Stochastic Resonance in Underdamped, Bistable Systems

We carry out a detailed numerical investigation of stochastic resonance in underdamped systems in the non-perturbative regime. We point out that an important distinction between stochastic resonance in overdamped and underdamped systems lies in the lack of dependence of the amplitude of the noise-averaged trajectory on the noise strength, in the latter case. We provide qualitative explanations for the observed behavior and show that signatures such as the initial decay and long-time oscillatory behaviour of the temporal correlation function and peaks in the noise and phase averaged power spectral density, clearly indicate the manifestation of resonant behaviour in noisy, underdamped bistable systems in the weak to moderate noise regime.Comment: Revtex; (10+8)pp including 8 figure

CXCL12 Mediates Trophic Interactions between Endothelial and Tumor Cells in Glioblastoma

Emerging evidence suggests endothelial cells (EC) play a critical role in promoting Glioblastoma multiforme (GBM) cell proliferation and resistance to therapy. The molecular basis for GBM-EC interactions is incompletely understood. We hypothesized that the chemokine CXCL12 and its receptor CXCR4 could mediate direct interactions between GBM cells and tumor-associated endothelial cells and that disruption of this interaction might be the molecular basis for the anti-tumor effects of CXCR4 antagonists. We investigated this possibility in vivo and in an in vitro co-culture model that incorporated extracellular matrix, primary human brain microvascular ECs (HBMECs) and either an established GBM cell line or primary GBM specimens. Depletion of CXCR4 in U87 GBM cells blocked their growth as intracranial xenografts indicating that tumor cell CXCR4 is required for tumor growth in vivo. In vitro, co-culture of either U87 cells or primary GBM cells with HBMECs resulted in their co-localization and enhanced GBM cell growth. Genetic manipulation of CXCL12 expression and pharmacological inhibition of its receptors CXCR4 and CXCR7 revealed that the localizing and trophic effects of endothelial cells on GBM cells were dependent upon CXCL12 and CXCR4. These findings indicate that the CXCL12/CXCR4 pathway directly mediates endothelial cell trophic function in GBMs and that inhibition of CXCL12-CXCR4 signaling may uniquely target this activity. Therapeutic disruption of endothelial cell trophic functions could complement the structural disruption of anti-angiogenic regimens and, in combination, might also improve the efficacy of radiation and chemotherapy in treating GBMs

Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions

Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1(–/–)) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males

Resonant Production of Topological Defects

We describe a novel phenomenon in which vortices are produced due to resonant oscillations of a scalar field which is driven by a periodically varying temperature T, with T remaining much below the critical temperature $T_c$. Also, in a rapid heating of a localized region to a temperature {\it below} $T_c$, far separated vortex and antivortex can form. We compare our results with recent models of defect production during reheating after inflation. We also discuss possible experimental tests of our predictions of topological defect production {\it without} ever going through a phase transition.Comment: Revtex, 13 pages including 5 postscript figure

Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma

Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551. When doses of POL5551 were increased to overcome an mcr84-induced improvement in vascular barrier function, combinatorial therapy significantly inhibited intracranial tumor growth and improved survival. Anti-tumor activity was associated with significant changes in tumor cell proliferation and apoptosis, and a reduction in the numbers of perivascular cells expressing the TIC marker nestin. A direct effect on TICs was demonstrated for POL5551, but not mcr84, in three primary patient-derived GBM isolates. These findings indicate that targeting the structure and function of the PVN has superior anti-tumor effect and provide a strong rationale for clinical evaluation of POL5551 and Avastin in patients with GBM

Forming a Single, Large, DCC Domain in a Heavy-Ion Collision

We demonstrate the possibility of forming a single, large domain of disoriented chiral condensate (DCC) in a heavy-ion collision. In our scenario, rapid initial heating of the parton system provides a driving force for the chiral field, moving it away from the true vacuum and forcing it to go to the opposite point on the vacuum manifold. This converts the entire hot region into a single DCC domain. Subsequent rolling down of the chiral field to its true vacuum will then lead to emission of a large number of (approximately) coherent pions. The requirement of suppression of thermal fluctuations to maintain the (approximate) coherence of such a large DCC domain, favors three dimensional expansion of the plasma over the longitudinal expansion even at very early stages of evolution. This also constrains the maximum temperature of the system to lie within a window. We roughly estimate this window to be about 200 - 400 MeV. These results lead us to predict that extremely high energy collisions of {\it very small nuclei} (possibly hadrons) are better suited for observing signatures of a large DCC. Another possibility is to focus on {\it peripheral} collisions of heavy nuclei.Comment: RevTex, 22 pages, including 5 figures. Considerably expanded version with results of improved numerical calculation

Stochastic Production Of Kink-Antikink Pairs In The Presence Of An Oscillating Background

We numerically investigate the production of kink-antikink pairs in a $(1+1)$ dimensional $\phi^4$ field theory subject to white noise and periodic driving. The twin effects of noise and periodic driving acting in conjunction lead to considerable enhancement in the kink density compared to the thermal equilibrium value, for low dissipation coefficients and for a specific range of frequencies of the oscillating background. The dependence of the kink-density on the temperature of the heat bath, the amplitude of the oscillating background and value of the dissipation coefficient is also investigated. An interesting feature of our result is that kink-antikink production occurs even though the system always remains in the broken symmetry phase.Comment: Revtex, 21 pages including 7 figures; more references adde

CXCR7 Protein Expression in Human Adult Brain and Differentiated Neurons

Background: CXCR7 and CXCR4 are receptors for the chemokine CXCL12, which is involved in essential functions of the immune and nervous systems. Although CXCR7 transcripts are widely expressed throughout the central nervous system, little is known about its protein distribution and function in the adult brain. To evaluate its potential involvement in CXCL12/CXCR4 signaling in differentiated neurons, we studied CXCR7 protein expression in human brain and cultured neurons. Methodology/Principal Findings: Immunohistochemistry and RT-PCR analyses of cortex and hippocampus from control and HIV-positive subjects provided the first evidence of CXCR7 protein expression in human adult neurons, under normal and pathological conditions. Furthermore, confocal microscopy and binding assays in cultured neurons show that CXCR7 protein is mainly located into cytoplasm, while little to no protein expression is found on neuronal plasma membrane. Interestingly, specific CXCR7 ligands that inhibit CXCL12 binding to CXCR7 do not alter CXCR4-activated survival signaling (pERK/pAkt) in rat cortical neurons. Neuronal CXCR7 co-localizes to some extent with the endoplasmic reticulum marker ERp29, but not with early/late endosome markers. Additionally, large areas of overlap are detected in the intracellular pattern of CXCR7 and CXCR4 expression. Conclusions/Significance: Overall, these results implicate CXCR4 as the main CXCL12 signaling receptor on the surface o