bluuebunny/crossref_metadata_2025 huggingface dataset:
GBT-BASED LOCAL AND GLOBAL VIBRATION ANALYSIS OF LOADED COMPOSITE OPEN-SECTION THIN-WALLED MEMBERS
Authors: SILVESTRE N. , CAMOTIM D.
Published: March 2006

This paper begins by presenting a Generalized Beam Theory (GBT) formulation for analyzing the vibration behavior of loaded composite thin-walled members, which accounts for the effects of (i) cross-section in-plane deformation, (ii) shear deformation, (iii) geometric and material coupling, (iv) primary, secondary and non-linear warping, and (v) rotary inertia. This formulation is then used to investigate the local and global vibration behavior of lipped channel columns and beams displaying cross-ply orthotropy, focusing on issues dealing with the variation of the fundamental frequency and vibration mode nature with the member length and applied stress level. For validation purposes, some GBT-based results are also compared with values obtained by means of 4-node shell finite element analyses using ABAQUS. Some relevant conclusions are drawn concerning the dependence of the member vibration mode shape (wave number) on the compression/bending level (applied-to-critical ratio).
EFFECTIVENESS OF SEISMIC ISOLATION FOR CABLE-STAYED BRIDGES
Authors: SONEJI B. B. , JANGID R. S.
Published: March 2006

This paper investigates the effectiveness of elastomeric and sliding types of isolation systems for the seismic response control of cable-stayed bridges. A simplified two-dimensional lumped-mass finite-element model of the Quincy Bay-view Bridge at Illinois was developed for the investigation. The seismic isolation of cable-stayed bridges is achieved using three different isolators, namely, high damping rubber bearings (HDRB), lead rubber bearings (LRB) and friction pendulum system (FPS). Time history analysis is performed for the bridge with four different earthquake ground motions applied in the longitudinal direction using Newmark's method with linear variation of acceleration over the time interval. The seismic response of the isolated cable-stayed bridge is compared with that of the bridge with no isolation system. The results show that the isolation systems are effective for reducing the absolute acceleration of the deck and the base shear response of the tower. Further, a parametric study is performed by varying the damping ratio, yield strength and friction coefficient of HDRB, LRB and FPS to investigate the influence of these parameters on the seismic response of the bridge. From such a study, optimal values can be found for the isolators for reducing the bridge responses.
SEISMIC ANALYSIS OF OFFSHORE TRIANGULAR TENSION LEG PLATFORMS
Authors: CHANDRASEKARAN S. , JAIN A. K. , CHANDAK N. R.
Published: March 2006

Oil and gas production from deep-water offshore fields represent a major structural engineering challenge for the industry. The tension leg platform (TLP) is a well-established concept for deep-water oil exploration. It is necessary to design an offshore TLP such that it can respond to moderate environmental loads without damage, and is capable of resisting severe environmental loads without seriously endangering the occupants. Seismic analysis of triangular TLP under moderate regular waves is investigated. The analysis considers nonlinearities due to the change in tether tension and nonlinear hydrodynamic drag forces. The coupled response of TLP under moderate regular sea waves due to change in initial pretension in the tethers caused by seismic forces (vertical direction) is then investigated. Seismic forces are imposed at the bottom of each tether as axial forces. The tether tension becomes unbalanced when the hull is under offset position. The vertical component of seismic force is an important item to take into consideration, because it is directly superposed to pretension of tethers. The change in initial pretension due to the vertical component of the earthquake affects the response of the triangular TLP in degrees-of-freedom experiencing such forces. The tether tension varies nonlinearly when the platform is subjected to seismic forces caused by the El Centro earthquake and artificially generated earthquake using Kanai–Tajimi's power spectrum. The response due to earthquakes varies with the intensity of the input ground motion. The seismic response of the triangular TLP exhibits nonlinear behavior in the presence of waves and it is non-proportionately influenced by the wave period and the wave height.
SOME CONVENTIONAL AND UNCONVENTIONAL EDUCATIONAL COLUMN STABILITY PROBLEMS
Authors: ELISHAKOFF I. , GENTILINI C. , SANTORO R.
Published: March 2006

Two interesting problems are considered for enriching the curriculum of the Strength of Materials course, in the light of recently developed functionally graded materials (FGMs), characterized with the smooth variation of the elastic modulus. These are problems associated with buckling of columns with variable flexural rigidity along the axis of the column. A simple semi-inverse method is proposed for determining closed-form solutions of axially inhomogeneous columns. In order for the presentation to be given in one package, the conventional problems are also recapitulated along with the novel ones. The main approach adopted here is the use of the second-order differential equation, instead of the fourth-order one, obtained by integrating twice and having a physical meaning, since it could be derived based on moment equilibrium. This is essentially the same idea as utilized in the textbook by Timoshenko and Gere;1 the difference is that this paper develops a semi-inverse formulation.
FUNCTION DEPLOYMENT MODEL FOR CONTINUOUS AND DISCONTINUOUS INNOVATION PRODUCT DEVELOPMENT
Authors: KO SUI-MAN , YUNG KAI-LEUNG
Published: March 2006

This paper proposes the use of a Function Deployment Model (FDM) for continuous and discontinuous innovation product development. To demonstrate its usefulness in a real situation, the model was applied to the design problem of a multi-function sampling instrument used in the ESA (European Space Agency) Beagle2 Mars Express mission. The proposed model is based on Quality Function Deployment (QFD) techniques for translating customer needs to engineering characteristics. An Analytic Hierarchy Process (AHP) is used to prioritize customer requirements while a Linear Programming (LP) optimization method is used to determine the feasible solution of the design variables within limited resources. An application of the new model is made on a real life example to show the proposed model's ability and its applicability to other disciplines.
ON THE RIEMANN HYPOTHESIS AND TACHYONS IN DUAL STRING SCATTERING AMPLITUDES
Authors: CASTRO CARLOS
Published: March 2006

It is the purpose of this work to pursue a novel physical interpretation of the nontrivial Riemann zeta zeros and prove why the location of these zeros zn = 1/2+iλn corresponds physically to tachyonic-resonances/tachyonic-condensates, originating from the scattering of two on-shell tachyons in bosonic string theory. Namely, we prove that if there were nontrivial zeta zeros (violating the Riemann hypothesis) outside the critical line Realz = 1/2 (but inside the critical strip), these putative zeros do not correspond to any poles of the bosonic open string scattering (Veneziano) amplitude A(s, t, u). The physical relevance of tachyonic-resonances/tachyonic-condensates in bosonic string theory, establishes an important connection between string theory and the Riemann Hypothesis. In addition, one has also a geometrical interpretation of the zeta zeros in the critical line in terms of very special (degenerate) triangular configurations in the upper-part of the complex plane.
BIDIFFERENTIAL CALCULI, BICOMPLEX STRUCTURE AND ITS APPLICATION TO BIHAMILTONIAN SYSTEMS
Authors: GUHA PARTHA
Published: March 2006

In this exposition, we study the relationship between the bihamiltonian formalism of completely integrable systems using the bidifferential calculi introduced by Dimakis and Müller-Hoissen in [1] and the bihamiltonian formulation of integrable systems with a finite number of degrees of freedom via the Frölicher–Nijenhuis geometry. This pair of bidifferetial operators are used to construct alternative Lie algebroids as shown by Camacaro and Carinena. We find its connection to Finsler geometry. We also find the dispersionless integrable hierarchies using the bidifferential ideals. Finally, we lay out its connection to Gelfand–Zakharevich bihamiltonian geometry.
IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration
Authors: Brand Stephan , Beigel Florian , Olszak Torsten , Zitzmann Kathrin , Eichhorst Sören T. , Otte Jan-Michel , Diepolder Helmut , Marquardt Andreas , Jagla Wolfgang , Popp Andreas , Leclair Stéphane , Herrmann Karin , Seiderer Julia , Ochsenkühn Thomas , Göke Burkhard , Auernhammer Christoph J. , Dambacher Julia
Published: March 2006

IL-22 is produced by activated T cells and signals through a receptor complex consisting of IL-22R1 and IL-10R2. The aim of this study was to analyze IL-22 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal epithelial cells (IEC). Expression studies were performed by RT-PCR. Signal transduction was analyzed by Western blot experiments, cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and Fas-induced apoptosis by flow cytometry. IEC migration was studied in wounding assays. The IEC lines Caco-2, DLD-1, SW480, HCT116, and HT-29 express both IL-22 receptor subunits IL-22R1 and IL-10R2. Stimulation with TNF-α, IL-1β, and LPS significantly upregulated IL-22R1 without affecting IL-10R2 mRNA expression. IL-22 binding to its receptor complex activates STAT1/3, Akt, ERK1/2, and SAPK/JNK MAP kinases. IL-22 significantly increased cell proliferation ( P = 0.002) and phosphatidylinsitol 3-kinase-dependent IEC cell migration ( P < 0.00001) as well as mRNA expression of TNF-α, IL-8, and human β-defensin-2. IL-22 had no effect on Fas-induced apoptosis. IL-22 mRNA expression was increased in inflamed colonic lesions of patients with Crohn’s disease and correlated highly with the IL-8 expression in these lesions ( r = 0.840). Moreover, IL-22 expression was increased in murine dextran sulfate sodium-induced colitis. IEC express functional receptors for IL-22, which increases the expression of proinflammatory cytokines and promotes the innate immune response by increased defensin expression. Moreover, our data indicate intestinal barrier functions for this cytokine-promoting IEC migration, which suggests an important function in intestinal inflammation and wound healing. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and IEC migration.
Cancer Cell Mitochondria Are Direct Proapoptotic Targets for the Marine Antitumor Drug Lamellarin D
Authors: Kluza Jérôme , Gallego Miguel-Angel , Loyens Anne , Beauvillain Jean-Claude , Sousa-Faro José-Maria Fernandez , Cuevas Carmen , Marchetti Philippe , Bailly Christian
Published: March 2006

Lamellarin D is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cell lines and is a potent inhibitor of topoisomerase I. However, lamellarin D maintains a marked cytotoxicity toward cell lines resistant to the reference topoisomerase I poison camptothecin. We therefore hypothesized that topoisomerase I is not the only cellular target for the drug. Using complementary cell-based assays, we provide evidence that lamellarin D acts on cancer cell mitochondria to induce apoptosis. Lamellarin D, unlike camptothecin, induces early disruption of the inner mitochondrial transmembrane potential (Δψm) in the P388 leukemia cell line. The functional alterations are largely prevented by cyclosporin A, an inhibitor of the mitochondrial permeability transition (MPT), but not by the inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone. Δψm disruption is associated with mitochondrial swelling and cytochrome c leakage. Using a reliable real-time flow cytometric monitoring of Δψm and swelling of mitochondria isolated from leukemia cells, we show that lamellarin D has a direct MPT-inducing effect. Furthermore, mitochondria are required in a cell-free system to mediate lamellarin D–induced nuclear apoptosis. The direct mitochondrial effect of lamellarin D accounts for the sensitivity of topoisomerase I–mutated P388CPT5 cells resistant to camptothecin. Interestingly, a tumor-active analogue of lamellarin D, designated PM031379, also exerts a direct proapoptotic action on mitochondria, with a more pronounced activity toward mitochondria of tumor cell lines compared with nontumor cell lines. Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells. (Cancer Res 2006; 66(6): 3177-87)
Tumor Susceptibility and Apoptosis Defect in a Mouse Strain Expressing a Human p53 Transgene
Authors: Dudgeon Crissy , Kek Calvina , Demidov Oleg N. , Saito Shin-ichi , Fernandes Kenneth , Diot Alexandra , Bourdon Jean-Christophe , Lane David P. , Appella Ettore , Fornace Albert J. , Bulavin Dmitry V.
Published: March 2006

Activation of apoptosis is believed to be critical for the role of p53 as a tumor suppressor. Here, we report a new mouse strain carrying a human p53 transgene in the mouse p53-null background. Expression of human p53 in these mice was comparable with wild-type murine p53; however, transactivation, induction of apoptosis, and G1-S checkpoint, but not transrepression or regulation of a centrosomal checkpoint, were deregulated. Although multiple functions of p53 were abrogated, mice carrying the human p53 transgene did not show early onset of tumors as typically seen for p53-null mice. In contrast, human p53 in the p53-null background did not prevent accelerated tumor development after genotoxic or oncogenic stress. Such behavior of human p53 expressed at physiologic levels in transgenic cells could be explained by unexpectedly high binding with Mdm2. By using Nutlin-3a, an inhibitor of the interaction between Mdm2 and p53, we were able to partially reconstitute p53 transactivation and apoptosis in transgenic cells. Our findings indicate that the interaction between p53 and Mdm2 controls p53 transcriptional activity in homeostatic tissues and regulates DNA damage– and oncogene-induced, but not spontaneous, tumorigenesis.(Cancer Res 2006; 66(6): 2928-36)
Overexpression of the Oncoprotein Prothymosin α Triggers a p53 Response that Involves p53 Acetylation
Authors: Kobayashi Takahiko , Wang Ting , Maezawa Masaji , Kobayashi Masanobu , Ohnishi Shunsuke , Hatanaka Kazuteru , Hige Shuhei , Shimizu Yuichi , Kato Mototsugu , Asaka Masahiro , Tanaka Junji , Imamura Masahiro , Hasegawa Kiminori , Tanaka Yoshiyuki , Brachmann Rainer K.
Published: March 2006

Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and β-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin α (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation. (Cancer Res 2006; 66(6): 3137-44)
Dynamic Interactions of Cortactin and Membrane Type 1 Matrix Metalloproteinase at Invadopodia: Defining the Stages of Invadopodia Formation and Function
Authors: Artym Vira V. , Zhang Ying , Seillier-Moiseiwitsch Françoise , Yamada Kenneth M. , Mueller Susette C.
Published: March 2006

Metastatic tumor cells that actively migrate and invade surrounding tissues rely on invadopodia to degrade extracellular matrix (ECM) barriers. Invadopodia are membrane protrusions that localize enzymes required for ECM degradation. Little is known about the formation, function, and regulation of invadopodia. Here, we show that invadopodia have two distinct aspects: (a) structural for organizing the cellular actin cytoskeleton to form membrane protrusions and (b) functional for using proteolytic enzyme(s) for ECM degradation. Small interfering RNA (siRNA) inhibition established that organization of invadopodia structure requires cortactin, whereas protease inhibitor studies identified membrane type 1 matrix metalloproteinase (MT1-MMP) as the key invadopodial enzyme responsible for gelatin matrix degradation in the breast carcinoma cell line MDA-MB-231. The inhibition of invadopodial structure assembly by cortactin depletion resulted in a block of matrix degradation due to failure of invadopodia formation. Either protease inhibition or MT1-MMP siRNA depletion moderately decreased the formation of invadopodial structures that were identified as actin-cortactin accumulations at the ventral cell membrane adherent to matrix. The invadopodia that were able to form upon MT1-MMP inhibition or depletion retained actin-cortactin accumulations but were unable to degrade matrix. Examination of cells at different time points as well as live-cell imaging revealed four distinct invadopodial stages: membrane cortactin aggregation at membranes adherent to matrix, MT1-MMP accumulation at the region of cortactin accumulation, matrix degradation at the invadopodia region, and subsequent cortactin dissociation from the area of continued MT1-MMP accumulation associated with foci of degraded matrix. Based on these results, we propose a stepwise model of invadopodia formation and function. (Cancer Res 2006; 66(6): 3034-43)
Delocalization and Destabilization of the Arf Tumor Suppressor by the Leukemia-Associated NPM Mutant
Authors: Colombo Emanuela , Martinelli Paola , Zamponi Raffaella , Shing Danielle C. , Bonetti Paola , Luzi Lucilla , Volorio Sara , Bernard Loris , Pruneri Giancarlo , Alcalay Myriam , Pelicci Pier Giuseppe
Published: March 2006

One third of acute myeloid leukemias (AMLs) are characterized by the aberrant cytoplasmic localization of nucleophosmin (NPM) due to mutations within its putative nucleolar localization signal. NPM mutations are mutually exclusive with major AML-associated chromosome rearrangements and are frequently associated with a normal karyotype, suggesting that they are critical during leukemogenesis. The underlying molecular mechanisms are, however, unknown. NPM is a nucleocytoplasmic shuttling protein that has been implicated in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, and stress response. It has been recently shown that NPM is required for the stabilization and proper nucleolar localization of the tumor suppressor p19Arf. We report here that the AML-associated NPM mutant localizes mainly in the cytoplasm due to an alteration of its nucleus-cytoplasmic shuttling equilibrium, forms a direct complex with p19Arf, but is unable to protect it from degradation. Consequently, cells or leukemic blasts expressing the NPM mutant have low levels of cytoplasmic Arf. Furthermore, we show that expression of the NPM mutant reduces the ability of Arf to initiate a p53 response and to induce cell cycle arrest. Inactivation of p19Arf, a key regulator of the p53-dependent cellular response to oncogene expression, might therefore contribute to leukemogenesis in AMLs with mutated NPM. (Cancer Res 2006; 66(6): 3044-50)
The Secretory Leukocyte Protease Inhibitor Is a Type 1 Insulin-Like Growth Factor Receptor–Regulated Protein that Protects against Liver Metastasis by Attenuating the Host Proinflammatory Response
Authors: Wang Ni , Thuraisingam Thusanth , Fallavollita Lucia , Ding Aihao , Radzioch Danuta , Brodt Pnina
Published: March 2006

The secretory leukocyte protease inhibitor (SLPI) can attenuate the host proinflammatory response by blocking nuclear factor κB (NF-κB)–mediated tumor necrosis factor α (TNF-α) production in macrophages. We have previously shown that highly metastatic human and mouse carcinoma cells, on their entry into the hepatic microcirculation, trigger a rapid host proinflammatory response by inducing TNF-α production in resident Kupffer cells. Using GeneChip microarray analysis, we found that in mouse Lewis lung carcinoma subclones, SLPI expression was inversely correlated with tumor cell ability to induce a proinflammatory response and metastasize to the liver and with type 1 insulin-like growth factor receptor expression levels. To establish a causal relationship between SLPI expression and the metastatic phenotype, we generated, by transfection, multiple clones of the highly metastatic subline (H-59) that overexpress SLPI. We show here that the ability of these cells to elicit a host proinflammatory response in the liver was markedly decreased, as evidenced by reduced TNF-α production and vascular E-selectin expression, relative to controls. Moreover, these cells formed significantly fewer hepatic metastases (up to 80% reduction) as compared with mock-transfected controls. Our findings show that SLPI can decrease the liver-metastasizing potential of carcinoma cells and that this protective effect correlates with a decrease in the production of hepatic TNF-α and E-selectin. They suggest that factors that attenuate the host proinflammatory response may have a therapeutic potential in the prevention of liver metastasis. (Cancer Res 2006; 66(6): 3062-70)
In vivo Margin Assessment during Partial Mastectomy Breast Surgery Using Raman Spectroscopy
Authors: Haka Abigail S. , Volynskaya Zoya , Gardecki Joseph A. , Nazemi Jon , Lyons Joanne , Hicks David , Fitzmaurice Maryann , Dasari Ramachandra R. , Crowe Joseph P. , Feld Michael S.
Published: March 2006

We present the first demonstration of in vivo collection of Raman spectra of breast tissue. Raman spectroscopy, which analyzes molecular vibrations, is a promising new technique for the diagnosis of breast cancer. We have collected 31 Raman spectra from nine patients undergoing partial mastectomy procedures to show the feasibility of in vivo Raman spectroscopy for intraoperative margin assessment. The data was fit with an established model, resulting in spectral-based tissue characterization in only 1 second. Application of our previously developed diagnostic algorithm resulted in perfect sensitivity and specificity for distinguishing cancerous from normal and benign tissues in our small data set. Significantly, we have detected a grossly invisible cancer that, upon pathologic review, required the patient to undergo a second surgical procedure. Had Raman spectroscopy been used in a real-time fashion to guide tissue excision during the procedure, the additional reexcision surgery might have been avoided. These preliminary findings suggest that Raman spectroscopy has the potential to lessen the need for reexcision surgeries resulting from positive margins and thereby reduce the recurrence rate of breast cancer following partial mastectomy surgeries. (Cancer Res 2006; 66(6): 3317-22)
Spontaneous and UV Radiation–Induced Multiple Metastatic Melanomas in Cdk4R24C/R24C/TPras Mice
Authors: Hacker Elke , Muller H. Konrad , Irwin Nicole , Gabrielli Brian , Lincoln Douglas , Pavey Sandra , Powell Marianne Broome , Malumbres Marcos , Barbacid Mariano , Hayward Nicholas , Walker Graeme
Published: March 2006

Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4R24C/R24C mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4R24C/R24C/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4R24C/+/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4R24C/R24C/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4R24C/R24C/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4R24C/R24C/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors. (Cancer Res 2006; 66(6): 2946-52)
Promoter Hypermethylation of Multiple Genes in Sputum Precedes Lung Cancer Incidence in a High-Risk Cohort
Authors: Belinsky Steven A. , Liechty Kieu C. , Gentry Frederick D. , Wolf Holly J. , Rogers Justin , Vu Kieu , Haney Jerry , Kennedy Tim C. , Hirsch Fred R. , Miller York , Franklin Wilbur A. , Herman James G. , Baylin Stephen B. , Bunn Paul A. , Byers Tim
Published: March 2006

A sensitive screening approach for lung cancer could markedly reduce the high mortality rate for this disease. Previous studies have shown that methylation of gene promoters is present in exfoliated cells within sputum prior to lung cancer diagnosis. The purpose of the current study is to conduct a nested case-control study of incident lung cancer cases from an extremely high-risk cohort for evaluating promoter methylation of 14 genes in sputum. Controls (n = 92) were cohort members matched to cases (n = 98) by gender, age, and month of enrollment. The comparison of proximal sputum collected within 18 months to >18 months prior to diagnosis showed that the prevalence for methylation of gene promoters increased as the time to lung cancer diagnosis decreased. Six of 14 genes were associated with a >50% increased lung cancer risk. The concomitant methylation of three or more of these six genes was associated with a 6.5-fold increased risk and a sensitivity and specificity of 64%. This is the first study to prospectively examine a large panel of genes for their ability to predict lung cancer and shows the promise of gene promoter hypermethylation in sputum as a molecular marker for identifying people at high risk for cancer incidence. (Cancer Res 2006; 66(6): 3338-44)
Common Cancer Biomarkers
Authors: Basil Christopher F. , Zhao Yingdong , Zavaglia Katia , Jin Ping , Panelli Monica C. , Voiculescu Sonia , Mandruzzato Susanna , Lee Hueling M. , Seliger Barbara , Freedman Ralph S. , Taylor Phil R. , Hu Nan , Zanovello Paola , Marincola Francesco M. , Wang Ena
Published: March 2006

There is an increasing interest in complementing conventional histopathologic evaluation with molecular tools that could increase the sensitivity and specificity of cancer staging for diagnostic and prognostic purposes. This study strove to identify cancer-specific markers for the molecular detection of a broad range of cancer types. We used 373 archival samples inclusive of normal tissues of various lineages and benign or malignant tumors (predominantly colon, melanoma, ovarian, and esophageal cancers). All samples were processed identically and cohybridized with an identical reference RNA source to a custom-made cDNA array platform. The database was split into training (n = 201) and comparable prediction (n = 172) sets. Leave-one-out cross-validation and gene pairing analysis identified putative cancer biomarkers overexpressed by malignant lesions independent of tissue of derivation. In particular, seven gene pairs were identified with high predictive power (87%) in segregating malignant from benign lesions. Receiver operator characteristic curves based on the same genes could segregate malignant from benign tissues with 94% accuracy. The relevance of this study rests on the identification of a restricted number of biomarkers ubiquitously expressed by cancers of distinct histology. This has not been done before. These biomarkers could be used broadly to increase the sensitivity and accuracy of cancer staging and early detection of locoregional or systemic recurrence. Their selective expression by cancerous compared with paired normal tissues suggests an association with the oncogenic process resulting in stable expression during disease progression when the presently used differentiation markers are unreliable. (Cancer Res 2006; 66(6): 2953-61)
DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer
Authors: Yang Huiling , Wen Yu-Ye , Zhao Ruiying , Lin Yu-Li , Fournier Keith , Yang Heng-Yin , Qiu Yun , Diaz Jose , Laronga Christine , Lee Mong-Hong
Published: March 2006

14-3-3 σ is induced by tumor suppressor protein p53 in response to DNA damage. p53 can directly transactivate the expression of 14-3-3 σ to cause a G2 cell cycle arrest when cell DNA is damaged. The expression of 14-3-3 σ protein is down-regulated in various tumors, but its function has not been fully established. Protein kinase B/Akt, a crucial regulator of oncogenic signal involved in cell survival and proliferation, is deregulated in many types of cancer. Akt activation can enhance p53 degradation, but its role in DNA damage response is not clear. Here, we show that Akt activation is diminished when p53 and 14-3-3 σ is up-regulated in response to DNA damage. Evidence is provided that 14-3-3 σ binds and inhibits Akt. In keeping with this concept, Akt-mediated cell survival is inhibited by 14-3-3 σ. Significantly, we show that 14-3-3 σ inhibits Akt-mediated cell growth, transformation, and tumorigenesis. Low expression of 14-3-3 σ in human primary breast cancers correlates with Akt activation. These data provide an insight into Akt regulation and rational cancer gene therapy by identifying 14-3-3 σ as a molecular regulator of Akt and as a potential anticancer agent for Akt-activated cancers. (Cancer Res 2006; (66)6: 3096-105)
Increased EP4 Receptor Expression in Colorectal Cancer Progression Promotes Cell Growth and Anchorage Independence
Authors: Chell Simon D. , Witherden Ian R. , Dobson Richard R. , Moorghen Morganaden , Herman Andrew A. , Qualtrough David , Williams Ann C. , Paraskeva Christos
Published: March 2006

Cyclooxygenase-2 and prostaglandin E2 (PGE2) levels are increased in colorectal cancers and a subset of adenomas. PGE2 signaling through the EP4 receptor has previously been associated with colorectal tumorigenesis. However, changes in EP4 expression during adenoma to carcinoma progression have not been investigated, neither has whether levels of EP4 influence important markers of malignant potential, such as anchorage-independent growth or the tumors growth response to PGE2. We report using immunohistochemistry that in vivo EP4 receptor protein expression was increased in colorectal cancers (100%) as well as adenomas (36%) when compared with normal colonic epithelium. EP4 expression was also higher in colorectal carcinoma compared with adenoma cell lines and increased with in vitro models of tumor progression. Adenoma (PC/AA/C1 and RG/C2) and carcinoma cell lines (HT29) were growth stimulated by PGE2 up to 0.5 μmol/L. However, although carcinoma and transformed adenoma (PC/AA/C1SB10C, a transformed derivative of PC/AA/C1) cells remain stimulated by higher doses of PGE2 (10 μmol/L), the adenoma cell lines were inhibited. Interestingly, enforced expression of EP4 in the adenoma cell line, RG/C2, resulted in stimulation of growth by 10 μmol/L PGE2 and promoted anchorage-independent growth. Both in vivo and in vitro data from this study suggest that increased EP4 receptor expression is important during colorectal carcinogenesis. We propose that high levels of PGE2 in a tumor microenvironment would select for cells with increased EP4 expression, and that the EP4 receptor may therefore represent an important target for colorectal cancer prevention and treatment. (Cancer Res 2006; 66(6): 3106-13)
Global Gene Expression Profiling of Pleural Mesotheliomas: Overexpression of Aurora Kinases and P16/CDKN2A Deletion as Prognostic Factors and Critical Evaluation of Microarray-Based Prognostic Prediction
Authors: López-Ríos Fernando , Chuai Shannon , Flores Raja , Shimizu Shigeki , Ohno Takatoshi , Wakahara Kazuhiko , Illei Peter B. , Hussain Sanaa , Krug Lee , Zakowski Maureen F. , Rusch Valerie , Olshen Adam B. , Ladanyi Marc
Published: March 2006

Most gene expression profiling studies of mesothelioma have been based on relatively small sample numbers, limiting their statistical power. We did Affymetrix U133A microarray analysis on 99 pleural mesotheliomas, in which multivariate analysis showed advanced-stage, sarcomatous histology and P16/CDKN2A homozygous deletion to be significant independent adverse prognostic factors. Comparison of the expression profiles of epithelioid versus sarcomatous mesotheliomas identified many genes significantly overexpressed among the former, including previously unrecognized ones, such as uroplakins and kallikrein 11, both confirmed by immunohistochemistry. Examination of the gene expression correlates of survival showed that more aggressive mesotheliomas expressed higher levels of Aurora kinases A and B and functionally related genes involved in mitosis and cell cycle control. Independent confirmation of the negative effect of Aurora kinase B was obtained by immunohistochemistry in a separate patient cohort. A role for Aurora kinases in the aggressive behavior of mesotheliomas is of potential clinical interest because of the recent development of small-molecule inhibitors. We then used our data to develop microarray-based predictors of 1 year survival; these achieved a maximal accuracy of 68% in cross-validation. However, this was inferior to prognostic prediction based on standard clinicopathologic variables and P16/CDNK2A status (accuracy, 73%), and adding the microarray model to the latter did not improve overall accuracy. Finally, we evaluated three recently published microarray-based outcome prediction models, but their accuracies ranged from 63% to 67%, consistently lower than reported. Gene expression profiling of mesotheliomas is an important discovery tool, but its power in clinical prognostication has been overestimated. (Cancer Res 2006; 66(6): 2970-9)
Antibody-Drug Conjugates Designed to Eradicate Tumors with Homogeneous and Heterogeneous Expression of the Target Antigen
Authors: Kovtun Yelena V. , Audette Charlene A. , Ye Yumei , Xie Hongsheng , Ruberti Mary F. , Phinney Sara J. , Leece Barbara A. , Chittenden Thomas , Blättler Walter A. , Goldmacher Victor S.
Published: March 2006

Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells. Furthermore, we showed that, in vivo, these conjugates were effective in eradicating tumors containing both antigen-positive and antigen-negative cells. The presence of antigen-positive cells was required for this killing of bystander cells. This target cell–activated killing of bystander cells was dependent on the nature of the linker between the antibody and the drug. Conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect whereas equally potent conjugates linked via a nonreducible thioether bond were not. Our data offer a rationale for developing optimally constructed antibody-drug conjugates for treating tumors that express the target antigen either in a homogeneous or heterogeneous manner. (Cancer Res 2006; 66(6): 3214-21)
Oncogene-Induced Senescence: Putting the Brakes on Tumor Development
Authors: Braig Melanie , Schmitt Clemens A.
Published: March 2006

Cellular senescence, a permanent cell cycle arrest, is considered a safeguard mechanism that may prevent aged or abnormal cells from further expansion. Although the term “replicative senescence” stands for the widely accepted model of a terminal growth arrest due to telomere attrition, the significance of “oncogene-inducible senescence” remained an issue of debate over the years. A number of recent studies now show the effect of this acute and telomere-independent form of senescence as a tumor-protective, fail-safe mechanism in vivo that shares conceptual and possibly therapeutic similarities with the genetically encoded apoptosis machinery. (Cancer Res 2006; 66(6): 2881-4)
Prostaglandin E Receptor EP4 Antagonism Inhibits Breast Cancer Metastasis
Authors: Ma Xinrong , Kundu Namita , Rifat Salah , Walser Tonya , Fulton Amy M.
Published: March 2006

Cyclooxygenase-2 (COX-2) expression in epithelial tumors is frequently associated with a poor prognosis. In a murine model of metastatic breast cancer, we showed that COX-2 inhibition is associated with decreased metastatic capacity. The COX-2 product, prostaglandin E2 (PGE2), acts through a family of G protein–coupled receptors designated EP1-4 that mediate intracellular signaling by multiple pathways. We characterized EP receptor expression on three murine mammary tumor cell lines and show that all four EP isoforms were detected in each cell. Stimulation of cells with either PGE2 or the selective EP4/EP2 agonist PGE1-OH resulted in increased intracellular cyclic AMP and this response was inhibited with either EP2 or EP4 antagonists. Nothing is known about the function of EP receptors in tumor metastasis. We tested the hypothesis that the prevention of EP receptor signaling would, like inhibition of PGE2 synthesis, inhibit tumor metastasis. Our results show for the first time that antagonism of the EP4 receptor with either AH23848 or ONO-AE3-208 reduced metastasis as compared with vehicle-treated controls. The therapeutic effect was comparable to that observed with the dual COX-1/COX-2 inhibitor indomethacin. EP3 antagonism had no effect on tumor metastasis. Mammary tumor cells migrated in vitro in response to PGE2 and this chemotactic response was blocked by EP receptor antagonists. Likewise, the proliferation of tumor cells was also directly inhibited by antagonists of either EP4 or EP1/EP2. These studies support the hypothesis that EP receptor antagonists may be an alternative approach to the use of COX inhibitors to prevent tumor metastasis. (Cancer Res 2006; 66(6): 2923-7)
Reducing the “Risk” of Chemoprevention: Defining and Targeting High Risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture
Authors: Lippman Scott M. , Lee J. Jack
Published: March 2006

Two large-scale, phase III cancer prevention trials, the Breast Cancer Prevention Trial (BCPT) of tamoxifen and Prostate Cancer Prevention Trial (PCPT) of finasteride, concluded with strikingly positive and simultaneously problematic results: reduced cancer risks but a major adverse finding with each agent that prevented its widespread use in the community. For most moderate-risk people, such as those studied in the BCPT and PCPT, the benefit of reduced breast or prostate cancer does not outweigh the major risk of tamoxifen (endometrial cancer in the BCPT) or apparent risk of finasteride (high-grade prostate cancer in the PCPT). Promising interventions with biologically active substances are likely to have adverse, perhaps unforeseen effects, especially with long-term preventive use. Acceptance of such agents will depend heavily on the level of cancer risk of the target population. This article outlines research in molecularly identified high-risk oral intraepithelial neoplasia that creates the clinical opportunity for optimizing the risk-benefit ratio of agents to prevent oral cancer. Two other major research efforts focused on improving preventive agent risk-benefit ratios are molecular-targeted research designed to target away from known adverse signaling pathways and multidisciplinary research based on the PCPT that will develop comprehensive models of prostate cancer risk (especially of aggressive prostate cancer) and pharmacoecogenetic models for identifying high-risk men most likely to benefit from (and not be harmed by) finasteride or similar (5α-reductase inhibiting) agents. Defining and targeting high-risk populations, developing molecular-targeted approaches, and developing accurate pharmacoecogenetic models promise to reduce the risk of chemoprevention and ultimately to reduce the risk and burden of major cancers. (Cancer Res 2006; 66(6): 2893-903)
Psychological Distress in Alcohol-Dependent Patients
Authors: Sander Wiebke , Jux Michaela
Published: March 2006

The aim of this study was to evaluate the change of psychological distress measured by the symptom checklist in alcohol dependent inpatients during treatment and at follow-up. In addition, psychological distress as a predictive variable for abstinence or relapse during a 1-year follow-up was investigated. In a sample of 314 alcohol-dependent inpatients, we found a statistically significant reduction of psychological distress during therapy. Comparison of patients within 1-year follow-up showed a significant reduction of psychological distress only for the later abstinent subgroup. Later abstinent patients were significantly less distressed at the end of therapy and at follow-up. Logistic regression indicated that a higher Global Severity Index (GSI) of psychological distress at the end of therapy increases the relapse risk.
Feasibility and Acceptability of an Intranasal Diamorphine Spray as an Alternative to Injectable Diamorphine for Maintenance Treatment
Authors: Mitchell Timothy B. , Lintzeris Nicholas , Bond Alyson , Strang John
Published: March 2006

An intranasal (IN) diamorphine spray was investigated as a possible alternative to injectable diamorphine for maintenance treatment. Plasma morphine and 6-monoacetylmorphine (6MAM) concentrations and pharmacodynamic responses were measured for 4 h following intravenous (IV) and IN administration of 40 mg diamorphine in 4 patients prescribed injectable diamorphine. The two routes were primarily differentiated by the significantly greater speed and magnitude of peak plasma morphine and 6MAM concentrations for IV versus IN diamorphine. Beyond this initial peak, mean ratings suggested that withdrawal suppression and positive effects were at least as strong for IN compared to IV administration. All subjects gave favourable appraisals of the IN diamorphine spray, citing advantages including ease of use, the avoidance of needle hazards, and reduced stigma. IN administration may be an alternative or supplementary form of diamorphine maintenance and deserves serious further investigation.
What Characterizes Substance Abusers Who Commit Suicide Attempts? Factors Related to Axis I Disorders and Patterns of Substance Use Disorders
Authors: Landheim A.S. , Bakken K. , Vaglum P.
Published: March 2006

Objective: The frequency of suicide attempts and clinical characteristics of attempters among poly-substance abusers and alcoholics were examined. Methods: A consecutive sample (n = 260) of in- and outpatients from two Norwegian counties were assessed by Composite International Diagnostic Interview (Axis I disorders), Millon’s Clinical Multiaxial Inventory (Axis II disorders) and the Norwegian National Client Assessment Form. When analysing the association between suicide attempters and the range of predictor variables, logistic regression analysis was conducted. Results: Almost half (47%) of the sample reported lifetime suicide attempts; significantly more frequently in poly-substance abusers (58%) than alcoholics (38%). A substance use disorder with duration of ≧15 years and an early onset (<18 years of age) were independently associated with being a suicide attempter after controlling for Axis I disorders. In addition, eating disorders, agoraphobia and major depression were strongly and independently associated with being a suicide attempter. Conclusion: Attempts at preventing suicidal behaviour should not ignore the suicide risk among poly-substance abusers. In addition, prevention of suicidal behaviour demands a treatment programme focusing concomitantly on both addictive behaviour and comorbid psychiatric disorders.
Morphine-Induced Reduction of Intraocular Pressure and Pupil Diameter: Role of Nitric Oxide
Authors: Dortch-Carnes Juanita , Russell Karen R.M.
Published: March 2006

The present study was performed to evaluate the role of nitric oxide in the intraocular pressure (IOP) lowering effect and in the miotic action of morphine. The IOP was measured in conscious, normal, dark-adapted New Zealand white rabbits using a calibrated pneumatonometer. Experiments were conducted, in which rabbits’ eyes were treated with morphine topically and unilaterally, while the fellow eyes received vehicle. IOP and pupil diameter (PD) measurements were taken 0.5 and 0 h before morphine administration and 0.5, 1, 2, 3, 4, and 5 h thereafter. The effects of a nonselective opioid receptor antagonist (naloxone), a nitric oxide synthase inhibitor (Nω-nitro-L-arginine methyl ester; L-NAME), and a sulfhydryl reagent (reduced L-glutathione; GSH) on morphine-mediated changes in IOP and PD were also determined. Morphine (10, 33, and 100 µg) produced concen- tration-dependent decreases in IOP and reduced PD in both treated and untreated eyes of New Zealand white rabbits. IOP-lowering effect of morphine (100 µg) and reduction in PD were both significantly inhibited by pretreatment with naloxone (100 µg), L-NAME (0.5%), or GSH (100 µg). The results from this study indicate that morphine-induced ocular hypotension and reduction in PD are opioid-receptor-mediated responses that are associated with the release of nitric oxide. Because the µ3 opioid receptor subtype has a nitric-oxide-releasing activity and is sensitive to inactivation by GSH, it is concluded that morphine-induced ocular hypotension and miosis are mediated, in part, by activation of µ3 opioid receptors.