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Most of the time the mechanical equipment is in normal operation state, which results in high imbalance between fault data and normal data. In addition, traditional signal processing methods rely heavily on expert experience, making it difficult for classification or prediction algorithms to obtain accurate results. In view of the above problem, this paper proposed a method to augment failure data for mechanical equipment diagnosis based on Wasserstein generative adversarial networks with gradient penalty (WGAN-GP). First, the multi-dimensional sensor data are converted into two-dimensional gray images in order to avoid the interference of tedious parameters preset on the model and the dependence on the professional knowledge of signal preprocessing. Based on this foundation, the gray images of the minority sample are used as the input of WGAN-GP to carry out adversarial training until the network reaches the Nash Equilibrium. Then the generated images are added to the original failure samples, reducing the imbalance of the original data samples. Finally, by calculating the structural similarity index between the generated images and the original images, the difficulty of quantitative evaluation of WGAN-GP data generated by itself is solved. Taking the accelerated bearing failure dataset as an example, the classification prediction effects of different classifiers are compared. The results of multiple experiments shown that the proposed method can more effectively improve the prediction accuracy in the case of sparse fault samples.

A deep understanding of the role of Ca in geopolymers exposed to various environments is essential for geopolymerization. This work evaluates the role of Ca by observing the behavior of hierarchically calciferous geopolymers under different environments including air, carbonization and freezing-thawing cycles. The structural and morphological differences between the geopolymers and the related mechanisms in various environmental conditions are assessed based on compressive strength, brunauer emmett teller, X-ray diffraction, fourier transform infrared spectoscopy, nuclear magnetic resonance spectroscopy and scanning electron microscopy measurements. It is found that two kinds of geopolymer gels, calcium silicate hydrate and sodium aluminosilicate hydrate, are formed in the geopolymerization of blast furnace slag and fly ash. Regardless of the specific air, carbonization or freezing-thawing cycle environment, the former gel dominates the properties in low Ca geopolymers, while the latter gel determines the properties in medium and high Ca geopolymers. Moreover, the carbonization environment enables calciferous geopolymers with higher surface areas and smaller pore sizes. Such adequate pore structures can significantly improve the performance of the geopolymers. This study presents novel insights into the influence of Ca on geopolymerization and in strengthening geopolymer properties.

Stress has a significant influence on gas diffusion, which is a key factor for methane recovery in coal mines. In this study, a series of experiments were performed to investigate effect of stress on the gas diffusivity during desorption in tectonic coal. Additionally, the desorbed data were modeled using the unipore and bidisperse models. The results show that the bidisperse model better describes the diffusion kinetics than the unipore model in this study. Additionally, the modeling results using the bidisperse approach suggest that the stress impact on the macropore diffusivity is greater than the stress on the micropore diffusivity. Under the same equilibrium pressure, the diffusivity varies with stress according to a four-stage function, which shows an 'M-shape'. As the equilibrium gas pressure increased from 0.6 to 1.7 MPa, the critical point between stage 2 and stage 3 and between stage 3 and stage 4 transferred to a low stress. This difference is attributed to the gas pressure effects on the physical and mechanical properties of coal. These observations indicate that both the stress and gas pressure can significantly impact gas diffusion and may have significant implications on methane recovery in coal mines.

Redshift drift is a tool to directly probe the expansion history of the universe. Based on the Friedmann-Robertson-Walker framework, we reconstruct the velocity drift and deceleration factor for several cosmological models using observational H(z) data from the differential ages of galaxies and baryon acoustic oscillation peaks, luminosity distance of Type Ia supernovae, cosmic microwave background shift parameter, and baryon acoustic oscillation distance parameter. They can, for the first time, provide an objective and quantifiable measure of the redshift drift. We find that reconstructed velocity drift with different peak values and corresponding redshifts can potentially provide a method to distinguish the quality of competing dark energy models at low redshifts. Better fitting between models and observational data indicate that current data are insufficient to distinguish the quality of these models. However, by comparing with the simulated velocity drift from Liske et al, we find that the Dvali-Gabadadze-Porrati model is inconsistent with the data at high redshift, which originally piqued the interest of researchers in the topic of redshift drift. Considering the deceleration factor, we are able to give a stable instantaneous estimation of a transition redshift of z t ~ 0.7 from joint constraints, which incorporates a more complete set of values than the previous study that used a single data set.

Recently, Nation et al. confirmed that fluxes of Hawking radiation energy and entropy from a black hole can be regarded as a one-dimensional (1D) non-equilibrium Landauer transport process. Their work can be extended to background space-times with gauge potential. The result shows that the energy flux of charged particles, which is shown to be equal to the energy–momentum tensor flux, contains not only the contribution of thermal flux but also that of particle flux. It is found that the charge can also be transported by the 1D quantum channel. Moreover, the entropy production rate is also investigated, which is shown to be larger than the case without chemical potential.

Thinking of Hawking radiation calculation from a Schwarzschild black hole using Damour-Ruffini method, some key requirements of the tortoise coordinate transformation are pointed out. Extending these requirements to a dynamical black hole, a dynamical tortoise coordinate transformation is proposed. Under this new dynamical tortoise coordinate transformation, Hawking radiation from a Vaidya black hole can be got successfully using Damour-Ruffini method. Moreover, we also find that the radiation should be regarded as originating from the apparent horizon rather than the event horizon at least from the viewpoint of the first law of thermodynamics.

We use the recently released data of lookback time (LT)-redshift relation, the cosmic microwave background shift parameter and the baryon acoustic oscillation measurements to constrain cosmological parameters of f(R) gravity in the Palatini formalism by considering the f(R) form of type (a) f(R) = R − β/R n and (b) f(R) = R + α ln R − β . Under the assumption of a Friedmann-Robertson-Walker universe, we achieved the best fitting results of the free parameters (Ω m 0 , n ) for (a) and (Ω m 0 , α) for (b). We find that current LT data can provide interesting and effective constraints on gravity models. Compared with other data, the LT constraints favor a smaller value of the non-relativistic matter energy density.

Recently, a renormalizable gravity theory has been proposed by Hořava, and it might be an ultraviolet completion of general relativity or its infrared modification. Particular limit of the theory allows for the Minkowski vacuum. A spherical asymptotically flat black hole solution that represents the analogy of Schwarzschild solution of general relativity has been obtained. It will be very interesting to find the difference between traditional general relativity and Hořava-Lifshitz gravity theory. The three classical tests of general relativity including gravitational red-shift, perihelion precession of the planet Mercury, and light deflection in gravitational field in the spherical asymptotically flat black hole solution of infrared modified Hořava-Lifshitz gravity are investigated. The first order corrections from the standard general relativity is obtained. The result can be used to limit the parameters in Hořava-Lifshitz gravity and to show the viability of the theory.

We use the newly released observational H(z) data (OHD), the Cosmic Microwave Background (CMB) shift parameter, and the Baryon Acoustic Oscillation (BAO) measurements data to constrain cosmological parameters of f(R) gravity in Palatini formalism in which the f(R) form is defined as f(R) = R − β/Rn. Under the assumption of a spatially flat FRW universe, we get the best fitting results of the free parameters (Ωm0, n). In the calculation, we marginalize the likelihood function over H0 by integrating the probability density \(P \propto e^{{{ - \chi ^2 } \mathord{\left/ {\vphantom {{ - \chi ^2 } 2}} \right. \kern-\nulldelimiterspace} 2}} \) to obtain the best fitting results and the confidence regions in the Ωm0-n plane. The constraints results of (Ωm0, n) = (0.33, 0.41) by OHD only and (Ωm0, n) = (0.23, 0.08) by the combination of OHD+CMB+BAO both indicate that the universe goes through three last phases, i.e., radiation dominated, matter-dominated, and late time accelerated expansion without introduction of dark energy.

Both dark energy and the thermodynamics on apparent horizon in cosmology have been broadly investigated in recent several years. In order to maintain the continuity equation of the total matter in the universe, a new interacting dark energy in the framework of Brans-Dicke theory is proposed. Considering this new interacting dark energy, an equilibrium thermodynamics in Brans-Dicke theory is constructed successfully. Moreover, this new interacting dark energy can be regarded as arising from the “Holographic Dark Energy” models.

Electrical-to-kinetic energy conversion efficiency of synchronous induction coilguns (SICG) is the main limiting factor of its development. In the system of SICG, the change of any electromagnetic parameters can directly or indirectly affects the electrical-to-kinetic energy conversion efficiency. In order to improve the electrical-to-kinetic energy conversion efficiency of SICG, the electromechanical model of SICG was built at first in this paper. Then, the structural parameters of SICG with 60-mm caliber were optimized with ant colony optimization algorithm. The electrical-to-kinetic energy conversion efficiency of the system was regarded as the target function, while the center-to-center space between the drive coil and the armature, and the structural parameters of the drive coil and the armature were regarded as variables. Results of research indicated that the electrical-to-kinetic energy conversion efficiency of the system was improved through parameter optimization. In order to validate the results of parameter optimization, an experiment was carried out with the first stage of SICG.

Using Damour-Ruffini method, Hawking radiation from the apparent horizon of a Vaidya black hole is calculated. The thermodynamics can be built successfully on the apparent horizon. In the meantime, when a time-dependent perturbation is given to the apparent horizon, the first law of thermodynamics can also be constructed successfully at a new supersurface near the apparent horizon. The expressions of the characteristic position and temperature are consistent with the previous results. It is concluded that the thermodynamics should be constructed on the apparent horizon exactly while the event horizon thermodynamics is just one of the perturbations near the apparent horizon. These conclusions can be regarded as providing some new evidences for our previous viewpoint.

Cyclic loading influences coal permeability and methane production. Experiments examining methane diffusion in a tectonic coal were performed at an adsorption equilibrium pressure of 0.6 MPa over a range of stresses from 0 MPa to 16 MPa. The results show that the methane diffusion in a coal matrix under cyclic loading can be modelled by a power-langmuir model, Qt = ati / (1 + bti). The parameters a, b and i are demonstrated to be related to the effective diffusion coefficient in the unipore model. The ultimate diffusion amount tended first to decrease, rise rapidly and finally decline again with increasing loading stress. The methane diffusion rates under several loading stresses exhibited three stages: rapid attenuation, slow attenuation and steady diffusion. Both the initial diffusion rate and the attenuation coefficient of the diffusion rate fluctuated slightly at first, increased steeply, and finally dropped as the stress increased. [Received: March 2, 2017; Accepted: October 24, 2017]

Using Parikh's tunneling method, the Hawking radiation on the apparent horizon of a Vaidya–Bonner black hole is calculated. When the back-reaction of particles is neglected, the thermal spectrum can be precisely obtained. Then, the black hole thermodynamics can be calculated successfully on the apparent horizon. When a relativistic perturbation is applied to the apparent horizon, a similar calculation can also lead to a purely thermal spectrum. The first law of thermodynamics can also be derived successfully at the new supersurface near the apparent horizon. When the event horizon is thought of as a deviation from the apparent horizon, the expressions of the characteristic position and temperature are consistent with the previous viewpoint which asserts that the thermodynamics should be based on the event horizon. It is concluded that the thermodynamics should be constructed exactly on the apparent horizon while the event horizon thermodynamics is just one of the perturbations near the apparent horizon.

The thermal character of inner horizon in a Reissner-Nordstrom black hole is studied via Hamilton-Jacobi method. There is “Hawking absorption” as a quantum effect near the inner horizon, and a negative temperature of the inner horizon was attained by choosing an observer outside the black hole. Using a redefined entropy of the black hole, we give a new expression of Bekenstein-Smarr formula. The redefined entropy satisfies Nernst Theorem, so it can be regarded as Planck absolute entropy of the Reissner-Nordstrom black hole.

Hawking radiation on the apparent horizon of a Vaidya black hole is investigated using Parikh's tunneling method. When back-reaction of particles is neglected, precisely thermal spectrum can be obtained. Then the black hole thermodynamics can be built successfully on the apparent horizon. When a relativistic perturbation is given to the apparent horizon, similar calculation can also lead to a purely thermal spectrum, which is corresponding to a modified temperature from the former. The first law of thermodynamics can also be constructed successfully at a new supersurface which has a small deviation from the apparent horizon. When the event horizon is thought as such a deviation from the apparent horizon, the expressions of the characteristic position and temperature are consistent with the previous viewpoint which asserts that the thermodynamics should be built on the event horizon. It is concluded that the thermodynamics should be constructed on the apparent horizon exactly while the event horizon thermodynamics is just one of the perturbations near the apparent horizon.

Hawking radiation from a Kerr–Newman black hole is investigated using Hamilton–Jacobi method more deeply. A direct computation will lead to a wrong result via Hamilton–Jacobi method. However, when the well-behaved Painleve coordinate system and Eddington coordinate system are considered, we can get the correct result. The reason of the discrepancy between naive coordinate and well-behaved coordinates is also discussed.

Using the Damour–Ruffini method, Hawking radiation from a four-dimensional charged rotating black string in asymptotically anti-de Sitter space–time is investigated. When energy, angular momentum, charge conservations, and the particles’ back-reaction to the space–time are taken into account, the exact emission spectrum near the horizon is calculated. The horizon is not spherical, but can be toroidal and cylindrical. Our results indicate that the spectrum is not purely thermal, which may be consistent with an underlying unitary theory. Moreover, it is a possible mechanism to explain the information loss paradox.

Hawking radiation can be viewed as a process of quantum tunneling near the black hole horizon. When a particle with angular momentum L ≠ ωa tunnels across the event horizon of Kerr or Kerr-Newman black hole, the angular momentum per unit mass a should be changed. The emission rate of the massless particles under this general case is calculated, and the result is consistent with an underlying unitary theory.

Hawking radiation from a general Kerr–Newman black hole is investigated using Damour–Ruffini's method. Considering the back-reaction of particle's energy, charge and angular momentum to the spacetime, we obtain a modified nonthermal spectrum. Maybe the information loss paradox can be explained, furthermore, the result is also consistent with the result obtained using Parikh and Wilczek's method.

Both the insulin-like growth factor-I receptor (IGF-IR) and cyclooxygenase-2 (COX-2) are frequently overexpressed in pancreatic cancer. We hypothesized that IGF-IR is directly involved in induction of COX-2 and sought to investigate signaling pathways mediating this effect. Pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative receptor (IGF-IR DN) construct or empty vector (pcDNA). Cells were stimulated with IGF-I to determine activated signaling intermediates and induction of COX-2. Signaling pathways mediating COX-2 induction were identified using signaling inhibitors. IGF-I up-regulated COX-2 selectively via the MAPK/(Erk-1/2) pathway. In addition, IGF-IR DN cells showed a marked decrease in constitutive COX-2 and a blunted response to IGF-I. Similarly, treatment with an anti-IGF-IR antibody effectively inhibited IGF-IR and MAPK/Erk activation and decreased COX-2 in parental cells. In conclusion, activation of IGF-IR mediates COX-2 expression in human pancreatic cancer cells.

Using Damour-Ruffini’s and Hamilton-Jacobi’s methods, Hawking radiation from a Vaidya black hole is investigated. Due to non-stationary black holes, the event horizon rH and the entropy S are all related to both the mass m(υ) and \(\dot{r}_{H}\) . When the back-reaction of particles’s energy to space-time is considered, we get the emission probability. It is found that the result is different from that of the stationary Schwarzschild black hole, because \(\dot{r}_{H}\) is the function of mass m(υ).

The Casimir effect has been studied for various quantum fields in both flat and curved spacetimes. As a further step along this line, we provide an explicit derivation of Casimir effect for massless spin-3/2 field with periodic boundary condition imposed in four-dimensional Minkowski spacetime. The corresponding results with Dirichlet and Neumann boundary conditions are also discussed., version to appear in Communications in Theoretical Physics

Considering energy conservation, angular momentum conservation, and the particles' back reaction to space–time, the scalar particles' Hawking radiation from a BTZ black hole was investigated using Damour–Ruffini method. The exact expression of the emission rate near the horizon is obtained and the result indicates that Hawking radiation spectrum is not purely thermal. The result obtained is consistent with the previous literatures. It is in agreement with an underlying unitary theory and offers a possible mechanism to explain the information loss paradox. Whereas, the method is more concise and understandable.

Purpose: Gastrointestinal neuroendocrine tumors (NET) are rare heterogeneous tumors that hypersecrete neuropeptides. The scarcity of good gastrointestinal NET models has limited the ability to study potential therapeutic agents. We describe and characterize the establishment of a human midgut carcinoid tumor cell line carcinoid tumor 2 (CNDT2). Experimental Design: Tumor cells (CNDT2) were isolated from a liver metastasis from a patient with a primary ileal carcinoid. After 9 weeks in culture, the cells were plated in soft agar, and cells from a single colony were put back in culture (CNDT2.1). Those CNDT2.1 cells were injected s.c. into nude mice. Cells were isolated from a single resultant tumor (CNDT2.5), cultured, and characterized by electron microscopy, reverse transcription-PCR, serotonin enzyme immunoassay, Western blotting, and immunohistochemical analysis for NET markers and potential therapeutic targets. Results: CNDT2 cells grew in monolayers in vitro, formed colonies in soft agar, and formed tumors in mice. Electron microscopy revealed round, pleomorphic, electron-dense neurosecretory granules characteristic of NETs. Tumor xenografts exhibited the appearance of NETs with small “salt-and-pepper” nuclei on H&E staining and chromogranin A, synaptophysin, and CD56 on immunohistochemical staining. CNDT2.5 cells produced serotonin and expressed insulin-like growth factor receptor-I, platelet-derived growth factor receptor-β, vascular endothelial growth factor receptor-1, cMET, epidermal growth factor receptor, neuropilin-1, and somatostatin receptors 1 to 5. Cytogenetic analysis revealed the presence of deletions at 2p and 6q and numerous translocations. Conclusion: The establishment of this human midgut carcinoid tumor cell line may serve as a useful model system for studying cell biology and novel targeted agents in preclinical models.

We hypothesized that overexpression of PDGF-BB in colorectal cancer (CRC) and pancreatic cancer cells would result in increased pericyte coverage of ECs in vivo, rendering the tumor vasculature more resistant to antiangiogenic therapy. We stably transfected the cDNA for the PDGF-B into HT-29 human CRC and FG human pancreatic cancer cells. Surprisingly, when HT-29 or FG parental and transfected cells were injected into mice (subcutaneously and orthotopically), we observed marked inhibition of tumor growth in the PDGF-BB–overexpressing clones. In the PDGF-BB–overexpressing tumors, we observed an increase in pericyte coverage of ECs. Treatment of PDGF-BB–overexpressing tumors with imatinib mesylate (PDGFR inhibitor) resulted in increased growth and decreased total pericyte content compared with those in untreated PDGF-BB–overexpressing tumors. In vitro studies demonstrated the ability of VSMCs to inhibit EC proliferation by approximately 50%. These data show that increasing the pericyte content of the tumor microenvironment inhibits the growth of angiogenesis-dependent tumors. Single-agent therapy targeting PDGF receptor must be used with caution in tumors when PDGFR is not the target on the tumor cell itself.

The massive particles’ Hawking radiation from a spherically symmetric static black hole is investigated with Parikh-Wilczek method, Hamilton–Jacobi method and Damour–Ruffini’s method. When energy conservation is considered, the same result can be concluded that the radiation spectrum is not precisely thermal. The corrected spectrum is consistent to the underlying unitary quantum theory, which can be used to explain the information loss paradox possibly.

Hawking radiation can be viewed as a process of particle quantum tunneling near a black hole horizon. When a particle with angular momentum tunnels across the event horizon of a Reissner–Nordstrom black hole, the black hole will change into a Kerr–Newman one. In previous papers, axisymmetric black hole has been studied only when a keeps constant. Changing from Reissner–Nordstrom to Kerr–Newman should be a simple case when a varies. After this, more general radiation including changed a in Kerr or Kerr–Newman spacetimes can be studied in the future. The emission rate of the massless particles with angular momentum is calculated, and the result is consistent with an underlying unitary theory.

Considering anomalies of quantum field in the (1+1)-dimensional Achucarro-Ortiz black hole background, the stress tensor near and out of the horizon is calculated, meanwhile, the relationship between anomalies and Hawking radiation of the black hole is discussed., 6 pages

Hawking radiation can be viewed as a process of quantum tunnelling near black hole horizon. When a particle with angular momentum tunnels across the event horizon of Schwarzschild black hole, the black hole will change into a Kerr black hole. The emission rate of the massless particles with angular momentum is calculated, and the result is consistent with an underlying unitary theory.

The stress tensor of a massless scalar field satisfying a mixed boundary condition in a (1+1)-dimensional Reissner–Nordstrom black hole background is calculated by using Wald's axiom. We find that Dirichlet stress tensor and Neumann stress tensor can be deduced by changing the coefficients of the stress tensor calculated under a mixed boundary condition. The stress tensors satisfying Dirichlet and Neumann boundary conditions are discussed. In addition, we also find that the stress tensor in conformal flat spacetime background differs from that in flat spacetime only by a constant.

Pancreatic carcinoma cells overexpress the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) and the hepatocyte growth factor (HGF) receptor, c-Met, which are both known to mediate tumor cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion of human pancreatic carcinoma cells and that IGF-I-mediated migration and invasion depend on c-Met. Migration and invasion assays were done with the human pancreatic cancer cell line L3.6pl treated with PBS, IGF-I, HGF, or IGF-I plus HGF. To determine if c-Met is necessary for IGF-IR-mediated migration and invasion, c-Met was down-regulated in L3.6pl cells via adenoviral infection with a c-Met ribozyme before IGF-I treatment. IGF-I and HGF increased cell migration and invasion. Furthermore, IGF-I plus HGF had a greater than additive effect on cell migration and invasion compared with either growth factor alone. Down-regulation of c-Met nearly completely inhibited IGF-I-mediated migration and invasion. Our findings suggest that IGF-IR and c-Met cooperate to induce migration and invasion of human pancreatic carcinoma cells. Furthermore, c-Met is required for both HGF- and IGF-I-mediated migration and invasion. Elucidation of the signaling pathways that contribute to tumor progression and metastasis should provide a foundation for the development of targeted therapies for pancreatic carcinoma. [Mol Cancer Ther 2006;5(7):1676–82]

Purpose: Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another's expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts.Experimental Design: L3.6pl human pancreatic cancer cells were s.c. implanted in nude mice. On day 6, mice were randomized to receive (a) PBS (control), (b) DC101 [VEGF receptor 2 (VEGFR-2) antibody] by i.p. injection, (c) N-nitro-l-arginine (NNLA; NOS inhibitor) in the drinking water, or (d) both DC101 and NNLA. Mice were killed on day 20.Results: DC101 and NNLA as single agents inhibited tumor growth by ∼50% to 60% (P < 0.008 for both). Furthermore, combined therapy inhibited mean tumor growth by 89% (P < 0.008). Combined inhibition of VEGFR-2 and NOS also decreased mean vessel counts by 65% (P < 0.03) and vessel area by 80% versus controls (P < 0.001). In contrast to DC101 where vessel diameter was similar to control, NNLA decreased mean vessel diameter by 42% (P < 0.001). NNLA also led to a 54% (P < 0.03) decrease in tumor uptake of the perfusion marker Hoechst 33342 versus controls whereas DC101 decreased Hoechst 33342 staining by 43% (P < 0.03). The combination of inhibitors decreased perfusion by 73% (P < 0.03).Conclusions: Although VEGFR-2 can mediate NOS activity, the combination of VEGFR-2 and NOS inhibition significantly increased the antivascular effect over single agent therapy. The addition of NOS inhibition led to an even further alteration of tumor vessel morphology and vascular perfusion compared with VEGFR-2 blockade, suggesting that NO and VEGFR-2 have distinct but complementary effects on the tumor vasculature.

Treating macro-black hole as quantum states, and using Brown–York's quasi-local gravitational energy definition and Heisenberg uncertainty principle, the GHS black hole's quantum horizon is constructed. The Hawking temperature is computed naturally, and the entropy can also be figured out without introducing the cutoff factor h. The Φ-field mode number is predicted too. The result is consistent with that of the Schwarzschild and R-N black hole.

Neuropilin-1 (NRP-1) is a co-receptor for vascular endothelial growth factor (VEGF). During neovascularization, vascular smooth muscle cells (VSMCs) and pericytes modulate the function of endothelial cells. Factors that mediate NRP-1 in human VSMCs (hVSMCs) remain to be elucidated. We studied various angiogenic cytokines to identify factors that increase NRP-1 expression in hVSMCs. Treatment of hVSMCs with basic fibroblast growth factor (b-FGF) induced expressions of NRP-1 mRNA and protein whereas epidermal growth factor, insulin-like growth factor-1, and interleukin-1beta did not. b-FGF induced phosphorylation of Erk-1/2 and JNK. MEK1/2 and nuclear factor kappa B (NF-kappaB) inhibitors (U0126 and TLCK, respectively) blocked the ability of b-FGF to induce NRP-1 mRNA expression, but inhibition of JNK (SP600125) or PI3-kinase activity (wortmannin) did not. Further, the increase in NRP-1 expression by b-FGF enhanced hVSMCs migration in response to VEGF(165). This effect was dependent on the binding of VEGF(165) to VEGFR-2, as blocking antibodies to VEGFR-2, but not VEGFR-1, inhibited VEGF(165)-induced migration. In conclusion, b-FGF increased NRP-1 expression in hVSMCs that in turn enhance the effect of VEGF(165) on cell migration. The enhanced migration of hVSMCs was mediated through binding of VEGF(165) to both NRP-1 and VEGFR-2, as inhibition of VEGFR-2 on these cells blocked the effect of VEGF-mediated cell migration.

Pancreatic carcinomas express high levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), both of which mediate cell migration and invasion. We investigated the hypotheses that (a) insulin-like growth factor-I (IGF-I)– and hepatocyte growth factor (HGF)–mediated migration and invasion of human pancreatic carcinoma cells require uPA and uPAR function and (b) inhibition of uPAR inhibits tumor growth, retroperitoneal invasion, and hepatic metastasis of human pancreatic carcinomas in mice. Using transwell assays, we investigated the effect of IGF-I and HGF on L3.6pl migration and invasion. We measured the induction of uPA and uPAR following treatment of cells with IGF-I and HGF using immunoprecipitation and Western blot analysis. The importance of uPA and uPAR on L3.6pl cell migration and invasion was studied by inhibiting their activities with amiloride and antibodies before cytokine treatment. In an orthotopic mouse model of human pancreatic carcinoma, we evaluated the effect of anti-uPAR monoclonal antibodies with and without gemcitabine on primary tumor growth, retroperitoneal invasion, and hepatic metastasis. IGF-I and HGF mediated cell migration and invasion in L3.6pl cells. In addition, IGF-I and HGF induced uPA and uPAR expression in L3.6pl cells. In vitro, blockade of uPA and uPAR activity inhibited IGF-I– and HGF-mediated cell migration and invasion. Treatment of mice with anti-uPAR monoclonal antibody significantly decreased pancreatic tumor growth and hepatic metastasis and completely inhibited retroperitoneal invasion. Our study shows the importance of the uPA/uPAR system in pancreatic carcinoma cell migration and invasion. These findings suggest that uPAR is a potential target for therapy in patients with pancreatic cancer.

Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by >30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing >50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.

In 2004, there were an estimated 147,000 new cases of colorectal carcinoma (CRC) and 57,000 deaths from this disease, ranking it third among causes of cancer-related death in the United States.1 Significant advances in systemic therapy for metastatic CRC, including targeted therapies, have improved survival, but even with combination therapy the median survival is only about 15 to 21 months.2,3 To continue to improve our therapies for metastatic CRC, we need a better understanding of the factors that lead to tumor progression and metastasis. In particular, the mechanisms regulating CRC cell invasion through the basement membrane of the colon and migration of the cells to form metastases need to be further investigated. Insulinlike growth factor-I (IGF-I) and its tyrosine kinase receptor (IGF-IR) have been implicated in the development and progression of a variety of human cancers,4–12 including CRC.13–15 IGF-I has been shown to be an important mediator of tumor cell migration and invasion,16–20 but the downstream pathways by which IGF-I induces these processes have not been fully elucidated. Hepatocyte growth factor/scatter factor (HGF) and its tyrosine kinase receptor c-Met have also been implicated in the pathogenesis of a wide variety of human malignancies,21–25 including CRC.26 Similar to IGF-I, HGF/c-Met signaling is known to induce tumor-cell migration and invasion.11,25,27–30 Recently, cooperation between receptors and their signaling pathways has been shown to be important in regulating cellular responses to various ligands. We theorized that IGF-IR and c-Met cooperate in mediating migration and invasion of human CRC cells, given the following findings. First, IGF-I and HGF lead to activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system in various malignancies.4,11,17,27,31,32 This is central to our hypothesis in that uPA has been shown to cleave pro-HGF to active HGF.33 Second, IGF-I signaling results in induction of hypoxia inducible factor-1α in pancreatic carcinoma cells,10 and hypoxia, likely acting via hypoxia inducible factor-1α, has been shown to increase c-Met levels in human lung, hepatocellular, and other carcinomas.34 Third, growth factor receptor-binding protein 2-associated binder-1 functions as the main substrate and docking protein regulating downstream signaling by c-Met and has been shown to function as a signaling intermediate for IGF-I as well.35 Fourth, IGF-I and HGF have been shown to function as comitogens in a rat hepatoma cell line.36 In the current study, we investigated the hypotheses that IGF-IR and c-Met cooperate to mediate migration and invasion of human CRC cells and that uPA/uPAR activation is required for IGF-I- and HGF-mediated migration and invasion. We used a c-Met ribozyme to inhibit c-Met function in KM12L4 human CRC cells and performed transwell migration and invasion assays. The c-Met ribozyme experiments demonstrated that c-Met function is critical for IGF-I-mediated cell migration and invasion and for constitutive invasion. In experiments inhibiting uPA or uPAR, we demonstrated that migration and invasion mediated by IGF-I and HGF are dependent on uPA/uPAR activation. This suggests that uPA and uPAR are downstream of IGF-I and IGF-IR and of HGF and c-Met. To our knowledge, this study is the first to identify tyrosine kinase receptor cooperation between IGF-IR and c-Met in human CRC and the role of uPA/uPAR in mediating IGF-I and HGF/c-Met effects.