The Role of EHD2 in Triple-Negative Breast Cancer Tumorigenesis and Progression

Triple-negative breast cancer (TNBC) comprises 10%-15% of all breast cancer cases, yet is clinically challenging due to lack of targeted therapies which leads to higher mortality. Molecular subtyping has identified the most aggressive subclasses of breast cancer to be enriched in components of caveolae. While caveolae have been linked to many biological processes, their precise role in TNBC is still poorly understood. EHD2, a member of the C-terminal EPS15-Homology Domain-containing (EHD) protein family, has emerged as a new regulator of caveolae dynamics and is essential to maintain a stable membrane pool of caveolae. Studies in model cells demonstrate that caveolae facilitate repair of plasma membrane injuries incurred under stressful conditions. Importantly, new evidence suggests the invasiveness of tumor cells makes them vulnerable to plasma membrane injuries and hence a robust repair mechanism is essential to protect injured tumor cells from cell death. EHD2 is found to be highly expressed within the basal myoepithelial layer throughout mammary gland development. High EHD2 mRNA and protein expression was observed in human TNBC cell lines and positively correlated with Caveolin-1 and Caveolin-2 expression. Furthermore, by analyzing publicly available gene expression databases, we found that high expression of EHD2 mRNA correlated with lower probability of survival in TNBC patients. This led us to hypothesize that EHD2 is a marker and crucial regulator of tumorigenicity in TNBC. Using a cohort of 840 highly-annotated human breast cancer tissue samples, we discovered that high cytoplasmic expression of EHD2 marked TNBC cases, and served as a robust prognostic indicator of metastasis and lower patient survival. ShRNA-mediated knockdown of EHD2 in TNBC cell lines reduced invasiveness, growth under anchorage-independent conditions, and membrane repair ability in vitro. Using orthotopic implantation of human breast cancer cell lines in mouse mammary gland, we observed a dramatic abrogation of tumor growth and a reduction in metastasis of TNBC cell lines with EHD2 knockdown compared to their controls. These findings indicate that EHD2 is a novel clinical biomarker of poor prognosis in TNBC, and serves a novel role as a positive regulator of caveolae-dependent protection of plasma membrane against injury, enabling tumorigenicity and metastasis in TNBC. Our results support the potential of targeting EHD2 to develop therapeutic approaches against TNBC

From collective periodic running states to completely chaotic synchronised states in coupled particle dynamics

We consider the damped and driven dynamics of two interacting particles evolving in a symmetric and spatially periodic potential. The latter is exerted to a time-periodic modulation of its inclination. Our interest is twofold: Firstly we deal with the issue of chaotic motion in the higher-dimensional phase space. To this end a homoclinic Melnikov analysis is utilised assuring the presence of transverse homoclinic orbits and homoclinic bifurcations for weak coupling allowing also for the emergence of hyperchaos. In contrast, we also prove that the time evolution of the two coupled particles attains a completely synchronised (chaotic) state for strong enough coupling between them. The resulting `freezing of dimensionality' rules out the occurrence of hyperchaos. Secondly we address coherent collective particle transport provided by regular periodic motion. A subharmonic Melnikov analysis is utilised to investigate persistence of periodic orbits. For directed particle transport mediated by rotating periodic motion we present exact results regarding the collective character of the running solutions entailing the emergence of a current. We show that coordinated energy exchange between the particles takes place in such a manner that they are enabled to overcome - one particle followed by the other - consecutive barriers of the periodic potential resulting in collective directed motion

Comparison of two regularization methods for Soft x-ray tomography at Tore Supra

International audienceSoft x-ray (SXR) emission in the range 0.1-20 keV is widely used to obtain valuable information on tokamak plasma physics, such as particle transport, magnetic configuration or magnetohydrodynamic activity. In particular, 2D tomography is the usual plasma diagnostic to access the local SXR emissivity. The tomographic inversion is traditionally performed from lineintegrated measurements of two or more cameras viewing the plasma in a poloidal cross-section, like at Tore Supra (TS). Unfortunately, due to the limited number of measured projections and presence of noise, the tomographic reconstruction of SXR emissivity is a mathematical ill-posed problem. Thus, obtaining reliable results of the tomographic inversion is a very challenging task. In order to perform the reconstruction, inversion algorithms implemented in present tokamaks use a priori information as additional constraints imposed on the plasma SXR emissivity. Among several potential inversion methods, some of them have been identified as well suited to tokamak plasmas. The purpose of this work is to compare two promising inversion methods, i.e. the minimum fisher information method already used at TS and planned for WEST configuration, and the alternative 2nd order Phillips-Tikhonov regularization with smoothness constraints imposed on the second derivative norm. Respective accuracy of both reconstruction methods as well as overall robustness and computational time are studied, using several synthetic SXR emissivity profiles. Finally, a real case is studied through tomographic reconstruction from TS SXR database

Fourier transform pure nuclear quadrupole resonance by pulsed field cycling

We report the observation of Fourier transform pure NQR by pulsed field cycling. For deuterium, well resolved spectra are obtained with high sensitivity showing the low frequency nu0 lines and allowing assignments of quadrupole couplings and asymmetry parameters to inequivalent deuterons. The technique is ideally applicable to nuclei with low quadrupolar frequencies (e.g., 2D, 7Li, 11B, 27Al, 23Na, 14N) and makes possible high resolution structure determination in polycrystalline or disordered materials

Femtosecond optical reflectivity measurements of lattice-mediated spin repulsions in photoexcited LaCoO3 thin films

We present results on the temperature dependence of ultrafast electron and lattice dynamics, measured with pump-probe transient reflectivity experiments, of an epitaxially grown LaCoO3 thin film under tensile strain. Probing spin-polarized transitions into the antibonding e(g) band provides a measure of the low-spin fraction, both as a function of temperature and time after photoexcitation. It is observed that femtosecond laser pulses destabilize the constant low-spin fraction (similar to 63%-64%) in equilibrium into a thermally activated state, driven by a subpicosecond change in spin gap Delta. From the time evolution of the low-spin fraction, it is possible to disentangle the thermal and lattice contributions to the spin state. A lattice mediated spin repulsion, identified as the governing factor determining the equilibrium spin state in thin-film LaCoO3, is observed. These results suggests that time-resolved spectroscopy is a sensitive probe of the spin state in LaCoO3 thin films, with the potential to bring forward quantitative insight into the complicated interplay between structure and spin state in LaCoO3

Random Time Forward Starting Options

We introduce a natural generalization of the forward-starting options, first discussed by M. Rubinstein. The main feature of the contract presented here is that the strike-determination time is not fixed ex-ante, but allowed to be random, usually related to the occurrence of some event, either of financial nature or not. We will call these options {\bf Random Time Forward Starting (RTFS)}. We show that, under an appropriate "martingale preserving" hypothesis, we can exhibit arbitrage free prices, which can be explicitly computed in many classical market models, at least under independence between the random time and the assets' prices. Practical implementations of the pricing methodologies are also provided. Finally a credit value adjustment formula for these OTC options is computed for the unilateral counterparty credit risk.Comment: 19 pages, 1 figur

Asymptotic analysis of stochastic manufacturing system with slow and fast machines

A dynamic flow-shop is considered consisting of one slow and one fast machine. Production capacities of both machines vary randomly according to a Markov chain whose transition rates are consistent with the time scale of the fast machine. The problem of minimization of a discounted cost of manufacturing is formulated. A conjecture is presented regarding the asymptotic behaviour of the value function for the above problem when the separation of slow and fast time scales becomes singular. Natural conditions are formulated under which the conjecture might be satisfied

Fixational Eye Movements in the Earliest Stage of Metazoan Evolution

All known photoreceptor cells adapt to constant light stimuli, fading the retinal image when exposed to an immobile visual scene. Counter strategies are therefore necessary to prevent blindness, and in mammals this is accomplished by fixational eye movements. Cubomedusae occupy a key position for understanding the evolution of complex visual systems and their eyes are assumedly subject to the same adaptive problems as the vertebrate eye, but lack motor control of their visual system. The morphology of the visual system of cubomedusae ensures a constant orientation of the eyes and a clear division of the visual field, but thereby also a constant retinal image when exposed to stationary visual scenes. Here we show that bell contractions used for swimming in the medusae refresh the retinal image in the upper lens eye of Tripedalia cystophora. This strongly suggests that strategies comparable to fixational eye movements have evolved at the earliest metazoan stage to compensate for the intrinsic property of the photoreceptors. Since the timing and amplitude of the rhopalial movements concur with the spatial and temporal resolution of the eye it circumvents the need for post processing in the central nervous system to remove image blur