Activated oncogenes induce premature cellular senescence, a permanent state of proliferative arrest in primary rodent and human fibroblasts. Recent studies suggest that generation of reactive oxygen species (ROS) is involved in oncogenic Ras-induced premature senescence. However, the signaling mechanism controlling this oxidant-mediated irreversible growth arrest is not fully understood. Here, we show that through the Ras/MEK pathway, Ras oncogene upregulated the expression of superoxide-generating oxidases, Nox1 in rat REF52 cells and Nox4 in primary human lung TIG-3 cells, leading to an increase in intracellular level of ROS. Ablation of Nox1 and Nox4 by small interfering RNAs (siRNAs) blocked the RasV12 senescent phenotype including b-galactosidase activity, growth arrest and accumulation of tumor suppressors such as p53 and p16Ink4a . This suggests that Nox-generated ROS transduce senescence signals by activating the p53 and p16Ink4a pathway. Furthermore, Nox1 and Nox4 siRNAs inhibited both Ras-induced DNA damage response and p38MAPK activation, whereas overexpression of Nox1 and Nox4 alone was able to induce senescence. The involvement of Nox1 in Ras-induced senescence was also confirmed with embryonic fibroblasts derived from Nox1 knockout mice. Together, these findings suggest that Nox1-and Nox4-generated ROS play an important role in Ras-induced premature senescence, which may involve DNA damage response and p38MAPK signaling pathways.

Lanthanum carbonate is one of the new phosphate binders used for the treatment of hyperphosphatemia in patients with chronic kidney disease. It is poorly absorbed from the gastrointestinal tract, forms insoluble complexes within the lumen, and prevents the absorption of dietary phosphate. A 63-year-old female with a 7-year history of peritoneal dialysis, who was treated with lanthanum carbonate for four years, underwent endoscopic submucosal dissection for intramucosal gastric cancer. Resected specimens showed massive accumulation of macrophages containing fine, granular, brown material in the lamina propria. This was confirmed as lanthanum deposition by scanning electron microscopy with energy dispersive x-ray spectroscopy. Although lanthanum may be poorly absorbed, increased tissue accumulation of lanthanum, particularly in the liver and bone, has been reported in animals with chronic kidney disease. This report indicates enhanced gastrointestinal absorption of lanthanum in some patients or conditions, although its clinical significance awaits further studies.

Autoimmune pancreatitis is a unique disease, characterized by lymphoplasmacytic inflammation in the acute stages. However, the active clinical features are unlikely to persist for longer periods. Through long-term follow-up, we investigated the disease course in 51 patients with autoimmune pancreatitis. We found recurrence in 21 (41%) and pancreatic stone formation in 9 (18%) patients. Pancreatic stone formation was significantly more frequent in the recurrence group (7/21; 33%), compared to the non-recurrence group (2/30; 7%). Moreover, we found high serum immunoglobulin-G4 concentrations in 13 of 175 (7.4%) patients with ordinary chronic pancreatitis. This suggested that pancreatic stone formation was closely associated with recurrence and that autoimmune pancreatitis may transform into ordinary chronic pancreatitis after several recurrences. We found that the immune complex level, with a cut-off value of 10 mg/dl, served as a good predictor of recurrence, with high sensitivity (61.9%), specificity (70.0%) and efficacy (66.7%). We also confirmed that human leukocyte antigen and cytotoxic T-lymphocyte antigen-4 polymorphism were useful predictors for autoimmune pancreatitis recurrence.3

Preoperative single ENBD in the future remnant lobe is effective treatment for B-C type I-III hilar cholangiocarcinoma. Preoperative ENBD was rarely complicated with segmental cholangitis.

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