CD44v6 expression is an independent prognostic factor in node-negative FIGO stage IB cervical carcinoma

Adhesion molecules such as CD44 play an important role in the metastatic cascade by mediating tumor cell interaction with the endothelium and the subendothelial matrix. As a so-called "lymphocyte homing receptor," CD44 is physiologically involved in migration of circulating lymphocytes to lymphatic tissue. In the present study, we investigated the expression of CD44v3 and v6 in 237 patients with stage IB, N0 cervical carcinoma by means of immunohistochemistry. These results were correlated with the GOG score and other prognostic variables. Median follow-up was 82.6 months (39–110 months). Thirty-nine patients recurred and 35 died from disease within the observation period. In univariate analysis, the GOG score, histologic subtype, and CD44v6 expression were statistically significant predictors for poor overall survival (OS). In multivariate (Cox regression) analysis, the GOG score (< 40 vs. 40–120, RR: 1.37 (95% CI: 1.10–1.71); 40–120 vs. > 120, RR: 2.23 (95% CI: 1.28–3.88); P = 0.004), histologic subtype (adenosquamous carcinomas) (RR: 4.56 (95% CI: 1.49–13.92), P = 0.007) and CD44v6 expression (RR: 2.42 (95% CI: 1.14–5.10), P = 0.021) were independent predictors for poor OS. The expression of CD44v3 did not correlate with prognosis. Furthermore we found a strong correlation between CD44v6 expression and lymphovascular space invasion (LVSI) (χ² = 17.01, P = 0.0001). Tumor expansion into the loco-regional lymphatic system is the preferred way of tumor spread in cervical carcinoma. The strong correlation of CD44v6 with LVSI produces a significant degree of suspicion that cervical carcinoma cells expressing CD44v6 could, by mimicking lymphocytes, exploit their pathways.     

Effects of 1,1-Dichloroethene and of Some of Its Metabolites on the Functional Viability of Mouse Hepatocytes

1,1-Dichloroethene (DCE) is hepatotoxic in rodents, and theexpression of its toxicity involves probably its metabolism.In this study the role of DCE metabolites in the generationof the hepatotoxic lesion was investigated. Hepatocytes frommale BALB/c mice in suspension were used as the experimentalmodel. Cells were incubated with DCE for up to 5 hr and cellularviability was assessed by measurement of the release of lactatedehydrogenase into the medium and by alterations in the reductionof the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide. After incubation for 3 hr DCE at 0.5 mM caused maximaltoxicity, whereas at 0.1 mM DCE was only marginally toxic. Cytotoxicitywas exacerbated by pretreatment of mice with buthionine sulfoximine(1.6 g/kg), an inhibitor of glutathione biosynthesis, given4 hr prior to hepatocyte isolation. Inclusion of N-acetylcysteine(10 mM) into the incubate protected cells against DCE-inducedcytotoxicity. Coincubation with octylamine (0.5 mM), an inhibitorof cytochrome P450, abolished the cytotoxic potential of 0.5mM DCE during incubation for 3 hr. DCE toxicity was increasedin hepatocytes from mice which had received ethanol or acetonein their drinking water, both of which induce levels of thehepatic cytochrome P450 isozyme P450 2E1. Incubation of cellswith the P450 2E1 inhibitors N,N-dimethylformamide (10 mM) ordiethyldithiocarbamate (100 µM) protected liver cellsagainst the detrimental effect of DCE. Pretreatment of animalswith phenobarbital, which induces the P450 2B subfamily, or3-methylcholan-threne, which induces P450 1A1, did not affectthe degree of hepatocytotoxicity elicited by DCE. The DCE metaboliteschloroacetic acid and dichloroacetaldehyde at 0.75 mM were toxictoward the cells; however, their toxic potency was inferiorto that of DCE. Dichloroacetic acid, another product of metabolicDCE oxidation, and S-(chloroacetyl)glutathione and glutathionylacetylglutathione,both of which are generated by conjugation of DCE metaboliteswith glutathione, at concentrations of up to 5 mM did not interferewith hepatocyte viability. The results suggest that (i) DCEundergoes metabolic toxification in mouse hepatocytes, (ii)P450 2E1 is responsible for the metabolic activation of DCE,and (iii) conjugation with glutathione is a detoxification step.     

The effect of gossypol acetic acid on the different stages of the spermatogenic cycle in the rat

The reversibility of the effect of gossypol on testicular histology and fertility was studied in rats. Adult males of proven fertility were treated orally with gossypol acetic acid (15 mg/kg) for 9 or 16 weeks (groups 1 and 2, respectively). Another groups of animals (group 3) was given gossypol (15 mg/kg) for 16 weeks and killed 6 weeks after the end of treatment. Control animals (group 4) were given the vehicle only by oral intubation. In the mating studies, although only 33% of the animals in group 1 were infertile, 100% infertility was observed following 16 weeks of gossypol treatment (group 2). All animals in group 3 regained their fertility 6 weeks after cessation of drug treatment. Damage was observed to 15.7% of the seminiferous tubules after 9 weeks of drug treatment, and to 78% after 16 weeks of treatment. Extensive vacuolization, increased numbers of lipid droplets, degeneration of germ cells, loosening of the epithelium, and a significant decrease in the number of pachytene spermatocytes (stages VII-X) and spermatids (steps 7-10 at stages VII-X) were observed after gossypol treatment. There was a decrease in the diameter of only stage VIII seminiferous tubules after 9 weeks of treatment, whereas a reduction was observed in the tubules of all stages after 16 weeks of gossypol treatment. In the recovery phase, the diameter of seminiferous tubules was similar to that of controls, except for tubules at stage VIII. No change in the area of the lumen of the seminiferous tubules and lipid bodies was observed after 9 weeks of drug treatment, but a marked reduction in the area of the lumen (stages II-X) and an increase in lipid bodies (all stages) was observed after 16 weeks of gossypol treatment. Six weeks after cessation of treatment, the area of the lumen and the number of lipid bodies were comparable to values in controls. A reduction in the area of the epithelium was restricted to just a few stages (VIII-XIV) in treated animals at 9 weeks, whereas after 16 weeks the area of the epithelium was decreased in all tubules. In the recovery phase, except for tubules at stage VIII, the area of the seminiferous epithelium was comparable to that in controls.     

Application of Pulsed-Doppler Tissue Imaging in Patients with Dual Chamber Pacing: The Importance of Conduction Time and AV Delay on Regional Left Ventricular Wall Dynamics

Pulsed-Doppler tissue imaging (pDTI) is able to measure myocardial wall velocities (systolic: S; early diastolic: E; late diastolic: A) and their timings. Relationships have been demonstrated between the preelection period and indexes of left ventricular systolic function. This study was designed to examine with pDTI the effects of variations in atrioventricular delay (A VD) (100 ms, 150 ms, 200 ms) on myocardial dynamics and on their timings at the basal interventricular septum (IVS) from an apical approach and at the posterior wall (PW) from the parasternal view. These data were compared with stroke volume measurements recorded from the left ventricular outflow tract. Seventeen patients with dual chamber pacemakers (7 because of complete heart block, 10 with sick sinus syndrome and first-degree AV block) were studied; full atrial and ventricular capture was present at any AVD. These data were also compared with those obtained in 10 age-matched healthy volunteers with comparable heart rates. Results: Optimal atrial contribution to left ventricular filling and, consequently, best systolic performance were achieved when AVD was programmed such that a mean interval of 77 ms was allowed between the end of the A wave and the beginning of the S wave, similar to what was measured in the healthy control group by pDTI. Conclusion: The noninvasive measurement of timings of the cardiac cycle by pDTI is helpful to determine the optimal AVD in individual patients.