Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261- 269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.      

Normal and disrupted lumbar longitudinal ligaments: correlative MR and anatomic study

The posterior and anterior longitudinal ligaments of the lumbar spine appear on magnetic resonance (MR) images as thin lines of very low signal intensity in all spin-echo sequences. They cover the periphery of the outer fibers of the anulus fibrosus on sagittal images. The lumbar spine of 17 patients with 19 disk herniations was prospectively evaluated with MR imaging, and these findings were correlated with surgical findings. At surgery the posterior ligament was found to be disrupted in eight cases and intact in 11. Absence of a low-signal peripheral line around the herniated nucleus pulposus (HNP) was the most reliable sign of ligament rupture (no false-negative or false-positive findings). The peripheral line appeared to be interrupted in four cases, two of which were falsely positive. The two false-positive cases were related to a chemical shift artifact between epidural fat and the HNP. Presence of a normal and continuous peripheral line outlining the HNP excluded ligament disruption. The overall sensitivity for detecting disruption was 100%, and the specificity was 78%.     

Relationship between peptide binding and T cell epitope selection: a study with subtypes of HLA-B27

The effect of HLA-B27 polymorphism on antigen presentation was analysed by comparing the binding of three Epstein-Barr virus-derived peptide epitopes to HLA-B27 subtypes with their immunogenicity and antigenicity in the context of these subtypes. The effect of altering the major anchor residue Arg2 on binding or on recognition by peptide-specific cytotoxic T lymphocytes (CTL) was also examined. The three peptides bound significantly to all the B*2701-B*2706 subtypes. This did not correlate with the peptides being immunogenic or recognized by specific CTL in the context of only particular subtypes. In addition, of the three viral epitopes tested, those that were immunogenic in B*2702- or B*2705-restricted responses bound to these subtypes less efficiently than one peptide that was immunogenic only in the B*2704 context. Thus, among several potentially immunogenic peptides from the same virus, the antiviral response is not necessarily directed against the one that binds best to the restricting subtype. These results indicate that HLA- B27 polymorphism influences antigen presentation in ways other than simply peptide affinity. Synthetic analogues lacking the canonical Arg2 motif of HLA-B27-bound peptides, even when binding much worse to the restricting subtype, were recognized equally by CTL specific for the parental peptide. This indicates that Arg2 is not required to maintain the structure of the epitope. The implications of these results for pathogenetic models of HLA-B27-associated disease are discussed.      

Positive margins in basal cell carcinoma: relationship to clinical features and recurrence risk. A retrospective study of 248 patients

BACKGROUND: Incomplete resection of a basal cell carcinoma does not necessarily imply tumour recurrence. OBJECTIVE: The purpose of our study was to determine the clinical features most often associated with positive surgical margins and to establish whether positive margins effectively imply tumour recurrence. METHODS: We did a retrospective evaluation of 273 basal cell carcinomas in a total of 248 subjects. For each case, data regarding tumour location, sex, histological type and the presence or absence of affected surgical margins were collected. Follow-up was available in 151 cases. RESULTS: Positive margins were most often observed in facial lesions, particularly in the nasal and perioral areas, and for morphoeic histological types. Tumours with margin involvement exhibited a higher recurrence rate (26%) than those with free margins (14%) over a 5-year follow-up period. CONCLUSIONS: Individualized management, with special considerations depending on tumour location and histological type, is needed to treat basal cell carcinomas and cases with affected margins. Re-excision, preferably with Mohs' surgery, is advised in the latter as recurrences are much more complicated to treat. Furthermore, all cases need adequate follow-up, even in cases with unaffected surgical margins.