Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells

Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-alpha) and IFN-beta induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7, HuH7, PLC/PRF/5, HLE, and HLF). This synergism was only observed when cells were pretreated with the acyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with antitype 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2', 5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably because of a lack of IFNR and STAT1 up-regulation. In conclusion, these results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-beta.     

Comparison of 2D and 3D digital subtraction angiography in evaluation of intracranial aneurysms

BACKGROUND AND PURPOSE: Although digital subtraction angiography (DSA) is considered the criterion standard for depiction of intracranial aneurysms, it is often difficult to determine the relationship of overlapping vessels to aneurysms when using 2D DSA. We compared 2D and 3D DSA in evaluation of intracranial aneurysms. METHODS: Thirty-six consecutive patients with cerebral aneurysms underwent 2D and 3D DSA. After standard 2D DSA, rotational DSA was performed. Maximum intensity projection (MIP) and shaded surface display (SSD) images were created from the rotational DSA data sets. All images were assessed randomly for overall image quality, presence of aneurysm, presence of aneurysmal lobulation, visualization of aneurysmal neck, and relationship to adjacent vessels. Data analysis was conducted for 40 aneurysms treated by clip placement. RESULTS: One aneurysm that was not detected at 2D DSA was classified as uncertain on the basis of rotational DSA. All aneurysms were classified as probably or definitively present on the basis of MIP and SSD findings. Overall image quality of rotational DSA, MIP, and SSD was statistically inferior to that of the standard 2D DSA for visualization of distal arteries. However, MIP and SSD images were significantly superior to those of standard 2D DSA for all other evaluations. For detection of lobulation, SSD images were significantly superior to other images, and for visualization of aneurysmal neck and relationship to neighboring arteries, SSD images were significantly superior to those of rotational DSA. For evaluation of the relationship to neighboring arteries, MIP images were significantly superior to those of rotational DSA. CONCLUSION: Three-dimensional DSA, especially SSD, provided more detailed information for evaluating cerebral aneurysms than did standard 2D and rotational DSA.     

Generation of pro-inflammatory and anti-inflammatory cytokines in the gut in zymosan-induced peritonitis

In major systemic inflammation such as severe peritonitis, various pro-inflammatory cytokines, such as TNF-alpha, IL-1 beta and IL-6, play important roles in the development of multiple organ dysfunction syndrome (MODS). The purpose of this study was to investigate the outflow of pro-inflammatory and anti-inflammatory cytokines from the efferent mesenteric lymphatic vessels under peritonitis. Mesenteric lymph samples were collected from adult male rats at 2, 4, 6, 8 and 10 hr after an intraperitoneal injection of zymosan at a dosage of 0.1 mg/g (non-lethal dose) or 0.5 mg/g (lethal dose). Blood samples were obtained at 10 hr after zymosan administration. The amounts of drained TNF-alpha and IL-6 in the lymph peaked at 2-4 hr and 4-8 hr after zymosan administration, respectively. The amounts of drained IL-10 in the lymph gradually increased until 10 hr. The amounts of drained TNF-alpha and IL-10 in the mesenteric lymph were significantly correlated with the dosage of zymosan. In conclusion, under intraperitoneal inflammation, pro-inflammatory cytokines (TNF-alpha and IL-6) increased in the mesenteric lymph and were drained into circulation. IL-10, one of the anti-inflammatory cytokines, also increased in the mesenteric lymph after several hours' delay and its increase was remarkable in several inflammations. These findings suggested that the gut might be one of the pro-inflammatory and anti-inflammatory cytokine-generating organs under peritonitis. The lymph-drained amounts of each cytokine under peritonitis are considered to differ with the time or severity of inflammation, which may cause different conditions in patients due to the imbalance of pro-inflammatory and anti-inflammatory cytokines.     

Dephosphorylation of WR-2721 with mouse tissue homogenates

Mouse liver homogenate had an optimum pH of 8.6 to 8.8 for dephosphorylation of WR-2721 in the analyzed pH range from 5.2 to 10.0. At this optimum pH condition, the dephosphorylation activities of six mouse tissue homogenates were analyzed. Kidney, liver and small intestine homogenates showed higher dephosphorylation activities (935, 336 and 314 nmoles/mg protein/hr, respectively) than spleen and lung homogenates (86, 49 nmoles/mg protein/hr, respectively). Furthermore, serum did not show any dephosphorylation activity. The high activity found in liver homogenate agrees well with our previous data with mouse L cells. However, optimum pH from 8.6 to 8.8 in liver homogenate is quite different from the data reported by using Ehrlich ascites tumor cells (optimum pH was 5.6). Therefore, it is suggested that WR-2721 administered into mouse is efficiently dephosphorylated in certain tissues such as liver to its active form with the enzyme(s) different from that found in Ehrlich ascites tumor cells.     

Relationship between hepatic hemodynamics and biliary pressure in dogs: Its significance in clinical shock following biliary decompression

The changes in the hepatic hemodynamics were promptly reflected in the biliary pressure in dogs. Both wedged hepatic venous pressure and portal venous pressure increased in response to the elevated biliary pressure, and conversely decreased following rapid biliary decompression, suggesting that the changes in the biliary pressure might affect the hepatic hemodynamics post-sinusoidally. It was supposed that too rapid biliary decompression might trigger the following consequences; 1) decrease in sinusoidal pressure, 2) increase in sinusoidal inflow, and 3) extravasation of intravascular fluid in the perivascular space. When these were not sufficiently compensated, they could trigger shock in the jaundiced patients.     

Interferon-based cytokine therapy for advanced renal cell carcinoma

Among 126 patients diagnosed with metastatic renal cell carcinoma at Hamamatsu University or its affiliated hospital between 1978 and 2004, pretreatment features associated with a shorter survival in the multivariate analysis were in symptomatic status at diagnosis and in multiple organ metastasis. The 1- and 3-year survival rate in patients with these two prognostic factors were 22.3 and 0.3%, respectively. The style of treatment did not influenced survival in these patients. Therefore, an accurate assessment of their survival benefits both them and physician while it is urgent that we develop novel agents and strategy.