Gene signature of the post-Chernobyl papillary thyroid cancer

Purpose: Following the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC. Methods: We investigated tissue samples from 65 children/young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized. Results: There were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p < 0.01), with 300 differently expressed probe sets (p < 0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient age at diagnosis had negligible effects. Ten genes (PPME1, HDAC11, SOCS7, CIC, THRA, ERBB2, PPP1R9A, HDGF, RAD51AP1, and CDK1) from the 19 investigated with quantitative RT-PCR were confirmed as being associated with radiation exposure in an independent, validation set of samples. Conclusion: Significant, but subtle, differences in gene expression in the post-Chernobyl PTC are associated with previous low-dose radiation exposure

Zeros and the functional equation of the quadrilateral zeta function

In this paper, we show that all real zeros of the bilateral Hurwitz zeta function $Z(s,a):=\zeta (s,a) + \zeta (s,1-a)$ with $1/4 \le a \le 1/2$ are on only the non-positive even integers exactly same as in the case of $(2^s-1) \zeta (s)$. We also prove that all real zeros of the bilateral periodic zeta function $P(s,a):={\rm{Li}}_s (e^{2\pi ia}) + {\rm{Li}}_s (e^{2\pi i(1-a)})$ with $1/4 \le a \le 1/2$ are on only the negative even integers just like $\zeta (s)$. Moreover, we show that all real zeros of the quadrilateral zeta function $Q(s,a):=Z(s,a) + P(s,a)$ with $1/4 \le a \le 1/2$ are on only the negative even integers. On the other hand, we prove that $Z(s,a)$, $P(s,a)$ and $Q(s,a)$ have at least one real zero in $(0,1)$ when $0<a<1/2$ is sufficiently small. The complex zeros of these zeta functions are also discussed when $1/4 \le a \le 1/2$ is rational or transcendental. As a corollary, we show that $Q(s,a)$ with rational $1/4 < a < 1/3$ or $1/3 < a < 1/2$ does not satisfy the analogue of the Riemann hypothesis even though $Q(s,a)$ satisfies the functional equation that appeared in Hamburger's or Hecke's theorem and all real zeros of $Q(s,a)$ are located at only the negative even integers again as in the case of $\zeta (s)$.Comment: 12 pages. We changed the title. Some typos are correcte

Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer

Abstract Background Drug resistance in breast cancer is the major obstacle to effective treatment with chemotherapy. While upregulation of multidrug resistance genes is an important component of drug resistance mechanisms in vitro, their clinical relevance remains to be determined. Therefore, identifying pathways that could be targeted in the clinic to eliminate anthracycline-resistant breast cancer remains a major challenge. Methods We generated paired native and epirubicin-resistant MDA-MB-231, MCF7, SKBR3 and ZR-75-1 epirubicin-resistant breast cancer cell lines to identify pathways contributing to anthracycline resistance. Native cell lines were exposed to increasing concentrations of epirubicin until resistant cells were generated. To identify mechanisms driving epirubicin resistance, we used a complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance. In addition, we tested its clinical relevance in a BR9601 adjuvant clinical trial. Results Characterisation of epirubicin-resistant cells revealed that they were cross-resistant to doxorubicin and SN-38 and had alterations in apoptosis and cell-cycle profiles. Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, confirming that histone pathways are associated with epirubicin resistance. Gene expression of a novel 18-gene histone pathway module analysis of the BR9601 adjuvant clinical trial revealed that patients with low expression of the 18-gene histone module benefited from anthracycline treatment more than those with high expression (hazard ratio 0.35, 95 % confidence interval 0.13–0.96, p = 0.042). Conclusions This study revealed a key pathway that contributes to anthracycline resistance and established model systems for investigating drug resistance in all four major breast cancer subtypes. As the histone modification can be targeted with small-molecule inhibitors, it represents a possible means of reversing clinical anthracycline resistance. Trial registration ClinicalTrials.gov identifier NCT00003012 . Registered on 1 November 1999

The role of interventions in the cancer evolution–an evolutionary games approach

We propose to endow evolutionary game models with changes of the phenotypes adjustment during the transient generations performed by the parameters in the payo matrix which determine the fitness resulting from di erent interactions between players. These changes represent an alteration of access to external resources which, in turn, may reflect anticancer treatment. In the case of spatial games, these functions are represented by an additional lattice where another and parallel game based on cellular automata is performed. The main assumption of the spatial games is that each cell on the lattice is represented by a player following only one strategy. We propose to consider cells on the spatial lattice as heterogeneous (instead of homogeneous), so that each particular player may contain mixed phenotypes. Spatial games of the type, proposed by us, are called multidimensional spatial evolutionary games (MSEG). It may happen that within the population, all of the players have diverse phenotypes (which probably better describes biological phenomena). The additional lattice representing the evolution of resources increases only the dimension of the lattice in the MSEG

Constant versus periodic fishing: Age structured optimal control approach

The paper investigates an age-structured infinite-horizon optimal control model of harvesting a biological resource, interpreted as fish. Time and age are considered as continuum variables. The main result shows that in case of selective fishing, where only fish of prescribed sizes is harvested, it may be advantageous in the log run to implement a periodic fishing effort, rather than constant (the latter suggested by single-fish models that disregard the age-heterogeneity). Thus taking into account the age-structure of the fish may qualitatively change the theoretically optimal fishing mode. This result is obtained by developing a technique for reliable numerical verification of second order necessary optimality conditions for the considered problem. This technique could be useful for other optimal control problems of periodic age-structured systems. © EDP Sciences, 2014

Optimal protocols for the anti-VEGF tumor treatment

Cancer treatment using the antiangiogenic agents targets the evolution of the tumor vasculature. The aim is to significantly reduce supplies of oxygen and nutrients, and thus starve the tumor and induce its regression. In the paper we consider well established family of tumor angiogenesis models together with their recently proposed modification, that increases accuracy in the case of treatment using VEGF antibodies. We consider the optimal control problem of minimizing the tumor volume when the maximal admissible drug dose (the total amount of used drug) and the final level of vascularization are also taken into account. We investigate the solution of that problem for a fixed therapy duration. We show that the optimal strategy consists of the drug-free, full-dose and singular (with intermediate values of the control variable) intervals. Moreover, no bang-bang switch of the control is possible, that is the change from the no-dose to full-dose protocol (or in opposite direction) occurs on the interval with the singular control. For two particular models, proposed by Hahnfeldt et al. and Ergun et al., we provide additional theorems about the optimal control structure. We investigate the optimal controls numerically using the customized software written in MATLAB®, which we make freely available for download. Utilized numerical scheme is based on the composition of the well known gradient and shooting methods. © EDP Sciences, 2014

Optimal control in coupled within-host and between-host models

We formulate an immuno-epidemiological model of coupled within-host model of ODEs and between-host model of ODE and PDE, using the Human Immunodeficiency Virus (HIV) for illustration. Existence and uniqueness of solution to the between-host model is established, and an explicit expression for the basic reproduction number of the between-host model derived. Stability of disease-free and endemic equilibria is investigated. An optimal control problem with drug-treatment control on the within-host system is formulated and analyzed; these results are novel for optimal control of ODEs linked with such first order PDEs. Numerical simulations based on the forward-backward sweep method are obtained. © EDP Sciences, 2014