Emerging targets in human lymphoma: targeting the MYD88 mutation

B cell neoplasms co-opt the molecular machinery of normal B cells for their survival. Technological advances in cancer genomics has significantly contributed to uncovering the root cause of aggressive lymphomas, revealing a previously unknown link between TLR signaling and B cell neoplasm. Recurrent oncogenic mutations in MYD88 have been found in 39% of the activated B cell-like subtype of diffuse large B cell lymphoma (ABC DLBCL). Interestingly, 29% of ABC DLBCL have a single amino acid substitution of proline for the leucine at position 265 (L265P), and the exact same variant has also been identified in a number of lymphoid malignancies. The MYD88 L265P variant was recently identified in 90% of Wadenstrom's macroglobulinemia patients. These recent developments warrant the need for novel diagnostic tools as well as targeted therapeutics. In this review, we discuss the physiological functions of MYD88 and focus on its role in B cell lymphomas, evaluating the potential for targeting oncogenic MYD88 in lymphoma

Gravitational waves from black hole-neutron star binaries I: Classification of waveforms

Using our new numerical-relativity code SACRA, long-term simulations for inspiral and merger of black hole (BH)-neutron star (NS) binaries are performed, focusing particularly on gravitational waveforms. As the initial conditions, BH-NS binaries in a quasiequilibrium state are prepared in a modified version of the moving-puncture approach. The BH is modeled by a nonspinning moving puncture and for the NS, a polytropic equation of state with $\Gamma=2$ and the irrotational velocity field are employed. The mass ratio of the BH to the NS, $Q=M_{\rm BH}/M_{\rm NS}$, is chosen in the range between 1.5 and 5. The compactness of the NS, defined by ${\cal C}=GM_{\rm NS}/c^2R_{\rm NS}$, is chosen to be between 0.145 and 0.178. For a large value of $Q$ for which the NS is not tidally disrupted and is simply swallowed by the BH, gravitational waves are characterized by inspiral, merger, and ringdown waveforms. In this case, the waveforms are qualitatively the same as that from BH-BH binaries. For a sufficiently small value of Q \alt 2, the NS may be tidally disrupted before it is swallowed by the BH. In this case, the amplitude of the merger and ringdown waveforms is very low, and thus, gravitational waves are characterized by the inspiral waveform and subsequent quick damping. The difference in the merger and ringdown waveforms is clearly reflected in the spectrum shape and in the "cut-off" frequency above which the spectrum amplitude steeply decreases. When an NS is not tidally disrupted (e.g., for Q=5), kick velocity, induced by asymmetric gravitational wave emission, agrees approximately with that derived for the merger of BH-BH binaries, whereas for the case that the tidal disruption occurs, the kick velocity is significantly suppressed.Comment: 25 pages, 3 jpg figures, accepted for publication in PRD; erratum is added on Jul 23. 201

Extended Quantum Dimer Model and novel valence-bond phases

We extend the quantum dimer model (QDM) introduced by Rokhsar and Kivelson so as to construct a concrete example of the model which exhibits the first-order phase transition between different valence-bond solids suggested recently by Batista and Trugman and look for the possibility of other exotic dimer states. We show that our model contains three exotic valence-bond phases (herringbone, checkerboard and dimer smectic) in the ground-state phase diagram and that it realizes the phase transition from the staggered valence-bond solid to the herringbone one. The checkerboard phase has four-fold rotational symmetry, while the dimer smectic, in the absence of quantum fluctuations, has massive degeneracy originating from partial ordering only in one of the two spatial directions. A resonance process involving three dimers resolves this massive degeneracy and dimer smectic gets ordered (order from disorder).Comment: 20 pages, 13 figures, accepted for publication in J. Stat. Mec

Deficiency in clonogenic endometrial mesenchymal stem cells in obese women with reproductive failure – a pilot study

The mechanisms of obesity associated reproductive complications remain poorly understood. Endometrial mesenchymal stem-cells are critical for cyclic renewal and uterine function. Recently, W5C5+ cells, with high clonogenicity, capable of producing endometrial stroma in vivo, have been described. We sought to investigate the abundance and cloning efficiency of W5C5+ and W5C5− endometrial cells in relation to Body Mass Index, age and reproductive outcome. Design W5C5+ and W5C5− cells were purified from mid-luteal endometrial biopsies (n = 54) by magnetic bead separation and subjected to in vitro colony-forming assays. Results First trimester pregnancy losses were significantly higher in obese subjects (n = 12) compared to overweight (n = 20) and subjects with normal Body Mass Index (n = 22) (P0.05). Conclusions Our observations suggest that the regenerative capacity and plasticity of the endometrium of obese women is suboptimal, which in turn may account for the increased risk of reproductive complications associated with obesity

Phase transitions of a tethered surface model with a deficit angle term

Nambu-Goto model is investigated by using the canonical Monte Carlo simulations on fixed connectivity surfaces of spherical topology. Three distinct phases are found: crumpled, tubular, and smooth. The crumpled and the tubular phases are smoothly connected, and the tubular and the smooth phases are connected by a discontinuous transition. The surface in the tubular phase forms an oblong and one-dimensional object similar to a one-dimensional linear subspace in the Euclidean three-dimensional space R^3. This indicates that the rotational symmetry inherent in the model is spontaneously broken in the tubular phase, and it is restored in the smooth and the crumpled phases.Comment: 6 pages with 6 figure

Quasiequilibrium sequences of black-hole--neutron-star binaries in general relativity

We construct quasiequilibrium sequences of black hole-neutron star binaries for arbitrary mass ratios by solving the constraint equations of general relativity in the conformal thin-sandwich decomposition. We model the neutron star as a stationary polytrope satisfying the relativistic equations of hydrodynamics, and account for the black hole by imposing equilibrium boundary conditions on the surface of an excised sphere (the apparent horizon). In this paper we focus on irrotational configurations, meaning that both the neutron star and the black hole are approximately nonspinning in an inertial frame. We present results for a binary with polytropic index n=1, mass ratio M_{irr}^{BH}/M_{B}^{NS}=5 and neutron star compaction M_{ADM,0}^{NS}/R_0=0.0879, where M_{irr}^{BH} is the irreducible mass of the black hole, M_{B}^{NS} the neutron star baryon rest-mass, and M_{ADM,0}^{NS} and R_0 the neutron star Arnowitt-Deser-Misner mass and areal radius in isolation, respectively. Our models represent valid solutions to Einstein's constraint equations and may therefore be employed as initial data for dynamical simulations of black hole-neutron star binaries.Comment: 5 pages, 1 figure, revtex4, published in Phys.Rev.

Quasiequilibrium black hole-neutron star binaries in general relativity

We construct quasiequilibrium sequences of black hole-neutron star binaries in general relativity. We solve Einstein's constraint equations in the conformal thin-sandwich formalism, subject to black hole boundary conditions imposed on the surface of an excised sphere, together with the relativistic equations of hydrostatic equilibrium. In contrast to our previous calculations we adopt a flat spatial background geometry and do not assume extreme mass ratios. We adopt a Gamma=2 polytropic equation of state and focus on irrotational neutron star configurations as well as approximately nonspinning black holes. We present numerical results for ratios of the black hole's irreducible mass to the neutron star's ADM mass in isolation of M_{irr}^{BH}/M_{ADM,0}^{NS} = 1, 2, 3, 5, and 10. We consider neutron stars of baryon rest mass M_B^{NS}/M_B^{max} = 83% and 56%, where M_B^{max} is the maximum allowed rest mass of a spherical star in isolation for our equation of state. For these sequences, we locate the onset of tidal disruption and, in cases with sufficiently large mass ratios and neutron star compactions, the innermost stable circular orbit. We compare with previous results for black hole-neutron star binaries and find excellent agreement with third-order post-Newtonian results, especially for large binary separations. We also use our results to estimate the energy spectrum of the outgoing gravitational radiation emitted during the inspiral phase for these binaries.Comment: 17 pages, 15 figures, published in Phys. Rev.

Traveling fronts in self-replicating persistent random walks with multiple internal states

Self-activation coupled to a transport mechanism results in traveling waves that describe polymerization reactions, forest fires, tumor growth, and even the spread of epidemics. Diffusion is a simple and commonly used model of particle transport. Many physical and biological systems are, however, better described by persistent random walks that switch between multiple states of ballistic motion. So far, traveling fronts in persistent random walk models have only been analyzed in special, simplified cases. Here, we formulate the general model of reaction-transport processes in such systems and show how to compute the expansion velocity for arbitrary number of states. For the two-state model, we obtain a closed-form expression for the velocity and report how it is affected by different transport and replication parameters. We also show that nonzero death rates result in a discontinuous transition from quiescence to propagation. We compare our results to a recent observation of a discontinuous onset of propagation in microtubule asters and comment on the universal nature of the underlying mechanism.Comment: 28 pages, 10 figure

Toll-Like Receptors and Cancer: MYD88 Mutation and Inflammation

Pattern recognition receptors (PRRs) expressed on immune cells are crucial for the early detection of invading pathogens, in initiating early innate immune response and in orchestrating the adaptive immune response. PRRs are activated by specific pathogen-associated molecular patterns that are present in pathogenic microbes or nucleic acids of viruses or bacteria. However, inappropriate activation of these PRRs, such as the Toll-like receptors (TLRs), due to genetic lesions or chronic inflammation has been demonstrated to be a major cause of many hematological malignancies. Gain-of-function mutations in the TLR adaptor protein MYD88 found in 39% of the activated B cell type of diffuse large B cell lymphomas and almost 100% of Waldenström's macroglobulinemia further highlight the involvement of TLRs in these malignancies. MYD88 mutations result in the chronic activation of TLR signaling pathways, thus the constitutive activation of the transcription factor NFκB to promote cell survival and proliferation. These recent insights into TLR pathway driven malignancies warrant the need for a better understanding of TLRs in cancers and the development of novel anti-cancer therapies targeting TLRs. This review focuses on TLR function and signaling in normal or inflammatory conditions, and how mutations can hijack the TLR signaling pathways to give rise to cancer. Finally, we discuss how potential therapeutic agents could be used to restore normal responses to TLRs and have long lasting anti-tumor effects