HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice.

HER-2/neu (neu-N) transgenic mice, which express the nontransforming rat proto-oncogene, develop spontaneous focal mammary adenocarcinomas beginning at 5-6 months of age. The development and histology of these tumors bears a striking resemblance to what is seen in patients with breast cancer. We have characterized the immunological responses to HER-2/neu (neu) in this animal model. neu-positive tumor lines, which were derived from spontaneous tumors that formed in neu-N animals, are highly immunogenic in parental, FVB/N mice. In contrast, a 100-fold lower tumor challenge is sufficient for growth in 100% of transgenic animals. Despite significant tolerance to the transgene, neu-specific immune responses similar to those observed in breast cancer patients can be demonstrated in neu-N mice prior to vaccination. Both cellular and humoral neu-specific responses in transgenic mice can be boosted with neu-specific vaccination, although to a significantly lesser degree than what is observed in FVB/N mice, indicating that the T cells involved are less responsive than in the nontoleragenic parental strain. Using irradiated whole-cell and recombinant vaccinia virus vaccinations we are able to protect neu-N mice from a neu-expressing tumor challenge. T-cell depletion experiments demonstrated that the observed protection is T cell dependent. The vaccine-dependent neu-specific immune response is also sufficient to delay the onset of spontaneous tumor formation in these mice. These data suggest that, despite tolerance to neu in this transgenic model, it is possible to immunize neu-specific T cells to achieve neu-specific tumor rejection in vivo. These transgenic mice provide a spontaneous tumor model for identifying vaccine approaches potent enough to overcome mechanisms of immune tolerance that are likely to exist in patients with cancer.

Reduced ratio of male to female births in several industrial countries: a sentinel health indicator?

CONTEXT: The sex ratio of 1.06:1, the ratio of male to female births, has declined over the past decades. Recent reports from a number of industrialized countries indicate that the proportion of males born has significantly decreased, while some male reproductive tract disorders have increased. OBJECTIVES: To examine the evidence for declines in the male proportion at birth and suspected causes for this decline, and to determine whether altered sex ratio can be considered a sentinel health event. DATA SOURCES: Birth records were analyzed from national statistical agencies. STUDY SELECTION: Published analyses of trends in ratio of males to females at birth and studies of sex determinants evaluating epidemiological and endocrinological factors. DATA EXTRACTION: Proportion of males born: 1950-1994 in Denmark; 1950-1994 in the Netherlands; 1970-1990 in Canada; and 1970-1990 in the United States. DATA SYNTHESIS: Since 1950, significant declines in the proportion of males born have been reported in Denmark and the Netherlands. Similar declines have been reported for Canada and the United States since 1970 and parallel declines also have occurred in Sweden, Germany, Norway, and Finland. In Denmark, the proportion of males declined from 0.515 in 1950 to 0.513 in 1994. In the Netherlands, the proportion of males declined from 0.516 in 1950 to 0.513 in 1994. Similar declines in the proportion of males born in Canada and the United States are equivalent to a shift from male to female births of 8600 and 38000 births, respectively. Known and hypothesized risk factors for reduced sex ratio at birth cannot fully account for recent trends. CONCLUSION: Patterns of reduced sex ratio need to be carefully assessed to determine whether they are occurring more generally, whether temporal or spatial variations are evident, and whether they constitute a sentinel health event.

Dissecting RNA-protein interactions: RNA-RNA recognition by Rop.

The ColE1 plasmid of E. coli encodes a small RNA-binding protein, Rop, which is involved in the regulation of plasmid copy number. Rop, a 4-helix bundle protein, facilitates sense-antisense RNA pairing by binding to the transiently formed hairpin pairs of RNA I and the complementary RNA II. We have identified the residues of Rop that are involved in RNA recognition. The residues form a narrow stripe down one face of the bundle and are symmetrically arranged, with recognition centered about two phenylalanine residues. Our results suggest that these phenylalanine residues interact with the loop region of the hairpin pair, with additional interactions between eight polar residues and the phosphate backbone. By modifying the identity of residue 14, we have created a variant of Rop that displays altered RNA binding specificity. The results of our studies allow us to present a detailed picture of RNA-protein recognition in a novel model system.