bluuebunny/crossref_metadata_2025 huggingface dataset:
In utero exposure to mycophenolate mofetil: A characteristic phenotype?
Authors: Perez‐Aytes Antonio , Ledo Ana , Boso Virginia , Sáenz Pilar , Roma Eva , Poveda José Luis , Vento Maximo
Published: December 2007

Mycophenolate mofetil (MMF) is a widely prescribed immunosuppressive agent after solid organ transplantation. Potential teratogenic effects after in utero exposure to MMF in experimental studies and clinical observations in humans has been postulated in recent literature. However, a specific pattern of malformation has not been identified yet. We present a newborn patient, born to a recipient of renal transplantation, who became pregnant while taking MMF as immunosuppressive therapy. The newborn exhibited cleft lip and palate, bilateral microtia and atretic external auditory canals, chorioretinal coloboma, hypertelorism, and micrognathia. An extensive review of the literature documented six other cases with similar malformations after in utero exposure to MMF. A consistent pattern of malformations comprising cleft lip and palate, microtia and external auditory canals could be observed in five of the six cases. A different malformative pattern observed in one of the patients could be attributed to a different agent rather than MMF. The possible teratogenic effects of other immunosuppressive drugs, such as tacrolimus and prednisone, to which this patient was also exposed, are discussed herein. In addition, the differential diagnosis with other dysmorphic syndromes that can present with a similar phenotype, such as CHARGE syndrome, 18q deletion and hypertelorism‐microtia‐clefting (HMC) syndrome, is presented. We conclude that in utero exposure to MMF can cause a characteristic phenotype and propose the existence of a mycophenolate‐associated embryopathy whose main features are: cleft lip and palate, microtia with atresia of external auditory canal, micrognathia and hypertelorism. Ocular anomalies, corpus callosum agenesis, heart defects, kidney malformations, and diaphragmatic hernia may be part of the phenotypic spectrum of MMF embryopathy. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed. © 2007 Wiley‐Liss, Inc.
Synthesis of monodisperse crosslinked polystyrene microspheres via dispersion copolymerization with the crosslinker‐postaddition method
Authors: Cui Hengli , Chen Hou , Qu Rongjun , Wang Chunhua , Ji Chunnuan , Sun Changmei , Zhou Wenying , Yu Mengmeng
Published: December 2007

Monodisperse crosslinked polystyrene microspheres were prepared by the dispersion copolymerization of styrene and divinylbenzene in a mixed solvent of ethanol and H2O. 2,2′‐Azobisisobutyronitrile and poly(N‐vinyl pyrrolidone) were used as the initiator and steric stabilizer, respectively. The crosslinker‐postaddition method was adopted through a slow addition of a crosslinking agent into the dispersion system at a certain time after the beginning of the polymerization. The effects of the postaddition recipe, postaddition beginning time, postaddition velocity, and agitation rate on the particle size, size distribution, and morphology were discussed. The resulting polymer microspheres were characterized with scanning electron microscopy and laser particle analysis. Crosslinked polystyrene microspheres with a narrow size distribution and a 12.0% crosslinker level were obtained with a size of 1.0 μm through the crosslinker‐postaddition method. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2008
Preparation of a three‐dimensional ordered macroporous titanium dioxide material with polystyrene colloid crystal as a template
Authors: Li Shi , Zheng Jingtang , Zhao Yucui , Liu Ying
Published: December 2007

Polystyrene (PS) photonic colloid crystals were assembled from PS spheres prepared by emulsion‐free polymerization through an improved vertical deposition method that could shorten the assembly time efficiently. The monodispersity of the spheres was appraised according to the standard deviation. The results showed that the PS spheres had a high monodispersity with a standard deviation of 3.7% and a dispersion coefficient of 0.02. The morphology and bandgap structure were observed with scanning electron microscopy images and transmission spectra, respectively. The mechanism of vertical deposition was analyzed simply. As an application of PS colloid crystals, ordered macroporous TiO2 photonic crystals were prepared, and the structure and properties of macroporous TiO2 were also studied with various analytical methods, which provided some values for the fabrication of photonic crystals with a complete bandgap. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
New Insights into the Polymerization of Methyl Methacrylate Initiated by Rare‐Earth Borohydride Complexes: A Combined Experimental and Computational Approach
Authors: Barros Noémi , Schappacher Michèle , Dessuge Paul , Maron Laurent , Guillaume Sophie M.
Published: December 2007

Polymerization of methyl methacrylate (MMA) initiated by the rare‐earth borohydride complexes [Ln(BH4)3(thf)3] (Ln=Nd, Sm) or [Sm(BH4)(Cp*)2(thf)] (Cp*=η‐C5Me5) proceeds at ambient temperature to give rather syndiotactic poly(methyl methacrylate) (PMMA) with molar masses M̄n higher than expected and quite broad molar mass distributions, which is consistent with a poor initiation efficiency. The polymerization of MMA was investigated by performing density functional theory (DFT) calculations on an η‐C5H5 model metallocene and showed that in the reaction of [Eu(BH4)(Cp)2] with MMA the borate [Eu(Cp)2{(OBH3)(OMe)CC(Me)2}] (e‐2) complex, which forms via the enolate [Eu(Cp)2{O(OMe)CC(Me)2}] (e), is calculated to be exergonic and is the most likely of all of the possible products. This product is favored because the reaction that leads to the formation of carboxylate [Eu(Cp)2{OOCC(Me)(CH2)}] (f) is thermodynamically favorable, but kinetically disfavored, and both of the potential products from a Markovnikov [Eu(Cp)2{O(OMe)CCH(Me)(CH2BH3)}] (g) or anti‐Markovnikov [Eu(Cp)2{O(OMe)CC(Me2)(BH3)}] (h) hydroboration reaction are also kinetically inaccessible. Similar computational results were obtained for the reaction of [Eu(BH4)3] and MMA with all of the products showing extra stabilization. The DFT calculations performed by using [Eu(Cp)2(H)] to model the mechanism previously reported for the polymerization of MMA initiated by [Sm(Cp*)2(H)]2 confirmed the favorable exergonic formation of the intermediate [Eu(Cp)2{O(OMe)CC(Me)2}] (e′′) as the kinetic product, this enolate species ultimately leads to the formation of PMMA as experimentally observed. Replacing H by BH4 thus prevents the 1,4‐addition of the [Eu(BH4)(Cp)2] borohydride ligand to the first incoming MMA molecule and instead favors the formation of the borate complex e‐2. This intermediate is the somewhat active species in the polymerization of MMA initiated by the borohydride precursors [Ln(BH4)3(thf)3] or [Sm(BH4)(Cp*)2(thf)].
Synthesis of a new C2‐symmetric chiral catalyst and its application in the catalytic asymmetric borane reduction of prochiral ketones
Authors: Zhou Yan , Wang Wen‐Hua , Dou Wei , Tang Xiao‐Liang , Liu Wei‐Sheng
Published: December 2007

A new C2‐symmetric chiral catalyst 3,5‐bis[(2S)‐(hydroxy‐diphenylmethyl)‐ pyrrolidin‐1‐ylmethyl]‐1,3,4‐oxadiazole was successfully synthesized by the reaction of 2,5‐dichloromethyl‐1,3,4‐oxadiazole with (S)‐α,α‐diphenyl‐2‐pyrrolidinemethanol, and applied to the catalytic asymmetric reduction of prochiral ketones with borane. When the catalyst loading was 1 mol %, enantiomeric excesses of up to 86.8% and 94.5% were observed in reduction of aromatic and α‐halo ketones, respectively. Chirality, 2008. © 2007 Wiley‐Liss, Inc.
Candida rugosa lipase‐catalysed kinetic resolution of 2‐substituted‐aryloxyacetic esters with dimethylsulfoxide and isopropanol as additives
Authors: Ammazzalorso Alessandra , Amoroso Rosa , Bettoni Giancarlo , De Filippis Barbara , Fantacuzzi Marialuigia , Giampietro Letizia , Maccallini Cristina , Tricca Maria Luisa
Published: December 2007

Candida rugosa lipase‐catalysed hydrolysis of three different 2‐substituted‐aryloxyacetic esters was performed in aqueous buffer containing dimethyl sulphoxide and isopropanol from 0 to 80% v/v as additives, in order to obtain an enhancement of the enantioselectivity. For 2‐(p‐chlorophenoxy)acetic acid and 2‐n‐butyl‐2‐(p‐chlorophenoxy)acetic acid ethyl esters, DMSO enhanced enzyme enantioselectivity more than IPA with an opposite enzymatic enantiopreference. The cosolvents moderately improved Candida rugosa lipase enantioselectivity for 2‐phenyl‐2‐(p‐chlorophenoxy)acetic acid ethyl ester. Chirality, 2008. © 2007 Wiley‐Liss, Inc.
Trends in childhood cancer incidence in the U.S. (1992–2004)
Authors: Linabery Amy M. , Ross Julie A.
Published: December 2007

BACKGROUND.

The etiology of most pediatric neoplasms remains elusive. Examination of population‐based incidence data provides insight regarding etiology among various demographic groups and may result in new hypotheses. The objective of the current study was to present updated information regarding childhood cancer incidence and trends in the U.S. overall and among demographic subgroups, including Asian/Pacific Islanders and Hispanics, for whom to the authors' knowledge trends have not been previously examined.

METHODS.

Data obtained by 13 registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program were evaluated to assess incidence and trends of common primary cancers diagnosed between 1992 and 2004 among children aged birth to 19 years. Frequencies, age‐adjusted incidence rates, and joinpoint regression results, including annual percent change (APC) in incidence rates (and 95% confidence intervals [95% CI]), were calculated.

RESULTS.

Between 1992 and 2004, a modest, nonsignificant increase in the average annual incidence rate (APC, 0.4%; 95% CI, −0.1%–0.8%) was observed for all pediatric cancer diagnoses combined. There was a suggestion of an increase in leukemia (APC, 0.7%; 95% CI, −0.1%–1.5%), and acute lymphoblastic leukemia in particular (APC, 0.8%; 95% CI, −0.4%–1.9%), whereas rates for central nervous system tumors overall were stable (APC, −0.1%; 95% CI, −1.1%–1.0%); 2 joinpoints were observed for astrocytoma. Rate increases were noted for hepatoblastoma (APC, 4.3%; 95% CI, 0.2%–8.7%) and melanoma (APC, 2.8%; 95% CI, 0.5%–5.1%). Differences by demographic group (sex, age, and race/ethnicity) are also described.

CONCLUSIONS.

The observed trends reinforce an ongoing need for population‐based surveillance and further etiologic studies. Cancer 2008. © 2007 American Cancer Society.
On the Energy Efficiency of Microwave‐Assisted Organic Reactions
Authors: Razzaq Tahseen , Kappe C. Oliver
Published: December 2007

The energy consumed for four different organic transformations carried out under microwave and conventional heating under otherwise identical reaction conditions was measured with the aid of a Wattmeter. In the case of open‐vessel reflux processing, microwave dielectric heating required significantly more energy than conventional techniques using oil baths or heating mantles. This is a consequence of the comparably low energy efficiency of the magnetron in converting electrical to microwave energy. Significant savings in energy were experienced by taking advantage of sealed‐vessel microwave processing at high temperatures. When comparing a conventionally heated reflux experiment with a microwave‐heated experiment using a superheated solvent in a sealed vessel, reaction times were reduced significantly from hours to minutes. The energy savings in these instances are, however, largely connected to the reduced reaction time and are not an inherent feature of microwave heating.
Regiodivergent Baeyer–Villiger Oxidation of Fused Ketones by Recombinant Whole‐Cell Biocatalysts
Authors: Mihovilovic Marko D. , Kapitán Peter , Kapitánová Petra
Published: December 2007

RecombinantEscherichia colicells expressing monooxygenases of different bacterial origin were evaluated in microbial Baeyer–Villiger oxidations of racemic fused ketones. During the enzymatic oxidation process, both the “normal” lactone generated by migration of the more‐substituted carbon atom and/or the “abnormal” lactone resulting from migration of the less‐substituted carbon atom can be formed. Depending on the nature of the Baeyer–Villiger monooxygenase, either a regiodivergent biooxygenation to both lactones in high optical purities was observed or essentially racemic “normal” rearrangement product was formed. The complementary behavior of enzymes was found to correlate with our previous observation of clustering of cycloketone‐oxidizing proteins into two distinct clusters based on phylogenetic relationship and biocatalyst performance.
Regulation of the Drosophila lin‐41 homologue dappled by let‐7 reveals conservation of a regulatory mechanism within the LIN‐41 subclade
Authors: O'Farrell Fergal , Esfahani Shiva Seyedoleslami , Engström Ylva , Kylsten Per
Published: December 2007

Drosophila Dappled (DPLD) is a member of the RBCC/TRIM superfamily, a protein family involved in numerous diverse processes such as developmental timing and asymmetric cell divisions. DPLD belongs to the LIN‐41 subclade, several members of which are micro RNA (miRNA) regulated. We re‐examined the LIN‐41 subclade members and their relation to other RBCC/TRIMs and dpld paralogs, and identified a new Drosophila muscle specific RBCC/TRIM: Another B‐Box Affiliate, ABBA. In silico predictions of candidate miRNA regulators of dpld identified let‐7 as the strongest candidate. Overexpression of dpld led to abnormal eye development, indicating that strict regulation of dpld mRNA levels is crucial for normal eye development. This phenotype was sensitive to let‐7 dosage, suggesting let‐7 regulation of dpld in the eye disc. A cell‐based assay verified let‐7 miRNA down‐regulation of dpld expression by means of its 3′‐untranslated region. Thus, dpld seems also to be miRNA regulated, suggesting that miRNAs represent an ancient mechanism of LIN‐41 regulation. Developmental Dynamics 237:196–208, 2008. © 2007 Wiley‐Liss, Inc.
HB‐EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development
Authors: Minami Seigo , Iwamoto Ryo , Mekada Eisuke
Published: December 2007

Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is a member of the EGF family of growth factors that is suggested to be involved in distal lung development. In HB‐EGF null (HBdel/del) newborns, a histopathologic analysis revealed abnormally thick saccular walls occurring from embryonic day 18.5 that reduced the terminal saccular space area. HB‐EGF gene deletion resulted in a significant increase in cell proliferation, indicating that HB‐EGF suppresses distal lung cell proliferation. Furthermore, an analysis of saccular morphology and proliferation in HB‐EGF and transforming growth factor‐α (TGFα) double‐mutant newborns revealed that HB‐EGF and TGFα function synergistically in this suppression. Finally, crosses between HBdel/del mice and waved 2 mice, a hypomorphic EGF receptor (EGFR) mutant strain, suggest that HB‐EGF and EGFR cooperate in this process. Thus, HB‐EGF has a novel suppressive function that contributes to decelerating distal lung cell proliferation synergistically with TGFα through EGFR in perinatal distal lung development. Developmental Dynamics 237:247–258, 2008. © 2007 Wiley‐Liss, Inc.
Ionic Liquid Based Approach to Luminescent LaPO4:Ce,Tb Nanocrystals: Synthesis, Characterization and Application
Authors: Zharkouskaya Aksana , Feldmann Claus , Trampert Klaus , Heering Wolfgang , Lemmer Uli
Published: December 2007

LaPO4:Ce,Tb as a nanoscale phosphor is prepared via a microwave‐accelerated synthesis in ionic liquids. The underlying approach results in non‐agglomerated nanocrystals, 9–12 nm in size, and exhibiting quantum yields of 70 % (Tb‐related emission) and 90 % (Ce/Tb‐related emission). Based on the underlying concept of synthesis, application‐oriented aspects are focused. Driven by the addition of oleylamine, first, phase transfer from the polar phase of synthesis to non‐polar alkanes can be initiated. As a second aspect, dispersions of the title compound in ethanol are applied for ink‐jet printing of transparent luminescent layers on polymer substrates. Finally, ethanolic dispersions of LaPO4:Ce,Tb are used to realize a fully transparent dielectric barrier discharge (DBD) lamp as a prototype of a “luminescent window”. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Self‐Assembled Chiral Dimeric Capsules from Difunctionalized N,C‐Linked Peptidocalix[4]arenes: Scope and Limitations
Authors: Baldini Laura , Sansone Francesco , Faimani Giovanni , Massera Chiara , Casnati Alessandro , Ungaro Rocco
Published: December 2007

In this paper we report the synthesis of the first examples of upper (wide) rim calix[4]arene amino acids 5 and 27, together with the conformational, self‐assembly and molecular inclusion properties of the N,C‐linked peptidocalix[4]arenes obtained from them. Whereas the dipropyl derivative 5 readily undergoes peptide synthesis allowing a small library of calix[4]arene pseudopeptides 12–21 to be obtained, the tetrapropoxy compound 27 preferentially gives upper‐rim‐bridged derivatives (e.g., 28) which are formed through an intramolecular condensation reaction. The tetrapropoxycalix[4]arene pseudopeptide 33 shows conformational and self‐assembly properties quite different to those of the dipropoxy derivatives 12–21. The observed differences are explained on the basis of the different conformational flexibilities of the two calix[4]arene scaffolds. Calixarene 5 is more rigid than 27 thanks to the presence of two OH groups at the lower (narrow) rim that are involved in strong intramolecular hydrogen bonds. Only peptidocalix[4]arenes 12–21 but not 33 form hydrogen‐bonded dimeric capsules in which the two macrocycles approach each other face‐to‐face and rotated by 180° with respect to the other in order to allow hydrogen‐bonding complementarity between the interacting peptide chains, which, in some cases (17–19), form an antiparallel β sheet enhancing the stability of the capsule. The structures of the chiral dimeric capsules were established by molecular modelling calculations and NOESY NMR experiments, which give consistent results, whereas their stability in CDCl3 (69 ≤ Kdim ≤ 950 M–1) was determined by dilution NMR experiments. Compound 12 forms both 1:1 and 2:1 [K11 = (7.8±1.2) × 102 M–1, K21 = (1.8±0.2) × 105 M–2] host:guest complexes with the methylpyridinium (MePy+) cation in CD2Cl2/CDCl3 (10:1, v/v). There is no evidence for a guest template effect in stabilizing the supramolecular capsule.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Formation of Bicyclic Pyrroles and Furans Through an Enone Allene Photocycloaddition and Fragmentation Sequence
Authors: Lutteke Ginger , AlHussainy Rana , Wrigstedt Pauli J. , Hue B. T. B. , de Gelder René , van Maarseveen Jan H. , Hiemstra Henk
Published: December 2007

The [2+2] photocycloaddition of allenes 15–18, 23 and 26 was studied. Irradiation of a solution of these substrates in acetonitrile at 300 nm resulted in the clean conversion of the starting materials into a mixture of photoproducts. The major product in all cases was a bicyclic pyrrole or furan fused to an eight membered ring (43–70 % yield). The formation of these products is thought to be a result of a heteroatom‐induced fragmentation of the straight adduct (7). This is supported by irradiation of the carbon analogue 32 which allowed the isolation of straight adduct 45 after catalytic hydrogenation in 27 %. The minor crossed photoproducts were isolated in 10–20 % yield. The observed major/minor ratio of 4:1 was not affected by the variation of substituents on the cyclohexene ring. Introduction of a substituent on the allene had a more significant effect on the ratio which changed to 2:1.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Lignosulfonate‐Modified Electrode for Electrocatalytic Reduction of Acidic Nitrite
Authors: Milczarek Grzegorz
Published: December 2007

Sodium lignosulfonate (LS) undergoes oxidative electropolymerization on a glassy carbon (GC) electrode from sulfuric acid solution to form a chemically modified electrode exhibiting anionic character and redox activity. Cyclic voltammetry reveals the existence of two redox systems at E°′ values of +0.29 and +0.53 V, respectively. Peak currents are proportional to the scan rate as expected for surface confined systems. The GC|poly‐LS electrode shows electrocatalytic activity toward the reduction of acidic nitrite. When operating in a constant potential amperometric mode (at 0.0 V, vs. Ag/AgCl), a linear relationship between nitrite concentration and reduction current is observed over the range of 1 to 250 μM. The detection limit reaches 0.3 μM (S/N=3). The electrode may be practically applied for nitrite determination in human saliva.
Low‐Potential Detection of Glucose with a Biosensor Based on the Immobilization of Glucose Oxidase on Polymer/Manganese Oxide Layered Nanocomposite
Authors: Xu Jing‐Juan , Feng Jiu‐Ju , Zhong Xue , Chen Hong‐Yuan
Published: December 2007

A nanocomposite with poly(diallyldimethylammonium), PDDA, intercalated between manganese oxide layers is constructed on a graphite electrode surface through one‐step electrodeposition and used to adsorb glucose oxidase (GOD). The immobilized GOD displays a pair of stable and quasireversible redox peaks with a formal potential of −468 mV in pH 7.0 buffer solutions and exhibits excellent electrocatalysis to the reduction of oxygen. In the presence of dissolved oxygen, the reduction peak current decreased gradually with the addition of glucose, indicating that the immobilized GOD kept its bioactivity. Thus a reagentless biosensor for glucose at a low detection potential was established. The linear concentration range is from 0.02 to 2.78 mM with a detection limit of 9.8 μM. The proposed glucose biosensor was insensitive to common interferences such as ascorbic and uric acids etc.
Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma
Authors: Forner Alejandro , Vilana Ramón , Ayuso Carmen , Bianchi Lluís , Solé Manel , Ayuso Juan Ramón , Boix Loreto , Sala Margarita , Varela María , Llovet Josep M , Brú Concepció , Bruix Jordi
Published: December 2007

This study prospectively evaluates the accuracy of contrast-enhanced ultrasound (CEUS) and dynamic magnetic resonance imaging (MRI) for the diagnosis of nodules 20 mm or smaller detected during ultrasound (US) surveillance. We included 89 patients with cirrhosis [median age, 65 years; male 53, hepatitis C virus 68, Child-Pugh A 80] without prior hepatocellular carcinoma (HCC) in whom US detected a small solitary nodule (mean diameter, 14 mm). Hepatic MRI, CEUS, and fine-needle biopsy (gold standard) (FNB) were performed at baseline. Non-HCC cases were followed (median 23 months) by CEUS/3 months and MRI/6 months. FNB was repeated up to 3 times and on detection of change in aspect/size. Intense arterial contrast uptake followed by washout in the delayed/venous phase was registered as conclusive for HCC. Final diagnoses were: HCC (n = 60), cholangiocarcinoma (n = 1), and benign lesions (regenerative/dysplastic nodule, hemangioma, focal nodular hyperplasia) (n = 28). Sex, cirrhosis cause, liver function, and alpha-fetoprotein (AFP) levels were similar between HCC and non-HCC groups. HCC patients were older and their nodules significantly larger (

P

< 0.0001). First biopsy was positive in 42 of 60 HCC patients. Sensitivity, specificity, and positive and negative predictive values of conclusive profile were 61.7%, 96.6%, 97.4%, and 54.9%, for MRI, 51.7%, 93.1%, 93.9%, and 50.9%, for CEUS. Values for coincidental conclusive findings in both techniques were 33.3%, 100%, 100%, and 42%. Thus, diagnosis of HCC 20 mm or smaller can be established without a positive biopsy if both CEUS and MRI are conclusive. However, sensitivity of these noninvasive criteria is 33% and, as occurs with biopsy, absence of a conclusive pattern does not rule out malignancy. These results validate the American Association for the Study of Liver Disease (AASLD) guidelines. (Hepatology 2007.)
Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial
Authors: Mangia Alessandra , Minerva Nicola , Bacca Donato , Cozzolongo Raffaele , Ricci Giovanni L. , Carretta Vito , Vinelli Francesco , Scotto Gaetano , Montalto Giuseppe , Romano Mario , Cristofaro Giuseppe , Mottola Leonardo , Spirito Fulvio , Andriulli Angelo
Published: December 2007

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48-week treatment. Patients (n = 696) received peginterferon alfa-2a, 180 mg/week, or peginterferon alfa-2b, 1.5 mg/kg/week, plus ribavirin, 1000-1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV-RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8-51.4] of the patients in the standard group and in 48.8% (CI 44.2-53.3) of the patients in the variable group (

P

= 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia ≥400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%,

P

= 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis.

Conclusion:

Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs. (Hepatology 2007.)
NQO1 and NFE2L2 polymorphisms, fruit and vegetable intake and smoking and the risk of colorectal adenomas in an endoscopy‐based population
Authors: Tijhuis Mariken J. , Visker Marleen H.P.W. , Aarts Jac M.M.J.G. , Laan Wijnand , de Boer Sybrand Y. , Kok Frans J. , Kampman Ellen
Published: December 2007

Both environment and genetics contribute to the pathogenesis and prevention of colorectal neoplasia. NAD(P)H:quinone oxidoreductase (NQO1) is a detoxification enzyme that is polymorphic and inducible. We investigated interactions between lifestyle factors and polymorphisms in NQO1 and its key regulatory transcription factor NFE2L2 in colorectal adenoma risk. The NQO1 c.609C>T and g.‐718A>G and NFE2L2 g.‐650C>A, g.‐684G>A and g.‐686A>G polymorphisms were determined among 740 Dutch adenoma cases and 698 endoscopy‐based controls. Dietary intake was assessed by food frequency questionnaire, other lifestyle information by questionnaire. The NQO1 609CT genotype was associated with a higher adenoma risk (OR 1.27, 95% CI 1.00–1.62) compared with the 609CC genotype, whereas the 609TT genotype was not (OR 1.03, 95% CI 0.56–1.88). The higher risk with the NQO1 609CT‐genotype was seen among smokers (OR 1.96, 95% CI 1.40–2.76), but not among nonsmokers (OR 0.91, 95% CI 0.62–1.35; interaction p = 0.030). Fruit and vegetable consumption did not protect smokers from adenomas and did not interact with the NQO1 609C>T polymorphism or the NFE2L2 polymorphisms. A higher adenoma risk seen with high fruit and vegetable consumption among NQO1 ‐718GG genotypes was absent among ‐718GA genotypes (interaction p = 0.071). Gene–gene interactions were observed between the NQO1 609C>T and NFE2L2 ‐686A>G polymorphisms (interaction p = 0.056) and between the NQO1 ‐718 G>A and NFE2L2 ‐650C>A polymorphisms (interaction p = 0.013). In conclusion: the NQO1 609CT genotype is associated with increased adenoma risk among smokers, which is not diminished by high fruit and vegetable consumption. The observed gene–gene interactions may point to a role for NFE2L2 polymorphisms in NQO1‐related adenoma formation. © 2007 Wiley‐Liss, Inc.
Type IV collagen α6 chain‐derived noncollagenous domain 1 (α6(IV)NC1) inhibits angiogenesis and tumor growth
Authors: Mundel Thomas M. , Yliniemi Anna‐Maija , Maeshima Yohei , Sugimoto Hikaru , Kieran Mark , Kalluri Raghu
Published: December 2007

Type IV collagen is a major component of vascular basement membranes. The noncollagenous (NC1) domains of several α‐chains of type IV collagen reveal a capacity to inhibit angiogenesis and tumor growth. Here, we demonstrate that the NC1 domain of the α6 chain of type IV collagen (α6NC1) is an endogenous inhibitor of angiogenesis and tumor growth. Recombinant α6NC1 inhibits human endothelial cell proliferation and neovascularization of Matrigel plugs in mice. The α6NC1 suppresses the growth of subcutaneously transplanted Lewis lung carcinoma and also spontaneous pancreatic insulomas that develop in the Rip1Tag2 mice. Inhibition of tumor growth is associated with significantly diminished microvascular density. Collectively, our results demonstrate that α6NC1 is an endogenous inhibitor of angiogenesis and tumor growth. © 2007 Wiley‐Liss, Inc.
Histone deacetylase inhibitor Helminthosporium carbonum (HC)‐toxin suppresses the malignant phenotype of neuroblastoma cells
Authors: Deubzer Hedwig E. , Ehemann Volker , Westermann Frank , Heinrich Ralf , Mechtersheimer Gunhild , Kulozik Andreas E. , Schwab Manfred , Witt Olaf
Published: December 2007

The survival rate of children with advanced neuroblastoma (NB) is dismal despite intensive multimodal therapy. The limited efficacy and the frequent and serious side effects of currently used therapeutic regimens necessitate the development of new, less toxic treatment strategies. This study shows that the histone deacetylase inhibitor Helminthosporium carbonum (HC)‐toxin suppresses the malignant phenotype of both established NB cell lines and primary NB cells with and without amplified MYCN at dosages lower than 20 nM. HC‐toxin induces cell cycle arrest and apoptosis as well as neuronal differentiation and diminishes both colony formation and invasive growth. These cellular changes are accompanied by the transcriptional repression of cell cycle regulators of the retinoblastoma (RB) tumor suppressor network found at high levels in NBs with poor prognosis, like E2F‐1 and its targets Skp2, N‐myc, Mad2 and survivin. The levels of the hypophosphorylated active form of RB, and of cyclin‐dependent kinase inhibitors including p15INK4b, p16INK4a, p21cip1/waf‐1 and p27kip1 are increased. In conclusion, nanomolar doses of the HDACI HC‐toxin cause a shift to a differentiated and benign phenotype of NB cells that is associated with an activation of the RB tumor suppressor network. © 2007 Wiley‐Liss, Inc.
Explicit ion, implicit water solvation for molecular dynamics of nucleic acids and highly charged molecules
Authors: Prabhu Ninad V. , Panda Manoranjan , Yang Qingyi , Sharp Kim A.
Published: December 2007

An explicit ion, implicit water solvent model for molecular dynamics was developed and tested with DNA and RNA simulations. The implicit water model uses the finite difference Poisson (FDP) model with the smooth permittivity method implemented in the OpenEye ZAP libraries. Explicit counter‐ions, co‐ions, and nucleic acid were treated with a Langevin dynamics molecular dynamics algorithm. Ion electrostatics is treated within the FDP model when close to the solute, and by the Coulombic model when far from the solute. The two zone model reduces computation time, but retains an accurate treatment of the ion atmosphere electrostatics near the solute. Ion compositions can be set to reproduce specific ionic strengths. The entire ion/water treatment is interfaced with the molecular dynamics package CHARMM. Using the CHARMM‐ZAPI software combination, the implicit solvent model was tested on A and B form duplex DNA, and tetraloop RNA, producing stable simulations with structures remaining close to experiment. The model also reproduced the A to B duplex DNA transition. The effect of ionic strength, and the structure of the counterion atmosphere around B form duplex DNA were also examined. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Thermodynamic and structural properties of methanol–water solutions using nonadditive interaction models
Authors: Zhong Yang , Warren G. Lee , Patel Sandeep
Published: December 2007

We study bulk structural and thermodynamic properties of methanol–water solutions via molecular dynamics simulations using novel interaction potentials based on the charge equilibration (fluctuating charge) formalism to explicitly account for molecular polarization at the atomic level. The study uses the TIP4P‐FQ potential for water–water interactions, and the CHARMM‐based (Chemistry at HARvard Molecular Mechanics) fluctuating charge potential for methanol–methanol and methanol–water interactions. In terms of bulk solution properties, we discuss liquid densities, enthalpies of mixing, dielectric constants, self‐diffusion constants, as well as structural properties related to local hydrogen bonding structure as manifested in radial distribution functions and cluster analysis. We further explore the electronic response of water and methanol in the differing local environments established by the interaction of each species predominantly with molecules of the other species. The current force field for the alcohol–water interaction performs reasonably well for most properties, with the greatest deviation from experiment observed for the excess mixing enthalpies, which are predicted to be too favorable. This is qualitatively consistent with the overestimation of the methanol–water gas‐phase interaction energy for the lowest‐energy conformer (methanol as proton donor). Hydration free energies for methanol in TIP4P‐FQ water are predicted to be −5.6 ± 0.2 kcal/mol, in respectable agreement with the experimental value of −5.1 kcal/mol. With respect to solution microstructure, the present cluster analysis suggests that the microscale environment for concentrations where select thermodynamic quantities reach extremal values is described by a bipercolating network structure. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
An improved pairwise decomposable finite‐difference Poisson–Boltzmann method for computational protein design
Authors: Vizcarra Christina L. , Zhang Naigong , Marshall Shannon A. , Wingreen Ned S. , Zeng Chen , Mayo Stephen L.
Published: December 2007

Our goal is to develop accurate electrostatic models that can be implemented in current computational protein design protocols. To this end, we improve upon a previously reported pairwise decomposable, finite difference Poisson–Boltzmann (FDPB) model for protein design (Marshall et al., Protein Sci 2005, 14, 1293). The improvement involves placing generic sidechains at positions with unknown amino acid identity and explicitly capturing two‐body perturbations to the dielectric environment. We compare the original and improved FDPB methods to standard FDPB calculations in which the dielectric environment is completely determined by protein atoms. The generic sidechain approach yields a two to threefold increase in accuracy per residue or residue pair over the original pairwise FDPB implementation, with no additional computational cost. Distance dependent dielectric and solvent‐exclusion models were also compared with standard FDPB energies. The accuracy of the new pairwise FDPB method is shown to be superior to these models, even after reparameterization of the solvent‐exclusion model. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Time‐averaged predictions of folded and misfolded peptides using a reduced physicochemical model
Authors: Clarke Oliver J. , Parker Martin J.
Published: December 2007

Energy‐based methods for calculating time‐averaged peptide structures are important for rational peptide design, for defining local structure propensities in large protein chains, and for exploring the sequence determinants of amyloid formation. High‐end methods are currently too slow to be practicable, and will remain so for the foreseeable future. The challenge is to create a method that runs quickly on limited computer resources and emulates reality sufficiently well. We have developed a simplified off‐lattice protein model, incorporating semi‐empirical physicochemical potentials, and combined it with an efficient Monte Carlo method for calculating time‐averaged peptide structures. Reasonably accurate predictions are found for a set of small α‐helical and β‐hairpin peptides, and we demonstrate a potential application in measuring local structure propensities in protein chains. Time‐averaged structures have also been calculated for a set of small peptides known to form β‐amyloid fibrils. The simulations were of three interacting peptides, and in each case the time‐averaged structure describes a three‐stranded β‐sheet. The performance of our method in measuring the propensities of small peptides to self‐associate into possible prefibrillar species compares favorably with more detailed and CPU‐intensive approaches. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Complete basis set limit ofAb initiobinding energies and geometrical parameters for various typical types of complexes
Authors: Min Seung Kyu , Lee Eun Cheol , Lee Han Myoung , Kim Dong Young , Kim Dongwook , Kim Kwang S.
Published: December 2007

Using basis‐set extrapolation schemes for a given data set, we evaluated the binding energies and geometries at the complete basis set (CBS) limit at the levels of the second order Møller–Plesset perturbation theory (MP2) and the coupled cluster theory with singles, doubles, and perturbative triples excitations [CCSD(T)]. The systems include the hydrogen bonding (water dimer), aromatic interaction (benzene dimer), π–H interaction (benzene–water), cation–water, anion–water, π–cation interaction (cation–benzene), and π–anion interaction (anion–triazine). One extrapolation method is to exploit both BSSE‐corrected and BSSE‐uncorrected binding energies for the aug‐cc‐pVNZ (N= 2, 3, 4, …) basis set in consideration that both binding energies give the same CBS limit (CBSB). Another CBS limit (CBSC) is to use the commonly known extrapolation approach to exploit that the electron correlation energy is proportional toN−3. Since both methods are complementary, they are useful for estimating the errors and trend of the asymptotic values. There is no significant difference between both methods. Overall, the values of CBSCare found to be robust because of their consistency. However, for smallN(in particular, forN= 2, 3), CBSis found to be slightly better for water–water interactions and cation–water and cation–benzene interactions, whereas CBSis found to be more reliable for bezene–water and anion–water interactions. We also note that the MP2 CBS limit value based onN= 2 and 3 combined with the difference between CCSD(T) and MP2 atN= 2 would be exploited to obtain a CCSD(T)/CBS value for aromatic–aromatic interactions and anion–π interactions, but not for cationic complexes. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Computational studies on the dimers and the thermal dimerization of norbornadiene
Authors: Wu Yong , Xue Ying , Kim Chan Kyung
Published: December 2007

In this study, 14 norbornadiene (NBD) dimers and the thermal dimerization mechanism were studied using the hybrid density functional theory (B3LYP) and the second‐order multiconfigurational perturbation theory (CASPT2). In the process of dimerization, the biradical stationary points were located using the unrestricted, broken‐spin, symmetry approach. The pathways were divided into eight parts to aid the analysis of their mechanisms. Our results indicated that the process for the formation of the cage‐like heptacyclo[6.6.0.0.2, 60.3, 130.4, 1105, 9.010, 14] tetradecane (HCTD, D14) is highly exothermic (92.15 kcal/mol), indicating that D14 is the most stable NBD dimer. However, the formation of D14 is very difficult to achieve kinetically because of a higher barrier in the thermal dimerization. On the contrary, the formation of exo‐cis‐exo (D5) is kinetically favorable, but thermodynamically unfavorable at higher temperature. Therefore, the combination of both thermodynamic and kinetic factors indicated that the formation of exo‐exo (D9), which resembles the product of the pseudo‐Diels‐Alder addition, is most likely in the NBD dimerization. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Microbial growth reduction in sewage sludge by stirred ball mill disintegration and estimation by respirometry
Authors: Lajapathi Rai Chockalingam , Mueller Johannes , Struenkmann Georg , Gangadhar Rao Paruchuri
Published: December 2007

BACKGROUND: Excess biomass generation in wastewater treatment plants is an unavoidable byproduct of the degradation process. Treatment and disposal of sewage sludge from wastewater treatment plants accounts for about half or even up to 60% of the total operating cost. The present study focuses on the reduction of excess sludge generation by engineering the microbes through mechanical energy inputs by means of stirred ball milling.

RESULTS: The significant achievement of this study is microbial growth reduction of up to 89% at an applied specific energy of 15301 kJ kg−1. The degree of disintegration of microbial cells was substantiated by estimating the degree of inactivation (DDO), degree of soluble chemical oxygen demand (COD) release (DDCOD), particle size and microscopic examination. The effect of disintegration on sludge microbial growth reduction is proved by respirometric studies.

CONCLUSIONS: Sludge disintegration employing stirred ball milling is proved to be a worthwhile pretreatment process for reducing the sludge microbial growth in activated sludge treatment processes. Copyright © 2007 Society of Chemical Industry
Evaluation of glycosylation and malonylation patterns in flavonoid glycosides during LC/MS/MS metabolite profiling
Authors: Kachlicki P. , Einhorn J. , Muth D. , Kerhoas L. , Stobiecki M.
Published: December 2007

Flavonoid conjugates constitute several classes of plant phenolic secondary metabolites including many isomeric compounds differing in the hydroxylation pattern and substitution of their rings with different groups such as alkyls, acyls or sugars. These compounds occur in plant tissues mainly as glycosides and in many cases it is necessary to have reliable and detailed information concerning the structure of these natural products. Our results were obtained using leaf extracts of Arabidopsis thaliana and Lupinus angustifolius in which different glycosides of flavones, flavonols and isoflavones are present. Analysis of collision‐induced dissociation (CID)/MS/MS spectra of protonated [M + H]+, sodiated [M + Na]+ or deprotonated [M − H]− molecules recorded during HPLC runs may bring needed information in this respect. However, registration of mass spectra of [M + Na]+ ions with a good efficiency is possible only after post‐column addition of a sodium acetate solution to the LC column eluate. The retention of sodium cation on the saccharidic parts of the molecule is observed after the CID fragmentation. In many cases, the location of this cation on the glycan attached to C‐3 hydroxyl group of flavonol led to assignment of its structure. Additionally, the determination of the structure of the aglycone and of the sequence of the glycan part was made possible through the CID data obtained from the [M + H]+ and [M − H]− ions. CID spectra show a different order of sugar elimination from hydroxyl groups at C‐3 and C‐7 in flavonol glycosides isolated from A. thaliana leaves and give sufficient information to discriminate flavonoid O‐diglycosides from flavonoid di‐O‐glycosides. Copyright © 2007 John Wiley & Sons, Ltd.
Binding constant determination of high‐affinity protein–ligand complexes by electrospray ionization mass spectrometry and ligand competition
Authors: Wortmann Arno , Jecklin Matthias C. , Touboul David , Badertscher Martin , Zenobi Renato
Published: December 2007

We describe an approach for the determination of binding constants for protein–ligand complexes with electrospray ionization mass spectrometry, based on the observation of unbound ligands competing for binding to a protein target. For the first time, dissociation constants lower than picomolar could be determined with good accuracy by electrospray ionization mass spectrometry. The presented methodology relies only on the determination of signal intensity ratios for free ligands in the low mass region. Therefore, all the advantages of measuring low masses with mass spectrometry, such as high resolution are preserved. By using a reference ligand with known binding affinity, the affinity of a second ligand can be determined. Since no noncovalently bound species are observed, assumptions about response factors are not necessary. The method is validated with ligands binding to avidin and applied to ligands binding to p38 mitogen‐activated protein kinase. Copyright © 2007 John Wiley & Sons, Ltd.
Effects of Graptopetalumparaguayense extract on tert‐ butylhydroperoxide‐induced oxidative stress
Authors: Chou Su‐Tze , Chung Yun‐Chin , Teng Kai‐Yun , Yeh Jan‐Ying
Published: December 2007

BACKGROUND: Graptopetalum paraguayense E. Walther is used in folk medicine to lower blood pressure, protect liver function and relieve pain and infection. The effect and mechanism of its 50% ethanolic extract (GE50) were investigated in tert‐butylhydroperoxide (t‐BHP)‐induced Wistar rats. The serum was analysed for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities while the tissue cytosols were analysed for lipid peroxidation, antioxidant level and enzyme activities.

RESULTS: The liver was the primary target organ while the heart appeared to be the least responsive organ for t‐BHP treatment among the three tissues investigated. t‐BHP treatment increased serum AST and ALT activities, which are indicators of liver toxicity, while GE50 pretreatment reduced t‐BHP‐induced liver damage. t‐BHP treatment induced lipid peroxidation in the liver and brain but not in the heart. GE50 pretreatment prevented t‐BHP‐induced lipid peroxidation by maintaining superoxide dismutase (SOD) activity as well as glutathione (GSH) and vitamin C levels in the liver and vitamin E level in the brain. Although t‐BHP treatment did not induce lipid peroxidation in the heart, it caused a decrease in antioxidant level. GE50 pretreatment prevented the t‐BHP‐induced decrease in vitamin C level in the heart.

CONCLUSION: GE50 pretreatment in rats protects the liver and brain from possible damage by t‐BHP‐induced lipid peroxidation. Copyright © 2007 Society of Chemical Industry
Protection of deoxyribose and DNA from degradation by using aqueous extracts of several wild plants
Authors: Gião Maria S , González‐Sanjosé M L , Muñiz Pilar , Rivero‐Pérez M D , Kosinska Monika , Pintado Manuela E , Malcata F Xavier
Published: December 2007

BACKGROUND: Aqueous extracts of 48 herbal plants were obtained via alternative extraction protocols, and were assayed for their capacity to protect deoxyribose and DNA itself from degradation (or, conversely, for their capacity to promote DNA degradation), using electrophoresis as analytical tool.

RESULTS: For a given (constant) volume of extract, deoxyribose protection ranged from 14.13 ± 1.35% (mean ± SD) inhibition by dwarf mallow powder infusion, up to 106.51 ± 15.93% inhibition by avocado powder infusion. DNA protection was tested at two extract concentrations, and was slightly greater at the higher concentration. Pro‐oxidant effects were essentially absent.

CONCLUSION: The anti‐oxidative roles of plants upon deoxyribose and DNA displayed by our experimental results were rather promising with regards to practical applications of those plants, viz. as ingredients in the formulation of nutraceutical beverages and/or foods. Copyright © 2007 Society of Chemical Industry