From 1977 to 1997, surgical resection was possible in 142 (80%) of 177 patients with hilar cholangiocarcinoma after relieving jaundice by single or multiple percutaneous transhepatic biliary drainage followed by percutaneous transhepatic cholangioscopy and/or percutaneous trans-hepatic portal vein embolization. Curative resection was possible in 108 (61%) of the 142 patients, and 100 of these patients underwent various types of hepatectomy with caudate lobectomy for a 30-day operative mortality rate of 6% and 9% hospital mortality. Combined portal vein resection was carried out in 43 cases including 41 hepatectomies and 2 bile duct resections. Hepatopancreatoduodenectomy was performed in 16 patients. Cancer recurrence was observed in 58 of the 108 patients undergoing curative resection. The 3-, 5-, and 10-year survival rates for 100 patients undergoing curative hepatectomy and 8 with curative bile duct resection were 43%, 26%, and 19%; and 31%, 16%, and 0%, respectively; those for 40 patients with positive lymph node metastasis, 84 with perineural invasion, and 43 with combined portal vein resection were 27%, 14%, and 7%; 34%, 21%, and 13%; and 18%, 6%, and 0%, respectively. These survival rates are significantly better than those for 35 patients with unresectable cancer. Curative resection after aggressive preoperative management is recommended as a reasonable surgical approach to hilar cholangiocarcinoma.

Most tumor cell membranes overexpress L-type amino acid transporter 1, while normal cell membranes contain L-type amino acid transporter 2; both are Na + -independent amino acid transporters. Therefore, compounds that selectively inhibit L-type amino acid transporter 1 offer researchers with a novel cancer molecular target. Synthetic chemistry efforts and in vitro screening have produced a variety of novel compounds possessing high in vitro L-type amino acid transporter 1 selectivity; KYT-0353 was one such compound. The present studies illustrate that KYT-0353 inhibited 14 C-leucine uptake and cell growth in human colon cancer-derived HT-29 cells; IC 50 s were 0.06 lM and 4.1 lM, respectively. KYT-0353 also inhibited 14 C-leucine uptake in mouse renal proximal tubule cells expressing L-type amino acid transporter 1, and inhibited cell growth; IC 50 s were 0.14 lM and 16.4 lM, respectively. Compared to control animals, intravenously administered KYT-0353 (12.5 mg/kg and 25.0 mg/kg) showed statistically significant growth inhibition against HT-29 tumors transplanted to nude mice with maximal inhibition ratios of 65.9% and 77.2%, respectively. Body weight increase with time -a safety indicator -was slightly depressed at 12.5 mg/kg and 25.0 mg/kg with maximal ratios of 3.7% (day 2) and 6.3% (day 11), respectively. Thus, KYT-0353 showed significant growth inhibitory effects on HT-29 cells both in vitro and in vivo, whereas it only caused a slight body weight depression. Therefore, KYT-0353 appears to have potential as a novel antitumor agent, presumably via selective in vivo L-type amino acid transporter 1 inhibition. (Cancer Sci 2010; 101: 173-179)

In this report, we first cloned a cDNA for a protein that is highly expressed in mouse kidney and then isolated its counterparts in human, rat hamster, and guinea pig by polymerase chain reaction-based cloning. The cDNAs of the five species encoded polypeptides of 244 amino acids, which shared more than 85% identity with each other and showed high identity with a human sperm 34-kDa protein, P34H, as well as a murine lungspecific carbonyl reductase of the short-chain dehydrogenase/reductase superfamily. In particular, the human protein is identical to P34H, except for one amino acid substitution. The purified recombinant proteins of the five species were about 100-kDa homotetramers with NADPH-linked reductase activity for ␣-dicarbonyl compounds, catalyzed the oxidoreduction between xylitol and L-xylulose, and were inhibited competitively by nbutyric acid. Therefore, the proteins are designated as dicarbonyl/L-xylulose reductases (DCXRs). The substrate specificity and kinetic constants of DCXRs for dicarbonyl compounds and sugars are similar to those of mammalian diacetyl reductase and L-xylulose reductase, respectively, and the identity of the DCXRs with these two enzymes was demonstrated by their co-purification from hamster and guinea pig livers and by protein sequencing of the hepatic enzymes. Both DCXR and its mRNA are highly expressed in kidney and liver of human and rodent tissues, and the protein was localized primarily to the inner membranes of the proximal renal tubules in murine kidneys. The results imply that P34H and diacetyl reductase (EC 1.1.1.5) are identical to Lxylulose reductase (EC 1.1.1.10), which is involved in the uronate cycle of glucose metabolism, and the unique localization of the enzyme in kidney suggests that it has a role other than in general carbohydrate metabolism.

C(+SS) is associated with less advanced, slower growing tumors and better survival compared with C(-SS). In many cases of C(+SS), the survival does not depend on the complete resection of all the superficial spread but on the stage of the main lesion.

In line with the recent development of fragment-based drug design, a new computational method for mapping of small ligand molecules on protein surfaces is proposed. The method uses three-dimensional (3D) spatial distribution functions of the atomic sites of the ligand calculated using the molecular theory of solvation, known as the 3D reference interaction site model (3D-RISM) theory, to identify the most probable binding modes of ligand molecules. The 3D-RISM-based method is applied to the binding of several small organic molecules to thermolysin, in order to show its efficiency and accuracy in detecting binding sites. The results demonstrate that our method can reproduce the major binding modes found by X-ray crystallographic studies with sufficient precision. Moreover, the method can successfully identify some binding modes associated with a known inhibitor, which could not be detected by X-ray analysis. The dependence of ligand-binding modes on the ligand concentration, which essentially cannot be treated with other existing computational methods, is also investigated. The results indicate that some binding modes are readily affected by the ligand concentration, whereas others are not significantly altered. In the former case, it is the subtle balance in the binding affinity between the ligand and water that determines the dominant ligand-binding mode.

In harvesting the right liver from a donor without a right hepatic duct, 2 or more bile duct stumps will be present in the plane of transection in the graft in 3 patterns based on their relation to the portal vein. Accurate knowledge of the variations in the hepatic confluence is essential for successful living donor liver transplantation.

Intrahepatic cholangiocarcinoma (ICC) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. We examined roles of CXCR4 and its ligand, stromal cell-derived factor (SDF) -

Inchin-ko-to (ICKT), an herbal medicine, and its ingredients exert potent choleretic effects by a "bile acid-independent" mechanism. The current study was designed to determine whether ICKT or its ingredients potentiate multidrug resistance-associated protein 2 (Mrp2; Abcc2)-mediated choleresis in vivo. Biliary secretion of Mrp2 substrates and the protein mass, subcellular localization, and messenger RNA (mRNA) level of Mrp2 were assessed in rat liver after infusion of genipin, an intestinal bacterial metabolite of geniposide, a major ingredient of ICKT. The function of Mrp2 was also assessed by the adenosine triphosphate (ATP)-dependent uptake of Mrp2-specific substrates using canalicular membrane vesicles (CMVs) from the liver. Infusion of genipin increased bile flow by 230%. It also increased biliary secretion of bilirubin conjugates and reduced glutathione (GSH) by 513% and 336%, respectively, but did not increase bile acid secretion. The ATP-dependent uptake of estradiol 17-␤-D-glucuronide (E 2 17␤G; by 265%), leukotriene C4 (LTC 4 ; by 161%), taurolithocholate-3-sulfate (TLC-3S; by 266%), and methotrexate (MTX; by 234%) was significantly stimulated in the CMVs from the liver. These effects were not observed in Mrp2-deficient rats. Under these conditions, genipin treatment increased the protein mass of Mrp2 in the CMVs but not the mRNA level. In immunoelectron microscopic studies, a marked increase in Mrp2 density in the canalicular membrane (CM) and microvilli was observed in the genipin-treated liver tissue sections when compared with the vehicle-treated liver tissue sections. In conclusion, genipin may enhance the bile acid-independent secretory capacity of hepatocytes, mainly by stimulation of exocytosis and insertion of Mrp2 in the bile canaliculi. ICKT may be a potent therapeutic agent for a number of cholestatic liver diseases. (HEPATOLOGY 2004;39:167-178.)