bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine
Authors: Morrell Martha J. , Hayes Frances J. , Sluss Patrick M. , Adams Judith M. , Bhatt Mohit , Ozkara Cigdem , Warnock M.S. Clay R. , Isojärvi Jouko
Published: September 2008

Objective

To evaluate development of components of polycystic ovary syndrome (PCOS) and PCOS in women with epilepsy initiating valproate or lamotrigine therapy.

Methods

Female individuals with epilepsy and regular menstrual cycles were eligible for this prospective study. Participants were randomized to 12 months of valproate (n = 225) or lamotrigine (n = 222) therapy. Serum androgen levels were measured every 3 months. Urinary pregnanediol glucuronide levels were measured weekly for two 3‐month periods. The primary end point was development of PCOS components (ie, hyperandrogenism or ovulatory dysfunction). A post hoc analysis was conducted in women more than 2 years after menarche (177 lamotrigine, (HA) 186 valproate) to exclude OD the confounding effect of puberty.

Results

More women in the valproate group than the lamotrigine group developed (OD) in the prospective (54% valproate, 38% lamotrigine; p = 0.010) and the post hoc (HA) analyses (36% valproate, 23% lamotrigine; p = 0.007). More women in the valproate group than the lamotrigine group developed PCOS (9 vs 2%; p = 0.007). Development of HA was more frequent with OD valproate than lamotrigine among those initiating treatment at age younger than 26 years (44% valproate, 23% lamotrigine; p = 0.002) but was similar if treatment was started at age 26 years or older (24% valproate, 22% lamotrigine).

Interpretation

Development of HA occurred more frequently with valproate than lamotrigine, especially if medication was started at age younger than 26 years. Ann Neurol 2008;64:200–211
An idiopathic epilepsy syndrome linked to 3q13.3‐q21 and missense mutations in the extracellular calcium sensing receptor gene
Authors: Kapoor Ashish , Satishchandra Parthasarathy , Ratnapriya Rinki , Reddy Ramesh , Kadandale Jayaram , Shankar Susarla K. , Anand Anuranjan
Published: September 2008

Objective

To identify the disease locus in a three‐generation south Indian family having several of its members affected with idiopathic epilepsy.

Methods

Genome‐wide parametric linkage analysis was performed with 382 autosomal markers. Mutational analysis of the positional candidate genes in linked interval was performed by direct sequencing of genomic DNA from the proband in the family. Expression analysis in human adult brain was performed by Western blotting.

Results

A novel epilepsy genetic locus on chromosome 3q13.3‐q21 was identified by linkage analysis. This locus comprises about 12 megabases of the genomic interval, with its proximal and distal genetic boundaries defined by microsatellite markers, D3S3675 and D3S1551, respectively. In this interval, we found a novel, patient‐specific, missense variant, Arg898Gln, at the extracellular calcium sensing receptor (CASR), a gene belonging to the G‐protein–coupled receptor family. CASR expression was detected in the temporal lobe, frontal lobe, parietal lobe, cerebellum, and hippocampus. Four additional, potentially pathogenic, missense CASR variants, Glu354Ala, Ile686Val, Ala988Val, and Ala988Gly, were observed in five individuals affected with idiopathic generalized epilepsy.

Interpretation

A novel idiopathic epilepsy locus has been mapped on chromosome 3q13.3‐q21, as evident by presence of significant genetic linkage. Identification of novel, rare missense CASR variants at evolutionary‐conserved residues in epilepsy patients and CASR expression in various subregions of human brain raises an interesting possibility of involvement of CASR in pathophysiology of epileptic disorders. Ann Neurol 2008;64:158–167
The continuing problem of human African trypanosomiasis (sleeping sickness)
Authors: Kennedy Peter G. E.
Published: September 2008

Human African trypanosomiasis, also known as sleeping sickness, is a neglected disease, and it continues to pose a major threat to 60 million people in 36 countries in sub‐Saharan Africa. Transmitted by the bite of the tsetse fly, the disease is caused by protozoan parasites of the genus Trypanosoma and comes in two types: East African human African trypanosomiasis caused by Trypanosoma brucei rhodesiense and the West African form caused by Trypanosoma brucei gambiense. There is an early or hemolymphatic stage and a late or encephalitic stage, when the parasites cross the blood–brain barrier to invade the central nervous system. Two critical current issues are disease staging and drug therapy, especially for late‐stage disease. Lumbar puncture to analyze cerebrospinal fluid will remain the only method of disease staging until reliable noninvasive methods are developed, but there is no widespread consensus as to what exactly defines biologically central nervous system disease or what specific cerebrospinal fluid findings should justify drug therapy for late‐stage involvement. All four main drugs used for human African trypanosomiasis are toxic, and melarsoprol, the only drug that is effective for both types of central nervous system disease, is so toxic that it kills 5% of patients who receive it. Eflornithine, alone or combined with nifurtimox, is being used increasingly as first‐line therapy for gambiense disease. There is a pressing need for an effective, safe oral drug for both stages of the disease, but this will require a significant increase in investment for new drug discovery from Western governments and the pharmaceutical industry. Ann Neurol 2008;64:116–126
Computerized grading of anatomy laboratory practical examinations
Authors: Krippendorf Beth B. , Bolender David L. , Kolesari Gary L.
Published: September 2008

At the Medical College of Wisconsin, a procedure was developed to allow computerized grading and grade reporting of laboratory practical examinations in the Clinical Human Anatomy course. At the start of the course, first year medical students were given four Lists of Structures. On these lists, numbered items were arranged alphabetically; the items were anatomical structures that could be tagged on a given lab practical examination. Each lab exam featured an anatomy laboratory component and a computer laboratory component. For the anatomy lab component, students moved from one question station to another at timed intervals and identified tagged anatomical structures. As students identified a tagged structure, they referred to a copy of the list (provided with their answer sheet) and wrote the number corresponding to the structure on their answer sheet. Immediately after the anatomy lab component, students were escorted to a computer instruction laboratory where they typed their answer numbers into a secured testing component of a learning management system that recorded their answers for automatic grading. After a brief review of examination scores and item analysis by faculty, exam scores were reported to students electronically. Adding this brief computer component to each lab exam greatly reduced faculty grading time, reduced grading errors and provided faster performance feedback for students without changing overall student performance. Anat Sci Ed 1:220–223, 2008. © 2008 American Association of Anatomists.
Accelerated embryonic development associated with increased risk of neural tube defects induced by maternal diet in offspring of SELH/Bc mice
Authors: Stoate Katharine L. , Harris Muriel J. , Juriloff Diana M.
Published: September 2008

BACKGROUND: The SELH/Bc mouse strain has a high risk of the NTD, exencephaly, caused by multifactorial genetics. All SELH/Bc embryos have delayed elevation of neural folds; some never elevate (future exencephalics). Maternal diets affect SELH/Bc exencephaly rates: 25–35% on Purina Diet 5015 versus 5–10% on Purina Diet 5001. We hypothesized that in SELH/Bc, the diets affect maternal blood glucose and embryonic developmental rate. METHODS: We compared mice fed the two diets. On GD 9.4 we tested maternal blood glucose and examined embryos for developmental age (somite count) and cranial neural fold morphology. We observed GD 14 exencephaly rates. RESULTS: Diet 5015 caused fivefold more exencephaly (40 vs. 7% on GD 14), significantly higher mean maternal blood glucose in replicate experiments (6.3 vs. 5.5, p < .05; 6.3 vs. 5.3 mmol/L, p < .05), and significantly higher mean litter somite count on GD 9.4 (18.4 vs. 15.0, p < .05; 16.7 vs. 14.4 somites, p < .05). Among midrange embryos (15–16 somites), embryos from Diet 5015 were significantly shifted to earlier stages of midbrain fold morphology and had significantly more distance between the tips of the folds (p < .05). CONCLUSIONS: In SELH/Bc mice, the 5015 diet causes higher maternal blood glucose, a faster overall embryonic developmental rate during neural tube closure, and delayed midbrain fold elevation relative to overall development. This pattern suggests that maternal dietary effects that modestly increase embryonic growth rate may exacerbate a lack of coordination between genetically delayed neural folds and normally developing underlying tissues, increasing risk of NTD. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.
Profilin, a multi‐modal regulator of neuronal plasticity
Authors: Birbach Andreas
Published: September 2008

Thirty years after its initial characterization and more than 1000 publications listed in PubMed describing its properties, the small (ca15 kDa) protein profilin continues to surprise us with new, recently discovered functions. Originally described as an actin‐binding protein, profilin has now been shown to interact with more than a dozen proteins in mammalian cells. Some of the more recently described and intriguing interactions are within neurons involving a neuronal profilin family member. Profilin is now regarded as a regulator of various cellular processes such as cytoskeletal dynamics, membrane trafficking and nuclear transport. Profilin is a necessary element in key steps of neuronal differentiation and synaptic plasticity, and embodies properties postulated for a synaptic tag. These findings identify profilin as an important factor linking cellular and behavioural plasticity in neural circuits. BioEssays 30:994–1002, 2008. © 2008 Wiley Periodicals, Inc.
Shaping segments: Hox gene function in the genomic age
Authors: Hueber Stefanie D. , Lohmann Ingrid
Published: September 2008

Despite decades of research, morphogenesis along the various body axes remains one of the major mysteries in developmental biology. A milestone in the field was the realisation that a set of closely related regulators, called Hox genes, specifies the identity of body segments along the anterior–posterior (AP) axis in most animals. Hox genes have been highly conserved throughout metazoan evolution and code for homeodomain‐containing transcription factors. Thus, they exert their function mainly through activation or repression of downstream genes. However, while much is known about Hox gene structure and molecular function, only a few target genes have been identified and studied in detail. Our knowledge of Hox downstream genes is therefore far from complete and consequently Hox‐controlled morphogenesis is still poorly understood. Genome‐wide approaches have facilitated the identification of large numbers of Hox downstream genes both in Drosophila and vertebrates, and represent a crucial step towards a comprehensive understanding of how Hox proteins drive morphological diversification. In this review, we focus on the role of Hox genes in shaping segmental morphologies along the AP axis in Drosophila, discuss some of the conclusions drawn from analyses of large target gene sets and highlight methods that could be used to gain a more thorough understanding of Hox molecular function. In addition, the mechanisms of Hox target gene regulation are considered with special emphasis on recent findings and their implications for Hox protein specificity in the context of the whole organism. BioEssays 30:965–979, 2008. © 2008 Wiley Periodicals, Inc.
Nonsense‐mediated decay: paving the road for genome diversification
Authors: Sánchez‐Sánchez Francisco , Mittnacht Sibylle
Published: September 2008

The expression of protein‐encoding genes is a complex process culminating in the production of mature mRNA and its translation by the ribosomes. The production of a mature mRNA involves an intricate series of processing steps. The majority of eukaryotic protein‐encoding genes contain intron sequences that disrupt the protein‐encoding frame, and hence have to be removed from immature mRNA prior to translation into protein. The mechanism involved in the selection of correct splice sites is incompletely understood. A considerable body of evidence suggests that the splicing machinery has suboptimal efficiency and fidelity leading to substantial processing inaccuracy. Here we discuss a recently published article1 that extends observations that cells rely on nonsense‐mediated mRNA decay (NMD) to compensate for such suboptimal processing accuracy. Intriguingly these authors provide evidence for a strong selective pressure in favour of premature termination of mRNA translation in the event of intron retention. The analysis presented implies a positive role of NMD in transcript diversification through alternative splicing and suggest that this ancient surveillance mechanism may have co‐evolved with intron acquisition born from the need for quality control of splicing patterns. BioEssays 30:926–928, 2008. © 2008 Wiley Periodicals, Inc.
Luminescent properties of a novel fluorene organic material
Authors: Lou Shuangling , Yu Junsheng , Qian Jincheng , Jiang Yadong , Zhang Qing , Xu Hongjie , Sun Limei
Published: September 2008

The photo‐physical properties of 6,6′‐(9H‐fluoren‐9,9‐diyl)bis(2,3‐bis(9,9‐dihexyl‐9H‐fluoren‐2‐yl)quinoxaline) (BFLBBFLYQ) and its blend doped withN′‐biphenyl‐N,N′‐bis‐(3‐methylphenyl)‐1,1′‐biphenyl‐4,4′‐diamine (TPD) were investigated. The absorption, photoluminescence (PL) and electroluminescence (EL) properties of pristine BFLBBFLYQ and blend in solution and spin‐coated film are outlined, including a discussion of charge‐transfer (CT) exciplex emission of BFLBBFLYQ:TPD blend in the solid state. The luminescent properties of BFLBBFLYQ films using different deposition processes were studied. It was found that the low‐energy emission bands at 530–570 nm appeared in the PL spectra of BFLBBFLYQ evaporated films in ultra‐high vacuum. Also, the low‐energy band was the exclusive emission in the EL spectra of BFLBBFLYQ films. Copyright © 2008 John Wiley & Sons, Ltd.
Engineering cell lines for production of replication defective HSV‐1 gene therapy vectors
Authors: Grant Kyle G. , Krisky David M. , Ataai Mohammed M. , Glorioso Joseph C.
Published: September 2008

Herpes simplex virus type 1 (HSV‐1) represents an attractive vehicle for a variety of gene therapy applications. To render this virus safe for clinical use, its cytotoxic genes must be removed without losing its ability to express transgenes efficiently. Our vectors are deleted for the essential immediate early genes ICP4 and ICP27. These genes are controlled by unique promoters having enhancer elements responsive to a viral structural protein VP16. The expression of these genes occurs prior to the activation of all other lytic functions and is thus required to initiate and complete the virus replication cycle. For large scale manufacture of clinical grade vectors, efficient cell lines must be generated that express the essential viral gene products in trans during vector propagation. Here we describe methods for engineering HSV‐1 production cell lines that improve vector growth by altering the kinetics of complementing gene expression. We examined the ability of Vero cells independently transduced with ICP4 and ICP27 under transcriptional control of their respective promoters to support the growth of a replication defective vector (JDTOZHE), deleted for ICP4, ICP27 and approximately 20 kb of internal elements that are not required for virus growth in Vero cells. Vector yield on this cell line was 3 logs lower than wild‐type virus grown on Vero cells. To understand the mechanism underlying poor vector yield, we examined the expression of ICP4 and ICP27 during virus complementation. While ICP27 was expressed immediately on vector infection, the expression of ICP4 was considerably delayed by 8–10 h, suggesting that the ICP4 promoter was not adequately activated by VP16 delivered by the infectious vector particle. Use of the ICP0 promoter to express ICP4 from the cellular genome resulted in higher induction levels and faster kinetics of ICP4 expression and a 10‐fold improvement in vector yield. This study suggests that vector complementation is highly dependent on the kinetics of complementing gene expression and can lead to large differences in vector yield. Biotechnol. Bioeng. 2009;102: 1087–1097. © 2008 Wiley Periodicals, Inc.
A clone screening method using mRNA levels to determine specific productivity and product quality for monoclonal antibodies
Authors: Lee Christina J. , Seth Gargi , Tsukuda Joni , Hamilton Robert W.
Published: September 2008

To meet increasing demands for efficient and streamlined production processes of therapeutic antibodies, improved methods of screening clones are required. In this article, we examined the potential of using antibody transcript levels as criteria for clone screening. We evaluated the QuantiGene Plex, a commercially available, high‐throughput assay for simultaneously measuring multiple transcripts from cell lysate. Using the development of stable Chinese hamster ovary cell lines as examples, we investigated the relationship between transcript and antibody levels through several rounds of screening. First, we observed that measured heavy chain transcript levels are generally correlated with specific productivity, enabling the identification of high‐producing clones from mRNA. Second, we observed that low ratios (<1.5) of light to heavy chain transcript levels may be indicative of high antibody aggregation levels, allowing for the rapid identification and elimination of clones of questionable product quality. Therefore, an efficient process of identifying high‐producing clones of desirable product quality is possible by using QuantiGene Plex assay to measure antibody transcript levels. Biotechnol. Bioeng. 2009;102: 1107–1118. © 2008 Wiley Periodicals, Inc.
Determination of a novel epothilone D analog (AV‐EPO‐106) in human plasma using ultra‐performance liquid chromatography–tandem mass spectrometry
Authors: Zhang Shuang‐Qing , Vinnakota Harsha , Jung Jae‐Chul , Carvalho Paulo , Chittiboyina Amar G. , Avery Mitchell A. , Avery Bonnie A.
Published: September 2008

A novel ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS‐MS) method has been established for the determination of a newly synthesized epothilone D analog (AV‐EPO‐106) in human plasma. The plasma samples were prepared by liquid–liquid extraction with cold tert‐butyl methyl ether. The chromatographic separation was achieved within 5 min on a C18 column with water–methanol (10:90, v/v) as mobile phase at a flow‐rate of 0.8 mL/min. Mass transition of m/z 568.2 to 386.1 was measured for AV‐EPO‐106 in positive atmospheric pressure chemical ionization mode. A detailed validation of the method was performed as per the USFDA guidelines. For AV‐EPO‐106 at the concentrations of 1.0, 5.0 and 10.0 µg/mL in human plasma, the absolute extraction recoveries were 86.17, 85.24 and 85.69%, respectively. The linear quantification range of the method was 0.10–20.0 µg/mL in human plasma with linear correlation coefficients greater than 0.999. The intra‐day and inter‐day accuracy for AV‐EPO‐106 at the levels of 1.0, 5.0 and 10.0 µg/mL in human plasma fell in the ranges of 98.25–100.47 and 94.19–97.25%, and the intra‐ and inter‐day precision were in the ranges of 4.75–6.30% and 8.89–10.45%, respectively. The method was successfully applied to quantify AV‐EPO‐106 in human plasma to determine the half‐life of this compound in human plasma. Copyright © 2008 John Wiley & Sons, Ltd.
Effect of chemically bonded stationary phases and mobile phase composition on β‐blockers retention in RP‐HPLC
Authors: Buszewski Boguslaw , Welerowicz Tomasz , Kowalkowski Tomasz
Published: September 2008

The effects of stationary and mobile phase on retention of 18 β‐adrenolytic drugs (β‐blockers) have been studied. Four ‘deactivated surface’ stationary phases (polar‐embedded or end‐capped) were examined. Special attention was drawn to the cholesterolic (SG‐CHOL) and alkylamide (SG‐AP) stationary phases, and their application for analysis of the compounds. The retention of analyzed substances was also examined in terms of mobile phase composition. Sixteen different configurations of mobile phases were prepared, all based on methanol and acetonitrile with ammonium acetate and ammonium formate. The difference in retention between ammonium formate and acetate water solutions, and peak shape changes related to the addition of triethylamine (TEA), were investigated. Principal component analysis was used to find the similarities between stationary phases. Polar‐embedded phases synthesized on the same sorbent possess very similar properties. All phases based on silica gel compared with the monolithic column also showed similarities in retention of β‐blockers. The addition of TEA to the mobile phase did not influence strongly the retention, and analysis of asymmetry factors showed only a little peak broadening for a few compounds on the monolithic column. Copyright © 2008 John Wiley & Sons, Ltd.
Determination of 3′,4′,5′,5,7‐pentamethoxyflavone in the plasma and intestinal mucosa of mice by HPLC with UV detection
Authors: Cai Hong , Brown Karen , Steward William P. , Gescher Andreas J.
Published: September 2008

In a preliminary experiment 3′,4′,5′,5,7‐pentamethoxyflavone (PMF) inhibited adenoma development in ApcMin mice, a model of the human heritable condition familial adenomatous polyposis. An HPLC method for tricin was modified and validated to permit measurement of PMF in mouse plasma and intestinal mucosa. HPLC analysis was carried out on a Hypersil‐BDS C18 column with detection at 324 nm and tricin as internal standard. The assay was linear in the range of 100–2000 ng/mL plasma and 1.0–40 µg/mL mucosa. PMF in plasma was efficiently extracted using solid‐phase columns. In the case of mucosa organic solvent protein precipitation displayed satisfactory accuracy and precision. The assay recovery at low, medium and high concentrations was between 85 and 103% for both biomatrices, with a relative standard deviation of <15%. The lower limits of quantitation for plasma and mucosa were 100 ng/mL and 1.0 µg/mL, respectively. This method allowed measurement of PMF steady‐state median concentrations in plasma (1.08 nmol/mL, n = 11; 10th and 90th percentiles: 0.633 and 2.385 nmol/mL) and mucosa (108.5 nmol/g, n = 9; 10th and 90th percentiles: 38.9 and 164.4 nmol/g) in mice which had received PMF (0.2%, w/w) with their diet. Copyright © 2008 John Wiley & Sons, Ltd.
Identification and quantification of two antihepatotoxic coumarinolignoids cleomiscosin A and cleomiscosin B in the seeds of Cleome viscosa using liquid chromatography–tandem mass spectrometry
Authors: Chattopadhyay Sunil K. , Kumar Satyanshu , Kaur Ranjeet , Tandon Sudeep , Rane Shailendra
Published: September 2008

A sensitive liquid chromatography/electrospray ionization tandem mass spectrometric (LC/ESI‐MS/MS) method was developed for the identification and quantification of two antihepatotoxic coumarinolignoids cleomiscosin A and cleomiscosin B in different extracts of the seeds of Cleome viscosa. The separation of cleomiscosin A and cleomiscosin B was achieved on an RP18 column using a solvent system consisting of a mixture of acetonitrile–methanol (1:2, v/v) and acetonitrile–water–formic acid (5:95:0.3, v/v) as a mobile phase in a gradient elution mode. A multiple‐reaction monitoring (MRM) method was developed for quantification of cleomiscosin A and cleomiscosin B in the seed extracts of Cleome viscosa. On the basis of signal‐to‐noise ratio of 3, the limit of detection in MRM mode for cleomiscosin A and cleomiscosin B were 1.0 and 4.0 ng/mL respectively. The method was validated in terms of linearity, accuracy and precision for 6 days. The method developed was found to be useful for identification and quantification of cleomiscosin A and cleomiscosin B in the different extracts of the seeds of Cleome viscosa. Copyright © 2008 John Wiley & Sons, Ltd.
Liver glycogen metabolism during short‐term insulin‐induced hypoglycemia in fed rats
Authors: Obici Simoni , Lopes‐Bertolini Gisele , Curi Rui , Bazotte Roberto Barbosa
Published: September 2008

The activities of glycogen phosphorylase and synthase during infusions of glucagon, isoproterenol, or cyanide in isolated liver of fed rats submitted to short‐term insulin‐induced hypoglycemia (IIH) was investigated. A condition of hyperinsulinemia/hypoglycemia was obtained with an intraperitoneal injection of regular insulin (1.0 U kg−1). The control group received ip saline. The experiments were carried out 60 min after insulin (IIH group) or saline (COG group) injection. The rats were anesthetized and after laparotomy, blood was collected from the vena cava for glucose and insulin measurements. The liver was then infused with glucagon (1 nM), isoproterenol (2 µM), or cyanide (0.5 mM) during 20 min and a sample of the organ was collected for determination of the activities of glycogen phosphorylase and synthase 5 min after starting and 10 min after stopping the infusions. The infusions of cyanide, glucagons, and isoproterenol did not change the activities of glycogen synthase and glycogen phosphorylase. However, glycogen catabolism was decreased during the infusions of glucagon and isoproterenol in IIH rats, being more intense with isoproterenol (p < 0.05), than glucagon. It was concluded that short‐term IIH promoted changes in the liver responsiveness of glycogen degradation induced by glucagon and isoproterenol without a change in the activities of glycogen phosphorylase and synthase. Copyright © 2008 John Wiley & Sons, Ltd.
Theoretical Insights into Enantioselective Catalysis: The Mechanism of the Kharasch–Sosnovsky Reaction
Authors: Mayoral José Antonio , Rodríguez‐Rodríguez Sergio , Salvatella Luis
Published: September 2008

The mechanism of the Kharasch–Sosnovsky reaction has been investigated using B3 LYP/6‐31G* calculations on a chiral reaction model [cyclohexene + tert‐butyl perbenzoate → cyclohex‐2‐enyl benzoate + tert‐butyl alcohol, catalyzed by a chiral bisoxazoline‐copper(I) complex]. Although two previous reaction mechanisms have been considered, the results are consistent with a new mechanistic pathway. This path involves ligand exchange between the catalyst–cyclohexene complex with tert‐butyl perbenzoate to give a catalyst–perester complex, which undergoes an (either one‐ or two‐step) oxidative addition reaction to yield a copper(III) complex. The limiting step of the Kharasch–Sosnovsky reaction consists of an intramolecular step involving the abstraction of an allylic hydrogen from cyclohexene [which is π‐bound to the copper(III) complex]. The resulting allyl‐copper(III) complex (subsequent to the loss of tert‐butanol) can undergo a haptotropic rearrangement by means of an η1‐allyl/η3‐allyl equilibrium, leading to scrambling between vinylic and allylic positions when an isotopically labeled substrate is used. The allyl‐copper(III) ion undergoes a stereospecific reductive elimination involving the π‐bond migration to yield a reaction product–catalyst complex, which can regenerate the alkene‐copper(I) complex by ligand exchange. The proposed reaction mechanism is consistent with all known experimental results (including enantioselectivity data).
Aldol Reactions between L‐Erythrulose Derivatives and Chiral α‐Amino and α‐Fluoro Aldehydes: Competition between Felkin–Anh and Cornforth Transition States
Authors: Díaz‐Oltra Santiago , Carda Miguel , Murga Juan , Falomir Eva , Marco J. Alberto
Published: September 2008

Both matched and mismatched diastereoselection have been observed in aldol reactions of a boron enolate of a protected L‐erythrulose derivative with several chiral α‐fluoro and α‐amino aldehydes. Strict adherence to the Felkin–Anh model for the respective transition structures does not account satisfactorily for all the observed results, as previously observed in the case of α‐oxygenated aldehydes. In some cases, only the Cornforth model provides a good explanation. The factors that influence this dichotomy are discussed and a general mechanistic model is proposed for aldol reactions with α‐heteroatom‐substituted aldehydes. Additional support for the model was obtained from density functional calculations.
Interferon‐α for recurrent World Health Organization grade 1 intracranial meningiomas
Authors: Chamberlain Marc C. , Glantz Michael J.
Published: September 2008

BACKGROUND.

Intracranial meningiomas are common, they frequently recur after surgery or radiotherapy, and there are limited data regarding the treatment of intracranial meningiomas with chemotherapy. A phase 2 study was designed to estimate the 6‐month progression‐free survival of patients with recurrent, treatment‐refractory, World Health Organization grade 1 meningiomas who were treated with interferon‐α.

METHODS.

Thirty‐five patients with recurrent meningiomas ranging in age from 36 years to 88 years (median age, 61 years) were treated according to a prospective phase 2 study. All patients had received prior surgery, radiotherapy, (involved‐field radiotherapy in 35 patients andstereotactic radiotherapy in 22 patients), and chemotherapy (hydroxyurea in 19 patients and other in 17 patients). On radiographic documentation of progressive disease, interferon‐α (at a dose of 10 million U/m2 administered subcutaneously every other day) was initiated. A complete blood count and chemistry panel was obtained before every cycle, and cranial magnetic resonance images were obtained every 3 months.

RESULTS.

The most common grade 3 and 4 toxicities were fatigue (6 patients; 17%), anemia (3 patients; 8.6%), and leukopenia (3 patients; 8.6%) (toxicities were graded according to the National Cancer Institute's Common Toxicity Criteria [version 3.0]). Three patients went off study because of toxicity, and 7 patients required a dose reduction. There were no treatment‐related deaths or delays in therapy reported. All patients were assessable for response. No patient demonstrated a neuroradiographic complete or partial response. Twenty‐six patients demonstrated stable disease after the first 3 cycles of interferon‐α, and 9 patients had progressive disease. The progression‐free survival rate was 54% at 6 months and 31% at 12 months. The median time to tumor progression was 7 months (range, 2‐24 months). The median survival was 8 months (range, 3‐28 months).

CONCLUSIONS.

Treatment with interferon‐α for recurrent meningiomas was found to be tolerated moderately well and was modestly effective. Cancer 2008. © 2008 American Cancer Society.
Clofarabine combinations as acute myeloid leukemia salvage therapy
Authors: Faderl Stefan , Ferrajoli Alessandra , Wierda William , Huang Xuelin , Verstovsek Srdan , Ravandi Farhad , Estrov Zeev , Borthakur Gautam , Kwari Monica , Kantarjian Hagop M.
Published: September 2008

BACKGROUND.

Outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory. Clofarabine is a nucleoside analog with activity in adult AML. Combinations with cytarabine in AML are feasible and effective. Idarubicin is another active AML drug, which has not yet been tested with clofarabine.

METHODS.

The authors therefore designed a phase I study of clofarabine ± cytarabine, plus idarubicin. Patients with primary refractory or first‐relapse AML were assigned to either clofarabine plus idarubicin (CI) if previously exposed to cytarabine with a response lasting <12 months, or clofarabine and idarubicin plus cytarabine (CIA) for responses ≥12 months, or if never exposed to cytarabine. A standard “3 + 3” phase 1 design was followed to define maximum tolerated dose (MTD). Forty‐four patients were treated (23 CI; 21 CIA).

RESULTS.

Dose‐limiting toxicities were hyperbilirubinemia and hepatic transaminase elevations for CI‐treated patients in addition to mucositis and diarrhea for CIA‐treated patients. MTD for CI was clofarabine 22.5 mg/m2 intravenously daily × 5 and idarubicin 10 mg/m2 intravenously daily × 3. MTD for CIA was clofarabine 22.5 mg/m2 intravenously × 5, idarubicin 6 mg/m2 intravenously × 3, and cytarabine 0.75 g/m2 intravenously × 5 days.

CONCLUSIONS.

A phase 2 randomized trial is in process to compare activity between treatment arms. Cancer 2008. © 2008 American Cancer Society.
A discrete geometric conservation law (DGCL) for a cell vertex finite‐volume algorithm on moving domains
Authors: Gil A. J. , Bonet J. , Silla J. , Hassan O.
Published: September 2008

This paper revisits the classical discrete geometric conservation law for the arbitrary Lagrangian–Eulerian conservation equations in a moving domain when the conservation laws are mapped to a fixed reference domain. The discretized form of the equations is formulated by means of a cell vertex finite‐volume algorithm with special emphasis on the implications of the discrete time–space algorithm for the preservation of free‐stream flows. Under these circumstances, two corrections are introduced in order to guarantee the preservation of a free‐stream flow evolving in time. A time correction is required to resolve the integration errors in the Jacobian of the transformation or mapping between fixed referential and current domains. A spatial correction is also needed to account for the inexact surface integration in the faces of the dual mesh. Copyright © 2008 John Wiley & Sons, Ltd.
Sulfate‐Bridged Dimeric Copper(II) Complexes with Three‐Dimensional Network: Synthesis, Structure and DFT Studies
Authors: Basu Chandrama , Biswas Saptashati , Chattopadhyay Asoke P. , Stoeckli‐Evans Helen , Mukherjee Soma
Published: September 2008

The 1:1 reaction of the diacetyl monoxime‐2‐pyridyl hydrazone HL1 (1) and the pyridine‐2‐carboxaldehyde‐2‐imidazoline hydrazone hydrobromide HL2 (2) with copper(II) sulfate pentahydrate in methanol affords a series of new sulfate‐bridged dimeric copper(II) complexes, [CuII2(HL1)2(μ‐SO4)2]·4H2O (1a) and [CuII2(HL2)2(μ‐SO4)Br2]·2H2O (2a), respectively. The room temperature magnetic moments of the complexes 1a and 2a are 1.82 μβ and 1.84 μβ, respectively. The bands appearing in the UV region (200–340 nm) are characteristic of the ligands HL1 (1) and HL2 (2). In complexes 1a and 2a, these ligand centred bands are accompanied by multiple bands extending into the visible region (370–480 nm). The association constant (Kass, UV/Vis) was found to be (1.120 ± 0.002) × 105 for 1a and (1.196 ± 0.002) × 104 for 2a at 298 K determined using UV/Vis spectroscopy. On excitation at 285 nm, ligand 1 emits strongly in the 364 nm region due to an intraligand 1(π–π*) transition. Upon complexation with copper(II), the emission peak is slightly blue shifted (354 nm, F/Fo 0.89) with a little quenching in the emission intensity as expected for divalent copper. Complexes 1a and 2a exhibit two consecutive oxidation couples for two copper(II) centres in deionised distilled water under a nitrogen atmosphere. DFT and TDDFT calculations were performed and the results are highly consistent with the spectroscopic behaviour of the complexes. The molecular structures of dinuclear 1a (Cu···Cu 4.555 Å) and 2a (Cu···Cu 6.106 Å) have been determined by single‐crystal X‐ray diffraction studies.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Photoreversible Zn2+ Ion Transportation Across an Interface Using Ion‐Chelating Substituted Photochromic 3,3′‐Indolospirobenzopyrans: Steric and Electronic Controlling Effects
Authors: Roxburgh Craig J. , Sammes Peter G. , Abdullah Ayse
Published: September 2008

The photoreversible transportation of Zn2+ ions across an interface using photochromic substituted‐spirobenzopyrans has been demonstrated. The inclusion of strategically placed sterically influencing 3′‐methyl‐3b and 3‐spirocyclohexyl‐3c groupings is investigated and compared to the unsubstituted analogue 3a. Significant control over the spiropyran ring‐opening↔closing reaction, and hence Zn2+ ion transportation has been realised. Additionally, the spiropyran ring‐opening↔closing reactions of two skeletally identical spirobenzopyrans 4 and 5, but possessing “electronically‐modifying” 5‐trifluoromethyl‐substitutents have been studied by 1H NMR spectroscopy: this has enabled us to realise the additional biasing, on the ring‐opening↔closing process, excerpted on these systems through both selectively placed, inductively controlling functional‐group substitution and/or, simultaneously, sterically influencing group substitution. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Isomeric Al2R4, Mg2R2 Species and Oligomerisation Products: Investigation of Al–Al and Mg–Mg σ Bonding
Authors: Pankewitz Tobias , Klopper Wim , Henke Patrick , Schnöckel Hansgeorg
Published: September 2008

Initiated by ongoing experimental work in the field of subvalent aluminium compounds and by recent results on isoelectronic Mg2R2 (s1 states) species, detailed theoretical work was necessary to explain the unusual bonding situation in some Al2R4 isomers (R = PtBu2), of a dimeric Al4R′8 (R′ = OtBu) as well as of subhalides Al2F4, Al2Cl4, Mg2Cl2 and some of their oligomers. These results are presented in this contribution. Especially the different isomers of the four‐membered heterocyclic RAlR2AlR molecule needed careful theoretical investigation, since on the way from monomeric AlR2 radicals to the most stable RAlR2AlR isomer with a butterfly shape, intermediates with different Al–Al interactions – exhibiting diradical as well as diradicaloid character – have to be considered. The presented results on the unusual bonding in these AlP2Al four‐membered heterocyclic systems are an important contribution to a better understanding of the bonding situations in many inorganic molecules containing, for example, B2P2, C2P2, Ge2N2, Sn2N2 and Si4 entities, which recently have drawn considerable interest. In analogy to the AlII compounds some isoelectronic MgI species have been investigated. Regarding the obtained results, special attention is drawn to MgCl oligomers, since we found unexpectedly high oligomerisation energies in our calculations. This high stabilisation is based on direct Mg–Mg bonding as well as on Mg–Cl–Mg bridging bonds. These mixed bonding motifs may also be present in the so far unknown solid MgCl. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Grecoketides A and B: New Naphthoquinones from Streptomyces sp. Acta 1362
Authors: Paululat Thomas , Katsifas Efstathios A. , Karagouni Amalia D. , Fiedler Hans‐Peter
Published: September 2008

Two novel naphthoquinones were produced by the streptomycete Acta 1362. It was determined by HPLC/diode‐array screening that freshly isolated actinomycete strains from selected European ecosystems produce new compounds. Grecoketides A and B were isolated and their structures determined. Both compounds have the same aglycon grecoketidone with a sugar side‐chain that differs in one of the two attached sugar units. Moreover, the biosynthesis of grecoketidone was studied by feeding singly and fully labelled acetate. The hexaketide formed is cyclized after s‐mode folding. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Boron‐Based Diastereomerism and Enantiomerism in Imine Complexes – Determination of the Absolute Configuration at Boron by CD Spectroscopy
Authors: Braun Manfred , Schlecht Sebastian , Engelmann Marco , Frank Walter , Grimme Stefan
Published: September 2008

Boron turns out to be a stable stereogenic center in imine complexes of aryl and alkyl boronates. Diastereomerically pure complexes 7a–c are obtained from chiral imine ligands 5a,b that are derived from the amino alcohol (R)‐4. The configuration at the boron atom is determined by crystal structure analyses. Racemic boronates 10a–c, available from a condensation of aryl boronic acids 6 with the achiral imine ligand 9, can be separated into stable enantiomers by HPLC on a chiral column. The racemization barrier ΔG≠ has been determined to amount to 105–115 kJ mol–1. The comparison of calculated and measured CD spectra permits to assign unambiguously the absolute configuration to boron in the enantiomeric boronate‐imine complex 10a.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
K‐ras cancer gene mutations in lung tumors from female Swiss (CD‐1) mice exposed transplacentally to 3′‐azido‐3′‐deoxythymidine
Authors: Koujitani Takatoshi , Ton Tai‐Vu T. , Lahousse Stephanie A. , Hong Hue‐Hua L. , Wakamatsu Nobuko , Sills Robert C.
Published: September 2008

A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD‐1) mice to 0, 50, 100, 200, or 300 mg 3′‐azido‐3′‐deoxythymidine (AZT)/kg body weight (BW) daily for the duration of gestation (18–19 days) [National Toxicology Program,2006]. The incidence of alveolar/bronchiolar adenomas and carcinomas in the 200 and 300 mg/kg groups was significantly higher (P = 0.027 and 0.007, respectively) in male offspring, but not in females (P = 0.338 and 0.315, respectively). The purpose of the present study was to evaluate K‐ras mutation status in lung tumors from the female offspring in AZT exposed groups and to determine whether at the molecular level there were signature K‐ras mutations in lung tumors that were different from spontaneous tumors. K‐ras mutation was detected by cycle sequencing of polymerase chain reaction (PCR)‐amplified DNA, isolated from formalin‐fixed, paraffin‐embedded lung tumors. K‐ras mutations were detected in 17 of 28 (61%) lung tumors from the female offspring in AZT exposed groups. No K‐ras mutations were detected in the 8 tumors examined from the female control group. The predominant mutations were Codon 12 G→T transversions in the 50, 100, and 300 mg/kg groups, and Codon 12 G→C transversions in the 200 and 300 mg/kg groups. K‐ras Codon 12 G→T transversions (TGT mutations) may be induced by oxidative DNA damage and 8‐oxoguanine (8‐oxoG), while K‐ras Codon 12 G→C transversions (CGT mutations) may be due to further oxidative lesions of guanine and 8‐oxoG. Environ. Mol. Mutagen., 2008. Published 2008 Wiley‐Liss, Inc.
Induction of hypothermic conditions associated with increased micronuclei formation in sigma‐1 receptor knockout mice after administration of the antipsychotic compound E‐5842
Authors: Guzmán Antonio , Marín Ana‐Paz , García Concepción , de Henestrosa Antonio R. Fernández , Ruiz María Teresa , Tortajada Araceli , Marcos Ricard
Published: September 2008

The antipsychotic sigma‐1 (σ1) receptor ligand E‐5842 has been shown to increase micronucleated polychromatic erythrocyte (MNPCE) frequency in mouse bone marrow secondary to compound‐induced hypothermia. Interaction with σ1receptor has been considered a plausible contributing factor for E‐5842‐induced hypothermia, raising concern for a possible class effect of sigma receptor ligands in the mouse micronucleus (MN) test. We assessed the potential of E‐5842 (200 mg/kg, oral) to produce hypothermic conditions associated with increased micronuclei formation in σ1receptor knockout (σ1R‐KO) and wild type (WT) mice. After administration, animal's rectal temperature was recorded and peripheral blood and bone marrow samples were obtained (48 hr) and assessed for induction of micronucleated reticulocytes (MNRET) and MNPCE, respectively. E‐5842 administration produced marked hypothermia both in σ1R‐KO and WT mice. Maximum decreases from preadministration temperature were 12.2 and 13.5°C in σ1R‐KO and WT mice, respectively. Temperature returned to normal approximately 32 hr after administration. Bone marrow examination revealed a statistical significant increase (P< 0.05) in MNPCE frequency both in σ1R‐KO and WT animals. Examination of peripheral blood samples showed a slight, although nonstatistical significant, increase in MNRET frequency in σ1R‐KO mice. No similar effect was observed among WT animals. The results obtained after E‐5842 administration to σ1R‐KO mice indicate that induction of hypothermic conditions associated with increased MNPCE formation is not mediated by compound interaction with σ1receptor, ruling out concern for a possible class effect of similar high affinity σ1receptor ligands in the mouse MN test. Environ. Mol. Mutagen., 2008. © 2008 Wiley‐Liss, Inc.
Kinetics of γ‐H2AX focus formation upon treatment of cells with UV light and alkylating agents
Authors: Staszewski Ori , Nikolova Teodora , Kaina Bernd
Published: September 2008

Histone H2AX is rapidly phosphorylated in response to DNA double‐strand breaks (DSBs) induced by ionizing radiation (IR). Here we show that DNA damage induced by alkylating agents [methyl methanesulfonate (MMS) and N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG)] and ultraviolet light (UV‐C) leads to a dose and time dependent accumulation of phosphorylated H2AX (γ‐H2AX). Time course experiments revealed that the number of γ‐H2AX foci reached peak levels 8 hr after MMS or MNNG treatment and declined to almost control values within 24 hr after exposure. Upon UV‐C treatment, a biphasic response was observed with a maximum 12 hr after treatment. In 43‐3B cells deficient in nucleotide excision repair (NER) the number of γ‐H2AX foci increased steadily. γ‐H2AX foci were preferentially formed in BrdU labeled cells. In proliferation compromised cells, the γ‐H2AX level was significantly reduced, indicating that most of the γ‐H2AX foci induced by UV‐C and alkylating agent treatments were replication dependent. The data are in line with the view that DNA damage induced by UV‐C light and simple alkylating agents, leads to the formation of DSBs during DNA replication giving rise to H2AX phosphorylation. In replicating NER defective cells, DSBs accumulate due to nonrepaired primary DNA lesions that produce a high level of DSBs during replication. The data support that γ‐H2AX foci are a useful marker of DSBs that are induced by S‐phase dependent genotoxins during replication. Environ. Mol. Mutagen., 2008. © 2008 Wiley‐Liss, Inc.
Diallyl trisulfide selectively causes Bax‐ and Bak‐mediated apoptosis in human lung cancer cells
Authors: Xiao Dong , Zeng Yan , Hahm Eun‐Ryeong , Kim Young‐Ae , Ramalingam Suresh , Singh Shivendra V.
Published: September 2008

Garlic‐derived organosulfur compounds (OSCs) are highly effective in affording protection against chemically induced pulmonary carcinogenesis in animal models. We now demonstrate that garlic constituent diallyl trisulfide (DATS) suppresses viability of cultured human lung cancer cell lines H358 (anon‐small cell lung cancer cell line) and H460 (a large cell lung cancer cell line) by causing G2‐M phase cell cycle arrest and apoptotic cell death. On the other hand, a normal human bronchial epithelial cell line BEAS‐2B was significantly more resistant to growth inhibition and apoptosis induction by DATS compared with lung cancer cells. We also found that even a subtle change in the OSC structure could have a significant impact on its biological activity. For example, DATS was significantly more effective than either diallyl sulfide or diallyl disulfide against proliferation of lung cancer cells. The DATS‐mediated G2‐M phase cell cycle arrest was explained by down‐regulation of cyclin‐dependent kinase 1 (Cdk1) and cell division cycle 25C protein expression leading to accumulation of Tyr15 phosphorylated (inactive) Cdk1. The DATS‐induced apoptosis correlated with induction of pro‐apoptotic proteins Bax, Bak and BID, and a decrease in the expression of anti‐apoptotic proteins Bcl‐2 and Bcl‐xL in lung cancer cells but not in BEAS‐2B. Knockdown of Bax and Bak proteins conferred significant protection against DATS‐induced apoptotic cytoplasmic histone‐associated DNA fragmentation. On the other hand, BID protein was dispensable for DATS‐induced apoptosis. In conclusion, the present study indicates that Bax and Bak proteins are critical targets of DATS‐induced apoptosis in human lung cancer cells. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.