Long-term albumin administration after first-onset ascites significantly improves patients' survival and decreases the risk of ascites recurrence.

The focus of this study was to use differential protein expression to investigate operative pathways in early stages of human colon cancer. Colorectal cancer represents an ideal model system to study the development and progression of human tumors, and the proteomic approach avoids overlooking posttranslational modifications not detected by microarray analyses and the limited correlation between transcript and protein levels. Colon cancer samples, confined to the intestinal wall, were analyzed by expression proteomics and compared with matched samples from normal colon tissue. Samples were processed by two-dimensional gel electrophoresis, and spots differentially expressed and consistent across all patients were identified by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analyses and by Western blot analyses. After differentially expressed proteins and their metabolic pathways were analyzed, the following main conclusions were achieved for tumor tissue: 1) a shift from beta-oxidation, as the main source of energy, to anaerobic glycolysis was observed owed to the alteration of nuclear- versus mitochondrial-encoded proteins and other proteins related to fatty acid and carbohydrate metabolism; 2) lower capacity for Na(+) and K(+) cycling; and 3) operativity of the apoptosis pathway, especially the mitochondrial one. This study of the human colon cancer proteome represents a step toward a better understanding of the metabolomics of colon cancer at early stages confined to the intestinal wall.

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Expression of the integrin, ␣6␤1, a receptor for laminins, is associated with the progression of hepatocellular carcinoma (HCC). The approach to investigating the ␣6␤1 integrin signaling in HCC cells was to express a deletion mutant of the ␤4 integrin cytoplasmic domain (␤4-⌬cyt) in 2 HCC cell lines, HepG2 and Huh7. Expression of this mutant prevents formation of the ␣6␤1 heterodimer. As expected, adhesion of both the HepG2/␤4-⌬cyt and Huh7/␤4-⌬cyt transfectants to laminin, but not to collagen, was reduced compared with the mock transfectants. However, migration of the ␤4-⌬cyt transfectants toward both collagen and laminin was inhibited, suggesting a role for ␣6␤1 in the signaling of migration. The pattern of integrins expressed by human hepatocytes is strikingly different from most other epithelial cells. Normal adult hepatocytes express low levels of only 3 integrins: ␣1␤1, a collagen and laminin receptor; ␣5␤1, a fibronectin receptor; and ␣9␤1, a tenascin receptor. In contrast, other integrin receptors such as ␣2␤1, ␣3␤1, ␣6␤1, and ␣6␤4 are undetectable on normal hepatocytes. One of the most frequent alterations during liver carcinogenesis is de novo expression of the integrin, ␣6␤1. In fact, the induction of ␣6␤1 expression is an early event in hepatocellular carcinogenesis, and it is reasonable to postulate that ␣6␤1 contributes to carcinogenesis based on several lines of evidence. [1][2][3][4] For this reason, it is important to understand the mechanism by which the ␣6␤1 integrin influences the function of hepatocellular carcinoma (HCC) cells. One likely possibility is that ␣6␤1 controls signaling pathways important for HCC function.In this study, we examined the hypothesis that ␣6␤1-mediated activation of FAK and MAP kinase is important for the function of HCC cells. Both focal adhesion kinase (FAK) and the mitogen-activated protein (MAP) kinase family members, extracellular-regulated kinase 1 (ERK1) and ERK2, are of interest, because they are regulated by integrin-mediated attachment to matrix, as well as growth factor stimulation, and they regulate important functions of tumor cells such as growth and migration. [5][6][7][8] The regulation of these kinases by the ␣6␤1 integrin, however, is not well understood and somewhat controversial. A previous study concluded that ␣6␤1 was unable to activate MAP kinase in NIH 3T3 cells despite being able to stimulate FAK tyrosine phosphorylation. 9 More recently, a study performed in macrophages demonstrated that ␣6␤1 integrin, and particularly the cytoplasmic domain of the ␣6 subunit, was able to regulate MAP kinase activation without inducing FAK tyrosine phosphorylation. 10,11 Most previous studies concerning the function of ␣6␤1 integrin have relied on the use of antibodies binding ␣6␤1 to perturb the interaction of ␣6␤1 with its ligand. The hypothesis that expression of the ␣6␤1 integrin is important for FAK and MAP kinase activation in HCC cells was assessed using a dominant-negative approach to inhibit expression of this integrin in HCC cell lines. [12][13][1...

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 ؎ 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N Gmonomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg ⅐ min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (؊13%) and increased systemic vascular resistance (؉26%), arterial pressure (؉9%), renal blood flow (؉12%), glomerular filtration rate (؉12%), and sodium excretion (؉25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves re- Patients with cirrhosis and portal hypertension eventually develop a hyperdynamic circulation, with high cardiac output, reduced systemic vascular resistance, and a trend towards arterial hypotension. 1 This abnormality, that contributes to worsen portal hypertension and plays a major role in the pathogenesis of other complications, including ascites and renal failure, has been related to peripheral arterial vasodilation, mainly occurring in the splanchnic circulation. 2 The cause(s) and mechanism(s) of arterial vasodilation are still unknown, but available evidence suggests that an increased synthesis of nitric oxide (NO) participates in the pathogenesis of the altered systemic hemodynamics in cirrhosis. 3,4 Animals with experimental cirrhosis have increased expression of nitric oxide synthase (NOS) and increased synthesis of NO in the vasculature. 5-9 They also have impaired response to vasoconstrictors in isolated aortic rings or splanchnic vasculature preparations, which is reversed by NOS inhibitors, 10,11 and increased pressor response to systemic administration of NOS inhibitors. 12,13 In addition, normalization of NO production by low-dose N G -nitro-L-arginine methyl ester, a NOS inhibitor, corrected the altered systemic hemodynamics, normalized the activity of the main vasoconstricting and sodiumretaining systems, 14 and improved renal sodium and water excretion in cirrhotic rats with ascites. 15 Evidence of an increased synthesis of NO has also ...

Advanced cirrhosis is associated with reduced platelet function and altered renal function and sodium handling. Arachidonic acid (AA) metabolites contribute to platelet aggregation and to maintain the response to diuretics in advanced cirrhosis. In the present study, we tested the effects of a dietary supplementation for 8 weeks with a triacylglycerol (triglyceride) enriched in AA (ARASCO; 4 g/day) or oleic acid (OA) on plasma and membrane fatty acid composition, platelet aggregation and renal prostaglandin (PG) metabolism. At baseline, all patients had reduced platelet aggregation. Patients treated with AA showed a significant increase in the percentage of AA in plasma lipids and membrane phospholipids. These changes were associated with an increased platelet aggregation in response to collagen (from 55.83 +/- 20.63 to 67.67 +/- 14.44%; P<0.05). At baseline, all urinary AA metabolites, including PGE2, 6-keto-PGF1alpha, 8-epi-PGF2alpha and 11-dehydro-thromboxane B2, were elevated in cirrhotic patients when compared with a group of normal subjects. After furosemide treatment, urinary excretion of 11-dehydro-thromboxane B2 increased significantly. Supplementation with AA did not result in any significant change in urinary PG excretion either before or after diuretic administration. The results of the present study show that dietary supplementation with AA effectively increases the levels of this fatty acid in plasma and membrane phospholipids and improves platelet aggregation. These data suggest a possible novel approach to the treatment of the haemostatic defect observed in these patients.

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