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The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally associated with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.

Carcinoma of the cervix is one of the most common malignancies. Papanicolaou (Pap) smear tests have reduced mortality by up to 70%. Nevertheless their interpretation is notoriously difficult with high false-negative rates and frequently fatal consequences. We have addressed this problem by using affinity-purified antibodies against human proteins that regulate DNA replication, namely Cdc6 and Mcm5. These antibodies were applied to sections and smears of normal and diseased uterine cervix by using immunoperoxidase or immunof luorescence to detect abnormal precursor malignant cells. Antibodies against Cdc6 and Mcm5 stain abnormal cells in cervical smears and sections with remarkably high specificity and sensitivity. Proliferation markers Ki-67 and proliferating cell nuclear antigen are much less effective. The majority of abnormal precursor malignant cells are stained in both low-grade and high-grade squamous intraepithelial lesions. Immunostaining of cervical smears can be combined with the conventional Pap stain so that all the morphological information from the conventional method is conserved. Thus antibodies against proteins that regulate DNA replication can reduce the high false-negative rate of the Pap smear test and may facilitate mass automated screening.

H epatocellular carcinoma (HCC), the fifth most common cancer worldwide with 564,000 new cases each year, is also the third most common cause of cancer-related death. 1 HCC arises most frequently in males with cirrhosis, which is most often a consequence of chronic hepatitis infection or alcohol abuse. 2 Recent reports from different countries suggest that the incidence of HCC is increasing, probably as a consequence of the increased prevalence of hepatitis C virus (HCV) infection, although increased alcohol consumption may be significant. 3 The only effective approaches for patients with HCC are resection or liver transplantation. Following transplantation, there is an 83% 4-year recurrence-free survival in highly selected patients (single tumor Ͻ5 cm in diameter or fewer than three tumors Ͻ3 cm in diameter). 4 However, the majority of patients do not meet such strict criteria or have other contraindications. Local therapies such as percutaneous ethanol injection, thermal ablation, and intra-arterial chemoembolization are less successful, 5 and less than 10% of patients with moderate disease (Okuda stage 2) survive for 3 years. 6 Immunological mechanisms are important in the surveillance of malignancy and control of tumor progression. Cytotoxic CD8 ϩ lymphocytes (CTLs) and natural killer cells are potential effector cells in the control of tumor growth, although both require CD4 ϩ T helper 1 immune responses for optimal function. 7 Tumor-infiltrating lym-

Political and academic interest in cross‐national migration has generated two very different and potentially polarized positions. One perspective emphasizes the continuing power of the nation state, while the other sees migration, and more specifically migrants' rights, as the manifestation of an emergent ‘post‐national’ society. This article offers a conceptual framework which addresses this polarization through the concept of civic stratification (Lockwood, 1996). In illustrating its application, the study shows how such an approach goes beyond a traditional citizenship framework (e.g., Marshall, 1950) in considering degrees of partial membership, but remains cautious with respect to claims about universal, transnational rights.

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Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.