Stochastic modelling of tumorigenesis in p53 deficient mice.

Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the 'multigate' model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten. The multigate model predicts a relationship between the time pattern of tumour occurrence and tumour genotype that should be experimentally testable. Stochastic modelling may help to distinguish 'gatekeeper' and 'caretaker' genes in other tumorigenic pathays

Immunocytochemical demonstration of p21 ras family oncogene product in normal mucosa and in premalignant and malignant tumours of the colorectum.

Study of the distribution of the p21 ras oncogene product as demonstrated by monoclonal antibody Y13-259 shows this protein to be apparently present in all epithelial populations of both premalignant and malignant tumours and throughout the normal foetal and adult epithelial crypt population in the colorectum. Metastatic tumour in liver shows a similar staining pattern which is less intense however than in the surrounding normal hepatocytes. Our results suggest that the presence of this protein is a widespread feature of normal cellular metabolism in certain cell types and is not restricted to those actively involved in cellular proliferation. It appears, furthermore, that neither cells at different stages of carcinogenesis nor those representing variants of a malignant phenotype can be identified using this particular antibody

Siddiqui, Negative refraction and focusing in hyperbolic transmission-line periodic grids

between an interface and the channel axes (cf. Ref. 3). This feature is counterintuitive to the conventional optical laws but it is totally consistent with the analysis based on the isofrequencies' for the channeled waves on anisotropic lattices discussed earlier. In the conventional isotropic periodic structures, a unit cell is representative of the respective finite arrangement when the edge cells are terminated into the matched loads. However, the feature of L-C mesh to funnel power from a point source into the narrow beam leads to the question whether load impedances of the edge cells nonadjacent to the beam axis affect the channel formation and properties of the propagating waves. To explore this effect, the load impedances outside the vicinities of the source and the channel output cells were varied. A comprehensive analysis of finite BM simulated in ADS has shown that only the first three edge nodes at the channel axis contribute to the beam formation. These observations led us to the conclusion that the channels arising on the anisotropic L-C mesh are well confined and guide waves along their axes as predicted by isofrequencies. To further elucidate the mechanism of wave channeling, the lattice portions were progressively removed to retain the mesh only around the channel axis. These alterations of the mesh arrangement incurred no visible changes of the beam shape and intensity on the truncated grids. Thus, the simulation results have proved that the propagation channel formed on the L-C mesh is truly confined to a few cells at the channel axis. This property of the L-C mesh suggests that a number of independent channels with their own impedances and axis orientations could be formed on the grid. Since the channel directions vary with frequency and the unit cell parameters, the L-C mesh can act as a spatial frequency discriminator CONCLUSIONS It has been shown that 2D periodic meshes composed of L-C circuits collimate waves from a point source into beams. The beam directions are prescribed by the lattice symmetry and the admittance ratio (Y 2 /Y 1 ) Ͻ 0. The basic properties of the channeled waves, determined by the isofrequencies, are invariant to the physical arrangements of the unit cells as long as the ratio (Y 2 /Y 1 ) remains constant. Effect of the unit cell structure on the channeled wave propagation has been explored for the unit cell configurations composed of double series (SSM), double parallel (PPM), and mixed parallel-series (PSM) L-C circuits. Analysis of these meshes has shown that the type (forward or backward) of channeled wave can be altered in the designed frequency band by varying only capacitance in the mesh arms. These findings are of particular significance for implementation of tunable meshes used in beam steering and phase compensation applications. Analysis of the channeled wave scattering at interfaces of dual L-C meshes showed that, in general, the "refracted" beams propagate only along the channel axes whose directions depend on the lattice parameters but not the angle of incidence onto interface. HIGH DIRECTIVITY IN LOW-PERMITTIVITY METAMATERIAL SLABS: RAY-OPTIC VS. LEAKY-WAVE MODEL

Current tidal power technologies and their suitability for small-scale applications in shallow near-shore areas

A considerable body of research is currently being performed to quantify available tidal energy resources and to develop efficient devices with which to harness them. This work is naturally focussed on maximising power generation from the most promising sites, and a review of the literature suggests that the potential for smaller scale, local tidal power generation from shallow near-shore sites has not yet been investigated. If such generation is feasible, it could have the potential to provide sustainable electricity for nearby coastal homes and communities as part of a distributed generation strategy, and would benefit from easier installation and maintenance, lower cabling and infrastructure requirements and reduced capital costs when compared with larger scale projects. This article reviews tidal barrages and lagoons, tidal turbines, oscillating hydrofoils and tidal kites to assess their suitability for small-scale electricity generation in shallow waters. This is achieved by discussing the power density, scalability, durability, maintainability, economic potential and environmental impacts of each concept. The performance of each technology in each criterion is scored against axial-flow turbines, allowing for them to be ranked according to their overall suitability. The review suggests that tidal kites and range devices are not suitable for small-scale shallow water applications due to depth and size requirements respectively. Cross-flow turbines appear to be the most suitable technology, as they have high power densities and a maximum size that is not constrained by water depth

Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility

11 páginas, 5 figuras, 1 tabla.-- et al.[Background]: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. [Results]: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4). [Conclusions]: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.This work was supported by the National Cancer Institute. AB acknowledges support from the Barbara Bass Bakar Chair of Cancer Genetics. MDT was supported in part by a Sandler Foundation postdoctoral research fellowship. JS was supported by the Swedish Research Council and the Tegger Foundation. KKL was supported by an NIH Kirschstein-NRSA postdoctoral research fellowship. JPL is partially supported by Carlos III (FIS)/FEDER, MICIIN/plan-E 2009, JCyL (’Biomedicina y Educación’) and CSIC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

A statistical model for the identification of genes governing the incidence of cancer with age

The cancer incidence increases with age. This epidemiological pattern of cancer incidence can be attributed to molecular and cellular processes of individual subjects. Also, the incidence of cancer with ages can be controlled by genes. Here we present a dynamic statistical model for explaining the epidemiological pattern of cancer incidence based on individual genes that regulate cancer formation and progression. We incorporate the mathematical equations of age-specific cancer incidence into a framework for functional mapping aimed at identifying quantitative trait loci (QTLs) for dynamic changes of a complex trait. The mathematical parameters that specify differences in the curve of cancer incidence among QTL genotypes are estimated within the context of maximum likelihood. The model provides testable quantitative hypotheses about the initiation and duration of genetic expression for QTLs involved in cancer progression. Computer simulation was used to examine the statistical behavior of the model. The model can be used as a tool for explaining the epidemiological pattern of cancer incidence

Allele-Specific Deletions in Mouse Tumors Identify Fbxw7 as Germline Modifier of Tumor Susceptibility

Genome-wide association studies (GWAS) have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs) and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5–10%). There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001), but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility

STK295900, a Dual Inhibitor of Topoisomerase 1 and 2, Induces G<inf>2</inf> Arrest in the Absence of DNA Damage

STK295900, a small synthetic molecule belonging to a class of symmetric bibenzimidazoles, exhibits antiproliferative activity against various human cancer cell lines from different origins. Examining the effect of STK295900 in HeLa cells indicates that it induces G2 phase arrest without invoking DNA damage. Further analysis shows that STK295900 inhibits DNA relaxation that is mediated by topoisomerase 1 (Top 1) and topoisomerase 2 (Top 2) in vitro. In addition, STK295900 also exhibits protective effect against DNA damage induced by camptothecin. However, STK295900 does not affect etoposide-induced DNA damage. Moreover, STK295900 preferentially exerts cytotoxic effect on cancer cell lines while camptothecin, etoposide, and Hoechst 33342 affected both cancer and normal cells. Therefore, STK295900 has a potential to be developed as an anticancer chemotherapeutic agent. © 2013 Kim et al