Pringle maneuver induces hepatic metastasis by stimulating the tumor vasculature.

BACKGROUND/AIMS: The Pringle maneuver is traditionally used to avoid hemorrhage during hepatectomy for hepatic metastasis. However, metastasis can occur under ischemic conditions due to some unknown mechanism. METHODOLOGY: An orthotopic model of murine colon cancer was established in syngeneic BALB/c mice. Viable CT-26 cells were implanted into the spleen of these mice. The mice underwent a laparotomy 5 days after the implantation and the hepato-duodenal ligament was clamped for 0 or 10 minutes (Pringle maneuver). The mice were sacrificed 7 days after this maneuver and the number of hepatic metastasis were counted. RESULTS: The mice that underwent the maneuver developed a greater number of hepatic metastasis. An immunohistochemical analysis revealed that the expression of microvessel density, VEGF and KDR/Flk-1 were higher in the hepatic metastasis in the mice treated with the maneuver. In addition, the mice which were treated by the maneuver had a higher level VEGF in the serum. CONCLUSION: These data suggest that the Pringle maneuver induces hepatic metastasis by stimulating the overexpression of tumor vasculature.

Loss of p53-regulatory protein IFI16 induces NBS1 leading to activation of p53-mediated checkpoint by phosphorylation of p53 SER37.

Our previous results that IFI16 is involved in p53 transcription activity under conditions of ionizing radiation (IR), and that the protein is frequently lost in human breast cancer cell lines and breast adenocarcinoma tissues suggesting that IFI16 plays a crucial role in controlling cell growth. Here, we show that loss of IFI16 by RNA interference in cell culture causes elevated phosphorylation of p53 Ser37 and accumulated NBS1 (nibrin) and p21WAF1, leading to growth retardation. Consistent with these observations, doxycyclin-induced NBS1 caused accumulation of p21WAF1 and increased phosphorylation of p53 Ser37, leading to cell cycle arrest in G1 phase. Wortmannin treatment was found to decrease p53 Ser37 phosphorylation in NBS-induced cells. These results suggest that loss of IFI16 activates p53 checkpoint through NBS1-DNA-PKcs pathway.

Endoscopic pancreatic duct drainage and stenting for acute pancreatitis and pancreatic cyst and abscess.

BACKGROUND/PURPOSE: Endoscopic drainage of pancreatic pseudocysts using transpapillary and transmural approaches has been reported. In this study, endoscopic nasopancreatic drainage (ENPD) and pancreatic stenting were performed in patients with pseudocyst and abscess associated with acute pancreatitis, and the usefulness and problems of the procedures were investigated. METHODS: After endoscopic retrograde pancreatography was done, ENPD and/or pancreatic stenting were performed in 13 patients with pancreatitis and pseudocyst or abscess that communicated with the main pancreatic duct. RESULTS: ENPD was performed in seven patients, and was effective in all five patients with cysts: the cysts disappeared or shrank. However, the condition in the two patients with abscess was unchanged, and percutaneous drainage was performed. Stenting was carried out in six patients, and the cyst disappeared or pancreatitis was improved in all six. The stent was removed from two patients, but no recurrence has been noted so far. CONCLUSIONS: ENPD and stenting are effective therapeutic choices for acute and chronic pancreatitis and pseudocysts, and they are superior to percutaneous drainage to avoid pancreatic fistula, but they may not be effective for pancreatic abscess. Selection of therapeutic methods corresponding to individual cases is important.

ATM activation by ionizing radiation requires BRCA1-associated BAAT1.

ATM (ataxia telangiectasia mutated) is required for the early response to DNA-damaging agents such as ionizing radiation (IR) that induce DNA double-strand breaks. Cells deficient in ATM are extremely sensitive to IR. It has been shown that IR induces immediate phosphorylation of ATM at Ser(1981), leading to catalytic activation of the protein. We recently isolated a novel BRCA1-associated protein, BAAT1 (BRCA1-associated protein required for ATM activation-1), by yeast two-hybrid screening and found that BAAT1 also binds to ATM, localizes to double-strand breaks, and is required for Ser(1981) phosphorylation of ATM. Small interfering RNA-mediated stable or transient reduction of BAAT1 resulted in decreased phosphorylation of both ATM at Ser(1981) and CHK2 at Thr(68). Treatment of BAAT1-depleted cells with okadaic acid greatly restored phosphorylation of ATM at Ser(1981), suggesting that BAAT1 is involved in the regulation of ATM phosphatase. Protein phosphatase 2A-mediated dephosphorylation of ATM was partially blocked by purified BAAT1 in vitro. Significantly, acute loss of BAAT1 resulted in increased p53, leading to apoptosis. These results demonstrate that DNA damage-induced ATM activation requires a coordinated assembly of BRCA1, BAAT1, and ATM.