Targeted therapy for breast cancer prevention.

With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer

Geluidmonitor 2014

Het RIVM heeft in 2013 geluidmetingen verricht op 23 locaties langs rijkswegen en op 26 locaties langs spoorwegen. Langs rijkswegen bleek het gemiddelde geluidniveau substantieel (2,4 decibel) hoger te liggen dan de berekende waarde. Langs het spoor was er gemiddeld geen significant verschil (0,5 dB). Afhankelijk van de meetlocatie kunnen de verschillen groter of kleiner zijn. De verschillen langs rijkswegen worden veroorzaakt door het feit dat de wettelijk voorgeschreven rekenmethode uitgaat van stille banden op een droog wegdek bij een standaardtemperatuur van 20 graden Celsius. De omstandigheden zijn vaak ongunstiger. Daarnaast draagt de variatie in akoestische kwaliteit van het wegdek bij aan de verschillen. Het meetprogramma vloeit voort uit een motie van de Tweede Kamer naar aanleiding van geluidwetgeving uit 2012. De wet stelt grenswaarden aan het geluid langs rijkswegen en spoorwegen. De wegen spoorbeheerder (Rijkswaterstaat en ProRail) dienen met een jaarlijkse berekening aan te tonen hieraan te voldoen. Onderdeel van de wet is ook een validatie van de rekenuitkomsten met metingen. Het RIVM verricht hiertoe jaarlijks geluidmetingen en vergelijkt die met de berekende geluidproductie die de weg- en spoorbeheerder rapporteren. Dit rapport gaat in op de verschillen tussen reken en meetresultaten in 2013. Het rapport geeft ook de meetresultaten uit 2014 langs rijkswegen en spoorwegen op 92 meetlocaties. Deze zullen worden vergeleken met de rekenresultaten die door de weg- en spoorbeheerder gepubliceerd worden in september 2015. Hierover zal het RIVM in 2016 rapporteren. Als blijkt dat de verschillen tussen de meet- en rekenwaarden structureel zijn, is nader onderzoek nodig naar de gezondheidskundige relevantie voor de Nederlandse bevolking en naar de vraag of aanpassingen van de rekenmethode nodig zijn.In 2013 RIVM has conducted noise measurements at 23 locations along motorways and at 26 locations along railways. Along motorways, the average measured noise level was substantially (2,4 dB) higher than the calculated value. Along the track, on average no significant difference was found (0,5 dB). Depending on the measurement location, larger or smaller differences can be found. The differences along motorways are partly due to the calculation method, which is based on low-noise tires on dry surfaces at a standard temperature of 20 degrees Celsius. The average conditions are less favorable. Also the variation in acoustic quality of the road surface contributes to the differences. For rail, no clear causes of differences are yet to be declared. The measurement program stems from a motion of the House in response to noise legislation (Swung) proposed and accepted in 2012. This Act sets limits on noise along motorways and railways. The administrators, Rijkswaterstaat and ProRail, annually demonstrate by a statutory calculation to fulfill this requirement. The legislation also requires validation of the calculation results by measurements. To this aim RIVM annually conducts measurements and compares the results with the calculated noise production as reported by the road- and railway administrator. This report discusses the differences between calculation and measurement results in 2013. It also contains the measurement results from 2014, along motorways and railroads on a sample of 92 measuring sites. These results will be compared with the calculation results, after they are published in September 2015 by the road- and railway administrator. If it appears that the differences between measurement and calculation are structural, further research is needed into the health implications for the Dutch population and whether adjustments to the calculation methods are needed.Ministerie van I&

Binary data corruption due to a Brownian agent

We introduce a model of binary data corruption induced by a Brownian agent (active random walker) on a d-dimensional lattice. A continuum formulation allows the exact calculation of several quantities related to the density of corrupted bits \rho; for example the mean of \rho, and the density-density correlation function. Excellent agreement is found with the results from numerical simulations. We also calculate the probability distribution of \rho in d=1, which is found to be log-normal, indicating that the system is governed by extreme fluctuations.Comment: 39 pages, 10 figures, RevTe

Trapping reactions with subdiffusive traps and particles characterized by different anomalous diffusion exponents

A number of results for reactions involving subdiffusive species all with the same anomalous exponent gamma have recently appeared in the literature and can often be understood in terms of a subordination principle whereby time t in ordinary diffusion is replaced by t^gamma. However, very few results are known for reactions involving different species characterized by different anomalous diffusion exponents. Here we study the reaction dynamics of a (sub)diffusive particle surrounded by a sea of (sub)diffusive traps in one dimension. We find rigorous results for the asymptotic survival probability of the particle in most cases, with the exception of the case of a particle that diffuses normally while the anomalous diffusion exponent of the traps is smaller than 2/3.Comment: To appear in Phys. Rev.

What do we not know (yet) about recovery colleges?:A study protocol on their (cost-)effectiveness, mechanisms of action, fidelity and positioning

BackgroundRecovery Colleges (RCs) have spread across the globe as a new way of supporting people with mental vulnerabilities in their recovery journey. RCs focus on ‘learning’ rather than ‘curing’ and in that line facilitate a transition from being a passive, dependent patient/client to an active, empowered student learning to live life, despite vulnerabilities. Peer support and co-creation are central in RCs, as peers learn from each other by sharing personal experiences with mental vulnerabilities in an accessible, inspiring and stimulating atmosphere. The implementation of RCs is highly encouraged internationally, and as a result RCs and related self-help initiatives increasingly emerge. However, high-quality research on RCs is scarce and there is a call for thorough investigation of (cost-)effectiveness, mechanisms of action, cross-border fidelity and positioning of RCs. In response, this research project aims to fill these gaps.MethodsThis research project entails (1) a prospective quasi-experimental effectiveness study and economic evaluation, (2) a multifaceted qualitative study to elaborate on the mechanisms of action of RCs for those involved (3) a study to develop a (Dutch) Fidelity Measure of Recovery Colleges, and (4) an organisational case study to describe the positioning of RCs in relation to other mental health care services and community-based initiatives. Following the ideals of co-creation and empowerment in RCs we conduct this research project in co-creation with RC students from Enik Recovery College in Utrecht, the Netherlands.DiscussionThis research project will lead to one of the first longitudinal controlled quantitative evaluations of both cost-effectiveness and effectiveness of RC attendance in a broad sense (beyond attending courses alone). Moreover, we will gather data on a micro level (i.e., impact on RC students), meso level (i.e., organisational fidelity) and macro level (i.e., positioning in the care and support domain), capturing all important perspectives when scrutinizing the impact of complex systems. Finally, we will demonstrate the validity and value of embracing experiential knowledge in science as a complementary source of information, leading to a more profound understanding of what is researched.<br/

The target problem with evanescent subdiffusive traps

We calculate the survival probability of a stationary target in one dimension surrounded by diffusive or subdiffusive traps of time-dependent density. The survival probability of a target in the presence of traps of constant density is known to go to zero as a stretched exponential whose specific power is determined by the exponent that characterizes the motion of the traps. A density of traps that grows in time always leads to an asymptotically vanishing survival probability. Trap evanescence leads to a survival probability of the target that may be go to zero or to a finite value indicating a probability of eternal survival, depending on the way in which the traps disappear with time

Quenched large deviation principle for words in a letter sequence

When we cut an i.i.d. sequence of letters into words according to an independent renewal process, we obtain an i.i.d. sequence of words. In the \emph{annealed} large deviation principle (LDP) for the empirical process of words, the rate function is the specific relative entropy of the observed law of words w.r.t. the reference law of words. In the present paper we consider the \emph{quenched} LDP, i.e., we condition on a typical letter sequence. We focus on the case where the renewal process has an \emph{algebraic} tail. The rate function turns out to be a sum of two terms, one being the annealed rate function, the other being proportional to the specific relative entropy of the observed law of letters w.r.t. the reference law of letters, with the former being obtained by concatenating the words and randomising the location of the origin. The proportionality constant equals the tail exponent of the renewal process. Earlier work by Birkner considered the case where the renewal process has an exponential tail, in which case the rate function turns out to be the first term on the set where the second term vanishes and to be infinite elsewhere. In a companion paper the annealed and the quenched LDP are applied to the collision local time of transient random walks, and the existence of an intermediate phase for a class of interacting stochastic systems is established.Comment: 41 pages, 2 figures. Acronym LDP spelled out in title, main result strengthened to cover more general "letter" spaces, application to collision local times removed (this part will become a separate manuscript

Transient Random Walks in Random Environment on a Galton-Watson Tree

We consider a transient random walk $(X_n)$ in random environment on a Galton--Watson tree. Under fairly general assumptions, we give a sharp and explicit criterion for the asymptotic speed to be positive. As a consequence, situations with zero speed are revealed to occur. In such cases, we prove that $X_n$ is of order of magnitude $n^{\Lambda}$, with $\Lambda \in (0,1)$. We also show that the linearly edge reinforced random walk on a regular tree always has a positive asymptotic speed, which improves a recent result of Collevecchio \cite{Col06}

Sanov and central limit theorems for output statistics of quantum Markov chains

In this paper, we consider the statistics of repeated measurements on the output of a quantum Markov chain. We establish a large deviations result analogous to Sanov’s theorem for the multi-site empirical measure associated to finite sequences of consecutive outcomes of a classical stochastic process. Our result relies on the construction of an extended quantum transition operator (which keeps track of previous outcomes) in terms of which we compute moment generating functions, and whose spectral radius is related to the large deviations rate function. As a corollary to this, we obtain a central limit theorem for the empirical measure. Such higher level statistics may be used to uncover critical behaviour such as dynamical phase transitions, which are not captured by lower level statistics such as the sample mean. As a step in this direction, we give an example of a finite system whose level-1 (empirical mean) rate function is independent of a model parameter while the level-2 (empirical measure) rate is not

Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.

Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50&nbsp;% of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells