Ryo Kodama

ROS‐generating oxidases Nox1 and Nox4 contribute to oncogenic Ras‐induced premature senescence

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 up‐regulated 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 β‐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.

Extensive lanthanum deposition in the gastric mucosa: the first histopathological report.

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.

Intestinal diffuse large B-cell lymphoma associated with celiac disease : A Japanese case

Intestinal non-Hodgkin’s lymphoma (NHL), especially the T-cell type, is well known to be associated with celiac disease (CD), an enteropathic disorder with a propensity for certain racial and genetic backgrounds. CD is typically characterized by gastrointestinal (GI) symptoms, anti-transglutaminase antibodies in the sera, and microscopical findings of the intestinal mucosa, which resolve with a gluten-free diet (GFD). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. We describe a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient’s lymphoma has been in a state of complete response, and his GI symptoms have improved with a GFD. This case suggests that the possibility of CD and its association with intestinal NHL should be kept in mind, even in Asian populations.

Small Bowel Tissue Concentration of Rebamipide: Study of Two Dosages in Healthy Subjects

Non-steroidal anti-inflammatory drug (NSAID)-related small intestinal complications exist, since developed new diagnostic modalities, such as balloon and capsule endoscopies. Some experiments have shown rebamipide to protect from NSAID-induced small intestinal complications. The purpose of this study is to investigate whether the effective concentrations of rebamipide (COR) are present in the small intestine after taking an ordinary clinical dose and double dose of this drug. Twelve healthy male subjects were enrolled. After taking 100 or 200 mg of rebamipide, balloon enteroscopy was performed at 1 and 3 h, and biopsy samples were obtained from the jejunum and the stomach. Venous blood samples were taken simultaneously. Samples were analyzed by high-performance liquid chromatography. The mean COR in the jejunum was higher than 100 µM at 1 h and higher than 10 µM at 3 h in both the 100 and 200 mg groups. Mean COR in the stomach was less than 100 µM at 1 h in the 100 mg group; however it was higher than 100 µM in the 200 mg group. In conclusion, the COR level in the jejunum was sufficient to protect for NSAID-induced gastrointestinal complications.

Endoscopic ultrasonography-guided drainage of infected intracystic papillary adenocarcinoma of the liver

Abstract We describe a case of effective use of endoscopic ultrasonography (EUS)-guided drainage of an infected intracystic papillary adenocarcinoma (ICPA) of the liver. The patient was an 84-year-old woman who was admitted with complaints of continuous epigastric pain and a slight fever. Laboratory data revealed severe inflammation. Computed tomography scanning showed a 110-mm cystic lesion with enhanced papillary tumors in the medial segment of the liver associated with a cyst in the right lobe and subcapsular cyst of the liver. Streptococcus species were detected in the culture of cystic fluid, and a diagnosis of infected ICPA was suspected. Although the patient was medicated by antibiotics, the fever did not resolve. EUS-guided transgastric drainage was performed for the abscess of the medial segment of the liver. Fourteen days after the endoscopic procedure, the plastic drainage tube was replaced with a metal stent. Inserting an endoscope into the liver cyst through the metal stent permitted observation and biopsy of an intracystic tumor, and the diagnosis of ICPA was confirmed. The patient was discharged with the internal metal stent still in place.

Pancreaticobiliary fistula associated with pancreatolithiasis

We report here a case of pancreaticobiliary fistula associated with pancreatolithiasis. A 47-year-old female without a habit of alcohol drinking was admitted by her family physician after suffering from mild acute pancreatitis. Computed tomography revealed mild acute pancreatitis with pancreatolithiasis at the head of the pancreas. The pancreatolithiasis was exposed to the inner surface of the common bile duct and possibly compressed and narrowed the Wirsung and Santorini ducts, resulting in the pancreatitis attack. We used extracorporeal shock wave lithotripsy to treat the pancreatolithiasis. After complete elimination of stones by extracorporeal shock wave lithotripsy, endoscopic retrograde cholangiography showed an apparent pancreaticobiliary fistula between a branch of the Santorini duct and the lower portion of the common bile duct. There was no communication between the bile duct and the Wirsung duct or its branches; therefore, the diagnosis was not pancreaticobiliary maljunction. There have only been a few reports of pancreaticobiliary fistula without an association with pancreatic pseudocysts or intraductal papillary-mucinous pancreatic neoplasm, and there have only been few reports of pancreaticobiliary fistula with pancreatolithiasis.