bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Planetary Needle Bearings on the Performance of Single and Double Pinion Planetary Systems
Authors: Singh Avinash
Published: December 2006

Planetary gears are widely used in automotive and aerospace applications. Due to demands for greater power density, these gearsets often operate at extremely high stress levels. This has caused system level influences once considered secondary to become critical to the success of planetary gears. One such system level effect that has been largely overlooked is the influence of support structures like planetary needle bearings. There are interactions between the gear distributed loads and the resulting bearing loads and deflections that have implications for both gear and bearing designs. Also, double pinion planetary arrangements are increasingly becoming common. There are still greater interactions between the gear and bearing components in double pinion planetary arrangements. In this paper, we will examine the influence of the bearing deflections (tilt) on the gear load distribution and contact pattern. We will also show the influence of distributed gear loads on the bearing loads (moments) and deflections (tilts). Both, single and double pinion planetary arrangements will be considered. It will be shown that the tilting stiffnesses of the needle bearings have a major influence on gear contact pattern and consequently on contact and bending stresses. It will also be shown that the double pinion planetary arrangement is more likely to result in off-centered loading. Parametric studies will be performed to show the influence of a few design parameters. Theoretical derivations will be validated by numerical simulations. A system level gear analysis model will be used to illustrate the issues involved and quantify the results.
Prediction of Mechanical Efficiency of Parallel-Axis Gear Pairs
Authors: Xu H. , Kahraman A. , Anderson N. E. , Maddock D. G.
Published: December 2006

A computational model is proposed for the prediction of friction-related mechanical efficiency losses of parallel-axis gear pairs. The model incorporates a gear load distribution model, a friction model, and a mechanical efficiency formulation to predict the instantaneous mechanical efficiency of a gear pair under typical operating, surface, and lubrication conditions. The friction model uses a new friction coefficient formula obtained by using a validated non-Newtonian thermal elastohydrodynamic lubrication (EHL) model in conjunction with a multiple linear regression analysis. The load and friction coefficient distribution predictions are used to compute instantaneous torque/power losses and the mechanical efficiency of a gear pair at any given rotational position. Efficiency measurements from gear pairs having various gear designs and surface treatments are compared to model predictions. Mechanical efficiency predictions are shown to be within 0.1% of the measured values, indicating that the proposed efficiency model is accurate. Results of a parametric study are presented at the end to highlight the influence of key basic gear geometric parameters, tooth modifications, operating conditions, surface finish, and lubricant properties on mechanical efficiency losses.
ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors
Authors: Chen Yu , Corriden Ross , Inoue Yoshiaki , Yip Linda , Hashiguchi Naoyuki , Zinkernagel Annelies , Nizet Victor , Insel Paul A. , Junger Wolfgang G.
Published: December 2006

Cells must amplify external signals to orient and migrate in chemotactic gradient fields. We find that human neutrophils release adenosine triphosphate (ATP) from the leading edge of the cell surface to amplify chemotactic signals and direct cell orientation by feedback through P2Y2 nucleotide receptors. Neutrophils rapidly hydrolyze released ATP to adenosine that then acts via A3-type adenosine receptors, which are recruited to the leading edge, to promote cell migration. Thus, ATP release and autocrine feedback through P2Y2 and A3 receptors provide signal amplification, controlling gradient sensing and migration of neutrophils.
Antibody Class Switching Mediated by Yeast Endonuclease-Generated DNA Breaks
Authors: Zarrin Ali A. , Del Vecchio Catherine , Tseng Eva , Gleason Megan , Zarin Payam , Tian Ming , Alt Frederick W.
Published: December 2006

Antibody class switching in activated B cells uses class switch recombination (CSR), which joins activation-induced cytidine deaminase (AID)–dependent double-strand breaks (DSBs) within two large immunoglobulin heavy chain (IgH) locus switch (S) regions that lie up to 200 kilobases apart. To test postulated roles of S regions and AID in CSR, we generated mutant B cells in which donor Sμ and accepter Sγ1 regions were replaced with yeast I-SceI endonuclease sites. We found that site-specific I-SceI DSBs mediate recombinational IgH locus class switching from IgM to IgG
1
without S regions or AID. We propose that CSR evolved to exploit a general DNA repair process that promotes joining of widely separated DSBs within a chromosome.
QUANTUM THEORY "WITHOUT MEASUREMENT"
Authors: KÜMMEL HERMANN G.
Published: December 2006

Attempting to describe the "collapse of the wave function" of the orthodox quantum theory as a physical process, a natural assumption is that the measurement apparatus is subject to the same physical laws as the measured object, leading to a theory without rules for measurement. This – together with the loss of classical-quantum correspondence for chaotic systems – enforces the inclusion of the environment. I very shortly describe the present state of the art in this field – a challenge for the quantum many body community.
APPLICATION OF SUPPORT VECTOR MACHINES TO GLOBAL PREDICTION OF NUCLEAR PROPERTIES
Authors: CLARK JOHN W. , LI HAOCHEN
Published: December 2006

Advances in statistical learning theory present the opportunity to develop statistical models of quantum many-body systems exhibiting remarkable predictive power. The potential of such "theory-thin" approaches is illustrated with the application of Support Vector Machines (SVMs) to global prediction of nuclear properties as functions of proton and neutron numbers Z and N across the nuclidic chart. Based on the principle of structural-risk minimization, SVMs learn from examples in the existing database of a given property Y, automatically and optimally identify a set of "support vectors" corresponding to representative nuclei in the training set, and approximate the mapping (Z, N) → Y in terms of these nuclei. Results are reported for nuclear masses, beta-decay lifetimes, and spins/parities of nuclear ground states. These results indicate that SVM models can match or even surpass the predictive performance of the best conventional "theory-thick" global models based on nuclear phenomenology.
THE PHYSICS OF LIQUID PARA-HYDROGEN
Authors: LINDENAU THOMAS , RISTIG MANFRED L. , GERNOTH KLAUS A. , DAWIDOWSKI JAVIER , BERMEJO FRANCISCO J.
Published: December 2006

Macroscopic systems of hydrogen molecules exhibit a rich thermodynamic phase behavior. Due to the simplicity of the molecular constituents a detailed exploration of the thermal properties of these boson systems at low temperatures is of fundamental interest. Here, we report theoretical and experimental results on various spatial correlation functions and corresponding distributions in momentum space of liquid para-hydrogen close to the triple point. They characterize the structure of the correlated liquid and provide information on quantum effects present in this Bose fluid. Numerical calculations employ Correlated Density-Matrix (CDM) theory and Path-Integral Monte-Carlo(PIMC)simulations. A comparison of these theoretical results demonstrates the accuracy of CDM theory. This algorithm therefore permits a fast and efficient quantitative analysis of the normal phase of liquid para-hydrogen. We compare and discuss the theoretical results with available experimental data.
NUCLEATION OF VORTICES IN THIN SUPERCONDUCTING DISKS
Authors: SOBNACK M. B. , KUSMARTSEV F. V. , GULEVICH D. R. , FUNG J. C. H.
Published: December 2006

We study the nucleation of vortices in a thin mesoscopic superconducting disk in an applied magnetic field perpendicular to the disc. We write down an expression for the free energy of the system with an arbitrary number of vortices and anti-vortices. For a given applied field, we minimize the free energy to find the optimal position of the vortices and anti-vortices. We also calculate the magnetization of the disk as a function of the applied field and hence the determine the different configurations possible in which a fixed number of fluxoids can penetrate the disk.
THE EMERGENCE OF SOCIAL NETWORK HIERARCHY USING CULTURAL ALGORITHMS
Authors: KOBTI ZIAD , REYNOLDS ROBERT G. , KOHLER TIM A.
Published: December 2006

In this paper we extend the cultural framework previously developed for the Village multi-agent simulation in Swarm to include the emergence of a hub network from two base networks. The first base network is kinship, over which generalized reciprocal exchange is defined, and the second is the economic network where agents carry out balanced reciprocal exchange. Agents, or households, are able to procure several resources. We use Cultural Algorithms as a framework for the emergence of social intelligence at both individual and cultural levels. Successful agents in both networks can promote themselves to be included in the hub network where they can develop exchange links to other hubs. The collective effect of the hub network is representative of the quality of life in the population and serves as an indicator for motives behind the mysterious emigration from the region. Knowledge represents the development and use of exchange relationships between agents. The presence of defectors in the hub network improved resilience of the social system while maintaining the population size at that observed where no defectors were present.
COORDINATION AND APPLICATIVE CATEGORIAL TYPE LOGIC
Authors: BISKRI ISMAÏL , DESCLÉS JEAN-PIERRE , BENSABER BOUCIF AMAR
Published: December 2006

Despite extensive theoretical work carried out on coordination during the last three decades, much research is still devoted to proving the merits of one model over another. In our article, we will show how the coordination process in French (with using the conjunction et (and)) can be explained through Applicative and Combinatory Categorial Grammar (ACCG).
COGNITIVELY INSPIRED NLP-BASED KNOWLEDGE REPRESENTATIONS: FURTHER EXPLORATIONS OF LATENT SEMANTIC ANALYSIS
Authors: LOUWERSE MAX , CAI ZHIQIANG , HU XIANGEN , VENTURA MATTHEW , JEUNIAUX PATRICK
Published: December 2006

Natural-language based knowledge representations borrow their expressiveness from the semantics of language. One such knowledge representation technique is Latent semantic analysis (LSA), a statistical, corpus-based method for representing knowledge. It has been successfully used in a variety of applications including intelligent tutoring systems, essay grading and coherence metrics. The advantage of LSA is that it is efficient in representing world knowledge without the need for manual coding of relations and that it has in fact been considered to simulate aspects of human knowledge representation. An overview of LSA applications will be given, followed by some further explorations of the use of LSA. These explorations focus on the idea that the power of LSA can be amplified by considering semantic fields of text units instead of pairs of text units. Examples are given for semantic networks, category membership, typicality, spatiality and temporality, showing new evidence for LSA as a mechanism for knowledge representation. The results of such tests show that while the mechanism behind LSA is unique, it is flexible enough to replicate results in different corpora and languages.
INTEGRATIVE BIOLOGY OF PROSTATE CANCER PROGRESSION
Authors: Tomlins Scott A. , Rubin Mark A. , Chinnaiyan Arul M.
Published: December 2006

Prostate cancer displays considerable clinical, morphological, and biological heterogeneity. Classical genetic techniques have provided only limited information about the pathogenesis of prostate cancer progression. Nevertheless, several candidate genes and pathways have been implicated in prostate cancer development. High-throughput techniques have exponentially expanded the number of candidate genes, including some whose role in prostate cancer pathogenesis has been studied. However, the techniques used to study the prostate cancer genome, transcriptome, and proteome generate massive amounts of data that have yet to be integrated and explored. To move beyond candidate gene identification and develop a comprehensive understanding of cancer pathogenesis, integrative approaches need to analyze this data on a global level. This review addresses candidate genes involved in prostate cancer pathogenesis in a biological and clinical context and demonstrates how integrated analysis of high-throughput data augments our understanding of prostate cancer.
SEVERE SEPSIS AND SEPTIC SHOCK: The Role of Gram-Negative Bacteremia
Authors: Munford Robert S.
Published: December 2006

Although Gram-negative bacteria have often been implicated in the pathogenesis of severe sepsis and septic shock, how they trigger these often lethal syndromes is uncertain. In particular, the role played by blood-borne bacteria is controversial. This review considers two alternatives. In the first, circulating Gram-negative bacteria induce toxic reactions directly within the vasculature; in the second, the major inflammatory stimulus occurs in local extravascular sites of infection and circulating bacteria contribute little to inducing toxic responses. Evidence for each alternative is found in the literature. Bacteremia and severe sepsis are not so closely linked that the most striking cases can be a model for the rest. Intravascular and extravascular triggers may warrant different approaches to prevention and therapy.
IMMUNOBIOLOGY AND PATHOGENESIS OF VIRAL HEPATITIS
Authors: Guidotti Luca G. , Chisari Francis V.
Published: December 2006

Among the many viruses that are known to infect the human liver, hepatitis B virus (HBV) and hepatitis C virus (HCV) are unique because of their prodigious capacity to cause persistent infection, cirrhosis, and liver cancer. HBV and HCV are noncytopathic viruses and, thus, immunologically mediated events play an important role in the pathogenesis and outcome of these infections. The adaptive immune response mediates virtually all of the liver disease associated with viral hepatitis. However, it is becoming increasingly clear that antigen-nonspecific inflammatory cells exacerbate cytotoxic T lymphocyte (CTL)-induced immunopathology and that platelets enhance the accumulation of CTLs in the liver. Chronic hepatitis is characterized by an inefficient T cell response unable to completely clear HBV or HCV from the liver, which consequently sustains continuous cycles of low-level cell destruction. Over long periods of time, recurrent immune-mediated liver damage contributes to the development of cirrhosis and hepatocellular carcinoma.
Cross-regulation of VPAC2receptor desensitization by M3receptors via PKC-mediated phosphorylation of RKIP and inhibition of GRK2
Authors: Huang Jiean , Mahavadi Sunila , Sriwai Wimolpak , Grider John R. , Murthy Karnam S.
Published: December 2006

In gastrointestinal smooth muscle cells, VPAC2receptor desensitization is exclusively mediated by G protein-coupled receptor kinase 2 (GRK2). The present study examined the mechanisms by which acetylcholine (ACh) acting via M3receptors regulates GRK2-mediated VPAC2receptor desensitization in gastric smooth muscle cells. Vasoactive intestinal peptide induced VPAC2receptor phosphorylation, internalization, and desensitization in both freshly dispersed and cultured smooth muscle cells. Costimulation with ACh in the presence of M2receptor antagonist (i.e., activation of M3receptors) inhibited VPAC2receptor phosphorylation, internalization, and desensitization. Inhibition was blocked by the selective protein kinase C (PKC) inhibitor bisindolylmaleimide, suggesting that the inhibition was mediated by PKC, derived from M3receptor activation. Similar results were obtained by direct activation of PKC with phorbol myristate acetate. In the presence of the M2receptor antagonist, ACh induced phosphorylation of Raf kinase inhibitory protein (RKIP), increased RKIP-GRK2 association, decreased RKIP-Raf-1 association, and stimulated ERK1/2 activity, suggesting that, upon phosphorylation by PKC, RKIP dissociates from its known target Raf to associate with, and block the activity of, GRK2. In muscle cells expressing RKIP(S153A), which lacks the PKC phosphorylation site, RKIP phosphorylation was blocked and the inhibitory effect of ACh on VPAC2receptor phosphorylation, internalization, and desensitization and the stimulatory effect on ERK1/2 activation were abolished. This study identified a novel mechanism of cross-regulation of Gs-coupled receptor phosphorylation and internalization by Gq-coupled receptors. The mechanism involved phosphorylation of RKIP by PKC, switching RKIP from association with Raf-1 to association with, and inhibition of, GRK2.
Delayed liver regeneration in mice lacking liver serum response factor
Authors: Latasa M. Ujue , Couton Dominique , Charvet Claude , Lafanechère Aurélie , Guidotti Jacques-Emmanuel , Li Zhenlin , Tuil David , Daegelen Dominique , Mitchell Claudia , Gilgenkrantz Hélène
Published: December 2006

Various immediate early genes (IEGs) upregulated during the early process of liver regeneration are transcriptional targets of the serum response factor (SRF). We show here that the expression of SRF is rapidly induced in rodent liver after partial hepatectomy. Because the inactivation of the SRF gene in mice is embryonic lethal, the in vivo role of SRF in liver regeneration after partial hepatectomy was analyzed in mutant mice conditionally deleted for SRF in the liver. We demonstrate that SRF is not an essential factor for liver ontogenesis. However, adult mutant mice show impaired liver regeneration after partial hepatectomy, associated with a blunted upregulation of various SRF target IEGs. In conclusion, our work suggests that SRF is an early response transcription factor that may contribute to the initial phases of liver regeneration through its activation of IEGs.
p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase
Authors: Jaswal Jagdip S. , Gandhi Manoj , Finegan Barry A. , Dyck Jason R. B. , Clanachan Alexander S.
Published: December 2006

Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.
Evidence for the presence of a glucosensor in hypothalamus, hindbrain, and Brockmann bodies of rainbow trout
Authors: Polakof Sergio , Míguez Jesús M. , Moon Thomas W. , Soengas José L.
Published: December 2006

The aim of this study was to evaluate the existence of a glucosensor in different regions of the brain and in the Brockmann bodies (BB) of the rainbow trout, Oncorhynchus mykiss. Five groups ( n = 12) of trout were injected intraperitoneally with saline alone (control) or saline-containing bovine glucagon (100 μg/kg), bovine insulin (4 mg/kg), 2-deoxy-d-glucose (100 mg/kg), or d-glucose (500 mg/kg) to promote hyperglycemia (glucagon, d-glucose, 2-deoxy-d-glucose) or hypoglycemia (insulin). Six hours after injection, samples from four brain regions (hypothalamus, telencephalon, hindbrain, and midbrain) and the entire BB were taken. Our results demonstrate within the BB and both the hypothalamus and hindbrain a metabolic response different to that observed in other tissues (midbrain, telencephalon) but similar to that described in tissues known to be glucosensors in mammals. The metabolic responses of these areas to changes in plasma glycemia were characterized by parallel changes in GLUT-2 expression, hexokinase-IV, or glucokinase activity and expression, glycolytic potential, and levels of glycogen and glucose. These changes are similar to those reported in mammalian pancreatic β-cells and glucose-excited (GE) neurons, two cell types containing glucosensors. This study provides evidence for the presence of glucosensors responsive to hyper- and hypoglycemia in rainbow trout BB, hypothalamus, and hindbrain.
Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias
Authors: Zeng Zhihong , Samudio Ismael J. , Munsell Mark , An Jing , Huang Ziwei , Estey Elihu , Andreeff Michael , Konopleva Marina
Published: December 2006

The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor 1α (SDF-1α)–producing bone marrow microenvironment. Using peptide-based CXCR4 inhibitors derived from the chemokine viral macrophage inflammatory protein II, we tested the hypothesis that the inhibition of CXCR4 increases sensitivity to chemotherapy by interfering with stromal/leukemia cell interactions. First, leukemic cells expressing varying amounts of surface CXCR4 were examined for their chemotactic response to SDF-1α or stromal cells, alone or in the presence of different CXCR4 inhibitors. Results showed that the polypeptide RCP168 had the strongest antagonistic effect on the SDF-1α– or stromal cell–induced chemotaxis of leukemic cells. Furthermore, RCP168 blocked the binding of anti-CXCR4 monoclonal antibody 12G5 to surface CXCR4 in a concentration-dependent manner and inhibited SDF-1α–induced AKT and extracellular signal-regulated kinase phosphorylation. Finally, RCP168 significantly enhanced chemotherapy-induced apoptosis in stroma-cocultured Jurkat, primary chronic lymphocytic leukemia, and in a subset of acute myelogenous leukemia cells harboring Flt3 mutation. Equivalent results were obtained with the small-molecule CXCR4 inhibitor AMD3465. Our data therefore suggest that the SDF-1α/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Disruption of these interactions by the peptide CXCR4 inhibitor RCP168 represents a novel strategy for targeting leukemic cells within the bone marrow microenvironment. [Mol Cancer Ther 2006;5(12):3113–21]
Direct targeting of αvβ3 integrin on tumor cells with a monoclonal antibody, Abegrin™
Authors: Mulgrew Kathy , Kinneer Krista , Yao Xiao-Tao , Ward Beth K. , Damschroder Melissa M. , Walsh Bill , Mao Su-Yau , Gao Changshou , Kiener Peter A. , Coats Steve , Kinch Michael S. , Tice David A.
Published: December 2006

The humanized monoclonal antibody Abegrin™, currently in phase II trials for treatment of solid tumors, specifically recognizes the integrin αvβ3. Due to its high expression on mature osteoclasts, angiogenic endothelial cells, and tumor cells, integrin αvβ3 functions in several pathologic processes important to tumor growth and metastasis. Targeting of this integrin with Abegrin™ results in antitumor, antiangiogenic, and antiosteolytic activities. Here, we exploit the species specificity of Abegrin™ to evaluate the effects of direct targeting of tumor cells (independent of targeting of endothelia or osteoclasts). Flow cytometry analysis of human tumor cell lines shows high levels of αvβ3 on many solid tumors, including cancers of the prostate, skin, ovary, kidney, lung, and breast. We also show that tumor growth of αvβ3-expressing tumor cells is inhibited by Abegrin™ in a dose-dependent manner. We present a novel finding that high-dose administration can actively impair the antitumor activity of Abegrin™. We also provide evidence that antibody-dependent cellular cytotoxicity contributes to in vitro and in vivo antitumor activity. Finally, it was observed that peak biological activity of Abegrin™ arises at serum levels that are consistent with those achieved in clinical trials. These results support a concept that Abegrin™ can be used to achieve selective targeting of the many tumor cells that express αvβ3 integrin. In combination with the well-established concept that αvβ3 plays a key role in cancer-associated angiogenesis and osteolytic activities, this triad of activity could provide new opportunities for therapeutic targeting of cancer. [Mol Cancer Ther 2006;5(12):3122–9]
Apoptosis induced by selenomethionine and methioninase is superoxide mediated and p53 dependent in human prostate cancer cells
Authors: Zhao Rui , Domann Frederick E. , Zhong Weixiong
Published: December 2006

Selenomethionine (SeMet) is the chemical form or major component of selenium used for cancer chemoprevention in several clinical trials. However, evidence from experimental studies indicates that SeMet has weaker anticancer effects than most other forms of selenium. Recent studies showed that the anticancer activity of SeMet can be enhanced by methioninase (METase), indicating that SeMet metabolites are responsible for its anticancer activity. In the present study, we showed that wild-type p53-expressing LNCaP human prostate cancer cells were more sensitive to cotreatment with SeMet and METase than p53-null PC3 human prostate cancer cells. SeMet and METase cotreatment significantly increased levels of superoxide and apoptosis in LNCaP cells. Cotreatment with SeMet and METase resulted in increased levels of phosphorylated p53 (Ser15), total p53, Bax, and p21Waf1 proteins. LNCaP cells treated with SeMet and METase also showed p53 translocation to mitochondria, decreased mitochondrial membrane potential, cytochrome c release into the cytosol, and activation of caspase-9. The effects of SeMet and METase were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. Reexpression of wild-type p53 in PC3 cells resulted in increases in superoxide production, apoptosis, and caspase-9 activity and a decrease in mitochondrial membrane potential following cotreatment with SeMet and METase. Our study shows that apoptosis induced by SeMet plus METase is superoxide mediated and p53 dependent via mitochondrial pathway(s). These results suggest that superoxide and p53 may play a role in cancer chemoprevention by selenium. [Mol Cancer Ther 2006;5(12):3275–84]
Association of insulin-like growth factor binding protein-3 expression with melanoma progression
Authors: Xi Yaguang , Nakajima Go , Hamil Tray , Fodstad Oystein , Riker Adam , Ju Jingfang
Published: December 2006

Previous studies from our laboratory have identified several endothelial cell–associated marker genes implicated in human melanoma metastasis via tumor vasculogenic mimicry. In this study, we used dual model systems composed of melanoma cell lines and clinical melanoma samples to validate the importance of insulin-like growth factor binding protein-3 (IGFBP-3) as a marker involved in disease progression. Gene expression analysis was done using a microarray approach for both primary and metastatic melanoma samples. The expression of IGFBP-3 was decreased using a small interfering RNA (siRNA) knockdown approach and quantified with real-time quantitative reverse transcription-PCR analysis. The expression of insulin-like growth factor binding protein 3 (IGFBP-3) was up-regulated by nearly 16-fold in WM266-4 compared with WM35 cells. A subsequent parallel analysis using freshly isolated primary and metastatic melanoma cell samples and melanoma tissue array confirmed the previous findings. The functional significance of IGFBP-3 in melanoma invasion was further investigated using a siRNA gene knockdown approach, with the expression of IGFBP-3 markedly reduced. Additionally, siRNA knockdown resulted in a significant reduction in cell motility, migration, and invasive capacity of WM266-4 cells in vitro. These results strongly suggest that IGFBP-3 expression may be a vital cell motility, migration, and proliferation factor necessary for melanoma metastasis and is an important biomarker in human melanoma. [Mol Cancer Ther 2006;5(12):3078–84]
Preclinical pharmacokinetics, tissue distribution, and antitumor activity of a folate-hapten conjugate–targeted immunotherapy in hapten-immunized mice
Authors: Lu Yingjuan , Xu Le-Cun , Parker Nikki , Westrick Elaine , Reddy Joseph A. , Vetzel Marilynn , Low Philip S. , Leamon Christopher P.
Published: December 2006

Folic acid (pteroylglutamic acid) represents a useful ligand for targeted cancer therapies because it binds to a common epithelial tumor antigen known as the folate receptor. We previously devised an immunotherapy strategy that uses a bispecific ligand, a folate-hapten (FITC) conjugate, to redirect endogenously induced anti-FITC antibodies to folate receptor–positive tumor cells following parenteral administration. Here, we present results from preclinical pharmacokinetic and tissue biodistribution studies using a radioactive folate-FITC conjugate and results from dose optimization studies done in tumor-bearing animals. Folate-FITC was found to be rapidly eliminated in non-immunized mice; however, in immunized hosts, folate-FITC was shown to form immune complexes with FITC-specific antibodies, the consequence of which was a ∼173-fold increase in drug exposure (i.e., area under the curve). Using a newly developed ELISA assay, the extent of circulating anti-FITC antibodies occupied by parenterally given folate-FITC was determined to be proportional to the given dose. Furthermore, high doses of folate-FITC were found to promote the cosaturation of tumor cell surface folate receptors and circulating FITC-specific antibodies, blocking the immune recognition of tumor cells and thereby reducing antitumor activity. Nonetheless, by extending the duration of treatment and administering subsaturating doses of folate-FITC, enhanced antitumor response was observed in mice bearing established folate receptor–positive M109 tumors. Overall, results from the present study may help to guide clinicians through on-going clinical investigations of folate-targeted immunotherapy. [Mol Cancer Ther 2006;5(12):3258–67]
In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy
Authors: Chen Kai , Wang Ketai , Kirichian Agop M. , Al Aowad Ayman F. , Iyer Lakshmanan K. , Adelstein S. James , Kassis Amin I.
Published: December 2006

As part of the development of enzyme-mediated cancer imaging and therapy, a novel technology to entrap water-insoluble radioactive molecules within solid tumors, we show that a water-soluble, radioactive quinazolinone prodrug, ammonium 2-(2′-phosphoryloxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ2-P), is hydrolyzed by alkaline phosphatase to a water-insoluble, radiolabeled drug, 2-(2′-hydroxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ2-OH). Biodistribution data suggest the existence of two isoforms of the prodrug (IQ2-P(I) and IQ2-P), and this has been confirmed by their synthesis and characterization. Structural differences of the two isoforms have been examined using in silico molecular modeling techniques and docking methods to describe the interaction/binding between the isoforms and human placental alkaline phosphatase (PLAP), a tumor cell, membrane-associated, hydrolytic enzyme whose structure is known by X-ray crystallographic determination. Docking data show that IQ2-P, but not IQ2-P(I), fits the active binding site of PLAP favorably and interacts with the catalytic amino acid Ser92, which plays an important role in the hydrolytic process. The binding free energies (ΔGbinding) of the isoforms to PLAP predict that IQ2-P will be the better substrate for PLAP. The in vitro incubation of the isoforms with PLAP leads to the rapid hydrolysis of IQ2-P only and confirms the in silico expectations. Fluorescence microscopy shows that in vitro incubation of IQ2-P with mouse and human tumor cells causes the extracellular, alkaline phosphatase–mediated hydrolysis of the molecule and precipitation of fluorescent crystals of IQ2-OH. No hydrolysis is seen in the presence of normal mouse and human cells. Furthermore, the intratumoral injection of 125IQ2-P into alkaline phosphatase–expressing solid human tumors grown s.c. in nude rats results in efficient hydrolysis of the compound and retention of ∼70% of the injected radioactivity, whereas similar injection into normal tissues (e.g., muscle) does not produce any measurable hydrolysis (∼1%) or retention of radioactivity at the injected site. These studies support the enzyme-mediated cancer imaging and therapy technology and show the potential of such quinazolinone derivatives in the in vivo radiodetection (123I/124I) and therapy (131I) of solid tumors. [Mol Cancer Ther 2006;5(12):3001–13]
Glenohumeral Mobility in Primates
Authors: Chan Lap Ki
Published: December 2006

This study refutes the traditional idea that the glenohumeral joint of hominoids is more mobile than that of other primates, a belief that forms a basis for the two prominent theories of hominoid evolution. According to the brachiation theory, many anatomical features of the hominoid shoulder (including those of the glenohumeral joint) increase shoulder mobility and are interpreted as adaptations for brachiation. The slow climbing theory explains the same set of features as adaptations for slow climbing. The slow-climbing primates should therefore also possess these features, and their glenohumeral mobility should be the same as that of hominoids and be higher than that of other primates. This study presents three-dimensional glenohumeral mobility data, measured using a single video camera method on fresh specimens. The results show that the hominoid glenohumeral joint is actually less mobile than those of non-hominoid primates, including the habitually slow-climbing lorines, but it is characterized by a smooth excursion in the scapulocranial direction.
Informed Consent and Subject Motivation to Participate in a Large, Population-Based Genomics Study: The Marshfield Clinic Personalized Medicine Research Project
Authors: McCarty Catherine A. , Nair Anuradha , Austin Diane M. , Giampietro Philip F.
Published: December 2006

Background: The objective of this study was to measure subject perspective and reaction to participation in the Personalized Medicine Research Project (PMRP) and to identify factors predicting understanding of the study elements. Method: Self-administered questionnaires were mailed to 1,593 subjects (10% sample). The questionnaire had three sections: section A consisted of 21 factual questions; section B consisted of 14 questions to assess the level of understanding about the PMRP concepts, and section C asked about the purpose of the PMRP. Results: The mean age of the 924 survey respondents was 52 years (SD = 16.9), with a range of 18–95 years. The majority of participants were female (n = 561, 61%). The percent of total correct responses for section A was significantly higher for females compared with males (males: 58.4% and females: 60.4%, t test = –2.18, p = 0.03) and age was significantly inversely related to percent of correct responses (β coefficient = –0.122, p < 0.001). More than one third of the participants indicated that the USD 20 greatly influenced their decision to participate in the project. In a multiple logistic regression model, people living outside of Marshfield were significantly more likely to indicate that the USD 20 greatly influenced their decision to participate (odds ratio = 1.40, 95% confidence limit = 1.06, 1.86) and age was inversely related to the monetary influence on decision to participate (odds ratio = 0.98, 95% confidence limit = 0.97, 0.98). Conclusion: Future community consultation efforts should highlight areas of lower understanding. In addition, research coordinators may need to take more time informing males and older individuals about project details so that they are making truly informed decisions about study participation.
Consanguineous Marriages in Iranian Folktales
Authors: Saadat Mostafa
Published: December 2006

Background: Using folktales we can find some aspects of social customs. Here, I show the situation of consanguineous marriages in folktales from different Iranian populations and try to compare it with the present situation of consanguineous marriages. Methods: The study includes tales from 11 different Iranian (ethnic and/or geographical) populations. Overall, the records of 585 marriages in 296 folktales from the study populations were found. Results: The estimated mean inbreeding coefficient (α) for different populations using folktale records is lower than that of the present values. However, there is a very high level of statistically significant correlation between them (r = 0.753, d.f. = 9, p = 0.007). Conclusion: The historical background is very important to attitude and practice regarding marriages between relatives.
Alternative Medicine Use in Dialysis Patients: Potential for Good and Bad!
Authors: Duncan Heather J. , Pittman Susan , Govil Amit , Sorn Lisa , Bissler Gloria , Schultz Tersea , Faith J. , Kant Shashi , Roy-Chaudhury Prabir
Published: December 2006

Although alternative medicines are widely used within the general population, the extent of their use within the dialysis population is unknown. It is possible that dialysis patients may be more likely to turn towards alternative therapies in view of the chronicity of their disease. In addition, this particular patient population could be at an increased risk of toxicity from these therapies due to an absence of renal excretion. A detailed assessment of complementary and alternative medicine use in our dialysis patients revealed that 18% of our patients had used or were using some form of alternative medicine therapy.An additional 63% of our patients, however, were willing to use a complementary or alternative medication. Our results suggest that hemodialysis patients are extremely receptive to the use of such therapies and are therefore exposed to all their potential benefit and harm.
Endothelial E-Selectin Potentiates Neovascularization via Endothelial Progenitor Cell–Dependent and –Independent Mechanisms
Authors: Nishiwaki Yasunobu , Yoshida Masayuki , Iwaguro Hideki , Masuda Haruchika , Nitta Noriko , Asahara Takayuki , Isobe Mitsuaki
Published: December 2006

Background—Although potential participation of bone marrow-derived circulating endothelial progenitor cells (EPCs) to neoangiogenesis has been proposed, the precise molecular mechanisms of EPC recruitment to vascular endothelium has not been fully elucidated.

Methods and Results—Peripheral blood mononuclear cells were isolated from healthy volunteers and cultured for 7 days to obtain EPCs. Tumor necrosis factor-α–activated human umbilical vein endothelial cells (HUVECs) supported significantly more rolling and adhesion of EPCs compared with inactivated HUVEC monolayer. Pretreatment of activated HUVEC with an adhesion-blocking mAb to E-selectin significantly reduced EPCs adhesion to HUVECs. When HUVECs were transduced with a recombinant adenovirus of E-selectin (AdRSVE-sel) or that of β-galactosidase (AdRSVLacZ), E-selectin-transduced but not LacZ-transduced HUVECs exhibited significantly more EPC rolling as well as adhesion. Further, effect of AdRSVE-sel or AdRSVLacZ was examined in mouse hind limb ischemic model. AdRSVE-sel–transduced mice showed significantly less limb necrosis and higher laser Doppler ratio when compared with AdRSVLacZ-transduced mice. Interestingly, blood flow recovery of ischemic limb observed in AdRSVE-sel–transduced mice was more prominent when combined with EPC administration compared with that of AdRSVLacZ-transduced mice.

Conclusions—Endothelial E-selectin plays a crucial role in EPC–endothelial interaction in vitro. The importance of E-selectin was also confirmed in vivo even in the absence of exogenous EPC. These data provide molecular background for novel cell-based therapy for ischemic atherosclerosis.
Increased Insulin-Stimulated Expression of Arterial Angiotensinogen and Angiotensin Type 1 Receptor in Patients With Type 2 Diabetes Mellitus and Atheroma
Authors: Hodroj Wassim , Legedz Liliana , Foudi Nabil , Cerutti Catherine , Bourdillon Marie-Claude , Feugier Patrick , Beylot Michel , Randon Jacques , Bricca Giampiero
Published: December 2006

Objective—

Because inhibition of the renin–angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients.

Methods and Results—

mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2- to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5- and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1–2 was 4-fold higher in MIT from T2D than from CTR patients.

Conclusions—

The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1–2 pathway by insulin.
A Mechanistic Model for Paradoxical Platelet Activation by Ligand-Mimetic αIIbβ3(GPIIb/IIIa) Antagonists
Authors: Bassler Nicole , Loeffler Christoph , Mangin Pierre , Yuan Yuping , Schwarz Meike , Hagemeyer Christoph E. , Eisenhardt Steffen U. , Ahrens Ingo , Bode Christoph , Jackson Shaun P. , Peter Karlheinz
Published: December 2006

Objective—Integrins are attractive therapeutic targets. Inhibition of integrin αIIbβ3effectively blocks platelet aggregation. However, limitations with intravenous αIIbβ3antagonists and failure of oral αIIbβ3antagonists prompted doubts on the current concept of ligand-mimetic integrin blockade.

Methods and Results—Evaluating P-selectin expression on platelets by flow cytometry, we report a mechanism of paradoxical platelet activation by ligand-mimetic αIIbβ3antagonists and define three requirements: (1) Induction of ligand-bound conformation of αIIbβ3, (2) receptor clustering, (3) prestimulation of platelets. Conformational change is inducible by clinically used ligand-mimetic αIIbβ3antagonists, RGD-peptides, and anti-LIBS antibodies. In a mechanistic experimental model, clustering is achieved by crosslinking integrins via antibodies, and preactivation is induced by low-dose ADP. Finally, we demonstrate that platelet adhesion on collagen represents an in vivo correlate of platelet prestimulation and receptor clustering, in which the presence of ligand-mimetic αIIbβ3antagonists results in platelet activation as detected by P-selectin, CD63, and CD40L expression as well as by measuring Ca2+-signaling. Blockade of the ADP receptor P2Y12by AR-C69931MX and clopidogrel inhibits αIIbβ3antagonist-induced platelet activation.

Conclusion—These findings can explain limitations of ligand-mimetic anti-αIIbβ3therapy. They describe potential benefits of concomitant ADP receptor blockade and support a shift in drug development from ligand-mimetic toward allosteric or activation-specific integrin antagonists.
Diaphanous 1 and 2 Regulate Smooth Muscle Cell Differentiation by Activating the Myocardin-Related Transcription Factors
Authors: Staus Dean P. , Blaker Alicia L. , Taylor Joan M. , Mack Christopher P.
Published: December 2006

Objective—

We have previously shown that smooth muscle cell (SMC) differentiation marker gene expression is regulated by the small GTPase, RhoA. The objective of the present study was to determine the contributions of the RhoA effectors, diaphanous 1 and 2 (mDia1 and mDia2), to this regulatory mechanism.

Methods and Results—

mDia1 and mDia2 are expressed highly in aortic SMCs and in a number of SMC-containing organs including bladder, lung, and esophagus. Activation of mDia1/2 signaling by RhoA strongly stimulated SMC-specific promoter activity in multiple cell-types including primary aortic SMCs, and stimulated endogenous SM α-actin expression in 10T1/2 cells. Expression of a dominant negative Dia1 variant that inhibits both mDia1 and mDia2 significantly decreased SMC-specific transcription in SMCs. The effects of mDia1 and mDia2 required the presence of SRF and the activity of the myocardin transcription factors and were dependent on changes in actin polymerization. Importantly, stimulation of mDia1/2 signaling synergistically enhanced the activities of the myocardin-related transcription factors, MRTF-A and MRTF-B, and this effect was attributable to increased nuclear localization of these factors.

Conclusions—

These results indicate that RhoA-dependent signaling through mDia1/2 and the MRTFs is important for SMC-specific gene expression in SMCs.
Blind and partially sighted people’s perceptions of their inclusion by family and friends
Authors: Bruce I. , Harrow J. , Obolenskaya P.
Published: December 2006

Blind and partially sighted people’s perceptions of inclusion by family and friends are examined in a major survey of over 900 adults with low vision in the UK. Findings demonstrate a complex picture, reporting high levels of severe lack of social support in comparison to the general population especially among men, and lack of social support expressed extensively by those who were rarely or never visited by family or neighbours. Levels of reported social support were not related to the degree of severity of sight loss or age; and economically inactive respondents of working age reported lower levels of social support than those who were working. Correlation between respondents’ having hobbies and going shopping and rising levels of social support was shown. With 40% of respondents living alone, having someone visiting as little as at least once a month meant that respondents were less likely to express severe lack of social support. The concept of ‘inclusion’ is recognized as more associated with formal ideas of citizenship and participation in community life than with informal support. It is suggested that increased focus should be given in public policy development and service provision to enabling greater levels of informal inclusion for people with visual impairments. Implications for general services development are noted.