bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 2 trial of docetaxel and gefitinib in the first‐line treatment of patients with advanced nonsmall‐cell lung cancer (NSCLC) who are 70 years of age or older
Authors: Simon George R. , Extermann Martine , Chiappori Alberto , Williams Charles C. , Begum Mubeena , Kapoor Rachna , Haura Eric B. , Ismail‐Khan Roohi , Schell Michael J. , Antonia Scott J. , Bepler Gerold
Published: February 2008

BACKGROUND

This is a phase 2 study of chemotherapy‐naive patients, 70 years of age or older, with nonsmall‐cell lung cancer (NSCLC) who were treated with docetaxel and gefitinib. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS) and progression‐free survival (PFS).

METHODS

Eligible patients were treated with docetaxel 75 mg/m2 every 3 weeks and gefitinib 250 mg orally, daily. Docetaxel and gefitinib were given for 2 cycles beyond maximal response. Gefitinib was continued until disease progression. Comorbidities and activities of daily living were assessed (IADL).

RESULTS

Forty‐four patients initiated therapy between March 2003 and May 2005. Seventeen patients (40%; 95% confidence interval [CI], 26%–57%) had a partial response and 48% had stable disease. The median PFS was 6.9 months (95% CI, 3.95–7.8 months). Median survival time was 9.6 months (95% CI, 4.6–16.3 months). On univariate analyses, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and Charlson comorbidities index (CCI) score were predictors of improved survival. On multivariate analyses female sex was a statistically significant predictor of survival. The median survivals were 22.8 months in women and 4.8 months in men. This regimen was well tolerated, with the most common adverse events being hyperglycemia, fatigue, and lymphopenia.

CONCLUSIONS

Docetaxel combined with gefitinib is active and well tolerated in patients with advanced NSCLC who are 70 years of age and older. This paradigm of treatment merits further investigation as a first‐line treatment strategy. Female sex‐specific confirmatory clinical trials with this regimen may be warranted. Cancer 2008. © 2008 American Cancer Society.
Lack of reliability of CA125 response criteria with anti‐VEGF molecularly targeted therapy
Authors: Azad Nilofer S. , Annunziata Christina M. , Steinberg Seth M. , Minasian Lori , Premkumar Ahalya , Chow Catherine , Kotz Herbert L. , Kohn Elise C.
Published: February 2008

BACKGROUND

CA125 is an accepted indicator of epithelial ovarian cancer (EOC) response and is used to monitor patients treated with cytotoxic chemotherapy. It is uncertain how CA125 is affected by molecularly targeted drugs. In this pilot study, the authors analyzed the utility of CA125 to predict disease behavior in patients who were receiving sorafenib, a Raf‐kinase/VEGFR2 inhibitor, and bevacizumab, an anti‐VEGF monoclonal antibody.

METHODS

Fifteen of 42 patients had recurrent EOC. Patients received sorafenib 200 mg orally twice daily or D1‐5 of 7 and bevacizumab 5 mg/kg to 10 mg/kg intravenously every 2 weeks for 28‐day cycles. Computed tomography (CT) scans were performed every 2 cycles for restaging, and CA125 was measured monthly. CA125 concentrations were retrospectively analyzed as a function of clinical behavior.

RESULTS

Fourteen of 15 patients had abnormal CA125 concentrations at study entry (median 1056 U/mL; range, 67 U/mL to 9813 U/mL). Seven (47%) patients had partial response by imaging criteria. Five of these 7 patients had partial response by CA125 criteria (71% sensitivity). Eight (53%) patients would have had partial responses if CA125 criteria were used; only 5 were confirmed by CT (63 % specificity). Imaging and CA125 criteria combined yielded a higher total response rate of 10 of 15 (67%). Three patients with objective partial response by imaging lasting >20, >22, and >24 cycles would have terminated treatment prematurely if CA125 had been used.

CONCLUSIONS

CA125 changes may not correspond to imaging response criteria for EOC patients who are receiving sorafenib and bevacizumab. Caution is recommended when using CA125 as a response criterion of molecularly targeted agents until prospective studies validate CA125 changes with objective imaging response results. Cancer 2008. © 2008 American Cancer Society.
A neurochemical signature of visual recovery after extrastriate cortical damage in the adult cat
Authors: Huxlin Krystel R. , Williams Jennifer M. , Price Tracy
Published: February 2008

In adult cats, damage to the extrastriate visual cortex on the banks of the lateral suprasylvian (LS) sulcus causes severe deficits in motion perception that can recover as a result of intensive direction discrimination training. The fact that recovery is restricted to trained visual field locations suggests that the neural circuitry of early visual cortical areas, with their tighter retinotopy, may play an important role in attaining perceptual improvements after damage to higher level visual cortex. The present study tests this hypothesis by comparing the manner in which excitatory and inhibitory components of the supragranular circuitry in an early visual cortical area (area 18) are affected by LS lesions and postlesion training. First, the proportion of LS‐projecting pyramidal cells as well as calbindin‐ and parvalbumin‐positive interneurons expressing each of the four AMPA receptor subunits was estimated in layers II and III of area 18 in intact animals. The degree to which LS lesions and visual retraining altered these expression patterns was then assessed. Both LS‐projecting pyramidal cells and inhibitory interneurons exhibited long‐term, differential reductions in the expression of glutamate receptor (GluR)1, ‐2, ‐2/3, and ‐4 following LS lesions. Intensive visual training post lesion restored normal AMPAR subunit expression in all three cell‐types examined. Furthermore, for LS‐projecting and calbindin‐positive neurons, this restoration occurred only in portions of the ipsi‐lesional area 18 representing trained visual field locations. This supports our hypothesis that stimulation of early visual cortical areas—in this case, area 18—by training is an important factor in restoring visual perception after permanent damage to LS cortex. J. Comp. Neurol. 508:45–61, 2008. © 2008 Wiley‐Liss, Inc.
Complexity of a modelling exercise: A discussion of the role of computer simulation in complex system science
Authors: Boschetti Fabio , McDonald David , Gray Randall
Published: February 2008

Shifting the emphasis from a model to a modeling task, which involves both a computer model and a modeler, we ask what makes a problem complex. We propose that a modeling task can be seen as a set of questions‐and‐answers, nested at multiple levels. The role of the modeler then lies in posing the questions and choosing the best procedure to answer them, while the role of the model lies in answering the questions, via algorithmic, thus logically simple, procedures. Within this framework, complexity is broadly related to the number of question‐answer levels involved in the process and the nature of the questions posed. Addressing this complexity depends crucially on the ingenuity and creativity of the modeler. This may lead to a view of complexity, which is no more observer‐independent, but rather accounts for both historical and cultural development, that is the context of the problem at hand. © 2008 Wiley Periodicals, Inc. Complexity, 2008.
An enhanced TCP for upward vertical handoff in integrated WLAN and cellular networks
Authors: Lee Jong Hyup , Lee Su Kyoung , Song Joo Seok
Published: February 2008

The integration of wireless local area networks (WLANs) and third generation (3G) cellular networks has been recently a subject of great interest, mainly aimed at augmenting cellular networks with high‐rate data services by WLANs in hotspots. The complementary characteristics of 3G cellular networks and 802.11 WLANs are expected to offer the best of both technologies. On the other hand, the drastically different characteristics of both networks could be a serious obstacle to providing seamless mobility in the integrated WLAN and cellular networks. In particular, mobile users suffer from a drastic decrease in data rate after a vertical handoff from a WLAN to a 3G cellular network. However, current TCP congestion control cannot adapt to the change in the data rate after the vertical handoff, resulting in significant throughput degradation. Thus, we propose a novel TCP scheme to enhance the throughput when a vertical handoff occurs from a WLAN to a cellular network. For the proposed scheme, the throughput performance is investigated via analytic modeling and simulation. Copyright © 2008 John Wiley & Sons, Ltd.
Signalling enhancement on multilevel turbo codes
Authors: Bayat Oguz , Shafai Bahram , Salehi Masoud , Ucan Osman N. , Osman Onur
Published: February 2008

The design of multilevel turbo codes usingM‐PSK is optimized to achieve a low bit error rate (BER). Unequal error protection is employed via group set partitioning in multi‐stage decoding to minimize the error propagation and BER. Simulation results are performed under Gaussian and Rayleigh fading channels to depict the superiority of the new scheme. Copyright © 2008 John Wiley & Sons, Ltd.
Centrifugal migration of mesenchymal cells in embryonic lung
Authors: Shan Lin , Subramaniam Meera , Emanuel Rodica L. , Degan Simone , Johnston Pamela , Tefft Denise , Warburton David , Sunday Mary E.
Published: February 2008

Murine lung development begins at embryonic day (E) 9.5. Normal lung structure and function depend on the patterns of localization of differentiated cells. Pulmonary mesenchymal cell lineages have been relatively unexplored. Importantly, there has been no prior evidence of clonality of any lung cells. Herein we use a definitive genetic approach to demonstrate a common origin for proximal and distal pulmonary mesenchymal cells. A retroviral library with 3,400 unique inserts was microinjected into the airway lumen of E11.5 lung buds. After 7–11 days of culture, buds were stained for placental alkaline phosphatase (PLAP). Most PLAP+ cells are peribronchial smooth muscle cells, initially localized laterally near the hilum, then migrating down airways to the subpleural region. Laser‐capture microdissection and polymerase chain reaction confirm the clonal identities of PLAP+ cells proximally and distally. Our observation of this fundamental process during lung development opens new avenues for investigation of maladaptive mesenchymal responses in lung diseases. Developmental Dynamics 237:750–757, 2008. © 2008 Wiley‐Liss, Inc.
Novel tool to suppress cell proliferation in vivo demonstrates that myocardial and coronary vascular growth represent distinct developmental programs
Authors: Lavine Kory J. , Schmid Gregory J. , Smith Craig S. , Ornitz David M.
Published: February 2008

Cell proliferation, differentiation, and vascular growth are coordinated processes that are essential for embryonic development, tissue repair, and disease pathogenesis. Of interest, whether these critical processes are dependent upon each other has not been thoroughly explored. We have generated mice that conditionally express the cell cycle inhibitor p27Kip1, following Cre‐mediated recombination, as a tool to separate tissue proliferation from other cellular processes. Using the embryonic heart as a model, we show that myocardial proliferation and coronary development are genetically separable processes. Forced expression of p27, in both a wild‐type and in a genetically sensitized background, resulted in ventricular hypoplasia without having any substantial effects on coronary development. We further demonstrate that Hedgehog signaling, which is essential for coronary vascular growth, does not control myocardial proliferation. Together, these studies strongly suggest that myocardial cell proliferation and coronary development are genetically separable programs exemplifying one of the many potential uses of this genetic tool. Developmental Dynamics 237:713–724, 2008. © 2008 Wiley‐Liss, Inc.
Primary cilia sensitize endothelial cells for fluid shear stress
Authors: Hierck Beerend P. , Van der Heiden Kim , Alkemade Fanneke E. , Van de Pas Simone , Van Thienen Johannes V. , Groenendijk Bianca C.W. , Bax Wilhelmina H. , Van der Laarse Arnoud , DeRuiter Marco C. , Horrevoets Anton J.G. , Poelmann Robert E.
Published: February 2008

Primary cilia are mechanosensors for fluid shear stress, and are involved in a number of syndromes and congenital anomalies. We identified endothelial cilia in areas of low shear stress in the embryonic heart. The objective of the present study was to demonstrate the role of primary cilia in mechanosensing. Ciliated embryonic endothelial cells were cultured from the heart, and non‐ciliated cells from the arteries. Non‐ciliated cells that were subjected to fluid shear stress showed significantly less induction of the shear marker Krüppel‐Like Factor‐2, as compared to ciliated cells. In addition, ciliated cells from which the cilia were chemically removed show a similar decrease in flow response. This shows that primary cilia sensitize endothelial cells for fluid shear stress. In addition, we targeted and stabilized the connection of the cilium to the cytoplasm by treatment with Colchicine and Taxol/Paclitaxel, respectively, and show that microtubular integrity is essential to sense shear stress. Developmental Dynamics 237:725–735, 2008. © 2008 Wiley‐Liss, Inc.
Alternative splicing and expression analysis of bovine DNA methyltransferase 1
Authors: Russell D. Fischer , Betts D. H.
Published: February 2008

Methylation of specific CG residues in the mammalian genome results in tissue‐specific patterns of gene expression, which are critical for cell differentiation. Embryos that fail to establish and maintain proper DNA methylation patterns show severe developmental abnormalities as is the case of DNA methyltransferase 1 (Dnmt1) ‐deficient embryos. Dnmt1 is the main maintenance methyltransferase in the mouse and its expression is regulated by a splicing mechanism that dictates the expression of stage‐specific isoforms. Little is known about Dnmt1 expression in the cow and isoforms of Dnmt1 are yet unknown in this species. Here we demonstrate that the previously described bovine Dnmt1 transcript is ubiquitously expressed in embryos and fetal tissue. In addition, we report the identification of a splice variant of the bovine Dnmt1, which shows a ubiquitous expression pattern. This new transcript was detected using 5′RACE and genomic mapping and its expression pattern was shown to be consistent with a tissue‐specific mode of regulation. Furthermore, our analysis shows that the expression of an oocyte‐specific isoform of Dnmt1 is unlikely to occur in cattle. The newly reported isoform of Dnmt1 was demonstrated to be, similarly to Dnmt1a, polyadenylated and if translated possess the functional domains necessary for maintenance and de novo methyltransferase activity. Developmental Dynamics 237:1051–1059, 2008. © 2008 Wiley‐Liss, Inc.
Transcriptional activity and developmental expression of liver X receptor (lxr) in Zebrafish
Authors: Archer Amena , Lauter Gilbert , Hauptmann Giselbert , Mode Agneta , Gustafsson Jan‐Åke
Published: February 2008

Mammalian liver‐X‐receptors (LXRs) are transcription factors activated by oxysterols. They play an essential role in lipid and glucose metabolism. We have cloned the open reading frame of zebrafish lxr and describe its genomic organization. Zebrafish lxr encodes a 50‐kDa protein with high sequence similarity to mammalian LXRα. In transfection assays, the encoded protein showed transcriptional activity in response to LXR‐ligands. Treatment of adult zebrafish with the synthetic LXR ligand, GW3965, induced expression of genes involved in hepatic cholesterol and lipid pathways. Using qPCR and in situ hybridization, we found ubiquitous expression of lxr mRNA during the first 24 hr of development, followed by more restricted expression, particularly to the liver at 3dpf and the liver and intestine at 4dpf. In adult fish, all examined organs expressed lxr. In addition to a metabolic role of lxr, the temporal expression pattern suggests a developmental role in, e.g., the liver and CNS. Developmental Dynamics 237:1090–1098, 2008. © 2008 Wiley‐Liss, Inc.
Inactivation of zebrafish mrf4 leads to myofibril misalignment and motor axon growth disorganization
Authors: Wang Yun‐Hsin , Li Chun‐Kai , Lee Gang‐Hui , Tsay Huey‐Jen , Tsai Huai‐Jen , Chen Yau‐Hung
Published: February 2008

Mrf4 is a basic helix‐loop‐helix (bHLH) transcription factor associated with myogenesis. Two mrf4 transcripts, mrf4_tv1 and mrf4_tv2, were identified in zebrafish generated by alternative splicing. To study their biological functions, we separately injected the Mrf4‐morpholinos, including MO1 (mrf4_tv1:mrf4_tv2 knockdown), MO2+MO3 (mrf4_tv1:mrf4_tv2 knockdown), MO3 (mrf4_tv1 knockdown), and MO4 (mrf4_tv2 knockdown), into zebrafish embryos to observe mrf4 gene knockdown phenotypes. No phenotypic abnormalities were observed following injection with 0.5 ng of MO1 but those injected with 4.5, 9, or 13.5 ng displayed curved‐body phenotypes, such as indistinct somite boundaries, and a lack of uniformly sized cell blocks. Similar results were also observed in the (MO2+MO3)‐, MO3‐, and MO4‐injected groups. To further investigate the molecular mechanisms that lead to curved‐body phenotypes, we stained embryos with α‐bungrotoxin and specific monoclonal antibodies F59, Znp1, and Zn5 to detect morphological changes in acetyl‐choline receptor (AChR) clusters, muscle fibers, common path of the primary neurons, and secondary neurons axonal projections, respectively. Our results show that the muscle fibers of mrf4_(tv1:tv2)‐morphant aligned disorderly and lost their integrity and attachment, while the defects became milder in either mrf4_tv1‐morphant or mrf4_tv2‐morphant. On the other hand, reduced axonal projections and AChR clusters were found in both mrf4_tv2‐morphant and mrf4_(tv1:tv2)‐morphant but distributed normally in the mrf4_tv1‐morphant. We conclude that Mrf4_tv2 is involved in alignment of muscle fibers, and Mrf4_tv1 might have cooperative function with Mrf4_tv2 in muscle fiber alignment, without affecting the muscle‐nerve connection. Developmental Dynamics 237:1043–1050, 2008. © 2008 Wiley‐Liss, Inc.
Synthesis and Characterization of a Ladder‐Like Coordination Polymer Composed of Trimanganese Clusters Formed and Linked by Isophthalato Ligands
Authors: Ma Cheng‐Bing , Chen Chang‐Neng , Liu Qiu‐Tian , Liao Dai‐Zheng , Li Li‐Cun
Published: February 2008

A new isophthalatomanganese(II) coordination polymer, [Mn3(ip)2(Hip)2(bipy)2]n·2.5nH2O [H2ip = isophthalic acid, bipy = 2,2′‐bipyridine], has been obtained directly by heating to reflux a weakly acidic solution containing bipy, Mn(OAc)2·4H2O, and H2ip. The polymer was characterized by single‐crystal X‐ray diffraction and magnetic measurements. The complex contains rare isophthalato‐bridged trimanganese cluster building units further linked by isophthalato ligands in a newly observed binding mode, forming a one‐dimensional, ladder‐like chain network. The magnetic interactions within the complex were quantitatively evaluated by using a combination of a trimeric model and a mean molecular field approximation model. The complex was shown to be antiferromagnetic like other discrete trimanganese clusters with a structurally similar core.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Facile Synthesis of Large meso‐Pentafluorophenyl‐Substituted Expanded Porphyrins (Eur. J. Org. Chem. 8/2008)
Authors: Tanaka Yasuo , Shin Ji‐Young , Osuka Atsuhiro
Published: February 2008

The cover picture shows the crystal structures and colors of meso‐pentafluorophenyl‐substituted expanded porphyrins. [18]Porphyrin, [26]hexaphyrin, [36]octaphyrin, [44]decaphyrin, [52]dodecaphyrin, [62]tetradecaphyrin, [72]hexadecaphyrin, and [80]octadecaphyrin were synthesized and characterized. As indicated, the absorption bands of these expanded porphyrins are redshifted as their size increases, and [80]octadecaphyrin shows its absorption maximum at 953 nm. Their solutions exhibit various colors, reflecting the macrocyclic conjugation like a rainbow. Details are discussed in the article by A. Osuka et al. on p. 1341 ff.
Development of a simple and highly sensitive mutation screening system by enzyme mismatch cleavage with optimized conditions for standard laboratories
Authors: Tsuji Takanori , Niida Yo
Published: February 2008

Efficient screening of unknown DNA variations is one of the substantive matters of molecular biology even today. Historically, SSCP and heteroduplex analysis (HA) are the most commonly used methods for detecting DNA variations everywhere in the world because of their simplicity. However, the sensitivity of these methods is not satisfactory for screening purpose. Recently, several new PCR‐based mutation screening methods have been developed, but most of them require special instruments and adjustment of conditions for each DNA sequence to attain the maximum sensitivity, eventually becoming as inconvenient as old methods. Enzyme mismatch cleavage (EMC) is potentially an ideal screening method. With high‐performance nucleases and once experimental conditions are optimized, it requires only conventional staff and conditions remain the same for each PCR product. In this study we tested four commercially available endonucleases for EMC and optimized the electrophoresis and developing conditions. We prepared 25 known DNA variations consisting of 18 single base substitutions (8 transitions and 10 transversions, including all possible sets of mismatches) and 7 small deletions or insertions. The combination of CEL nuclease, 12% PAGE and rapid silver staining can detect all types of mutations and achieved 100% sensitivity.
Single‐index and portfolio models for forecasting value‐at‐risk thresholds
Authors: McAleer Michael , da Veiga Bernardo
Published: February 2008

The variance of a portfolio can be forecast using a single index model or the covariance matrix of the portfolio. Using univariate and multivariate conditional volatility models, this paper evaluates the performance of the single index and portfolio models in forecasting value‐at‐risk (VaR) thresholds of a portfolio. Likelihood ratio tests of unconditional coverage, independence and conditional coverage of the VaR forecasts suggest that the single‐index model leads to excessive and often serially dependent violations, while the portfolio model leads to too few violations. The single‐index model also leads to lower daily Basel Accord capital charges. The univariate models which display correct conditional coverage lead to higher capital charges than models which lead to too many violations. Overall, the Basel Accord penalties appear to be too lenient and favour models which have too many violations. Copyright © 2008 John Wiley & Sons, Ltd.
Forecasting for the LCD monitor market
Authors: Lo Shin‐Lian , Wang Fu‐Kwun , Lin James T.
Published: February 2008

The TFT‐LCD (thin‐film transistor–liquid crystal display) industry is one of the key global industries with products that have high clock speed. In this research, the LCD monitor market is considered for an empirical study on hierarchical forecasting (HF). The proposed HF methodology consists of five steps. First, the three hierarchical levels of the LCD monitor market are identified. Second, several exogenously driven factors that significantly affect the demand for LCD monitors are identified at each level of product hierarchy. Third, the three forecasting techniques—regression analysis, transfer function, and simultaneous equations model—are combined to forecast future demand at each hierarchical level. Fourth, various forecasting approaches and disaggregating proportion methods are adopted to obtain consistent demand forecasts at each hierarchical level. Finally, the forecast errors with different forecasting approaches are assessed in order to determine the best forecasting level and the best forecasting approach. The findings show that the best forecast results can be obtained by using the middle‐out forecasting approach. These results could guide LCD manufacturers and brand owners on ways to forecast future market demands. Copyright 2008 John Wiley & Sons, Ltd.
The occurrence and research potential of microfossils in inorganic archaeological materials
Authors: Quinn Patrick Sean
Published: February 2008

The microscopic remains of organisms, or “microfossils,” can occur within or attached to a range of different inorganic archaeological materials. Because of their small size, these inconspicuous phenomena can be easily overlooked. However, as this paper illustrates, the detailed biological and palaeontological analysis of microfossils in such contexts may be an important source of archaeological data. By critically reviewing a range of specialized cross‐disciplinary analyses, it is shown how microfossils can be used to provenance inorganic artifacts, reconstruct aspects of their manufacturing technology, and infer their function. © 2008 Wiley Periodicals, Inc.
Palaeoeskimo site burial by solifluction: Periglacial geoarchaeology of the tayara site (KbFk‐7), Qikirtaq Island, Nunavik (Canada)
Authors: Todisco Dominique , Bhiry Najat
Published: February 2008

The geoarchaeological study of the Palaeoeskimo Tayara site on Qikirtaq Island (Nunavik) has led to a better understanding of archaeological site formation in the arctic periglacial environment. The surrounding geomorphology (extra‐site) is characterized by fine‐grained, low plastic and leached postglacial glaciomarine sediments that have been reworked by sheet‐like solifluction. This process buried the northern part of the Tayara site with mean annual rates between 1.68 and 2.86 cm/yr over approximately 350 years (1330–980 yr B.P.). The physicochemical and mineralogical properties of the frost‐susceptible glaciomarine sediments may explain their susceptibility to solifluction. This process was probably enhanced by longer thawing periods or warmer/moister summer months that induced active layer thickening or rapid soil thawing. The dates we obtained in the downstream valley show that solifluction occurred during short warm periods in the Late Holocene between ca. 1500 and 1000 yr B.P., after 1000 yr B.P. (or after 500 yr B.P.) and recently (90–60 yr B.P.). Our data provide insights on the site factors and climate factors that govern site burial by solifluction. Solifluction promoted the preservation of the three superposed archaeological levels in the Tayara site; however, the waterlogging of the site related to solifluction also likely caused the subsequent abandonment of the site by the Palaeoeskimo people. © 2008 Wiley Periodicals, Inc.
Estimation of significance thresholds for genomewide association scans
Authors: Dudbridge Frank , Gusnanto Arief
Published: February 2008

The question of what significance threshold is appropriate for genomewide association studies is somewhat unresolved. Previous theoretical suggestions have yet to be validated in practice, whereas permutation testing does not resolve a discrepancy between the genomewide multiplicity of the experiment and the subset of markers actually tested. We used genotypes from the Wellcome Trust Case‐Control Consortium to estimate a genomewide significance threshold for the UK Caucasian population. We subsampled the genotypes at increasing densities, using permutation to estimate the nominal P‐value for 5% family‐wise error. By extrapolating to infinite density, we estimated the genomewide significance threshold to be about 7.2 × 10−8. To reduce the computation time, we considered Patterson's eigenvalue estimator of the effective number of tests, but found it to be an order of magnitude too low for multiplicity correction. However, by fitting a Beta distribution to the minimum P‐value from permutation replicates, we showed that the effective number is a useful heuristic and suggest that its estimation in this context is an open problem. We conclude that permutation is still needed to obtain genomewide significance thresholds, but with subsampling, extrapolation and estimation of an effective number of tests, the threshold can be standardized for all studies of the same population. Genet. Epidemiol. 2008. © 2008 Wiley‐Liss, Inc.
Enterprise risk management: A best practice approach
Authors: Francis Sebastian , Paladino Bob
Published: February 2008

What do leading companies with robust, best practice‐based enterprise risk management (ERM) programs know that could benefit your organization? This article, which draws on research with 17 leading private‐ and public‐sector organizations, details ERM practices your organization can use to define, manage, and integrate ERM programs. © 2008 Wiley Periodicals, Inc.
Incentive compensation: Bridging theory and practice
Authors: Fisher Joseph G. , Sprinkle Geoffrey B. , Walker Lynda L.
Published: February 2008

This article discusses the four roles that compensation and reward programs serve in organizations—motivating effort, directing attention, extracting information, and attracting able individuals. The article highlights the delicate interplay between compensation theory and practice—and the importance of matching the compensation program to the needs at hand. © 2008 Wiley Periodicals, Inc.
Implementation of the balanced scorecard at Barberton citizens hospital
Authors: Josey Chuck , Kim Il‐woon
Published: February 2008

Increasing competition in the health care industry has caused many hospitals to use innovative management tools to improve performance and maintain competitive advantages. At Barberton Citizens Hospital, a balanced scorecard was implemented recently when senior management redefined the hospital's mission and corporate values. The results were impressive. Operational measures improved during the first year of the implementation, and they led to a significant increase in revenues and profit. © 2008 Wiley Periodicals, Inc.
TGF‐β signaling preserves RECK expression in activated pancreatic stellate cells
Authors: Lee Hongsik , Lim Chaeseung , Lee Jungeun , Kim Nayoung , Bang Sangsu , Lee Hojae , Min Bonhong , Park Gilhong , Noda Makoto , Stetler‐Stevenson William G. , Oh Junseo
Published: February 2008

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane‐anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs‐5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF‐β1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs‐P2) led to the loss of RECK protein expression. These findings suggest that RECK is post‐translationally processed in pre‐activated PSCs but protected from proteolytic degradation by TGF‐β signaling. Furthermore, collagenolytic activity of PSCs‐5d was greatly reduced by TGF‐β1, whereas that of PSCs‐P2 was increased by anti‐RECK antibody. Increased RECK levels were also observed in cerulein‐induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF‐β signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK. J. Cell. Biochem. 104: 1065–1074, 2008. © 2008 Wiley‐Liss, Inc.
The role of nerve growth factor in hyperosmolar stress induced apoptosis
Authors: Chang Eun‐Ju , Im Young Sun , Kay EunDuck P. , Kim Jong Youl , Lee Jong Eun , Lee Hyung Keun
Published: February 2008

Nerve growth factor (NGF) is a neurotrophic factor that plays an important role in the differentiation and growth of neuronal cells. It is also regarded as an inflammatory mediator in non‐neuronal tissues under physiological stress conditions. The mechanisms of NGF production and its roles in hyperosmolar stress conditions have not been established. In this study, we show that NGF levels in cultured human corneal epithelial cells (HCECs) were up‐regulated during hyperosmolar stress by IL‐1β, but not TNF‐α. NF‐κB activity, but not AP‐1, increased significantly under hyperosmolar conditions, and NF‐κB was involved in IL‐1β‐induced NGF production. IL‐1β‐induced NGF production reduced JNK phosphorylation and HCEC apoptosis. These changes were accompanied by down‐regulated Bax and caspase‐3, ‐8, ‐9 activities. NGF siRNA and the tyrosine kinase inhibitor K252a significantly enhanced Bax up‐regulation. Thus, up‐regulated NGF under hyperosmolar stress conditions may contribute, at least in part, to reduced HCEC apoptosis. This conclusion suggests that enhanced NGF expression may be beneficial in recovering corneal damage due to chronic hyperosmolar stress. J. Cell. Physiol. 216: 69–77, 2008. © 2008 Wiley‐Liss, Inc.
Autocrine signaling involved in cell volume regulation: The role of released transmitters and plasma membrane receptors
Authors: Franco Rodrigo , Panayiotidis Mihalis I. , Ochoa de la Paz Lenin D.
Published: February 2008

Cell volume regulation is a basic homeostatic mechanism transcendental for the normal physiology and function of cells. It is mediated principally by the activation of osmolyte transport pathways that result in net changes in solute concentration that counteract cell volume challenges in its constancy. This process has been described to be regulated by a complex assortment of intracellular signal transduction cascades. Recently, several studies have demonstrated that alterations in cell volume induce the release of a wide variety of transmitters including hormones, ATP and neurotransmitters, which have been proposed to act as extracellular signals that regulate the activation of cell volume regulatory mechanisms. In addition, changes in cell volume have also been reported to activate plasma membrane receptors (including tyrosine kinase receptors, G‐protein coupled receptors and integrins) that have been demonstrated to participate in the regulatory process of cell volume. In this review, we summarize recent studies about the role of changes in cell volume in the regulation of transmitter release as well as in the activation of plasma membrane receptors and their further implications in the regulation of the signaling machinery that regulates the activation of osmolyte flux pathways. We propose that the autocrine regulation of Ca2+‐dependent and tyrosine phosphorylation‐dependent signaling pathways by the activation of plasma membrane receptors and swelling‐induced transmitter release is necessary for the activation/regulation of osmolyte efflux pathways and cell volume recovery. Furthermore, we emphasize the importance of studying these extrinsic signals because of their significance in the understanding of the physiology of cell volume regulation and its role in cell biology in vivo, where the constraint of the extracellular space might enhance the autocrine or even paracrine signaling induced by these released transmitters. J. Cell. Physiol. 216: 14–28, 2008. © 2008 Wiley‐Liss, Inc.
Comparative study of aromatization selectivity during N‐heptane reforming on sintered Pt/Al2O3 and Pt‐Re/Al2O3 catalysts
Authors: Susu Alfred A
Published: February 2008

BACKGROUND: The metal dispersed over a support can be present as small crystallites with sizes less than 5 nm. The smaller crystallites favour aromatization while larger crystallites favour cracking/hydrogenolysis. Sintering results in the agglomerization of smaller metal crystallites. Correlation of size with aromatization selectivity was investigated.

RESULTS: The primary products of n‐heptane reforming on fresh Pt were methane, toluene, and benzene, while on fresh Pt‐Re, the only product was methane. Both catalysts exhibited enhanced aromatization selectivity at different oxygen sintering temperatures. The reaction products ranged from only toluene at 500 °C sintering temperature to methane at a sintering temperature of 650 °C with no reaction at 800 °C for the Pt/Al2O3 catalyst. On Pt‐Re/Al2O3 catalyst, methane was the sole product at a sintering temperature of 500 °C while only toluene was produced at a sintering temperature of 800 °C.

CONCLUSION: This is the first time that sintering has been used to facilitate aromatization of supported Pt and Pt‐Re catalysts. A superior selectivity behaviour associated with bi‐metallic Pt catalysts is established. It was found that no reaction occurred on Pt catalyst after sintering at 800 °C whereas sintering Pt‐Re at 800 °C promoted aromatization solely to toluene. Copyright © 2008 Society of Chemical Industry
Novel interactions of perlecan: Unraveling perlecan's role in angiogenesis
Authors: Bix Gregory , Iozzo Renato V.
Published: February 2008

Perlecan, a highly conserved and ubiquitous basement membrane heparan sulfate proteoglycan, is essential for life, inasmuch as its absence results in embryonic lethality in mice and C. elegans, and neonatal lethality in humans. Perlecan plays an essential role in vasculogenesis and chondrogenesis, as well as in pathological states where these processes are maladapted. Although a large body of evidence supports a pro‐angiogenic role for perlecan, recent findings suggests that portions of the perlecan protein core can be antiangiogenic, requiring a further evaluation of the functioning of this complex molecule. This review is focused on the genetics of mammalian and nonmammalian perlecan, the elucidation of its novel interacting partners and its role in angiogenesis. By more fully understanding perlecan's functioning in angiogenesis, we may gain invaluable insight that could lead to therapeutic interventions in cancer and other pathologic states. Microsc. Res. Tech., 2008. © 2008 Wiley‐Liss, Inc.
Sparse approximate inverse preconditioning of deflated block‐GMRES algorithm for the fast monostatic RCS calculation
Authors: Rui P. L. , Chen R. S.
Published: February 2008

A sparse approximate inverse (SAI) preconditioning of deflated block‐generalized minimal residual (GMRES) algorithm is proposed to solve large dense linear systems with multiple right‐hand sides arising from monostatic radar cross section (RCS) calculations. The multilevel fast multipole method (MLFMM) is used to accelerate the matrix–vector product operations, and the SAI preconditioning technique is employed to speed up the convergence rate of block‐GMRES (BGMRES) iterations. The main purpose of this study is to show that the convergence rate of the SAI preconditioned BGMRES method can be significantly improved by deflating a few smallest eigenvalues. Numerical experiments indicate that the combined effect of the SAI preconditioning technique that clusters most of eigenvalues to one, coupled with the deflation technique that shifts the rest of the smallest eigenvalues in the spectrum, can be very beneficial in the MLFMM, thus reducing the overall simulation time substantially. Copyright © 2008 John Wiley & Sons, Ltd.
UV‐B climatology in Central Spain
Authors: Bilbao Julia , González Pablo Salvador , Castrillo Argimiro De Miguel
Published: February 2008

Broadband ultraviolet‐B solar irradiance, 280–315 nm, at ground level in Valladolid (Spain) has been recorded for a 45‐month period, from July 2002 to March 2006.

Daily maximum of hourly average irradiance values occur in July, 2.02 W m−2, and minimum, 0.3 W m−2, in December at solar noon. UV‐B daily values follow the pattern of the solar elevation angle; the total accumulated UV‐B irradiation along a mean year reaches 7.04 MJ m−2.

A study of the most representative statistical characteristics of hourly average UV‐B irradiance and daily irradiation values has been carried out and the results show that the inter‐quartile range is small in winter and increases in spring and summer; maximum stability in UV‐B takes place at solar noon and around summer; it can be concluded that this maximum may be considered representative of the UV‐B irradiance values.

The inter‐annual variability has been examined; the monthly‐integrated UV‐B irradiation values show a large annual cycle with a maximum in July, when the influences of the annual ozone column and summer solstice occur.

The UV‐B potential and extraterrestrial irradiation has been calculated and determined in order to know the attenuation of UV‐B radiation through the atmosphere. It has been obtained that the UV‐B percentage transmitted by the atmosphere increases from winter to summer, a maximum value of 10% is obtained in July and a minimum of 4% in December. The atmospheric transparency without clouds oscillates between 10% in spring and 3% in November. Copyright © 2008 Royal Meteorological Society
Affinity capillary electrophoretic DNA separation using PEG‐oligodeoxyribonucleotide block copolymers: Relationship between peak resolution and affinity strength
Authors: Kanayama Naoki , Takarada Tohru , Kimura Ayumi , Shibata Hideaki , Maeda Mizuo
Published: February 2008

Capillary electrophoretic separation of chemically synthesized ssDNA and a single‐base‐substituted one (normal and mutant ssDNA, respectively) was demonstrated using a PEG‐oligodeoxyribonucleotide block copolymer (PEG‐b‐ODN) as an affinity ligand. When the base sequence of PEG‐b‐ODN was designed to be complementary to part of normal ssDNA including the base‐substituted site, the electrophoretic mobility of normal ssDNA significantly decreased whereas that of mutant ssDNA slightly changed. Resolution of the separation strongly depended on the ODN length of the copolymer, the capillary temperature, and the Mg2+ concentration in the running buffer, indicating that the retardation of migration of normal ssDNA was induced by the reversible hybridization with PEG‐b‐ODN. It was found that the dissociation constant (Kd) of the duplex between normal ssDNA and the affinity probe ODN should be smaller than 10–6 M to achieve the good peak separation. In addition, we calculated the mobility of the complex (μC) between normal ssDNA and PEG‐b‐ODN using a two‐state model. The base sequence of affinity probe ODN appropriate to achieve the sufficient resolution will be predicted on the basis of the μC and Kd values.
Pesticide analysis by MEKC on a microchip with hydrodynamic injection from organic extract
Authors: Smirnova Adelina , Shimura Kiyohito , Hibara Akihide , Proskurnin Mikhail A. , Kitamori Takehiko
Published: February 2008

An integrated microchip for monitoring carbamate pesticides in environmental water using continuous flow chemical processes is under development, i. e., the integration of hydrolysis, azo‐derivatization, liquid–liquid extraction, electrophoretic separation, and quantification. The separation of the derivatives of four carbamate pesticides (carbaryl, carbofuran, propoxur, and bendiocarb) extracted in the continuous flow of a 1‐butanol phase was studied in a silica microchip using micellar EKC. A baseline separation of four pesticide derivatives was achieved on a silica chip using hydrodynamic injection with electroosmotic gating. Detection using a thermal lens microscope showed good linearity in the concentration range of 10–6 –10–5 M with an LOD of 5×10–7 M, which is superior to that of conventional CE with UV absorption detection at a level of 10–4 M.
A critical comparison of tourism policies of Hong Kong and Singapore — an avenue to mutual learning
Authors: Wong Emma P. Y. , Bauer Thomas G. , Wong Kevin K. F.
Published: February 2008

This study examines how mutual learning can potentially enhance the destination competitiveness and sustainability of Hong Kong and Singapore. By comparing the recent tourism policies of the two city states, and by interviewing key government officials, major industrial players, academic experts and representatives of international tourism organisations, it was found that both governments can learn from each other in various aspects. The Hong Kong government can learn from its Singapore counterpart the recognition and proactive support it provides to the industry, its visionary leadership, and its eagerness to learn. At the same time, the Singapore government can learn from Hong Kong in promoting entrepreneurship within the tourism industry. Copyright © 2008 John Wiley & Sons, Ltd.
Increased susceptibility of chronic ulcerative colitis‐induced carcinoma development in DNA repair enzyme Ogg1 deficient mice
Authors: Liao Jie , Seril Darren N. , Lu Gary G. , Zhang Meng , Toyokuni Shinya , Yang Allison L. , Yang Guang‐Yu
Published: February 2008

Ogg1 DNA repair enzyme recognizes and excises oxidative stress‐caused 8‐hydroxyl‐deoxyguanosine (8‐OHdG) from GC base‐pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8‐OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV‐induced skin tumors. To elucidate the mechanistic role of inflammation‐caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)‐induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)‐induced UC model without the use of a carcinogen. Ogg1 (−/−), Ogg1 (+/−), and wild type C57BL/6 mice were subjected to long‐term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1% (7/29 mice), with a tumor volume of 27.9 ± 5.2 mm3. Ogg1 (−/−) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1% (12 of 21 mice, P < 0.05) and a tumor volume of 35.1 ± 6.1 mm3. Ogg1 mice (+/−) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 ± 7.2 mm3. Histopathologic analyses revealed that colorectal tumors were well‐differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (−/−) and (+/−) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8‐OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation‐caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis. © 2008 Wiley‐Liss, Inc.
Joint venture evolution: extending the real options approach
Authors: Li Jing , Dhanaraj Charles , Shockley Richard L.
Published: February 2008

Real options theory has emerged as a promising avenue to study joint venture (JV) evolution as a strategic response to managing uncertainty. We extend the real options approach by integrating it with game theory. Such a combined method enriches the valuation functions of each partnering firm and helps to identify the optimal decisions for exercising options in a JV. In our model, each firm's synergy from the joint operation and its knowledge acquisition capability (KAC) can significantly influence the competitive dynamics between partners, potentially affecting how each firm decides to acquire, divest, or dissolve. We employ a new solution technique in real options theory to capture the stochastic process of three factors, and use computer simulation to test the model under varying conditions. The results are stated in five testable propositions, providing a better understanding of the dynamics of a JV. We find that symmetries between partners in synergy or KAC contribute to stability or dissolution of the JV, whereas asymmetries in synergy or KAC make acquisition of the JV assets by one partner desirable. Copyright © 2008 John Wiley & Sons, Ltd.