Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter

Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model

Imaginary chemical potential and finite fermion density on the lattice

Standard lattice fermion algorithms run into the well-known sign problem at real chemical potential. In this paper we investigate the possibility of using imaginary chemical potential, and argue that it has advantages over other methods, particularly for probing the physics at finite temperature as well as density. As a feasibility study, we present numerical results for the partition function of the two-dimensional Hubbard model with imaginary chemical potential. We also note that systems with a net imbalance of isospin may be simulated using a real chemical potential that couples to I_3 without suffering from the sign problem.Comment: 9 pages, LaTe

Finding the Pion in the Chiral Random Matrix Vacuum

The existence of a Goldstone boson is demonstrated in chiral random matrix theory. After determining the effective coupling and calculating the scalar and pseudoscalar propagators, a random phase approximation summation reveals the massless pion and massive sigma modes expected whenever chiral symmetry is spontaneously broken.Comment: 3 pages, 1 figure, revte

Quantum Chaos in the Yang-Mills-Higgs System at Finite Temperature

The quantum chaos in the finite-temperature Yang-Mills-Higgs system is studied. The energy spectrum of a spatially homogeneous SU(2) Yang-Mills-Higgs is calculated within thermofield dynamics. Level statistics of the spectra is studied by plotting nearest-level spacing distribution histograms. It is found that finite temperature effects lead to a strengthening of chaotic effects, i.e. spectrum which has Poissonian distribution at zero temperature has Gaussian distribution at finite-temperature.Comment: 6 pages, 5 figures, Revte

Impossibility of spontaneously breaking local symmetries and the sign problem

Elitzur's theorem stating the impossibility of spontaneous breaking of local symmetries in a gauge theory is reexamined. The existing proofs of this theorem rely on gauge invariance as well as positivity of the weight in the Euclidean partition function. We examine the validity of Elitzur's theorem in gauge theories for which the Euclidean measure of the partition function is not positive definite. We find that Elitzur's theorem does not follow from gauge invariance alone. We formulate a general criterion under which spontaneous breaking of local symmetries in a gauge theory is excluded. Finally we illustrate the results in an exactly solvable two dimensional abelian gauge theory.Comment: Latex 6 page

The Fractal Geometry of Critical Systems

We investigate the geometry of a critical system undergoing a second order thermal phase transition. Using a local description for the dynamics characterizing the system at the critical point T=Tc, we reveal the formation of clusters with fractal geometry, where the term cluster is used to describe regions with a nonvanishing value of the order parameter. We show that, treating the cluster as an open subsystem of the entire system, new instanton-like configurations dominate the statistical mechanics of the cluster. We study the dependence of the resulting fractal dimension on the embedding dimension and the scaling properties (isothermal critical exponent) of the system. Taking into account the finite size effects we are able to calculate the size of the critical cluster in terms of the total size of the system, the critical temperature and the effective coupling of the long wavelength interaction at the critical point. We also show that the size of the cluster has to be identified with the correlation length at criticality. Finally, within the framework of the mean field approximation, we extend our local considerations to obtain a global description of the system.Comment: 1 LaTeX file, 4 figures in ps-files. Accepted for publication in Physical Review

Future aspects of renal transplantation

New and exciting advances in renal transplantation are continuously being made, and the horizons for organ transplantation are bright and open. This article reviews only a few of the newer advances that will allow renal transplantation to become even more widespread and successful. The important and exciting implications for extrarenal organ transplantation are immediately evident. © 1988 Springer-Verlag

Investigation of the Possible Functions of PACAP in Human Trophoblast Cells

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide having a widespread distribution both in the nervous system and peripheral organs including the female reproductive system. Both the peptide and its receptors have been shown in the placenta but its role in placental growth, especially its human aspects, remains unknown. The aim of the present study was to investigate the effects of PACAP on invasion, proliferation, cell survival, and angiogenesis of trophoblast cells. Furthermore, cytokine production was investigated in human decidual and peripheral blood mononuclear cells. For in vitro studies, human invasive proliferative extravillous cytotrophoblast (HIPEC) cells and HTR-8/SVneo human trophoblast cells were used. Both cell types were used for testing the effects of PACAP on invasion and cell survival in order to investigate whether the effects of PACAP in trophoblasts depend on the examined cell type. Invasion was studied by standardized invasion assay. PACAP increased proliferation in HIPEC cells, but not in HTR-8 cells. Cell viability was examined using MTT test, WST-1 assay, and annexin V/propidium iodide flow cytometry assay. Survival of HTR-8/SVneo cells was studied under oxidative stress conditions induced by hydrogen peroxide. PACAP as pretreatment, but not as co-treatment, significantly increased the number of surviving HTR-8 cells. Viability of HIPEC cells was investigated using methotrexate (MTX) toxicity, but PACAP1-38 could not counteract its toxic effect. Angiogenic molecules were determined both in the supernatant and the cell lysate by angiogenesis array. In the supernatant, we found that PACAP decreased the secretion of various angiogenic markers, such as angiopoietin, angiogenin, activin, endoglin, ADAMTS-1, and VEGF. For the cytokine assay, human decidual and peripheral blood lymphocytes were separated and treated with PACAP1-38. Th1 and Th2 cytokines were analyzed with CBA assay and the results showed that there were no significant differences in control and PACAP-treated cells. In summary, PACAP seems to play various roles in human trophoblast cells, depending on the cell type and microenvironmental influences

Hatano-Nelson model with a periodic potential

We study a generalisation of the Hatano-Nelson Hamiltonian in which a periodic modulation of the site energies is present in addition to the usual random distribution. The system can then become localized by disorder or develop a band gap, and the eigenspectrum shows a wide variety of topologies. We determine the phase diagram, and perform a finite size scaling analysis of the localization transition.Comment: 7 pages, 10 figure