Morbillivirus downregulation of CD46

There is evidence that CD46 (membrane cofactor protein) is a cellular receptor for vaccine and laboratory-passaged strains of measles virus (MV). Following infection with these MV strains, CD46 is downregulated from the cell surface, and consequent complement-mediated lysis has been shown to occur upon infection of a human monocytic cell line. The MV hemagglutinin (H) protein alone is capable of inducing this downregulation. Some wild-type strains of MV fail to downregulate CD46, despite infection being prevented by anti-CD46 antibodies. In this study we show that CD46 is also downregulated to the same extent by wild-type, vaccine, and laboratory-passaged strains of rinderpest virus (RPV), although CD46 did not appear to be the receptor for RPV. Expression of the RPV H protein by a nonreplicating adenovirus vector was also found to cause this downregulation. A vaccine strain of peste des petits ruminants virus caused slight downregulation of CD46 in infected Vero cells, while wild-type and vaccine strains of canine distemper virus and a wild-type strain of dolphin morbillivirus failed to downregulate CD46. Downregulation of CD46 can, therefore, be a function independent of the use of this protein as a virus receptor.     

Microsatellite instability in gynecological sarcomas and in hMSH2 mutant uterine sarcoma cell lines defective in mismatch repair activity

We have examined a panel of gynecological sarcomas for microsatellite instability. The genomic DNA from 11 of 44 sarcomas contained somatic alterations in the lengths of one or more di-, tri-, tetra-, or pentanucleotide microsatellite sequence markers, and 6 of these cases had alterations in two or more markers. In addition, di-, tri-, and tetranucleotide microsatellites were found to be highly unstable in single cell clones of two cell lines derived from a uterine mixed mesodermal tumor. Since such instability is characteristic of cells defective in postreplication mismatch repair, we examined mismatch repair activity in extracts made from these lines. Both extracts were repair deficient, while an extract of another gynecological sarcoma cell line not exhibiting microsatellite instability was repair proficient. The repair deficiency was complemented by a colon tumor cell extract that was defective in the hMLH1 protein but not by an extract defective in hMSH2 protein. This suggested that the defect in the uterine sarcoma line could be in hMSH2. Subsequent analysis of the gene revealed a 2-bp deletion in exon 14, leading to premature truncation of the hMSH2 protein at codon 796 and no detectable wild-type gene present. These data suggest that the microsatellite instability observed in these cell lines, and possibly in a significant number of gynecological sarcomas, is due to defective postreplication mismatch repair. There was no apparent correlation with microsatellite instability and clinical outcome.     

Frequency tracking using hidden Markov models with amplitude andphase information

It is demonstrated how the hidden Markov model (HMM) frequency tracker can be extended by the addition of amplitude and phase information. The HMM tracker as originally formulated uses a gate of spectral bins from fast Fourier transform (FFT) processing, and associates each cell with a state of the hidden Markov chain. A measurement sequence based on the output of a simple threshold detector forms the input to the HMM tracker. Two extensions to the original tracker are proposed. The first, the HMM/A tracker, incorporates the FFT amplitudes in the cells of the measurement sequence. The second, the HMM/AP tracker, does not use a measurement sequence, but uses instead the FFT amplitude and phase values in all cells within the gate. A comparison of the results obtained in using the three HMM-based trackers with simulated data reveals that the extended trackers outperform the original. An analysis of the effect of parameter mismatch for the three trackers is presented. Their use as detectors is also discussed     

New trends in the development of cancer vaccines

Recent advances in understanding of the molecular mechanisms of antigen processing and presentation, and the identification of tumor-associated antigens in melanoma and other cancers, have stimulated the development of a new generation cancer vaccines. This review summarizes the most recent approaches for the design of safe and more effective vaccines for cancer. Peptide-based vaccines are safe and can be synthesized with high purity and reproducibility. Recombinant viruses encoding tumor-associated antigens allow efficient delivery and precise control over the form and the quantity of the delivered antigens. DNA-based vaccines induce long-lasting immune responses and are considered very safe. Antigen-loaded dendritic cells, and the use of newly developed adjuvants are also very promising new approaches. In this review, we also discuss the possible clinical applications and future directions for vaccine development.     

High-power potassium-titanyl-phosphate (KTP/532) laser vaporization prostatectomy: 24 hours later

All persons 65 years and older are recommended to be immunised against influenza each autumn. As immunisation rates remain low, we conducted a randomised control trial in a three-partner urban general practice to evaluate the differential effectiveness of a single postcard reminder in a general practice setting compared to usual care. All non-residential patients aged 65 years and over were identified from the age/sex/disease register. After exclusions, 325 patients were stratified by sex (125 men and 200 women) and randomised to receive either a postcard reminder in large print mailed in April or usual care. General practitioners (GPs) were blind to the randomisation. A blinded record audit performed in July demonstrated that the postcard was effective in increasing immunisation for men (chi(2)1df = 3.85; p = 0.05) but not for women (chi(2)1df = 0.45; p = 0.50). After adjusting for 1995 immunisation status, the effect of the postcard on immunisation rates was even stronger in men (Wald chi(2)1df = 6.20; p = 0.01) but remained non-significant in women (Wald chi(2)1df = 1.38; p = 0.24). With this adjustment, the odds of having the 1996 flu vaccine for men sent the postcard reminder were three times that of men in the control group (OR = 3.0; 95% CI 1.3-6.9). In a general practice setting, a single postcard reminder appears to be a promising way to boost influenza immunisation rates among ageing men. Replication of the study is recommended.     

An Abstract Decision Procedure for Satisfiability in the Theory of Recursive Data Types

The theory of recursive data types is a valuable modeling tool for software verification. In the past, decision procedures have been proposed for both the full theory and its universal fragment. However, previous work has been limited in various ways. In this paper, we present a general algorithm for the universal fragment. The algorithm is presented declaratively as a set of abstract rules which are terminating, sound, and complete. We show how other algorithms can be realized as strategies within our general framework. Finally, we propose a new strategy and give experimental results showing that it performs well in practice.     

Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair

Many human tumours have length alterations in repetitive sequence elements. Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, many sporadic tumours exhibit instability but no detectable mutations in these genes. It is therefore of interest to identify other genes that contribute to this instability. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability. Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12-14). Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites. Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides. A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene. Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair.