Pathologic and epidemiologic investigations carried out over the past several years have provided evidence that carcinogenesis in the uterine cervix is a multi-step process involving discreet preinvasive stages. Molecular epidemiologic data also indicate that human papillomavirus (HPV) infection is a critical factor in the tumor progression process. In vitro studies have shown that for the initiation and maintenance of the malignant phenotype, the expression of the HPV-transforming protein E6 is required. The E6 protein produced by the high-risk HPV types 16 and 18 can bind to and inactivate the tumor suppressor protein p53 leading to deregulated proliferation and defective apoptosis, thus facilitating tumor progression. Therefore, determination of the HPV genotype alone may not be sufficient in assessing tumor progression in the uterine cervix. In the present study, a total of 623 cervical tissue samples at various phases of tumor progression were assessed for HPV infection by nonisotopic in situ hybridization (NISH) and for HPV 16/18 E6 protein expression by immunocytochemistry. There was significant correlation between the extent of histological abnormality and HPV infection. Significant correlation (r = 0.707, p = 0.000) was observed between the presence of HPV 16 and high-grade squamous intraepithelial lesions (SILs) and invasive cancer. The odds ratio of a cervical tissue infected with HPV 16 falling into these two categories was 44.57 (95% CI: 27.10, 73.30). The E6 protein also was mostly detected in high-grade SILs and cervical cancer tissue expressing either HPV 16 or 18. It was less frequent in low-grade SILs infected with HPV 16/18 and was absent in benign cervical tissue infected with HPV 16. The odds ratio of an HPV-16/18-infected cervical tissue positive for E6 being a high-grade SIL or invasive cancer was 16.20 (95% CI: 6.06, 43.33). These results thus show the clinical utility of HPV characterization along with the analysis of the transforming protein E6 in the assessment of tumor progression in the uterine cervix.

These results therefore suggest that c-myc and N-ras oncoproteins are important during tumor progression in the uterine cervix.

Purpose: To study the role of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cervical tumorigenesis, we analyzed 70 cervical tissue specimens that included 15 low-grade squamous intraepithelial lesions (SILs), 20 high-grade SILs, 25 squamous cell carcinomas (SCCs) and 10 specimens of normal cervical tissue. Methods: The gelatinolytic activity of MMP-9 and MMP-2 was determined by zymographic analysis. The expression of MMP-9 and MMP-2 and TIMP-1 and TIMP-2 was determined by immunohistochemistry. Results: All the samples had 72/ 66 kDa gelatinase activity; 92 kDa gelatinase activity was detected only in high-grade SILs and SCCs. Immunohistochemical analysis showed weak positivity for MMP-2 in normal cervical epithelium and low-grade SILs. However, high-grade SILs and SCCs showed intense cellular and stromal reactivity for MMP-2 and MMP-9. For TIMP-1 and TIMP-2, normal cervical epithelium and low-grade SILs showed intense immunostaining, >50% of highgrade SILs showed positivity, and 95% of SCCs showed intense stromal and cellular reactivity. Conclusions: Increasein the relative activity of these gelatinases and enhanced immunostaining for MMPs and TIMPs with tumor progression suggest that they may play a crucial role in cervical cancer progression. A significant association between stage of the lesion and expression of MMPs and TIMPs (P<0.01) was found. Immunohistochemical studies indicate that these MMPs may be of basal cell origin in cervical tissue, although the mechanism of their upregulation is not clearly understood.

Pancreatic degenerative lesions of identical nature could be induced in bonnet monkeys (Macaca radiata) fed protein-deficient tapioca or cassava starch-based and cornstarch-based diets for 3 or 5 months. Marked to severe lobular and acinar cell atrophy in animals fed low-protein diets resembled human pancreatic atrophy resulting from protein deficiency. Animals fed low-protein, high-carbohydrate diets showed lesions akin to tropical chronic calculus pancreatopathy with diabetes mellitus. The pancreatic lesions comprised moderate to marked acinar cell atrophy, marked islet hyperplasia or nesidioblastosis with hypertrophy and mucoid metaplasia of the duct epithelium. Mucoid vasculopathy of the pancreatic artery and arterioles was observed in all animals given proteindeficient diets. It was enhanced in those given additional carbohydrate. Identical lesions were observed after using either

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