Mesothelioma, a malignancy associated with asbestos, has been recently linked to simian virus 40 (SV40). We found that infection of human mesothelial cells by SV40 is very different from the semipermissive infection thought to be characteristic of human cells. Mesothelial cells are uniformly infected but not lysed by SV40, a mechanism related to p53, and undergo cell transformation at an extremely high rate. Exposure of mesothelial cells to asbestos complemented SV40 mutants in transformation. Our data provide a mechanistic explanation for the ability of SV40 to transform mesothelial cells preferentially and indicate that asbestos and SV40 may be cocarcinogens. M alignant mesothelioma (MM) is a tumor of the serosal lining the pleural, pericardial, and peritoneal cavities that causes about 2,500 deaths per year in the United States (1). MM arises from the malignant transformation of mesothelial cells, which are undifferentiated cells representing the adult remnants of the surface coelomic mesoderm (1). Although MM has been associated with past exposure to asbestos fibers, the mechanisms through which asbestos causes mesothelial cell transformation are unclear. The capacity of asbestos to induce autophosphorylation of the epidermal growth factor receptor, which leads to activation protein-1 activity in human mesothelial cells (HM; ref.2); the production of reactive oxygen species by cells exposed to asbestos (3); and the local and systemic immunosuppressive effects of asbestos (4) may all contribute to carcinogenesis (1). Other factors act alone or synergistically with asbestos in causing MM, because only 5-10% of individuals exposed to high levels of asbestos develop MM, and 10-20% of MM occurs in individuals with no known exposure (1).Recently, simian virus 40 (SV40) has been associated with human mesothelioma and brain and bone tumors (reviewed in refs. 1 and 5-7). SV40 (5-8) is a DNA tumor virus encoding two transforming proteins (the large tumor antigen, or Tag; and the small tumor antigen, or tag), and three capsid proteins (VP1-3). Tag is the replicase of SV40. Expression of Tag in the absence of cell lysis leads to cellular transformation through several mechanisms, including Tag-mediated inhibition of cellular p53 and Rb family proteins, induction of insulin-like growth factor-I and its receptor, and the direct mutagenic effect of Tag. SV40 tag enhances Tag functions by inhibiting protein phosphatase 2A, contributing to malignancy (1, 9). SV40 infects cells from different species, and the cell type determines the outcome of SV40 infection (5-8). Permissive monkey cells support SV40 replication, which results in cell lysis. In nonpermissive rodent cells SV40 DNA cannot be replicated, and cells are not lysed and can be transformed. Human cells are termed semipermissive because only a fraction of cells express SV40 Tag after infection, these infected cells are lysed, and cell transformation is a very rare event.SV40 is highly oncogenic in rodents (5-7). We found that intracardial injection of SV40 induced MM...

Juxtaglomerular cell tumor is a rare renal neoplasm arising from the juxtaglomerular apparatus. Approximately 70 cases have been reported in the English literature since it was first described by Robertson et al in 1967. This tumor has been considered benign and resection has so far been curative. In this paper, we report the first metastatic juxtaglomerular cell tumor. The 15-cm tumor occurred in the right kidney of a 46-year-old man. It invaded the renal vein, and was treated by radical nephrectomy in 1995. The diagnosis at that time was renal cell carcinoma. The patient was well for 6 years and then developed bilateral lung masses, which were resected. Microscopically, the tumors from the kidney and the lungs were similar, consisting of solid sheets of uniformly round-to-polygonal cells intermixed with abundant delicate vasculature. Both renal and pulmonary tumors were positive for vimentin, renin, and only focally to CD34. Electron microscopic studies performed on the paraffin-embedded renal tumor and formalin-fixed lung tumor revealed the typical rhomboid crystals of proto-renin. In consideration of the characteristic morphologic features, immunohistochemistry, and the presence of rhomboid crystals of proto-renin, the diagnosis was modified to malignant juxtaglomerular cell tumor.

Scar and fibrosis are often the end result of mechanical injury and inflammatory diseases. One chemokine that is repeatedly linked to fibrotic responses is monocyte chemoattractant protein-1 (MCP-1). We utilized a murine fibrosis model that produces dermal lesions similar to scleroderma to evaluate collagen fibrillogenesis in the absence of MCP-1. Dermal fibrosis was induced by subcutaneous injection of bleomycin into the dorsal skin of MCP-1-/- and wild-type C57BL/6 mice. After 4 weeks of daily injections, bleomycin treatment led to thickened collagen bundles with robust inflammation in the lesional dermis of wild-type mice. In contrast, the lesional skin of MCP-1-/- mice exhibited a dermal architecture similar to phosphate-buffered saline (PBS)-injected control and normal skin, with few inflammatory cells. Ultrastructural analysis of the lesional dermis from bleomycin-injected wild-type mice revealed markedly abnormal arrangement of collagen fibrils, with normal large diameter collagen fibrils replaced by small collagen fibrils of 41.5 nm. In comparison, the dermis of bleomycin-injected MCP-1-/- mice displayed a uniform pattern of fibril diameters that was similar to normal skin (average diameter 76.7 nm). The findings implicate MCP-1 as a key determinant in the development of skin fibrosis induced by bleomycin, and suggest that MCP-1 may influence collagen fiber formation in vivo.

In the present investigations the molecular unfolding of yeast tRNA(Gly) has been studied by a combination of nuclear magnetic resonance spectroscopy, melting techniques, and relaxation kinetics. From these studies the following pathway of unfolding was found. In a coupled melting transition the tertiary, the DHU, and the anticodon structure are disrupted. This is followed by the melting of the acceptor arm, while the T psi C arm, which only contains G-C pairs, melts out last. Interestingly, during the first melting transition a new structure not belonging to the original cloverleaf structure is formed. The thermodynamic and kinetic parameters of the melting transitions were determined and are discussed in relation to earlier work. The present nuclear magnetic resonance (NMR) experiments as well as earlier studies show that the ring current calculations based on the cloverleaf structure provide a good first-order interpretation of the NMR spectra of tRNA.

Determination of the plasma concentrations of beta-thromboglobulin (BTG), thromboxane B2 (TxB2) and platelet factor 4 (PF4) were made at the time of birth in 18 newborns and their respective mothers. Both groups show significant elevation of all these molecular markers, suggesting marked platelet activation. The elevated TxB2 levels in the newborn group, 25 +/- 8 pg/ml, are compatible with a normally functioning and activated platelet prostaglandin pathway. Mode of delivery, vaginal or caesarean section, does not significantly influence the degree of activation in either group. Ultrastructural platelet examination did not reveal any morphologic differences between maternal and newborn platelets. There appears to be marked activation of the newborn and maternal platelet systems at the time of birth, and we postulate that this may explain in part the transient platelet dysfunction observed in newborns.

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Mixed epithelial and stromal tumor of the kidney is a rare biphasic tumor composed of cysts and tubules embedded in the spindle cell stroma. Although the histogenesis of this tumor is unknown, it has been proposed that both components of the tumor, i.e., stromal and epithelial, are neoplastic. The authors report preliminary immunohistochemical and electron microscopic studies of the epithelial component from one case of a typical, benign, mixed epithelial, and stromal tumor of the kidney. In this study, some tubules showed positivity for proximal, while others showed positivity for distal, nephron immunomarkers. By electron microscopy, some tubules had features of proximal tubular epithelium, while other tubules had features of the loop of Henle (thin segments). The authors believe that in a benign tumor such morphologic heterogeneity is inconsistent with neoplastic proliferation. Therefore, they postulate that in mixed epithelial and stromal tumor of the kidney the tubules are entrapped rather than neoplastic. Additional studies are needed to address this issue and electron microscopy should play a significant role in this process.