bluuebunny/crossref_metadata_2025 huggingface dataset:
Langjährige Erfahrungen des Tragverhaltens von Bewehrte‐Erde‐Brückenwiderlagern
Authors: Brüggemann Marko
Published: February 2010

Das Bauverfahren „Bewehrte Erde“ wurde nach der Einführung in den frühen 60‐er Jahren des letzten Jahrhunderts zum Bau von zahlreichen Stützwänden und Brückenwiderlagern angewandt. Der Beginn der Erforschung des Tragverhaltens von Bewehrte‐Erde‐Brückenwiderlagern liegt mehr als 40 Jahre zurück. Seitdem sind durch Modellversuche, Messungen an Test‐ und reellen Bauwerken zahlreiche Verbesserungen und Optimierungen am entwickelten Berechnungsverfahren erreicht worden. Dieser Beitrag soll Bauherren, Ingenieurbüros und bauausführenden Firmen für den Anwendungsfall „Brückenwiderlager“ im Bauverfahren „Bewehrte Erde“ sensibilisieren und daran erinnern, dass, bedingt durch seine zahlreichen technischen und ökonomischen Vorteile, dieses Bauverfahren bei unseren europäischen Nachbarn sowie weltweit für Brückenwiderlager nahezu als Standardbauweise gilt.

A long experience in structural behaviour of Reinforced Earth for the application of bridge abutments. Since Reinforced Earth was invented in the early 60s of the last century, many retaining walls and bridge abutments had been erected using this technique. The main research of the load bearing behaviour of reinforced earth bridge abutments started more than 40 year ago. Since that many improvements by exploring scale models, measurements on test and real structures had been executed. This article shall remind clients, contractors and engineers the Reinforced Earth is combining technical and economical advantages for the application of bridge abutments.
Verformungsverhalten weicher Böden im spannungsgesteuerten Kompressionsversuch
Authors: Soumaya Bassem , Kempfert Hans‐Georg
Published: February 2010

Anhand von spannungsgesteuerten Kompressionsversuchen kann das Verformungsverhalten weicher Böden wirklichkeitsnäher beschrieben werden, da durch die Wahl einer geeigneten Spannungsrate eine Ähnlichkeit zu den Belastungsbedingungen in situ vorliegt. Die Versuchsergebnisse werden in kontinuierlichen Kurven dargestellt, die eine lückenlose Interpretation der Versuchsergebnisse ermöglichen. Die Versuchsdauer wird dabei maßgeblich reduziert.

Im vorliegenden Beitrag werden die mathematischen Grundlagen in kontinuierlichen Kurven dargestellt, die eine lückenlose Interpretation der Versuchsergebnisse ermöglichen. Außerdem werden die Versuchsdauer, labor‐ und bodenmechanischen Grundlagen zur Ausführung von spannungsgesteuerten Kompressionsversuchen dargestellt. Versuchsergebnisse von aufbereiteten Kaolin‐ und ungestörten Seetonproben werden ebenfalls präsentiert und mit den Ergebnissen des Standardkompressionsversuchs verglichen. Schließlich wird eine Modellierung des geschwindigkeitsabhängigen Kompressionsverhaltens vorgestellt.

Constant rate of loading consolidation tests on soft soils. The one‐dimensional consolidation tests under constant rate of loading (CRL‐test) have the ability to describe the behaviour of soft soils realistically because of its similarity to the field loading conditions. The test results can be presented in continues curves, which enable a steeples Interpretation of the test results. Moreover the testing time will be enormously reduced.

In the present paper the mathematical and the procedural basics are presented in order to carry out the CRL‐test. Test results of remoulded kaolin as well as undisturbed lacustrine clay are shown and compared to the results from the incremental loading consolidation tests (IL‐Test). Finally a modelling of the compressibility behaviour depending on the loading rate will be presented.
Einheit von Wissenschaft und Kunst im Brückenbau: Hellmut Homberg (1909–1990) – Das Werk (Teil III)
Authors: Kurrer Karl‐Eugen , Pelke Eberhard , Stiglat Klaus
Published: February 2010

Das Werkverzeichnis des leidenschaftlichen Brückenbauers Hellmut Homberg ist umfassend und facettenreich. Anhand kennzeichnender Bauwerke wird seine konstruktive Entwicklung transparent. Sein Werk entsteht im Wettbewerb zu anderen großen beratenden Ingenieuren und in der Zusammenarbeit mit ausführenden Baufirmen.

Harmony between science and art in bridge‐building: Hellmut Homberg (1909–1990) – his work (part III). The Catalogue Raisonné of this impassionate bridge engineer Hellmut Homberg is comprehensive and multi facetted. Distinguished bridge structures make his structural development transparent. His work evolves in cooperation with construction companies, competing with consulting engineers.
Formulation and biopharmaceutical evaluation of a transdermal patch containing letrozole
Authors: Li Li , Fang Liang , Xu Xinlan , Liu Yu , Sun Yinghua , He Zhonggui
Published: February 2010

The purpose of this study was to formulate a drug‐in‐adhesive (DIA) transdermal patch containing letrozole, a third generation aromatase inhibitor for the treatment of breast cancer, using pressure‐sensitive‐adhesives (PSAs) and to evaluate the percutaneous penetration and pharmacokinetics of letrozole after transdermal administration, compared with that for the oral route. The formulation factors for such a patch, including the PSAs, enhancers and amount of drug loaded were investigated. Among the tested preparations, the formulation with DURO‐TAK 87‐4098, Azone and propylene glycol showed the highest letrozole permeation. The pharmacokinetic characteristics of an optimized DIA patch containing letrozole were determined using rats, while orally administered letrozole in solution was used as a control. The pharmacokinetic parameter, such as the mean residence time (MRT) was significantly (p<0.05) different following transdermal administration compared with oral administration. The in vivo results observed with the patches in rats were in good agreement with the plasma concentrations predicted from the in vitro penetration data. As a patient‐friendly, convenient, high local drug concentration and sustained dosing therapeutic system, the transdermal patches incorporating letrozole provide a useful strategy for the prevention and treatment of breast cancer. Copyright © 2010 John Wiley & Sons, Ltd.
Separation of viable and nonviable animal cell using dielectrophoretic filter
Authors: Hakoda Masaru , Wakizaka Yoshikazu , Hirota Yusuke
Published: February 2010

Selective separation of cells using dielectrophoresis (DEP) has recently been studied and methods have been proposed. However, these methods are not applicable to large‐scale separation because they cannot be performed efficiently. In DEP separation, the DEP force is effective only when it is applied close to the electrodes. Utilizing a DEP filter is a solution for large‐scale separation. In this article, the separation efficiency for viable and nonviable cells in a DEP filter was examined. The effects of an applied AC electric field frequency and the gradient of the squared electric field intensity on a DEP velocity for the viable and nonviable animal cells (3‐2H3 cell) were discussed. The frequency response of the DEP velocity differed between the viable and the nonviable cells. We deducted an empirical equation that can be used as guiding principle for the DEP separation. The results indicate that the viable and the nonviable cells were separated using the DEP filter, and the best operating conditions such as the applied voltage and the flow rate were discussed. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010
Fluid flow through a high cell density fluidized‐bed during centrifugal bioreactor culture
Authors: Detzel Christopher J. , Van Wie Bernard J. , Ivory Cornelius F.
Published: February 2010

An increasing demand for products such as tissues, proteins, and antibodies from mammalian cell suspension cultures is driving interest in increasing production through high‐cell density bioreactors. The centrifugal bioreactor (CCBR) retains cells by balancing settling forces with surface drag forces due to medium throughput and is capable of maintaining cell densities above 108 cells/mL. This article builds on a previous study where the fluid mechanics of an empty CCBR were investigated showing fluid flow is nonuniform and dominated by Coriolis forces, raising concerns about nutrient and cell distribution. In this article, we demonstrate that the previously reported Coriolis forces are still present in the CCBR, but masked by the presence of cells. Experimental dye injection observations during culture of 15 μm hybridoma cells show a continual uniform darkening of the cell bed, indicating the region of the reactor containing cells is well mixed. Simulation results also indicate the cell bed is well mixed during culture of mammalian cells ranging in size from 10 to 20 μm. However, simulations also allow for a slight concentration gradient to be identified and attributed to Coriolis forces. Experimental results show cell density increases from 0.16 to 0.26 when centrifugal force is doubled by increasing RPM from 650 to 920 at a constant inlet velocity of 6.5 cm/s; an effect also observed in the simulation. Results presented in this article indicate cells maintained in the CCBR behave as a high‐density fluidized bed of cells providing a homogeneous environment to ensure optimal growth conditions. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010
Antifibrillizing agents catalyze the formation of unstable intermediate aggregates of beta‐amyloid
Authors: Wang Min S. , Boddapati Shanta , Sierks Michael R.
Published: February 2010

Although Alzheimer's disease (AD) is characterized by the extracellular deposition of fibrillar aggregates of beta‐amyloid (Aβ), transient oligomeric species of Aβ are increasingly implicated in the pathogenesis of AD. Natively unfolded monomeric Aβ can misfold and progressively assemble into fibrillar aggregates, following a well‐established “on pathway” seeded‐nucleation mechanism. Here, we show that three simple saccharides, mannose, sucrose, and raffinose, alter Aβ aggregation kinetics and morphology. The saccharides inhibit formation of Aβ fibrils but promote formation of various oligomeric aggregate species through different “off pathway” aggregation mechanisms at 37°C but not at 60°C. The various oligomeric Aβ aggregates formed when coincubated with the different saccharides are morphologically distinct but all are toxic toward SH‐SY5Y human neuroblastoma cells, increasing the level of toxicity and greatly prolonging toxicity compared with Aβ alone. As a wide variety of anti‐Aβ aggregation strategies are being actively pursued as potential therapeutics for AD, these studies suggest that care must be taken to ensure that the therapeutic agents also block toxic oligomeric Aβ assembly as well as inhibit fibril formation. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010
The improvement of chloroperoxidase activities in the presence of ammonium salts and cationic surfactants
Authors: Ru Xuejiao , Wu Jinyue , Guo Huan , Jiang Yucheng , Hu Mancheng , Zhai Quanguo , Li Shuni
Published: February 2010

The catalytic activities of chloroperoxidase (CPO) including halogenation, oxidation, and peroxidation were investigated in the presence of ammonium salts: tetramethylammonium bromide (TMABr), tetraethylammonium bromide (TEABr), tetrapropylammonium bromide (TPABr), tetrabutylammonium bromide (TBABr), and cationic surfactants: dodecyltrimethylammonium bromide (DTABr) and cetyltrimethylammonium bromide (CTABr). All the mentioned activities were promoted in most cases. The highest modified activity (ABTS peroxidation) was 18.16 times higher in the presence of TMABr than that in pure buffer. The activity enhancement was strongly dependent on the concentration and the hydrophobic chain length of additives, and the structure of substrates. The kinetic parameters showed that the activation was mainly attributed to an increase in kcat due probably to a catalytically favorable conformation of CPO induced by the additives. Moreover, a lower Km and higher ratio of kcat/Km (specificity constant) was obtained, indicating that both the affinity and specificity of CPO to substrates were improved in the presence of additives. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010
Transcriptomic responses to sodium chloride‐induced osmotic stress: A study of industrial fed‐batch CHO cell cultures
Authors: Shen Duan , Kiehl Thomas R. , Khattak Sarwat F. , Li Zheng Jian , He Aiqing , Kayne Paul S. , Patel Vishal , Neuhaus Isaac M. , Sharfstein Susan T.
Published: February 2010

The rapidly expanding market for monoclonal antibody and Fc‐fusion‐protein therapeutics has increased interest in improving the productivity of mammalian cell lines, both to alleviate capacity limitations and control the cost of goods. In this study, we evaluated the responses of an industrial CHO cell line producing an Fc‐fusion‐protein to hyperosmotic stress, a well‐known productivity enhancer, and compared them with our previous studies of murine hybridomas (Shen and Sharfstein, Biotechnol Bioeng. 2006;93:132–145). In batch culture studies, cells showed substantially increased specific productivity in response to increased osmolarity as well as significant metabolic changes. However, the final titer showed no substantial increase due to the decrease in viable cell density. In fed batch cultures, hyperosmolarity slightly repressed the cellular growth rate, but no significant change in productivity or final titer was detected. To understand the transcriptional responses to increased osmolarity and relate changes in gene expression to increased productivity and repressed growth, proprietary CHO microarrays were used to monitor the transcription profile changes in response to osmotic stress. A set of osmotically regulated genes was generated and classified by extracting their annotations and functionalities from online databases. The gene list was compared with results previously obtained from similar studies of murine‐hybridoma cells. The overall transcriptomic responses of the two cell lines were rather different, although many functional groups were commonly perturbed between them. Building on this study, we anticipate that further analysis will establish connections between productivity and the expression of specific gene(s), thus allowing rational engineering of mammalian cells for higher recombinant‐protein productivity. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010
Microarray data classification using inductive logic programming and gene ontology background information
Authors: Ryeng Einar , Alsberg Bjørn Kåre
Published: February 2010

There exists many databases containing information on genes that are useful for background information in machine learning analysis of microarray data. The gene ontology and gene ontology annotation projects are among the most comprehensive of these. We demonstrate how inductive logic programming (ILP) can be used to build classification rules for microarray data which naturally incorporates the gene ontology and annotations to it as background knowledge without removing the inherent graph structure of the ontology. The ILP rules generated are parsimonious and easy to interpret. Copyright © 2010 John Wiley & Sons, Ltd.
Efficient Intramolecular Hydroalkoxylation of Unactivated Alkenols Mediated by Recyclable Lanthanide Triflate Ionic Liquids: Scope and Mechanism
Authors: Dzudza Alma , Marks Tobin J.
Published: February 2010

Lanthanide triflate complexes of the type [Ln(OTf)3] (Ln=La, Sm, Nd, Yb, Lu) serve as effective, recyclable catalysts for the rapid intramolecular hydroalkoxylation (HO)/cyclization of primary/secondary and aliphatic/aromatic hydroxyalkenes in imidazolium‐based room‐temperature ionic liquids (RTILs) to yield the corresponding furan, pyran, spirobicyclic furan, spirobicyclic furan/pyran, benzofuran, and isochroman derivatives. Products are straightforwardly isolated from the catalytic solution, conversions exhibit Markovnikov regioselectivity, and turnover frequencies are as high as 47 h−1 at 120 °C. The ring‐size rate dependence of the primary alkenol cyclizations is 5>6, consistent with a sterically controlled transition state. The hydroalkoxylation/cyclization rates of terminal alkenols are slightly more rapid than those of internal alkenols, which suggests modest steric demands in the cyclic transition state. Cyclization rates of aryl‐functionalized hydroxyalkenes are more rapid than those of the linear alkenols, whereas five‐ and five/six‐membered spirobicyclic skeletons are also regioselectively closed. In cyclization of primary, sterically encumbered alkenols, turnover‐frequency dependence on metal‐ionic radius decreases by approximately 80‐fold on going from La3+ (1.160 Å) to Lu3+ (0.977 Å), presumably reflecting steric impediments along the reaction coordinate. The overall rate law for alkenol hydroalkoxylation/cyclization is v≈k[catalyst]1[alkenol]1. An observed ROH/ROD kinetic isotope effect of 2.48 (9) is suggestive of a catalytic pathway that involves kinetically significant intramolecular proton transfer. The present activation parameters—enthalpy (ΔH≠)=18.2 (9) kcal mol−1, entropy (ΔS≠)=−17.0 (1.4) eu, and energy (Ea)=18.2 (8) kcal mol−1—suggest a highly organized transition state. Proton scavenging and coordinative probing results suggest that the lanthanide triflates are not simply precursors of free triflic acid. Based on the kinetic and mechanistic evidence, the proposed catalytic pathway invokes hydroxyl and olefin activation by the electron‐deficient Ln3+ center, and intramolecular H+ transfer, followed by alkoxide nucleophilic attack with ring closure.
Mechanistic Exploration of Intramolecular Aminodiene Hydroamination/Cyclisation Mediated by Constrained Geometry Organoactinide Complexes: A DFT Study
Authors: Tobisch Sven
Published: February 2010

The present computational mechanistic study explores comprehensively the organoactinide‐mediated intramolecular hydroamination/cyclisation (IHC) of aminodienes by employing a reliable DFT method. All the steps of a plausible catalytic reaction course have been scrutinised for the IHC of (4E,6)‐heptadienylamine 1 t by [(CGC)Th(NMe2)2] precatalyst 2 (CGC=[Me2Si(η5‐Me4C5)(tBuN)]2−). For each of the relevant elementary steps the most accessible pathway has been identified from a multitude of mechanistic possibilities. The operative mechanism involves rapid substrate association/dissociation equilibria for the 3 t‐S resting state and also for azacyclic intermediates 4 a, 4 s, easily accessible and reversible exocyclic ring closure, supposedly facile isomerisation of the azacycle’s butenyl tether prior to turnover‐limiting protonolysis. The following aspects are in support of this scenario: 1) the derived rate law is consistent with the experimentally obtained empirical rate law; 2) the accessed barrier for turnover‐limiting protonolysis does agree remarkably well with observed performance data; 3) the ring‐tether double‐bond selectivity is consistently elucidated, which led to predict the product distribution correctly. This study provides a computationally substantiated rationale for observed activity and selectivity data. Steric demands at the CGC framework appear to be an efficient means for modulating both performance and ring‐tether double‐bond selectivity. The careful comparison of (CGC)4f‐element and (CGC)5f‐element catalysts revealed that aminodiene IHC mediated by organoactinides and organolanthanides proceeds through a similar mechanistic scenario. However, cyclisation and protonolysis steps, in particular, feature a markedly different reactivity pattern for the two catalyst classes, owing to enhanced bond covalency of early actinides when compared to lanthanides.
Functionalization of Organic Molecules by Transition‐Metal‐Catalyzed C(sp3)H Activation
Authors: Jazzar Rodolphe , Hitce Julien , Renaudat Alice , Sofack‐Kreutzer Julien , Baudoin Olivier
Published: February 2010

Transition‐metal‐catalyzed CH activation has recently emerged as a powerful tool for the functionalization of organic molecules. While many efforts have focused on the functionalization of arenes and heteroarenes by this strategy in the past two decades, much less research has been devoted to the activation of non‐acidic CH bonds of alkyl groups. This Minireview highlights recent work in this area, with a particular emphasis on synthetically useful methods.
Chelation versus Binucleation: Metal Complex Formation with the Hexadentate all‐cis‐N1,N2‐Bis(2,4,6‐trihydroxy‐3,5‐diaminocyclohexyl)ethane‐1,2‐diamine
Authors: Bartholomä Mark , Gisbrecht Sergej , Stucky Stefan , Neis Christian , Morgenstern Bernd , Hegetschweiler Kaspar
Published: February 2010

The hexadentate ligand all‐cis‐N1,N2‐bis(2,4,6‐trihydroxy‐3,5‐diaminocyclohexyl)ethane‐1,2‐diamine (Le) was synthesized in five steps with an overall yield of 39 % by using [Ni(taci)2]SO4⋅4 H2O as starting material (taci=1,3,5‐triamino‐1,3,5‐trideoxy‐cis‐inositol). Crystal structures of [Na0.5(H6Le)](BiCl6)2Cl0.5⋅4 H2O (1), [Ni(Le)]‐ Cl2⋅5 H2O (2), [Cu(Le)](ClO4)2⋅H2O (3), [Zn(Le)]CO3⋅7 H2O (4), [Co(Le)](ClO4)3 (5 c), and [Ga(H−2Le)]‐ NO3⋅2 H2O (6) are reported. The Na complex 1 exhibited a chain structure with the Na+ cations bonded to three hydroxy groups of one taci subunit of the fully protonated H6(Le)6+ ligand. In 2, 3, 4, and 5 c, a mononuclear hexaamine coordination was found. In the Ga complex 6, a mononuclear hexadentate coordination was also observed, but the metal binding occurred through four amino groups and two alkoxo groups of the doubly deprotonated H−2(Le)2−. The steric strain within the molecular framework of various M(Le) isomers was analyzed by means of molecular mechanics calculations. The formation of complexes of Le with MnII, CuII, ZnII, and CdII was investigated in aqueous solution by using potentiometric and spectrophotometric titration experiments. Extended equilibrium systems comprising a large number of species were observed, such as [M(Le)]2+, protonated complexes [MHz(Le)]2+z and oligonuclear aggregates. The pKa values of H6(Le)6+ (25 °C, μ=0.10 m) were found to be 2.99, 5.63, 6.72, 7.38, 8.37, and 9.07, and the determined formation constants (log β) of [M(Le)]2+ were 6.13(3) (MnII), 20.11(2) (CuII), 13.60(2) (ZnII), and 10.43(2) (CdII). The redox potentials (vs. NHE) of the [M(Le)]3+/2+ couples were elucidated for Co (−0.38 V) and Ni (+0.90 V) by cyclic voltammetry.
Spermine‐Functionalized Perylene Bisimide Dyes—Highly Fluorescent Bola‐Amphiphiles in Water
Authors: Rehm Stefanie , Stepanenko Vladimir , Zhang Xin , Rehm Thomas H. , Würthner Frank
Published: February 2010

A series of four spermine‐functionalized perylene bisimide dyes without linkers (1) and with linkers (2–4) between the chromophore and the polyamine was synthesized. Protonation of the spermine moieties resulted in the formation of highly water‐soluble dyes with up to six positively charged ammonium ions. The aggregation behavior of these strongly fluorescent bola‐amphiphiles was studied in pure water as solvent by UV/Vis and fluorescence spectroscopy, and an astonishingly high fluorescence quantum yield of up to Φfl=0.90 was observed for PBI 1. Atomic force microscopy and transmission electron microscopy were applied for the visualization of the aggregates on surfaces. Molecular modeling studies were performed by force‐field calculations to explore the aggregate morphologies, which also provided valuable information on the influence of the additional alkylcarbonyl linkers. Our detailed spectroscopic and microscopic investigations revealed that the excellent optical properties of perylene bisimide chromophores can be used even in pure deionized water if their aggregation is efficiently suppressed.
Determination of catechin diastereomers from the leaves of Byrsonima species using chiral HPLC‐PAD‐CD
Authors: Rinaldo Daniel , Batista João M. , Rodrigues Juliana , Benfatti Ana C. , Rodrigues Clenilson M. , Dos Santos Lourdes C. , Furlan Maysa , Vilegas Wagner
Published: February 2010

When catechins are found in plant extracts, they are almost always identified as catechin and/or epicatechin probably due to stereoselectivity of the enzymes involved in the biosynthesis of these substances. However, the lack of reports regarding to ent‐catechin as well as ent‐epicatechin does not necessarily mean that these compounds have not been produced. In fact, most of the previous reports used chromatographic conditions not suitable for such separation. This article describes a simple and reliable analytical HPLC‐PAD‐CD method for simultaneous determination of catechin diastereomers both in infusions and extracts from the leaves of Byrsonima species. The direct separation of catechin, ent‐catechin, epicatechin, and ent‐epicatechin was obtained in normal phase by HPLC‐PAD‐CD using Chiralcel OD‐H as chiral stationary phase and n‐hexane/ethanol with 0.1% of TFA as mobile phase. Chirality, 2010. © 2010 Wiley‐Liss, Inc.
MR molecular imaging of HER‐2 in a murine tumor xenograft by SPIO labeling of anti‐HER‐2 affibody
Authors: Kinoshita Manabu , Yoshioka Yoshichika , Okita Yoshiko , Hashimoto Naoya , Yoshimine Toshiki
Published: February 2010

In vivo molecular imaging is a rapidly growing research area both for basic and clinical science. Non‐invasive imaging of in vivo conditions at the molecular level increases understanding of the biological characteristics of normal and diseased tissues without the need for invasive surgical procedures. Among the various imaging modalities, magnetic resonance imaging (MRI) has garnered interest as a molecular imaging modality due to its high spatial resolution. Here, we have demonstrated that the combined use of HER‐2 targeting affibody, a small 7 kDa molecule that behaves similarly to antibodies, and superparamagnetic iron oxide (SPIO) can non‐invasively image HER‐2 expressing cells or tissues both in vitro and in vivo by MRI. This preliminary study demonstrates that affibody‐SPIO is a feasible, target‐specific contrast agent for in vivo MR molecular imaging. Copyright © 2010 John Wiley & Sons, Ltd.
Evaluation of rHA labeled with Gd–DTPA for blood pool imaging and targeted contrast delivery
Authors: Wild Jim M. , Woodrow John , van Beek Edwin J.R. , Misselwitz Bernd , Johnson Richard
Published: February 2010

A new contrast agent was developed by linking Gd–DTPA chelate to recombinant human albumin in the laboratory. The molar relaxivity of the new agent was tested in aqueous solution at B0 1.5 T and temperature 20°C. The soluble compound had a higher molar longitudinal relaxivity and molar transverse relaxivity in water (r1 = 7.2 s−1 mM−1, r2 = 18.4 s−1 mM−1) than those measured for Gd–DTPA solution (r1 = 3.5 s−1 mM−1, r2 = 5.5 s−1 mM−1). The performance of the compound as a blood pool agent was investigated with soluble and microparticulate forms of the compound and comparisons were made with Gd–DTPA and the polymeric blood‐pool agent, Gadomer. T1‐weighted imaging experiments show that the soluble compound acts as a highly effective blood pool agent with hyperintensity in the vasculature persisting beyond 2 h post administration, compared with free Gd–DTPA, which was cleared from the blood pool after approximately 10 min. The clearance kinetics of the new agents were examined, due to the incomplete elimination within 14 days post injection; both rHA labeled compounds are probably not suitable for development as routine blood pool contrast media. However, with free sites on the Gd‐loaded rHA molecule, there are possibilities for binding the agent to antibodies in the laboratory, which was demonstrated, and thus there exist potential applications for in vivo molecular imaging with this agent. Copyright © 2010 John Wiley & Sons, Ltd.
The role of socioeconomic status in adjustment after ductal carcinoma in situ
Authors: de Moor Janet S. , Partridge Ann H. , Winer Eric P. , Ligibel Jennifer , Emmons Karen M.
Published: February 2010

BACKGROUND:

A large body of literature suggests that socioeconomic status (SES) is positively associated with mental and physical health. However, little research has examined the impact of SES on psychological adjustment after a major stressor. The current study examined whether SES (education and financial status) was associated with distress (anxiety and depression) in women diagnosed with ductal carcinoma in situ (DCIS). This study also explored whether social support explained the association between SES and distress and whether social support buffered the impact of low SES on distress.

METHODS:

A total of 487 women with newly diagnosed DCIS were enrolled in the study. Participants completed questions about sociodemographic, psychosocial, and clinical characteristics at the time of enrollment and 9 months after their diagnosis.

RESULTS:

Financial status was inversely associated with anxiety and depression at the 9‐month follow‐up. Financial status also predicted change in anxiety and depression. Women with high financial status reported a decline in anxiety and depression during the study period, whereas women with medium or low financial status reported an increase in anxiety and depression. In addition, the probability of exceeding the screening threshold suggestive of clinical depression increased with decreasing financial status. Education was not associated with anxiety or depression. The presence of social support did not explain the association between financial status and change in distress. Social support did not buffer the effect of low SES on anxiety and depression.

CONCLUSIONS:

Women with medium or low SES were vulnerable to escalating anxiety and depression after a DCIS diagnosis. Cancer 2010. © 2010 American Cancer Society.
Ability of integrated positron emission and computed tomography to detect significant colonic pathology
Authors: Weston Brian R. , Iyer Revathy B. , Qiao Wei , Lee Jeffrey H. , Bresalier Robert S. , Ross William A.
Published: February 2010

BACKGROUND:

The ability of integrated positron emission tomography and computed axial tomography (PET‐CT) to detect colonic pathology is not fully defined. The purpose of this study was to assess the ability of PET‐CT to detect colonic pathology and to determine the significance of (18F)2‐fluoro‐2‐deoxyglucose (18F‐FDG) activity noted incidentally in the colon on PET‐CT.

METHODS:

Records for all patients who underwent PET‐CT and colonoscopy at our institution were reviewed. Patients with history of colonic malignancy or colon surgery were excluded.

RESULTS:

Fifty‐eight patients had incidental colonic 18F‐FDG activity on PET (Group A) and 272 had none (Group B). In Group A, 65% of patients had pathologic findings detected on colonoscopy that corresponded to the site of PET activity. Standardized uptake value (SUV) readings were not helpful in distinguishing true‐positives from false‐positives. In Group B, 11.8% of patients were found to have significant colonic findings. Lesions not detected by PET‐CT included 4 colon cancers, 7 advanced adenomas, and 10 patients with colonic lymphoma. Overall, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET‐CT for detecting significant pathology were 53%, 93%, 65%, 89%, and 85%, respectively. For detecting colon cancer and adenomas 10 mm or more, the sensitivity, specificity, PPV, NPV, and accuracy of PET‐CT were 72%, 90%, 45%, 96%, and 88%, respectively.

CONCLUSIONS:

Incidental colonic activity detected by PET‐CT warrants further evaluation with colonoscopy. However, negative PET‐CT does not rule out significant colonic pathology including colon cancer, advanced adenomas, or lymphoma. Cancer 2010. © 2010 American Cancer Society.
Differential methylation of cell‐free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis
Authors: Liggett Thomas , Melnikov Anatoliy , Yi Qi‐long , Replogle Charles , Brand Randall , Kaul Karen , Talamonti Mark , Abrams Ross A. , Levenson Victor
Published: February 2010

BACKGROUND:

Although patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer (PanCa), the timely detection of PanCa often is difficult, because the symptoms of CP and PanCa are very similar. Moreover, secondary inflammation may be identified in PanCa, further complicating diagnosis. To improve the survival of patients with PanCa, a reliable test to differentiate CP from PanCa is needed. In this article, the authors describe a methylation profile of cell‐free plasma DNA that distinguished CP from PanCa with >90% accuracy.

METHODS:

Methylation in cell‐free, plasma DNA was compared among 30 samples from patients with CP, 30 samples from patients with PanCa, and 30 samples from healthy controls (N) using a microarray‐mediated methylation analysis of 56 fragments in each sample (MethDet56). Statistical analysis was done by using the Fisher exact test, a naive Bayes algorithm, and 25 rounds of 5‐fold cross‐validation.

RESULTS:

The MethDet56 methylation analysis technique identified 17 gene promoters as informative (8 for distinguishing N from CP and 14 for distinguishing CP from PanCa). It achieved 81.7% sensitivity and 78% specificity (P<.01) in the detection of CP (N vs CP) and 91.2% sensitivity and 90.8% specificity (P<.01) in the differential detection of PanCa (PanCa vs CP).

CONCLUSIONS:

The current data suggested that, among patients with pancreatic disease, the methylation profiles of inflammatory disease and cancer are different and open a new venue for the development of biomarkers for differential diagnosis. Further investigation of diagnostic biomarkers for pancreatic cancer based on methylation in cell‐free, circulating DNA appears to be warranted. Cancer 2010. © 2010 American Cancer Society.
Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma
Authors: Hino Ryosuke , Kabashima Kenji , Kato Yu , Yagi Hiroaki , Nakamura Motonobu , Honjo Tasuku , Okazaki Taku , Tokura Yoshiki
Published: February 2010

BACKGROUND:

Melanoma tends to be refractory to various immunotherapies because of tumor‐induced immunosuppression. To investigate the mechanism underlining the immunosuppression of melanoma patients, the authors focused on programmed cell death‐1 (PD‐1)/PD‐1 ligand 1 (PD‐L1) interaction between tumor cells and T cells.

METHODS:

Melanoma specimens were collected from 59 primary tumors, 16 lymph nodes, and 4 lesions of in‐transit metastasis. Specimens stained with anti‐PD‐L1 monoclonal antibodies were digitalized to jpg files. To evaluate the intensity of PD‐L1 expression, histograms were used, and the red density (RD) was measured. PD‐1 expression on T cells was analyzed in blood samples from 10 patients who had stage IV melanoma and in 4 samples of in‐transit metastases.

RESULTS:

Twenty‐five patients comprised the “low” PD‐L1 expression group (RD value, <90), and 34 patients comprised the “high” group (RD value, ≥90). Breslow tumor thickness in the high‐expression group was significantly higher than in the low‐expression group. Univariate and multivariate analyses revealed that the overall survival rate of the high‐expression group was significantly lower than that of the low‐expression group. In all patients with stage IV disease who were examined, both CD8‐positive and CD4‐positive T cells had significantly higher PD‐1 expression levels in the peripheral blood. Tumor‐infiltrating T cells expressed high levels of PD‐1, and its expression was elevated further during the clinical course.

CONCLUSIONS:

The current results indicated that there is a correlation between the degree of PD‐L1 expression and the vertical growth of primary tumors in melanoma. Multivariate analysis demonstrated that PD‐L1 expression is an independent prognostic factor for melanoma. Cancer 2010. © 2010 American Cancer Society.
In‐hospital mortality from liver resection for hepatocellular carcinoma
Authors: Simons Jessica P. , Ng Sing Chau , Hill Joshua S. , Shah Shimul A. , Zhou Zheng , Tseng Jennifer F.
Published: February 2010

BACKGROUND:

There is a wide spectrum of disease burden in hepatocellular carcinoma accompanied by several options for surgical management. However, the associated mortality of such procedures is not well defined. Accurate predictions of patients' perioperative risk would be helpful to guide decision making.

METHODS:

The Nationwide Inpatient Sample was queried for data from 1998 to 2005. A cohort of patients who were discharged for hepatic procedures with a diagnosis of primary liver neoplasm was assembled. Procedures were categorized as hepatic lobectomy, wedge resection, or enucleation/ablation. Logistic regression and bootstrap methods were used to create an integer risk score for estimating the risk of in‐hospital mortality using procedure type, patient demographics, comorbidities, and hospital type. A randomly selected sample of 80% of the cohort (n = 2263) was used to create the score with validation conducted in the remaining 20% (n = 571).

RESULTS:

In total, 2834 patient discharges were identified. Overall in‐hospital mortality was 6.52%. Factors that were included in the final model were age, sex, Charlson comorbidity score, procedure type, and teaching hospital status. Integer values were assigned to these characteristics and were used to calculate an additive score. Four clinically relevant score groups were assembled to stratify the risk of in‐hospital mortality, with a 19‐fold gradient of mortality that ranged from 1.5% to 28.3%. In the derivation set, as in the validation set, the score discriminated well with c‐statistics of 0.75 and 0.73, respectively.

CONCLUSIONS:

The current results indicated that an integer‐based risk score can be used to predict in‐hospital mortality after surgery for hepatocellular carcinoma, and it may be useful for preoperative risk stratification and patient counseling. Cancer 2010. © 2010 American Cancer Society.
Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three‐dimensional lung cancer xenograft model
Authors: Xu Xiaoyu , Prestwich Glenn D.
Published: February 2010

BACKGROUND:

We developed an engineered three‐dimensional (3D) tumor xenograft model of nonsmall cell lung cancer (NSCLC) in nude mice, and we used this model to evaluate a dual‐activity inhibitor of lysophosphatidic acid (LPA) biosynthesis and receptor activation.

METHODS:

First, BrP‐LPA, a pan‐antagonist for 4 LPA receptors and inhibitor of the lyosphospholipase D activity of autotaxin, was examined for inhibition of cell migration and cell invasion by human NSCLC A549 cells. Second, A549 cells were encapsulated in 3D in 3 semisynthetic extracellular matrices (ECMs) based on chemically modified glycosaminoglycans, and injected subcutaneously in nude mice. Tumor volume and vascularity were determined as a function of semisynthetic ECMs composition. Third, engineered NSCLC xenografts were formed from A549 cells in either Extracel‐HP or Matrigel, and mice were treated with 4 intraperitoneal injections of 3 mg/kg of BrP‐LPA.

RESULTS:

First, BrP‐LPA inhibited cell migration and invasiveness of A549 cells in vitro. Second, tumor growth and microvessel formation for 3D encapsulated A549 cells in vivo in nude mice increased in the following order: buffer only < Extracel < Extracel‐HP < Extracel‐HP containing growth factorss plus laminin. Third, tumor volumes increased rapidly in both Matrigel and Extracel‐HP encapsulated A549 cells, and tumor growth was markedly inhibited by BrP‐LPA treatment. Finally, tumor vascularization was dramatically reduced in the A549 tumors treated with BrP‐LPA.

CONCLUSIONS:

Engineered A549 lung tumors can be created by 3D encapsulation in an ECM substitute with user controlled composition. The engineered tumors regress and lose vascularity in response to a dual activity inhibitor of the LPA signaling pathway. Cancer 2010. © 2010 American Cancer Society.
Tumor progression by immune evasion in melanoma
Authors: Kashani‐Sabet Mohammed
Published: February 2010

In this editorial, the author reviews evidence supporting the role of the programmed cell death‐1/programmed cell death‐1 ligand 1 (PD‐L1) interaction in the progression of melanoma and the role of PD‐L1 as a potential prognostic factor for melanoma.
Trimodality therapy without a platinum compound for localized carcinoma of the esophagus and gastroesophageal junction
Authors: Ajani Jaffer A. , Correa Arlene M. , Walsh Garrett L. , Komaki Ritsuko , Lee Jeffrey H. , Vaporciyan Ara A. , Rice David C. , Yao James C. , Maru Dipen M. , Hofstetter Wayne L. , Phan Alexandria T. , Swisher Stephen G.
Published: February 2010

BACKGROUND:

The use of platinum‐based chemoradiation for esophageal cancer is routine, but it is unclear which class of cytotoxic are optimum. It was hypothesized that chemoradiotherapy with fluoropyrimidine, taxane, and camptothecin would have preserved or improved efficacy with no compromise in safety.

METHODS:

Patients with histologically confirmed, resectable esophageal carcinoma were eligible. In addition to other tests, a baseline endoscopic ultrasonography (EUS) was obtained. Patients were medically fit and had near–normal organ functions. Patients received docetaxel and irinotecan, plus 5–fluorouracil as induction therapy and then the same cytotoxics with 50.4 grays of radiotherapy followed by an attempted surgery. Pathologic complete response (pathCR) at a rate of ≥20% was the primary endpoint. The pathCR and R0 resection were correlated with overall survival (OS). Safety was documented.

RESULTS:

Fifty‐five patients were enrolled. Seven were women, and the median age was 56 years. Fifty‐three (96%) patients had EUST3, and 41 (75%) had EUSN1 disease. Forty‐three (78%) patients underwent surgery, 20% achieved a pathCR, and 76.4% underwent an R0 resection. The median survival (n = 55 patients) was 43.3 months (range, 19‐75 months). Baseline clinical parameters were not found to be predictive of OS; however, patients with a pathCR (P = .005) and who underwent R0 resection (P ≤ .0001) had an improved OS. There was 1 treatment‐related postsurgical death reported. Grade 3 or 4 toxicity (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) was observed in 62% of patients.

CONCLUSIONS:

The results of the current study documented that this 3‐drug, noncisplatin‐based chemoradiotherapy was feasible, safe, and active but not better than the published cisplatin‐based chemoradiotherapy. A fluoropyrimidine and another cytotoxic (from any class) may be adequate to establish a baseline chemoradiotherapy regimen to combine biologics. Cancer 2010. © 2010 American Cancer Society.
Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study
Authors: Thomas Xavier , Raffoux Emmanuel , Renneville Aline , Pautas Cecile , de Botton Stephane , Terre Christine , Gardin Claude , Hayette Sandrine , Preudhomme Claude , Dombret Herve
Published: February 2010

BACKGROUND:

Priming with granulocytic hematopoietic growth factors may modulate cell cycle kinetics of leukemic cells and render them more susceptible to phase‐specific chemotherapeutic agents. In a first report, we have shown that priming with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) may enhance complete remission (CR) rate and event‐free survival (EFS) in younger adults with acute myeloid leukemia (AML).

METHODS:

In this randomized trial, 259 patients with AML were randomized at baseline to receive or not receive GM‐CSF concurrently with all cycles of chemotherapy. The effects of GM‐CSF on survival were reported herein with a long‐term follow‐up and studied according to distinct biological subgroups defined on cytogenetics and molecular markers.

RESULTS:

The EFS rate was better in the GM‐CSF group (43% vs 34%; P = .04). GM‐CSF did not improve the outcome in patients from good risk subgroups, while patients from poor risk subgroups benefited from GM‐CSF therapy. In this population, the difference in terms of EFS probability was mainly observed in patients with high initial white blood cell count and in those with FLT3‐ITD or MLL rearrangement. When combining these 2 molecular abnormalities for comparison of the effect of GM‐CSF priming, the difference in terms of EFS was highly significant (5‐year EFS, 39% with GM‐CSF vs 8% without GM‐CSF; P = .007).

CONCLUSIONS:

Sensitization of leukemic cells and their progenitors by GM‐CSF appears as a plausible strategy for improving the outcome of patients with newly diagnosed AML. Patients with poor‐prognosis FLT3‐ITD or MLL rearrangement might be a good target population to further investigate priming strategies. Cancer 2010. © 2010 American Cancer Society.
Reduced incidence of infusion‐related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication
Authors: Siena Salvatore , Glynne‐Jones Robert , Adenis Antoine , Thaler Josef , Preusser Peter , Aguilar Enrique Aranda , Aapro Matti S. , Loos Anja H. , Esser Regina , Wilke Hansjochen
Published: February 2010

BACKGROUND:

The multinational MABEL study of 1147 patients with metastatic colorectal cancer (mCRC) who had recently failed an irinotecan‐containing regimen confirmed in a community practice setting the efficacy and safety of cetuximab combined with irinotecan.

METHODS:

This report describes a post hoc analysis of the influence of prophylactic premedication on the incidence of infusion‐related reactions (IRRs) in the MABEL study. The analysis was focused on the subpopulation of patients premedicated with antihistamines either with (n = 700) or without (n = 422) corticosteroids. Stepwise Cox regression modeling was used to examine the explanatory value of the type of premedication on progression‐free survival (PFS) and overall survival (OS) times.

RESULTS:

The incidence of IRRs was lower in the group of patients who received antihistamine plus corticosteroid (9.6%) compared with those who received antihistamine alone (25.6%). A similar trend was seen for grade 3 or 4 IRRs (1.0% vs 4.7%, respectively). The 12‐week PFS rates (61% vs 60%), median PFS (16.1 vs 13.1 weeks) and OS (9.2 vs 9.0 months) times for patients who received, respectively, antihistamines with and without corticosteroids were similar. Cox regression modeling did not identify any impact of type of premedication used (antihistamine with or without corticosteroids) on the efficacy of treatment in relation to PFS or OS.

CONCLUSIONS:

Prophylactically premedicating mCRC patients with both antihistamine and a corticosteroid appeared to reduce the frequency of cetuximab‐associated IRRs. Given that this was a post hoc analysis, caution must be exercised in the interpretation of these data, which require formal confirmation in a randomized study. Cancer 2010. © 2010 American Cancer Society.