T cells and the anti-tumor efficacy of PD-1 blockade in a subcutaneous PAN02 syngeneic tumor model. Our results suggest that oncolytic adenovirus-mediated p53 overexpres-sion augments ICD and the efficacy of PD-1 blockade therapy against cold PDAC tumors. Further in vivo experiments would be warranted to evaluate the survival benefit of tumor-bearing mice in combination therapy with OBP-702 and PD-1 blockade

Attenuated response to liver injury in moesin-deficient mice: Impaired stellate cell migration and decreased fibrosis

AbstractHepatic stellate cells (HSCs) respond to injury with a coordinated set of events (termed activation), which includes migration and upregulation of matrix protein production. Cell migration requires an intact actin cytoskeleton that is linked to the plasma membrane by ezrin–radixin–moesin (ERM) proteins. We have previously found that the linker protein in HSCs is exclusively moesin. Here, we describe HSC migration and fibrogenesis in moesin-deficient mice. We developed an acute liver injury model that involved focal thermal denaturation and common bile duct ligation. HSC migration and collagen deposition were assessed by immunohistology and quantitative real-time PCR. Activated HSCs were isolated from wild-type or moesin-deficient mice for direct examination of migration. Activated HSCs from wild-type mice were positive for moesin. Migration of moesin-deficient HSCs was significantly reduced. In a culture assay, 22.1% of normal HSCs migrated across a filter in 36h. In contrast, only 1.3% of activated moesin-deficient HSCs migrated. Collagen deposition around the injury area similarly was reduced in moesin-deficient liver. The linker protein moesin is essential for HSC activation and migration in response to injury. Fibrogenesis is coupled to migration and reduced in moesin-deficient mice. Agents that target moesin may be beneficial for chronic progressive fibrosis

Research Activities in the Department of Medical Engineering

The Department of Medical Engineering is dedicated to the research and educational activities to fulfill its mission as educating medical professionals in medical engineering under the diploma policy and curriculum policy, that is, "research and education aiming for fostering professionals competent in comprehensive resolving capacity based upon a wide field of knowledge and vision in clinical engineering, which can be attained by wearing the basic knowledge of medical science and engineering." For this reason, the Faculty of the Department of Medical Engineering is composed of the two areas; PhDs in engineering-based clinical medicine, and mainly MDs in medical sciences and clinical medicine. To summarize the research activities at the Department of Medical Engineering, the authors will describe the overview of research activities being performed in the Department of Medical Engineering Fields, by dividing into 1) Research in Biomedical Engineering Fields, and 2) Research in Medical Science and Clinical Engineering Fields