Studies on the involvement of the human papillomavirus (HPV) in initiation and progression of oral neoplasia have generated conflicting results. The observed discrepancy is attributable mainly to the varying sensitivity of the applied methodologies and to epidemiologic factors of the examined patient groups. To evaluate the role of HPV in oral carcinogenesis, we analyzed 53 potentially neoplastic and neoplastic oral lesions consisting of 29 cases of hyperplasia, 5 cases of dysplasia, and 19 cases of squamous cell carcinomas, as well as 16 oral specimens derived from healthy individuals. A highly sensitive nested polymerase chain reaction (PCR) assay was used, along with type-specific PCR, restriction fragment length polymorphism analysis, dot blotting, and nonisotopic in situ hybridization. Nested PCR revealed the presence of HPV DNA in 48 of the 53 (91%) pathologic samples analyzed, whereas none (0%) of the normal specimens was found to be infected. Positivity for HPV was independent of histology and the smoking habits of the analyzed group of patients. At least one "high risk" type, such as HPV 16, 18, and 33, was detected by type-specific PCR in 47 (98%) infected specimens, whereas only 1 (2%) squamous cell carcinoma was solely infected by a "low risk" type (HPV 6). HPV 16 was the prevailing viral type, being present in 71% of infected cases. Single HPV 16 and HPV 18 infections were confirmed by restriction fragment length polymorphism. HPV 58 was detected by dot blotting in three hyperplastic lesions. HPV positivity and genotyping were further confirmed, and the physical status of this virus was evaluated by nonisotopic in situ hybridization. Diffuse and punctate signals, indicative of the episomal and integrative pattern of HPV infection, were observed for low-and high-risk types, respectively. Our findings are suggestive of an early involvement of high-risk HPV types in oral carcinogenesis.

Background: Down-regulation or overexpression of the cyclin-dependent kinase inhibitor p27 have been observed in a range of malignancies, including lung cancer. To further elucidate the role of the molecule in tumor growth regulation, we evaluated p27 expression in a series of non-small cell lung carcinomas (NSCLCs), and examined its relation with histology, kinetic parameters, ploidy, and overall survival. We extended our investigation into the association of p27 levels with the presence of Ki-ras mutations, as well as with the expression status of p53 and pRb in tumor cells. Material and Methods: p27, p53, and pRb status were immunohistochemically evaluated in a total of 69 NSCLCs. In situ assays were employed to assess the kinetic parameters (Ki-67 immunohistochemistry for proliferation index, Tdt-mediated dUTP nick end labeling assay for apoptotic index). The ploidy status of the tumors was assessed after staining nuclei with the Feulgen procedure, and the presence of Ki-ras mutations was examined by restriction fragment length polymorphisms. All possible associations were assessed with a series of statistical methods. Results: Immunoreactivity for p27 was observed in the entire series of specimens, with the mean percentage of positive cells being 33%.

Insulin is the principal anabolic hormone in mammals, and its level in the circulation is regulated by a diverse range of molecules which reflect the metabolic status of the animal. These include nutrients (such as sugars, amino acids, and fatty acids), hormones, and neurotransmitters, all of which can impinge upon the pancreatic Bcell to elicit changes in the insulin secretion rate.' To respond to this array of signals, the B-cell is equipped with numerous receptor and signal transduction mechanisms that allow the various inputs to be sensed and integrated.The primary determinant of the rate of insulin secretion is the prevailing glucose concentration, and it is well established that oxidative metabolism of the sugar is used to generate the signals that initiate ~ecretion.'.~ In contrast, hormones and neurotransmitters utilize more classical receptor-mediated signaling mechanisms to elicit their effects in the pancreatic B-cell. Thus, there must be certain critical components of the stimulus-secretion coupling pathway that can be controlled by both metabolic and receptor-mediated events.Very few of these common components have been identified; however, potassium permeability of the B-cell plasma membrane is one of the most important events controlled by metabolic Under basal conditions potassium permeability is high and efflux of potassium ions maintains the cell in a hyperpolarized state. An increase in glucose metabolism results in a reduction in potassium efflux and leads to depolarization of the plasma membrane, gating of voltage-sensitive calcium channels, and a subsequent increase in insulin secretion. The central regulator of these events is a class of potassium channels whose open state varies according to the ratio of ATP to ADP in the cell and which close in response to a net increase in this ratio (i.e., in response to increased metabolic flux). Therefore, these channels (KATP channels) perform a critical role in coupling metabolic changes to electrical activity in the B-celLM KATp channels also serve as targets for pharmacological agents in that they mediate the insulin secretory effects of hypoglycemic s~lfonylureas.~*~ In addition, there is

Aim: To study simultaneously the actions of maspin and CXCR4, which share several similar pathways in cancer, including apoptosis and angiogenesis. Methods: Our material consisted of 151 invasive breast carcinomas arranged in a tissue microarray setting. Maspin and CXCR4 expression was evaluated by immunohistochemistry. Microvessel density was assessed by CD34 immunodetection and apoptosis by the Tdt-mediated dUTP nick end labelling assay. Results: Maspin expression was related to CXCR4 expression, apoptosis, patient age and the Nottingham prognostic index. The expression of both maspin and CXCR4 progressively increased in high-grade tumours. In patients with lymph node negative breast cancer, maspin overexpression was associated with increased risk of death. High CXCR4 expression was associated with prolonged survival of patients with high maspin expression. Conclusions: Our results show that maspin overexpression could prove to be a potentially useful marker, especially for the clinically important group of patients with lymph node negative breast cancer. The expression of CXCR4 is of less significance in our study, but may be informative for specific patient subsets or in a longer time frame.

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