Tunicate cytostatic factor TC14-3 induces a polycomb group gene and histone modification through Ca(2+) binding and protein dimerization.

BACKGROUND: As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, Polyandrocarpa misakiensis, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from P. misakiensis. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except Drosophila, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood. RESULTS: When Phe(65) of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr(69) with Arg(69) made dimers unstable. When Glu(106) was changed to Gly(106), the resultant mutant protein completely lost Ca(2+) binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. Polyandrocarpa Eed, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to Polyandrocarpa cells, only wild-type TC14-3 could induce Eed without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. PmEed knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3. CONCLUSION: These results show that in P. misakiensis, the cytostatic activity of TC14-3 is mediated by PmEed and resultant histone modification, and that the gene expression requires both the protein dimerization and Ca(2+)-binding of TC14-3. This system consisting of a humoral factor, PcG, and histone methylation would contribute to the homeostatic regulation of cell growth and terminal differentiation of invertebrate multipotent cells.

Endoscopic submucosal dissection for colorectal epithelial neoplasms.

PURPOSE: Endoscopic submucosal dissection permits removal of colorectal epithelial neoplasms en bloc, but long-term clinical outcomes remain unknown. METHODS: Endoscopic submucosal dissection was performed in 282 patients having 296 colorectal tumors that fulfilled the inclusion criteria, which included lesions greater than 20 mm in size for which en bloc resection would be difficult with endoscopic mucosal resection, lesions with fibrotic scar due to previous endoscopic treatment or biopsies, locally residual lesions after endoscopic resection, or invasive carcinoma with slight submucosal penetration. En bloc or piecemeal resection, complete (en bloc with tumor-free lateral/basal margins) or incomplete resection, and complications were assessed, and factors related to each were analyzed using logistic regression. Patients with early colon cancer received endoscopic follow-up and metastatic surveys for a median of 34 months. RESULTS: En bloc resection was achieved in 89.2% (264/296) and 234 lesions (79.1%) were deemed to have undergone complete resection. A right-side colonic location was the significant contributor to incomplete resection. Perforation was seen in 24 cases (8.1%) in association with tumor size and the presence of fibrosis. There was 1 case of locally recurrent tumor with incomplete resection, whereas neither recurrence nor residual disease was observed in the complete resection group. Neither cancer-related nor cancer-unrelated death was observed. CONCLUSIONS: Precise assessment of curability with successful en bloc resection may reduce tumor recurrence after endoscopic submucosal dissection. The prognosis of early colorectal cancer in patients treated by endoscopic submucosal dissection is likely to be excellent, although further longer follow-up studies are warranted.

Clinical outcomes of endoscopic submucosal dissection in elderly patients with early gastric cancer.

OBJECTIVES: Endoscopic submucosal dissection (ESD) has advantages over conventional endoscopic mucosa resection. The number of elderly patients (more than 75 years old) with early gastric cancer (EGC) has been steadily increasing. We sought to assess clinical outcomes of ESD for EGC in elderly. METHODS: ESD was performed for patients with EGC, who fulfilled the criteria for ESD: mucosal cancer without ulcer findings irrespective of tumor size; mucosal cancer with ulcer findings 3 cm or less in diameter; and minute submucosal invasive cancer 3 cm or less in size. Two hundred and sixty elderly patients (> or =75 years old) with 279 lesions, and 401 non-elderly patients with 434 lesions were enrolled to this study. The patients underwent ESD and then received periodic endoscopic follow-up and metastatic surveys for 6-89 months (median: 30 months). Resectability (en-bloc or piecemeal resection), curability (curative or noncurative resection), completeness (complete or incomplete resection), complications, and survival rates were assessed. RESULTS: The one-piece resection rate was significantly lower in elderly patients (93.9%) than in non-elderly patients (97.9%). The complete resection rate was significantly lower in elderly patients (87.4%) than in non-elderly patients (96.6%). Pneumonia, but not bleeding or perforation, developed in association with ESD more frequently in the elderly patients by 2.2%. Local tumor recurrence was quite rare, and the overall and disease-free survival rates were acceptable irrespective of age. CONCLUSION: En-bloc and complete resections were achieved less frequently in elderly patients, but the long-term outcomes in elderly EGC patients may be excellent, and ESD is a feasible treatment in the elderly.

Clinical outcomes of endoscopic submucosal dissection for early gastric cancer by indication criteria.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) can remove early gastric cancer (EGC) en bloc. We sought to assess the feasibility and efficacy of ESD and the clinical outcomes based on the indication criteria. PATIENTS AND METHODS: 551 patients with 589 EGC lesions were divided into the guideline criteria group (elevated lesion < or =20 mm in diameter and depressed lesion < or =10 mm without ulceration) and the expanded criteria group (mucosal cancer without ulcer findings irrespective of tumor size; mucosal cancer with ulcer findings < or =3 cm in diameter; and minute submucosal invasive cancer < or =3 cm in size). RESULTS: En bloc, complete and curative resection were achieved in 98.6 and 93.0, 95.1 and 88.5, and 97.1 and 91.1%, for the guideline and expanded criteria lesions, respectively; the differences between the 2 groups were significant for each. The expanded criteria lesions were at significantly higher risk of ESD-associated bleeding and perforation. Overall survival was adequate irrespective of the indications, and the disease-specific survival rates were 100% in both. CONCLUSION: ESD for EGCs that met the expanded criteria was acceptable, though the resection rates and safety were decreased compared to those for the guideline criteria lesions.

[A case of double common bile duct with gastric ulcer].

A 51-year-old man visited the Sasebo General Hospital because of a niche and a ductal lesion with reflux of barium in the lesser curvature of the gastric body in the upper gastrointestinal series of an annual medical checkup. Endoscopic examination showed an ulcer and a depressed lesion draining yellowish serous liquid in the stomach. Abdominal CT scan and MRCP revealed the ductal structure reached from the lesser curvature of the gastric body to the left lobe of the liver besides the ordinary pancreatobiliary system. ERCP showed normal common bile duct, gall bladder, and right intrahepatic bile duct, while the fistulography using cannula through the gastric depressed lesion revealed an accessory bile duct communicating to the left intrahepatic bile duct. The both biliary systems were completely separated, resulting in the diagnosis of double common bile duct of type IIIa.