bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustainable Management of the Global Carbon Cycle Through Geostorage of Wood
Authors: Kreysa Gerhard
Published: June 2009

Combustion of fossil energy sources has caused the carbon inventory of the atmosphere to increase by more than 200 Gt. It will be almost impossible to prevent it from growing by at least another 400 Gt in the present century. Theoretically, there exists only one single possibility to effect a decline of the resultant increase in atmospheric CO2 concentration: the excess carbon has to be removed from the carbon cycle by transferring it into an environment in which it is safe from oxidation, just as is the case for the deposits of fossil fuels. Only natural photosynthesis offers the possibility of efficiently fixing carbon dioxide from the air and removing it from the carbon cycle through geostorage of the resulting biomass. The present paper shows, in the context of an initial feasibility study, that the use of forests and the geostorage of wood in an environment corresponding to lignite deposits represents the ecologically most sensible and economical variant of removal of carbon from the carbon cycle and, thereby, reclamation of the atmosphere.
Validation and ecosystem applications of the EDEN water‐surface model for the Florida Everglades
Authors: Liu Zhongwei , Volin John C. , Dianne Owen V. , Pearlstine Leonard G. , Allen Jenny R. , Mazzotti Frank J. , Higer Aaron L.
Published: June 2009

The Everglades Depth Estimation Network (EDEN) is an integrated network of real‐time water‐level monitoring, ground‐elevation modelling, and water‐surface modelling that provides scientists and water managers with current (2000‐present), on‐line water‐level and water‐depth information for the freshwater Everglades. Continuous daily spatial interpolations of surface water‐level gage data from the EDEN water‐surface model are presented on grid with 400‐m spacing. The direct model output is continuous daily surface‐water level, and other hydrologic data such as water depth and hydroperiod can be derived together with ground digital elevation models.

This paper validated the spatially continuous EDEN water‐surface model for the Everglades, Florida by using an independent field‐measured dataset. Three model applications were also demonstrated: to estimate site‐specific ground elevation, to create water‐depth time series for tree islands, and to generate contiguous water coverage areas. We found that there were no statistically significant differences between model‐predicted and field‐observed water‐level data in central Everglades (p = 0·51). Over 95% of the predicted‐water levels matched observed‐water levels within the range of ± 5 cm. Overall, the model is reliable by a root mean square error (RMSE) of 3·3 cm.

The accurate, high‐resolution hydrological data, generated over broad spatial and temporal scales by the EDEN water‐surface model, provides a previously missing key to understanding the habitat requirements and linkages among native and invasive populations, including fish, wildlife, wading birds, and plants. The EDEN model is a powerful tool that could be adapted for other ecosystem‐scale restoration and management programs worldwide. Copyright © 2009 John Wiley & Sons, Ltd.
The TLR‐independent DNA recognition pathway in murine macrophages: Ligand features and molecular signature
Authors: Karayel Evren , Bürckstümmer Tilmann , Bilban Martin , Dürnberger Gerhard , Weitzer Stefan , Martinez Javier , Superti‐Furga Giulio
Published: June 2009

Recognition of foreign DNA by cytosolic innate immune receptors triggers the production of IFN‐β. However, it is unclear whether different types of DNA ligands are recognized by similar receptors and whether the resulting response is distinct from the endosomal TLR response. To address these questions, we compared the two most commonly used types of DNA ligands (IFN‐stimulatory DNA (ISD) and poly(dAdT)) and assessed the minimal structural requirements for stimulatory capacity in RAW264.7 cells. Gene expression signatures and competition experiments suggest that ISD and poly(dAdT) are qualitatively indistinguishable and differ from the CpG‐containing oligonucleotides triggering the TLR9 pathway. Structure – activity relationship analyses revealed that a minimal length of two helical turns is sufficient for ISD‐mediated IFN‐β induction, while phosphorylation at the 5′‐end is dispensable. Altogether, our data suggest that, in murine macrophages, only one major cytosolic DNA recognition pathway is operational.
Relaxometric, Thermodynamic and Kinetic Studies of Lanthanide(III) Complexes of DO3A‐Based Propylphosphonates
Authors: Mamedov Ilgar , Táborský Petr , Lubal Přemysl , Laurent Sophie , Vander Elst Luce , Mayer Hermann A. , Logothetis Nikos K. , Angelovski Goran
Published: June 2009

Two DO3A‐based ligands appended with the propylphosphonate side arm and their Ln3+ complexes were investigated. Proton relaxometric in vitro studies at 20 MHz and 60 MHz and 37 °C of the Gd3+ complex containing free acid exhibited relative changes of up to 56 % in r1 relaxivity when the pH of the medium was changed from 4 to 7. This change is explained by the decrease in the number of coordinated water molecules from two to one. Temperature‐dependent relaxivity and NMRD profiles of Gd3+ complexes showed a fast water exchange and a slightly increased rotational correlation time, which is characteristic of phosphonate‐containing compounds. Thermodynamic and kinetic studies of the Gd3+ and Eu3+ complexes were performed by means of potentiometry and luminescence spectroscopy. The results indicate that the thermodynamic stability and kinetic inertness of these complexes are sufficient for their in vivo application. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Electroanalysis of Dopamine at RuO2 Modified Vertically Aligned Carbon Nanotube Electrode
Authors: Jiang Liao‐Chuan , Zhang Wei‐De
Published: June 2009

Electrochemical behavior of dopamine at the RuO2‐modified vertically aligned carbon nanotubes electrode was investigated by cyclic voltammetry, differential pulse voltammetry and chronoamperometry. The RuO2‐modified carbon nanotube electrode showed higher electrocatalytic activity towards the oxidation of dopamine than the MWNTs electrode in 0.10 M phosphate buffer solution. At an applied potential of +0.4 V, the RuO2/MWNTs electrode exhibited a wide detection range up to 3.6×10−3 M with detection limit of 6.0×10−8 M (signal/noise=3) for dopamine determination. Meanwhile, the optimized sensor for dopamine displayed a sensitivity of 83.8 μA mM−1 and response time of 5 s with addition of 0.20 mM dopamine. In addition, DPV experiment revealed that interfering species such as ascorbic acid and uric acid could be effectively avoided. The RuO2/MWNTs electrode presents stable, highly sensitive, favorable selectivity and fast amperometric response of dopamine.
Concordance analysis of an in vitro micronucleus screening assay and the regulatory chromosome aberration assay using pharmaceutical drug candidates
Authors: Homiski Michael L. , Muehlbauer Paula A. , Dobo Krista L. , Schuler Maik J. , Aubrecht Jiri
Published: June 2009

The in vitro micronucleus assay is under consideration by regulatory agencies as a suitable alternative to the in vitro chromosome aberration (CA) assay. At Pfizer, we utilized a non‐Good Laboratory practices cytokinesis‐block in vitro micronucleus (CBMN) assay in CHO cells as a screen to predict the regulatory outcome of the human lymphocyte CA assay, and we have retrospectively analyzed a highly select set of 112 internal drug candidates to measure concordance. Overall, our exploratory CBMN correctly classified 97 of 112 (86.6%) compounds in the CA assay. Specificity was high with 87 of 92 (94.6%) CA negative compounds correctly classified by CBMN. Sensitivity was low at 50% with 10 of 20 CA positive compounds correctly classified by CBMN; this may be attributed to the low number of CA positives in the select set. In an attempt to improve sensitivity, we increased the number of CA positives by combining our internal set with an industrial data set previously published (Miller B et al. 1997: Mutat Res 392:45–59). When combined, concordance was 86.7% (143/165), specificity was 91.2% (114/125), and sensitivity increased to 72.5% (29/40). Because cytotoxicity is considered a confounding factor of in vitro test systems, we also examined, within the Pfizer data set, the influence of cytotoxicity in the CBMN assay, and the results indicated that seemingly low (<50%) or excessively high (>70%) levels of cytotoxicity did not significantly alter predicted CA outcome. These collective analyses contribute to growing evidence that the CBMN assay is a suitable regulatory option in the standard battery of genetic toxicology tests. Environ. Mol. Mutagen., 2010. © 2009 Wiley‐Liss, Inc.
Time domain finite element method analysis of multi‐conductor transmission lines
Authors: Lucic Rino , Juric‐Grgic Ivica , Kurtovic Mate
Published: June 2009

This paper presents the finite element time domain (FETD) model for numerical solution of the multi‐conductor transmission line (MTL) problem. Based on the finite element method (FEM) and the generalised trapezoidal rule, a novel numerical procedure for solution of a system of the telegraph equations is presented. The method presented here is an extension of the method proposed in previous research, where electromagnetic transients in single networks with linear lossy transmission lines have been modelled. In order to show the principles of this numerical method, for sake of simplicity, we restrict the FETD model of the MTL problem only to the low frequency regime. The proposed numerical method has been tested and compared to the analytical and FDTD solutions, and excellent correlation has been demonstrated. Copyright © 2009 John Wiley & Sons, Ltd.
Thermogravimetric and Electrocatalytic Study of Carbon Deposition of Ag‐doped Ni/YSZ Electrodes under Internal CH4 Steam Reforming Conditions
Authors: Gavrielatos I. , Montinaro D. , Orfanidi A. , Neophytides S. G.
Published: June 2009

The effect of Ag addition on Ni/YSZ Carbon tolerance was studied by means of thermogravimetric, catalytic and electrocatalytic experiments. Ni/YSZ activity towards C deposition can be significantly decreased by adding 1 to 5 at.‐% (atomic ratio) Ag with respect to Ni. It was found that the activation energy of CH4 dissociation was increased from 61 kJ mol–1 on Ni/YSZ to 137 kJ mol–1 on Ni(5Ag)/YSZ. The electrode was significantly improved with regard to its C tolerance, even at a methane to water ratio as high as 4.35, at temperatures ranging between 923–1,023 K. At higher temperature most probably due to Ag evaporation from Ag‐doped Ni/YSZ surface, a severe anode catalytic and electrocatalytic activity degradation was observed.
The effect of presentation paradigm on syntactic processing: An event‐related fMRI study
Authors: Lee Donghoon , Newman Sharlene D.
Published: June 2009

An event‐related fMRI study was conducted to investigate the effect of two different sentence presentation paradigms—rapid serial visual presentation (RSVP) and whole sentence presentation—on syntactic processing. During scanning, sentences were presented using one of the two presentation paradigms and were followed by a short delay and a probe to verify sentence comprehension. The delay was included in an attempt to separate sentence‐related activity from probe‐related activity. The behavioral data showed a main effect of syntactic complexity for reaction time and accuracy, and accuracy revealed an interaction between complexity and the presentation paradigm employed—RSVP produced many more errors for syntactically complex sentences than did whole sentence presentation. The imaging data revealed a syntactic complexity effect during the sentence phase in left BA 44 and during the probe phase in left BA 44 and the left posterior MTG. In addition, timecourse analysis revealed that these two regions also showed an interaction between complexity and presentation paradigm such that there was no complexity effect during RSVP but a significant effect during whole sentence presentation. In addition to finding that these two presentation paradigms differentially affected syntactic processing, there were main effects within the visual pathway (V1/V2 vs. V5) and the hippocampus that revealed significant differences in activation between the paradigms. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.
The value of informal care–a further investigation of the feasibility of contingent valuation in informal caregivers
Authors: de Meijer Claudine , Brouwer Werner , Koopmanschap Marc , van den Berg Bernard , van Exel Job
Published: June 2009

Including informal care in economic evaluations is increasingly advocated but problematic. We investigated three well‐known concerns regarding contingent valuation (CV): (1) the item non‐response of CV values, (2) the sensitivity of CV values to the individual circumstances of caring, and (3) the choice of valuation method by comparing willingness‐to‐pay (WTP) and willingness‐to‐accept (WTA) values for a hypothetical marginal change in hours of informal care currently provided.

The study sample consisted of 1453 caregivers and 787 care recipients. Of the caregivers, 603 caregivers (41.5%) provided both WTP and WTA values, 983 (67.7%) provided at least one. Determinants of non‐response were dependent on the valuation method; primary determinants were education and satisfaction with amount of informal care provided. Caregivers' mean WTP (WTA) for reducing (increasing) informal care by 1 h was €9.13 (10.52). Care recipients' mean WTA (WTP) for reducing (increasing) informal care by 1 h was €8.88 (€6.85). Values were associated with a variety of characteristics of the caregiving situation; explanatory variables differed between WTP and WTA valuations. The differences between WTP and WTA valuations were small.

Based on sensitivity CV appears to be a useful method to value informal care for use in economic evalations, non‐response, however, remains a matter of concern. Copyright © 2009 John Wiley & Sons, Ltd.
Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma #
Authors: Liu Ling Xiao , Lee Nikki P. , Chan Vivian W. , Xue Wen , Zender Lars , Zhang Chunsheng , Mao Mao , Dai Hongyue , Wang Xiao Lin , Xu Michelle Z. , Lee Terence K. , Ng Irene O. , Chen Yangchao , Kung Hsiang-fu , Lowe Scott W. , Poon Ronnie T.P. , Wang Jian Hua , Luk John M.
Published: June 2009

Hepatocellular carcinoma (HCC) is a lethal malignancy for which there are no effective therapies. To develop rational therapeutic approaches for treating this disease, we are performing proof-of-principle studies targeting molecules crucial for the development of HCC. Here, we show that cadherin-17 (CDH17) adhesion molecule is up-regulated in human liver cancers and can transform premalignant liver progenitor cells to produce liver carcinomas in mice. RNA interference–mediated knockdown of CDH17 inhibited proliferation of both primary and highly metastatic HCC cell lines in vitro and in vivo. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt signaling, because growth inhibition and cell death were accompanied by relocalization of β-catenin to the cytoplasm and a concomitant reduction in cyclin D1 and an increase in retinoblastoma. Conclusion: Our results identify CDH17 as a novel oncogene in HCC and suggest that CDH17 is a biomarker and attractive therapeutic target for this aggressive malignancy. (Hepatology 2009.)
The velocity‐related firing property of hippocampal place cells is dependent on self‐movement
Authors: Lu Xiaodong , Bilkey David K.
Published: June 2009

Hippocampal place cells have the interesting property of increasing their firing rate when a freely moving animal increases its running speed through the cell's place field. A previous study from this laboratory showed that this movement‐related firing property is disrupted by lesions of the perirhinal cortex (PrhC). It is possible, therefore, that PrhC lesions disrupt speed‐modulated sensory information such as optic flow or motor efferent or proprioceptive input that might be available to the hippocampus from the PrhC. To test this hypothesis, rats with single unit recording electrodes implanted in the CA1 region of the hippocampus received different levels of optic flow stimulation in both a freely moving and a passive movement condition. The effects of PrhC lesions were also tested. Although increasing the amount of optic flow information available decreased place field size, it had no discernable effect on the movement‐firing rate relationship in the place cells of control animals run in the free‐movement condition. In lesioned animals the relationship was disrupted, replicating our previous results. In the passive movement condition many place cells stopped firing. In those cells that did fire, however, the movement‐firing rate relationship was no longer evident. These data indicate that the movement‐firing rate relationship is not driven by vestibular or optic flow cues, but rather depends on either motor efferent or proprioceptive input, or that it results from some other form of input that may be modulated by self‐motion, such as from the vibrissae. © 2009 Wiley‐Liss, Inc.
β‐Cyclodextrin‐Promoted Addition of Benzeneselenol to Conjugated Alkenes in Water
Authors: Srinivas Boga , Kumar Vydyula Pavan , Sridhar Regati , Reddy Vutukuri Prakash , Nageswar Yadavalli Venkata Durga , Rao Kakulapati Rama
Published: June 2009

magnified image

For the first time, a mild and efficient procedure was developed for the conjugate addition of α,β‐unsaturated compounds to benzeneselenol providing β‐(phenylseleno)‐substituted compounds (Scheme). The reaction was promoted by β‐cyclodextrin, proceeded in H2O at room temperature, and gave impressive yields (Table). The mechanism of the addition reaction, taking place within the cyclodextrin cavity, was supported by the analysis of the guests and host signals in the 1H‐NMR spectra (Fig. 1).
Chemical Constituents from Clerodendrum bungei and Their Cytotoxic Activities
Authors: Liu Shan‐Shan , Zhou Tong , Zhang Shu‐Wei , Xuan Li‐Jiang
Published: June 2009

magnified image

A new phenylethanoid glycoside, two new cyclohexylethanoids, one new phenolic glycoside, and a new farnesane‐type sesquiterpenoid, namely 2‐phenylethyl 3‐O‐(6‐deoxy‐α‐L‐mannopyranosyl)‐β‐D‐glucopyranoside (1), 6″‐O‐[(E)‐caffeoyl] rengyoside B (2), clerodenone A (3), 2‐({6‐O‐[(4‐hydroxy‐3‐methoxyphenyl)carbonyl]‐β‐D‐glucopyranosyl}oxy)‐2‐methylbutanoic acid (4), 2‐{(2S,5R)‐5‐[(1E)‐4‐hydroxy‐4‐methylhexa‐1,5‐dien‐1‐yl]‐5‐methyltetrahydrofuran‐2‐yl}propan‐2‐yl β‐D‐glucopyranoside (5), together with 16 known compounds, were isolated from the roots of Clerodendrum bungei. All structures were elucidated by spectroscopic methods. The new compounds showed modest in vitro inhibition of the proliferation of the HeLa human cervical carcinoma cell line (CCL‐2), with IC50 values in the range of 3.5–8.7 μM, adriamycin being used as positive control, with an IC50 value of 0.026±0.001 μM.
Donor–Acceptor‐Substituted Oligo(1,4‐phenylene)s
Authors: Kim Soungkyoo , Oehlhof Annette , Beile Bernhard , Meier Herbert
Published: June 2009

magnified image

Oligo(para‐phenylene)s (DAOPPs) 2a–2d (n=1–4) with terminal donor–acceptor substitution (D=C6H13O, A=NO2) were prepared by applying Suzuki cross‐couplings for chain extension and end capping. The push–pull effect induces short‐reaching polarizations of the chain consisting of conjugated but twisted benzene rings, which was studied by NMR measurements. Electron excitation from the ground‐state S0 to the more planar first‐excited singlet state S1 is combined with a strong intramolecular charge transfer (ICT), which is documented by the red shift of the long‐wavelength absorption (charge‐transfer band) for short chains (one or two repeat units, n = 1 or 2). The opposite influence of decreasing ICT and increasing conjugation length leads to a bathochromic series (λmax(n+1)≥λmax(n)) with a fast saturation of λmax (n). The effective conjugation length nECL=4 corresponds to λ∞ 349 nm. These results are discussed in the context of other oligo(para‐phenylene)s (OPPs).
Synthesis, Structural Diversity, and Ligand‐Transfer Potential of (Carbene)copper(I) Complexes
Authors: Venkatachalam Galmari , Heckenroth Marion , Neels Antonia , Albrecht Martin
Published: June 2009

magnified image

Copper(I) complexes comprising different N‐heterocyclic carbene ligands were prepared via in situ deprotonation and metallation. Depending on the wingtip groups on the carbene ligand (alkyl vs. aryl, chelating or monodentate), a variety of different structural motifs were identified, such as a trigonal planar geometry (alkyl wingtips) and an unprecedented see‐saw‐type structure (pyridinyl wingtip groups). While aryl wingtip groups increase the stability of the complexes, alkyl substituents induce rapid demetallation in the presence of moisture. The reactivity of these complexes was used to establish a carbene‐transfer protocol, which is illustrated by the formation of new cyclic thiourea compounds (transfer to sulfur) and new (carbene)ruthenium(II) complexes (transfer to ruthenium). This suggests that (carbene)copper(I) complexes could become valuable alternatives to (carbene)silver(I) complexes for synthesizing (carbene)metal systems via transmetallation.
First Authentication of Kostanecki's Triketone and Multimolecular Reaction of Aromatic Aldehydes with Acetophenone
Authors: Shan Zixing , Hu Xiaoyun , Hu Lin , Peng Xitian
Published: June 2009

magnified image

A double‐component, multimolecular reaction between acetophenone and aromatic aldehydes was achieved under catalysis by the solid‐base mixture NaOH/K2CO3, and Kostanecki's triketone, supposed to exist for more than 110 years, was successfully separated for the first time as an accompaniment of a pentane‐1,5‐dione or a 1,2,3,4,5‐pentasubstituted cyclohexanol (Scheme 1) and authenticated by spectroscopic and single‐crystal X‐ray diffraction analysis. Thus, the multimolecular‐reaction mechanism of the formation of 1,2,3,4,5‐pentasubstituted cyclohexanols from 1‐phenylalkan‐1‐ones and aromatic aldehydes was fully validated based on the results (Scheme 3).
New Cembranoids from the Hainan Soft Coral Sarcophyton glaucum
Authors: Yao Li‐Gong , Liu Hai‐Li , Guo Yue‐Wei , Mollo Ernesto
Published: June 2009

magnified image

From the soft bodied coral Sarcophyton glaucum collected from the South China Sea two new cembranoids, (7R,8S)‐dihydroxydeepoxy‐ent‐sarcophine (1) and secosarcophinolide (2), together with one known related compound, ent‐sarcophine (3), were isolated. The structures of the new compounds were determined by extensive analysis of their spectroscopic data and chemical correlation. The absolute configuration of 1 was determined by chemical correlation with 3 and by comparison of its optical rotation value with that of its corresponding enantiomer, (7S,8R)‐dihydroxydeepoxysarcophine (5).
Proline‐Containing Dipeptides from a Marine Sponge of a Callyspongia Species
Authors: Yang Bin , Dong Junde , Zhou Xuefeng , Yang Xianwen , Lee Kyung Jin , Wang Lishu , Zhang Si , Liu Yonghong
Published: June 2009

magnified image

A detailed analysis of the chemical constituents of a marine sponge of Callyspongia sp. was performed. A new proline‐containing dipeptide, callyspongidipeptide A (cyclo‐((S)‐Pro‐8‐hydroxy‐(R)‐Ile); 1) along with cyclo‐((S)‐Pro‐(R)‐Leu) (3) and seco‐((S)‐Pro‐(R)‐Val) (2) were isolated. The structures were determined on the basis of NMR and MS analysis, and the absolute configuration was determined by comparison of the optical rotation with known compounds.
Oligonucleotide Analogues with Integrated Bases and Backbone. Part 20
Authors: Peifer Manuel , De Giacomo Fabio , Schandl Martin , Vasella Andrea
Published: June 2009

magnified image

Hydrazide‐ and amide‐linked oligonucleoside analogues with integrated bases and backbone were designed to allow for a rapid synthesis of long and water‐soluble oligomers. The uracil‐, cytosine‐, and adenine‐derived hydrazide building blocks 13–15 were synthesized by nucleophilic substitution with the hydrazine 23 of the halides 19, 28, and 34, derived from the alcohols 18, 27, and 33, respectively, while the uracil‐, cytosine‐, and adenine‐derived amide building blocks 45–47 were synthesized by a Curtius degradation of the carboxylic acids 51, 56, and 61. These acids were obtained by Wittig reaction of the aldehydes 49, 53, and 58. The guanine‐derived monomers 44 and 48 were synthesized by reductive cyclisation of the nitroso amides 38 and 63, respectively, resulting from acylation of the known 2,6‐diamino‐4‐(benzyloxy)‐5‐nitrosopyrimidine (37).
Melatonin as a potential therapeutic agent in psychiatric illness
Authors: Maldonado Maria D. , Reiter Russel J. , Pérez‐San‐Gregorio Maria A.
Published: June 2009

The aim of this review was to summarize the potential use of melatonin in the treatment of mental disorders, specifically bipolar disorders, depression, and schizophrenia. To date, melatonin has been most commonly used in psychiatry because of its hypnotic, rhythm resynchronizing, and antioxidant actions. Here, we examine other properties of the melatonin including its anti‐inflammatory, antinociceptive, anxiolytic, and drug detoxification actions as well as its protective effects against neural loss. The brain is an intricate sensory and motor organ which receives information from both the external and internal environments. It transduces information into complex chemical and electrical signals which are transmitted throughout the central nervous system (CNS) and the organism. The pathogenesis of mental disorders remains ambiguous and neuroinflammation has been proposed as a causative agent. We consider the potential contributions of melatonin as therapeutic agent in CNS and during neuroinflammation in mental disorders. Copyright © 2009 John Wiley & Sons, Ltd.
Melperone, an aytpical antipsychotic drug with clozapine‐like effect on plasma prolactin: contrast with typical neuroleptics
Authors: Bobo William V. , Jayathilake Karuna , Lee Myung A. , Meltzer Herbert Y.
Published: June 2009

Objective

To evaluate the effect of melperone, a butyrophenone with atypical antipsychotic properties, on plasma prolactin (PRL) concentrations compared with clozapine and typical neuroleptics.

Methods

Analysis of pre‐ and post‐treatment PRL levels collected prospectively per protocol in a non‐randomized study of 26 melperone‐, 76 clozapine‐, and 66 neuroleptic‐treated patients with schizophrenia or schizoaffective disorder. Cross‐sectional analysis of a larger sample of patients with PRL data was also performed.

Results

For males, post‐treatment PRL levels were significantly higher in the typical neuroleptic group compared with the melperone (p = 0.0001) and clozapine (p = 0.0001) groups, with no significant difference between clozapine and melperone. For females, post‐treatment PRL levels were significantly higher in the melperone group as compared to the clozapine group (p = 0.004). There were too few typical neuroleptic‐treated females to permit analysis of this sample. However, the cross‐sectional analysis of PRL data confirmed the results for melperone‐ and clozapine‐treated females, and showed higher PRL levels in typical neuroleptic‐treated females as compared with those who received melperone and clozapine.

Conclusion

Melperone did not significantly increase PRL levels in male patients. However, melperone and typical neuroleptics caused increase in PRL levels in females. Further study of melperone's effects on PRL concentration is warranted. Copyright © 2009 John Wiley & Sons, Ltd.
A safety and tolerability laboratory study of the combination of aripiprazole and topiramate in volunteers who drink alcohol
Authors: Kenna George A. , Leggio Lorenzo , Swift Robert M.
Published: June 2009

Objective

There are no reports examining the safety of taking both topiramate and aripiprazole together with alcohol. The ultimate aim for this research is to determine whether this combination is safe and is superior to either drug taken alone in reducing alcohol use in alcohol dependent patients.

Method

This was an open‐label trial. Thirteen heavy drinking participants not seeking treatment for alcoholism were randomized. Participants were titrated up to 300 mg of topiramate and 30 mg of aripiprazole a day over 35 days. Participants reported adverse events (AEs) daily alcohol use and participated in an alcohol challenge session (ACS).

Results

The eight participants who completed the study achieved the maximum doses of drugs. The AEs of the drugs would suggest that the AEs profile is broader but not additive. Alcohol use from the 28 days before screening to the seven days before the ACS was reduced (p = 0.08).

Conclusion

There was no evidence that AEs of aripiprazole and topiramate are additive and can, therefore, be administered safely together with a modest amount of alcohol. There was also a trend for a reduction of alcohol use by participants. This finding has implications for further investigation of this combination of drugs for alcohol dependence. Copyright © 2009 John Wiley & Sons, Ltd.
Genetic variation and circulating levels of IGF‐I and IGFBP‐3 in relation to risk of proliferative benign breast disease
Authors: Su Xuefen , Colditz Graham A. , Willett Walter C. , Collins Laura C. , Schnitt Stuart J. , Connolly James L. , Pollak Michael N. , Rosner Bernard , Tamimi Rulla M.
Published: June 2009

Insulin‐like growth factor‐I (IGF‐I) and its major binding protein IGFBP‐3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF‐I and IGFBP‐3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses' Health Study II (NHSII). Participants were 359 pathology‐confirmed proliferative BBD cases and 359 matched controls. Circulating IGF‐I and IGFBP‐3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF‐I, IGFBP‐1, and IGFBP‐3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF‐I levels were not associated with proliferative BBD risk. Higher circulating IGFBP‐3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) [95% confidence interval (CI)], 1.70 (1.06–2.72); p‐trend = 0.03). The minor alleles of 2 IGFBP‐3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild‐type OR (95% CI): rs3110697: 0.6 (0.4–0.9), p‐trend = 0.02; rs2132570: 0.2 (0.1–0.6), p‐trend = 0.02). Three other IGFBP‐3 SNPs (rs2854744, rs2960436 and rs2854746) were significantly associated with circulating IGFBP‐3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP‐3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP‐3 may play a role in the early stage of breast carcinogenesis.
Metabolic regulation and redox activity as mechanisms for angioprevention by dietary phytochemicals
Authors: Tosetti Francesca , Noonan Douglas M. , Albini Adriana
Published: June 2009

The existence of active principles in numerous foods and beverages has been recognized by traditional medicines worldwide after centuries of empirical trial. Epidemiological studies support the concepts linking diet to survival, particularly in the incidence rates of specific cancers. Molecular studies have provided evidence that a wide range of food‐derived phytochemicals and other diet‐associated compounds or their synthetic derivatives represent a cornucopia of potential new compounds for prevention and treatment of chronic or acute diseases. Many have entered clinical practice or are under clinical testing. A remarkable property shared by several phytochemicals is the capacity to restrain inflammation and angiogenesis, two complex physiologic processes kept under control by strict rules, which can backfire in cancer and in pathologic conditions such as metabolic, cardiovascular and neurological disorders. We termed this concept “angioprevention”. Here, we discuss recent findings on the metabolic effects of several phytochemicals with anticancer properties. The different molecular targets shared by these compounds seem to converge on crosstalking signaling networks involved in controlling energy metabolism through a redox‐regulated code. The redox imbalance produced in the tissue microenvironment elicits an adaptive response that seems to provide cytoprotective effects potentially beneficial in cardiovascular and neurological disorders or energy balancing effects in metabolic disorders. However, in transformed and overt tumor cells, this redox imbalance favors cell death while curbing tumor inflammation and angiogenesis, thus engaging an overall antitumor response. These concepts provide a broader framework for pharmacological application of phytochemical‐derived drugs against cancer. © 2009 UICC
Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer
Authors: Udler Miriam S. , Azzato Elizabeth M. , Healey Catherine S. , Ahmed Shahana , Pooley Karen A. , Greenberg David , Shah Mitul , Teschendorff Andrew E. , Caldas Carlos , Dunning Alison M. , Ostrander Elaine A. , Caporaso Neil E. , Easton Douglas , Pharoah Paul D.
Published: June 2009

Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population‐based case–control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69–0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted. © 2009 UICC
Housekeeping genes in prostate tumorigenesis
Authors: Byun Jinyoung , Logothetis Christopher J. , Gorlov Ivan P.
Published: June 2009

Housekeeping (HK) genes are involved in basic cellular functions and tend to be constitutively expressed across various tissues and conditions. A number of studies have analyzed the value of HK genes as an internal standard for assessing gene expression, but the role of HK genes in cancer development has never been specifically addressed. In this study, we sought to evaluate the expression of HK genes during prostate tumorigenesis. We performed a meta‐analysis of gene expression during the transition from normal prostate (NP) to localized prostate cancer (LPC) (i.e., NP > LPC) and from localized to metastatic prostate cancer (MPC) (i.e., LPC > MPC). We found that HK genes are more likely to be differentially expressed during prostate tumorigenesis than is the average gene in the human genome, suggesting that prostate tumorigenesis is driven by modulation of the expression of HK genes. Cell‐cycle genes and proliferation markers were up‐regulated in both NP > LPC and LPC > MPC transitions. We also found that the genes encoding ribosomal proteins were up‐regulated in the NP > LPC and down‐regulated in the LPC > MPC transition. The expression of heat shock proteins was up‐regulated during the LPC > MPC transition, suggesting that in its advanced stages, prostate tumor is under cellular stress. The results of these analyses suggest that during prostate tumorigenesis, there is a period when the tumor is under cellular stress and, therefore, may be the most vulnerable and responsive to treatment. © 2009 UICC
The mechanisms underlying MMR deficiency in immunodeficiency‐related non‐Hodgkin lymphomas are different from those in other sporadic microsatellite instable neoplasms
Authors: Borie Claire , Colas Chrystelle , Dartigues Peggy , Lazure Thierry , Rince Patricia , Buhard Olivier , Folliot Patrick , Chalastanis Alexandra , Muleris Martine , Hamelin Richard , Mercier Dominique , Oliveira Carla , Seruca Raquel , Chadburn Amy , Leblond Véronique , Barete Stéphane , Gaïdano Gianluca , Martin Antoine , Gaulard Philippe , Fléjou1 Jean‐François , Raphael Martine , Duval Alex
Published: June 2009

The spectrum of tumors showing microsatellite instability (MSI) has recently been enlarged to sporadic neoplasms whose incidence is favored in the context of chronic immunosuppression. We investigated the biological, therapeutic and clinical features associated with MSI in immunodeficiency‐related non‐Hodgkin lymphomas (ID‐RL). MSI screening was performed in 275 ID‐RL. MSI ID‐RL were further analyzed for MMR gene expression and for BRAF/KRAS mutations since these genes are frequently altered in MSI cancers. We also assessed the expression of O6‐methylguanine‐DNA methyltransferase (MGMT), an enzyme whose inactivation has been reported in lymphomas and may help in the selection of MMR deficient clones. Unlike other sporadic MSI neoplasms, MSI ID‐RL (N = 17) presented with heterogeneous MMR defects and no MLH1 promoter methylation. About one third of these tumors presented with normal expression of MLH1, MSH2, MSH6 and PMS2. They accumulated BRAF activating mutations (33%). Unlike other ID‐RL, MSI ID‐RL were primarily EBV‐negative NHL of T‐cell origin, and arose after long‐term immunosuppression in patients who received azathioprine as part of their immunosuppressive regimen (p = 0.05) and/or who exhibited methylation‐induced loss of expression of MGMT in tumor cells (p= 0.02). Overall, these results highlight that, in the context of deficient immune status, some MSI neoplasms arise through alternative mechanism when compared to other sporadic MSI neoplasms. They give the exact way how to make the diagnosis of MSI in these tumors and may help to define biological and clinicalrisk factors associated with their emergence in such a clinicalcontext. © 2009 UICC
N‐glycosylation status of β‐haptoglobin in sera of patients with colon cancer, chronic inflammatory diseases and normal subjects
Authors: Park Seung‐Yeol , Yoon Seon‐Joo , Jeong Yeon‐Tae , Kim Jin‐Man , Kim Ji‐Yeon , Bernert Bradford , Ullman Thomas , Itzkowitz Steven H. , Kim Jung‐Hoe , Hakomori Sen‐itiroh
Published: June 2009

N‐glycosylation status of purified β‐haptoglobin from sera of 17 patients, and from sera of 14 healthy volunteer subjects, was compared by blotting with various lectins and antibodies. Patients in this study were diagnosed as having colon cancer through histological examination of each tumor tissue by biopsy. Blotting index of serum β‐haptoglobin with Aleuria aurantia lectin (AAL) was clearly higher for cancer patients than for healthy subjects. No such distinction was observed for blotting with three other lectins and two monoclonal antibodies. To determine tumor‐associated reactivity of AAL binding as compared to inflammatory processes in colonic tissues, β‐haptoglobin separated from sera of 5 patients with Crohn's disease (CD), and 4 patients with ulcerative colitis (UC), was studied. All these cases, except one case of UC, showed AAL index lower than that in cancer cases, similarly to healthy subjects. The higher AAL binding of β‐haptoglobin in colon cancer patients than in healthy subjects appeared to be due to α‐L‐fucosyl residue, since it was eliminated by bovine kidney α‐fucosidase treatment. N‐linked glycans of serum haptoglobin from colon cancer patients vs. healthy subjects were released by N‐glycanase, fluorescence‐labeled, and subjected to normal‐phase high performance liquid chromatography (NP‐HPLC). Glycan structures were determined based on glucose unit (GU) values and their changes upon sequential treatment with various exoglycosidases. Glycosyl sequences and their branching status of glycans from 14 cases of serum β‐haptoglobin were characterized. The identified glycans were sialylated or nonsialylated, bi‐antennary or tri‐antennary structures, with or without terminal fucosylation.
Methylation of cystatin M promoter is associated with unfavorable prognosis in operable breast cancer
Authors: Kioulafa Magdalini , Balkouranidou Ioanna , Sotiropoulou Georgia , Kaklamanis Loukas , Mavroudis Dimitris , Georgoulias Vassilis , Lianidou Evi S.
Published: June 2009

The methylation status of cystatin M (CST6) gene in breast tumors was investigated and its prognostic significance as a novel breast cancer biomarker was evaluated. Using methylation‐specific PCR (MSP), CST6 promoter methylation was examined in 134 formalin fixed paraffin‐embedded tissues (FFPEs): 10 pairs of breast tumors and their surrounding normal tissues, 10 breast fibroadenomas, 11 normal breast tissues and 93 breast tumors. Methylation of CST6 promoter was observed in 2/21 (9.5%) noncancerous breast tissues, 1/10 (10%) benign breast tumors (fibroadenomas) and 52 (55.9%) operable breast cancer tumor samples. CST6 was rarely methylated in the normal tissue surrounding the tumor (10%). During the follow‐up period, 24 (25.8%) patients relapsed and 19 (20.4%) died. CST6 methylation was detected in 19 (79.2%) of patients who relapsed and in 15 (78.9%) of patients who died. Disease‐free‐interval (DFI) and overall survival (OS) were significantly associated with CST6 promoter methylation (p = 0.004 and p = 0.001 respectively). Multivariate analysis revealed that CST6 methylation is an independent prognostic factor for DFI (HR = 3.484; 95% CI: 1.155–10.511; p = 0.027). and OS (HR = 9.190; 95% CI: 1.989–42.454; p = 0.004). CST6 promoter methylation status in tumor cells seems to provide important prognostic information in operable breast cancer and merits to be further evaluated and validated in a larger cohort of patients. © 2009 UICC
The YSNSG cyclopeptide derived from tumstatin inhibits tumor angiogenesis by down‐regulating endothelial cell migration
Authors: Thevenard Jessica , Ramont Laurent , Devy Jérome , Brassart Bertrand , Dupont‐Deshorgue Aurélie , Floquet Nicolas , Schneider Laurence , Ouchani Farid , Terryn Christine , Maquart François‐Xavier , Monboisse Jean‐Claude , Brassart‐Pasco Sylvie
Published: June 2009

We previously demonstrated that the CNYYSNS peptide derived from tumstatin inhibited in vivo tumor progression. The YSNS motif formed a β‐turn crucial for biological activity. More recently, a YSNSG cyclopeptide with a constrained β‐turn on the YSNS residues was designed. Intraperitoneal administration of the YSNSG cyclopeptide inhibited in vivo melanoma progression more efficiently than the native linear peptide. In the present article, we showed that the YSNSG cyclopeptide also triggered an inhibition of in vivo tumor neovascularization and we further analyzed its in vitroantiangiogenic effect. The YSNSG cyclopeptide did not alter endothelial cell proliferation but inhibited cell migration by 83% in an in vitro wound healing model. The inhibition was mediated by a decrease in active MT1‐MMP at the migration front as well as a decrease in u‐PA and u‐PAR expression. The cyclopeptide also altered β1‐integrin distribution in endothelial cell lamellipodia, induced a strong decrease in the phosphorylated focal adhesion kinase (p125FAK), disorganized F‐actin stress fibers and decreased the number of lamellipodia, resulting in a non migratory phenotype. Our results confirm the YSNSG cyclopeptide as a potent antitumor agent, through both the inhibition of invasive properties of tumor cells and the antiangiogenic activity.
Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis‐promoted hepatocarcinogenesis in rats
Authors: Wang Yan , Ausman Lynne M. , Greenberg Andrew S. , Russell Robert M. , Wang Xiang‐Dong
Published: June 2009

Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high‐fat diet (HFD)‐induced nonalcoholic steatohepatitis (NASH) promoted diethylnitrosamine (DEN)‐initiated hepatocarcinogenesis in a rat model. Using this model, we investigated the efficacy of an equivalent dosage of dietary LY from either a pure compound or a tomato extract (TE) against NASH‐promoted hepatocarcinogenesis. Six groups of rats were injected with DEN and then fed either Lieber‐DeCarli control diet or HFD with or without LY or TE for 6 weeks. Results showed that both LY and TE supplementations significantly decreased the number of altered hepatic foci expressing the placental form of glutathione S‐transferase in the livers of HFD‐fed rats. This was associated with significantly lower proliferating cell nuclear antigen positive hepatocytes and cyclinD1 protein, as well as decreased activation of extracellular signal‐regulated kinase and nuclear NF‐κB. Although both LY and TE supplementations reduced HFD‐induced lipid peroxidation in the livers, we observed significantly decreased cytochrome P450 2E1, inflammatory foci and mRNA expression of proinflammatory cytokines (TNF‐α, IL‐1β and IL‐12) in the HFD+TE fed group but increased nuclear NF‐E2‐related factor‐2 and heme oxygenase‐1 proteins in the HFD+LY fed group, relative to HFD feeding alone. These data indicate that LY and TE can inhibit NASH‐promoted hepatocarcinogenesis mainly as a result of reduced oxidative stress, which could be fulfilled through different mechanisms.
How hot? Systematic convergence of the replica exchange method using multiple reservoirs
Authors: Ruscio Jory Z. , Fawzi Nicolas L. , Head‐Gordon Teresa
Published: June 2009

We have devised a systematic approach to converge a replica exchange molecular dynamics simulation by dividing the full temperature range into a series of higher temperature reservoirs and a finite number of lower temperature subreplicas. A defined highest temperature reservoir of equilibrium conformations is used to help converge a lower but still hot temperature subreplica, which in turn serves as the high‐temperature reservoir for the next set of lower temperature subreplicas. The process is continued until an optimal temperature reservoir is reached to converge the simulation at the target temperature. This gradual convergence of subreplicas allows for better and faster convergence at the temperature of interest and all intermediate temperatures for thermodynamic analysis, as well as optimizing the use of multiple processors. We illustrate the overall effectiveness of our multiple reservoir replica exchange strategy by comparing sampling and computational efficiency with respect to replica exchange, as well as comparing methods when converging the structural ensemble of the disordered Aβ21‐30 peptide simulated with explicit water by comparing calculated Rotating Overhauser Effect Spectroscopy intensities to experimentally measured values. © 2009 Wiley Periodicals, Inc. J Comput Chem 31: 620–627, 2010