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Immortalization (senescence bypass) is a critical rate-limiting step in the malignant transformation of mammalian somatic cells. Human cells must breach at least two distinct senescence barriers to permit unfettered clonal evolution during cancer development: (1) stress- or oncogene-induced premature senescence (SIPS/OIS), mediated via the p16-Rb and/or ARF-p53-p21 tumour-suppressive pathways, and (2) replicative senescence triggered by telomere shortening. In contrast, because their telomerase is constitutively active, cells from small rodents possess only the SIPS/OIS barrier, and are therefore useful for studying SIPS/OIS bypass in isolation. Dermal fibroblasts from the Syrian hamster (SHD cells) are exceptionally resistant to spontaneous SIPS bypass, but it can be readily induced following exposure to a wide range of chemical and physical carcinogens. Here we show that a spectrum of carcinogen-specific mutational and epigenetic alterations involving the INK4A (p16), p53 and INK4B (p15) genes are associated with induced SIPS bypass. With ionizing radiation, immortalization is invariably accompanied by efficient biallelic deletion of the complete INK4/CDKN2 locus. In comparison, SHD cells immortalized by the powerful polycyclic hydrocarbon carcinogen benzo(a)pyrene display transversion point mutations in the DNA-binding domain of p53 coupled with INK4 alterations such as loss of expression of p15. Epimutational silencing of p16 is the primary event associated with immortalization by nickel, a human non-genotoxic carcinogen. As SIPS/OIS bypass is a prerequisite for the immortalization of normal diploid human epithelial cells, our results with the SHD model will provide a basis for delineating combinations of key molecular changes underpinning this important event in human carcinogenesis.

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This paper presents new results showing the application of polyomino-based subarrays to limited field of view and wideband, wide-angle scanning. This technology can reduce the number of phase controls in arrays used for limited sector coverage or the number of time delay devices for wideband radar or communications, and so can reduce the cost of space-based active arrays. We concentrate on the wideband application. Results are presented by comparing the gain and peak sidelobe results of irregular polyomino subarray-based arrays with those of rectangular subarrays. It is shown that using irregular polyomino subarrays can result in a major decrease in sidelobes while presenting, in most cases, only a few tenths of a dB gain reduction compared to rectangular subarrays.

Molecular cloning of the breakpoints of a t(1;10)(p22q21) constitutional translocation breakpoint in a patient with stage 4S neuroblastoma has identified two genes which are fused in-frame to generate a novel gene. The 1p22 gene, which we have called NB4S , encodes a 7.5 kb transcript with an 810 amino acid open reading frame and is expressed in a wide variety of tissues. NB4S has >88% homology with the mouse EVI -5 gene within the coding region and shows strong homology over a 200 amino acid region with TBC1 box motif genes involved in cell growth and differentiation. The C-teminal end of the protein contains a number of coiled coil domains, indicating a possible protein-protein binding function. The chromosome 10 breakpoint interrupts a novel transcript (TRNG10) which could only be detected in tumor cells. This transcript has no exon/intron structure or significant open reading frame, suggesting that it is a structural RNA which is transcribed but not translated. The chromosome rearrangement creates a fusion gene product which combines the TBC1 motif of NB4S with a polyadenylation signal from TRNG10 , potentially generating a truncated protein with oncogenic properties.

Some existing auroral data products are insufficient for ionospheric simulation input on subkilometer spatial scales and high (second) time resolution near the boundaries of arc structures. Ideally, two-dimensional data maps of the relevant parameters over these small scales would provide models with constraining inputs. Available in situ data have the time and spatial resolution for small-scale features but only provide a 1-D cut through the structure. Ground-based data can provide 2-D maps but have lower resolution in time and space than is required to accurately interpret the small-scale structure near an arc. This paper provides a method to construct two-dimensional maps of auroral parameters from the combination of one-dimensional in situ data cuts with two-dimensional ground-based (and time dependent) camera imagery. Arc boundaries for each image are defined, and the available 1-D ionospheric flow data are replicated into many 1-D cuts at different points along the arc, yielding an irregularly sampled 2-D flow map. These mapped data are fitted to a regular grid via a divergence minimization routine to generate a regularly sampled flow field that is enforced as divergence free. Comparison of the generated 2-D data maps to available information from camera inversions and other data products is shown, as are assumptions made through the replication process and alternative strategies. Reconstructed flow maps are shown to maintain the small-scale features near arc boundaries while increasing the dimensionality to 2-D and to follow the time evolution of the arc structure by comparisons to imagery. The average electric field magnitudes per unit area of the reconstructed and divergence-minimized flow fields are also calculated and compared between different data sources.

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