HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas

Abstract Background Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation. Previously, we examined the anti-lymphoma activity of MI-319, the laboratory grade of a new class of HDM2 SMI, the spiro-oxindole, in follicular lymphoma. Since then, MI-219, the clinical grade has become readily available. This study further examines the preclinical effects and mechanisms of MI-219 in a panel of human lymphoma cell lines as well as a cohort of patient-derived B-lymphcytes for its potential clinical use. Results Preclinical assessment of MI-219 was evaluated by means of an in vitro and ex vivo approach and compared to Nutlin-3, the gold standard. Characterization of p53 activity and stability were assessed by quantitative PCR, Western blot, and immunoprecipitation. Biological outcome was measured using Trypan blue exclusion assay, Annexin V/PI, PARP and caspase-3 cleavage. Surprisingly, the overall biological effects of Nutlin-3 were more delayed (48 h) while MI-219 triggered an earlier response (12-24 h), predominantly in the form of apoptotic cell death. Using a cell free autoubiquitination assay, neither agent interfered with HDM2 E3 ligase function. MI-219 was more effective in upregulating wt-p53 stabilization compared to Nutlin-3. MI-219, but not Nutlin-3, enhanced the autoubiquitination and degradation of HDM2. Conclusions Our data reveals unexpected differences between MI-219 and the well-studied Nutlin-3 in lymphoma cell lines and patient samples. We suggest a novel mechanism for MI-219 that alters the functional activity of HDM2 through enhanced autoubiquitination and degradation. Additionally, this mechanism appears to correspond to biological outcome. Our results provide evidence that different classes of HDM2 SMIs elicit molecular events that extend beyond HDM2-p53 dissociation which may be of biological and potentially therapeutic importance

Fast Frictionless Expansion of an Optical Lattice

We investigate fast frictionless expansion of an optical lattice with dynamically variable spacing (accordion lattice). We design an expansion trajectory that yields a final state identical to the initial state up to an irrelevant phase factor. We discuss the effect of additional force and nonlinear interaction on the fast frictionless expansion.Comment: To be published in PL

Collapse of triaxial bright solitons in atomic Bose-Einstein condensates

We study triaxial bright solitons made of attractive Bose-condensed atoms characterized by the absence of confinement in the longitudinal axial direction but trapped by an anisotropic harmonic potential in the transverse plane. By numerically solving the three-dimensional Gross-Pitaevskii equation we investigate the effect of the transverse trap anisotropy on the critical interaction strength above which there is the collapse of the condensate. The comparison with previous predictions [Phys. Rev. A {\bf 66}, 043619 (2002)] shows significant differences for large anisotropies.Comment: Accepted for the publication in Phys. Lett.

Mean field effects in a trapped classical gas

In this article, we investigate mean field effects for a bosonic gas harmonically trapped above the transition temperature in the collisionless regime. We point out that those effects can play also a role in low dimensional system. Our treatment relies on the Boltzmann equation with the inclusion of the mean field term. The equilibrium state is first discussed. The dispersion relation for collective oscillations (monopole, quadrupole, dipole modes) is then derived. In particular, our treatment gives the frequency of the monopole mode in an isotropic and harmonic trap in the presence of mean field in all dimensions.Comment: 4 pages, no figure submitted to Phys. Rev.

Nonlinear dynamics of Bose-condensed gases by means of a low- to high-density variational approach

We propose a versatile variational method to investigate the spatio-temporal dynamics of one-dimensional magnetically-trapped Bose-condensed gases. To this end we employ a \emph{q}-Gaussian trial wave-function that interpolates between the low- and the high-density limit of the ground state of a Bose-condensed gas. Our main result consists of reducing the Gross-Pitaevskii equation, a nonlinear partial differential equation describing the T=0 dynamics of the condensate, to a set of only three equations: \emph{two coupled nonlinear ordinary differential equations} describing the phase and the curvature of the wave-function and \emph{a separate algebraic equation} yielding the generalized width. Our equations recover those of the usual Gaussian variational approach (in the low-density regime), and the hydrodynamic equations that describe the high-density regime. Finally, we show a detailed comparison between the numerical results of our equations and those of the original Gross-Pitaevskii equation.Comment: 11 pages, 12 figures, submitted to Phys. Rev. A, January 200

Creation of a monopole in a spinor condensate

We propose a method to create a monopole structure in a spin-1 spinor condensate by applying the basic methods used to create vortices and solitons experimentally in single-component condensates. We show, however, that by using a two-component structure for a monopole, we can simplify our proposed experimental approach and apply it also to ferromagnetic spinor condensates. We also discuss the observation and dynamics of such a monopole structure, and note that the dynamics of the two-component monopole differs from the dynamics of the three-component monopole.Comment: The focus of the paper is shifted towards creation and observation of monopole

't Hooft-Polyakov Monopoles in an Antiferromagnetic Bose-Einstein Condensate

We show that an antiferromagnetic spin-1 Bose-Einstein condensate, which can for instance be created with Na-23 atoms in an optical trap, has not only singular line-like vortex excitations, but also allows for singular point-like topological excitations, i.e., 't Hooft-Polyakov monopoles. We discuss the static and dynamic properties ofthese monopoles.Comment: Four pages of ReVTeX and 1 postscript figur

Beyond Gross-Pitaevskii Mean Field Theory

A large number of effects related to the phenomenon of Bose-Einstein Condensation (BEC) can be understood in terms of lowest order mean field theory, whereby the entire system is assumed to be condensed, with thermal and quantum fluctuations completely ignored. Such a treatment leads to the Gross-Pitaevskii Equation (GPE) used extensively throughout this book. Although this theory works remarkably well for a broad range of experimental parameters, a more complete treatment is required for understanding various experiments, including experiments with solitons and vortices. Such treatments should include the dynamical coupling of the condensate to the thermal cloud, the effect of dimensionality, the role of quantum fluctuations, and should also describe the critical regime, including the process of condensate formation. The aim of this Chapter is to give a brief but insightful overview of various recent theories, which extend beyond the GPE. To keep the discussion brief, only the main notions and conclusions will be presented. This Chapter generalizes the presentation of Chapter 1, by explicitly maintaining fluctuations around the condensate order parameter. While the theoretical arguments outlined here are generic, the emphasis is on approaches suitable for describing single weakly-interacting atomic Bose gases in harmonic traps. Interesting effects arising when condensates are trapped in double-well potentials and optical lattices, as well as the cases of spinor condensates, and atomic-molecular coupling, along with the modified or alternative theories needed to describe them, will not be covered here.Comment: Review Article (19 Pages) - To appear in 'Emergent Nonlinear Phenomena in Bose-Einstein Condensates: Theory and Experiment', Edited by P.G. Kevrekidis, D.J. Frantzeskakis and R. Carretero-Gonzalez (Springer Verlag

Theory of Multidimensional Solitons

We review a number of topics germane to higher-dimensional solitons in Bose-Einstein condensates. For dark solitons, we discuss dark band and planar solitons; ring dark solitons and spherical shell solitons; solitary waves in restricted geometries; vortex rings and rarefaction pulses; and multi-component Bose-Einstein condensates. For bright solitons, we discuss instability, stability, and metastability; bright soliton engineering, including pulsed atom lasers; solitons in a thermal bath; soliton-soliton interactions; and bright ring solitons and quantum vortices. A thorough reference list is included.Comment: review paper, to appear as Chapter 5a in "Emergent Nonlinear Phenomena in Bose-Einstein Condensates: Theory and Experiment," edited by P. G. Kevrekidis, D. J. Frantzeskakis, and R. Carretero-Gonzalez (Springer-Verlag

Glucocorticoids—All-Rounders Tackling the Versatile Players of the Immune System

Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia