bluuebunny/crossref_metadata_2025 huggingface dataset:
NEUTRINO SPIN OSCILLATIONS IN GRAVITATIONAL FIELDS
Authors: DVORNIKOV MAXIM
Published: September 2006

We study neutrino spin oscillations in gravitational fields. The quasi-classical approach is used to describe the neutrino spin evolution. First we examine the case of a weak gravitational field. We obtain the effective Hamiltonian for the description of neutrino spin oscillations. We also receive the neutrino transition probability when a particle propagates in the gravitational field of a rotating massive object. Then we apply the general technique to the description of neutrino spin oscillations in the Schwarzschild metric. The neutrino spin evolution equation for the case of the neutrino motion in the vicinity of a black hole is obtained. The effective Hamiltonian and the transition probability are also derived. We examine the neutrino oscillations process on different circular orbits and analyze the frequencies of spin transitions. The validity of the quasi-classical approach is also considered.
A NEW KIND OF UNIFORMLY ACCELERATED REFERENCE FRAMES
Authors: HUANG CHAO-GUANG , GUO HAN-YING
Published: September 2006

A new kind of uniformly accelerated reference frames with a line-element different from the Møller and Rindler ones is presented, in which every observer at x, y, z = const. has the same constant acceleration. The laws of mechanics are checked in the new kind of frames. Its thermal property is studied. The comparison with the Møller and Rindler uniform accelerated reference frames is also made.
ANISOTROPIC SELF-SIMILAR COSMOLOGICAL MODEL WITH DARK ENERGY
Authors: PEREIRA P. R. , DA SILVA M. F. A. , CHAN R.
Published: September 2006

We study space–times having spherically symmetric anisotropic fluid with self-similarity of zeroth kind. We find a class of solutions to the Einstein field equations by assuming a shear-free metric and that the fluid moves along time-like geodesics. The energy conditions, and geometrical and physical properties of the solutions are studied and we find that it can be considered as representing an accelerating universe. At the beginning all the energy conditions were fulfilled but beyond a certain time (a maximum geometrical radius) none of them is satisfied, characterizing a transition from normal matter (dark matter, baryon matter and radiation) to dark energy.
Building Capability through Cognitive Apprenticeship: The Singapore Armed Forces Competency-Based Learning Project
Authors: Quek Pek Noi
Published: September 2006

The Singapore Armed Forces (SAF) Competency-Based Learning (CBL) Project is a cognitive apprenticeship designed by the Learning Development Project Office in SAFTI Military Institute, Singapore to assist SAF in establishing long-term indigenous capability in the CBL methodology to facilitate curriculum development in the Third Generation SAF. This project aims to translate the SAF Leadership Competency Model through an infusion of the CBL methodology in selected SAF schoolhouse training and educational curricula in an engagement with an external consultancy, and ensure SAF internalises the CBL methodology from the consultancy for large-scale independent implementation and sustainability in the long-term. Situated cognition, social constructivism and knowledge-creation through socialisation theories from which cognitive apprenticeship is based are also briefly discussed. In addition, the SAF CBL Project also requires SAF-consultancy interactions to be designed for optimisation of learning and knowledge acquisition (KA) outcomes. Specifically, the SAF CBL cognitive apprenticeship uses knowledge elicitation tools and techniques in a SAF CBL KA process to learn and construct knowledge of the CBL methodology through participation in shared experiences with the consultant team, and capturing of lessons learnt and best practices from which individual learning and team learning through socialisation can take place.
CLARA and ScienTI Networks: Technology and Information for Knowledge Building in the Latin American Scientific Community
Authors: Sartori Rejane , Pacheco Roberto Carlos Dos Santos
Published: September 2006

Knowledge-based development produces wealth and opens the frontiers of competitiveness, technological innovation and wealth distribution. In developed countries the process is intrinsically bound to the ability of innovative production and the dynamics of network knowledge construction. Within this process the academic and research communities participate effectively in the dynamics of knowledge and innovation, an environment strongly based on information and communication technology. However, when compared to the dynamics of developed countries, the formation of such communities in Latin America is rare. In this context CLARA (Latin American Cooperation in Advanced Networks) and ScienTI (Information and Knowledge Network in Science, Technology and Innovation) networks are strategies for the establishment, dissemination and foment of scientific knowledge in Latin America. CLARA integrates national academy networks in Latin America which links about 700 universities and research centers in the area. ScienTI network establishes and links scientific information sources in eleven countries within the area. The formation of a gigantic Latin American research community which links researchers, projects, and studies has an important role in building a world of science and education in the future. The formation and the functioning of the networks will be discussed from the community's knowledge building point of view in Latin America.
Mapping Knowledge in Product Development through Process Modelling
Authors: Deng Qianwang , Yu Dejie
Published: September 2006

The product development capability is a core competence in a company, and the product development process is a knowledge-intensive process. The evolution of engineering design shows that knowledge is a key factor of a successful product development. From the 70's in the last century, artificial intelligence has been introduced into this field. It evolves from expert system through knowledge-based system to current knowledge management. Knowledge taxonomy is a core component in knowledge management. A new approach of mapping knowledge in product development through process modelling is proposed. Product development process modelling can help people structure knowledge and the employees linking to each activity in the product development process. According to the analysis of product development process models, there exist three basic kinds of objects: product states, process elements, and resources. The state-process-resource model provides available ontologies of knowledge in the product development domain. In this way, knowledge is hierarchically classified into six knowledge subjects: product, product process, process element, method, tool, and application specific domain. Furthermore, each of the knowledge subjects is divided into three types of knowledge: course, practice, and expertise location.
A STATIC ANALOG OF MOLECULAR DYNAMICS METHOD FOR CRYSTALS
Authors: VINOGRADOV OLEG
Published: September 2006

A new method of molecular statics based on independent displacements of atoms converging to an equilibrium state is proposed. It is analogous to the molecular dynamics method and thus has similar advantages in terms of the system size which can be simulated, as well as the utilization of parallel computation. At the same time, it allows the study of fracture, crack nucleation and propagation, etc. without the computer time constraints associated with time steps in molecular dynamics. The method is demonstrated for a 2D crystal with one deficiency.
GRID-BASED ACO ALGORITHM FOR PARAMETERS TUNING OF NLPID CONTROLLER AND ITS APPLICATION IN FLIGHT SIMULATOR
Authors: DUAN HAI-BIN , WANG DAO-BO , YU XIU-FEN
Published: September 2006

This paper presents an application of Ant Colony Optimization (ACO) algorithm to tune the parameters in the design of a novel type of nonlinear proportional-integral-differential (NLPID) controller, which is used in flight simulator. A differential tracker and a reference generator are included in the NLPID controller. The differential tracker is used to track output position and its differential, while the reference generator is used to generate reference input signals. ACO algorithm is a novel heuristic algorithm, which is based on the process of real ants in the nature searching for food. In order to tune the parameters of the NLPID controller using the new proposed grid-based ACO algorithm, an objective function based on position tracing error is constructed. The parameters tuning of NLPID can be summed up as the typical continual spatial optimization problem, grid-based searching strategy is adopted in the improved ACO algorithm, and self-adaptive control strategy for the pheromone decay parameter is also adopted. In order to enhance the searching speed, pair ants which searched from two different mesh points at the same time are used. The body structure and control system architecture of a type of flight simulator with the grid-based ACO algorithm optimized NLPID are also proposed. The simulation results demonstrate that both for the standard and random input signals, the tracking error is very small, and the whole control system with grid-based ACO algorithm optimized NLPID has quick response performance and strong robustness.
ANALYSIS OF A RIGID-PLASTIC ROLLING PROBLEM WITH SLIGHTLY COMPRESSIBLE MATERIAL MODEL
Authors: ANGELOV T. A.
Published: September 2006

A steady-state rolling problem with rigid-plastic, strain-rate sensitive, slightly compressible material model and nonlinear Coulomb friction law is considered. For the corresponding variational problem, existence, uniqueness and convergence results, at compressibility parameter approaching zero, are obtained. A regularized variational problem is stated and studied and its finite element approximation is analyzed. Two computational algorithms are proposed and applied to solve an illustrative example.
EFFICIENT COMPUTATION OF MULTIPLIERLESS FILTERS IN EMBEDDED SYSTEMS EMPLOYING AN OPTIMAL APPROXIMATION METHOD
Authors: ZHANG WEI , YEARY MARK , TRELEWICZ J. Q. , TULL MONTE
Published: September 2006

An integerization technique for creating fixed integer transforms with computationally optimal representations is presented, and the improved performance in embedded systems by employing these integerized implementations is explored. This technique uses an optimal approximation algorithm that finds the lowest-length fractional representation of the rational numbers. The integer transform approximation allows multiplication to be replaced by shift-and-add operations in hardware systems; where multiplication can take several cycles, shifts and adds take one or fewer cycles each. The multiplierless implementation furthermore benefits from employing the proposed method to represent the floating-point coefficients in very high precision requirement areas, like decimation filter design. This paper is strongly oriented around the design of coefficients with hardware constraints in mind, such as minimizing the number of required adds/subtracts and shifts required for some engineering algorithms.
Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes
Authors: Aghi Manish , Cohen Kenneth S. , Klein Rachael J. , Scadden David T. , Chiocca E. Antonio
Published: September 2006

Mechanisms underlying tumor vasculogenesis, the homing and engraftment of bone marrow–derived vascular progenitors, remain undefined. We hypothesized that tumor cell–secreted factors regulate vasculogenesis. We studied vasculogenic and nonvasculogenic intracranial murine gliomas. A PCR screen identified stromal-derived factor-1 (SDF-1/CXCL12) and vascular endothelial growth factor (VEGF) expression by vasculogenic glioma cells and spontaneously arising vasculogenic tumors in NF1+/−:Trp53+/− mice, but not by nonvasculogenic glioma cells. Enforced SDF-1, not VEGF, expression in nonvasculogenic cells caused vasculogenesis. Combined SDF-1 and VEGF expression augmented vasculogenesis over SDF-1 expression alone. Blocking SDF-1 receptor CXCR4 reduced short-term homing and long-term engraftment of vascular progenitors. Implanting tumor cells secreting SDF-1 was therefore necessary and sufficient to incorporate marrow-derived precursors into tumor endothelium. SDF-1 seemed to exert these effects by acting locally intratumorally and did not cause an efflux of marrow-derived progenitors into circulation. Tumor microenvironment determined additional fates of marrow-derived cells. Hypoxia, observed with ectopic s.c. murine tumors at levels approximating that of intracranial human glioblastoma, interacted with tumor-secreted SDF-1 to expand engrafted vascular progenitor differentiated phenotypes to include pericytes as well as endothelium. In contrast, less hypoxic orthotopic intracranial murine gliomas contained only marrow-derived endothelium without marrow-derived pericytes. Furthermore, we found that vasculogenesis is significant for tumors because it generates endothelium with a higher mitotic index than endothelium derived from local sources. Although CXCR4 blockade selectively targeted endothelium generated by vasculogenesis, completely inhibiting vessel formation may require combination therapy targeting locally derived and marrow-derived endothelium. (Cancer Res 2006; 66(18): 9054-64)
Chemosensitization by Knockdown of Adenine Nucleotide Translocase-2
Authors: Le Bras Morgane , Borgne-Sanchez Annie , Touat Zahia , El Dein Ossama Sharaf , Deniaud Aurélien , Maillier Evelyne , Lecellier Gael , Rebouillat Dominique , Lemaire Christophe , Kroemer Guido , Jacotot Etienne , Brenner Catherine
Published: September 2006

Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization. (Cancer Res 2006; 66(18): 9143-52)
EPHB4 and Survival of Colorectal Cancer Patients
Authors: Davalos Veronica , Dopeso Higinio , Castaño Julio , Wilson Andrew J. , Vilardell Felip , Romero-Gimenez Jordi , Espín Eloy , Armengol Manel , Capella Gabriel , Mariadason John M. , Aaltonen Lauri A. , Schwartz Simo , Arango Diego
Published: September 2006

The family of receptor tyrosine kinases EPH and their Ephrin ligands regulate cell proliferation, migration, and attachment. An important role in colorectal carcinogenesis is emerging for some of its members. In this study, we evaluate the role of EPHB4 in colorectal cancer and its value as a prognostic marker. EPHB4 levels were assessed by immunohistochemical staining of tissue microarrays of 137 colorectal tumors and aberrant hypermethylation of the EPHB4 promoter was investigated using methylation-specific PCR. We found that EPHB4 expression is frequently reduced or lost in colorectal tumors. Patients with low EPHB4 tumor levels had significantly shorter survival than patients in the high EPHB4 group (median survival, 1.8 and >9 years, respectively; P < 0.01, log-rank test), and this finding was validated using an independent set of 125 tumor samples. In addition, we show that EPHB4 promoter hypermethylation is a common mechanism of EPHB4 inactivation. Moreover, reintroduction of EPHB4 resulted in a significant reduction in the clonogenic potential of EPHB4-deficient cells, whereas abrogation of EPHB4 in cells with high levels of this receptor lead to a significant increase in clonogenicity. In summary, we identified EPHB4 as a useful prognostic marker for colorectal cancer. In addition, we provide mechanistic evidence showing that promoter methylation regulates EPHB4 transcription and functional evidence that EPHB4 can regulate the long-term clonogenic potential of colorectal tumor cells, revealing EPHB4 as a potential new tumor suppressor gene in colorectal cancer. (Cancer Res 2006; 66(18): 8943-8)
Heat Shock Protein 90 Inhibition in Imatinib-Resistant Gastrointestinal Stromal Tumor
Authors: Bauer Sebastian , Yu Lynn K. , Demetri George D. , Fletcher Jonathan A.
Published: September 2006

Inhibition of KIT oncoproteins by imatinib induces clinical responses in most gastrointestinal stromal tumor (GIST) patients. However, many patients develop imatinib resistance due to secondary KIT mutations. Heat shock protein 90 (HSP90) protects KIT oncoproteins from proteasome-mediated degradation, and we therefore did preclinical validations of the HSP90 inhibitor, 17-allylamino-18-demethoxy-geldanamycin (17-AAG), in an imatinib-sensitive GIST cell line (GIST882) and in novel imatinib-resistant GIST lines that are either dependent on (GIST430 and GIST48) or independent of (GIST62) KIT oncoproteins. 17AAG (>100 nmol/L) inhibited imatinib-sensitive and imatinib-resistant KIT oncoproteins, with substantially reduced phospho-KIT and total KIT expression after 30 minutes and 6 hours, respectively. KIT signaling intermediates, including AKT and mitogen-activated protein kinase, were inactivated by 17-AAG in the KIT-positive GIST lines, but not in the KIT-negative GIST62. Likewise, cell proliferation and survival were inhibited in the KIT-positive GISTs but not in GIST62. These findings suggest that 17-AAG biological effects in KIT-positive GISTs result mainly from KIT oncoprotein inhibition. The dramatic inactivation of imatinib-resistant KIT oncoproteins suggests that HSP90 inhibition provides a therapeutic solution to the challenge of heterogeneous imatinib resistance mutations in GIST patients. (Cancer Res 2006; 66(18): 9153-61)
Cytogenetic Instability in Ovarian Epithelial Cells from Women at Risk of Ovarian Cancer
Authors: Pejovic Tanja , Yates Jane E. , Liu Hong Y. , Hays Laura E. , Akkari Yassmine , Torimaru Yumi , Keeble Winifred , Rathbun R. Keaney , Rodgers William H. , Bale Allen E. , Ameziane Najim , Zwaan C. Michael , Errami Abdellatif , Thuillier Philippe , Cappuccini Fabio , Olson Susan B. , Cain Joanna M. , Bagby Grover C.
Published: September 2006

Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer. (Cancer Res 2006; 66(18): 9017-25)
Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member
Authors: O'Toole Jennifer M. , Rabenau Karen E. , Burns Kerri , Lu Dan , Mangalampalli Venkat , Balderes Paul , Covino Nicole , Bassi Rajiv , Prewett Marie , Gottfredsen Kimberly J. , Thobe Megan N. , Cheng Yuan , Li Yiwen , Hicklin Daniel J. , Zhu Zhenping , Waltz Susan E. , Hayman Michael J. , Ludwig Dale L. , Pereira Daniel S.
Published: September 2006

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG–treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in ∼100 cancer cell lines and ∼300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers. (Cancer Res 2006; 66(18): 9162-70)
Extracellular Calcium as a Candidate Mediator of Prostate Cancer Skeletal Metastasis
Authors: Liao Jinhui , Schneider Abraham , Datta Nabanita S. , McCauley Laurie K.
Published: September 2006

Prostate cancer almost exclusively metastasizes to skeletal sites, indicating that the bone provides a favorable microenvironment for its localization and progression. A natural yet understudied factor in bone that could facilitate tumor localization is elevated extracellular calcium ([Ca2+]o). The present study found that elevated [Ca2+]o (2.5 mmol/L) enhanced proliferation of skeletal metastatic prostate cell lines (PC-3 and C4-2B), but not the nonskeletal metastatic, epithelial-derived prostate cell line LNCaP. The proliferative effect of elevated [Ca2+]o was associated with higher expression of the calcium-sensing receptor (CaSR), a heterotrimeric G-protein–coupled receptor that is the predominant cell-surface sensor for [Ca2+]o. Knockdown of the CaSR via RNA interference reduced cell proliferation in vitro and metastatic progression in vivo. CaSR signaling in PC-3 cells was evaluated by measuring the elevated [Ca2+]o-dependent inhibition of cyclic AMP accumulation, induced by either prostaglandin E2 or forskolin. Elevated [Ca2+]o stabilized expression of cyclin D1, a protein required for cell cycle transition. Furthermore, elevated [Ca2+]o triggered activation of the Akt signaling pathway and enhanced PC-3 cell attachment. Both pertussis toxin (a G-protein inhibitor) and LY294002 (an inhibitor of Akt signaling) reduced cell attachment. These data suggest that elevated [Ca2+]o following increased bone remodeling could facilitate metastatic localization of prostate cancer via the CaSR and the Akt signaling pathway. Taken together, [Ca2+]o is a candidate mediator of prostate cancer bone metastasis. (Cancer Res 2006; 66(18): 9065-73) (Cancer Res 2006; 66(18): 9065-73)
Identification of New Compounds That Trigger Apoptosome-Independent Caspase Activation and Apoptosis
Authors: Aleo Emanuela , Henderson Clare J. , Fontanini Alessandra , Solazzo Barbara , Brancolini Claudio
Published: September 2006

Identification of alternative pathways of caspase activation is an important step to develop new antitumor treatments. We report here the result of a screening with a small chemical library, the Developmental Therapeutics Program-National Cancer Institute “challenge set,” on cells expressing mutated caspase-9. We have identified two molecules capable of activating an apoptosome-independent apoptotic pathway. These compounds, named F6 and G5, target the ubiquitin-proteasome system by inhibiting the ubiquitin isopeptidases. We have shown that F6 and G5 induce a rather unique apoptotic pathway, which includes a Bcl-2-dependent but apoptosome-independent mitochondrial pathway with up-regulation of the BH3-only protein Noxa, stabilization of the inhibitor of apoptosis antagonist Smac, but also the involvement of the death receptor pathway. Noxa plays an important role in the induction of mitochondrial fragmentation and caspase activation, whereas the death receptor pathway becomes critical in the absence of a functional apoptosome. This study suggests that screening of chemical libraries on cancer cells with defined mutations in apoptotic key elements can lead to the identification of compounds that are useful to characterize alternative pathways of caspase activation. (Cancer Res 2006; 66(18): 9235-44)
IQGAP1 Protein Specifies Amplifying Cancer Cells in Glioblastoma Multiforme
Authors: Balenci Laurent , Clarke Ian D. , Dirks Peter B. , Assard Nicole , Ducray François , Jouvet Anne , Belin Marie-Françoise , Honnorat Jerôme , Baudier Jacques
Published: September 2006

The accurate identification and thorough characterization of tumorigenic cells in glioblastomas are essential to enhance our understanding of their malignant behavior and for the design of strategies that target this important cell population. We report here that, in rat brain, the scaffolding protein IQGAP1 is a marker of brain nestin+ amplifying neural progenitor cells. In a rat model of glioma, IQGAP1 also characterizes a subpopulation of nestin+ amplifying tumor cells in glioblastoma-like tumors but not in tumors with oligodendroglioma features. We next confirmed that IQGAP1 represents a new marker that may help to discriminate human glioblastoma from oligodendrogliomas. In human glioblastoma exclusively, IQGAP1 specifies a subpopulation of amplifying nestin+ cancer cells. Neoplastic IQGAP1+ cells from glioblastoma can be expanded in culture and possess all the characteristics of cancer stem-like progenitors. The similarities between amplifying neural progenitors and glioblastoma amplifying cancer cells may have significant implications for understanding the biology of glioblastoma. (Cancer Res 2006; 66(18): 9074-82)
Adenomatous Polyposis Coli Determines Sensitivity to Histone Deacetylase Inhibitor–Induced Apoptosis in Colon Cancer Cells
Authors: Huang Xiangwei , Guo Bin
Published: September 2006

Inhibitors of histone deacetylases (HDAC) inhibit malignant cell growth and induce apoptosis through unknown mechanisms. Here, we report that the expression status of adenomatous polyposis coli (APC) protein determines the relative sensitivity of colon cancer cells to HDAC inhibitor–induced apoptosis. HCA-7 cells (expressing wild-type β-catenin and APC proteins) are more sensitive to apoptosis induced by HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid than SW620 or HT-29 cells (both expressing mutant APC). When wild-type APC protein was expressed using an inducible expression system, HT-29 cells became sensitive to apoptosis in response to VPA. Conversely, knocking down of endogenous APC protein by small interfering RNA (siRNA) blocked VPA-induced apoptosis in HCA-7 cells. APC mediated VPA-induced apoptosis through down-regulation of survivin. The level of survivin protein decreased in HCA-7 and HT-29/APC cells, but not in SW620 and HT-29/β-Gal cells after VPA treatment. Whereas knocking down of survivin by siRNA sensitized SW620 cells to VPA-induced apoptosis, overexpression of survivin blocked VPA-induced apoptosis in HCA-7 cells. Down-regulation of survivin transcription occurred through changes in GSK-3β/β-catenin/Tcf-4 signaling molecules. VPA also induced proteasome-mediated degradation of survivin protein in HCA-7 cells. Furthermore, we have shown that APC mutation–mediated resistance to apoptosis can be overcome by cotreatment with Flavopiridol, which promotes survivin degradation. These results suggest that APC is a critical determinant of HDAC inhibitor–induced apoptosis in colon cancer cells and survivin is a potential target to enhance apoptotic response to HDAC inhibitors. (Cancer Res 2006; 66(18): 9245-51)
Autoantibody Cancer Biomarker: Extracellular Protein Kinase A
Authors: Nesterova Maria V. , Johnson Natalie , Cheadle Christopher , Bates Susan E. , Mani Sridhar , Stratakis Constantine A. , Kahn Islam , Gupta Rishab K. , Cho-Chung Yoon S.
Published: September 2006

In cancer cells, cyclic AMP–dependent protein kinase (PKA) is secreted into the conditioned medium. This PKA, designated as extracellular protein kinase A (ECPKA), is markedly up-regulated in the sera of patients with cancer. The currently available tumor markers are based on the antigen determination method and lack specificity and sensitivity. Here, we present an ECPKA autoantibody detection method for a universal biomarker that detects cancer of various cell types. We tested sera from 295 patients with cancers of various cell types, 155 normal controls, and 55 patients without cancer. The specificity and sensitivity of this autoantibody enzyme immunoassay method were compared with the conventional antigen determination method by receiver-operating characteristic plots. In the sera, the presence of autoantibody directed against ECPKA was highly correlated with cancer. High anti-ECPKA autoantibody titers (frequency, 90%; mean titer, 3.0) were found in the sera of patients with various cancers, whereas low or negative titers (frequency, 12%; mean titer, 1.0) were found in the control group. The receiver-operating characteristic plot showed that autoantibody enzyme immunoassay exhibited 90% sensitivity and 88% specificity, whereas the enzymatic assay exhibited 83% sensitivity and 80% specificity. These results show that the autoantibody method distinguished between patients with cancer and controls better than the antigen method could. Our results show that autoantibody ECPKA is a universal serum biomarker for cancers of various cell types. (Cancer Res 2006; 66(18): 8971-4)
MicroRNA Regulates the Expression of Human Cytochrome P450 1B1
Authors: Tsuchiya Yuki , Nakajima Miki , Takagi Shingo , Taniya Takao , Yokoi Tsuyoshi
Published: September 2006

MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression through translational repression or mRNA cleavage. Here, we found that cytochrome P450 (CYP), a superfamily of drug-metabolizing enzymes, is a target of miRNA. Human CYP1B1, which is highly expressed in estrogen target tissues, catalyzes the metabolic activation of various procarcinogens and the 4-hydroxylation of 17β-estradiol. CYP1B1 protein is abundant in cancerous tissues. We identified a near-perfect matching sequence with miR-27b in the 3′-untranslated region of human CYP1B1. Luciferase assays revealed that the reporter activity of the plasmid containing the miR-27b recognition element was decreased in MCF-7 cells (miR-27 positive) but not in Jurkat cells (miR-27b negative). Exogenously expressed miR-27b could decrease the luciferase activity in Jurkat cells. In MCF-7 cells, the antisense oligoribonucleotide for miR-27b restored the luciferase activity and increased the protein level and enzymatic activity of endogenous CYP1B1. These results suggested that human CYP1B1 is post-transcriptionally regulated by miR-27b. The expression levels of miR-27b and CYP1B1 protein in breast cancerous and adjacent noncancerous tissues from 24 patients were evaluated. In most patients, the expression level of miR-27b was decreased in cancerous tissues, accompanied by a high level of CYP1B1 protein. A significant inverse association was observed between the expression levels of miR-27b and CYP1B1 protein. Thus, the decreased expression of miR-27b would be one of causes of the high expression of CYP1B1 protein in cancerous tissues. This is the first study to show that miRNAs regulate not only essential genes for physiologic events but also drug-metabolizing enzymes. (Cancer Res 2006; 66(18): 9090-8)
Cancer's Molecular Sweet Tooth and the Warburg Effect
Authors: Kim Jung-whan , Dang Chi V.
Published: September 2006

More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's “sweet tooth” for cancer therapy. (Cancer Res 2006; 66(18): 8927-30)
Endogenous Inhibition of Histone Deacetylase 1 by Tumor-Suppressive Maspin
Authors: Li Xiaohua , Yin Shuping , Meng Yonghong , Sakr Wael , Sheng Shijie
Published: September 2006

Maspin, a noninhibitory serine protease inhibitor, exerts multifaceted tumor-suppressive effects. Maspin expression is associated with better differentiated phenotypes, better cancer prognosis, and better drug sensitivity. Consistently, maspin also correlates with increased expression of Bax and p21WAF1/CIP1. Interestingly, histone deacetylase 1 (HDAC1), a major HDAC responsible for histone deacetylation, was shown to interact with maspin in a yeast two-hybrid screening. In this study, we confirmed the maspin/HDAC1 interaction in human prostate tissues, in prostate cancer cell lines, and with purified maspin. We produced several lines of evidence that support an inhibitory effect of maspin on HDAC1 through direct molecular interaction, which was detected in both the nucleus and the cytoplasm. Both endogenously expressed maspin and purified maspin inhibited HDAC1. In contrast, small interfering RNA (siRNA) silencing of maspin in PC3 cells increased HDAC activity. Accordingly, maspin-transfected DU145 cells exhibited increased expression of HDAC1 target genes Bax, cytokeratin 18 (CK18), and p21WAF1/CIP1, whereas maspin siRNA decreased CK18 expression in PC3 cells. The maspin effect on HDAC1 correlated with an increased sensitivity to cytotoxic HDAC inhibitor M344. Interestingly, glutathione S-transferase (GST, another maspin partner) was detected in the maspin/HDAC1 complex. Furthermore, a COOH-terminally truncated maspin mutant, which bound to HDAC1 but not GST, did not increase histone acetylation. Although HDACs, especially the highly expressed HDAC1, are promising therapeutic targets in cancer intervention, our data raise a novel hypothesis that the endogenous inhibitory effect of maspin on HDAC1 is coupled with glutathione-based protein modification, and provide new leads toward future developments of specific HDAC1-targeting strategies. (Cancer Res 2055; 66(18): 9323-9) (Cancer Res 2006; 66(18): 9323-9)
(−)−Epigallocatechin Gallate Overcomes Resistance to Etoposide-Induced Cell Death by Targeting the Molecular Chaperone Glucose-Regulated Protein 78
Authors: Ermakova Svetlana P. , Kang Bong Seok , Choi Bu Young , Choi Hong Seok , Schuster Todd F. , Ma Wei-Ya , Bode Ann M. , Dong Zigang
Published: September 2006

Many beneficial properties have been attributed to (−)−epigallocatechin gallate (EGCG), including chemopreventive, anticarcinogenic, and antioxidant actions. In this study, we investigated the effects of EGCG on the function of glucose-regulated protein 78 (GRP78), which is associated with the multidrug resistance phenotype of many types of cancer cells. Our investigation was directed at elucidating the mechanism of the EGCG and GRP78 interaction and providing evidence about whether EGCG modulates the activity of anticancer drugs through the inhibition of GRP78 function. We found that EGCG directly interacted with GRP78 at the ATP-binding site of protein and regulated its function by competing with ATP binding, resulting in the inhibition of ATPase activity. EGCG binding caused the conversion of GRP78 from its active monomer to the inactive dimer and oligomer forms. Further, we showed that EGCG interfered with the formation of the antiapoptotic GRP78-caspase-7 complex, which resulted in an increased etoposide-induced apoptosis in cancer cells. We also showed that EGCG significantly suppressed the transformed phenotype of breast cancer cells treated with etoposide. Overall, these results strongly suggested that EGCG could prevent the antiapoptotic effect of GRP78, which usually suppresses the caspase-mediated cell death pathways in drug-treated cancer cells, contributing to the development of drug resistance. (Cancer Res 2006; 66(18): 9260-9) (Cancer Res 2006; 66(18): 9260-9)
Population-Based Study of Natural Variation in the Melanocortin-1 Receptor Gene and Melanoma
Authors: Kanetsky Peter A. , Rebbeck Timothy R. , Hummer Amanda J. , Panossian Saarene , Armstrong Bruce K. , Kricker Anne , Marrett Loraine D. , Millikan Robert C. , Gruber Stephen B. , Culver Hoda Anton , Zanetti Roberto , Gallagher Richard P. , Dwyer Terence , Busam Klaus , From Lynn , Mujumdar Urvi , Wilcox Homer , Begg Colin B. , Berwick Marianne ,   for the Genes Environment and Melanoma Study Group
Published: September 2006

Natural variation in the coding region of the melanocortin-1 receptor (MC1R) gene is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. We investigated the effect of MC1R variants on melanoma using a large, international population-based study design with complete determination of all MC1R coding region variants. Direct sequencing was completed for 2,202 subjects with a single primary melanoma (controls) and 1,099 subjects with second or higher-order primary melanomas (cases) from Australia, the United States, Canada, and Italy. We observed 85 different MC1R variants, 10 of which occurred at a frequency >1%. Compared with controls, cases were more likely to carry two previously identified red hair (“R”) variants [D84E, R151C, R160W, and D294H; odds ratio (OR), 1.6; 95% confidence interval (95% CI), 1.1-2.2]. This effect was similar among individuals carrying one R variant and one r variant (defined as any non-R MC1R variant; OR, 1.6; 95% CI, 1.3-2.2) and among those carrying only one R variant (OR, 1.5; 95% CI, 1.1-1.9). There was no statistically significant association among those carrying only one or two r variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low-penetrance susceptibility locus for melanoma, show that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported in part due to the study design. (Cancer Res 2006; 66(18): 9330-7)
Inhibition of Mitogen-Elicited Signal Transduction and Growth in Prostate Cancer with a Small Peptide Derived from the Functional Domain of DOC-2/DAB2 Delivered by a Unique Vehicle
Authors: Zhou Jian , Fan Jinhai , Hsieh Jer-Tsong
Published: September 2006

Differentially expressed in ovarian cancer-2/disabled 2 (DOC-2/DAB2) protein, often lost in prostate cancer and other cancer types, is a part of homeostatic machinery in normal prostate epithelium. DOC-2/DAB2 modulates mitogen-elicited mitogen-activated protein kinase (MAPK) signal transduction by sequestering several adaptor or effector molecules, such as growth factor receptor bound protein 2 and c-Src. We have shown that the proline-rich sequence in DOC-2/DAB2 is the key functional domain for this action. In this study, we further synthesized peptide based on the functional proline-rich domain and examined its biological function in prostate cancer using cell-permeable peptide (CPP) as a delivery system. From screening of several CPPs in prostate cancer cell lines, a polyarginine peptide (R11) seemed to be the best delivery vehicle because of its highly efficient uptake. In addition, we also observed a similar in vitro half-life and cellular location of R11 in four different prostate cancer cell lines. By conjugating a proline-rich sequence (PPL) or control sequence (AAL) derived from DOC-2/DAB2 to the COOH terminus of R11, we showed that R11PPL but not R11 or R11AAL was able to suppress either serum- or androgen-induced cell proliferation in prostate cancer cells without endogenous DOC-2/DAB2 expression. Consistently, the activation status of MAPK elicited by these mitogens was significantly inhibited by R11PPL but not by R11AAL or R11. Taken together, we conclude that a functional peptide derived from proline-rich domain in DOC-2/DAB2 has growth-inhibitory activity as its native protein, and CPP seems to be an efficient delivery system in prostate cancer cells. (Cancer Res 2006; 66(18): 8954-8)
Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells
Authors: Cai Dongpo , Latham Vaughan M. , Zhang Xinxin , Shapiro Geoffrey I.
Published: September 2006

Selective cyclin-dependent kinase (cdk) 2 inhibition is readily compensated. However, reduced cdk2 activity may have antiproliferative effects in concert with other family members. Here, inducible RNA interference was used to codeplete cdk2 and cdk1 from NCI-H1299 non–small cell lung cancer and U2OS osteosarcoma cells, and effects were compared with those mediated by depletion of either cdk alone. Depletion of cdk2 slowed G1 progression of NCI-H1299 cells and depletion of cdk1 slowed G2-M progression in both cell lines, with associated endoreduplication in U2OS cells. However, compared with the incomplete cell cycle blocks produced by individual depletion, combined depletion had substantial consequences, with G2-M arrest predominating in NCI-H1299 cells and apoptosis the primary outcome in U2OS cells. In U2OS cells, combined depletion affected RNA polymerase II expression and phosphorylation, causing decreased expression of the antiapoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis (XIAP), effects usually mediated by inhibition of the transcriptional cdk9. These events do not occur after individual depletion of cdk2 and cdk1, suggesting that reduction of cdk2, cdk1, and RNA polymerase II activities all contribute to apoptosis in U2OS cells. The limited cell death induced by combined depletion in NCI-H1299 cells was significantly increased by codepletion of cdk9 or XIAP or by simultaneous treatment with the cdk9 inhibitor flavopiridol. These results show the potency of concomitant compromise of cell cycle and transcriptional cdk activities and may guide the selection of clinical drug candidates. (Cancer Res 2006; 66(18): 9270-80)
Estrogen Receptor Positive Breast Cancer Metastasis: Altered Hormonal Sensitivity and Tumor Aggressiveness in Lymphatic Vessels and Lymph Nodes
Authors: Harrell Joshua Chuck , Dye Wendy W. , Allred D. Craig , Jedlicka Paul , Spoelstra Nicole S. , Sartorius Carol A. , Horwitz Kathryn B.
Published: September 2006

Breast cancers commonly spread to lymph nodes (LNs). If the primary tumors are estrogen receptor (ER) and/or progesterone receptor (PR) positive, then the likelihood that LN metastases express receptors exceeds 80%. However, due to lack of ER+ models, little is known about the role of hormones in breast cancer spread or the effects of the LN microenvironment on hormone responsiveness. We have developed metastasis models using ZsGreen labeled MCF-7 and T47D human breast cancer cells. Tumors are tracked in living mice by whole-body imaging, and macrometastases or micrometastases are detected by intravital imaging or fluorescence microscopy. Tumor growth is estrogen dependent and required for intratumoral lymphangiogenesis. Seventy-five percent of all tumors and >95% of larger tumors generate LN metastases. Occasionally more distant metastases are also observed. “Triads” of primary tumors, tumor-filled draining lymphatic vessels, and tumor-filled LNs from the same mouse show that (a) proliferation, as measured by 5-bromo-2′-deoxyuridine uptake, is higher in the LN than in the primary tumor. (b) High ER levels are extensively down-regulated by estradiol in primary tumors. However, there is partial failure of ER down-regulation in LNs associated with (c) reduced PR expression. This suggests that ER are dysfunctional in the LN microenvironment and perhaps hormone resistant. (d) CD44 is sparsely expressed in primary tumor cells but homogeneously overexpressed in cells transiting the lymphatics and populating LNs. We hypothesize that CD44 expression targets tumor cells for transport to, and uptake in, LNs. If so, the CD44 pathway could be targeted therapeutically to slow or prevent LN metastases. (Cancer Res 2006; 66(18): 9308-15)