Vascular endothelial growth factor regulates melanoma cell adhesion and growth in the bone marrow microenvironment via tumor cyclooxygenase-2

Background: Human melanoma frequently colonizes bone marrow (BM) since its earliest stage of systemic dissemination, prior to clinical metastasis occurrence. However, how melanoma cell adhesion and proliferation mechanisms are regulated within bone marrow stromal cell (BMSC) microenvironment remain unclear. Consistent with the prometastatic role of inflammatory and angiogenic factors, several studies have reported elevated levels of cyclooxygenase-2 (COX-2) in melanoma although its pathogenic role in bone marrow melanoma metastasis is unknown. Methods: Herein we analyzed the effect of cyclooxygenase-2 (COX-2) inhibitor celecoxib in a model of generalized BM dissemination of left cardiac ventricle-injected B16 melanoma (B16M) cells into healthy and bacterial endotoxin lipopolysaccharide (LPS)-pretreated mice to induce inflammation. In addition, B16M and human A375 melanoma (A375M) cells were exposed to conditioned media from basal and LPS-treated primary cultured murine and human BMSCs, and the contribution of COX-2 to the adhesion and proliferation of melanoma cells was also studied. Results: Mice given one single intravenous injection of LPS 6 hour prior to cancer cells significantly increased B16M metastasis in BM compared to untreated mice; however, administration of oral celecoxib reduced BM metastasis incidence and volume in healthy mice, and almost completely abrogated LPS-dependent melanoma metastases. In vitro, untreated and LPS-treated murine and human BMSC-conditioned medium (CM) increased VCAM-1-dependent BMSC adherence and proliferation of B16M and A375M cells, respectively, as compared to basal medium-treated melanoma cells. Addition of celecoxib to both B16M and A375M cells abolished adhesion and proliferation increments induced by BMSC-CM. TNF alpha and VEGF secretion increased in the supernatant of LPS-treated BMSCs; however, anti-VEGF neutralizing antibodies added to B16M and A375M cells prior to LPS-treated BMSC-CM resulted in a complete abrogation of both adhesion-and proliferation-stimulating effect of BMSC on melanoma cells. Conversely, recombinant VEGF increased adherence to BMSC and proliferation of both B16M and A375M cells, compared to basal medium-treated cells, while addition of celecoxib neutralized VEGF effects on melanoma. Recombinant TNFa induced B16M production of VEGF via COX-2-dependent mechanism. Moreover, exogenous PGE2 also increased B16M cell adhesion to immobilized recombinant VCAM-1. Conclusions: We demonstrate the contribution of VEGF-induced tumor COX-2 to the regulation of adhesion-and proliferation-stimulating effects of TNFa, from endotoxin-activated bone marrow stromal cells, on VLA-4-expressing

Variations in year-class strength and estimates of the catchability coefficient of yellowfin tuna, Thunnus albacares, in the Eastern Pacific Ocean

ENGLISH: Year-class composition of catch, virtual population size and yearclass strength were determined from serial samples of size composition of catches and catch records. Murphy's Solution to the catch equation, which is free from the effects caused by changes in fishing pressure, was used to estimate year-class strength, i.e. the total population of fish age 3/4 years. The resultant estimates indicated that the X55, X56, X57, X62 and X63 year classes were above average and the X58, X59, X60, X61 and X64 year classes were below average. The year-class designation refers to the year of actual entry or presumed year of entry into the commercial fishery (at approximately 1 year of age). The strongest and poorest year classes were the X57 and X61 classes, respectively. The ratio of the strongest to the weakest year class was 2.6. This amount of variation is small compared to that found for other species of fish. It was found that the relationship between stock size and yearclass strength is of no value in predicting year-class strength. As a by-product of the analysis, estimates of the catchability coefficients (qN) of the age groups in the fishery were obtained, These estimates were found to vary with age and time. Age-two fish apparently showed the greatest vulnerability to fishing gear, followed by ages three and one, respectively. The average estimate of the catchability coefficient in weight was calculated and found to compare favorably with Schaefer's estimate. The influence of sea-surface water temperature upon year-class strength was investigated to determine whether the latter can be predicted from a knowledge of sea-surface temperatures prevailing during and following spawning. No correlation was evident. SPANISH: La composición de la clase anual en la captura, el tamaño de la población virtual y la fuerza de clase anual, fueron determinados según una serie de muestras de la composición de tamaño de las capturas y de los registros de captura. La Solución de Murphy de la ecuación de captura, que está libre de los efectos causados por los cambios de la presión de pesca, fue usada para estimar la fuerza de la clase anual, i.e. la población total de peces de 3/4 años. Las estimaciones resultantes indican que las clases anuales X55, X56, X57, X62 y X63 fueron superiores al promedio y que las clases anuales X58, X59, X60, X61 y X64 fueron inferiores al promedio. La designación de la clase anual se refiere al año actual de entrada o al año supuesto de entrada en la pesca comercial (aproximadamente a la edad de 1 año). Las clases anuales más fuertes y más pobres fueron la X57 y X61 respectivamente. La razón de la clase anual más fuerte en relación a la más débil fue 2.6. Esta cantidad de variación es pequeña comparada con la encontrada para otras especies de peces. Se encontró que la relación entre en tamaño del stock y la fuerza de la clase anual no tiene valor en predecir la fuerza de la clase anual. Se obtuvieron estimaciones de los coeficientes de capturabilidad (qN) de los grupos de edad en la pesquería como un producto derivado del análisis. Se encontraron que estas estimaciones variaron con la edad y tiempo. Los peces de edad dos aparentemente presentaron la vulnerabilidad más grande en relación al arte pesquero, seguidos por las edades tres y una, respectivamente. La estimación promedio del coeficiente de capturabilidad en peso fue calculada y se encontró que podía compararse favorablemente con la estimación de Schaefer. La influencia de la temperatura del agua superficial del mar sobre la fuerza de la clase anual fue investigada para determinar si se podía predecir esta última según el conocimíento de las temperaturas superficiales del mar prevalecientes durante el desove y después de éste. No hubo correlación evidente. (PDF contains 44 pages.)

Atomistic Simulation On Size-Dependent Yield Strength And Defects Evolution Of Metal Nanowires

A simple derivation based on continuum mechanics is given, which shows the surface stress is critical for yield strength at ultra-small scales. Molecular dynamics (MD) simulations with modified embedded atom method (MEAM) are employed to investigate the mechanical behaviors of single-crystalline metal nanowires under tensile loading. The calculated yield strengths increasing with the decrease of the cross-sectional area of the nanowires are in accordance with the theoretical prediction. Reorientation induced by stacking faults is observed at the nanowire edge. In addition. the mechanism of yielding is discussed in details based on the snapshots of defects evolution. The nanowires in different crystallographic orientations behave differently in stretching deformation. This study on the plastic properties of metal nanowires will be helpful to further understanding of the mechanical properties of nanomaterials. (C) 2009 Elsevier B.V. All rights reserved.

Orientation-Dependent Adhesion Strength Of A Rigid Cylinder In Non-Slipping Contact With A Transversely Isotropic Half-Space

Recently, Chen and Gao [Chen, S., Gao, H., 2007. Bio-inspired mechanics of reversible adhesion: orientation-dependent adhesion strength for non-slipping adhesive contact with transversely isotropic elastic materials. J. Mech. Phys. solids 55, 1001-1015] studied the problem of a rigid cylinder in non-slipping adhesive contact with a transversely isotropic solid subjected to an inclined pulling force. An implicit assumption made in their study was that the contact region remains symmetric with respect to the center of the cylinder. This assumption is, however, not self-consistent because the resulting energy release rates at two contact edges, which are supposed to be identical, actually differ from each other. Here we revisit the original problem of Chen and Gao and derive the correct solution by removing this problematic assumption. The corrected solution provides a proper insight into the concept of orientation-dependent adhesion strength in anisotropic elastic solids. (c) 2008 Elsevier Ltd. All rights reserved.

High-Strength Composite Fibers: Realizing True Potential of Carbon Nanotubes in Polymer Matrix through Continuous Reticulate Architecture and Molecular Level Couplings

Carbon nanotubes have unprecedented mechanical properties as defect-free nanoscale building blocks, but their potential has not been fully realized in composite materials due to weakness at the interfaces. Here we demonstrate that through load-transfer-favored three-dimensional architecture and molecular level couplings with polymer chains, true potential of CNTs can be realized in composites as Initially envisioned. Composite fibers with reticulate nanotube architectures show order of magnitude improvement in strength compared to randomly dispersed short CNT reinforced composites reported before. The molecular level couplings between nanotubes and polymer chains results in drastic differences in the properties of thermoset and thermoplastic composite fibers, which indicate that conventional macroscopic composite theory falls to explain the overall hybrid behavior at nanoscale.

A Trabecular Bone Explant Model of Osteocyte–Osteoblast Co-Culture for Bone Mechanobiology

The osteocyte network is recognized as the major mechanical sensor in the bone remodeling process, and osteocyte-osteoblast communication acts as an important mediator in the coordination of bone formation and turnover. In this study, we developed a novel 3D trabecular bone explant co-culture model that allows live osteocytes situated in their native extracellular matrix environment to be interconnected with seeded osteoblasts on the bone surface. Using a low-level medium perfusion system, the viability of in situ osteocytes in bone explants was maintained for up to 4 weeks, and functional gap junction intercellular communication (GJIC) was successfully established between osteocytes and seeded primary osteoblasts. Using this novel co-culture model, the effects of dynamic deformational loading, GJIC, and prostaglandin E-2 (PGE(2)) release on functional bone adaptation were further investigated. The results showed that dynamical deformational loading can significantly increase the PGE(2) release by bone cells, bone formation, and the apparent elastic modulus of bone explants. However, the inhibition of gap junctions or the PGE(2) pathway dramatically attenuated the effects of mechanical loading. This 3D trabecular bone explant co-culture model has great potential to fill in the critical gap in knowledge regarding the role of osteocytes as a mechano-sensor and how osteocytes transmit signals to regulate osteoblasts function and skeletal integrity as reflected in its mechanical properties.

Fluid flow induced calcium response in bone cell network

In our previous work, bone cell networks with controlled spacing and functional intercellular gap junctions had been successfully established by using microcontact printing and self assembled monolayers technologies [Guo, X. E., E. Takai, X. Jiang, Q. Xu, G. M. Whitesides, J. T. Yardley, C. T. Hung, E. M. Chow, T. Hantschel, and K. D. Costa. Mol. Cell. Biomech. 3:95-107, 2006]. The present study investigated the calcium response and the underlying signaling pathways in patterned bone cell networks exposed to a steady fluid flow. The glass slides with cell networks were separated into eight groups for treatment with specific pharmacological agents that inhibit pathways significant in bone cell calcium signaling. The calcium transients of the network were recorded and quantitatively evaluated with a set of network parameters. The results showed that 18 alpha-GA (gap junction blocker), suramin (ATP inhibitor), and thapsigargin (depleting intracellular calcium stores) significantly reduced the occurrence of multiple calcium peaks, which were visually obvious in the untreated group. The number of responsive peaks also decreased slightly yet significantly when either the COX-2/PGE(2) or the NOS/nitric oxide pathway was disrupted. Different from all other groups, cells treated with 18 alpha-GA maintained a high concentration of intracellular calcium following the first peak. In the absence of calcium in the culture medium, the intracellular calcium concentration decreased slowly with fluid flow without any calcium transients observed. These findings have identified important factors in the flow mediated calcium signaling of bone cells within a patterned network.