Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.     

S 17092: a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment. Preclinical and clinical studies

Any treatment that could positively modulate central neuropeptides levels would provide a promising therapeutic approach to the treatment of cognitive deficits associated with aging and/or neurodegenerative diseases. Therefore, based on the activity in rodents, S 17092 (2S,3aS,7aS)-1][(R,R)-2-phenylcyclopropyl]carbonyl]-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole) has been selected as a potent inhibitor of cerebral prolyl-endopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short-term, long-term, reference and working memory in aged mice, as well as in rodents and monkeys with chemically induced amnesia or spontaneous memory deficits. S 17092 has also been safely administered to humans, and showed a clear peripheral expression of its mechanism of action through its inhibitory effect upon PEP activity in plasma. S 17092 exhibited central effects, as evidenced by EEG recording in healthy volunteers, and could improve a delayed verbal memory task. Collectively, the preclinical and clinical effects of S 17092 have suggested a promising role for this compound as an agent for the treatment of cognitive disorders associated with cerebral aging.     

Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling

A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [(35)S]-GTP gamma S binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.     

Alexis Carrel: Genius,Innovator and Ideologist

Alexis Carrel was a Frenchman from Lyon, who gained fame at the Rockefeller Institute in New York at the beginning of the 20th century. He was the first to demonstrate that arteriovenous anastomoses were possible. Alexis Carrel was awarded the Nobel Prize for his contributions to vascular surgery and transplantation in 1912. He was a versatile scientist, who made numerous discoveries from the design of an antiseptic solution to treat injuries during the First World War to tissue culture and engineering, and organ preservation, making him the father of solid organ transplantation. Together, with the famous aviator and engineer Charles Lindbergh, they were the first scientists capable of keeping an entire organ alive outside of the body, using a perfusion machine. Due to his many dubious ideas and his association with fascism in the 1930s and during the Second World War, many of his scientific achievements have been forgotten today and taken for granted.     

Follow-up after partial interruption of the vena cava with the Günther filter

We have treated 34 patients with the Günther filter. Follow-up ranged from 5 to 891 days (median 129). Eight patients died 5–352 days (median 26) after filter insertion, without relation to the procedure. Six of them had extensive cancer. At 2 weeks, a mean caudal migration of 27±20 mm of the Günther filter was observed (n=24). No significant migration occurred later than 2 weeks. In 2 patients, downward displacement of the device to the iliocaval junction was observed, with recurrent embolism in 1 case. A second filter, was placed in the infrarenal vena cava in both cases. There was no other recurrent embolism and no sign of vena caval occlusion.     

Calpain inhibition prevents sinusoidal endothelial cell apoptosis in the cold ischemic rat liver.

BACKGROUND: Cold preservation of the liver followed by reperfusion results in sinusoidal endothelial cell (SEC) apoptosis. Calpain-like activity is dramatically increased during reperfusion and inhibition of calpains results in lower graft injury and longer survival. Recently, calpains have been implicated in inducing apoptosis. Our aim was to determine the effect of calpain inhibition on SEC apoptosis. METHODS: Livers were stored in the University of Wisconsin solution for 24 hr (survival conditions) and 40 hr (nonsurvival conditions) and ex vivo reperfused for 1 hr at 37 degrees C. Calpain-like activity was inhibited in some experiments using an i.p. injection of a selective inhibitor 2 hr before explantation. Apoptosis was quantified using the terminal deoxynucleotidyl trans. ferase-mediated dUTP nick end-labeling assay. Cross-inhibition by the inhibitor was determined for caspases 1 and 3. RESULTS: Apoptosis of exclusively the SEC was a key feature of reperfusion injury after both storage periods in University of Wisconsin solution after 1 hr normothermic reperfusion. Inhibition of calpain activity with Cbz-Val-Phe methyl ester resulted in a 50% reduction of apoptotic SEC in the 40-hr preserved liver, and an almost complete abrogation of SEC apoptosis after 24 hr preservation. Only minimal cross-inhibition of caspases was determined at high concentrations in vitro by the calpain inhibitor. CONCLUSION: Apoptosis of exclusively SEC is a key feature of reperfusion injury partially mediated through calpain-dependent processes. Calpain inhibition reduces the number of apoptotic SEC. Based on these data and our previous work, calpain inhibition may prove to be useful in clinical transplantation.     

A population pharmacokinetic screen to identify demographic-clinical covariates of basiliximab in liver transplantation

BACKGROUND: Basiliximab is a high-affinity interleukin-2 receptor (CD25) chimeric monoclonal antibody used for immunoprophylaxis in organ transplantation. It was assessed in a randomized, double-blind, placebo-controlled efficacy trial in de novo liver allograft recipients who received 40 mg of basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppression with cyclosporine (INN, ciclosporin) microemulsion and corticosteroids. METHODS: Serial blood samples (8.3 +/- 1.4 per patient) were collected during 12 weeks after transplantation from 184 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. Demographic-clinical covariates were explored with regression methods. RESULTS: Basiliximab clearance was 55 +/- 26 mL/h, the distribution volume was 9.7 +/- 4.2 L, and the half-life was 8.7 +/- 6.7 days. Patient weight, age, sex, ethnicity, history of alcoholism, hepatitis C seropositivity, and notable postoperative bleeding had no clinically relevant influences on basiliximab disposition; however, the cumulative volume of drained ascites fluid in the first week was positively correlated with clearance. Receptor-saturating basiliximab concentrations (> or =0.1 microg/mL) were maintained for 38 +/- 16 days, and this was negatively correlated with the cumulative volume of drained ascites fluid in week 1. Patients who experienced an acute rejection episode did not clear basiliximab at a faster rate than their rejection-free peers nor did they maintain CD25-saturating concentrations for a shorter period. CONCLUSIONS: Although the standard dose regimen of 20 mg of basiliximab on days 0 and 4 after transplantation appears to be appropriate for the majority of patients with liver transplants, a supplemental dose at the end of the first week may be considered for those with substantial (>10 L) postoperative ascites fluid drainage.     

“State of the Art” in Liver Resection and Living Donor Liver Transplantation: A Worldwide Survey of 100 Liver Centers

Background  New strategies have been developed to expand indications for liver surgery. The objective was to evaluate the current practice worldwide regarding critical liver mass and manipulation of the liver volume. Methods  A survey was sent to 133 liver centers worldwide, which focused on (a) critical liver volume, (b) preoperative manipulation of the liver mass, and (c) use of liver biopsy and metabolic tests. Results  The overall response rate to the survey was 75%. Half of the centers performed more than 100 resections per year; 86% had an associated liver transplant program. The minimal remnant liver volume for resection was 25% (15–40%) in cases of normal liver parenchyma and 50% (25–90%) in the presence of underlying cirrhosis. The minimal remnant liver volume for living donors was 40% (30–50%), whereas the accepted graft body weight ratio was 0.8 (0.6–1.2). Portal vein occlusion to manipulate the liver volume before resection was performed in 89% of the centers. Conclusions  Limits of liver volume and the current practice of liver manipulation before resection were comparable among different centers and continents. The minimal remnant liver volume in normal liver was 25%, and more than 80% of the centers performed portal vein occlusion. S. Breitenstein and C. Apestegui contributed equally to this work. Henrik Petrowsky is the recipient of the Novartis fellowship in Hepato-Pancreato-Biliary surgery and liver transplantation at the Swiss HPB Center at the University of Zurich.     

Systematic review and meta‐analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis

Background:

A combined antiviral and tumoricidal effect of interferon (IFN) is assumed to occur after resection or ablation of hepatocellular carcinoma (HCC).

Methods:

An electronic search of the Medline, Embase and Central databases from January 1998 to October 2007 was conducted to identify randomized controlled trials evaluating adjuvant effects of IFN after curative treatment of HCC. A meta‐analysis was performed to estimate the effects of IFN on 2‐year outcome.

Results:

Seven trials enrolling a total of 620 patients were included in the meta‐analysis. Adjuvant treatment with IFN significantly reduced the 2‐year mortality rate after curative treatment of HCC, with a pooled risk ratio of 0·65 (95 per cent confidence interval 0·52 to 0·80); P < 0·001) in absence of any significant heterogeneity (I² = 0 per cent, P = 0·823 for χ²). The effect on reduction of tumour recurrence was less pronounced but still significant (pooled risk ratio 0·86 (95 per cent c.i. 0·76 to 0·97); P = 0·013). IFN had to be discontinued in 8–20 per cent of patients.

Conclusion:

IFN has a significant beneficial effect after curative treatment of HCC in terms of both survival and tumour recurrence. Copyright © 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.