The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation.

At the invasion front of well-differentiated colorectal adenocarcinomas, the oncogene beta-catenin is found in the nuclear compartment of tumor cells. Under these conditions, beta-catenin can function as a transcription factor and thus activate target genes. One of these target genes, cyclin D1, is known to induce proliferation. However, invasion front of well-differentiated colorectal adenocarcinomas are known to be zones of low proliferation and express the cell cycle inhibitor p16INK4A. Therefore, we investigated the expression profiles of nuclear beta-catenin, cyclin D1, p16INK4A, and the Ki-67 antigen, a marker for proliferation, in serial sections of well-differentiated colorectal adenocarcinomas. Invasion fronts with nuclear beta-catenin were compared with areas from central parts of the tumors without nuclear beta-catenin, for the expression of cyclin D1, p16INK4A, and Ki-67. It was observed that expression of nuclear beta-catenin, cyclin D1, and p16INK4A at the invasion front are significantly correlated. Such areas exhibit low Ki-67 expression indicating a low rate of proliferation. Thus, in colorectal carcinogenesis the function of beta-catenin and its target gene cyclin D1 does not appear to be the induction of tumor cell proliferation. In particular, the function of cyclin D1 should be reconsidered in view of these observations.

In vitro activity of rilopirox against fluconazole-susceptible and fluconazole-resistant Candida isolates from patients with HIV infection.

The in vitro antifungal activity of the new hydroxypyridone antimycotic rilopirox has been evaluated against 38 fluconazole-susceptible and -resistant clinical isolates of Candida albicans together with other Candida species isolated from patients with human immunodeficiency virus (HIV) infection and oropharyngeal candidosis. Minimum inhibitory concentrations (MICs) of both rilopirox and fluconazole were measured by a microdilution method using high-resolution medium supplemented with asparagine and glucose at pH 7.0. In comparison, an agar dilution technique was carried out for susceptibility testing of the antifungal agents. Rilopirox was found to be able to inhibit growth of all clinical yeast isolates. The rilopirox MICs at which 50% and 90% of strains were inhibited (MIC50 and MIC90 respectively), as determined by the microdilution method, were 4 and 8 micrograms ml-1 respectively. The highest MIC values for rilopirox using microdilution and the agar dilution method were 32 or 25 micrograms ml-1 respectively. On the other hand, for fluconazole, the MIC50 and MIC90 achieved were 0.5 and 128 micrograms ml-1, respectively, which means that the MIC90 value of fluconazole was 16-fold higher than that of rilopirox. Using the agar dilution technique, the MIC values of rilopirox were in the range 0.006-25 micrograms ml-1 with a median of 3.12 micrograms ml-1. For fluconazole, the MIC90 value was four-fold higher than that for rilopirox, indicating a considerable proportion of yeast strains with high MICs of 100 micrograms ml-1, suggesting in vitro resistance to this azole antifungal. All strains with diminished fluconazole susceptibility were susceptible to rilopirox. Even Candida krusei and Candida glabrata exhibited good in vitro susceptibility to rilopirox. Therefore, this new antifungal agent may be used as an alternative not only in the treatment of vaginal candidosis, but also in oropharyngeal Candida infections, e.g. in AIDS patients.

In vitro susceptibility of yeasts for fluconazole and itraconazole. Evaluation of a microdilution test.

In vitro susceptibilities were determined for a total of 159 clinical isolates and 12 reference strains of yeasts belonging to different Candida species including 94 Candida albicans strains, and further genera such as Cryptococcus, Trichosporon, Geotrichum and Saccharomyces. Minimum inhibitory concentration (MIC) values for fluconazole and itraconazole were assessed using a microdilution technique with the semisynthetic high resolution (HR) medium supplemented with glucose and asparagine but without sodium hydrogen carbonate (pH 7.0), according to a proposal of the working group 'Clinical Mycology' of the German Speaking Mycological Society. Fluconazole MIC values for C. albicans were between 0.125 and > or = 128 micrograms ml-1. Thus, the median of 1 microgram ml-1 showed that the overall fluconazole susceptibility was good. As expected, Candida krusei (seven strains) exhibited diminished in vitro susceptibility with MIC values for fluconazole of 8 to 128 micrograms ml-1 with a median of 64 micrograms ml-1. Some Candida kefyr strains seemed to be less susceptible against fluconazole which was indicated by a MIC90 of 64 micrograms ml-1. Surprisingly, no Candida glabrata isolate exhibited a MIC value greater than 16 micrograms ml-1. Other Candida species, Trichosporon cutaneum, Geotrichum candidum and Saccharomyces cerevisiae showed low MICs to fluconazole. In vitro susceptibility testing of itraconazole revealed that all Candida species except C. albicans, but also Trichosporon cutaneum, Geotrichum candidum, and Saccharomyces cerevisiae exhibited acceptable low MIC values against itraconazole (0.03-2 micrograms ml-1). Their MIC90 values for itraconazole were in the close range between 0.125 and 2 micrograms ml-1. MIC values between 0.125 and 2 micrograms ml-1 were obtained, even for C. krusei strains. On the other hand, the range of C. albicans MICs was between 0.0125 and > or = 16 micrograms ml-1 with MIC50 and MIC90 values of 0.125 and > or = 16 micrograms ml-1, respectively, indicating that a considerable number of yeast strains have high MICs. The comparative evaluation of different experimental conditions revealed that there exists a marked influence both of inoculum size and incubation time on the results of susceptibility testing. Therefore, for routine usage 10(2) CFU ml-1 and 18-24 h incubation time for this microdilution method with HR medium are recommended.