bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing the assumptions of linear prediction analysis in normal vowels
Authors: Little M. A. , McSharry P. E. , Moroz I. M. , Roberts S. J.
Published: January 2006

In this paper we develop an improved surrogate data test to show experimental evidence, for all the simple vowels of U.S. English, for both male and female speakers, that Gaussian linear prediction analysis, a ubiquitous technique in current speech technologies, cannot be used to extract all the dynamical structure of real speech time series. The test provides robust evidence undermining the validity of these linear techniques, supporting the assumptions of either dynamical nonlinearity and∕or non-Gaussianity common to more recent, complex, efforts at dynamical modeling speech time series. However, an additional finding is that the classical assumptions cannot be ruled out entirely, and plausible evidence is given to explain the success of the linear Gaussian theory as a weak approximation to the true, nonlinear∕non-Gaussian dynamics. This supports the use of appropriate hybrid linear∕nonlinear∕non-Gaussian modeling. With a calibrated calculation of statistic and particular choice of experimental protocol, some of the known systematic problems of the method of surrogate data testing are circumvented to obtain results to support the conclusions to a high level of significance.
Wave reflection and transmission reduction using a piezoelectric semipassive nonlinear technique
Authors: Guyomar D. , Faiz A. , Petit L. , Richard C.
Published: January 2006

This study addresses the problem of noise reduction using piezoelements. The nonlinear technique, synchronized switch damping (SSD), is implemented. The device is a pulse-tube termination equipped with piezoelements, which allows performant damping of the vibration resulting from an incident acoustic wave. Due to this damping, both reflected and transmitted wave are reduced. In the semipassive damping approach proposed in this paper, energy degradation is strongly enhanced when the piezoelements are continuously switched from open to short circuit synchronously to the strain. This technique has been developed following two strategies. The first is SSD on a short circuit in which the piezoelement is always in open circuit, except for a very brief period at each strain extremum where it is short-circuited. The second approach is SSD on an inductor. The process is very similar, except that instead of forcing the voltage to zero, the voltage is exactly reversed using a controlled oscillating discharge of the piezoelement capacitor on an inductor during switch drive. Due to this switching mechanism, a phase shift appears between the strain and the resulting voltage, thus creating energy dissipation. Following SSD on an piezoelement, attenuations of 15dB in reflection and 7dB in transmission were obtained.
When Does "Economic Man" Dominate Social Behavior?
Authors: Camerer Colin F. , Fehr Ernst
Published: January 2006

The canonical model in economics considers people to be rational and self-regarding. However, much evidence challenges this view, raising the question of when “Economic Man” dominates the outcome of social interactions, and when bounded rationality or other-regarding preferences dominate. Here we show that strategic incentives are the key to answering this question. A minority of self-regarding individuals can trigger a “noncooperative” aggregate outcome if their behavior generates incentives for the majority of other-regarding individuals to mimic the minority's behavior. Likewise, a minority of other-regarding individuals can generate a “cooperative” aggregate outcome if their behavior generates incentives for a majority of self-regarding people to behave cooperatively. Similarly, in strategic games, aggregate outcomes can be either far from or close to Nash equilibrium if players with high degrees of strategic thinking mimic or erase the effects of others who do very little strategic thinking. Recently developed theories of other-regarding preferences and bounded rationality explain these findings and provide better predictions of actual aggregate behavior than does traditional economic theory.
Planktonic Foraminifera of the California Current Reflect 20th-Century Warming
Authors: Field David B. , Baumgartner Timothy R. , Charles Christopher D. , Ferreira-Bartrina Vicente , Ohman Mark D.
Published: January 2006

It is currently unclear whether observed pelagic ecosystem responses to ocean warming, such as a mid-1970s change in the eastern North Pacific, depart from typical ocean variability. We report variations in planktonic foraminifera from varved sediments off southern California spanning the past 1400 years. Increasing abundances of tropical/subtropical species throughout the 20th century reflect a warming trend superimposed on decadal-scale fluctuations. Decreasing abundances of temperate/subpolar species in the late 20th century indicate a deep, penetrative warming not observed in previous centuries. These results imply that 20th-century warming, apparently anthropogenic, has already affected lower trophic levels of the California Current.
Empirical Analysis of an Evolving Social Network
Authors: Kossinets Gueorgi , Watts Duncan J.
Published: January 2006

Social networks evolve over time, driven by the shared activities and affiliations of their members, by similarity of individuals' attributes, and by the closure of short network cycles. We analyzed a dynamic social network comprising 43,553 students, faculty, and staff at a large university, in which interactions between individuals are inferred from time-stamped e-mail headers recorded over one academic year and are matched with affiliations and attributes. We found that network evolution is dominated by a combination of effects arising from network topology itself and the organizational structure in which the network is embedded. In the absence of global perturbations, average network properties appear to approach an equilibrium state, whereas individual properties are unstable.
Integration of Plant Responses to Environmentally Activated Phytohormonal Signals
Authors: Achard Patrick , Cheng Hui , De Grauwe Liesbeth , Decat Jan , Schoutteten Hermien , Moritz Thomas , Van Der Straeten Dominique , Peng Jinrong , Harberd Nicholas P.
Published: January 2006

Plants live in fixed locations and survive adversity by integrating growth responses to diverse environmental signals. Here, we show that the nuclear-localized growth-repressing DELLA proteins of Arabidopsis integrate responses to independent hormonal and environmental signals of adverse conditions. The growth restraint conferred by DELLA proteins is beneficial and promotes survival. We propose that DELLAs permit flexible and appropriate modulation of plant growth in response to changes in natural environments.
Coevolved Crypts and Exocrine Glands Support Mutualistic Bacteria in Fungus-Growing Ants
Authors: Currie Cameron R. , Poulsen Michael , Mendenhall John , Boomsma Jacobus J. , Billen Johan
Published: January 2006

Attine ants engage in a quadripartite symbiosis with fungi they cultivate for food, specialized garden parasites, and parasite-inhibiting bacteria. Molecular phylogenetic evidence supports an ancient host-pathogen association between the ant-cultivar mutualism and the garden parasite. Here we show that ants rear the antibiotic-producing bacteria in elaborate cuticular crypts, supported by unique exocrine glands, and that these structures have been highly modified across the ants' evolutionary history. This specialized structural evolution, together with the absence of these bacteria and modifications in other ant genera that do not grow fungus, indicate that the bacteria have an ancient and coevolved association with the ants, their fungal cultivar, and the garden parasite.
The Late Miocene Radiation of Modern Felidae: A Genetic Assessment
Authors: Johnson Warren E. , Eizirik Eduardo , Pecon-Slattery Jill , Murphy William J. , Antunes Agostinho , Teeling Emma , O'Brien Stephen J.
Published: January 2006

Modern felid species descend from relatively recent (<11 million years ago) divergence and speciation events that produced successful predatory carnivores worldwide but that have confounded taxonomic classifications. A highly resolved molecular phylogeny with divergence dates for all living cat species, derived from autosomal, X-linked, Y-linked, and mitochondrial gene segments (22,789 base pairs) and 16 fossil calibrations define eight principal lineages produced through at least 10 intercontinental migrations facilitated by sea-level fluctuations. A ghost lineage analysis indicates that available felid fossils underestimate (i.e., unrepresented basal branch length) first occurrence by an average of 76%, revealing a low representation of felid lineages in paleontological remains. The phylogenetic performance of distinct gene classes showed that Y-chromosome segments are appreciably more informative than mitochondrial DNA, X-linked, or autosomal genes in resolving the rapid Felidae species radiation.
ASYMPTOTIC GROWTH OF CONJUGACY CLASSES IN FINITELY-GENERATED FREE GROUPS
Authors: COORNAERT MICHEL
Published: January 2006

We give an asymptotic estimate for the growth of prime conjugacy classes in a finitely generated free group.
ON AUTOMORPHISMS OF LOCAL ISOMETRY GROUPS OF COMPACT ULTRAMETRIC SPACES
Authors: LAVRENYUK YAROSLAV
Published: January 2006

Completeness of the group of local isometries of compact ultrametric space is established for transitive group.
A PROBABILISTIC ZETA FUNCTION FOR ARITHMETIC GROUPS
Authors: MANN AVINOAM
Published: January 2006

A profinite group G is positively finitely generated (PFG) if for some k, the probability P(G,k) that k random elements generate G is positive. It was conjectured that if G is PFG, then the function P(G,k) can be interpolated to an analytic function defined in some right half-plane. Here that conjecture is formulated more precisely, and verified for (the profinite completion of) arithmetic groups satisfying the congruence subgroup property.
GROWTH OF SUBALGEBRAS FOR RESTRICTED LIE ALGEBRAS AND TRANSITIVE ACTIONS
Authors: PETROGRADSKY V. M.
Published: January 2006

We study a growth of subalgebras for restricted Lie algebras over a finite field 𝔽q. This kind of growth is an analog of the subgroup growth in the group theory. Let L be a finitely generated restricted Lie algebra. Then an(L) is the number of restricted subalgebras H ⊂ L such that dim 𝔽q L/H = n, n ≥ 0. We compute the numbers an(Fd) explicitly and find asymptotics, where Fd is the free restricted Lie algebra of rank d, d ≥ 1. As an important instrument, we use the notion of transitive L-action on coalgebras and algebras.
INNER PRODUCT TRUTH-VALUED FLOW INFERENCE
Authors: ZENG WENYI , LI HONGXING
Published: January 2006

Inference problems are one of the main research topics in the artificial intellect field. So far there have been various inference systems, some of them have been applied in fuzzy control according to their feature. In 1989, the concept of truth-valued flow inference was introduced by Wang1, and its mathematical theory of truth-valued flow inference was set up by Wang2 in 1995. In this paper, aimed at the real meaning of the truth-valued in the truth-valued flow inference, we introduce the concepts of the inner product truth-valued and inner product truth-valued flow inference, and analyze some inference algorithms of fuzzy control at present in detail. We reveal that the fuzzy inference algorithms in fuzzy control at present are all regarded as inner product truth-valued flow inference algorithm. Finally, inner product truth-valued flow inference approach is generalized in the multiple inputs and single output.
Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium
Authors: Ahmed Nuzhat , Maines-Bandiera Sarah , Quinn Michael A. , Unger Waldemar G. , Dedhar Shoukat , Auersperg Nelly
Published: January 2006

The ovarian surface epithelium (OSE) is the precursor of common epithelial ovarian carcinomas. In the present study, we examined the molecular mechanisms and possible physiological basis for the propensity of OSE cells to undergo epithelio-mesenchymal transition (EMT) in response to environmental influences. We hypothesized that EMT may be a homeostatic mechanism that permits displaced OSE to assume a stromal phenotype within the ovarian cortex. We report that EGF in conjunction with hydrocortisone is the EMT-inducing factor of OSE as shown by changes to a fibroblast-like morphology and growth pattern. EGF increased cell motility, enhanced the activities of secreted pro-matrix metalloproteinase (MMP)-2 and -9, and enhanced expression and activation of Erk and integrin-linked kinase (ILK). Increased ILK expression correlated with the activation of PKB/Akt, the phosphorylation of GSK-3β, and the increased expression of cyclin E and cdk2 kinase. EGF withdrawal resulted in a more epithelial morphology and reversal of the EGF-induced activation of signaling pathways and pro-MMP activity. In contrast, treatment of EGF-treated cells with specific inhibitors of phosphatidylinositol 3-kinase, Mek, or ILK inhibited the inhibitor-specific pathways. The inhibitors caused suppression of EGF-induced migration and pro-MMP-2/-9 activities but did not lead to any change in EGF-induced mesenchymal morphology. ILK small interfering RNA inhibited Akt phosphorylation and reduced pro-MMP-2/-9 activities but had no effect on Erk activation or cell morphology. These results indicate that the EGF-induced morphological and functional changes in OSE cells are controlled by distinct signaling mechanisms working in concert. EMT of OSE cells displaced by ovulation likely permits their survival and integration with a fibroblast-like identity within the stroma. Failure to do so may lead to the formation of epithelium-derived inclusion cysts, which are known preferential sites of malignant transformation.
Characterization of regulatory mechanisms and states of human organic cation transporter 2
Authors: Biermann Jürgen , Lang Detlef , Gorboulev Valentin , Koepsell Hermann , Sindic Aleksandra , Schröter Rita , Zvirbliene Aurelija , Pavenstädt Hermann , Schlatter Eberhard , Ciarimboli Giuliano
Published: January 2006

Polyspecific organic cation transporters (OCTs) have a large substrate binding pocket with different interaction domains. To determine whether OCT regulation is substrate specific, suitable fluorescent organic cations were selected by comparing their uptake in wild-type (WT) human embryonic kidney (HEK)-293 cells and in HEK-293 cells stably transfected with hOCT2. N-amidino-3,5-diamino-6-chloropyrazine-carboxamide (amiloride) and 4-[4-(dimethylamino)-styryl]- N-methylpyridinium (ASP) showed concentration-dependent uptake in hOCT2 at 37°C. After subtraction of unspecific uptake determined in WT at 37°C or in hOCT2 at 8°C saturable specific uptake of both substrates was measured. Kmvalues of hOCT2-mediated uptake of 95 μM amiloride and 24 μM ASP were calculated. Inhibition of amiloride and ASP uptake by several organic cations was also measured [IC50(in μM) for amiloride and ASP, respectively, tetraethylammonium (TEA) 98 and 30, cimetidine 14 and 26, and tetrapentylammonium (TPA) 7 and 2]. Amiloride and ASP uptake were significantly reduced by inhibition of Ca2+/CaM complex (−55 ± 5%, n = 10 and −63 ± 2%, n = 15, for amiloride and ASP, respectively) and stimulation of PKC (−54 ± 5%, n = 14, and −31 ± 6%, n = 26) and PKA (−16 ± 5%, n = 16, and −18 ± 4%, n = 40), and they were increased by inhibition of phosphatidylinositol 3-kinase (+28 ± 6%, n = 8, and +55 ± 17%, n = 16). Inhibition of Ca2+/CaM complex resulted in a significant decrease of Vmax(160–99 photons/s) that can be explained in part by a reduction of the membrane-associated hOCT2 (−22 ± 6%, n = 9) as determined using FACScan flow cytometry. The data indicate that saturable transport by hOCT2 can be measured by the fluorescent substrates amiloride and ASP and that transport activity for both substrates is regulated similarly. Inhibition of the Ca2+/CaM complex causes changes in transport capacity via hOCT2 trafficking.
Matrix Factorization Algorithms for the Identification of Muscle Synergies: Evaluation on Simulated and Experimental Data Sets
Authors: Tresch Matthew C. , Cheung Vincent C. K. , d'Avella Andrea
Published: January 2006

Several recent studies have used matrix factorization algorithms to assess the hypothesis that behaviors might be produced through the combination of a small number of muscle synergies. Although generally agreeing in their basic conclusions, these studies have used a range of different algorithms, making their interpretation and integration difficult. We therefore compared the performance of these different algorithms on both simulated and experimental data sets. We focused on the ability of these algorithms to identify the set of synergies underlying a data set. All data sets consisted of nonnegative values, reflecting the nonnegative data of muscle activation patterns. We found that the performance of principal component analysis (PCA) was generally lower than that of the other algorithms in identifying muscle synergies. Factor analysis (FA) with varimax rotation was better than PCA, and was generally at the same levels as independent component analysis (ICA) and nonnegative matrix factorization (NMF). ICA performed very well on data sets corrupted by constant variance Gaussian noise, but was impaired on data sets with signal-dependent noise and when synergy activation coefficients were correlated. Nonnegative matrix factorization (NMF) performed similarly to ICA and FA on data sets with signal-dependent noise and was generally robust across data sets. The best algorithms were ICA applied to the subspace defined by PCA (ICAPCA) and a version of probabilistic ICA with nonnegativity constraints (pICA). We also evaluated some commonly used criteria to identify the number of synergies underlying a data set, finding that only likelihood ratios based on factor analysis identified the correct number of synergies for data sets with signal-dependent noise in some cases. We then proposed an ad hoc procedure, finding that it was able to identify the correct number in a larger number of cases. Finally, we applied these methods to an experimentally obtained data set. The best performing algorithms (FA, ICA, NMF, ICAPCA, pICA) identified synergies very similar to one another. Based on these results, we discuss guidelines for using factorization algorithms to analyze muscle activation patterns. More generally, the ability of several algorithms to identify the correct muscle synergies and activation coefficients in simulated data, combined with their consistency when applied to physiological data sets, suggests that the muscle synergies found by a particular algorithm are not an artifact of that algorithm, but reflect basic aspects of the organization of muscle activation patterns underlying behaviors.
Neural Mechanisms Underlying Co-Activation of Functionally Antagonistic Motoneurons During aClioneFeeding Behavior
Authors: Norekian Tigran P. , Malyshev Aleksey Y.
Published: January 2006

The ability of some neural networks to produce multiple motor patterns required during different behaviors is a well-documented phenomenon. We describe here a dramatic transition from coordinated inhibition between two functionally antagonistic groups of motoneurons to their co-activation in the feeding neural network of the predatory mollusk Clione limacina. To seize its prey, Clione uses specialized oral appendages, called buccal cones, which are controlled by two groups of motoneurons: cerebral A (Cr-A) neurons controlling buccal cone protraction and cerebral B (Cr-B) neurons controlling buccal cone retraction. When Cr-A neurons are active, Cr-B neurons usually receive strong inhibitory inputs that terminate their firing, which leads to the full protraction and elongation of the buccal cones. We have found, however, that the Cr-A and Cr-B motoneurons sometimes burst simultaneously without any traces of inhibition in the Cr-B motoneurons. This transformation of the neural network activity from inhibitory interactions to co-activation presumably occurs during the late “extraction” period of the feeding behavior when buccal cones become partially retracted and rhythmically active. The transition from the inhibitory interaction to co-activation is controlled by the activity of a single pair of cerebral interneurons (Cr-Aint interneurons), which are electrically coupled to the Cr-A neurons and monosynaptically inhibit Cr-B neurons. Normally, the Cr-Aint interneurons are active along with Cr-A motoneurons and inhibit Cr-B motoneurons. During a period of co-activation, however, these interneurons do not produce spikes, thus allowing Cr-A motoneuron activation without inhibition of the Cr-B motoneurons.
Interleukin-17 Receptor-Like Gene Is a Novel Antiapoptotic Gene Highly Expressed in Androgen-Independent Prostate Cancer
Authors: You Zongbing , Shi Xu-Bao , DuRaine Grayson , Haudenschild Dominik , Tepper Clifford G. , Hao Lo Su , Gandour-Edwards Regina , de Vere White Ralph W. , Reddi A. Hari
Published: January 2006

We have recently identified a new gene, interleukin-17 receptor-like (IL-17RL), which is expressed in normal prostate and prostate cancer. This investigation is focused on the role of IL-17RL in prostate cancer. We found that IL-17RL was expressed at significantly higher levels in several androgen-independent prostate cancer cell lines (PC3, DU145, cds1, cds2, and cds3) and tumors compared with the androgen-dependent cell lines (LNCaP and MLC-SV40) and tumors. In an in vivo model of human prostate tumor growth in nude mice (CWR22 xenograft model), IL-17RL expression in tumors was induced by androgen deprivation. The relapsed androgen-independent tumors expressed higher levels of IL-17RL compared with the androgen-dependent tumors. Overexpression of IL-17RL in tumor necrosis factor α (TNFα)–sensitive LNCaP cells inhibited TNFα-induced apoptosis by blocking activation of caspase-3 downstream to caspase-2 and caspase-8. Reciprocally, knocking down IL-17RL expression by small interfering RNA induced apoptosis in all the prostate cancer cell lines studied. Taken together, these results show that IL-17RL is a novel antiapoptotic gene, which may confer partially the property of androgen-independent growth of prostate cancer by promoting cell survival. Thus, IL-17RL is a potential therapeutic target in the treatment of prostate cancer. (Cancer Res 2006; 66(1): 175-83)
Identification of Potential Human Oncogenes by Mapping the Common Viral Integration Sites in Avian Nephroblastoma
Authors: Pajer Petr , Pečenka Vladimír , Králová Jarmila , Karafiát Vít , Průková Dana , Zemanová Zdena , Kodet Roman , Dvořák Michal
Published: January 2006

Gene deregulation is a frequent cause of malignant transformation. Alteration of the gene structure and/or expression leading to cellular transformation and tumor growth can be experimentally achieved by insertion of the retroviral genome into the host DNA. Retrovirus-containing host loci found repeatedly in clonal tumors are called common viral integration sites (cVIS). cVIS are located in genes or chromosomal regions whose alterations participate in cellular transformation. Here, we present the chicken model for the identification of oncogenes and tumor suppressor genes in solid tumors by mapping the cVIS. Using the combination of inverse PCR and long terminal repeat-rapid amplification of cDNA ends technique, we have analyzed 93 myeloblastosis-associated virus type 2–induced clonal nephroblastoma tumors in detail, and mapped >500 independent retroviral integration sites. Eighteen genomic loci were hit repeatedly and thus classified as cVIS, five of these genomic loci have previously been shown to be involved in malignant transformation of different human cell types. The expression levels of selected genes and their human orthologues have been assayed in chicken and selected human renal tumor samples, and their possible correlation with tumor development, has been suggested. We have found that genes associated with cVIS are frequently, but not in all cases, deregulated at the mRNA level as a result of proviral integration. Furthermore, the deregulation of their human orthologues has been observed in the samples of human pediatric renal tumors. Thus, the avian nephroblastoma is a valid source of cancer-associated genes. Moreover, the results bring deeper insight into the molecular background of tumorigenesis in distant species. (Cancer Res 2006; 66(1): 78-86)
Inhibition of DNA Methyltransferase Activity Prevents Tumorigenesis in a Mouse Model of Prostate Cancer
Authors: McCabe Michael T. , Low Jonathan A. , Daignault Stephanie , Imperiale Michael J. , Wojno Kirk J. , Day Mark L.
Published: January 2006

Transcriptional silencing of tumor suppressor genes by DNA methylation plays an important role in tumorigenesis. These aberrant epigenetic modifications may be mediated in part by elevated DNA methyltransferase levels. DNA methyltransferase 1 (DNMT1), in particular, is overexpressed in many tumor types. Recently, we showed that Dnmt1 is transcriptionally regulated by E2F transcription factors and that retinoblastoma protein (pRb) inactivation induces Dnmt1. Based on these observations, we investigated regulation of Dnmt1 by polyomavirus oncogenes, which potently inhibit the pRb pocket protein family. Infection of primary human prostate epithelial cells with BK polyomavirus dramatically induced Dnmt1 transcription following large T antigen (TAg) translation and E2F activation. For in vivo study of Dnmt1 regulation, we used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which expresses the SV40 polyomavirus early region, including TAg, under control of a prostate-specific promoter. Analysis of TRAMP prostate lesions revealed greatly elevated Dnmt1 mRNA and protein levels beginning in prostatic intraepithelial neoplasia and continuing through advanced prostate cancer and metastasis. Interestingly, when TRAMP mice were treated in a chemopreventive manner with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza), 0 of 14 mice developed prostate cancer at 24 weeks of age, whereas 7 of 13 (54%) control-treated mice developed poorly differentiated prostate cancer. Treatment with 5-aza also prevented the development of lymph node metastases and dramatically extended survival compared with control-treated mice. Taken together, these data suggest that Dnmt1 is rapidly activated by pRb pathway inactivation, and that DNA methyltransferase activity is required for malignant transformation and tumorigenesis. (Cancer Res 2006; 66(1): 385-92)
Interplay between Two Hormone-Independent Activation Domains in the Androgen Receptor
Authors: Callewaert Leen , Van Tilborgh Nora , Claessens Frank
Published: January 2006

The androgen receptor (AR) plays a key role in prostate cancer development, as well as its treatments, even for the hormone-refractory state. Here, we report that an earlier described lysine-to-arginine mutation at position 179 in AR leads to a more potent AR. We show that two activation domains (Tau-1 and Tau-5) are necessary and sufficient for the full activity of AR and the intrinsic activity of the AR-NTD. Two α-helices surrounding the Lys179 define the core of Tau-1, which can act as an autonomous activation function, independent of p160 coactivators. Furthermore, we show that although the recruitment of p160 coactivators is mediated through Tau-5, this event is attenuated by core Tau-1. This better definition of the mechanisms of action of both Tau-1 and Tau-5 is instrumental for the design of alternative therapeutic strategies against prostate cancer. (Cancer Res 2006; 66(1): 543-53)
Identification of the NKG2D Haplotypes Associated with Natural Cytotoxic Activity of Peripheral Blood Lymphocytes and Cancer Immunosurveillance
Authors: Hayashi Tomonori , Imai Kazue , Morishita Yukari , Hayashi Ikue , Kusunoki Yoichiro , Nakachi Kei
Published: January 2006

We have previously shown that natural cytotoxic activity of peripheral blood lymphocytes was inversely related to cancer development based on a prospective cohort study. The genetic fraction of cytotoxic activity needs to be clarified, identifying individuals immunogenetically susceptible to cancer. A case-control study within the cohort members was designed: 102 cancer cases with peripheral lymphocyte DNA available and three control groups, each of which consisted of 204 subjects with each tertile level of cytotoxic activity. We first compared two control groups with high and low cytotoxic activity in terms of the single nucleotide polymorphisms in the natural killer complex gene region on chromosome 12p, identifying the haplotype alleles that were associated with the activity. Next, cancer risks were assessed for these haplotypes. We found two haplotype blocks, each of which generated two major haplotype alleles: low-activity-related LNK1 (frequency 0.478 and 0.615 in groups with high and low activity, respectively; P < 0.00008) and high-activity-related HNK1 (0.480 and 0.348; P < 0.0001), LNK2 (0.711 and 0.821; P < 0.0002), and HNK2 (0.272 and 0.174; P < 0.0008). These NKG2D haplotype alleles showed a significant difference between cases (0.632 for LNK1 and 0.333 for HNK1) and controls (0.554 for LNK1 and 0.406 for HNK1). The haplotype HNK1/HNK1 revealed a decreased risk of cancer (odds ratio, 0.471; 95% confidence interval, 0.233-0.952) compared with LNK1/LNK1. Individuals who are genetically predisposed to have low or high natural cytotoxic activity can in part be determined by NKG2D haplotyping, which in turn reveals an increased or decreased risk of cancer development. (Cancer Res 2006; 66(1): 563-70)
Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone
Authors: Thibaudeau Jean , Lépine Johanie , Tojcic Jelena , Duguay Yannick , Pelletier Georges , Plante Marie , Brisson Jacques , Têtu Bernard , Jacob Simon , Perusse Louis , Bélanger Alain , Guillemette Chantal
Published: January 2006

The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (Vmax) and affinities (Km). The −79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P < 0.001) in human endometrial carcinoma-1B cells. Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the −79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE–induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. (Cancer Res 2006; 66(1): 125-33)
Histone Deacetylase Inhibitors Modulate the Sensitivity of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Resistant Bladder Tumor Cells
Authors: Earel James K. , VanOosten Rebecca L. , Griffith Thomas S.
Published: January 2006

Urothelial carcinoma of the bladder accounts for ∼5% of all cancer deaths in humans. The large majority of tumors are superficial at diagnosis and, after local surgical therapy, have a high rate of local recurrence and progression. Current treatments extend time to recurrence but do not alter disease survival. The objective of the present study was to investigate the tumoricidal potential of combining the apoptosis-inducing protein tumor necrosis factor–related apoptosis inducing ligand (TRAIL) with histone deacetylase inhibitors (HDACi) against TRAIL-resistant bladder tumor cells. Pretreatment with HDACi at nontoxic doses, followed by incubation with TRAIL, resulted in a marked increase in TRAIL-induced apoptosis of T24 cells but showed no significant increase in toxicity to SV40 immortalized normal human uroepithelial cell-1. HDAC inhibition, especially with sodium butyrate and trichostatin A, led to increased TRAIL-R2 gene transcription that correlated with increased TRAIL-R2 surface expression. The increased TRAIL-R2 levels also resulted in accelerated death-inducing signaling complex (DISC) formation, caspase activation, and loss of mitochondrial membrane potential, which all contributed to the increase in tumor cell death. Collectively, these results show the therapeutic potential of combining HDAC inhibition with TRAIL as an alternative treatment for bladder cancer. (Cancer Res 2006; 66(1): 499-507)
Vascular Endothelial Growth Factor Receptor-1 Activation Mediates Epithelial to Mesenchymal Transition in Human Pancreatic Carcinoma Cells
Authors: Yang Anthony D. , Camp E. Ramsay , Fan Fan , Shen Lanlan , Gray Michael J. , Liu Wenbiao , Somcio Ray , Bauer Todd W. , Wu Yan , Hicklin Daniel J. , Ellis Lee M.
Published: January 2006

Our laboratory has shown that vascular endothelial growth factor receptor-1 (VEGFR-1) expression on human pancreatic cancer cell lines mediates cell migration and invasion. Because epithelial to mesenchymal transition (EMT) also plays a role in cell motility by altering the cell phenotype and morphology, we hypothesized that VEGFR-1 activation induces molecular alterations that mediate EMT. Our treatment of the human pancreatic cancer cell line L3.6pl with the VEGFR-1 ligands VEGF-A and VEGF-B led to morphologic changes characteristic of EMT, including loss of polarity, increased intercellular separation, and the presence of pseudopodia. Immunofluorescent staining with antibodies to E-cadherin and β-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and β-catenin from their usual cell membrane–bound location to the cytoplasm and nucleus, respectively. Western blotting showed that VEGFR-1 activation led to decreased expression of the epithelial markers E-cadherin and plakoglobin, increased expression of the mesenchymal markers vimentin and N-cadherin, and increased nuclear expression of β-catenin. Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced immunohistochemical and molecular changes in E-cadherin. VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug. The changes mediated by VEGFR-1 in this pancreatic carcinoma cell line are highly consistent with the changes characteristic of EMT. Given our previous finding of VEGFR-1-mediated tumor cell invasion and migration in pancreatic carcinoma cells, we hypothesize that VEGFR-1 plays a role in tumor progression in pancreatic cancer through the induction of EMT. (Cancer Res 2006; 66(1): 46-51)
Cyclin B1 and Other Cyclins as Tumor Antigens in Immunosurveillance and Immunotherapy of Cancer
Authors: Egloff Ann Marie , Vella Laura A. , Finn Olivera J.
Published: January 2006

Uncontrolled cell division is an indispensable event in tumor progression, and numerous molecules involved in this process have been the focus of intense investigation in tumor biology. Cyclins, molecules that orchestrate normal cell cycle progression, are abnormally overexpressed in various human cancers. We review evidence that the immune system recognizes some abnormally expressed cyclins as tumor antigens, such as cyclin B1, and we analyze the potential of cyclins D, E, and A to serve a similar function in cancer immunosurveillance. (Cancer Res 2006; 66(1): 6-9)
Pancreatic Cancer in Mice and Man: The Penn Workshop 2004
Authors: Hruban Ralph H. , Rustgi Anil K. , Brentnall Teresa A. , Tempero Margaret A. , Wright Christopher V. , Tuveson David A.
Published: January 2006

A three-day conference cosponsored by the National Cancer Institute Mouse Models of Human Cancer Consortium and the Abramson Cancer Center of the University of Pennsylvania was convened on December 1, 2004, in Philadelphia, Pennsylvania. The purpose of the conference was to compare the histopathologic changes in murine models of exocrine pancreatic cancer to human disease and to discuss potential preclinical applications of these models. The participants of this international meeting included over 100 physicians and scientists with expertise in pancreatic cancer pathology, therapy, detection, and biology, and they were organized accordingly into working groups. The format of the meeting was a series of short presentations by individual participants followed by working group breakout sessions. The working groups presented their reports on the final day of the conference, and highlights of selected individual presentations and working group recommendations are summarized here and in an accompanying pathology consensus report. (Cancer Res 2006; 66(1): 14-7)
Hypermetabolism in ALS: Correlations with Clinical and Paraclinical Parameters
Authors: Desport Jean-Claude , Torny Frédéric , Lacoste Mathieu , Preux Pierre-Marie , Couratier Philippe
Published: January 2006

Despite a reduction in fat-free mass (FFM), a hypermetabolism has been reported with an average of 10% in amyotrophic lateral sclerosis (ALS) patients as compared with a healthy population. The objectives of this study were to confirm the level of hypermetabolism determined by using indirect calorimetry in 168 patients with a probable or a definite ALS and to study correlations with survival. Consecutive evaluations of resting energy expenditure (REE) were performed from diagnosis to the proximity of death in 44 ALS patients. Differences with the calculated value determined a ΔREE. FFM was given by bioimpedance. At T1, REE was significantly increased by an average of 14% as compared with the calculated value. 62.3% of ALS patients were considered as hypermetabolic. REE was correlated in univariate analysis with age, sex, clinical form at onset, presence of a denutrition, weight, FFM, phase angle and ALS Functional Rating Scale (ALSFRS). In multivariate analysis, REE was linked to age and FFM. ΔREE was correlated in univariate analysis with sex, phase angle and manual muscle testing (MMT). In multivariate analysis, age and sex remained significantly correlated. During progression of ALS, REE levels remained higher than calculated values with a trend to decrease at proximity of death, whereas FFM remained stable. From T1, survival was linked to MMT, ALSFRS, vital capacity, REE and phase angle. We confirmed the existence of a stable hypermetabolic state in ALS which depends mainly on age, sex and FFM. REE is a prognostic factor for survival in univariate analysis.
A Simple Model of Linkage Disequilibrium and Genetic Drift in Human Genomic SNPs: Importance of Demography and SNP Age
Authors: Polanska Joanna , Kimmel Marek
Published: January 2006

We propose a simple model of evolution at a pair of SNP loci, under mutation, genetic drift and recombination. The developed model allows to consider evolution of SNPs under different demographic scenarios. We applied it to SNP data containing polymorphisms spanning 19 gene regions. We initially matched the linkage disequilibrium (LD) data only, and then we reconciled both LD and heterozygosity data. The imbalance between LD and heterozygosity data, observed for some of the analyzed genomic regions, may be a signature of selection acting in these regions. However, assuming neutrality, we obtain estimates of the age of population expansion of modern humans, which are consistent with the consensus estimates. In addition, we are able to estimate the ages of the polymorphisms observed in different genomic regions and we find that they vary widely with respect to their age. Polymorphisms at loci implicated in human disease, seem to be younger than average. Our results supplement the conclusions originally obtained by Reich and co-workers for the same set of data.
Serotonin Transporter Imaging with [123I]β-CIT SPECT before and after One Year of Citalopram Treatment of Obsessive-Compulsive Disorder
Authors: Stengler-Wenzke Katarina , Müller Ulrich , Barthel Henryk , Angermeyer Matthias C. , Sabri Osama , Hesse Swen
Published: January 2006

Background: Two thirds of patients with obsessive-compulsive disorder (OCD) respond to treatment with selective serotonin reuptake inhibitors (SSRIs). The neurobiological mechanisms of SSRI action and failure to respond to SSRI treatment remain to be elucidated. Objectives: The aim of this pilot study was to quantify changes in the availability of serotonin transporter (SERT) in the course of SSRI treatment and to relate these changes to improvements of clinical symptoms. Methods: Ten patients with OCD were investigated at baseline and 5 of them after 1 year of SSRI treatment with citalopram 60 mg per day using brain single photon emission computed tomography and [123I]β-CIT. Specific-to-nondisplaceable [123I]β-CIT binding ratios (V3″) were calculated in SERT-rich brainstem, midbrain and thalamus using a magnetic resonance imaging-based region of interest (ROI) analysis. Symptom severity was evaluated with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Results: V3″ differed significantly between pretreatment and follow-up scans in all three brain regions, thalamus, midbrain as well as in brainstem. In thalamic ROI, differ ences in SERT availability and Y-BOCS ratings correlated. In midbrain, a trend toward a significant association was found. In brainstem, no relationship was revealed. Conclusions: Higher occupancy of SERT by citalopram seems to be associated with better clinical response after 1 year of SSRI treatment of patients with OCD.
Eco‐efficiency and Its xsTerminology
Authors: Huppes Gjalt , Ishikawa Masanobu
Published: January 2006

Eco‐efficiency has been defined as a general goal of creating value while decreasing environmental impact. Leaving out the normative part of this concept, the empirical part refers to a ratio between environmental impact and economic cost or value. Two basic choices must be made in defining practical eco‐efficiency: which variable is in the denominator and which is in the numerator; and whether to specify environmental impact or improvement and value created or cost. Distinguishing between two situations, the general one of value creation and the specific one of environmental improvement efforts, and leaving the numerator‐denominator choice to the user, as diverging practices have developed, four basic types of ecoefficiency result: environmental intensity and environmental productivity in the realm of value creation; and environmental improvement cost and environmental cost‐effectiveness in the realm of environmental improvement measures.
The Sustainability Balanced Scorecard as a Framework for Eco‐efficiency Analysis
Authors: Möller Andreas , Schaltegger Stefan
Published: January 2006

To provide valuable support for successful decision‐making, managers need a balanced set of financial and nonfinancial measures that represent different requirements, strategic goals, strategies, resources, and capabilities and the causal relationships between these domains. The balanced scorecard is such a measurement system. As an open system the balanced scorecard facilitates the consideration of sustainability issues. But enhanced balanced scorecards require a new type of data. This is where eco‐efficiency analysis comes into play.

This article discusses the relationship between so‐called sustainability balanced scorecards and eco‐efficiency analysis. Eco‐efficiency analysis not only provides a data source for sustainability balanced scorecards; in the perspective of environmental information systems it also serves as a link between the balanced scorecard and corporate environmental accounting systems so that eco‐efficiency as a component of an environmental information system becomes an adapter with two interfaces, which are characterized in this article. The main focus is on the principle of cause and effect, its different forms, and the implications for the design of appropriate information system components.
A Practical Method for Quantifying Eco‐efficiency Using Eco‐design Support Tools
Authors: Kobayashi Yoshinori , Kobayashi Hideki , Hongu Akinori , Sanehira Kiyoshi
Published: January 2006

Eco‐efficiency at the product level is defined as product value per unit of environmental impact. In this paper we present a method for quantifying the eco‐efficiency using quality function deployment (QFD) and life‐cycle impact assessment (LCIA). These well‐known tools are widely used in the manufacturing industry.

QFD, which is one of the methods used in product development based on consumer preferences, is introduced to calculate the product value. An index of the product value is calculated as the weighted average of improvement rates of quality characteristics. The importance of customer requirements, derived from the QFD matrix, is applied.

Environmental impacts throughout a product life cycle are calculated based on an LCIA method widely used in Japan. By applying the LCIA method of endpoint type, the endpoint damage caused by various life‐cycle inventories is calculated. Willingness to pay is applied to integrate it into a single index.

Eco‐design support tools, namely, the life‐cycle planning (LCP) tool and the life‐cycle assessment (LCA) tool, have already been developed. Using these tools, data required for calculation of the eco‐efficiency of products can be collected. The product value is calculated based on QFD data stored in the LCP tool and the environmental impact is calculated using the LCA tool.

Case studies of eco‐efficiency are adopted and the adequacy of this method is clarified. Several advantages of this method are characterized.
Supply Curves for Eco‐efficient Environmental Improvements Using Different Weighting Methods
Authors: Nieuwlaar Evert , Warringa Geert , Brink Corjan , Vermeulen Walter
Published: January 2006

Eco‐efficiency implies environmental improvement at the lowest possible cost. When several environmental measures are possible, these can be ranked according to their cost per unit of environmental improvement, after which an eco‐efficient set of measures can be selected that yields a given level of environmental improvement at least cost. This procedure can be visualized as a supply curve for environmental improvement. Such a curve plots cumulative cost or cost per unit of environmental improvement against cumulative environmental improvement, with measures ordered according to increasing cost per unit of environmental improvement. This paper presents supply curves for environmental improvement on the basis of a set of possible environmental measures for a company in the Dutch oil and gas producing industry.

To measure aggregated potential environmental improvement for a given measure, different environmental impacts are lumped together using weighting factors. We compare five methods for weighting environmental impacts, covering a wide range of current practices.

The supply curves that were determined for each of the five weighting methods show relatively small differences, except for one (the distance‐to‐target method). The ranking of measures differs significantly, though, and as a result, so do the measures that are selected if total costs are restricted to a certain budget. Also, the consequent reduction in emissions of specific substances, in particular nitrogen oxides (NOx), depends on the weighting method selected.