BRCA1 and BRCA2 mutations in a population-based study of male breast cancer

Background: The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear. Methods: We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk. Results: Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives. Conclusion: These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found

Widest Paths and Global Propagation in Bounded Value Iteration for Stochastic Games

Solving stochastic games with the reachability objective is a fundamental problem, especially in quantitative verification and synthesis. For this purpose, bounded value iteration (BVI) attracts attention as an efficient iterative method. However, BVI's performance is often impeded by costly end component (EC) computation that is needed to ensure convergence. Our contribution is a novel BVI algorithm that conducts, in addition to local propagation by the Bellman update that is typical of BVI, global propagation of upper bounds that is not hindered by ECs. To conduct global propagation in a computationally tractable manner, we construct a weighted graph and solve the widest path problem in it. Our experiments show the algorithm's performance advantage over the previous BVI algorithms that rely on EC computation.Comment: v2: an URL to the implementation is adde

A Modeling Study on How Cell Division Affects Properties of Epithelial Tissues Under Isotropic Growth

Cell proliferation affects both cellular geometry and topology in a growing tissue, and hence rules for cell division are key to understanding multicellular development. Epithelial cell layers have for long times been used to investigate how cell proliferation leads to tissue-scale properties, including organism-independent distributions of cell areas and number of neighbors. We use a cell-based two-dimensional tissue growth model including mechanics to investigate how different cell division rules result in different statistical properties of the cells at the tissue level. We focus on isotropic growth and division rules suggested for plant cells, and compare the models with data from the Arabidopsis shoot. We find that several division rules can lead to the correct distribution of number of neighbors, as seen in recent studies. In addition we find that when also geometrical properties are taken into account other constraints on the cell division rules result. We find that division rules acting in favor of equally sized and symmetrically shaped daughter cells can best describe the statistical tissue properties

Value Iteration for Simple Stochastic Games: Stopping Criterion and Learning Algorithm

Simple stochastic games can be solved by value iteration (VI), which yields a sequence of under-approximations of the value of the game. This sequence is guaranteed to converge to the value only in the limit. Since no stopping criterion is known, this technique does not provide any guarantees on its results. We provide the first stopping criterion for VI on simple stochastic games. It is achieved by additionally computing a convergent sequence of over-approximations of the value, relying on an analysis of the game graph. Consequently, VI becomes an anytime algorithm returning the approximation of the value and the current error bound. As another consequence, we can provide a simulation-based asynchronous VI algorithm, which yields the same guarantees, but without necessarily exploring the whole game graph.Comment: CAV201

LNCS

We study turn-based stochastic zero-sum games with lexicographic preferences over reachability and safety objectives. Stochastic games are standard models in control, verification, and synthesis of stochastic reactive systems that exhibit both randomness as well as angelic and demonic non-determinism. Lexicographic order allows to consider multiple objectives with a strict preference order over the satisfaction of the objectives. To the best of our knowledge, stochastic games with lexicographic objectives have not been studied before. We establish determinacy of such games and present strategy and computational complexity results. For strategy complexity, we show that lexicographically optimal strategies exist that are deterministic and memory is only required to remember the already satisfied and violated objectives. For a constant number of objectives, we show that the relevant decision problem is in NP∩coNP , matching the current known bound for single objectives; and in general the decision problem is PSPACE -hard and can be solved in NEXPTIME∩coNEXPTIME . We present an algorithm that computes the lexicographically optimal strategies via a reduction to computation of optimal strategies in a sequence of single-objectives games. We have implemented our algorithm and report experimental results on various case studies

Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis

The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestation of tuberculosis in humans and some animal models. In this study we measured the byproducts of oxidative stress in granulomatous lesions as well as the systemic antioxidant capacity of BCG vaccinated and non-vaccinated guinea pigs experimentally infected with Mycobacterium tuberculosis. In non-vaccinated guinea pigs, oxidative stress was evident within 2 weeks of infection as measured by a decrease in the serum total antioxidant capacity and blood glutathione levels accompanied by an increase in malondialdehyde, a byproduct of lipid peroxidation, within lesions. Despite a decrease in total and reduced blood glutathione concentrations, there was an increase in lesion glutathione by immunohistochemistry in response to localized oxidative stress. In addition there was an increase in the expression of the host transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione. Despite the increase in cytoplasmic expression of Nrf2, immunohistochemical staining revealed a defect in Nrf2 nuclear translocation within granulomatous lesions as well as a decrease in the expression of the Nrf2-regulated antioxidant protein NQO1. Treating M. tuberculosis–infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restored blood glutathione concentrations and the serum total antioxidant capacity. Treatment with NAC also decreased spleen bacterial counts, as well as decreased the lung and spleen lesion burden and the severity of lesion necrosis. These data suggest that the progressive oxidative stress during experimental tuberculosis in guinea pigs is due in part to a defect in host antioxidant defenses, which, we show here, can be partially restored with antioxidant treatment. These data suggest that the therapeutic strategies that reduce oxidant-mediated tissue damage may be beneficial as an adjunct therapy in the treatment and prevention of tuberculosis in humans

Uptake and Accumulation of Oxidized Low-Density Lipoprotein during Mycobacterium tuberculosis Infection in Guinea Pigs

The typical host response to infection of humans and some animals by M. tuberculosis is the accumulation of reactive oxygen species generating inflammatory cells into discrete granulomas, which frequently develop central caseous necrosis. In previous studies we showed that infection of immunologically naïve guinea pigs with M. tuberculosis leads to localized and systemic oxidative stress that results in a significant depletion of serum total antioxidant capacity and the accumulation of malondialdehyde, a bi-product of lipid peroxidation. Here we show that in addition, the generation of excessive reactive oxygen species in vivo resulted in the accumulation of oxidized low density lipoproteins (OxLDL) in pulmonary and extrapulmonary granulomas, serum and lung macrophages collected by bronchoalveolar lavage. Macrophages from immunologically naïve guinea pigs infected with M. tuberculosis also had increased surface expression of the type 1 scavenger receptors CD36 and LOX1, which facilitate the uptake of oxidized host macromolecules including OxLDL. Vaccination of guinea pigs with Bacillus Calmette Guerin (BCG) prior to aerosol challenge reduced the bacterial burden as well as the intracellular accumulation of OxLDL and the expression of macrophage CD36 and LOX1. In vitro loading of guinea pig lung macrophages with OxLDL resulted in enhanced replication of bacilli compared to macrophages loaded with non-oxidized LDL. Overall, this study provides additional evidence of oxidative stress in M. tuberculosis infected guinea pigs and the potential role OxLDL laden macrophages have in supporting intracellular bacilli survival and persistence

Inter- and intrachromosomal asynchrony of cell division cycle events in root meristem cells of Allium cepa: possible connection with gradient of cyclin B-like proteins

Alternate treatments of Allium cepa root meristems with hydroxyurea (HU) and caffeine give rise to extremely large and highly elongated cells with atypical images of mitotic divisions, including internuclear asynchrony and an unknown type of interchromosomal asynchrony observed during metaphase-to-anaphase transition. Another type of asynchrony that cannot depend solely on the increased length of cells was observed following long-term incubation of roots with HU. This kind of treatment revealed both cell nuclei entering premature mitosis and, for the first time, an uncommon form of mitotic abnormality manifested in a gradual condensation of chromatin (spanning from interphase to prometaphase). Immunocytochemical study of polykaryotic cells using anti-β tubulin antibodies revealed severe perturbations in the microtubular organization of preprophase bands. Quantitative immunofluorescence measurements of the control cells indicate that the level of cyclin B-like proteins reaches the maximum at the G2 to metaphase transition and then becomes reduced during later stages of mitosis. After long-term incubation with low doses of HU, the amount of cyclin B-like proteins considerably increases, and a significant number of elongated cells show gradients of these proteins spread along successive regions of the perinuclear cytoplasm. It is suggested that there may be a direct link between the effects of HU-mediated deceleration of S- and G2-phases and an enhanced concentration of cyclin B-like proteins. In consequence, the activation of cyclin B-CDK complexes gives rise to an abnormal pattern of premature mitotic chromosome condensation with biphasic nuclear structures having one part of chromatin decondensed, and the other part condensed