bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Latent Autoimmune Diabetes in Adults Distinct From Type 1 Diabetes or Just Type 1 Diabetes at an Older Age?
Authors: Palmer Jerry P. , Hampe Christiane S. , Chiu Harvey , Goel Amit , Brooks-Worrell Barbara M.
Published: March 2007

Diabetes is classified clinically into two types: type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune diabetes, whereas, in contrast, type 2 diabetes is nonautoimmune. However, there is a group of phenotypic adult type 2 diabetic patients (∼10%) who have islet autoantibodies similar to type 1 diabetes. These patients are said to have latent autoimmune diabetes in adults (LADA) or type 1.5 diabetes. T-cells reacting with islet proteins have been demonstrated in type 1 and type 1.5 diabetic patients. In contrast, classic autoantibody-negative type 2 diabetic patients are also negative for T-cell responses to islet proteins. Therefore, we questioned whether type 1 and type 1.5 diabetes are similar or different autoimmune diseases. We have investigated the immunological and metabolic differences between type 1, type 1.5, and classic type 2 diabetic patients. We have identified autoantibody differences, differences in islet proteins recognized by T-cells, and differences in insulin resistance. We have also identified a small group of patients who have T-cells responsive to islet proteins but who are autoantibody negative. These patients appear to be similar to type 1.5 patients in having decreased stimulated C-peptide values. These immunological differences between type 1 and type 1.5 diabetes suggest at least partially distinct disease processes.
Latent Autoimmune Diabetes in Adults
Authors: Stenström Gunnar , Gottsäter Anders , Bakhtadze Ekaterine , Berger Bo , Sundkvist Göran
Published: March 2007

Latent autoimmune diabetes in adults (LADA) is a disorder in which, despite the presence of islet antibodies at diagnosis of diabetes, the progression of autoimmune β-cell failure is slow. LADA patients are therefore not insulin requiring, at least during the first 6 months after diagnosis of diabetes. Among patients with phenotypic type 2 diabetes, LADA occurs in 10% of individuals older than 35 years and in 25% below that age. Prospective studies of β-cell function show that LADA patients with multiple islet antibodies develop β-cell failure within 5 years, whereas those with only GAD antibodies (GADAs) or only islet cell antibodies (ICAs) mostly develop β-cell failure after 5 years. Even though it may take up to 12 years until β-cell failure occurs in some patients, impairments in the β-cell response to intravenous glucose and glucagon can be detected at diagnosis of diabetes. Consequently, LADA is not a latent disease; therefore, autoimmune diabetes in adults with slowly progressive β-cell failure might be a more adequate concept. In agreement with proved impaired β-cell function at diagnosis of diabetes, insulin is the treatment of choice.
Role of Endoplasmic Reticulum Stress and c-Jun NH2-Terminal Kinase Pathways in Inflammation and Origin of Obesity and Diabetes
Authors: Hotamisligil Gökhan S.
Published: March 2007

Metabolic and immune systems are the most fundamental requirements for survival, and many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily highly conserved. Consequently, metabolic and immune pathways are also highly integrated and interdependent. In the past decade, it became apparent that this interface plays a critical role in the pathogenesis of chronic metabolic diseases, particularly obesity and type 2 diabetes. Importantly, the inflammatory component in obesity and diabetes is now firmly established with the discovery of causal links between inflammatory mediators, such as tumor necrosis factor (TNF)-α and insulin receptor signaling and the elucidation of the underlying molecular mechanisms, such as c-Jun NH2-terminal kinase (JNK)- and inhibitor of nuclear factor-κB kinase–mediated transcriptional and posttranslational modifications that inhibit insulin action. More recently, obesity-induced endoplasmic reticulum stress has been demonstrated to underlie the initiation of obesity-induced JNK activation, inflammatory responses, and generation of peripheral insulin resistance. This article will review the link between stress, inflammation, and metabolic disease, particularly type 2 diabetes, and discuss the mechanistic and therapeutic opportunities that emerge from this platform by focusing on JNK and endoplasmic reticulum stress responses.
Multifaceted Therapeutic Approaches for a Multigenic Disease
Authors: Bottino Rita , Trucco Massimo
Published: March 2007

Diabetes is a severe chronic disease that affects ∼200 million individuals worldwide, with extremely debilitating effects and considerably high health care costs. The two major classes of diabetes, known as type 1 (previously known as insulin-dependent or juvenile-onset diabetes) and type 2 (non-insulin-dependent diabetes), share common symptoms such as hyperglycemia and the development of long-term complications, but they differ in many aspects, including their etiopathogenesis. New insights suggest that overlapping factors, formerly considered typical hallmarks of each specific type, can coexist in the same diabetic patient, making it difficult to support a sharp distinction between the two classes and, more importantly, to adopt appropriate therapeutic solutions. In type 1 and type 2 diabetic subjects, but even more in patients with combined types, multiple genetic factors play a role in determining susceptibility or resistance to the disease, and perhaps also the time of onset, the severity of the symptoms, the possibility of developing complications and, ultimately, the response to therapy. In this review, the therapeutic treatments currently under investigation, as well as the curative strategies envisioned for future applications, are reanalyzed considering the multifaceted and complex aspects of a continuum that can be just defined as “diabetes.”
Role of β-Cells in Type 1 Diabetes Pathogenesis
Authors: Faideau Béatrice , Larger Etienne , Lepault Françoise , Carel Jean Claude , Boitard Christian
Published: March 2007

Whether autoimmunity results primarily from a defect of the immune system, target organ dysfunction, or both remains an open issue in most human autoimmune diseases. The highly multigenic background on which diabetes develops in the NOD mouse and in the human suggests that numerous gene variants associate in contributing to activation of autoimmunity to β-cells. Both immune genes and islet-related genes are involved. The presence of β-cells is required for initiation of diabetes autoimmunity to proceed. Available experiments in the NOD mouse and epidemiological evidence in the human point to proinsulin as a key autoantigen in diabetes. The functional importance of insulin, the high number of autoantigens characterized at different stages of diabetes, and their clustering within β-cell subparticles point to the islet as a starting point in the initiation phase of the disease. Genes that direct the autoimmune reaction toward the β-cell target, autoantigens that are recognized by autoreactive B- and T-cells along the autoimmune process, the importance of β-cells in the activation of autoreactive lymphocytes, and the expression level of key β-cell molecules along diabetes development are successively considered in this review.
Molecular photochromic systems: a theoretical and experimental investigation on zinc(II) dithizonate
Authors: Armelao L. , Bandoli G. , Barreca D. , Bottaro G. , Tondello E. , Venzo A. , Vittadini A.
Published: March 2007

Zinc(II)‐dithizone based molecular systems [Zn(HDz)2] are intriguing candidates for the development of optical devices thanks to their interesting photochromic and nonlinear optical properties. In the present work, the behavior of Zn(HDz)2 in different solvents was investigated by a combined theoretical and experimental approach. In particular, solutions of both dithizone (H2Dz) and Zn(HDz)2 were analyzed by optical absorption spectroscopy and nuclear magnetic resonance (NMR) techniques, with particular attention to structure–properties relationships. Density functional and time‐dependent density functional calculations were performed on the stable and the activated forms of the complex, obtaining information on the energetics of their interconversion, as well as on the nature of their electronic excitations. Copyright © 2007 John Wiley & Sons, Ltd.
Metal‐based antibacterial and antifungal amino acid derived Schiff bases: their synthesis, characterization and in vitro biological activity
Authors: Chohan Zahid H. , Arif M. , Sarfraz M.
Published: March 2007

A new series of antibacterial and antifungal amino acid derived Schiff bases and their cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes have been synthesized and characterized by their elemental analyses, molar conductances, magnetic moments, IR and electronic spectral measurements. The spectral data indicated the Schiff base ligands (L1–L5) derived by condensation of salicylaldehyde with glycine, alanine, phenylalanine, methionine and cysteine, to act as tridentate towards divalent metal ions (cobalt, copper, nickel and zinc) via the azomethine‐N, deprotonated carboxyl group of the respective amino acid and deprotonated oxygen atom of salicylaldehyde by a stoichiometric reaction of M:L (1:2) to form complexes of the type K2[M(L)2] [where M = Co(II), Cu(II), Ni(II) and Zn(II)]. The magnetic moments and electronic spectral data suggested that all complexes have an octahedral geometry. Elemental analyses and NMR spectral data of the ligands and their Zn (II) complexes agree with their proposed structures. The synthesized ligands, along with their metal complexes, were screened for their in‐vitro antibacterial activity against four Gram‐negative (Escherichia coli, Shigella flexeneri, Pseudomonas aeruginosa and Salmonella typhi) and two Gram‐positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains and for in‐vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. The results of these studies show the metal complexes to be more antibacterial/antifungal against one or more species as compared with the uncomplexed Schiff base ligands. The brine shrimp bioassay was also carried out to study their in‐vitro cytotoxic properties. Only three compounds (2, 11 and 17) displayed potent cytotoxic activity as LD50 = 8.196 × 10−4, 7.315 × 10−4 and 5.599 × 10−4 M/ml respectively, against Artemia salina. Copyright © 2007 John Wiley & Sons, Ltd.
An ortho‐lithiated derivative of protected phenylboronic acid: an approach to ortho‐functionalized arylboronic acids and 1,3‐dihydro‐1‐hydroxybenzo[c][2,1]oxaboroles
Authors: Da̧browski Marek , Kurach Paweł , Luliński Sergiusz , Serwatowski Janusz
Published: March 2007

2‐(2′‐Bromophenyl)‐6‐butyl‐[1,3,6,2]dioxazaborocan, prepared readily by the esterification of 2‐bromophenylboronic acid with N‐butyldiethanolamine (BDEA), undergoes Br/Li exchange using BuLi/THF at − 78 °C. A resulting intermediate proved useful in synthesis of various ortho‐functionalized arylboronic acids. Specifically, reactions with benzaldehydes provide a convenient access to 1,3‐dihydro‐1‐hydroxy‐3‐arylbenzo[c][2,1]oxaboroles that exhibit a remarkably high rotational barrier around the Caryl bond. In addition, the molecular structure of sterically hindered 1,3‐dihydro‐1‐hydroxy‐3‐(2′, 6′‐dimethoxyphenyl)benzo[c][2,1]oxaborole is reported. Copyright © 2007 John Wiley & Sons, Ltd.
The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies
Authors: Goldman Jerome M. , Murr Ashley S. , Cooper Ralph L.
Published: March 2007

While an evaluation of the estrous cycle in laboratory rodents can be a useful measure of the integrity of the hypothalamic‐pituitary‐ovarian reproductive axis, it can also serve as a way of insuring that animals exhibiting abnormal cycling patterns are disincluded from a study prior to exposure to a test compound. Assessment of vaginal cytology in regularly cycling animals also provides a means to establish a comparable endocrine milieu for animals at necropsy. The procedure for obtaining a vaginal smear is relatively non‐invasive and is one to which animals can become readily accustomed. It requires few supplies, and with some experience the assessments can be easily performed in fresh, unstained smears, or in fixed, stained ones. When incorporated as an adjunct to other endpoint measures, a determination of a female's cycling status can contribute important information about the nature of a toxicant insult to the reproductive system. In doing so, it can help to integrate the data into a more comprehensive mechanistic portrait of the effect, and in terms of risk assessment, may provide some indication of a toxicant's impact on human reproductive physiology. Birth Defects Res (Part B), 2007. Published 2007 Wiley‐Liss, Inc.
Electron‐ and Energy‐Transfer Properties of Hydrophilic Carotenoids
Authors: Sliwka Hans‐Richard , Melø Thor‐Bernt , Foss Bente Jeanette , Abdel‐Hafez Shams H. , Partali Vassilia , Nadolski Geoff , Jackson Henry , Lockwood Samuel F.
Published: March 2007

The antioxidant activities—expressed as the electron‐donating properties—of five hydrophilic carotenoids (carotenoid surfactants) and three related hydrophobic carotenoids were investigated by flash photolysis. The electron‐transfer rates of the carotenoids to the triplet state of the sensitizer 2‐nitronaphthalene and the energy transfer rates of triplet 2‐nitronaphthalene to the carotenoids were determined. The results demonstrate that the electron‐donating effects of the hydrophilic and hydrophobic carotenoids were comparable when evaluated in acetonitrile. In the presence of water, however, electron transfer (i.e., antioxidant efficiency) was enhanced by a factor of four for the hydrophilic carotenoids. The increased hydrophilicity of carotenoids, therefore, could expand their antioxidant properties, thus facilitating their use as aqueous‐phase radical scavengers. At the same time, it was shown that supramolecular assembly (“aggregation”) of the amphiphilic carotenoids prevented electron transfer, thus deactivating the antioxidant function. Modulation of the biophysical properties of carotenoids through synthetic modification is capable of increasing the biological and medical utility of this natural class of predominantly hydrophobic antioxidant compound.
Rearrangement of microtubule polarity orientation during conversion of dendrites to axons in cultured pyramidal neurons
Authors: Takahashi Daisuke , Yu Wenqian , Baas Peter W. , Kawai‐Hirai Rika , Hayashi Kensuke
Published: March 2007

Axons and dendrites of neurons differ in the polarity orientation of their microtubules. Whereas the polarity orientation of microtubules in axons is uniform, with all plus ends distal, that in dendrites is nonuniform. The mechanisms responsible for establishment and maintenance of microtubule polarity orientation in neuronal processes remain unclear, however. We previously described a culture system in which dendrites of rat cortical neurons convert to axons. In the present study, we examined changes in microtubule polarity orientation in such dendrites. With the use of the hooking procedure and electron microscopy, we found that microtubule polarity orientation changed from nonuniform to uniform, with a plus end‐distal arrangement, in dendrites that gave rise to axons during culture of neurons for 24 h. Microtubule polarity orientation remained nonuniform in dendrites that did not elongate. Axon regeneration at the dendritic tip thus triggered the disappearance of minus end‐distal microtubules from dendrites. These minus end‐distal microtubules also disappeared from dendrites during axon regeneration in the presence of inhibitors of actin polymerization, suggesting that actin‐dependent transport of microtubules is not required for this process and implicating a previously unidentified mechanism in the establishment and maintenance of microtubule polarity orientation in neuronal processes. Cell Motil. Cytoskeleton 2007. © 2007 Wiley‐Liss, Inc.
Rho plays a central role in regulating local cell‐matrix mechanical interactions in 3D culture
Authors: Lakshman N. , Kim A. , Bayless K. J. , Davis G. E. , Petroll W. M.
Published: March 2007

The purpose of this study was to assess quantitatively the role of the small GTPase Rho on cell morphology, f‐actin organization, and cell‐induced matrix remodeling in 3D culture. Human corneal fibroblasts (HTK) were infected with adenoviruses that express green fluorescent protein (GFP) or GFP‐N19Rho (dominant negative Rho). One day later cells were plated inside collagen matrices and allowed to spread for 24 h. Cells were fixed and stained for f‐actin. Fluorescent (for f‐actin) and reflected light (for collagen fibrils) images were acquired using confocal microscopy. Fourier transform analysis was used to assess local collagen fibril alignment, and changes in cell morphology and collagen density were measured using MetaMorph. The decrease in matrix height was used as an indicator of global matrix contraction. HTK and HTK‐GFP cells induced significant global matrix contraction; this was inhibited by N19Rho. HTK and HTK‐GFP fibroblasts generally had a bipolar morphology and occasional intracellular stress fibers. Collagen fibrils were compacted and aligned parallel to stress fibers and pseudopodia. In contrast, HTK‐GFPN19 cells were elongated, and had a more cortical f‐actin distribution. Numerous small extensions were also observed along the cell body. In addition, both local collagen fibril density and alignment were significantly reduced. Rho plays a key role in regulating both the morphology and mechanical behavior of corneal fibroblasts in 3D culture. Overall, the data suggest that Rho‐kinase dependent cell contractility contributes to global and local matrix remodeling, whereas Rho dependent activation of mDia and/or other downstream effectors regulates the structure and number of cell processes. Cell Motil. Cytoskeleton 2007. © 2007 Wiley‐Liss, Inc.
Microtubule‐binding proteins CLASP1 and CLASP2 interact with actin filaments
Authors: Tsvetkov Andrey S. , Samsonov Andrey , Akhmanova Anna , Galjart Niels , Popov Sergey V.
Published: March 2007

Cell morphogenesis requires dynamic communication between actin filaments and microtubules which is mediated, at least in part, by direct structural links between the two cytoskeletal systems. Here, we examined interaction between the CLIP‐associated proteins (CLASP) CLASP1 and CLASP2, and actin filaments. We demonstrate that, in addition to a well‐established association with the distal ends of microtubules, CLASP2α co‐localizes with stress fibers, and that both CLASP1α and CLASP2α co‐immunoprecipitate with actin. GFP‐CLASP2α exhibits retrograde flow in the lamellipodia of Xenopus primary fibroblasts and in the filopodia of Xenopus spinal cord neurons. A deletion mapping analysis reveals that both the microtubule‐binding domain of CLASP2 (which is homologous between all CLASPs) and the N‐terminal dis1/TOG domain of CLASP2α (which is homologous between α isoforms) possess actin‐binding activity. Fluorescence resonance energy transfer experiments demonstrate significant energy transfer between YFP‐CLASP2α and CFP‐actin. Our results indicate that CLASPs function as actin/microtubule crosslinkers in interphase cells. We propose that CLASPs facilitate recognition of actin filaments by the plus ends of growing microtubules at the initial stages of actin‐microtubule interaction. Cell Motil. Cytoskeleton 2007. © 2007 Wiley‐Liss, Inc.
Virtual Screening Leads to the Discovery of an Effective Antagonist of Lymphocyte Function‐Associated Antigen‐1
Authors: Shoda Miyuki , Harada Takeo , Yano Kazuo , Stahura Florence L. , Himeno Takeshi , Shiojiri Satoshi , Kogami Yuji , Kouji Hiroyuki , Bajorath Jürgen
Published: March 2007

The binding of lymphocyte function‐associated antigen‐1 (LFA‐1) to its ligand on endothelial cells, intercellular adhesion molecule‐1 (ICAM‐1), is a crucial step in the migration of leukocytes during the early stages of inflammation and is also involved in T‐cell activation. In this paper, we report the identification of a series of novel antagonists of the LFA‐1/ICAM‐1 interaction using ligand‐based virtual screening (VS), analogue design, and structure–activity relationship (SAR) analysis. Candidate compounds were evaluated in protein binding and cell adhesion assays. Experimental evaluation of only 25 candidates selected from a pool of ∼2.5 million database compounds identified an initial hit that could be expanded and converted into a lead that effectively blocked the interaction between LFA‐1 and ICAM‐1.
Measurement of intracellular sodium with NMR methods
Authors: Hutchison Robert B. , Shapiro Joseph I.
Published: March 2007

The measurement and monitoring of intracellular sodium concentrations is critically important to elucidating normal and abnormal cellular physiology. NMR approaches to this problem using 23Na NMR spectroscopy have included detailed analysis of relaxation time constants, the use of chemical shift agents, and detection of multiple‐quantum‐filtered signals. These methods have been applied to isolated cells as well as to perfused organs and in situ tissues. The theoretical framework for as well as the practical applications and limitations of these methods are discussed.
Relaxation time measurements in NMR imaging. Part I: Longitudinal relaxation time
Authors: Kaldoudi Eleni , Williams Steve C. R.
Published: March 2007

Relaxation time measurements are important in magnetic resonance imaging. This paper discusses the need for creating calculated relaxation time images and it reviews current practices in the field. Imaging techniques based on inversion recovery, partial saturation, and variable‐tip‐angle experiments, as well as single‐shot methods that employ stimulated echoes or multiple‐readout pulses are considered. Virtues and limitations of each method are reported.
Correlated vector model of multiple‐spin systems
Authors: Lowry David F.
Published: March 2007

A vector model correctly predicts the correlated motion of weakly coupled spins. The model is semiclassical when the spins are interacting and fully classical when all spins are transverse and not interacting. A simple two‐pulse experiment and the Heteronuclear Multiple Quantum Coherence (HMQC) experiment are analyzed. The model is extended to the relativistic limit and discussed in the context of the Einstein, Rosen, Podolsky gedanken experiment and the twin paradox.
Curve fitting in nuclear magnetic resonance spectroscopy: Illustrative examples using a spreadsheet and microcomputer
Authors: Irwin Peter L. , Damert William C. , Doner Landis W.
Published: March 2007

A simplified explanation of the modified Gauss‐Newton linearization (curve‐fitting) procedure is presented by translating this algorithm into a spreadsheet with examples from various single‐ and multiple‐pulse NMR experiments. Comparisons are made with linear regression analysis of mathematically manipulated data.
Echo phenomena and nonlinearity
Authors: Hahn Erwin L.
Published: March 2007

Echoes as a result of resonant pulse excitation occur only in nonlinearly interactive systems. The role of nonlinear coupling with pulses is emphasized in an elementary review of two‐ and three‐pulse spin echo formation using the vector model.
Absence of conservation laws and the reciprocity relation in polarization‐transfer experiments
Authors: Zhang Shanmin , Xu Ping , Sørensen Ole W. , Ernst Richard R.
Published: March 2007

Conservation, creation, and destruction of polarization in nuclear magnetic polarization‐transfer experiments are discussed. In general, polarization is not conserved during NMR pulse experiments, although a useful reciprocity relation is formulated. The features of polarization‐transfer experiments are illustrated by liquid‐ and solid‐state NMR.
Homonuclear and heteronuclear correlation experiments using pulsed‐field gradients
Authors: Tolman Joel R. , Prestegard James H.
Published: March 2007

The underlying theoretical aspects for the application of pulsed‐field gradients to heteronuclear NMR experiments are developed within the density matrix and product operator formalisms. Specific rules allow the straightforward product operator analysis of many pulsed‐field‐gradient NMR experiments. Using these rules, experiments for coherence selection in two‐dimensional NMR spectroscopy are discussed and compared with experiments that use coherence selection by phase cycling. Methods for obtaining pure‐phase lineshapes are discussed in detail. Finally, pulsed‐field‐gradient experiments that achieve resolution and sensitivity comparable to their corresponding phase‐cycled versions are reviewed.
Pulse techniques for CIDNP
Authors: Goez Martin
Published: March 2007

The peculiarities of measurements of chemically induced dynamic nuclear polarization (CIDNP) with pulsed and Fourier transform NMR spectrometers are discussed. If detection is accomplished in this way, new classes of experiments become possible. First, CIDNP net and multiplet effects can be separated by pulse techniques. Second, kinetic measurements (“flash” CIDNP) can be performed with a time resolution in the submicrosecond range. Third, pseudostationary experiments allow recording of time‐independent CIDNP spectra that are free from the effects of nuclear spin relaxation in the products and that possess improved signal‐to‐noise ratios while maintaining excellent suppression of unchanging background magnetization. Finally, signals of unpolarized nuclei in the products can be made observable by means of coherence transfer techniques.
Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall‐cell lung cancer
Authors: Chen Allen M. , Jahan Thierry M. , Jablons David M. , Garcia Joaquin , Larson David A.
Published: March 2007

BACKGROUND.

The incidence and pattern of brain metastases was analyzed among patients who achieved a pathological complete response (pCR) after neoadjuvant chemotherapy or chemoradiotherapy for locally advanced nonsmall‐cell lung cancer (NSCLC).

METHODS.

Between 1990 and 2004, 211 patients were treated with neoadjuvant therapy before surgical resection for stage III NSCLC. The clinical course of 51 patients who demonstrated a pCR were reviewed. The neoadjuvant regimen consisted of either chemotherapy (29 patients) or chemoradiotherapy (22 patients). Histology was 45% adenocarcinoma, 41% squamous cell, and 14% large cell carcinoma. No patient received prophylactic cranial irradiation (PCI).

RESULTS.

Overall survival at 1, 3, and 5 years was 82%, 63%, and 42%, respectively. The most common site of initial recurrence was the brain. Twenty‐two (43%) patients developed brain metastasis as the site of first failure, which represented 71% of all isolated recurrences. Ultimately, 28 (55%) patients developed brain metastases at some point during their clinical course. The 5‐year estimates of brain metastasis‐free survival for patients with squamous and nonsquamous cancers were 57% and 34%, respectively (P = .02). Median survival from the time of brain metastasis was 10 and 5 months for those with isolated and nonisolated recurrences, respectively.

CONCLUSION.

Patients with a pCR after multimodality therapy for locally advanced NSCLC are at excessively high risk for the subsequent development of brain metastases. Implications for management strategies including PCI and stereotactic radiosurgery (SRS) are discussed. Cancer 2007. © 2007 American Cancer Society.
Male breast cancer in the veterans affairs population
Authors: Nahleh Zeina A. , Srikantiah Roopa , Safa Malek , Jazieh Abdul‐Rahman , Muhleman Albert , Komrokji Rami
Published: March 2007

BACKGROUND.

The incidence of male breast cancer (MBC) continues to rise. The Veterans Affairs (VA) Central Cancer Registry (VACCR) provides a unique source for the study of MBC. The objective of this retrospective analysis was to compare the characteristics and outcome of patients with MBC and patients with female breast cancer (FBC) in the VA population.

METHODS.

VACCR data were used to analyze the database of VA patients who had breast cancer diagnosed between 1995 and 2005. It includes 120 VA medical centers. Primary site codes were identified for breast cancer (500–508). Data were entered and analyzed using biostatistical software.

RESULTS.

In total, 3025 patients' records were reviewed, and 612 patients who had MBC were compared with 2413 patients who had FBC. The mean age at diagnosis was 67 years for patients with MBC and 57 years for patients with FBC (P < .005). More patients with MBC were black, and patients with MBC presented with higher disease stage and more lymph node‐positive disease. The dominant histology in MBC was ductal carcinoma. No difference in grade or laterality was observed. Estrogen and progesterone receptor‐positive tumors were more common in MBC compared with FBC. Overall, patients with MBC received less chemotherapy, whereas no statistical difference was observed in the use of hormone treatment. The median overall survival for patients who had MBC was 7 years compared with 9.8 years for patients who had FBC (log‐rank test; P < .005). There was no statistically significant difference in median survival for patients with stage III disease and stage IV disease. However, the median survival differed significantly for patients with stage I disease and stage II disease. In lymph node‐negative patients, the median survival was 6.1 years for patients with MBC and 14.6 years for patients with FBC (P < .005), whereas the median survival did not differ significantly in lymph node‐positive patients. Using Cox regression analysis age, sex, clinical stage, and lymph node status were independent prognostic factors for survival, whereas race, histology, and grade were not.

CONCLUSIONS.

To the authors' knowledge, this is the largest series of MBC and FBC to date in the veterans population. The results suggested the presence of differences in the biology, pathology, presentation, ethnicity, and survival between patients with MBC and patients with FBC in the VA population. It is noteworthy that the survival of patients with MBC was inferior for those with early‐stage disease and lymph node‐negative tumors, suggesting that there are differences between the sexes in the pathogenesis and biology of breast cancer. In patients with hormone receptor‐positive MBC, survival was inferior despite similar hormone treatment practices between MBC and FBC. This observational study calls for a better understanding of this disease that would allow new opportunities for specific therapeutic intervention. Cancer 2007. © 2007 American Cancer Society.
A cracked beam finite element for through‐cracked tube
Authors: Schoefs F. , Le Van A. , Rguig M.
Published: March 2007

The reassessment of existing structures leads to analyse the impact of local defects on the structural behaviour. This paper proposes a cracked beam finite element with a view to introducing the effect of large through‐cracks in the structural analysis for framed structures like jacket offshore platforms. The model parameters are identified for several joint typologies using 3D finite element results. Copyright © 2007 John Wiley & Sons, Ltd.
Flow analysis and sorting of microchromosomes (<3 Mb)
Authors: Ng Bee L. , Yang Fengtang , Carter Nigel P.
Published: March 2007

Background:

The analysis and isolation of high numbers of chromosomes smaller than 3 Mb in size (microchromosomes) with good purity is dependent primarily on the detection sensitivity of the flow cytometer and the precision of the sort unit. The aim of this study was to investigate the capability of using a conventional flow cytometer for the detection and sorting at high purity microchromosomes with an estimated size of 2.7 Mb.

Methods:

Chromosomes were isolated from a human cell line containing a pair of X‐derived microchromosomes, using a modified polyamine isolation buffer. The chromosome preparation was labeled with Hoechst and Chromomycin and analyzed and purified using a MoFlo sorter (DAKO) configured for high‐speed sorting. The purity of the flow‐sorted microchromosomes was assessed by reverse chromosome painting.

Results:

Improved resolution of the peak of microchromosomes in a bivariate plot of Hoechst versus Chromomycin fluorescence was obtainable after discriminating clumps and debris based on gating data within a FSC versus pulse width plot.

Conclusions:

Chromosomes of smaller size, less than 3 Mb, can be detected with high resolution and flow‐sorted with high purity using a conventional flow sorter. © 2007 International Society for Analytical Cytology
Alterations of centromere positions in nuclei of immortalized and malignant mouse lymphocytes
Authors: Sarkar Rahul , Guffei Amanda , Vermolen Bart J. , Garini Yuval , Mai Sabine
Published: March 2007

Background:

The three‐dimensional (3D) positions of centromeres have been studied in several cell systems. However, data on centromere positions during cellular transformation remain elusive. This study has focused on mouse lymphocytes and investigated the centromere positions in primary, immortalized, and tumor cells.

Methods:

Eighty‐to‐ninety z‐slices of each mouse lymphocyte nucleus were acquired using a sampling distance of 107 nm in the xy plane and 200 nm along z for each z‐stack, using an Axioplan 2 microscope, an AxioCam HR CCD, a 63×/1.4 oil objective, and the Axiovision 3.1 software (Carl Zeiss, Canada). A constrained iterative algorithm (Schaefer et al., J Microsc 2001;204:99–107) was used for deconvolution. Centromere positions in 3D images were analyzed using CentroView, a program we developed to measure nuclear centromere positions.

Results:

Using CentroView we determined the positions of centromeres in primary lymphocytes, immortalized and malignant mouse B cells. We show that centromeres exhibit altered nuclear positions in immortalized and malignant B cells. These changes are independent of previously described cell cycle‐dependent centromere dynamics.

Conclusions:

The 3D positions of centromeres are altered during cellular transformation. In lymphocytes, centromeres are found in more central nuclear positions following immortalization and transformation. These nuclear changes reflect structural remodeling of mammalian nuclei during oncogenesis and may impact on the structural organization of chromosomes. How centromeric changes are linked to nuclear remodeling can now be quantitatively examined using the tools of this study. © 2007 International Society for Analytical Cytology
Phosphoinositide 3‐kinase acts through RAC and Cdc42 during agrin‐induced acetylcholine receptor clustering
Authors: Nizhynska Viktoria , Neumueller Ralph , Herbst Ruth
Published: March 2007

The formation of the neuromuscular junction (NMJ) is regulated by the nerve‐derived heparan sulfate proteoglycan agrin and the muscle‐specific kinase MuSK. Agrin induces a signal transduction pathway via MuSK, which promotes the reorganization of the postsynaptic muscle membrane. Activation of MuSK leads to the phosphorylation and redistribution of acetylcholine receptors (AChRs) and other postsynaptic proteins to synaptic sites. The accumulation of high densities of AChRs at postsynaptic regions represents a hallmark of NMJ formation and is required for proper NMJ function. Here we show that phosphoinositide 3‐kinase (PI3‐K) represents a component of the agrin/MuSK signaling pathway. Muscle cells treated with specific PI3‐K inhibitors are unable to form full‐size AChR clusters in response to agrin and AChR phosphorylation is reduced. Moreover, agrin‐induced activation of Rac and Cdc42 is impaired in the presence of PI3‐K inhibitors. PI3‐K is localized to the postsynaptic muscle membrane consistent with a role during agrin/MuSK signaling. These results put PI3‐K downstream of MuSK as regulator of AChR phosphorylation and clustering. Its role during agrin‐stimulated Rac and Cdc42 activation suggests a critical function during cytoskeletal reorganizations, which lead to the redistribution of actin‐anchored AChRs. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Protein synthesis in distal axons is not required for axon growth in the embryonic spinal cord
Authors: Blackmore Murray , Letourneau Paul C.
Published: March 2007

It is now well established that new proteins are synthesized in the distal segments of elongating axons, where they may play an essential role in some guidance decisions. It remains unclear, however, whether distal protein synthesis also plays an essential role in axon growth per se. Previous in vitro experiments have shown that blocking protein synthesis in distal axons has no effect on the rate of axonal advance. However, because these experiments were performed in vitro and over a relatively short time period, the role of distal protein synthesis over longer periods and in a native tissue environment remained untested. Here, we tested whether protein synthesis in distal axons plays an essential role in the elongation of descending axons in the embryonic spinal cord. We developed an in situ model of the brainstem‐spinal projection of the embryonic chick, and developed a split‐chamber method in which inhibitors of proteins synthesis could be applied independently to cell bodies in the brainstem or to distal axons in the spinal cord. When protein synthesis was blocked in distal axons, axon growth remained robust for 2 days, which is the length of the experiment. However, when protein synthesis was blocked only in the brainstem, axonal elongation in the spinal cord ceased within 6 h. These data showed that protein synthesis in the distal axon is not essential to continue the advance of axons. Rather, essential proteins are synthesized more proximally and then transported rapidly to the distal axon. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007.
Supramolecular Helical Architectures Dictated by Folded and Extended Conformations of the Amino Acid in Ternary CuII/Diamine/Racemic Amino Acid Complexes
Authors: Subramanian Palani Sivagnana , Suresh Eringathodi , Casella Luigi
Published: March 2007

The ternary CuII complexes [Cu(D,L‐phe)(bpy)]·(ClO4) (1), [Cu(D,L‐phe)(phen)(H2O)]·ClO4·H2O (2), and [Cu(L‐phe)(bpy)(H2O)]·ClO4·H2O (3) (bpy = 2,2′‐bipyridine, phen = 1,10‐phenanthroline) adopt helical structures in the crystal state, as determined by an X‐ray structural analysis. The supramolecular helical assembly of these complexes was also investigated by single‐crystal X‐ray crystallography. The complexes derived from racemic amino acids (1 and 2) undergo spontaneous resolution in the solid state to form separate helical chains of the ternary complex that carry a single enantiomer of the amino acid. In the case of complex 1, the two helical chains resulting from the L‐ and D‐phe complexes bear opposite chirality, which means that the bulk crystalline sample is racemic. In contrast, the two helical chains generated by L‐ and D‐phe complexes in 2 have the same twist and pack together in a right‐handed assembly. The (P)/(M) handedness of the helical chains is dictated by the conformational chirality (λ/δ) of the chelate rings of the D/L‐aminoacids.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Purines Bearing Phenanthroline or Bipyridine Ligands and Their RuII Complexes in Position 8 as Model Compounds for Electrochemical DNA Labeling – Synthesis, Crystal Structure, Electrochemistry, Quantum Chemical Calculations, Cytostatic and Antiviral Activity
Authors: Vrábel Milan , Hocek Michal , Havran Luděk , Fojta Miroslav , Votruba Ivan , Klepetářová Blanka , Pohl Radek , Rulíšek Lubomír , Zendlová Lucie , Hobza Pavel , Shih I‐hung , Mabery Eric , Mackman Richard
Published: March 2007

A series of ethynyl‐ or (4‐boronophenyl)bipyridines and‐phenanthrolines were prepared as versatile building blocks for attachment of bidentate N‐ligands to other molecules via cross‐coupling reactions. Their complexation with Ru(bpy)2Cl2 gave the corresponding RuII complexes. 9‐Benzyladenine derivatives bearing the bipyridine or phenanthroline complexes in position 8, attached via a conjugate acetylene or phenylene linker were prepared by cross‐coupling reactions of the ethynyl‐ or 4‐boronophenylbipyridines and ‐phenanthrolines with 9‐benzyl‐8‐bromoadenine. Their complexation with Ru(bpy)2Cl2 afforded the corresponding Ru complexes as model compounds for electrochemical DNA labeling. The same compounds were also prepared directly by cross‐coupling of 9‐benzyl‐8‐bromoadenine with Ru complexes of the alkynes and boronic acids. Both approaches are compared in terms of potential applications for labeling of nucleic acids. The crystal structures of two Ru complexes were determined by X‐ray diffraction. The electrochemistry of the model purines bearing the phenanthroline or bipyridine ligands and the Ru complexes was studied by means of cyclic or square‐wave voltammetry with carbon paste and mercury electrodes. The experimental redox potentials of the title compounds were compared with quantum chemical calculations. A very good agreement between experiment and theory was obtained, with a standard deviation of 0.13 V. It was shown that theoretical calculations can be of a limited predictive power for new RuII complexes, though it was difficult to reproduce differences smaller than 0.05 V. Several compounds of this series exhibited a considerable cytostatic effect and activity against the hepatitis C virus (HCV). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Diastereoselective and Regioselective Synthesis of Conformationally Restricted Thio‐dioxa‐ and Oxo‐oxathiaphosphorinane Dinucleotides Featuring Noncanonical α/β Torsion Angle Combinations (α,β‐CNAs)
Authors: Le Clézio Ingrid , Vigroux Alain , Escudier Jean‐Marc
Published: March 2007

Control of the regioselective cyclisation of a stereodefined 5′‐C‐tosyloxy phosphorothioate dinucleotide unit to provide conformationally restricted dinucleotides of either thio‐dioxa‐ or oxo‐oxathiaphosphorinane types is described. NMR structural analysis of the newly synthesized building units showed the α and β torsional angles to be constrained to noncanonical values {gauche(+), trans} or {anticlinal(–), trans}.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Thermoset polyester as an alternative material for microchip electrophoresis/electrochemistry
Authors: Vickers Jonathan A. , Dressen Brian M. , Weston Melissa C. , Boonsong Kanokporn , Chailapakul Orawan , Cropek Donald M. , Henry Charles S.
Published: March 2007

Microchip CE coupled with electrochemical detection (MCE‐EC) is a good method for the direct detection of many small molecule analytes because the technique is sensitive and readily miniaturized. Polymer materials are being increasingly used with MCE due to their affordability and ease of fabrication. While PDMS has become arguably the most widely used material in MCE‐EC due to the simplicity of microelectrode incorporation, it suffers from a lack of separation efficiency, lower surface stability, and a tendency for analyte sorption. Other polymers, such as poly(methylmethacrylate) (PMMA) and poly(carbonate) (PC), have higher separation efficiencies but require more difficult fabrication techniques for electrode incorporation. In this report, thermoset polyester (TPE) was characterized as an alternative material for MCE‐EC. TPE microchips were characterized in their native and plasma oxidized forms and after coating with polyelectrolyte multilayers (PEMs). TPE provides higher separation efficiencies when compared to PDMS microchips, while still using simple fabrication protocols. In this work, separation efficiencies as high as 295 000 N/m were seen when using TPE MCE‐EC devices. Furthermore, the EOF was higher and more consistent as a function of pH for both native and plasma‐treated TPE than PDMS. Finally, TPE is amenable to modification using simple PEM coatings as another way to control surface chemistry and surface charge.
How important is the selection of computational analysis method to the accuracy of rainwater tank behaviour modelling?
Authors: Mitchell V. Grace
Published: March 2007

As the concept of sustainable urban water management is incorporated into the practice of urban water resource managers, actions, such as the utilization of roof runoff via rainwater tanks, which have multiple benefits, are increasingly being built into urban water systems. Modelling tools are frequently used to predict the yield from rainwater tanks and to estimate the storage capacity required to achieve a given potable supply reduction level, with these estimates used in both urban water resources policy development and engineering design. Therefore, it is important that the accuracy of commonly used models is understood. This paper investigates the impact of computational time step, computational operating rule, initial storage level, and the length of simulation period on the accuracy of the storage–yield–reliability relationship calculated using a simple rainwater tank behaviour model. Four time steps (ranging from 6 min to 24 h), two operational rules (supply before spillage and supply after spillage), two initial storage level states (empty and full), and three simulation periods (50 years, 10 years and 1 year) were applied to a wide range of rainwater tank system configurations and three different locations in Australia. It was found that the supply‐after‐spillage computational operating rule is preferable, while the ratio of the average demand volume in a single computational time step divided by the storage capacity (ΔD/S) can be used to assess whether a given combination of demand, storage, inflow, and computational time step will provide long‐term yield estimates that are within ± 5% of the values produced by a simulation that used a 50‐year time series of climate, 6‐min time step, and a supply‐after‐spillage operational rule (50‐6‐YAS). Copyright © 2007 John Wiley & Sons, Ltd.
Role of binding entropy in the refinement of protein–ligand docking predictions: Analysis based on the use of 11 scoring functions
Authors: Ruvinsky Anatoly M.
Published: March 2007

We present results of testing the ability of eleven popular scoring functions to predict native docked positions using a recently developed method (Ruvinsky and Kozintsev, J Comput Chem 2005, 26, 1089) for estimation the entropy contributions of relative motions to protein‐ligand binding affinity. The method is based on the integration of the configurational integral over clusters obtained from multiple docked positions. We use a test set of 100 PDB protein‐ligand complexes and ensembles of 101 docked positions generated by (Wang et al. J Med Chem 2003, 46, 2287) for each ligand in the test set. To test the suggested method we compared the averaged root‐mean square deviations (RMSD) of the top‐scored ligand docked positions, accounting and not accounting for entropy contributions, relative to the experimentally determined positions. We demonstrate that the method increases docking accuracy by 10–21% when used in conjunction with the AutoDock scoring function, by 2–25% with G‐Score, by 7–41% with D‐Score, by 0–8% with LigScore, by 1–6% with PLP, by 0–12% with LUDI, by 2–8% with F‐Score, by 7–29% with ChemScore, by 0–9% with X‐Score, by 2–19% with PMF, and by 1–7% with DrugScore. We also compared the performance of the suggested method with the method based on ranking by cluster occupancy only. We analyze how the choice of a clustering‐RMSD and a low bound of dense clusters impacts on docking accuracy of the scoring methods. We derive optimal intervals of the clustering‐RMSD for 11 scoring functions. © 2007 Wiley Periodicals, Inc. J Comput Chem 2007