Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non‐alcoholic fatty liver disease: Comparison with telomere‐specific quantitative FISH and p21 immunohistochemistry

Telomere‐specific quantitative fluorescent in situ hybridization (Q‐FISH) accurately evaluates hepatocellular aging on histological sections, but it requires appropriate tissue processing. To establish a more simple method for the assessment of hepatocellular aging, the usefulness of nuclear size measurement was clarified using biopsy liver samples from 64 patients with non‐alcoholic fatty liver disease (NAFLD), a model for oxidative stress‐associated hepatocellular aging, and 11 control individuals. Relative telomere intensity (RTI) was measured on Q‐FISH, and the relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. In normal individuals and NAFLD patients, the RTI and RNS were negatively correlated. The degree of nuclear enlargement in NAFLD patients was larger than that in normal individuals with the same telomere length, possibly reflecting telomere‐independent senescence. In NAFLD patients with RNS >2.0, the regenerative responses, indicated by the ratio of Ki‐67‐positive index to serum alanine aminotransferase level, were significantly reduced. The RNS positively correlated with the p21 expression, another marker of senescence. This all indicates that nuclear enlargement progresses in parallel with reduced regenerative responses, telomere shortening, and p21 upregulation. Nuclear size measurement is an effective method for estimation of hepatocellular aging.     

Activity‐dependent localization in spines of the F‐actin capping protein CapZ screened in a rat model of dementia

Actin reorganization in dendritic spines is hypothesized to underlie neuronal plasticity. Actin‐related proteins, therefore, might serve as useful markers of plastic changes in dendritic spines. Here, we utilized memory deficits induced by fimbria‐fornix transection (FFT) in rats as a dementia model to screen candidate memory‐associated molecules by using a two‐dimensional gel method. Comparison of protein profiles between the transected and control sides of hippocampi after unilateral FFT revealed a reduction in the F‐actin capping protein (CapZ) signal on the FFT side. Subsequent immunostaining of brain sections and cultured hippocampal neurons revealed that CapZ localized in dendritic spines and the signal intensity in each spine varied widely. The CapZ content decreased after suppression of neuronal firing by tetrodotoxin treatment in cultured neurons, indicating rapid and activity‐dependent regulation of CapZ accumulation in spines. To test input specificity of CapZ accumulation in vivo, we delivered high‐frequency stimuli to the medial perforant path unilaterally in awake rats. This path selectively inputs to the middle molecular layer of the dentate gyrus, where CapZ immunoreactivity increased. We conclude that activity‐dependent, synapse‐specific regulation of CapZ redistribution might be important in both maintenance and remodeling of synaptic connections in neurons receiving specific spatial and temporal patterns of inputs.     

Endoscopic treatment of biliary complications after right-lobe living-donor liver transplantation with duct-to-duct biliary anastomosis

Background/Purpose

The aims of this study were to characterize the features of the biliary complications that occur after right-lobe living-donor liver transplantation (RL-LDLT) with duct-to-duct biliary anastomosis, and to evaluate the efficacy of treating biliary complications endoscopically.

Methods

The records of 273 consecutive patients who underwent RL-LDLT with duct-to-duct biliary anastomosis from July 1999 through July 2005 at Kyoto University Hospital were reviewed to determine the overall incidence of postoperative biliary complications and the outcome of endoscopic repair of those complications.

Results

Biliary complications occurred in 93 (34.1%) of the patients. These complications were: 80 biliary strictures (75 anastomotic and 5 nonanastomotic) and 16 biliary leakages (5 patients with biliary leakage also had a biliary stricture); most (72%) of the anastomotic strictures were complex (i.e., fork-shaped or trident-shaped). The strictures and leakages were repaired by the endoscopic placement of multiple inside stents above the sphincter of Oddi, and by nasobiliary drainage, respectively. The procedure was successful in repairing 51 (68.0%) of the anastomotic strictures and 8 (50.0%) of the biliary leakages.

Conclusions

Endoscopic stenting of the bile ducts is efficacious in treating biliary complications related to RL-LDLT with duct-to-duct biliary anastomosis and the stenting should be attempted before surgical revision of strictures and leakages.     

Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis

Stat3 mediates a complex spectrum of cellular responses, including inflammation, cell proliferation, and apoptosis. Although evidence exists in support of a positive role for Stat3 in cancer, its role has remained somewhat controversial because of insufficient study of how its genetic deletion may affect carcinogenesis in various tissues. In this study, we show using epithelium-specific knockout mice (Stat3(Δ/Δ)) that Stat3 blunts rather than supports antitumor immunity in carcinogen-induced lung tumorigenesis. Although Stat3(Δ/Δ) mice did not show any lung defects in terms of proliferation, apoptosis, or angiogenesis, they exhibited reduced urethane-induced tumorigenesis and increased antitumor inflammation and natural killer (NK) cell immunity. Comparative microarray analysis revealed an increase in Stat3(Δ/Δ) tumors in proinflammatory chemokine production and a decrease in MHC class I antigen expression associated with NK cell recognition. Consistent with these findings, human non-small cell lung cancer (NSCLC) cells in which Stat3 was silenced displayed an enhancement of proinflammatory chemokine production, reduced expression of MHC class I antigen, and increased susceptibility to NK cell-mediated cytotoxicity. In addition, supernatants from Stat3-silenced NSCLC cells promoted monocyte migration. Collectively, our findings argue that Stat3 exerts an inhibitory effect on antitumor NK cell immunity in the setting of carcinogen-induced tumorigenesis.     

Amphiregulin is a prognostic factor in colorectal cancer

Amphiregulin is an epidermal growth factor (EGF) which is a ligand of epidermal growth factor receptor (EGFR). Amphiregulin is the most enhanced EGFR ligand in colon cancer. Here we report on the expression of Amphiregulin using immunohistochemical staining in primary colorectal cancer, and the correlations between prognosis and various clinicopathological factors. We examined 174 consecutive patients who underwent curative resection of colorectal cancer, from January 2002 to December 2004. Amphiregulin was positive in 156 (90%) patients. Amphiregulin was found to be an independent predictor of overall survival [hazard ratio=6.25 (95% confidence interval=1.3-111.5; p=0.0144)] and relapse-free survival [hazard ratio=6.94 (95% confidence interval=1.5-123.2; p=0.0075)]. We conclude that the expression of Amphiregulin in a primary colorectal tumor is useful as an indicator of prognosis and as a predictor of recurrence.     

Successful resection of esophageal carcinoma associated with double aortic arch: a case report

Double aortic arch (DAA) is an extremely rare vascular malformation which causes tracheal and esophageal compression, resulting in respiratory symptoms such as stridor and wheezing, or feeding problems such as dysphagia, usually during the first few months of life. In contrast, this disorder is rarely diagnosed in adults. We herein present an elderly case with thoracic esophageal carcinoma with DAA. To the best of our knowledge, this is only the second report of a successfully resected case of esophageal cancer associated with DAA in the English literature. Moreover, this is the first reported case of symptomatic DAA with esophageal carcinoma. Spiral computed tomography and three-dimensional reconstruction was very useful for preoperative assessment of the abnormal vessels.