bluuebunny/crossref_metadata_2025 huggingface dataset:
Some new algebraic criteria for chaos synchronization of Chua's circuits by linear state error feedback control
Authors: Wu Xiaofeng , Cai Jianping , Zhao Yi
Published: March 2006

The research on the sufficient criterion for chaos synchronization of the master–slave Chua's circuits by linear state error feedback control has received much attention and some synchronization criteria for special control matrix were proposed. In this paper, the above synchronization issue is investigated in the situation of general linear state error feedback controller with propagation delay of control signals from the master Chua's circuit. First of all, a master–slave synchronization scheme for Chua's circuits with propagation delay is given and the relevant error system is derived. Using a quadratic Lyapunov function and frequency domain method, three new algebraic synchronization criteria for the synchronization scheme with general control matrix are proven. They are applied to derive the synchronization criteria for simple control matrices. Some examples are given to show the sharpness of these new criteria compared with the known criteria. Copyright © 2006 John Wiley & Sons, Ltd.
Drug abuse in women with eating disorders
Authors: Herzog David B. , Franko Debra L. , Dorer David J. , Keel Pamela K. , Jackson Safia , Manzo Mary Pat
Published: March 2006

Objective:

Drug abuse in women with eating disorders has received relatively little attention. The frequency of drug use disorder (DUD) by specific drug type was examined in the current longitudinal study.

Method:

In a prospective study, women diagnosed with either anorexia nervosa (AN; n = 136) or bulimia nervosa (BN; n = 110), were interviewed and assessed for research diagnostic criteria (RDC) DUD every 6–12 months over 8.6 years.

Results:

Forty‐two (17%) women in the current longitudinal study had a lifetime history of DUD, with 19 prospective onsets over the course of the study (9 AN and 10 BN). The most commonly abused illicit drugs were amphetamines, cocaine, and marijuana, and rates of DUD did not differ between intake diagnoses of AN and BN.

Conclusion:

Drug abuse in women with eating disorders is an area of clinical concern and should be monitored routinely throughout the treatment process. © 2006 by Wiley Periodicals, Inc. Int J Eat Disord 2006.
Syntheses, Crystal Structures, and Characterizations of a Series of New Layered Lanthanide Carboxylate‐Phosphonates
Authors: Tang Si‐Fu , Song Jun‐Ling , Mao Jiang‐Gao
Published: March 2006

Hydrothermal reactions of different lanthanide(III) salts with (H2O3PCH2)2NCH2COOH (H5L1) led to two new layeredlanthanide(III) carboxylate‐diphosphonates, namely La(H2L1)(H2O)2·H2O (1) and La(H2L1)(H2O) (2). The structure of compound 1 features a layered architecture in which the nine‐coordinate La3+ ions are bridged by phosphonate groups of the ligands. The carboxylate group of the phosphonate ligand remains protonated and is involved in the interlayer hydrogen bonding. Compound 2 features a double layer structure in which the La3+ ion is eight‐coordinated and the carboxylate group of the ligand is chelated to a La3+ ion in a bidentate fashion. Hydrothermal reactions of lanthanide(III) salts with 4‐HOOC–C6H4–CH2N(CH2PO3H2)2 (H5L2) afforded three new compounds, namely, La(H4L2)(H3L2)(H2O)·2H2O (3), Er(H3L2)(H4L2) (4), and Er(HL3)(H2L3)(H2O) (5) [H2L3 = H2O3PCH2N(CHO)(CH2–C6H4–COOH)]. H2L3 was formed by the in situ oxidation of one P–C bond of the H5L2 ligand. Compound 3 features a (002) lanthanum(III) phosphonate layer in which the seven‐coordinate La3+ ions are bridged by diphosphonate moieties of the ligands. The carboxylate group remains protonated and is involved in the interlayer hydrogen bonding. The structure of compound 4 contains a 1D chain along the a axis in which each pair of ErO6 octahedra is bridged by a pair of phosphonate groups. These 1D chains are further interconnected by hydrogen bonds between noncoordinated phosphonate oxygen atoms into a (002) layer with the phenyl carboxylate groups hanging on the interlayer space. The structure of compound 5 is also layered. The interconnection of Er3+ ions by bidentate and tetradentate bridging phosphonate groups resulted in a (002) inorganic layer with the organic groups orientated to the interlayer space. Luminescence properties of compounds 4 and 5 have also been studied.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Determination of Nanomolar Concentrations of Pb(II) Using Carbon Paste Electrode Modified with Zirconium Phosphated Amorphous Silica
Authors: Shams Esmaeil , Alibeygi Fatemeh , Torabi Roohollah
Published: March 2006

A sensitive and selective method for the determination of Pb(II) with a zirconium phosphated silica gel (SiZrPH) modified carbon paste electrode has been developed. The measurements were carried out in three steps including an open circuit accumulation following by electrolysis of accumulated Pb(II) at the modified carbon paste electrode and differential pulse voltammetric determination. The analytical performance was evaluated with respect to the carbon paste composition, pH of solution at the accumulation step, pH and concentration of supporting electrolyte, electrolysis potential, accumulation time and electrolysis time. Two linear calibration graphs were obtained in the concentration ranges 2.5×10−9 mol L−1–5.0×10−8 mol L−1 and 5.0×10−8 mol L−1–5.0×10−6 mol L−1 with an accumulation time of 120 s. The detection limit was found to be 3.5×10−10 mol L−1. The effects of potential interfering ions were studied, and it was found that the proposed procedure is free from interferences of common interfering ions such as tin, thallium and etc. The developed method was applied to Pb(II) determination in a wastewater sample.
Evaluation use in nonformal education settings
Authors: Clavijo Kate , Fleming M. Lynette , Hoermann Elizabeth F. , Toal Stacie A. , Johnson Kelli
Published: March 2006

This chapter describes some of the challenges presented by nonformal education settings and discusses strategies for increasing evaluation use in nonformal education programs.
Another perspective: An interview with David Smith
Authors: Bowman Ruth A. , Johnson Kelli
Published: March 2006

This chapter offers insights related to the value of involving evaluation early in the program development process and helping funders understand the benefits of evaluation.
Analysis of fluid flow through micro‐fluidic devices using characteristic‐based‐split procedure
Authors: Celik Bayram , Edis Firat Oguz
Published: March 2006

Gas flow in micro‐electro‐mechanical systems can be considered as rarefied since the ratio of free molecular path length to the characteristic length of the device is high. It is possible to analyse these flows using a conventional Navier–Stokes solver with modified boundary conditions to account for temperature‐jump and slip‐velocity on solid walls. In this study, characteristic‐based‐split (CBS) algorithm is modified to account for slip‐velocity and temperature‐jump boundary conditions in order to perform compressible flow analysis for a micro sized geometry. The CBS algorithm is a split procedure which yields a unified solution method valid for both compressible and incompressible flows. To verify the modified CBS solver, straight micro channel and micro step duct geometries are selected as test cases. To reduce the size of the implicit part of the algorithm, pseudo‐quadratic velocity/linear pressure elements (pP2P1) are employed. The results obtained using CBS algorithm, are compared with other analytical and computational results available in the literature. It is shown that this implementation of the CBS algorithm is applicable and effective for micro gas flows. It is also shown that, increasing Knudsen number results in increased temperature‐jump and slip‐velocity. This effect, however, is limited, especially for high Mach number flows. Copyright © 2006 John Wiley & Sons, Ltd.
Numerical approximation of the heat transfer between domains separated by thin walls
Authors: Codina Ramon , Houzeaux Guillaume
Published: March 2006

In this paper, we analyse the numerical approximation of the heat transfer problem between two subdomains that we will consider filled with a fluid and separated by a thin solid wall. First of all, we state the problem in the whole domain with discontinuous physical properties. As an alternative and under certain assumptions on the separating walls, a classical Robin boundary condition between the fluid domains is obtained, thus eliminating the solid wall, and according to which the heat flux is proportional to the temperature difference between the two subdomains. Apart from discussing the relation between both approaches, we consider their numerical approximation, considering different alternatives for the first case, that is, the case in which temperatures are also computed in the solid wall. Copyright © 2006 John Wiley & Sons, Ltd.
Two approaches to repetition suppression
Authors: Noppeney Uta , Penny Will. D.
Published: March 2006

Repetition suppression refers to the phenomenon that prior processing of stimuli (or stimulus attributes) decreases activation elicited by processing subsequent stimuli with identical attributes. We present two complementary approaches to identify regions that show repetition suppression for subsequent sentences with either identical: (1) sentence forms or (2) speakers. The first categorical approach simply compares sentences that are presented in Same and Different blocks. The second factorial approach operationally defines repetition suppression as decreased activation for the subsequent Same stimulus relative to its preceding sentence. To account for nonspecific time confounds, this approach tests for a repetition × condition (Same or Different) interaction. Surprisingly, the two approaches revealed different results: Only the categorical analysis detected sentence repetition effects in multiple regions within a bilateral frontotemporal system that has previously been implicated in sentence processing. These discrepancies might be due to the different efficiencies with which the particular contrasts were estimated or spurious differences in stimuli or attentional set that could not be entirely controlled within a single subject. Finally, we combined the two approaches in a [global null] conjunction analysis. Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.
Exploring predictive and reproducible modeling with the single‐subject FIAC dataset
Authors: Chen Xu , Pereira Francisco , Lee Wayne , Strother Stephen , Mitchell Tom
Published: March 2006

Predictive modeling of functional magnetic resonance imaging (fMRI) has the potential to expand the amount of information extracted and to enhance our understanding of brain systems by predicting brain states, rather than emphasizing the standard spatial mapping. Based on the block datasets of Functional Imaging Analysis Contest (FIAC) Subject 3, we demonstrate the potential and pitfalls of predictive modeling in fMRI analysis by investigating the performance of five models (linear discriminant analysis, logistic regression, linear support vector machine, Gaussian naive Bayes, and a variant) as a function of preprocessing steps and feature selection methods. We found that: (1) independent of the model, temporal detrending and feature selection assisted in building a more accurate predictive model; (2) the linear support vector machine and logistic regression often performed better than either of the Gaussian naive Bayes models in terms of the optimal prediction accuracy; and (3) the optimal prediction accuracy obtained in a feature space using principal components was typically lower than that obtained in a voxel space, given the same model and same preprocessing. We show that due to the existence of artifacts from different sources, high prediction accuracy alone does not guarantee that a classifier is learning a pattern of brain activity that might be usefully visualized, although cross‐validation methods do provide fairly unbiased estimates of true prediction accuracy. The trade‐off between the prediction accuracy and the reproducibility of the spatial pattern should be carefully considered in predictive modeling of fMRI. We suggest that unless the experimental goal is brain‐state classification of new scans on well‐defined spatial features, prediction alone should not be used as an optimization procedure in fMRI data analysis. Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.
Determining hierarchical functional networks from auditory stimuli fMRI
Authors: Patel Rajan S. , Bowman F. DuBois , Rilling James K.
Published: March 2006

We determined connectivity of the human brain using functional magnetic resonance imaging (fMRI) while subjects experienced auditory stimuli in a 2‐by‐2 factorial design. The two factors in this study were “speaker” (same or different speaker) and “sentence” (same or different sentences). Connectivity studies allow us to ask how spatially remote brain regions are neurophysiologically related given these stimuli. In the context of this study, we examined how the “speaker” effect and “sentence” effect influenced these relationships. We applied a Bayesian connectivity method that determines hierarchical functional networks of functionally connected brain regions. Hierarchy in these functional networks is determined by conditional probabilities of elevated activity. For example, a brain region that becomes active a superset of the time of another region is considered ascendant to that brain region in the hierarchical network. For each factor level, we found a baseline functional network connecting the primary auditory cortex (Brodmann's Area [BA] 41) with the BA 42 and BA 22 of the superior temporal gyrus (STG). We also found a baseline functional network that includes Wernicke's Area (BA 22 posterior), STG, and BA 44 for each factor level. However, we additionally observed a strong ascendant connection from BA 41 to the posterior cingulate (BA 30) and Broca's Area and a stronger connection from Wernicke's Area to STG and the posterior cingulate while passively listening to different sentences rather than the same sentence repeatedly. Finally, our results revealed no significant “speaker” effect or interaction between “speaker” and “sentence.” Hum. Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.
Applying FSL to the FIAC data: Model‐based and model‐free analysis of voice and sentence repetition priming
Authors: Beckmann Christian F. , Jenkinson Mark , Woolrich Mark W. , Behrens Timothy E.J. , Flitney David E. , Devlin Joseph T. , Smith Stephen M.
Published: March 2006

This article presents results obtained from applying various tools from FSL (FMRIB Software Library) to data from the repetition priming experiment used for the HBM'05 Functional Image Analysis Contest. We present analyses from the model‐based General Linear Model (GLM) tool (FEAT) and from the model‐free independent component analysis tool (MELODIC). We also discuss the application of tools for the correction of image distortions prior to the statistical analysis and the utility of recent advances in functional magnetic resonance imaging (FMRI) time series modeling and inference such as the use of optimal constrained HRF basis function modeling and mixture modeling inference. The combination of hemodynamic response function (HRF) and mixture modeling, in particular, revealed that both sentence content and speaker voice priming effects occurred bilaterally along the length of the superior temporal sulcus (STS). These results suggest that both are processed in a single underlying system without any significant asymmetries for content vs. voice processing. Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.
Functional segregation of cortical language areas by sentence repetition
Authors: Dehaene‐Lambertz Ghislaine , Dehaene Stanislas , Anton Jean‐Luc , Campagne Aurelie , Ciuciu Philippe , Dehaene Guillaume P. , Denghien Isabelle , Jobert Antoinette , LeBihan Denis , Sigman Mariano , Pallier Christophe , Poline Jean‐Baptiste
Published: March 2006

The functional organization of the perisylvian language network was examined using a functional MRI (fMRI) adaptation paradigm with spoken sentences. In Experiment 1, a given sentence was presented every 14.4 s and repeated two, three, or four times in a row. The study of the temporal properties of the BOLD response revealed a temporal gradient along the dorsal–ventral and rostral–caudal directions: From Heschl's gyrus, where the fastest responses were recorded, responses became increasingly slower toward the posterior part of the superior temporal gyrus and toward the temporal poles and the left inferior frontal gyrus, where the slowest responses were observed. Repetition induced a decrease in amplitude and a speeding up of the BOLD response in the superior temporal sulcus (STS), while the most superior temporal regions were not affected. In Experiment 2, small blocks of six sentences were presented in which either the speaker voice or the linguistic content of the sentence, or both, were repeated. Data analyses revealed a clear asymmetry: While two clusters in the left superior temporal sulcus showed identical repetition suppression whether the sentences were produced by the same speaker or different speakers, the homologous right regions were sensitive to sentence repetition only when the speaker voice remained constant. Thus, hemispheric left regions encode linguistic content while homologous right regions encode more details about extralinguistic features like speaker voice. The results demonstrate the feasibility of using sentence‐level adaptation to probe the functional organization of cortical language areas. Hum Brain Mapp, 2006. © 2006 Wiley‐Liss, Inc.
Synthesis of 2‐Azabicyclo[3.2.2]nonane‐Derived Monosaccharide Mimics and Their Evaluation as Glycosidase Inhibitors
Authors: Buser Stephan , Vasella Andrea
Published: March 2006

The racemic 2‐azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as β‐glycosidase inhibitors. The intramolecular Diels–Alder reaction of the masked o‐benzoquinone generated from 2‐(allyloxy)phenol (6) gave the α‐keto acetal 7 which was reduced with SmI2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (→ 12), and Beckmann rearrangement provided lactam 15. N‐Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail β‐mannosidase (IC50 > 10 mM), Caldocellum saccharolyticum β‐glucosidase (IC50 > 10 mM), sweet almond β‐glucosidase (IC50 > 10 mM), yeast α‐glucosidase (5: IC50 > 10 mM; 19: IC50 = 1.2 mM), and Jack bean α‐mannosidase (no inhibition detected).
The First Ring‐Enlargement of a 1‐Azabicyclo[1.1.0]butane to a 1‐Azabicyclo[2.1.1]hexane
Authors: Mlostoń Grzegorz , Heimgartner Heinz
Published: March 2006

The reactions of 3‐phenyl‐1‐azabicyclo[1.1.0]butane (4) with dimethyl dicyanofumarate ((E)‐8) and dimethyl dicyanomaleate ((Z)‐8) lead to the same mixture of cis‐ and trans‐4‐phenyl‐1‐azabicyclo[2.1.1]hexane 2,3‐dicarboxylates (cis‐11 and trans‐11, resp.; Scheme 3). This result of a formal cycloaddition to the central CN bond of 4 is interpreted by a stepwise reaction mechanism via a relatively stable zwitterionic intermediate 10, which could be intercepted by morpholine to give a 1 : 1 : 1 adduct 12, which undergoes a spontaneous elimination of HCN to yield the fumarate 13 (Scheme 4).
Two New Compounds from the Ascomycete Daldinia concentrica
Authors: Qin Xiang‐Dong , Dong Ze‐Jun , Liu Ji‐Kai
Published: March 2006

Two new compounds, 1‐isopropyl‐2,7‐dimethylnaphthalene (1) and 21‐(acetyloxy)‐6,13,14‐trihydroxy‐16,18‐dimethyl‐10‐phenyl[11]cytochalasa‐7,19‐dien‐1‐one (2), were isolated from the fruiting bodies of Daldinia concentrica. The structures were established by spectroscopic methods.
Numerical Simulation of the Pressure Denaturation of a Helical β‐Peptide Heptamer Solvated in Methanol
Authors: Gee Peter J. , van Gunsteren Wilfred F.
Published: March 2006

The effect of elevated pressure on the conformational behavior of a β‐peptide heptamer (1) in MeOH solution was considered. The response of the peptide to elevated pressure was probed by means of molecular dynamics (MD) simulations, and described in atomic terms. The most‐striking features of the response are that the region of the ‘unfolded’ state of the peptide accessible at elevated pressure is narrow, and that thermal and pressure denaturation produce similar ‘unfolded’ states in the case of 1.
Solid‐Supported Green Synthesis of Substituted Hydrocinnamic Esters by Focused Microwave Irradiation
Authors: Kumar Vinod , Sharma Anuj , Sinha Arun K.
Published: March 2006

An efficient chemoselective hydrogenation protocol for substituted cinnamic esters is developed for the synthesis in quantitative yield of corresponding bioactive dihydrocinnamic esters with solid‐supported palladium chloride/ammonium formate (cat.) in HCOOH/H2O 1 : 2 as a hydrogenating agent under focused‐microwave irradiation for 10 min.
Reaction of Elemol with Acetic Acid/Perchloric Acid: Characterization of a Novel Oxide and (+)‐β‐Cyperone
Authors: Wahidulla Solimabi , Govenkar Mangala Babu , Paknikar Sashikumar Keshav
Published: March 2006

The minor unidentified compounds of the acetic acid/perchloric acid dehydration of elemol (1) were fully characterized. The structure and relative configuration of the less polar fragrant compound 2, named elemoxide, was deduced by 1D‐ and 2D‐NMR data including C,C‐connectivity, NOE, and NOESY experiments. The absolute configuration was established as (3S,3aR,7aR)‐1,3,3a,4,7,7a‐hexahydro‐6‐isopropyl‐1,1,3,3a‐tetramethylisobenzofuran (2) on the basis of its preparation from elemol (1). (+)‐β‐cyperone (3), a known sesquiterpene, was also identified as a minor product of the reaction. A plausible mechanistic explanation for the formation of elemoxide (2) and (+)‐β‐cyperone (3) is presented.
Paranolin: a New Xanthene‐Based Metabolite from Paraphaeosphaeria nolinae
Authors: Ge Hui Ming , Song Yong Chun , Chen Jing Rong , Hu Sha , Wu Jian Yong , Tan Ren Xiang
Published: March 2006

A new xanthene‐based, polycyclic metabolite, paranolin (= (2R,3aS,12aR)‐3,3a‐dihydro‐3a‐hydroxy‐8‐(hydroxymethyl)‐2‐(1‐hydroxy‐1‐methylethyl)‐9‐methoxy‐10‐methylfuro[3,2‐d]xanthen‐6(2H)‐one; 1) was isolated from a culture of Paraphaeosphaeria nolinae (IFB‐E011), an endophytic fungus residing in the normal stem of the artemisinin‐producing plant Artemisia annua (Asteraceae). The structure of 1 was elucidated by extensive spectroscopic analyses. Although not substantially active against the human colon (SW1116) and human cervical carcinoma (Hela) cell lines, this metabolite seems to be the first example of a xanthene‐derived secondary metabolite. Its possible biosynthetic origin (Scheme) and its significance as a phyllogenetic marker are discussed in brief.
A Practical, Water‐Soluble, Ionic Scavenger for the Solution‐Phase Syntheses of Amides
Authors: Lei Ming , Tao Xiao‐Le , Wang Yan‐Guang
Published: March 2006

A new ionic, water‐soluble scavenger for acyl chlorides, 1‐(2‐aminoethyl)pyridinium bromide (1), has been investigated. Compound 1 was used for the rapid and simple purification of a series of benzamides and sulfonamides (Table) obtained by solution‐phase synthesis from the corresponding amines (Scheme). The inexpensive scavenger, which can be prepared on large scale, was shown to readily ‘eliminate’ excess acyl chlorides (reagent) by simple aqueous extraction. The amides purified in this way were obtained in excellent yields and purities (Table), which makes 1 a versatile new reagent, especially for the combinatorial solution‐phase synthesis of amide libraries.
Three New, 1‐Oxygenated ent‐8,9‐Secokaurane Diterpenes from Croton kongensis
Authors: Chen Wei , Yang Xiao‐Dong , Zhao Jing‐Feng , Yang Jing‐Hua , Zhang Hong‐Bin , Li Zi‐Yan , Li Liang
Published: March 2006

Three new ent‐8,9‐secokaurane diterpenes, kongensins A–C (1–3), were isolated from the aerial parts of Croton kongensis, together with two known compounds, rabdoumbrosanin (4) and (7α,14β)‐7,14‐dihydroxy‐ent‐kaur‐16‐en‐15‐one (5). The structures of the new compounds were elucidated by HR‐MS as well as in‐depth 1D‐ and 2D‐NMR analyses. Compounds 1–3 showed an unusual oxygenation pattern, with an AcO or OH group at C(1), in combination with a Δ8(14) unsaturation (1) or an 8,14‐epoxide function (2, 3).
Enantioselective Synthesis of (−)‐(19R)‐Ibogamin‐19‐ol
Authors: Höck Stefan , Borschberg Hans‐Jürg
Published: March 2006

The first total synthesis of the natural product (−)‐(19R)‐ibogamin‐19‐ol ((−)‐1) is reported (biogenetic atom numbering). Starting with L‐glutamic acid from the chiral pool and (2S)‐but‐3‐en‐2‐ol, the crucial aliphatic isoquinuclidine (= 2‐azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self‐immolating chirality transfer in an Ireland–Claisen rearrangement and an intramolecular nitrone‐olefin 1,3‐dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)‐protected 1H‐indole‐3‐acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7‐membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (−)‐1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).
A New Cembranoid Diterpene and Other Related Metabolites from the South‐China‐Sea Soft Coral Lobophytum crassum
Authors: Yin Shuai‐Wen , Shi Yan‐Ping , Li Xiao‐Ming , Wang Bin‐Gui
Published: March 2006

A new hydroperoxy‐substituted cembranoid diterpene, 2‐hydroperoxysarcophine (= (1aR*,4E,11E,14aR*)‐2,3,6,7,10a,13,14,14a‐octahydro‐10a‐hydroperoxy‐1a,5,8,12‐tetramethyloxireno[9,10]cyclotetradeca[1,2‐b]furan‐9(1aH)‐one; 1), was isolated from the marine soft coral Lobophytum crassum. Also isolated were two other cembranoid diterpenes, obtained for the first time from a natural source, i.e., 7β,8β‐epoxy‐4α‐hydroxycembra‐1(15),2,11‐trien‐16,2‐olide (2) and 7β,8β‐epoxy‐4β‐hydroxycembra‐1(15),2,11‐trien‐16,2‐olide (3), along with three further cembranoid derivatives, five sterols, and two open‐chain metabolites. Their structures and relative configurations were elucidated on the basis of extensive spectroscopic analyses including 1D‐ and 2D‐NMR, and HR‐ESI‐MS experiments.
Molecular determinants of response to RTK‐targeting agents in nonsmall cell lung cancer
Authors: Reinmuth Niels , Meister Michael , Muley Thomas , Steins Martin , Kreuter Michael , Herth Felix J.F. , Hoffmann Hans , Dienemann Hendrik , Thomas Michael
Published: March 2006

Receptor tyrosine kinases (RTKs) are essential components of the cellular signaling apparatus and are often mutated or otherwise deregulated in nonsmall cell lung cancer (NSCLC). These receptors are not solely expressed by cancer cells but also by multiple other cell types, including stromal cells that, in turn, may modulate cancer cell functions by various direct and indirect interactions. Recently, clinical studies have successfully evaluated the inhibition of RTKs by specific RTK‐targeting agents, including tyrosine kinase inhibitors (TKIs). Although the response was impressive in some studies, only a limited proportion of patients benefit from these new drugs. Therefore, an intensive search for markers has started to determine which patients and tumor types are most likely to respond favorably to this new kind of treatment. Considerable attention has been focused onto molecular changes in cancer cells such as receptor expression, gene amplification, changes in intracellular signaling and receptor mutations. In this article, we explore the current data regarding molecular alterations as surrogate markers of response to specific RTK‐targeting agents in NSCLC. Defined alterations may serve as key markers helping to preselect NSCLC patients for an individualized therapeutic approach in the future. © 2006 Wiley‐Liss, Inc.
Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells A relay for chemotherapy?
Authors: Demidem Aicha , Morvan Daniel , Madelmont Jean Claude
Published: March 2006

In a previous study, it was reported that secondary untreated melanoma tumors implanted several weeks after and at distance from primary chloroethylnitrosourea (CENU)‐treated tumors underwent differentiation and growth inhibition. To see whether the primary treated tumor released soluble factors that mediated the secondary tumor response, serum transfer experiments were performed in vivo. Administration of serum from CENU‐treated tumor‐bearing donors arrested tumor proliferation, decreased vessel formation and induced tumor metabolite alterations encompassing glutathione decrease and polyunsaturated fatty acid and phosphoethanolamine increase. These changes mimicked secondary tumor phenotype. To reproduce the model in vitro, cell culture supernatant transfer experiments were performed. CENU‐treated cell cultures showed polyploidy and reactive oxygen species (ROS) production. Cell cultures challenged by a conditioned medium of CENU‐treated cells underwent growth inhibition, cytoskeleton disorders, cytokinesis retardation, metabolite alterations, glutathione decrease and phosphoethanolamine increase, without ROS elicitation. Proteomics of CENU‐treated cell conditioned media revealed altered protein secretion activity by CENU‐treated cells. Among de novo secreted proteins, the most expressed were phosphatidylethanolamine‐binding protein (PEBP), cardiovascular heat shock protein (cHsp), Rho‐associated coiled‐coil forming kinase 2 (ROCK) and actin fragments. These proteins testified of cytoskeleton disorders, growth inhibition and metabolite alterations. This article demonstrates the release by CENU‐treated tumors of growth inhibitory differentiation‐inducing soluble factors. These factors mediate remote bystander effects and attest persistent biological activity of residual tumors after chemotherapy. © 2006 Wiley‐Liss, Inc.
Tumor iNOS predicts poor survival for stage III melanoma patients
Authors: Ekmekcioglu Suhendan , Ellerhorst Julie A. , Prieto Victor G. , Johnson Marcella M. , Broemeling Lyle D. , Grimm Elizabeth A.
Published: March 2006

Inducible nitric oxide synthase (iNOS) produces nitric oxide, which has growth promoting activity in melanoma. A preliminary study of tumors from patients with Stage III melanoma who had received neo‐adjuvant therapy revealed an association of tumor iNOS expression with shortened survival. The objective of the present study was to determine whether iNOS expression in tumors of newly diagnosed, untreated Stage III patients is predictive of survival. iNOS expression was examined by immunohistochemistry in tumors from 132 patients. The staining was evaluated for percentage of positive cells (Number score) and the intensity of staining (Intensity score). The association of iNOS expression with overall and disease‐specific survival was tested in univariate and multivariate Cox proportional hazards regression models that included other known prognostic factors. Results of the univariate analysis demonstrated that the presence of iNOS in a patient's tumor, whether graded on the basis of Number or Intensity score, was associated with a significant increase in the hazard ratio of death from melanoma. These findings were corroborated by median survival data estimated from Kaplan Meier analysis. In the multivariate model including iNOS number or intensity, gender, age, number of lymph nodes, macroscopic disease and in‐transit disease, only iNOS expression predicted survival. We conclude that a significant association exists between tumor iNOS expression and shortened survival in untreated Stage III melanoma patients. The ability of iNOS to predict outcomes for these patients may be independent of other known prognostic factors, providing a new molecular marker with significant potential for clinical utility. © 2006 Wiley‐Liss, Inc.
Proteasome inhibition with bortezomib: A new therapeutic strategy for non‐Hodgkin's lymphoma
Authors: Leonard John P. , Furman Richard R. , Coleman Morton
Published: March 2006

The incidence of non‐Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3–4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second‐line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast‐track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single‐agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18–60% in FL and 39–56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future. © 2006 Wiley‐Liss, Inc.
Synergistic effects of docetaxel and S‐1 by modulating the expression of metabolic enzymes of 5‐fluorouracil in human gastric cancer cell lines
Authors: Wada Yoshiyuki , Yoshida Kazuhiro , Suzuki Takahisa , Mizuiri Hirozumi , Konishi Kazuo , Ukon Kei , Tanabe Kazuaki , Sakata Yu , Fukushima Masakazu
Published: March 2006

We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S‐1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5‐FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5‐FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK‐1, and MKN‐1, ‐28, ‐45 and ‐74), in a time‐ and dose‐dependent manner. Moreover, striking synergistic effects were observed in TMK‐1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5‐FU. Furthermore, in TMK‐1 xenografts, 5‐FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S‐1 and TXT, however, exhibited greater growth‐inhibitory effects than the 5‐FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S‐1 and TXT were examined by expression and activity analyses of the 5‐FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9‐fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S‐1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors. © 2006 Wiley‐Liss, Inc.
Hepatocyte growth factor activation inhibitors (HAI‐1 and HAI‐2) regulate HGF‐induced invasion of human breast cancer cells
Authors: Parr Christian , Jiang Wen G.
Published: March 2006

Hepatocyte growth factor (HGF) plays a plethora of roles in cancer metastasis and tumour growth. The interaction between tumour cells and their surrounding stromal environment is a crucial factor regulating tumour invasion and metastasis. Stromal fibroblasts are the main source of HGF in the body, and release HGF as an inactive precursor (pro‐HGF). HGF activator (HGFA), matriptase, urokinase‐type plasminogen activator and hepsin are the main factors responsible for converting pro‐HGF into active HGF. HAI‐1 and HAI‐2 are 2 novel Kunitz‐type serine protease inhibitors that regulate HGF activity through inhibition of HGFA, matriptase and hepsin action. Recent studies demonstrate that HAI‐1 and HAI‐2 may also potently inhibit a number of other pro‐metastatic serine proteases and therefore have direct bearing on the spread of tumours. Our study examined the potential of these HAI's to suppress the influence of HGF and regulate cancer metastasis. We generated a retroviral expression system that induced HAI expression in a human fibroblast cell line. Forced expression of either HAI‐1 or HAI‐2 in these fibroblasts resulted in a dramatic decrease in the production of bioactive hepatocyte growth factor (HGF). This reduction in HGF activity subsequently suppressed HGF's metastatic influence on breast cancer cells. To further assess the anti‐cancer properties of HAI‐1 and HAI‐2 we generated recombinant HAI proteins. These recombinant HAI proteins possessed the ability to potently quench HGF activity. We also demonstrate that these recombinant HAI's suppressed fibroblast‐mediated breast cancer invasion. An additional ribozyme transgenes study revealed that elimination of HAI‐1 and HAI‐2 expression, in an MDA‐MB‐231 breast cancer cell line, significantly enhanced the migratory, proliferative and invasive nature of these breast cancer cells. Overall, our data demonstrates the important roles of HAI‐1 and HAI‐2 in cancer metastasis, and reveals that these serine protease inhibitors display strong therapeutic potential. © 2006 Wiley‐Liss, Inc.
Social class is an important and independent prognostic factor of breast cancer mortality
Authors: Bouchardy Christine , Verkooijen Helena M. , Fioretta Gérald
Published: March 2006

Reasons of the important impact of socioeconomic status on breast cancer prognosis are far from established. This study aims to evaluate and explain the social disparities in breast cancer survival in the Swiss canton of Geneva, where healthcare costs and life expectancy are among the highest in the world. This population‐based study included all 3,920 female residents of Geneva, who were diagnosed with invasive breast cancer before the age of 70 years between 1980 and 2000. Patients were divided into 4 socioeconomic groups, according to the woman's last occupation. We used Cox multivariate regression analysis to identify reasons for the socioeconomic inequalities in breast cancer survival. Compared to patients of high social class, those of low social class had an increased risk (unadjusted hazard ratio [HR] 2.4, 95% CI: 1.6–3.5) of dying as a result of breast cancer. These women were more often foreigners, less frequently had screen‐detected cancer and were at more advanced stage at diagnosis. They less frequently underwent breast‐conserving surgery, hormonal therapy, and chemotherapy, in particular, in case of axillary lymph node involvement. When adjusting for all these factors, patients of low social class still had a significantly increased risk of dying of breast cancer (HR 1.8, 95% CI: 1.2–2.6). Overmortality linked to low SES is only partly explained by delayed diagnosis, unfavorable tumor characteristics and suboptimal treatments. Other factors, not measured in this study, also could play a role. While waiting for the outcome of other researches, we should consider socioeconomic status as an independent prognostic factor and provide intensified support and surveillance to women of low social class. © 2006 Wiley‐Liss, Inc.
Cancer risk among patients with condylomata acuminata
Authors: Nordenvall Caroline , Chang Ellen T. , Adami Hans‐Olov , Ye Weimin
Published: March 2006

Condylomata acuminata have been shown to increase the risk of anogenital cancers. However, previous studies have been of limited sample size and/or short follow‐up duration, which prevent precise estimates of long‐term excess risk, especially for specific cancer sites. We estimated the risk of specific cancers in a large cohort of hospitalized patients with condylomata acuminata, as recorded in the Swedish Inpatient Register between 1965 and 1999. Altogether, 10,971 patients (1,685 men and 9,286 women) were followed through 1999 for a median of 13 years. The standardized incidence ratio (SIR)—the ratio of the observed number of cancers to the number expected on the basis of the incidence in the Swedish population at large—was used as a measure of relative risk. After excluding the first‐year of follow‐up, we observed 43 cases of anogenital cancer in women, and 7 cases in men. Risks were elevated for cancers of the vulva (N = 13, SIR = 10.2, 95% confidence interval (CI) = 5.4–17.4), vagina (N = 4, SIR = 12.0, 95% CI = 3.3–30.7) and penis (N = 5, SIR = 21.9, 95% CI = 7.1–51.2). There was a moderate excess risk of cervical cancer in situ (N = 259, SIR = 1.9, 95% CI = 1.7–2.1), but not invasive cervical cancer. Excess risks of esophageal, buccal cavity, nonmelanoma skin, lung and bladder cancers, and Hodgkin and non‐Hodgkin lymphoma, were also observed in both men and women. In conclusion, condylomata acuminata are strongly associated with increased risk of cancers of the vulva, vagina, penis and anus, as well as some nonanogenital malignancies, but not invasive cervical cancer. © 2006 Wiley‐Liss, Inc.
Tumor infiltrating lymphocytes in seminoma lesions comprise clonally expanded cytotoxic T cells
Authors: Hadrup Sine Reker , Brændstrup Otto , Jacobsen Grete Krag , Mortensen Svend , Pedersen Lars Østergaard , Seremet Tina , Andersen Mads Hald , Becker Jürgen C. , Straten Per thor
Published: March 2006

Seminoma lesions are characterized by a brisk inflammatory infiltrate containing both CD4 and CD8 T cells, which is of prognostic significance. However, whether seminoma cells express the HLA molecules required for classical T‐cell recognition remains controversial. In the present study, we conducted a molecular, phenotypical and functional characterization of tumor infiltrating lymphocytes (TILs) from seminoma lesions. T‐cell receptor clonotype mapping demonstrated the presence of clonally expanded T cells in the majority of the lesions. The cytotoxic capacity of TILs was indicated by expression of CD107a, which is a recently described surrogate marker for cytolytic activity. Indeed, the frequency of CD107a positive cells was substantially higher in TILs when compared to peripheral blood mononuclear cells. Moreover, fluorescence activated cell sorting of CD107a positive TILs allowed comparison of the clonotypic T‐cell receptor fingerprint and demonstrated the ability of expanded clones to express this cytotoxic marker, suggesting cytotoxic activity at the tumor site. The cytotoxicity was confirmed by in situ granzyme B expression. Furthermore, by staining with multimeric HLA‐peptide complexes, we could demonstrate the presence of Mage‐3 specific T cells among TILs. In summary, specific and functional T‐cell responses are operative in seminoma, indicating that the inflammatory infiltrate is indeed involved in the immunological control of the tumor. © 2006 Wiley‐Liss, Inc.
Prostasome‐derived proteins capable of eliciting an immune response in prostate cancer patients
Authors: Ronquist Karl Göran , Carlsson Lena , Ronquist Gunnar , Nilsson Sten , Larsson Anders
Published: March 2006

Prostate cancer consistently remains a difficult clinical enigma. Therefore, the development of novel strategies for diagnosis and treatment (e.g. immunotherapy) of prostate cancer is essential. We tried to identify the prostasome‐derived proteins that were immunogenic in prostate cancer patients. Prostate cancer patients' sera (n = 44) with high enzyme‐linked immunosorbent assay (ELISA) titers against prostasomes were selected for immunoblotting against purified seminal prostasomes. The SDS‐PAGE and immunoblotting experiments were performed with Bio‐Rad systems. Twenty‐five of the recognized proteins were isolated and analyzed by means of mass spectrometry. Out of 44 patients' sera, 31 (70%) demonstrated in immunoblotting experiments reactivity against several prostasomal protein bands in the molecular weight range of 10–200 kDa. Some of the bands (55, 70 and 170 kDa) were more frequently recognized by the patients' sera. Concomitantly run control sera generated only very weak or no bands at all. The most frequently occurring prostasomal proteins were identified as heat shock proteins (HSP 70, 71) and clusterin. This study identified the most important molecular targets of autoantibodies against prostasomes generated in connection with the development of prostate cancer in man. These immunogenic prostasomal proteins could be appropriate target molecules for specific immunotherapy of prostate cancer patients. © 2006 Wiley‐Liss, Inc.
MUTYH‐associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype
Authors: Aretz Stefan , Uhlhaas Siegfried , Goergens Heike , Siberg Kirsten , Vogel Matthias , Pagenstecher Constanze , Mangold Elisabeth , Caspari Reiner , Propping Peter , Friedl Waltraut
Published: March 2006

To determine the frequency, mutation spectrum and phenotype of the recently described autosomal recessive MUTYH‐associated polyposis (MAP), we performed a systematic search for MUTYH (MYH) mutations by sequencing the complete coding region of the gene in 329 unselected APC mutation‐negative index patients with the clinical diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (AFAP). Biallelic germline mutations in MUTYH were identified in 55 of the 329 unselected patients (17%) and in another 9 selected index cases. About one‐fifth (20%) of the 64 unrelated MAP patients harboured none of the 2 hot‐spot missense mutations Y165C and/or G382D. Including 7 affected relatives, almost all MAP patients presented with either an attenuated (80%) or with an atypical phenotype (18%). Fifty percentage of the MAP patients had colorectal cancer at diagnosis. Duodenal polyposis was found in 18%, thyroid and stomach cancer in 1 case, other extraintestinal manifestations associated with FAP were not observed. In 8 families, vertical segregation was suspected; in 2 of these families, biallelic mutations were identified in 2 generations. Monoallelic changes with predicted functional relevance were found in 0.9% of the 329 patients, which is in accordance with the carrier frequency in the general population. In conclusion, biallelic MUTYH mutations are the underlying genetic basis in a substantial fraction of patients with adenomatous polyposis. The phenotype of MAP is best characterised as attenuated or atypical, respectively. Colorectal surveillance starting at about 18 years of age is recommended for biallelic mutation carriers and siblings of MAP patients, who refuse predictive testing. © 2006 Wiley‐Liss, Inc.