Histone Deacetylase Inhibitors in Malignant Pleural Mesothelioma: Preclinical Rationale and Clinical Trials

AbstractMalignant pleural mesothelioma (MPM) is a rare and aggressive cancer of the mesothelium with only a limited range of treatment options that are largely ineffective in improving survival. Recent efforts have turned toward the analysis of specific, dysregulated biologic pathways for insight into new treatment targets. Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis. A family of histone acetyltransferases and deacetylases regulates this balance, with the latter facilitating chromatin condensation, thus preventing gene transcription, resulting in the loss of heterozygosity of tumor suppressors. Inhibition of this process, coupled with a similar inhibition of nonhistone protein deacetylation, ultimately leads to the promotion of apoptosis, cell cycle arrest, and inhibition of angiogenesis. An increasing amount of preclinical data highlighting the effectiveness of histone deacetylase inhibition in MPM cell lines and mouse xenograft models has led to a number of early phase clinical trials in patients with MPM. The results of these efforts have led to a multicenter, randomized, placebo-controlled phase III study of the histone deacetylase inhibitor vorinostat in patients with advanced MPM, offering hope for a new and effective therapy in patients with this disease

Localized defects in a cellular automaton model for traffic flow with phase separation

We study the impact of a localized defect in a cellular automaton model for traffic flow which exhibits metastable states and phase separation. The defect is implemented by locally limiting the maximal possible flow through an increase of the deceleration probability. Depending on the magnitude of the defect three phases can be identified in the system. One of these phases shows the characteristics of stop-and-go traffic which can not be found in the model without lattice defect. Thus our results provide evidence that even in a model with strong phase separation stop-and-go traffic can occur if local defects exist. From a physical point of view the model describes the competition between two mechanisms of phase separation.Comment: 14 pages, 7 figure

Sign-time distributions for interface growth

We apply the recently introduced distribution of sign-times (DST) to non-equilibrium interface growth dynamics. We are able to treat within a unified picture the persistence properties of a large class of relaxational and noisy linear growth processes, and prove the existence of a non-trivial scaling relation. A new critical dimension is found, relating to the persistence properties of these systems. We also illustrate, by means of numerical simulations, the different types of DST to be expected in both linear and non-linear growth mechanisms.Comment: 4 pages, 5 ps figs, replaced misprint in authors nam

Why We Read Wikipedia

Wikipedia is one of the most popular sites on the Web, with millions of users relying on it to satisfy a broad range of information needs every day. Although it is crucial to understand what exactly these needs are in order to be able to meet them, little is currently known about why users visit Wikipedia. The goal of this paper is to fill this gap by combining a survey of Wikipedia readers with a log-based analysis of user activity. Based on an initial series of user surveys, we build a taxonomy of Wikipedia use cases along several dimensions, capturing users' motivations to visit Wikipedia, the depth of knowledge they are seeking, and their knowledge of the topic of interest prior to visiting Wikipedia. Then, we quantify the prevalence of these use cases via a large-scale user survey conducted on live Wikipedia with almost 30,000 responses. Our analyses highlight the variety of factors driving users to Wikipedia, such as current events, media coverage of a topic, personal curiosity, work or school assignments, or boredom. Finally, we match survey responses to the respondents' digital traces in Wikipedia's server logs, enabling the discovery of behavioral patterns associated with specific use cases. For instance, we observe long and fast-paced page sequences across topics for users who are bored or exploring randomly, whereas those using Wikipedia for work or school spend more time on individual articles focused on topics such as science. Our findings advance our understanding of reader motivations and behavior on Wikipedia and can have implications for developers aiming to improve Wikipedia's user experience, editors striving to cater to their readers' needs, third-party services (such as search engines) providing access to Wikipedia content, and researchers aiming to build tools such as recommendation engines.Comment: Published in WWW'17; v2 fixes caption of Table

Diffusive persistence and the `sign-time' distribution

We present a new method for extracting the persistence exponent theta for the diffusion equation, based on the distribution P of `sign-times'. With the aid of a numerically verified Ansatz for P we derive an exact formula for theta in arbitrary spatial dimension d. Our results are in excellent agreement with previous numerical studies. Furthermore, our results indicate a qualitative change in P above d ~ 36, signalling the existence of a sharp change in the ergodic properties of the diffusion field.Comment: 5 pages, 2 tar gzip figures (Latex), subm. to PRE (Rapid Comm), new reference adde

Structural and magnetic dimers in the spin-gapped system CuTe2O5

We investigated the magnetic properties of the system CuTe2O5 by susceptibility and electron spin resonance measurements. The anisotropy of the effective g-factors and the ESR linewidth indicates that the anticipated structural dimer does not correspond to the singlet-forming magnetic dimer. Moreover, the spin susceptibility of CuTe2O5 can only be described by taking into account interdimer interactions of the same order of magnitude than the intradimer coupling. Analyzing the exchange couplings in the system we identify the strongest magnetic coupling between two Cu ions to be mediated by super-super exchange interaction via a bridging Te ligand, while the superexchange coupling between the Cu ions of the structural dimer only results in the second strongest coupling

Probability distribution of the free energy of a directed polymer in a random medium

We calculate exactly the first cumulants of the free energy of a directed polymer in a random medium for the geometry of a cylinder. By using the fact that the n-th moment of the partition function is given by the ground state energy of a quantum problem of n interacting particles on a ring of length L, we write an integral equation allowing to expand these moments in powers of the strength of the disorder gamma or in powers of n. For n small and n of order (L gamma)^(-1/2), the moments take a scaling form which allows to describe all the fluctuations of order 1/L of the free energy per unit length of the directed polymer. The distribution of these fluctuations is the same as the one found recently in the asymmetric exclusion process, indicating that it is characteristic of all the systems described by the Kardar-Parisi-Zhang equation in 1+1 dimensions.Comment: 18 pages, no figure, tu appear in PRE 61 (2000

Clinical Characteristics of Patients with Malignant Pleural Mesothelioma Harboring Somatic BAP1 Mutations

IntroductionGenomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BRCA-associated protein 1(BAP1) gene. In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown. We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.MethodsWe reviewed the charts of 121 patients with MPM tumors diagnosed between 1991 and 2009 tested for BAP1 mutation, and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.ResultsTwenty-four of the 121 tumors (20%) harbored somatic BAP1 mutations. The percentage of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% versus 42%; p = 0.006). However, the types of nucleotide substitutions in BAP1 did not suggest that this association was because of a causative role of smoking in BAP1 mutations. No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM. There was also no difference in survival according to somatic BAP1 mutation status.ConclusionThere is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation. The significance of the more frequent history of smoking among patients with BAP1-mutated MPM warrants further study

Exactly solvable statistical model for two-way traffic

We generalize a recently introduced traffic model, where the statistical weights are associated with whole trajectories, to the case of two-way flow. An interaction between the two lanes is included which describes a slowing down when two cars meet. This leads to two coupled five-vertex models. It is shown that this problem can be solved by reducing it to two one-lane problems with modified parameters. In contrast to stochastic models, jamming appears only for very strong interaction between the lanes.Comment: 6 pages Latex, submitted to J Phys.

Absence of phase coexistence in disordered exclusion processes with bypassing

Adding quenched disorder to the one-dimensional asymmetric exclusion process is known to always induce phase separation. To test the robustness of this result, we introduce two modifications of the process that allow particles to bypass defect sites. In the first case, particles are allowed to jump l sites ahead with the probability p_l ~ l^-(1+sigma), where sigma>1. By using Monte Carlo simulations and the mean-field approach, we show that phase coexistence may be absent up to enormously large system sizes, e.g. lnL~50, but is present in the thermodynamic limit, as in the short-range case. In the second case, we consider the exclusion process on a quadratic lattice with symmetric and totally asymmetric hopping perpendicular to and along the direction of driving, respectively. We show that in an anisotropic limit of this model a regime may be found where phase coexistence is absent.Comment: 18 pages, 10 figures, to appear in JSTA