Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Alkaline sphingomyelinase (alk-SMase) is expressed in the intestine and human liver. It may inhibit colonic tumorigenesis, and loss of function mutations have been identified in human colon cancer. The present study investigates its expression in human liver cancer. In HepG2 liver cancer cells, RT–PCR identified three transcripts with 1.4, 1.2 and 0.4 kb, respectively. The 1.4 kb form is the wild-type cDNA with five translated exons, the 1.2 kb product lacks exon 4 and the 0.4 kb form is a combination of exons 1 and 5. Genomic sequence showed that these aberrant transcripts were products of alternative splicing. Transient expression of the 1.2 kb form showed no alk-SMase activity. In HepG2 cells, the alk-SMase activity is low in monolayer condition and increased with cell polarisation. Coexistence of 1.4 and 1.2 kb forms was also identified in one hepatoma biopsy. GenBank search identified a cDNA clone from human liver tumour, which codes a protein containing full length of alk-SMase plus a 73-amino-acid tag at the N terminus. The aberrant form was translated by an alternative starting codon upstream of the wild-type mRNA. Expression study showed that linking the tag markedly reduced the enzyme activity. We also analysed human liver biopsy samples and found relatively low alk-SMase activity in diseases with increased risk of liver tumorigenesis. In conclusion, expression of alk-SMase is changed in hepatic tumorigenesis, resulting in loss or marked reduction of the enzyme function

Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation?

The hydrolysis of sphingomyelin generates key molecules regulating cell growth and inducing apoptosis. Data from animal cancer models support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. In the intestinal tract, a sphingomyelinase with an optimum alkaline pH has been identified. We recently found that the activity of alkaline sphingomyelinase is significantly decreased in colorectal adenocarcinomas, indicating a potential anticarcinogenic role of this enzyme. To further examine whether the reduction of sphingomyelinase is present already in the premalignant state of neoplastic transformation, we measured sphingomyelinase activities in patients with familial adenomatous polyposis (FAP) and in sporadic colorectal tubulovillous adenomas. Tissue samples were taken from adenomas and surrounding macroscopically normal mucosa from 11 FAP patients operated with ileorectal anastomosis, from three FAP patients with intact colon, from 13 patients with sporadic colorectal adenomas and from 12 controls. Activities of acid, neutral and alkaline sphingomyelinase were measured together with alkaline phosphatase. In FAP adenoma tissue, alkaline sphingomyelinase activity was reduced by 90% compared to controls (P < 0.0001), acid sphingomyelinase by 66% (P < 0.01) and neutral sphingomyelinase by 54% (P < 0.05). Similar reductions were found in the surrounding mucosa. In sporadic adenoma tissue, only alkaline sphingomyelinase was reduced significantly, by 57% (P < 0.05). Alkaline phosphatase was not changed in FAP adenomas, but decreased in the sporadic adenomas. We conclude that the markedly reduced levels of alkaline sphingomyelinase activities in FAP adenomas and in the surrounding mucosa may be a pathogenic factor that can lead to unrestrained cell proliferation and neoplastic transformation. © 1999 Cancer Research Campaig

The role of the nurse in enhancing quality of life in patients with an implantable cardioverter-defibrillator: the Swedish experience.

During the last 10-15 years, the implantable cardioverter-defibrillator (ICD) has become an important mode of treatment for patients suffering from grave ventricular arrhythmias, but ICD implantation involves psychosocial adjustments for both patients and relatives. The aim of this pilot study was to design a plan of education and to follow a selected group of patients with interviews, observations, and a questionnaire. The goals included seeing how well they accepted their situation after the operation when they had ongoing support of the nurse, in comparison to a control group who received conventional patient education by the physician. The patients were randomly allocated into two groups. Twenty patients were recruited, 10 in the study group and 10 in the control group, between February, 1997 and April, 1998. There were 16 men (average age, 63) and four women (average age, 57). The Nottingham Health Profile was used to measure health-related quality of life. Sleep disturbances were the greatest problem in both the study group and the control group before ICD implantation. In the study group, there was a significant improvement (p<0.05) after ICD implantation in four patients. The study also revealed a difference between men and women, with women having more sleep disturbances before ICD implantation than men (p<0.05). In both groups, there was a lack of energy and emotional reactions, both before and after ICD implantation. Few considered family life a problem before or after the study. In the control group, the patients missed the lack of contact with health care personnel more than in the study group. There was also a greater need for group meetings after the hospital stay. By means of the questionnaire, interviews, and observations, it became evident that there was a great need for information, and a plan of patient education in addition to follow-up by the nurse was felt to be very important. (c)2002 CHF, Inc

Sulindac induces apoptosis, inhibits proliferation and activates caspase-3 in Hep G2 cells

Background: It has recently been reported that sulindac has an apoptotic effect on KYN-2 cells, an undifferentiated hepatoma cell line. The present work investigates whether sulindac also has an apoptotic effect on well-differentiated hepatoma cells and what its potential mechanism might be. Materials and Methods: Hep G2 cells were treated with sulindac at different concentrations. Apoptosis rate, cell proliferation and 3H-thymidine incorporation were measured. The activities of caspase-3, acid and neutral sphingomyelinase and the changes of sphingomyelin content were also assayed. Results: Sulindac dose-dependently induced apoptosis in Hep G2 cells; both sulindac sulfone and sulfide had similar effects. The apoptosis was accompanied by an increase 3 of caspase-3 activity and a decrease of cell proliferation and H-3-thymidine incorporation. No significant change could be observed for the activity of sphingomyelinase and sphingomyelin content. Conclusion: Sulindac induces apoptosis and inhibits proliferation in Hep G2 cells. The effect may, be mediated by, a pathway related to caspase-3 activation but independent of sphingomyelin metabolism

Electroanatomic mapping of right atrial activation in patients with and without paroxysmal atrial fibrillation

Inter-atrial conduction delay in patients with atrial fibrillation (AF) has been reported. However, the area of this conduction delay has not been well identified. The activation time and conduction velocity over the right atrial endocardium were evaluated during sinus rhythm using the CARTO mapping technique in 6 patients with paroxysmal AF (AF group) and 11 patients without history of AF (control group). No significant differences were observed between the 2 groups in the mean activation times and conduction velocities from the earliest activation site to the superior septum. His bundle area and coronary sinus ostium, or in the total activation times of the right atrium. There was no significant difference between the two groups in the local conduction velocity between 2 adjacent sites in the free wall, septum and bottom of the right atrium. This study suggests the previously reported conduction delay in the posteroseptal region in patients with paroxysmal AF might locate within the posterior inter-atrial septum