Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients

<b>Purpose</b>: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer. <b>Experimental Design</b>: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival. <b>Results</b>: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (<i>P</i>=0.03). <b>Conclusion</b>: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit

Particle number projection with effective forces

The particle number projection method is formulated for density dependent forces and in particular for the finite range Gogny force. Detailed formula for the projected energy and its gradient are provided. The problems arising from the neglection of any exchange term, which may lead to divergences, are throughly discussed and the possible inaccuracies estimated. Numericala results for the projection after variation method are shown for the nucleus 164Er and for the projection before variation approach for the nuclei 48-50Cr. We also confirm the Coulomb antipairing effect found in mean field theories.Comment: 33 pages, 8 figures. Submit to Nuc. Phys.

Time-reversal violating rotation of polarization plane of light in gas placed in electric field

Rotation of polarization plane of light in gas placed in electric field is considered. Different factors causing this phenomenon are investigated. Angle of polarization plane rotation for transition 6S_{1/2} - 7S_{1/2} in cesium (lambda=539 nm) is estimated. The possibility to observe this effect experimentally is discussed.Comment: 10 pages, Late

Anisotropic fractal magnetic domain pattern in bulk Mn1.4PtSn

The tetragonal compound Mn1.4PtSn with D2d symmetry recently attracted attention as the first known material that hosts magnetic antiskyrmions, which differ from the skyrmions known so far by their internal structure. The latter have been found in a number of magnets with the chiral crystal structure. In previous works, the existence of antiskyrmions in Mn1.4PtSn was unambiguously demonstrated in real space by means of Lorentz transmission electron microscopy on thin-plate samples (∼100 nm thick). In the present study, we used small-angle neutron scattering and magnetic force microscopy to perform reciprocal- and real-space imaging of the magnetic texture of bulk Mn1.4PtSn single crystals at different temperatures and in applied magnetic field. We found that the magnetic texture in the bulk differs significantly from that of thin-plate samples. Instead of spin helices or an antiskyrmion lattice, we observe an anisotropic fractal magnetic pattern of closure domains in zero field above the spin-reorientation transition temperature, which transforms into a set of bubble domains in high field. Below the spin-reorientation transition temperature the strong in-plane anisotropy as well as the fractal self-affinity in zero field is gradually lost, while the formation of bubble domains in high field remains robust. The results of our study highlight the importance of dipole-dipole interactions in thin-plate samples for the stabilization of antiskyrmions and identify criteria which should guide the search for potential (anti)skyrmion host materials. Moreover, they provide consistent interpretations of the previously reported magnetotransport anomalies of the bulk crystals. © 2020 authors. Published by the American Physical Society. Published by the American Physical Society under the terms of the "https://creativecommons.org/licenses/by/4.0/"Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI. Open access publication funded by the Max Planck Society

Curved Tails in Polymerization-Based Bacterial Motility

The curved actin ``comet-tail'' of the bacterium Listeria monocytogenes is a visually striking signature of actin polymerization-based motility. Similar actin tails are associated with Shigella flexneri, spotted-fever Rickettsiae, the Vaccinia virus, and vesicles and microspheres in related in vitro systems. We show that the torque required to produce the curvature in the tail can arise from randomly placed actin filaments pushing the bacterium or particle. We find that the curvature magnitude determines the number of actively pushing filaments, independent of viscosity and of the molecular details of force generation. The variation of the curvature with time can be used to infer the dynamics of actin filaments at the bacterial surface.Comment: 8 pages, 2 figures, Latex2

Random field sampling for a simplified model of melt-blowing considering turbulent velocity fluctuations

In melt-blowing very thin liquid fiber jets are spun due to high-velocity air streams. In literature there is a clear, unsolved discrepancy between the measured and computed jet attenuation. In this paper we will verify numerically that the turbulent velocity fluctuations causing a random aerodynamic drag on the fiber jets -- that has been neglected so far -- are the crucial effect to close this gap. For this purpose, we model the velocity fluctuations as vector Gaussian random fields on top of a k-epsilon turbulence description and develop an efficient sampling procedure. Taking advantage of the special covariance structure the effort of the sampling is linear in the discretization and makes the realization possible

Tracing a toad invasion: lack of mitochondrial DNA variation, haplotype origins, and potential distribution of introduced Duttaphrynus melanostictus in Madagascar

The black-spined toad, Duttaphrynus melanostictus, is widespread in South and South-East (SE) Asia, although recent molecular analyses have revealed that it represents a species complex (here called the D. melanostictus complex). Invasive populations of this toad have been detected in Madagascar since, at least, 2014. We here trace the origin of this introduction based on mitochondrial DNA sequences of 340 samples. All 102 specimens from Madagascar have identical sequences pointing to a single introduction event. Their haplotype corresponds to a lineage occurring in Cambodia, China, Laos, Thailand, Vietnam, and some locations of eastern Myanmar and northern Malaysia, here named the SE Asian lineage. Within this lineage, specimens from one location in Cambodia and three locations in Vietnam have the same haplotype as found in Madagascar. This includes Ho Chi Minh City, which has a major seaport and might have been the source for the introduction. Species distribution models suggest that the current range of the Madagascan invasive population is within the bioclimatic space occupied by the SE Asian lineage in its native range. The potential invasion zone in Madagascar is narrower than suggested by models from localities representing the full range of the D. melanostictus complex. Thus, an accurate taxonomy is essential for such inferences, but it remains uncertain if the toad might be able to spread beyond the potential suitable range because (1) knowledge on species-delimitation of the complex is insufficient, and (2) the native range in SE Asia might be influenced by historical biogeography or competition

Development of functionally selective, small molecule agonists at kappa opioid receptors

The kappa opioid receptor (KOR) is widely expressed in the CNS and can serve as a means to modulate pain perception, stress responses, and affective reward states. Therefore, the KOR has become a prominent drug discovery target toward treating pain, depression, and drug addiction. Agonists at KOR can promote G protein coupling and βarrestin2 recruitment as well as multiple downstream signaling pathways, including ERK1/2 MAPK activation. It has been suggested that the physiological effects ofKORactivation result from different signaling cascades, with analgesia being G protein-mediated and dysphoria being mediated through βarrestin2 recruitment. Dysphoria associated with KOR activation limits the therapeutic potential in the use of KOR agonists as analgesics; therefore, it may be beneficial to develop KOR agonists that are biased toward G protein coupling and away from βarrestin2 recruitment. Here, we describe two classes of biased KOR agonists that potently activateGprotein coupling but weakly recruitβarrestin2. These potent and functionally selective small molecule compounds may prove to be useful tools for refining the therapeutic potential of KOR-directed signaling in vivo

Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat

L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson’s disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure