bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact Dynamics of Elastic Stiffened Supercavitating Underwater Vehicles
Authors: Ruzzene Massimo , Soranna Francesco
Published: June 2004

The dynamic behavior of and the vibration in supercavitating underwater vehicles are here investigated and controlled. Supercavitating vehicles exploit supercavitation as a means to reduce drag and increase their underwater speed. The forces acting on supercavitating vehicles are completely different from those on conventional submerged bodies, since only a tiny percentage of their external surface area is wetted and water-vapor forces are almost negligible. The hydrodynamic stability of supercavitating bodies is achieved through after-body planing, or surfing, along the internal surface of the cavity, or through periodic impacts, or 'tail-slaps', with the interior surface of the cavity. The interactions between the vehicle and the water/cavity interface are sources of structural strains and vibrations, which undermine the structural reliability of the vehicle and affect its guidance. The dynamic behavior of supercavitating vehicles is here analyzed. The vehicles are modeled as slender elastic beams in order to predict their dynamic response under 'tail-slap' conditions both in terms of rigid body motion as well as dynamic strains and vibrations. The developed numerical model predicts the response of the considered class of supercavitating vehicles and it is used to estimate the effect of periodically placed stiffening rings on the amplitude of the vibrations induced by the tail-slap impacts. The analysis is motivated by the need to accurately model the structural characteristics of supercavitating vehicles in order to estimate the vibration transmission paths along the structure and to envision and design systems that improve their guidance and control efficiency. The models here presented will be included in a simulation-based design procedure for supercavitating vehicles, where optimal design configurations will be identified through a multidisciplinary design optimization (MDO) approach. The MDO process will consider structural performance trade-offs in order to determine configurations that simultaneously provide minimum vibrations and maximum structural reliability, with minimum added weight and costs.
Gain Scheduling Feedback Control of Tower Cranes with Friction Compensation
Authors: Omar Hanafy M , Nayfeh Ali H
Published: June 2004

We have designed a controller based on gain-scheduling feedback to move a load from point to point within one oscillation cycle and without inducing large swings. The settling time of the system is taken to be equal to the period of oscillation of the load. This criterion enables us to calculate the controller feedback gains for varying load weight and cable length. First, we designed the controller for gantry cranes and then extended it to tower cranes by considering the coupling between the translational and rotational motions. Numerical simulations show that the controller is effective for reducing load oscillations and transferring the load in a reasonable time compared with that of optimal control.

To experimentally validate the theory, we had to compensate for friction. To this end, we estimated the friction, then applied an opposite control action to cancel it. To estimate the friction force, we assumed a mathematical model, then we estimated the model coefficients using an off-line identification technique, the least-squares method. First, the process of identification was applied to a theoretical model of a dc motor with known friction coefficients. From this example, some guidelines and rules were deduced for the choice of the least-squares parameters. Then, the friction coefficients of the gantry crane model were estimated and validated.
Fuzzy Logic Control of the End-Point Vibration in an Experimental Flexible Beam
Authors: Jnifene A. , Andrews W
Published: June 2004

This paper is concerned with the design and implementation of a fuzzy logic controller (FLC) to control the end-point vibration in a single flexible beam mounted on a two-degrees-of-freedom platform. The angular position of the hub and the signal from a strain gage mounted on the beam are used as the two inputs to the FLC. In order to add more damping, the strain gage signal is combined with the hub angular velocity represented by the output of a tachometer attached to the motor shaft. We discuss how to build the rule base for the flexible beam based on the relation between the angular displacement of the hub and the end-point deflection, as well as the effect of different scaling gains on the performance of the FLC. We present several experimental results showing the effectiveness of the FLC in reducing the end-point vibration of the flexible beam.
A Hybrid Contml of Seismically Excited Structures by Confinement of Vibrations*
Authors: Choura S. , El-Borgi S. , Nayfeh A. H.
Published: June 2004

We propose a hybrid control strategy, aimed at confining and suppressing simultaneously the vbratory motion in seismically excited structures. It is assumed that these structures are composed of n floors that are sensitive to vibrations, resulting from earthquake excitations. A number (m) of inter-story bracing elements, assumed to be the non-sensitive parts, are added to the structures to confine the vibration. The proposed strategy makes use of (n + p) force actuators that are placed at all floors of the structure and p < m active bracing elements. The design objective is to devise a feedback scheme that leads to transferring the vibrational energy in the floors to the bracing elements. In order to keep away from the buildup of transferred energy into the bracing elements, the feedback scheme considers, along with the confinement, the suppression of vibrations in the floors and bracing elements. A three-floor structure is used to demonstrate the viability of the proposed strategy.
Volterra Kernel Identification Using Triangular Wavelets
Authors: Prazenica Richard J. , Kurdila Andrew J.
Published: June 2004

The Nblterra series provides a convenient framework for the representation of nonlinear dynamical systems. One of the main drawbacks of this approach, however, is the large number of terns that are often needed to represent Wblterra kernels. In this paper we present an approach whereby wavelets are used to obtain low-order estimates of first-order and second-order blterra kernels. Several constructions of tensorproduct wavelets have been employed for some%blterra kernel approximations. In this paper, a triangular wavelet basis is constructed for the representation of the triangular fonn of the second-order kernel. These wavelets are piecewise-constant, orthonormal, and are supported over the triangular domain over which the second-order kernel is defined. The well-known Haar wavelet is used concurrently for the identification of the first-order kernel. This kernel identification algorithm is demonstrated on a prototypical nonlinear oscillator. It is shown that accurate kemel estimates can be obtained in terms of a relatively small number of wavelet coefficients. It is also demonstrated that, for this particular system, the derived Volterra model is valid for input amplitudes below a specified bound. When the input amplitude exceeds this threshold, higher-order kernels are needed to adequately describe the system dynamics. Thus, the approach taken in this paper is applicable to a large class of nonlinear systems provided that the input excitation is sufficiently bounded.
Constrained Damping Layer Treatments: Finite Element Modeling
Authors: Moreira R. , Rodrigues J. D.
Published: June 2004

In this paper we assess the performance of finite element models in modeling structures with sheer damping treatments. We analyze the finite element modeling of constrained layer damping (CLD) and integrated layer damping (ILD) treatments using viscoelastic materials, devoting special attention to the spatial modeling of the treatment and to the characterization of the viscoelastic material properties. In this work, we used a finite element commercial software (MSC.Nastran) to simulate the dynamic response of aluminum plates with both treatment configurations (CLD and ILD). The spatial modeling of the treatment was devel-oped using three different models, all based on a layered assembly of plate/brick conventional finite elements. The dynamic properties of the viscoelastic material were taken into account in the numerical simulation using the complex modulus approach. The numerical results are correlated with experimental data obtained for four treated specimens by direct comparison of the frequency response functions (FRFs) and by using FRF-based correlation indicators. The analyzed finite element models are found to provide very reliable results when compared with experimental acquired data.
A Thermomechanical Framework for the Transition of a Miscoelastic Liquid to a Viscoelastic Solid
Authors: Kannan K. , Rajagopal K. R.
Published: June 2004

We present a thermomechanical framework to describe the transition from a viscoelastic fluid to a viscoelastic solid, in which the kinetics associated with the transition and the change of response ch acteristics prior to, during, and after the transition are modeled within a unified setting. The procedures fit within the general thermodynamic framework that has been developed to describe the response of materials that can exist stress free in multiple configurations. The current study is a generalization of the studies by Rao and Rajagopal and Kannan et al. that addresses the solidification of a polymeric melt into an elastic solid.
Asmptoticaliy Approximate Model Equations for Weakly Nonlinear Long Waves in Compressible Elastic Rods and their Comparisons with Other Simplified Model Equations
Authors: Dai Hui-Hui , Fan Xiaojun
Published: June 2004

Weakly nonlinear long waves in a cylindrical elastic rod composed of a compressible Murnaghan material are studied in this paper. Four types of model equations describing nonlinear dispersive waves are derived, two of which can satisfy the lateral boundary conditions asymptotically The dispersion relations for these types of model equations are obtained and compared with the exact dispersion relation from the three-dimensional elasticity. Solitary wave solutions of the far-field equations of these models are shown. By comparison of these four types of model, some conclusions about their advantages and disadvantages are drawn.
Additional Universal Relations for Transversely Isotropic Elastic Materials
Authors: Saccomandi Giuseppe , Batra R. C.
Published: June 2004

For the case of distinct eigenvalues of the left Cauchy-Green tensor universal relations for a transversely isotropic elastic material are expressed in a compact form. Also, two new universal relations are derived for an incompressible transversely isotropic elastic material.
A Note on the Constitutive Equation for an Isotropic Elastic Material
Authors: Rivlin Ronald S.
Published: June 2004

The relation is established between the constitutive equations for the stress in an isotropic elastic material based on strain-energy functions that are functions of the right Cauchy-Green strain matrix and the right stretch matrix. It is shown that results to problems obtained on the basis of the latter can be simply obtained from those derived on the basis of the former.
Restrictions on the Strain-Energy Function for an Elastic Material
Authors: Rivlin Ronald S.
Published: June 2004

Conditions are obtained for the incremental shear modulus to be positive for small simple shear superposed on a pure homogeneous deformation of an elastic material, the direction and plane of shear being parallel to a principal direction and principal plane respectively. Results are obtained for an isotropic elastic material and for a transversely isotropic elastic material in which the axis of rotational symmetry is in a principal direction of the pure homogeneous deformation. For an isotropic material, it is shown that the Baker-Ericksen condition on the strain-energy function follows from the assumption that the incremental shear modulus is positive. A number of further conditions that have been proposed are shown to be unacceptable.
An Example of Application of Limit State Approach for Reliability Analysis of Moisture Performance of a Building Component
Authors: Pietrzyk K. , Kurkinen K. , Hagentoft C. -E.
Published: June 2004

Application of limit state approach for the reliability analysis of building performance in the context of building physics characteristics is presented. Analysis of the probability of surface condensation on windows carried out on the basis of statistical description of the climatic parameters and the moisture production is shown as an example of application of this technique for reliability analysis of moisture performance of a building component. The first-order reliability method (FORM) is employed to estimate the probability of performance failure. The results of probabilistic approximations are verified with the help of statistical analysis of the results obtained from deterministic simulations.
A Hot Box–Cold Box Investigation of the Corrosion Behavior of Highly Insulated Zinc Roofing Systems
Authors: Zheng R. , Carmeliet J. , Hens H. , Janssens A. , Bogaerts W.
Published: June 2004

This paper investigates the effect of roofing systems on the humidityinduced corrosion of zinc sheeting in highly insulated zinc roofs. Ten types of roofing systems (U< 0.25 W/(m2K)) were tested in a hot box–cold box apparatus. The measurements and investigations include the relative humidity under the zinc sheeting, the corrosion type, the corrosion product, and the corrosion rate. The influence of a well performing air-vapor retarder below the insulation on the underside corrosion of zinc sheeting is slight for zinc roofs with a good cavity ventilation, but significant if the ventilation is poor. For nonventilated zinc roofs, installing a perfect air-vapor retarder under the insulation only is not sufficient to control the sheeting underside corrosion. Further introducing a dry capillary and sorption active material between the sheeting and the insulation greatly reduces that corrosion.
Becoming a (Virile) Member: Women and the Military Body
Authors: Höpfl Heather J.
Published: June 2004

This article seeks to examine the process by which women are incorporated into the military body and considers the extent to which this is achieved both by demonstrating mastery and by the acquisition of the metaphorical penis. Specifically, the article puts forward the view that incorporation into the military body is achieved via a cancellation of the feminine. Women, it is argued, can either be playthings or else quasi men. The point is, and this is the meaning of the title, that either way women are dis-membered to maintain good order. To become a member of the military body, a woman must either conform to the male projection offered her or else acquire a metaphorical ‘member’ as the price of entry into ‘membership’. Women who do conform are assumed into the body and made homologues/homomorphs of men. However, in order to achieve this status of honorary man, they must accept impotence. They are not and do no possess real members. They are rewarded for not re-membering the body.
Advertising Theory: Reconceptualizing the Building Blocks
Authors: Nan Xiaoli , Faber Ronald J.
Published: June 2004

A large amount of research in advertising utilizes theories from other disciplines and simply uses an advertising message as a stimulus or focal content topic. The actual elements that make advertising unique are often ignored in this work. It is proposed here that advertising theory and research needs to become more focused on what makes advertising a distinct phenomenon and these elements need to be incorporated in our thoughts and research. Four examples of possible elements are suggested here. These are skepticism, repetition, message coordination and clutter. Research in each of these areas is reviewed and illustrations of how they may impact theory development and theory testing in advertising are presented.
Explaining the Special Case of Incongruity in Advertising: Combining Classic Theoretical Approaches
Authors: Lee Eun-Ju , Schumann David W.
Published: June 2004

In order to assess the effectiveness of an advertisement employing incongruity, it would be most helpful to determine when and how incongruity is likely to be processed by consumers and the nature of the response it is likely to evoke. By combining the tenets of two classic processing theories, Petty and Cacioppo’s Elaboration Likelihood Model (1981, 1986) and Mandler’s Schema Incongruity Theory (1982), this article develops an integrative framework for better understanding viewer responses to incongruity.
Beyond Visual Metaphor: A New Typology of Visual Rhetoric in Advertising
Authors: Phillips Barbara J. , McQuarrie Edward F.
Published: June 2004

The goal of rhetorical theory is always to organize the possibilities for persuasion within a domain and to relate each possible stratagem to specific desired outcomes. In this article we develop a visual rhetoric that differentiates the pictorial strategies available to advertisers and links them to consumer response. We propose a new typology that distinguishes nine types of visual rhetorical figures according to their degree of complexity and ambiguity. We then derive empirically testable predictions concerning how these different types of visual figures may influence such consumer responses as elaboration and belief change. The article concludes with a discussion of the importance of marrying textual analysis, as found in literary, semiotic and rhetorical disciplines, with the experimental methodology characteristic of social and cognitive psychology.
Consumer Responses to Perceived Telepresence in the Online Advertising Environment: The Moderating Role of Involvement
Authors: Hopkins Christopher D. , Raymond Mary Anne , Mitra Anu
Published: June 2004

Cyber technology creates new shopping experiences for consumers and ways of searching for product information that are not possible in traditional advertising contexts. Telepresence, defined as the sense of being present in the remote environment, can simulate direct experience, and is useful for conceptualizing consumers’ experiences in computer-mediated environments. We focus on perceived telepresence in seeking to broaden our understanding of the effects of persuasive communications in the cyber environment. We examine effects of perceived telepresence on consumer responses such as attitude toward the ad, attitude toward the brand, and purchase intention, and also examine how these effects are moderated by consumer involvement. Hypotheses derived from a proposed conceptual model are tested via a laboratory experiment. Data is then analyzed with multi-sample structural analysis. Results show that perceived telepresence significantly affects consumer responses to online advertising and that involvement moderates these effects. Theoretical and managerial implications of the results are discussed.
Doing Work That Matters Despite the Obstacles
Authors: Bradbury Hilary
Published: June 2004

This is the third interview for the journal section we call ‘ influential ideas’. Here we introduce (and invite others to introduce) influential thinkers in a digestible format so that action researchers may be inspired to enrich their own research and practice. This interview is with Riane Eisler, who is known primarily as an author. Her best known book, The Chalice and the Blade, was published by Harper and Row in 1988 and became a bestseller which has since been translated into 20 foreign languages. Other books include Sacred Pleasure, Tomorrow’s Children, and The Power of Partnership. Eisler places what would commonly be called feminist concerns at the center of her inquiry. In doing so she has explored the deep foundations of a dominator culture that permeate not just our gender relationships, but also our very modes of thinking and doing research. She offers suggestions for action research projects we might undertake, in programmatic fashion, to create more of a partnership orientation in many walks of life.
Lewin’s Action Research Model as a Tool for Theory Building
Authors: White Anastasia M.
Published: June 2004

This article explores the importance of first-person research strategies in enhancing practice and theory within the field of conflict resolution. The core of the article is a case study that describes a first-person experience working with police and community members to establish local community–police forums in post-apartheid South Africa. The case study echoes the processes of reconciliation and healing that took place at the community and national level. Using the Lewinian model of action research (Lewin, 1951) as a structured reflection process, the author analyzes this process of conflict transformation from the perspective of a participant, practitioner and researcher over an eight-year period. This reflection process combines first-, second-, and third-person data to develop and test a grounded theory of identity-based conflict. The application of the Lewin model to conflict resolution illustrates how action research can inform both research and practice by more closely aligning lived experience with theory.
Towards a Theory of Inclusive Practice
Authors: Friedman Victor , Razer Michal , Sykes Israel
Published: June 2004

This article demonstrates how action research can fill a theoretical gap in the literature on ‘social exclusion’. Although the literature points to the centrality of ‘relationships’ in overcoming exclusion, it offers little theory on the nature of these relationships and how they are formed. This article presents ‘actionable knowledge’ for creating interpersonal relationships that interrupt processes of exclusion. It draws on the findings of an ‘action science’ inquiry process carried out by the staff of an intervention program that helps schools work more effectively with students characterized by chronic failure. The article describes how the concept of ‘social exclusion’ entered the discourse of the inquiry and helped practitioners frame their practice problem and intervention strategy. It then analyzes the program’s specific ‘theory of action’ for forming inclusive relationships. Finally it addresses the validity and the generalizability of action science research aimed at developing a theory of inclusive practice.
Participatory Research in Constrained Settings
Authors: Busza Joanna
Published: June 2004

This article presents the integration of traditional data collection methods for the evaluation of an HIV-prevention programme for Vietnamese sex workers in Cambodia with a participatory approach to project implementation. Local instability and powerlessness posed serious challenges to maintaining our commitment to the principles of participation and ensuring rigorous research. The project consequently focused on negotiating these challenges and adapting the study. Although our efforts did not fully harness the empowering potential of participation and raised a series of contradictions in our design, we gained a rich understanding of the complex community dynamics in this marginalized population. Our experience highlights the need for careful consideration of what participation can feasibly hope to achieve in severely constrained settings, but suggests it can contribute to critical knowledge for the development of appropriate interventions.
Styrene Block Copolymer Modified Food Wrap Film
Authors: Maris Catherine , Modic Michael
Published: June 2004

Stretch wrapping film has been used for over 30 years to protect and preserve food from moisture, dirt, and abrasion. These films allow increased food shelf lives and give the package an appealing smooth and shiny appearance. Styrenic block copolymers can be blended with polypropylene and co-extruded with ethylene vinyl acetate to form multi-layer structures suitable for food wrap applications. These films offer an excellent balance of properties combined with a low density.
Improving Functionality of Polyolefin Films Through the Use of Additives
Authors: Landuzzi Andrea , Ghosh Jay
Published: June 2004

Polyolefin films are the workhorses of the packaging and agricultural industries. Their omnipresence is driven by their good mechanical and durability properties as well as their excellent cost/performance ratio. However, polyolefin chemistry has some intrinsic properties, e.g., lack of optical transparency, hydrophobicity, static generation leading to dust attraction and inadequate barrier properties, which need to be significantly altered so that films made from these resins are suitable for some specific markets and applications. This paper shows how additives can play a significant role to overcome some of these shortcomings and create differentiated film products with added value.
Variables that Affect/Control High-Density Polyethylene Film Oxygen–Moisture Barrier
Authors: Todd William G.
Published: June 2004

Multiple layer polyolefin-based films continue to be one of the preferred packages for both the food and medical industries. The technology of these films has advanced over the years from simple monolayer structures to multilayer hybrid structures. These affordable packages not only provide tamper proof evidence, but also protection from insects, bacteria, germs, and dust and are very effective in providing moisture and oxygen barrier. This paper will discuss these latter two properties, moisture and oxygen barrier, when polyethylene is used as the primary film component.

Many variables affect high-density polyethylene (HDPE) film’s oxygen transmission rates (OTR), and water vapor transmission rates (WVTR). These variables include film crystalline structure, relaxation rates of molten polyethylene, polyethylene manufacturing technology, polyethylene resin physical properties, atmospheric conditions, and film fabrication technology and structure. This paper will describe how permeation rates are measured and how each of the above variables affects the permeation rates.
Platelet-associated CD154 in immune thrombocytopenic purpura
Authors: Solanilla Anne , Pasquet Jean-Max , Viallard Jean-François , Contin Cécile , Grosset Christophe , Déchanet-Merville Julie , Dupouy Maryse , Landry Marc , Belloc Francis , Nurden Paquita , Blanco Patrick , Moreau Jean-François , Pellegrin Jean-Luc , Nurden Alan T. , Ripoche Jean
Published: June 2004

CD40-ligand (CD154) is expressed on activated CD4+ T lymphocytes and is essential for the T cell–dependent activation of B lymphocytes. CD154 is also expressed at the activated platelet surface. In this study, we show that platelet-associated CD154 is increased in immune thrombocytopenic purpura (ITP), a disease characterized by an autoimmune response against proteins of the platelet membrane. CD154 and its messenger RNA were also present in increased amounts in the megakaryocytes of patients with ITP. We found that platelet-associated CD154 is competent to induce the CD40-dependent proliferation of B lymphocytes, and we observed an in vitro CD154-dependent production of antibodies to the GPIIb/IIIa complex (integrin αIIbβ3) when platelets and peripheral blood B lymphocytes from ITP patients with circulating anti-GPIIb/IIIa antibody were cultured together. Therefore, platelet-associated CD154 expression is increased in ITP and is able to drive the activation of autoreactive B lymphocytes in this disease.
Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias
Authors: Shetzline Susan E. , Rallapalli Ravikumar , Dowd Kelley J. , Zou Shaomin , Nakata Yuji , Swider Cezary R. , Kalota Anna , Choi John K. , Gewirtz Alan M.
Published: June 2004

The c-myb proto-oncogene has been implicated in leukemogenesis, but possible mechanisms remain ill defined. To gain further insight to this process, we used transcript profiling in K562 cells expressing a dominant-negative Myb (MERT) protein. A total of 105 potential Myb gene targets were identified. Neuromedin U (NmU), a peptide affecting calcium transport, underwent the greatest expression change (∼ 5-fold decrease). To verify a linkage between c-myb and NmU, their mRNA levels were quantitated using real-time polymerase chain reaction in primary acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as well as normal hematopoietic cells. We found that c-myb was elevated in AML and ALL samples, but NmU expression was increased only in AML cells. Significantly, only AML cells expressed the cognate receptor of NmU, NMU1R, suggesting the presence of a novel autocrine loop. We examined this possibility in detail. Exogenous NmU “rescued” growth suppression in K562-MERT cells and stimulated the growth of primary AML cells. Short interfering RNA “knockdown” of NmU in K562 cells arrested cell growth. Exposing Indo-1–labeled K562 cells to NmU induced an intracellular Ca++ flux consistent with engagement of the NMU1R. Combined, these results suggest that NmU expression is related to Myb and that the NmU/NMU1R axis constitutes a previously unknown growth-promoting autocrine loop in myeloid leukemia cells.
Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion
Authors: Abe Masahiro , Hiura Kenji , Wilde Javier , Shioyasono Atsushi , Moriyama Keiji , Hashimoto Toshihiro , Kido Shinsuke , Oshima Takashi , Shibata Hironobu , Ozaki Shuji , Inoue Daisuke , Matsumoto Toshio
Published: June 2004

Multiple myeloma (MM) expands in the bone marrow and causes devastating bone destruction by enhancing osteoclastic bone resorption in its vicinity, suggesting a close interaction between MM cells and osteoclasts (OCs). Here, we show that peripheral blood mononuclear cell-derived OCs enhanced growth and survival of primary MM cells as well as MM cell lines more potently than stromal cells, and that OCs protected MM cells from apoptosis induced by serum depletion or doxorubicin. OCs produced osteopontin (OPN) and interleukin 6 (IL-6), and adhesion of MM cells to OCs increased IL-6 production from OCs. In addition, IL-6 and OPN in combination enhanced MM cell growth and survival. However, the effects of OCs on MM cell growth and survival were only partially suppressed by a simultaneous addition of anti–IL-6 and anti-OPN antibodies and were completely abrogated by inhibition of cellular contact between MM cells and OCs. These results demonstrate that OCs enhance MM cell growth and survival through a cell-cell contact-mediated mechanism that is partially dependent on IL-6 and OPN. It is suggested that interactions of MM cells with OCs augment MM growth and survival and, thereby, form a vicious cycle, leading to extensive bone destruction and MM cell expansion.
Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium
Authors: Göthert Joachim R. , Gustin Sonja E. , van Eekelen J. Anke M. , Schmidt Uli , Hall Mark A. , Jane Stephen M. , Green Anthony R. , Göttgens Berthold , Izon David J. , Begley C. Glenn
Published: June 2004

Tumor growth is dependent in part on “neoangiogenesis.” Functional involvement of bone marrow (BM)-derived cells in this process has been demonstrated. However, it remains controversial as to whether tumor endothelium itself is BM derived. Here we sought to address this issue with an endothelial-specific, inducible transgenic model. We generated Cretransgenic mice (endothelial-SCL-Cre-ERT) using the tamoxifen-inducible Cre-ERT recombinase driven by the 5′ endothelial enhancer of the stem cell leukemia (SCL) locus. These mice were intercrossed with Cre reporter strains in which β-galactosidase (LacZ) or enhanced yellow fluorescent protein (EYFP) are expressed upon Cre-mediated recombination. After tamoxifen administration, endothelial LacZ staining was observed in embryonic and adult tissues. Cre-mediated recombination was also observed in newly generated tumor endothelium. In adult BM cells we could only detect trace amounts of recombination by flow cytometry. Subsequently, BM from endothelial-SCL-Cre-ERT;R26R mice was transplanted into irradiated recipients. When tumors were grown in recipient mice, which received tamoxifen, no tumor LacZ staining was detected. However, when tumors were grown in endothelial-SCL-Cre-ERT;R26R mice 3 weeks after the cessation of tamoxifen treatment, there was widespread endothelial LacZ staining present. Thus, this genetic model strongly suggests that BM cells do not contribute to tumor endothelium and demonstrates the lineage relation between pre-existing endothelium and newly generated tumor endothelial cells. (Blood. 2004;104:1769-1777)
New anticoagulants
Authors: Hirsh Jack , O'Donnell Martin , Weitz Jeffrey I.
Published: June 2004

Anticoagulants are pivotal agents for prevention and treatment of thromboembolic disorders. Limitations of existing anticoagulants, vitamin K antagonist and heparins, have led to the development of newer anticoagulant therapies. These anticoagulants have been designed to target specific coagulation enzymes or steps in the coagulation pathway. New anticoagulants that are under evaluation in clinical trials include: (1) inhibitors of the factor VIIa/tissue factor pathway; (2) factor Xa inhibitors, both indirect and direct; (3) activated protein C and soluble thrombomodulin; and (4) direct thrombin inhibitors. Although most of these are parenteral agents, several of the direct inhibitors of factor Xa and thrombin are orally active. Clinical development of these therapies often starts with studies in the prevention of venous thrombosis before evaluation for other indications, such as prevention of cardioembolism in patients with atrial fibrillation or prosthetic heart valves. At present, the greatest clinical need is for an oral anticoagulant to replace warfarin for long-term prevention and treatment of patients with venous and arterial thrombosis. Ximelagatran, an oral direct thrombin inhibitor, is the first of a series of promising new agents that might fulfill this need. Large phase 3 trials evaluating ximelagatran for the secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with atrial fibrillation have been completed.
Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-Jκ
Authors: MacKenzie Farrell , Duriez Patrick , Larrivée Bruno , Chang Linda , Pollet Ingrid , Wong Fred , Yip Calvin , Karsan Aly
Published: June 2004

Notch proteins comprise a family of transmembrane receptors. Ligand activation of Notch releases the intracellular domain of the receptor that translocates to the nucleus and regulates transcription through the DNA-binding protein RBP-Jκ. Previously, it has been shown that the Notch4 intracellular region (N4IC) can inhibit endothelial sprouting and angiogenesis. Here, N4IC deletion mutants were assessed for their ability to inhibit human microvascular endothelial cell (HMEC) sprouting with the use of a quantitative endothelial sprouting assay. Deletion of the ankyrin repeats, but not the RAM (RBP-Jκ associated module) domain or C-terminal region (CT), abrogated the inhibition of fibroblast growth factor 2 (FGF-2)- and vascular endothelial growth factor (VEGF)-induced sprouting by Notch4, whereas the ankyrin repeats alone partially blocked sprouting. The ankyrin repeats were also the only domain required for up-regulation of RBP-Jκ-dependent gene expression. Interestingly, enforced expression of the ankyrin domain alone was sufficient to up-regulate some, but not all, RBP-Jκ-dependent genes. Although N4IC reduced VEGF receptor-2 (VEGFR-2) and vascular endothelial (VE)-cadherin expression, neither of these events is necessary and sufficient to explain N4IC-mediated inhibition of sprouting. A constitutively active RBP-Jκ mutant significantly inhibited HMEC sprouting but not as strongly as N4IC. Thus, Notch4-induced inhibition of sprouting requires the ankyrin repeats and appears to involve RBP-Jκ-dependent and -independent signaling. (Blood. 2004;104:1760-1768)
Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis
Authors: Yamazaki Tohru , Akada Tetsuya , Niizeki Osamu , Suzuki Takahiro , Miyashita Hiroki , Sato Yasufumi
Published: June 2004

Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) plays an important role in angiogenesis by regulating the proliferation and migration of endothelial cells (ECs). Here we characterize the mechanism by which PILSAP regulates the vascular endothelial growth factor (VEGF)–stimulated proliferation of ECs. The specific elimination of PILSAP expression or its enzymatic activity inhibited VEGF-stimulated G1/S transition in ECs. This G1 arrest correlated with reduced cyclin dependent kinase 4/6 (CDK4/6) activity and retinoblastoma (Rb) protein phosphorylation. Analyses of signaling molecules upstream of CDK4/6 revealed that S6 kinase (S6K) activation was affected by PILSAP, whereas that of phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal-related kinase 1/2 (ERK1/2) was not. We further demonstrated that PILSAP bound phosphatidylinositol-dependent kinase 1 (PDK1) and removed 9 amino acids from its N-terminus, which allowed S6K to associate with PDK1 and PILSAP upon VEGF stimulation. We constructed mutant PILSAP, which lacked the aminopeptidase activity but bound PDK1. Mutant PILSAP abrogated S6K activation upon VEGF stimulation in a dominant-negative manner. An N-terminal truncated form of PDK1 abolished the dominant-negative effect of mutant PILSAP. Finally, the introduction of a mutated PILSAP gene in ECs inhibited angiogenesis and retarded tumor growth in vivo. These results indicate that PILSAP plays a crucial role in the cell cycle progression of ECs and angiogenesis via the binding and modification of PDK1.
In a model of tumor dormancy, long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis
Authors: Saudemont Aurore , Quesnel Bruno
Published: June 2004

In tumor dormancy, tumor cells persist in the host over a long period of time but do not grow. We investigated in the DA1-3b mouse model of acute myeloid leukemia how leukemic cells could persist for months in spite of an effective antileukemic immune response. Mice were immunized with irradiated interleukin 12 (IL12)- or CD154-transduced DA1-3b cells, challenged with wild-type DA1-3b cells, and randomly killed during 1-year follow-up. Quantification of residual disease 1 year after challenge showed that persistent leukemic cells represented less than 0.02% of spleen cells in most animals. These residual cells were still able to kill naive hosts, even when isolated after 1 year of persistence. Persistent leukemic cells were more resistant to specific cytotoxic T-cell (CTL)-mediated killing and had enhanced B7-H1 and B7.1 expression proportional to the time they had persisted in the host. Blocking B7-H1 or B7.1/cytotoxic T-lymphocyte-associated antigen (CTLA-4) interaction enhanced CTL-mediated killing of the persistent cells, and blocking B7-H1, B7.1, or CTLA-4 in vivo prolonged survival of naive mice injected with persistent leukemic cells. Thus, escape of leukemic cells from tumor immunity via overexpression of B7-H1 or B7.1 might represent a new mechanism of tumor dormancy in acute leukemia. (Blood. 2004;104:2124-2133)
Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event
Authors: Plenchette Stéphanie , Cathelin Séverine , Rébé Cédric , Launay Sophie , Ladoire Sylvain , Sordet Olivier , Ponnelle Tibor , Debili Najet , Phan Thi-Hai , Padua Rose-Ann , Dubrez-Daloz Laurence , Solary Eric
Published: June 2004

The caspase inhibitor and RING finger-containing protein cellular inhibitor of apoptosis protein 1 (c-IAP1) has been shown to be involved in both apoptosis inhibition and signaling by members of the tumor necrosis factor (TNF) receptor family. The protein is regulated transcriptionally (eg, is a target for nuclear factor-κB [NF-κB]) and can be inhibited by mitochondrial proteins released in the cytoplasm upon apoptotic stimuli. The present study indicates that an additional level of regulation of c-IAP1 may be cell compartmentalization. The protein is present in the nucleus of undifferentiated U937 and THP1 monocytic cell lines. When these cells undergo differentiation under phorbol ester exposure, c-IAP1 translocates to the cytoplasmic side of the Golgi apparatus. This redistribution involves a nuclear export signal (NES)-mediated, leptomycin B-sensitive mechanism. Using site-directed mutagenesis, we localized the functional NES motif in the caspase recruitment domain (CARD) of c-IAP1. A nucleocytoplasmic redistribution of the protein was also observed in human monocytes as well as in tumor cells from epithelial origin when undergoing differentiation. c-IAP1 does not translocate from the nucleus of cells whose differentiation is blocked (ie, in cell lines and monocytes from transgenic mice overexpressing B-cell lymphoma 2 [Bcl-2] and in monocytes from patients with chronic myelomonocytic leukemia). Altogether, these observations associate c-IAP1 cellular location with cell differentiation, which opens new perspectives on the functions of the protein. (Blood. 2004;104:2035-2043)
Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells
Authors: Rajantie Iiro , Ilmonen Maritta , Alminaite Agne , Ozerdem Ugur , Alitalo Kari , Salven Petri
Published: June 2004

Bone marrow (BM)-derived cells are thought to participate in the growth of blood vessels during postnatal vascular regeneration and tumor growth, a process previously attributed to stem and precursor cells differentiating to endothelial cells. We used multichannel laser scanning confocal microscopy of whole-mounted tissues to study angiogenesis in chimeric mice created by reconstituting C57BL mice with genetically marked syngeneic BM. We show that BM-derived endothelial cells do not significantly contribute to tumor- or cytokine-induced neoangiogenesis. Instead, BM-derived periendothelial vascular mural cells were persistently detected at sites of tumor- or vascular endothelial growth factor-induced angiogenesis. Subpopulations of these cells expressed the pericyte-specific NG2 proteoglycan, or the hematopoietic markers CD11b and CD45, but did not detectably express the smooth muscle markers smooth muscle α-actin or desmin. Thus, the major contribution of the BM to angiogenic processes is not endothelial, but may come from progenitors for periendothelial vascular mural and hematopoietic effector cells. (Blood. 2004;104: 2084-2086)
Mastermind critically regulates Notch-mediated lymphoid cell fate decisions
Authors: Maillard Ivan , Weng Andrew P. , Carpenter Andrea C. , Rodriguez Carlos G. , Sai Hong , Xu Lanwei , Allman David , Aster Jon C. , Pear Warren S.
Published: June 2004

During lymphoid development, Notch1 plays a critical role in the T-cell/B-cell lineage decision, while Notch2 is essential for marginal zone B-cell (MZB) development. Notch pathway activation induces translocation of intracellular Notch (ICN) to the nucleus, where it interacts with the transcription factor CSL (CBF1/RBP-Jk, Suppressor of Hairless, Lag-1). In vitro, ICN binds Mastermind-like proteins, which act as potent Notch coactivators. Three MAML family members (MAML1-3) have been identified in mammals, but their importance in vivo is unknown. To investigate the function of MAMLs in hematopoietic development, we introduced a dominant negative (DN) mutant of MAML1, capable of inhibiting Notch1-4, in murine hematopoietic stem cells. DNMAML1 resulted in early inhibition of T-cell development and the appearance of intrathymic B cells, phenotypes consistent with Notch1 inhibition. The T-cell differentiation block was as profound as that produced by enforced expression of the Notch modulator Deltex1. In DNMAML1-transduced spleen cells, a dramatic decrease in MZB cells was present, consistent with Notch2 inhibition. In contrast, Deltex1 did not decrease MZB cell numbers. These results suggest a critical role for MAMLs during Notch-mediated cell fate decisions in vivo and indicate that DNMAML1, but not Deltex1, can be used to interfere with the function of multiple Notch family members. (Blood. 2004;104:1696-1702)
Quiescent phenotype of tumor-specific CD8+ T cells following immunization
Authors: Monsurrò Vladia , Wang Ena , Yamano Yoshisha , Migueles Stephen A. , Panelli Monica C. , Smith Kina , Nagorsen Dirk , Connors Mark , Jacobson Steven , Marincola Francesco M.
Published: June 2004

In a human melanoma model of tumor antigen (TA)–based immunization, we tested the functional status of TA-specific CD8+ cytotoxic T lymphocytes. A “quiescent” phenotype lacking direct ex vivo cytotoxic and proliferative potential was identified that was further characterized by comparing its transcriptional profile to that of TA-specific T cells sensitized in vitro by exposure to the same TA and the T-cell growth factor interleukin 2 (IL-2). Quiescent circulating tumor-specific CD8+ T cells were deficient in expression of genes associated with T-cell activation, proliferation, and effector function. This quiescent status may explain the observed lack of correlation between the presence of circulating immunization-induced lymphocytes and tumor regression. In addition, the activation of TA-specific T cells by in vitro antigen recall and IL-2 suggests that a complete effector phenotype might be reinstated in vivo to fulfill the potential of anticancer vaccine protocols.
Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets
Authors: Hardy Adam R. , Jones Matthew L. , Mundell Stuart J. , Poole Alastair W.
Published: June 2004

Adenosine diphosphate (ADP), an important platelet agonist, acts through 2 G-protein-coupled receptors (GPCRs), P2Y1 and P2Y12, which signal through Gq and Gi, respectively. There is increasing evidence for cross-talk between signaling pathways downstream of GPCRs and here we demonstrate cross-talk between these 2 ADP receptors in human platelets. We show that P2Y12 contributes to platelet signaling by potentiating the P2Y1-induced calcium response. This potentiation is mediated by 2 mechanisms: inhibition of adenylate cyclase and activation of phosphatidylinositol 3 (PI 3)-kinase. Furthermore, the Src family kinase inhibitor PP1 selectively potentiates the contribution to the calcium response by P2Y12, although inhibition of adenylate cyclase by P2Y12 is unaffected. Using PP1 in combination with the inhibitor of PI 3-kinase LY294002, we show that Src negatively regulates the PI 3-kinase-mediated component of the P2Y12 calcium response. Finally, we were able to show that Src kinase is activated through P2Y1 but not P2Y12. Taken together, we present evidence for a complex signaling interplay between P2Y1 and P2Y12, where P2Y12 is able to positively regulate P2Y1 action and P2Y1 negatively regulates this action of P2Y12. It is likely that this interplay between receptors plays an important role in maintaining the delicate balance between platelet activation and inhibition during normal hemostasis. (Blood. 2004; 104:1745-1752)