bluuebunny/crossref_metadata_2025 huggingface dataset:
COMPUTATIONAL MODELING OF TURBULENT VELOCITY STRUCTURES FOR AN OPEN CHANNEL FLOW USING KARHUNEN–LOÉVE EXPANSION
Authors: CONNELL R. J. , KULASIRI D. , LENNON J. , HILL D. F.
Published: October 2007

This paper develops an analytical two-part covariance kernel from velocity correlations across a two-dimensional (vertical and flow directions) Particle Image Velocimetry (PIV) flow field. This will form the basis of a model of wave action in flood water that includes the underlying turbulence velocity field using Karhunen–Loéve (KL) expansion. The PIV data was from the supercritical flow area immediately upstream of an undular hydraulic jump. This paper derives a one-dimensional solution for the associated integral equations. It also discusses a relationship between the two parts of the kernel and the turbulent production and turbulent dissipation.
A LOCAL-PATCH BASED MULTI-STAGE ARTIFICIAL-NEURAL-NETWORK TRAINING PROCEDURE AND ITS APPLICATION TO MATERIAL CHARACTERIZATION
Authors: LUO YUNHUA , SHAH ARVIND
Published: October 2007

A local-patch based multi-stage artificial-neural-network (ANN) training procedure is proposed in this paper, to improve the accuracy of an ANN trained by a backpropagation (BP) algorithm and, at the same time, to reduce the overall training time. In the proposed procedure a conventional one-stage training procedure is split into multiple stages: an initial training stage and subsequent re-training stage(s). In the initial stage the training data are so selected that the trained ANN has adequate ability of generalization, that is, if provided with a set of new input, the ANN can predict the right region where the output is located, but the accuracy of the solution is not necessarily high. In the following re-training stage(s), local patches of training data, either selected from an existing data pool or generated by numerical methods such as finite element method, are used to re-train the ANN to improve the accuracy. Several factors that may have significant effects on the proposed procedure were investigated based on function approximation. As an example of application, the procedure was then used to train an ANN with finite element data to characterize material parameters.
THE METHOD OF FUNDAMENTAL SOLUTIONS WITH DUAL RECIPROCITY FOR SOME LINEAR ELASTIC PROBLEMS IN 3D
Authors: DE MEDEIROS GLAUCENY CIRNE , PARTRIDGE PAUL WILLIAM
Published: October 2007

The Method of Fundamental Solutions (MFS) is an indirect boundary method in which singularities are avoided through the use of a surface of fictitious points external to the problem geometry. The Method requires no mesh or integration, and is thus easier to implement than the Boundary Element Method (BEM). The method also permits that results for stresses, both on the boundary and inside the domain, be obtained without the use of special techniques. Here, some linear elastic problems, with and without body forces, in 3D, are considered. The MFS is combined with the Dual Reciprocity Method (DRM) in order to model nonhomogeneous terms in a similar way as is done in the BEM. Polyharmonic Spline approximation functions are employed with linear polynomial augmentation functions. Different types of surface are considered for positioning the fictitious points. Results are compared with the exact solutions.
THE UPPER BOUND PROPERTY FOR SOLID MECHANICS OF THE LINEARLY CONFORMING RADIAL POINT INTERPOLATION METHOD (LC-RPIM)
Authors: ZHANG G. Y. , LIU G. R. , NGUYEN T. T. , SONG C. X. , HAN X. , ZHONG Z. H. , LI G. Y.
Published: October 2007

It has been proven by the authors that both the upper and lower bounds in energy norm of the exact solution to elasticity problems can now be obtained by using the fully compatible finite element method (FEM) and linearly conforming point interpolation method (LC-PIM). This paper examines the upper bound property of the linearly conforming radial point interpolation method (LC-RPIM), where the Radial Basis Functions (RBFs) are used to construct shape functions and node-based smoothed strains are used to formulate the discrete system equations. It is found that the LC-RPIM also provides the upper bound of the exact solution in energy norm to elasticity problems, and it is much sharper than that of LC-PIM due to the decrease of stiffening effect. An effective procedure is also proposed to determine both upper and lower bounds for the exact solution without knowing it in advance: using the LC-RPIM to compute the upper bound, using the standard fully compatible FEM to compute the lower bound based on the same mesh for the problem domain. Numerical examples of 1D, 2D and 3D problems are presented to demonstrate these important properties of LC-RPIM.
THE ECONOMIC LIMITS OF TRUST: THE CASE OF A LATIN-AMERICAN URBAN INFORMAL COMMERCE SECTOR
Authors: JAFFE KLAUS , LEVY CARCIENTE SARY , ZANONI WLADIMIR
Published: October 2007

Social capital is thought to be an important source of social cohesion and a key ingredient for socioeconomic expansion in developing nations. We study its role among street vendors and their money lenders in Caracas, an illegal business based solely on trust and social bonds. We analyzed demand and supply of credit by informal street vendors and money lenders, exploring the relationship between street vendors' assets, income generated, financial and human capital and financial strategies, and those of the money lenders. We found that street vendors' main source of working capital were money lenders, despite charging the highest interest rate. The kind and amount of credit was not correlated to higher incomes. On the supply side, we found that money lenders based their business almost exclusively on trust and manage all clients personally, which limits the growth of their business. This study suggests that the main constraint for increased productivity in the informal sector is not the cost of capital, but the transaction costs involved in accessing credit and a lack of legal enforcements, and that improvement of the lending business is difficult without institutional support.
AN INCREMENTAL APPROACH TO MSE-BASED FEATURE SELECTION
Authors: GUAN SHENG-UEI , QI YINAN , BAO CHUNYU
Published: October 2007

Feature selection plays an important role in classification systems. Using classifier error rate as the evaluation function, feature selection is integrated with incremental training. A neural network classifier is implemented with an incremental training approach to detect and discard irrelevant features. By learning attributes one after another, our classifier can find directly the attributes that make no contribution to classification. These attributes are marked and considered for removal. Incorporated with a minimum squared error (MSE) based feature ranking scheme, four batch removal methods based on classifier error rate have been developed to discard irrelevant features. These feature selection methods reduce the computational complexity involved in searching among a large number of possible solutions significantly. Experimental results show that our feature selection methods work well on several benchmark problems compared with other feature selection methods. The selected subsets are further validated by a constructive backpropagation (CBP) classifier, which confirms increased classification accuracy and reduced training cost.
LARGE SCALE EXPERIMENTS ON EVOLUTION AND RUN-UP OF BREAKING SOLITARY WAVES
Authors: HWANG KAO-SHU , CHANG YU-HSUAN , HWUNG HWUNG-HWENG , LI YI-SYUAN
Published: October 2007

The evolution and run-up of breaking solitary waves on plane beaches are investigated in this paper. A series of large-scale experiments were conducted in the SUPER TANK of Tainan Hydraulics Laboratory with three plane beaches of slope 0.05, 0.025 and 0.017 (1:20, 1:40 and 1:60). Solitary waves of which relative wave heights, H/h0, ranged from 0.03 to 0.31 were generated by two types of wave-board displacement trajectory: the ramp-trajectory and the solitary-wave trajectory proposed by Goring (1979). Experimental results show that under the same relative wave height, the waveforms produced by the two generation procedures becomes noticeably different as the waves propagate prior to the breaking point. Meanwhile, under the same relative wave height, the larger the constant water depth is, the larger the dimensionless run-up heights would be. Scale effects associated with the breaking process are discussed.
NUMERICAL SIMULATIONS OF THE 2004 INDIAN OCEAN TSUNAMIS — COASTAL EFFECTS
Authors: WANG XIAOMING , LIU PHILIP L.-F.
Published: October 2007

The 2004 Sumatra earthquake and the associated tsunamis are one of the most devastating natural disasters in the last century. The tsunamis flooded a huge coastal area in the surrounding countries, especially in Indonesia, Thailand and Sri Lanka, and caused enormous loss of human lives and properties. In this paper, tsunami inundations in Trincomalee, Sri Lanka and North Banda Aceh, Indonesia were simulated by using a finite-difference model based on nonlinear shallow-water equations. The calculated tsunami heights and inundations in these two regions are compared with the field measurements and observations. Fairly good agreement is observed. Numerical results confirm again that the local bathymetric and topographic characteristics play important roles in determining the inundation area. Numerical simulations further indicate that although nonlinearity becomes important in many dynamic aspects when tsunamis approach the shore, its influence on determining the inundation area is relatively small in the regions examined for this tsunami event. Finally, the potential capability of sediment transport and a force index on a virtual structure in flooded areas are introduced and discussed.
Triboelectric Charge, Electrophysical Properties and ElectricalBeneficiation Potential of Chemically Treated Feldspar, Quartz and Wollastonite
Authors: Manouchehri H. R. , Hanumantha Rao K. , Forssberg K. S. E.
Published: October 2007

The triboelectric charge attributes of the pure feldspar, quartz and wollastonite mineral
samples, after contact with plate and cyclone type tribochargers made up of different
materials were investigated. The main electrical properties of the minerals, i.e., electrical
conductivity and dielectric constant, were measured and their energetic work functions
were estimated. In addition, the behaviour of mineral samples in the electric field of a
free‐fall separator before and after chemical treatment with different organic reagents
was deduced.

The results reveal that the cyclone tribochargers are more effective in imparting
charges on mineral grains. The reproducible charges with higher magnitudes are created
when cyclones are used for imparting charges on mineral grains. Furthermore, in spite of
having relatively similar energetic structures for the three minerals, the Teflon tribocharger
demonstrates the feasibility of quartz separation from wollastonite and feldspar.
The salicylic acid conditioning promotes feldspar‐wollastonite separation.
The Effect of Magnetic Field on the Performance of a Dense Medium Separator
Authors: Vatta L. L. , Kekana R. , Radebe B. , Myburgh I. , Svoboda J.
Published: October 2007

The application of a vertically oriented magnetic field external to a dense medium cyclone can be used to manipulate the density differential within the cyclone by influencing the cyclone′s internal ferrosilicon distribution. Tests were conducted on a well‐defined dense medium system using a pilot‐plant cyclone equipped with a solenoid magnet. The objective was to determine the yield to the dense medium cyclone underflow of a sample consisting predominantly of quartzite material, as a function of the magnetic field strength of the solenoid magnet, and as a function of solenoid position. It was observed that for a specific selection of magnetic field strength and solenoid position, the concentrate yield was reduced. A decrease in yield to concentrate is advantageous in that it reduces the mass of material to be processed downstream. The yield reduction was found to be a function of the applied magnetic field strength. Furthermore, it was found that a disruption in the ferrosilicon flow pattern inside the cyclone may occur beyond a certain magnetic field strength which leads to impaired cyclone operation.
Fetal Microchimerism in Women with Breast Cancer
Authors: Gadi Vijayakrishna K. , Nelson J. Lee
Published: October 2007

Fetal microchimerism (FMc) describes long-term persistence of small numbers of fetal-derived allogeneic cells in the mother. Although FMc has been implicated as a mechanism of autoimmune disease, it may confer a beneficial effect with immune surveillance of malignant cells. We hypothesized that allogeneic FMc imparts a protective effect against breast cancer. Two observations provided a rationale for the study hypothesis. First, allogeneic cells convey risk reduction for recurrent malignancy in hematopoietic cell transplantation. Second, reduced risk of breast cancer is well recognized among parous compared with nulliparous women. As an initial test of the hypothesis, we investigated 82 women, 35 with breast cancer and 47 who were healthy, for male DNA in peripheral blood, presumed from a prior pregnancy with a male fetus. The prevalence and levels of male DNA were determined by real-time quantitative PCR for the Y chromosome–specific gene DYS14 in DNA extracted from peripheral blood mononuclear cells. FMc was found significantly more often in healthy women than women with breast cancer (43% versus 14%, respectively). Considering the absence of FMc as a risk factor, the odds ratio was 4.4 [95% confidence intervals (95% CI), 1.34–16.99; P = 0.006]. Restricting analysis to women known to had given birth to a son, the odds ratio was 5.9 (95% CI, 1.26–6.69; P = 0.01). Our findings indicate that allogeneic FMc may contribute to reduction in risk of breast cancer. Further studies are indicated and, if confirmed, extended studies to examine whether allogeneic immune surveillance from FMc is deficient in women with breast cancer. [Cancer Res 2007;67(19):9035–8]
Cell Division Cycle 25B Phosphatase Is Essential for Benzo(a)Pyrene-7,8-Diol-9,10-Epoxide–Induced Neoplastic Transformation
Authors: Srivastava Sanjay K. , Bansal Pallavi , Oguri Tetsuya , Lazo John S. , Singh Shivendra V.
Published: October 2007

Cell division cycle 25B (Cdc25B) phosphatase controls entry into mitosis and regulates recovery from G2-M checkpoint-induced arrest. In the present study, we show that exposure of diploid mouse embryonic fibroblasts (MEF) to the ultimate carcinogen anti-benzo(a)pyrene (BP)-7,8-diol-9,10-epoxide (anti-BPDE) resulted in a concentration- and time-dependent increase in Cdc25B protein levels. Chronic exposure of wild-type (Cdc25B+/+) MEFs to anti-BPDE (0.1 μmol/L) caused neoplastic transformation characterized by colony formation in culture and tumor production in nude mice. In contrast, the Cdc25B null MEFs were resistant to anti-BPDE–induced transformation. Furthermore, a carcinogenic dose of the parent hydrocarbon (BP) increased Cdc25B protein levels in the target organ, lung. The biological importance of elevated Cdc25B levels was documented by the early reentry into mitosis of cells overexpressing ectopic Cdc25B levels even in the presence of DNA damage following anti-BPDE exposure, whereas control cells resumed only after DNA damage was repaired. We conclude that Cdc25B has an essential role in anti-BPDE–induced neoplastic transformation, including regulation of cell cycle resumption in the presence of DNA damage. [Cancer Res 2007;67(19):9150–7]
Reduced Body Size and Decreased Intestinal Tumor Rates in HDAC2-Mutant Mice
Authors: Zimmermann Stephan , Kiefer Franz , Prudenziati Michela , Spiller Carmen , Hansen Jens , Floss Thomas , Wurst Wolfgang , Minucci Saverio , Göttlicher Martin
Published: October 2007

Histone deacetylases (HDAC) reverse the acetylation of histone and nonhistone proteins and thereby modulate chromatin structure and function of nonhistone proteins. Many tumor cell lines and experimental tumors respond to HDAC inhibition. To assess the role of an individual HDAC isoenzyme in physiology and tumor development, HDAC2-mutant mice were generated from a gene trap embryonic stem cell clone. These mice express a catalytically inactive fusion protein of the NH2-terminal part of HDAC2 and β-galactosidase, which fails to integrate into corepressor complexes with mSin3B. They are the first class 1 HDAC mutant mice that are viable although they are ∼25% smaller than their littermates. Cell number and thickness of intestinal mucosa are reduced. Mutant embryonic fibroblasts fail to respond to insulin-like growth factor I (IGF) by the IGF-I–induced increase in cell number observed in wild-type cells. These data suggest a novel link between HDACs and IGF-I–dependent responses. Crossing of HDAC2-mutant with tumor-prone APCmin mice revealed tumor rates that are lower in HDAC2-deficient mice by 10% to 100% depending on segment of the gut and sex of the mice. These mice provide evidence that the key functions of HDAC2, although not essential for survival of the organism, play a rate-limiting role for tumor development in vivo. [Cancer Res 2007;67(19):9047–54]
Class III β-Tubulin Mediates Sensitivity to Chemotherapeutic Drugs in Non–Small Cell Lung Cancer
Authors: Gan Pei Pei , Pasquier Eddy , Kavallaris Maria
Published: October 2007

First line therapy for non–small cell lung carcinoma (NSCLC) commonly includes combination therapy with a tubulin-binding agent (TBA) and a DNA-damaging agent. TBAs suppress microtubule dynamics by binding to the β-tubulin subunit of α/β-tubulin, inducing mitotic arrest and apoptosis. Up-regulation of class III β-tubulin (βIII-tubulin) has been implicated in clinical resistance in NSCLC, ovarian and breast tumors treated in combination with a TBA and DNA-damaging agent. To investigate the functional significance of βIII-tubulin in resistance to both these classes of agents, small interfering RNA (siRNA) was used to silence the expression of this isotype in two NSCLC cell lines, NCI-H460 and Calu-6. Reverse transcription-PCR and immunoblotting showed that βIII-siRNA potently inhibited the expression of βIII-tubulin, without affecting the expression of other major β-tubulin isotypes. Clonogenic assays showed that βIII-siRNA cells were significantly more sensitive to TBAs, paclitaxel, vincristine, and vinorelbine, and for the first time, DNA-damaging agents, cisplatin, doxorubicin, and etoposide compared with controls. Cell cycle analysis of H460 βIII-siRNA cells showed reduced accumulation at the G2-M boundary and an increase in the sub-G1 population in response to TBA treatment compared with control cells. Importantly, βIII-siRNA cells displayed a significant dose-dependent increase in Annexin V staining when treated with either paclitaxel or cisplatin, compared with controls. These findings have revealed a novel role for βIII-tubulin in mediating response to both TBA and DNA-damaging agent therapy and may have important implications for improving the targeting and treatment of drug-refractory NSCLC. [Cancer Res 2007;67(19):9356–63]
Inhibitors of Ubiquitin-Activating Enzyme (E1), a New Class of Potential Cancer Therapeutics
Authors: Yang Yili , Kitagaki Jirouta , Dai Ren-Ming , Tsai Yien Che , Lorick Kevin L. , Ludwig Robert L. , Pierre Shervon A. , Jensen Jane P. , Davydov Ilia V. , Oberoi Pankaj , Li Chou-Chi H. , Kenten John H. , Beutler John A. , Vousden Karen H. , Weissman Allan M.
Published: October 2007

The conjugation of proteins with ubiquitin plays numerous regulatory roles through both proteasomal-dependent and nonproteasomal-dependent functions. Alterations in ubiquitylation are observed in a wide range of pathologic conditions, including numerous malignancies. For this reason, there is great interest in targeting the ubiquitin-proteasome system in cancer. Several classes of proteasome inhibitors, which block degradation of ubiquitylated proteins, are widely used in research, and one, Bortezomib, is now in clinical use. Despite the well-defined and central role of the ubiquitin-activating enzyme (E1), no cell permeable inhibitors of E1 have been identified. Such inhibitors should, in principle, block all functions of ubiquitylation. We now report 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) as the first such inhibitor. Unexpectedly, in addition to blocking ubiquitylation, PYR-41 increased total sumoylation in cells. The molecular basis for this is unknown; however, increased sumoylation was also observed in cells harboring temperature-sensitive E1. Functionally, PYR-41 attenuates cytokine-mediated nuclear factor-κB activation. This correlates with inhibition of nonproteasomal (Lys-63) ubiquitylation of TRAF6, which is essential to IκB kinase activation. PYR-41 also prevents the downstream ubiquitylation and proteasomal degradation of IκBα. Furthermore, PYR-41 inhibits degradation of p53 and activates the transcriptional activity of this tumor suppressor. Consistent with this, it differentially kills transformed p53-expressing cells. Thus, PYR-41 and related pyrazones provide proof of principle for the capacity to differentially kill transformed cells, suggesting the potential for E1 inhibitors as therapeutics in cancer. These inhibitors can also be valuable tools for studying ubiquitylation. [Cancer Res 2007;67(19):9472–81]
Heat Shock Protein 90α Recruits FLIPS to the Death-Inducing Signaling Complex and Contributes to TRAIL Resistance in Human Glioma
Authors: Panner Amith , Murray Joseph C. , Berger Mitchel S. , Pieper Russell O.
Published: October 2007

Heat shock protein 90 (HSP90) is a molecular chaperone that contributes to the proper folding and stability of target proteins. Because HSP90 has been suggested to interact with FLIPS, the key regulator of tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in glioma cells, we examined the role HSP90 played in controlling TRAIL response. HSP90α was found to associate with FLIPS in resting cells in a manner dependent on the ATP-binding NH2-terminal domain of HSP90α. Following TRAIL exposure, HSP90α and the client FLIPS protein were recruited to the death-inducing signaling complex (DISC). Short interfering RNA–mediated suppression of HSP90α did not alter the total cellular levels of FLIPS, but rather inhibited the recruitment of FLIPS and other antiapoptotic proteins such as RIP and FLIPL to the DISC, and sensitized otherwise resistant glioma cells to TRAIL-induced apoptosis. These results show that HSP90α, by localizing FLIPS to the DISC, plays a key role in the resistance of tumor cells to TRAIL, and perhaps other proapoptotic agents. The results also define a novel means of apoptotic control by a HSP90α that may in turn help explain the global antiapoptotic effects of this protein. [Cancer Res 2007;67(19):9482–9]
Reduction in IκB Kinase α Expression Promotes the Development of Skin Papillomas and Carcinomas
Authors: Park Eunmi , Zhu Feng , Liu Bigang , Xia Xiaojun , Shen Jianjun , Bustos Tracie , Fischer Susan M. , Hu Yinling
Published: October 2007

We reported recently a marked reduction in IκB kinase α (IKKα) expression in a large proportion of human poorly differentiated squamous cell carcinomas (SCC) and the occurrence of Ikkα mutations in human SCCs. In addition, overexpression of IKKα in the epidermis inhibited the development of skin carcinomas and metastases in mice. However, whether a reduction in IKKα expression promotes skin tumor development is currently unknown. Here, we assessed the susceptibility of Ikkα hemizygotes to chemical carcinogen-induced skin carcinogenesis. Ikkα+/− mice developed 2 times more papillomas and 11 times more carcinomas than did Ikkα+/+ mice. The tumors were larger in Ikkα+/− than in Ikkα+/+ mice, but tumor latency was shorter in Ikkα+/− than in Ikkα+/+ mice. Some of the Ikkα+/− papillomas and most Ikkα+/− carcinomas lost the remaining Ikkα wild-type allele. Somatic Ikkα mutations were detected in carcinomas and papillomas. The chemical carcinogen-induced H-Ras mutations were detected in all the tumors. The phorbol ester tumor promoter induced higher mitogenic and angiogenic activities in Ikkα+/− than in Ikkα+/+ skin. These elevated activities were intrinsic to keratinocytes, suggesting that a reduction in IKKα expression provided a selective growth advantage, which cooperated with H-Ras mutations to promote papilloma formation. Furthermore, excessive extracellular signal-regulated kinase and IKK kinase activities were observed in carcinomas compared with those in papillomas. Thus, the combined mitogenic, angiogenic, and IKK activities might contribute to malignant conversion. Our findings provide evidence that a reduction in IKKα expression promotes the development of papillomas and carcinomas and that the integrity of the Ikkα gene is required for suppressing skin carcinogenesis. [Cancer Res 2007;67(19):9158–68]
The Multikinase Inhibitor Sorafenib Potentiates TRAIL Lethality in Human Leukemia Cells in Association with Mcl-1 and cFLIPL Down-regulation
Authors: Rosato Roberto R. , Almenara Jorge A. , Coe Stefanie , Grant Steven
Published: October 2007

Interactions between the multikinase inhibitor sorafenib and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were examined in malignant hematopoietic cells. Pretreatment (24 h) of U937 leukemia cells with 7.5 μmol/L sorafenib dramatically increased apoptosis induced by sublethal concentrations of TRAIL/Apo2L (75 ng/mL). Similar interactions were observed in Raji, Jurkat, Karpas, K562, U266 cells, primary acute myelogenous leukemia blasts, but not in normal CD34+ bone marrow cells. Sorafenib/TRAIL–induced cell death was accompanied by mitochondrial injury and release of cytochrome c, Smac, and AIF into the cytosol and caspase-9, caspase-3, caspase-7, and caspase-8 activation. Sorafenib pretreatment down-regulated Bcl-xL and abrogated Mcl-1 expression, whereas addition of TRAIL sharply increased Bid activation, conformational change of Bak (ccBak) and Bax (ccBax), and Bax translocation. Ectopic Mcl-1 expression significantly attenuated sorafenib/TRAIL–mediated lethality and dramatically reduced ccBak while minimally affecting levels of ccBax. Similarly, inhibition of the receptor-mediated apoptotic cascade with a caspase-8 dominant-negative mutant significantly blocked sorafenib/TRAIL–induced lethality but not Mcl-1 down-regulation or Bak/Bax conformational change, indicating that TRAIL-mediated receptor pathway activation is required for maximal lethality. Sorafenib/TRAIL did not increase expression of DR4/DR5, or recruitment of procaspase-8 or FADD to the death-inducing signaling complex (DISC), but strikingly increased DISC-associated procaspase-8 activation. Sorafenib also down-regulated cFLIPL, most likely through a translational mechanism, in association with diminished eIF4E phosphorylation, whereas ectopic expression of cFLIPL significantly reduced sorafenib/TRAIL lethality. Together, these results suggest that in human leukemia cells, sorafenib potentiates TRAIL-induced lethality by down-regulating Mcl-1 and cFLIPL, events that cooperate to engage the intrinsic and extrinsic apoptotic cascades, culminating in pronounced mitochondrial injury and apoptosis. [Cancer Res 2007;67(19):9490–500]
Serial Assessment of Human Tumor Burdens in Mice by the Analysis of Circulating DNA
Authors: Rago Carlo , Huso David L. , Diehl Frank , Karim Baktiar , Liu Guosheng , Papadopoulos Nickolas , Samuels Yardena , Velculescu Victor E. , Vogelstein Bert , Kinzler Kenneth W. , Diaz Luis A.
Published: October 2007

Internal human xenografts provide valuable animal models to study the microenvironments and metastatic processes occurring in human cancers. However, the use of such models is hampered by the logistical difficulties of reproducibly and simply assessing tumor burden. We developed a high-sensitivity assay for quantifying human DNA in small volumes of mouse plasma, enabling in-life monitoring of systemic tumor burden. Growth kinetics analyses of various xenograft models showed the utility of circulating human DNA as a biomarker. We found that human DNA concentration reproducibly increased with disease progression and decreased after successful therapeutic intervention. A marked, transient spike in circulating human tumor DNA occurred immediately after cytotoxic therapy or surgery. This simple assay may find broad utility in target validation studies and preclinical drug development programs. [Cancer Res 2007;67(19):9364–70]
In vivo Imaging of the Systemic Recruitment of Fibroblasts to the Angiogenic Rim of Ovarian Carcinoma Tumors
Authors: Granot Dorit , Addadi Yoseph , Kalchenko Vyacheslav , Harmelin Alon , Kunz-Schughart Leoni A. , Neeman Michal
Published: October 2007

Tumor-associated stroma, in general, and tumor fibroblasts and myofibroblasts, in particular, play a role in tumor progression. We previously reported that myofibroblast infiltration into implanted ovarian carcinoma spheroids marked the exit of tumors from dormancy and that these cells contributed to vascular stabilization in ovarian tumors by expression of angiopoietin-1 and angiopoietin-2. Ex vivo labeling of fibroblasts with either magnetic resonance or optical probes rendered them detectable for in vivo imaging. Thus, magnetic resonance imaging (MRI) follow-up was feasible by biotin-bovine serum albumin-gadolinium diethylenetriaminepentaacetic acid or iron oxide particles, whereas labeling with near-IR and fluorescent vital stains enabled in vivo visualization by near-IR imaging and two-photon microscopy. Using this approach, we show here that prelabeled fibroblasts given i.p. to CD-1 nude mice can be followed in vivo by MRI and optical imaging over several days, revealing their extensive recruitment into the stroma of remote s.c. MLS human epithelial ovarian carcinoma tumors. Two-photon microscopy revealed the alignment of these invading fibroblasts in the outer rim of the tumor, colocalizing with the angiogenic neovasculature. Such angiogenic vessels remained confined to the stroma tracks within the tumor and did not penetrate the tumor nodules. These results provide dynamic evidence for the role of tumor fibroblasts in maintenance of functional tumor vasculature and offer means for image-guided targeting of these abundant stroma cells to the tumor as a possible mechanism for cellular cancer therapy. [Cancer Res 2007;67(19):9180–9]
Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer
Authors: Buchanan F. Gregory , Holla Vijay , Katkuri Sharada , Matta Pranathi , DuBois Raymond N.
Published: October 2007

Clinical and animal studies indicate a role for cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) in the development and progression of intestinal polyps and cancers. Although this combination of enzyme inhibition has shown synergy in intestinal polyp and tumor models, the exact mechanism for these effects remains undefined. Therefore, we sought to define the molecular mechanisms through which this process occurs. We observed a significant reduction in the number and size of small intestinal polyps in APCmin+/− mice treated with either celecoxib (a selective COX-2 inhibitor) or erlotinib (Tarceva, an EGFR inhibitor). However, in combination, there was an overall prevention in the formation of polyps by over 96%. Furthermore, we observed a 70% reduction of colorectal xenograft tumors in mice treated with the combination and microarray analysis revealed genes involved in cell cycle progression were negatively regulated. Although we did not observe significant changes in mRNAs of genes with known apoptotic function, there was a significant increase of apoptosis in tumors from animals treated with the combination. The inhibition of EGFR also induced the down-regulation of COX-2 and further inhibited prostaglandin E2 formation. We observed similar effects on the prevention of intestinal adenomas and reduction of xenograft tumor volume when nonselective COX inhibitors were used in combination with erlotinib. Together, these findings suggest that the inhibition of both COX-2 and EGFR may provide a better therapeutic strategy than either single agent through a combination of decreased cellular proliferation and prostaglandin signaling as well as increased apoptosis. [Cancer Res 2007;67(19):9380–8]
Aberrant Expression of Cortactin in Head and Neck Squamous Cell Carcinoma Cells Is Associated with Enhanced Cell Proliferation and Resistance to the Epidermal Growth Factor Receptor Inhibitor Gefitinib
Authors: Timpson Paul , Wilson Ashleigh S. , Lehrbach Gillian M. , Sutherland Robert L. , Musgrove Elizabeth A. , Daly Roger J.
Published: October 2007

The CTTN gene (formerly designated EMS1), encodes cortactin, a key regulator of dynamic actin networks. Both CTTN and CCND1, the latter encoding the cell cycle regulator cyclin D1, reside at chromosomal locus 11q13, a region commonly amplified in breast cancers and head and neck squamous cell carcinoma (HNSCC). Previously, we identified a novel role for cortactin in cancer cells, whereby cortactin overexpression attenuated ligand-induced down-regulation of the epidermal growth factor (EGF) receptor (EGFR), leading to sustained signaling. However, how this affected growth factor–induced cellular responses was unclear. Here, by modulation of cortactin expression in a panel of HNSCC cell lines, we show that cortactin overexpression enhances serum- and EGF-stimulated proliferation under both anchorage-dependent and anchorage-independent conditions and also increases resistance to anoikis (detachment-induced apoptosis). These effects are associated with increased activation of extracellular signal-regulated kinase and/or AKT. Furthermore, we report that cortactin stabilizes the c-MET receptor tyrosine kinase and enhances hepatocyte growth factor–induced mitogenesis and cell scattering. Therefore, cortactin may modulate signaling by a broader range of receptors than originally proposed and thereby affect a variety of responses. Finally, we have determined that cortactin overexpression, either alone or in combination with cyclin D1 up-regulation, promotes resistance to the EGFR kinase inhibitor gefitinib. These findings indicate that cortactin may play multiple roles in progression of HNSCC and should be evaluated as a marker of prognosis, disease progression, and therapeutic responsiveness, particularly to EGFR-directed agents. [Cancer Res 2007;67(19):9304–14]
Opposing Function of the Proprotein Convertases Furin and PACE4 on Breast Cancer Cells' Malignant Phenotypes: Role of Tissue Inhibitors of Metalloproteinase-1
Authors: Lapierre Marion , Siegfried Geraldine , Scamuffa Nathalie , Bontemps Yannick , Calvo Fabien , Seidah Nabil G. , Khatib Abdel-Majid
Published: October 2007

Proteolytic cleavage of various cancer-related substrates by the proprotein convertases (PC) was reported to be important in the processes of neoplasia. These enzymes are inhibited by their naturally occurring inhibitors, the prosegments (ppPC), and by the engineered general PC inhibitor, the serpin variant α1-PDX. In the present study, we sought to compare the effect of these PC inhibitors on malignant phenotypes of breast cancer cells. Overexpression in a stable manner of α1-PDX and the prosegment ppPACE4 in MDA-MB-231 breast cancer cells resulted in increased matrix metalloproteinase (MMP)-9 (but not MMP-2) activity and a reduced secretion of tissue inhibitor of metalloproteinase 1 (TIMP-1). This was associated with significant enhancement in cell motility, migration, and invasion of collagen in vitro. In contrast, ppFurin expression in these cells decreased MMP-9 activity and diminished these biological functions, but had no significant effect on TIMP-1 secretion. Taken together, these data showed the specific and opposing roles of Furin and PACE4 in the regulation of MMP-9/TIMP-1–mediated cell motility and invasion. [Cancer Res 2007;67(19):9030–4]
Local Administration of Interleukin-11 Ameliorates Intestinal Radiation Injury in Rats
Authors: Boerma Marjan , Wang Junru , Burnett Alexander F. , Santin Alessandro D. , Roman Juan J. , Hauer-Jensen Martin
Published: October 2007

Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 ± 0.6 in the vehicle group versus 4.0 ± 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 ± 0.1 versus 0.5 ± 0.03; P < 0.0001), and intestinal wall thickening (842 ± 66 μm versus 643 ± 54 μm; P = 0.02), reduced postradiation transforming growth factor-β overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic. [Cancer Res 2007;67(19):9501–6]
Snail-Induced Down-Regulation of ΔNp63α Acquires Invasive Phenotype of Human Squamous Cell Carcinoma
Authors: Higashikawa Koichiro , Yoneda Shingo , Tobiume Kei , Taki Masayuki , Shigeishi Hideo , Kamata Nobuyuki
Published: October 2007

p63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelial-to-mesenchymal transition (EMT) is accompanied by down-regulation of p63 in human squamous cell carcinomas (SCC). ΔNp63α is the predominantly expressed p63 isoform in SCC cells. ΔNp63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation of ΔNp63α and reduction of C/EBPα were observed in EMT phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of ΔNp63α blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail down-regulates ΔNp63α, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of ΔNp63α does not require down-regulation of E-cadherin. [Cancer Res 2007;67(19):9207–13]
Evidence for Calpain-Mediated Androgen Receptor Cleavage as a Mechanism for Androgen Independence
Authors: Libertini Stephen J. , Tepper Clifford G. , Rodriguez Veronica , Asmuth David M. , Kung Hsing-Jien , Mudryj Maria
Published: October 2007

Prostate carcinoma is the most commonly diagnosed cancer in men and the second leading cause of death due to cancer in Western civilization. Androgen ablation therapy is effective in treating androgen-dependent tumors, but eventually, androgen-independent tumors recur and are refractory to conventional chemotherapeutics. Hence, the emergence of androgen independence is the most challenging problem in managing prostate tumors. We report a novel mechanism of androgen independence: calpain cleaves the androgen receptor (AR) into an androgen-independent isoform. In vitro and in vivo analyses show that calpain removes the COOH-terminal ligand binding domain generating a constitutively active molecule. Analysis of human prostate tumors indicates that several tumors express higher levels of this truncated AR than noncancerous prostate tissue. In transient transfection studies, the truncated AR is three to five times more potent than the full-length receptor in transactivating transcription. The androgen-independent Rv1 cells express high levels of the truncated AR, and treatment of these cells with a calpain inhibitor reduces truncated AR expression. In the absence of androgen, inhibition of calpain activity induces apoptosis. The HIV protease inhibitor amprenavir inhibits calpain activity and is also effective in inducing apoptosis in the Rv1 cell line. The cell culture studies were reproduced in a mouse xenograft model, where, in the absence of androgens, amprenavir significantly reduces tumor growth. Together, these studies indicate that calpain-dependent proteolysis of the AR may be a mechanism of androgen independence. The calpain inhibition studies suggest that inhibiting this activity may be a potential treatment for some androgen-independent prostate tumors. [Cancer Res 2007;67(19):9001–5]
Whole-Genome Profiling in Liposarcomas Reveals Genetic Alterations Common to Specific Telomere Maintenance Mechanisms
Authors: Johnson Jay E. , Gettings Edward J. , Schwalm Jaclyn , Pei Jianming , Testa Joseph R. , Litwin Samuel , von Mehren Margaret , Broccoli Dominique
Published: October 2007

Telomere attrition ultimately leads to the activation of protective cellular responses, such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we use a liposarcoma model system to assay telomere maintenance mechanism (TMM)–specific genetic alterations. A multiassay approach was used to assess the TMMs active in tumors. Genomic DNA from these samples was then analyzed by high-resolution DNA mapping array to identify genetic alterations. Our data reveal a higher level of genome instability in alternative lengthening of telomere (ALT)–positive tumors compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance used. We also identified genetic changes specific to the ALT mechanism (e.g., deletion of chromosome 1q32.2-q44) as well as changes that are underrepresented among ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. [Cancer Res 2007;67(19):9221–8]
Smad7 Sensitizes Tumor Necrosis Factor–Induced Apoptosis through the Inhibition of Antiapoptotic Gene Expression by Suppressing Activation of the Nuclear Factor-κB Pathway
Authors: Hong Suntaek , Lee Chan , Kim Seong-Jin
Published: October 2007

Although tumor necrosis factor (TNF) induces apoptosis and cell death in many tumor cells, some cancer cells are still resistant to the TNF-induced death signal. In this report, we showed that Smad7, an inhibitory Smad of transforming growth factor-β (TGF-β) signaling, can overcome the TNF resistance in human breast and gastric cancer cells. Overexpression of Smad7 induces the degradation of poly(ADP-ribose) polymerase and the activation of caspase cascade. Although c-Jun NH2-terminal kinase (JNK) signaling is involved in TNF-induced cell death, the expression of Smad7 does not synergize the activation of JNK. However, the activation of nuclear factor-κB (NF-κB), the cell survival factor, is markedly decreased in Smad7-stable cells. Furthermore, the expression of antiapoptotic target genes of NF-κB is significantly reduced in accordance with the level of Smad7. In addition, Smad7 mediates the inhibitory activity of TGF-β on TNF-induced NF-κB activation and the synergistic activity of TGF-β on TNF-induced apoptosis. These findings suggest that Smad7 sensitizes the tumor cells to TNF-induced apoptosis through the inhibition of expression of antiapoptotic NF-κB target genes. [Cancer Res 2007;67(19):9577–83]
The Phosphoinositide Kinase PIKfyve Mediates Epidermal Growth Factor Receptor Trafficking to the Nucleus
Authors: Kim Jayoung , Jahng Wan Jin , Di Vizio Dolores , Lee Julie S. , Jhaveri Raj , Rubin Mark A. , Shisheva Assia , Freeman Michael R.
Published: October 2007

ErbB receptor tyrosine kinases can transit to nuclei in tumor cells, where they have been shown to regulate gene expression as components of transcriptional complexes. Quantitative analysis of a human bladder cancer tissue microarray identified nuclear epidermal growth factor receptor (EGFR) in tumor cells and also showed an increased frequency of this histologic feature in cancer relative to normal tissues. This observation suggests a potential role for nuclear EGFR in bladder cancer. We confirmed that EGFR could be induced to transit to nuclei in cultured human bladder cancer cells in response to the urothelial cell growth factor and EGFR ligand heparin-binding EGF-like growth factor (HB-EGF). Mass spectrometric analysis of EGFR immune complexes from a transitional carcinoma cell line (TCCSUP) identified the phosphoinositide kinase, PIKfyve, as a potential component of the EGFR trafficking mechanism. RNA silencing indicated that PIKfyve is a mediator of HB-EGF–stimulated EGFR nuclear trafficking, EGFR binding to the cyclin D1 promoter, and cell cycle progression. These results identify a novel mediator of the EGFR transcription function and further suggest that nuclear EGFR and the lipid kinase PIKfyve may play a role in bladder oncogenesis. [Cancer Res 2007;67(19):9229–37]
Relocalized p27Kip1 Tumor Suppressor Functions as a Cytoplasmic Metastatic Oncogene in Melanoma
Authors: Denicourt Catherine , Saenz Cheryl C. , Datnow Brian , Cui Xian-Shu , Dowdy Steven F.
Published: October 2007

The p27 tumor suppressor negatively regulates G1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membrane–confined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non–cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss. [Cancer Res 2007;67(19):9238–43]