bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure–Activity Relationship Refinement and Further Assessment of Indole‐3‐glyoxylamides as a Lead Series against Prion Disease
Authors: Thompson Mark J. , Louth Jennifer C. , Ferrara Steven , Sorrell Fiona J. , Irving Benjamin J. , Cochrane Edward J. , Meijer Anthony J. H. M. , Chen Beining
Published: December 2010

Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC50 <10 nM). After examining a range of substituents at the para‐position of the N‐phenylglyoxylamide moiety, five‐membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie‐infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole‐3‐glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.
Impact of DNA patents on pharmacogenomics research and development: economic and policy issues
Authors: Paci Daniele , Hopkins Michael M. , Zika Eleni , Ibarreta Dolores
Published: December 2010

The science of pharmacogenetics and pharmacogenomics (or collectively PGx) has advanced rapidly in recent years, and some technologies based on these developments have entered into use. It is notable that these advances have occurred in parallel with related advances in genetic testing, led by developments in testing services for the diagnosis of rare disorders that share Mendelian patterns of inheritance. However, a profusion of patents on nucleotide sequences (often termed “gene patents”) has led to widespread concern that disputes over intellectual property could hamper the development and diffusion of these technologies. This article outlines the recent evidence from major empirical studies on the complex landscape of diagnostic DNA patents in the United States and Europe and discusses the traditional arguments in favor and against gene patenting in PGx and genetic testing. It also explores the extent to which concerns in clinical genetics might be relevant to PGx. We find that although recent evidence on genetic testing suggests that many of the issues might have been overestimated or overemphasized, no dedicated studies have been published on the intellectual property aspects of PGx. Drug Dev Res 71: 485–491, 2010. © 2010 Wiley‐Liss, Inc.
The increasing role of health economic evaluations in drug development
Authors: Annemans Lieven , Cleemput Irina , Simoens Steven , Arickx Francis , Hulstaert Frank , Bogaert Marc
Published: December 2010

The goal of health care policies is to maximize the health of the population within the limits of the available budget and taking into account equity considerations. For innovative drugs, this means that an increasing number are being assessed in terms of their value for money, which is the amount of additional health that can be achieved per additional euro, pound, dollar, or other currency invested. Ideally such assessments and resulting appraisals and decisions should be made in a transparent and efficient way. Transparent means consisting of clear procedures and criteria such as relative effectiveness, cost effectiveness, budget impact, social, and ethical consequences. Transparent also means that stakeholders (physicians, patients, industry, and others) are involved in the assessment and decision‐making process. Efficient means that, on a European level, duplication of efforts is avoided by aligning the processes for market authorization and those for the assessment of value for money. Drug Dev Res 71: 457–462, 2010. © 2010 Wiley‐Liss, Inc.
Pharmaceutical market access and the challenges of health technology assessment in the United Kingdom
Authors: Tolley Keith
Published: December 2010

Health Technology Assessment (HTA) has been formally used in the United Kingdom for more than 10 years to help determine evidence‐based decisions on the access to new drugs, based on evidence of clinical and cost‐effectiveness. Separate HTA systems have developed in England and Wales (NICE, AWMSG), and Scotland (SMC). The primary clinical evidence desired for technology appraisal by the HTA bodies is the comparative randomized controlled trial because of its good internal validity, but the role and value of observational study designs for providing data on real‐world effectiveness have been recognized in the methods guidance of these bodies. To date HTA has had a fairly limited impact on drug development and clinical trial design in the United Kingdom, coupled with limited use to date of non‐RCT data for assessing treatment effect and outcomes in NICE/SMC appraisals. Nonetheless, with new initiatives such as closer regulatory and HTA coordination in Europe, and “conditional market access” schemes such as the Innovation Pass in the United Kingdom, in the future pharmaceutical companies are likely to need to adopt a more flexible approach to drug development and clinical data collection involving RCT, observational data collection, and indirect comparisons to meet the needs to provide relevant clinical and cost‐effectiveness evidence at drug launch and post launch. Drug Dev Res 71: 478–484, 2010. © 2010 Wiley‐Liss, Inc.
Economic evaluations of pharmacogenetic and genomic screening programs: update of the literature
Authors: Vegter Stefan , Jansen Esther , Postma Maarten J. , Boersma Cornelis
Published: December 2010

Pharmacogenetics and pharmacogenomics show great potential for developing individual treatment modalities to achieve optimal therapy effectiveness. Economic analyses are performed to determine whether pharmacogenetic screening strategies provide good value for money. The current review provides an update of published economic studies. Economic analyses of pharmacogenetic screening programs published between 2000 and July 2010 were included in the review. Information was extracted on research area, genetic information, type of economic analysis, key aspects of adherence to economic guidelines, costs and commercial availability of genetic tests, and the role of the funding party. A total of 42 economic studies on pharmacogenetic screening strategies were included. Over time, more cost‐utility analyses were performed, longer time windows were employed, and more extensive sensitivity analyses were conducted. Considerable differences in costs of screening tests for the same polymorphism were found, which often, but not always, had a large influence on the costs of screening strategies. Most studies were conducted from an academic or hospital perspective without direct links to pharmaceutical or diagnostic manufacturers. The quality of economic analyses of pharmacogenetic screening programs has improved over time. However, input variables are not always clearly described. In particular, substantial variation exists in the reported costs of the pharmacogenetic tests. Often these test costs are considered a major cost driver and could therefore be of particular importance for the interpretation of cost‐effectiveness results. Furthermore, the economic studies seem to be conducted to increase awareness of possibilities and perspectives of genetic testing rather than to influence policy decisions on reimbursement. Drug Dev Res 71: 492–501, 2010.  © 2010 Wiley‐Liss, Inc.
Implementation of innovative pharmacogenetic tests into practice in Taiwan: an institutional perspective
Authors: Chen Hsiang‐Yin , Chen Li‐Chia
Published: December 2010

Pharmacogenetic tests are proposed as a means of targeting therapy to patients such that ineffective medicine prescription and adverse events are reduced and overall benefit in terms of improved health outcomes is maximized. However, the true impact of introducing pharmacogenetic tests into clinical practice remains to be confirmed. This commentary presents some of the key requirements in developing a pharmacogenetic clinical practice model in a hospital setting. The analysis considers the need to select carefully which pharmacogenetic tests are best offered, while balancing the cost to the institution given the potential benefits to the patient population base. Drawing on our experience in Taiwan, we recommend that developing a hospital task force for pharmacogenetic testing is a recommended approach to: (1) set quality standards on how best to conduct the test, (2) provide a pro forma for interpreting results, (3) prescribe treatment appropriately according to results, and (4) design an educational program for all relevant health care team members. To further support the implementation of pharmacogenetic testing in the hospital setting, it is necessary to promote audit of clinical practice by building hospital‐based registries to facilitate the collection of health care resource use and outcome data that records the clinical uptake of testing. We suggest that well‐conducted economic evaluations, relevant to local practice, are essential pieces of information to guide institutional decision making on how best to develop the appropriate use of pharmacogenetic tests in clinical practice. Drug Dev Res 71: 502–506, 2010. © 2010 Wiley‐Liss, Inc.
Induction of transplantation tolerance converts potential effector T cells into graft‐protective regulatory T cells
Authors: Francis Ross S. , Feng Gang , Tha‐In Thanyalak , Lyons Ian S. , Wood Kathryn J. , Bushell Andrew
Published: December 2010

Naturally occurring FOXP3+CD4+ Treg have a crucial role in self‐tolerance. The ability to generate similar populations against alloantigens offers the possibility of preventing transplant rejection without indefinite global immunosuppression. Exposure of mice to donor alloantigens combined with anti‐CD4 antibody induces operational tolerance to cardiac allografts, and generates Treg that prevent skin and islet allograft rejection in adoptive transfer models. If protocols that generate Treg in vivo are to be developed in the clinical setting it will be important to know the origin of the Treg population and the mechanisms responsible for their generation. In this study, we demonstrate that graft‐protective Treg arise in vivo both from naturally occurring FOXP3+CD4+ Treg and from non‐regulatory FOXP3−CD4+ cells. Importantly, tolerance induction also inhibits CD4+ effector cell priming and T cells from tolerant mice have impaired effector function in vitro. Thus, adaptive tolerance induction shapes the immune response to alloantigen by converting potential effector cells into graft‐protective Treg and by expanding alloreactive naturally occurring Treg. In relation to clinical tolerance induction, the data indicate that while the generation of alloreactive Treg may be critical for long‐term allograft survival without chronic immunosuppression, successful protocols will also require strategies that target potential effector cells.
A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation
Authors: Bourgeois Elvire A. , Levescot Anaïs , Diem Séverine , Chauvineau Angélique , Bergès Hortense , Milpied Pierre , Lehuen Agnès , Damotte Diane , Gombert Jean‐Marc , Schneider Elke , Girard Jean‐Philippe , Gourdy Pierre , Herbelin André
Published: December 2010

Activation of invariant natural killer T (iNKT) cells by treatment with their α‐galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate‐cell‐driven lung inflammation induced by the cytokine/alarmin IL‐33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell‐deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti‐inflammatory function of iNKT cells depends on their IFN‐γ production and on endogenous IL‐12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.
CD28 costimulation regulates FOXP3 in a RelA/NF‐κB‐dependent mechanism
Authors: Soligo Marzia , Camperio Cristina , Caristi Silvana , Scottà Cristiano , Porto Paola Del , Costanzo Antonio , Mantel Pierre‐Yves , Schmidt‐Weber Carsten B. , Piccolella Enza
Published: December 2010

The molecular mechanisms whereby CD28 alone or associated with TCR can regulate FOXP3 expression are not understood, although the importance of CD28 as a pivotal regulator of CD4+CD25+FOXP3+ T cells is well recognized. We previously demonstrated that unique CD28‐induced, NF‐κB‐dependent signals were sufficient to activate FOXP3 transcription in human CD4+CD25− T cells; however, the exact mechanisms are currently unknown. In this study, we have identified novel κB‐binding sites on FOXP3 gene and demonstrated that CD28 signals mediated FOXP3 trans activation by nuclear translocation of RelA/NF‐κB and not of c‐Rel. The occupancy of FOXP3 κB‐binding sites by RelA dimers that correlated with histone acetylation and recruitment of Pol II were required both to initiate FOXP3 transcription and to control the promoter occupancy by NFAT. Interestingly, knockdown of RelA in CD4+CD25− T cells stimulated through TCR and CD28 significantly affected FOXP3 expression, confirming that also the transcriptional activation of FOXP3 gene by TCR in the presence of CD28‐costimulatory signals is RelA‐dependent. In conclusion, these data suggest a new mechanism by which FOXP3 is activated and supports the critical role of CD28 in the regulation of peripheral tolerance.
IL‐17 production by γδ T cells is important for the antitumor effect of Mycobacterium bovis bacillus Calmette‐Guérin treatment against bladder cancer
Authors: Takeuchi Ario , Dejima Takashi , Yamada Hisakata , Shibata Kensuke , Nakamura Risa , Eto Masatoshi , Nakatani Tatsuya , Naito Seiji , Yoshikai Yasunobu
Published: December 2010

Intravesical inoculation of Mycobacterium bovis bacillus Calmette‐Guérin (BCG) has been used for the treatment of bladder cancer. Recent studies implied the requirement of neutrophil infiltration for the antitumor effect. In this study, we found that IL‐17 was produced in the bladder after BCG treatment, preceding the infiltration of neutrophils. Neutrophils in the bladder after BCG treatment were reduced in IL‐17‐deficient mice, in which BCG‐induced antitumor effect against intravesically inoculated bladder cancer was abolished. Notably, the level of IL‐17 production and the number of neutrophils in BCG‐treated bladder was reduced in γδ T‐cell‐deficient mice but not in CD4‐depleted mice. Survival of bladder cancer‐inoculated γδ T‐cell‐deficient mice was not improved by BCG treatment. These results suggest that IL‐17‐producing γδ T cells play a key role in the BCG‐induced recruitment of neutrophils to the bladder, which is essential for the antitumor activity against bladder cancer.
Measles virus modulates dendritic cell/T‐cell communication at the level of plexinA1/neuropilin‐1 recruitment and activity
Authors: Tran‐Van Hieu , Avota Elita , Börtlein Charlene , Mueller Nora , Schneider‐Schaulies Sibylle
Published: December 2010

Measles virus (MV)‐infected DC fail to promote T‐cell expansion, and this could explain important aspects of measles immunosuppression. The efficiency of the immune synapse (IS) is determined by the formation of stable, stimulatory conjugates involving a spatially and timely controlled architecture. PlexinA1 (plexA1) and its co‐receptor neuropilin (NP‐1) have been implicated in IS efficiency, while their repulsive ligand, SEMA3A, likely acts in terminating T‐cell activation. Conjugates involving MV‐infected DC and T cells are unstable and not stimulatory, and thus we addressed the potential role of plexA1/NP‐1 and semaphorins (SEMAs) in this system. MV does not grossly affect expression levels of plexA1/NP‐1 on T cells or DC, yet prevents their recruitment towards stimulatory interfaces. Moreover, MV infection promoted early release of SEMA3A from DC, which caused loss of actin based protrusions on T cells as did the plexA4 ligand SEMA6A. SEMA3A/6A differentially modulated chemokinetic migration of T cells and conjugation with allogeneic DC. Thus, MV targets SEMA receptor function both at the level of IS recruitment, and by promoting a timely inappropriate release of their repulsive ligand, SEMA3A. To the best of our knowledge, this is the first example of viral targeting of SEMA receptor function in the IS.
Creek enlargement in a low‐energy degrading saltmarsh in southern England
Authors: Chen Yining , Collins Michael B. , Thompson Charlotte E.L.
Published: December 2010

A low‐energy saltmarsh in the Beaulieu River Estuary, southern England was investigated. A geomorphological survey revealed that the creek bank geometry was characterized by the presence of cantilevers, a result of the protection provided by roots over the upper part of the bank. The saltmarsh deposits, consisting mainly of clay and organic matter, have a high resistance to flow‐induced erosion. Short‐term hydrographic deployments revealed that the tidal currents and waves recorded were insufficient to cause erosion of the bank surface. However, pin measurements over a 2‐year period revealed that the tidal creeks within the saltmarsh did experience bank erosion, particularly below the cantilevers, in spite of this low‐energy setting. Bank face erosion was therefore considered to be related to long‐term processes. The bases of the cantilevers were found to be located at a precise level, in relation to the tides. Water level data over a 2‐year period were examined against erosion measured below the cantilevers. The results suggest that the erosion on the bank faces, particularly below the cantilevers, is associated with the frequency of water level variations and long‐term submergence/emergence cycles, which can decrease the bonds between the particles and enable erosion by low tidal and wind‐wave currents within this low‐energy environment. This mechanism is probably responsible for tidal creek enlargement via erosion of the bank face and subsequent bank failure, a process which acts over a long temporal scale (1–10 years). Copyright © 2010 John Wiley & Sons, Ltd.
Dynamic controls on wind erosion and dust generation on west‐central Free State agricultural land, South Africa
Authors: Wiggs Giles , Holmes Peter
Published: December 2010

The west‐central part of South Africa's Free State Province falls within the transition zone between South Africa's sub‐humid, temperate grasslands to the east, and the semi‐arid Karoo and arid Kalahari to the south and west, respectively. The area is characterized by low rainfall (typically 500 mm or less) with high variability, but environmental conditions allow widespread dryland commercial agriculture (maize, sunflowers and stock farming). However, human activity promotes wind erosion and the area is susceptible to dust emissions. This study is the first to quantify the degree of wind erosion on the agricultural soils in the region under prevailing winter to spring climatic conditions and land management practices. Using arrays of cup anemometers, dust deposition traps and saltation impact sensors (Safires), measurements were made of the key erosivity and erodibility drivers that control the degree of wind erosion. Results demonstrate that significant quantities of dust are mobilized, particularly during the months of September and October. Thresholds of wind erosion are shown to respond particularly closely to changes in surface and aerodynamic roughness (z0) with the amount of collected dust correlating well with measures of wind erosivity that weight the impact of higher wind speeds. Given the importance of surface roughness in controlling erosion thresholds, results show that the opportunity exists for well designed farming practices to control wind erosion. However, it is likely that climatically driven environmental change will impact on some of the identified controls on erosion (wind power, moisture availability) with the result that the wind erosion hazard is likely to increase within this marginal environment. Copyright © 2010 John Wiley & Sons, Ltd.
Application of BDI‐based intelligent multi‐agent systems for distribution system service restoration planning
Authors: Tsai Men‐Shen , Pan Yen‐Tsung
Published: December 2010

By changing the status of switches on distribution feeders, service to de‐energized customers can be restored after an occurrence of a fault. In this paper, multi‐agent system (MAS) is applied for the power distribution system service restoration task using local information by utilizing the characteristics of information sharing. Each software agent is running autonomously and is able to exchange information within limited distance. Every agent is capable of performing service restoration such that service restoration can be performed in parallel when a multiple fault scenario occurs. As a result, the outage period can be reduced. BDI (believe–desire–intention) agent architecture is implemented in this paper for group and zone service restoration for power distribution systems. Zone/switch relation table is built and used by agents in order to identify adequate switching actions during the service restoration planning stage. The proposed MAS is implemented on JADE (Java Agent Development) platform. The simulation results show that the proposed BDI‐based service restoration agent system is capable of providing adequate restoration switching plan in several scenarios. Copyright © 2010 John Wiley & Sons, Ltd.
Strategy as the focus for evaluation
Authors: Quinn Patton Michael , Patrizi Patricia A.
Published: December 2010

Strategic thinking and planning have long been the focus of management training and organizational development, but strategy is a new unit of analysis for evaluation. The authors examine the increasing attention given to being strategic in the private sector, in government, in philanthropy, and in the not‐for‐profit sectors. To respond and adapt to concerns about the implementation and impacts of strategy, strategy needs to be evaluated. The authors look at what strategy is, offer a framework for evaluating strategy, consider issues in strategic evaluation, and examine opportunities for strategic learning based on evaluating strategy. © Wiley Periodicals, Inc., and the American Evaluation Association.
The W. K. Kellogg Foundation's Devolution Initiative: An experiment in evaluating strategy
Authors: Sherwood Kay E.
Published: December 2010

When Congress passed and President Bill Clinton signed a major welfare reform law in 1996, there were significant concerns across the public policy spectrum about how it would be implemented and how it would affect poor families, in part because the law shifted much responsibility for decision making from the federal government to state and local officials, a process called “devolution.” The Kellogg Foundation was one of the concerned parties, and, as a result, it launched the Devolution Initiative to learn about the changes taking place and mobilize responses to the reform as its implications unfolded. The author revisits the Foundation's Devolution Initiative and its external evaluation from the perspective of evaluation as a strategic intervention. © Wiley Periodicals, Inc., and the American Evaluation Association.
Amantadine versus methylphenidate in children and adolescents with attention deficit/hyperactivity disorder: a randomized, double‐blind trial
Authors: Mohammadi Mohammad‐Reza , Kazemi Mohammad‐Reza , Zia Ebtehal , Rezazadeh Shams‐Ali , Tabrizi Mina , Akhondzadeh Shahin
Published: December 2010

Objective The aim of the present study was to further evaluate, under double blind and controlled conditions, the efficacy of amantadine for attention‐deficit/hyperactivity disorder (ADHD) in children and adolescents as compared to methylphenidate.

Methods This was a 6‐week randomized clinical trial. Forty patients (28 boys and 12 girls) with a DSM‐IV‐TR diagnosis of ADHD were the study population of this trial. All study subjects were randomly assigned to receive the treatment using capsule of amantadine at a dose of 100–150 mg/day depending on weight (100 mg/day for <30 kg and 150 mg/day for >30 kg) or methylphenidate at a dose of 20–30 mg/day for a 6‐week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent Attention deficit/hyperactivity disorder Rating Scale‐IV.

Results No significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores (df = 1; F = 0.02; p = 0.86 and df = 1; F = 0.01; p = 0.89, respectively). Side effects of decreased appetite and restlessness were observed more frequently in the methylphenidate group.

Conclusion The results of this study indicate that amantadine significantly improved symptoms of ADHD and was well tolerated and it may be beneficial in the treatment of children with ADHD. Nevertheless, the present results do not constitute proof of efficacy. Copyright © 2010 John Wiley & Sons, Ltd.
2‐Pyridyl Tosylate Derivatives—Building Blocks for Structural Diversity via Transition Metal Catalysis
Authors: Lindhardt Anders T. , Gøgsig Thomas M. , Gauthier Delphine , Lupp Daniel , Mantel Mette Louise Hallager , Bjerglund Klaus M. , Skrydstrup Troels
Published: December 2010

2‐Pyridyl tosylate derivatives have proved to be highly reactive electrophiles in palladium‐catalyzed Mizoroki–Heck reactions with electron‐rich olefins. These results suggest that the tosylate anion is able to dissociate from the catalyst’s metal center subsequent to the oxidative addition step, providing a tricoordinated cationic complex mandatory for a high degree of α‐regioselectivity. Further development of the 2‐pyridyl electrophiles as counterparts in palladium catalysis led to the development of several efficient protocols including amidation, amination, aminocarbonylations, Suzuki–Miyaura, and a fast iron‐catalyzed Kumada–Tamao–Curriu cross coupling. Interestingly, in all but one of the palladium‐catalyzed reactions, the optimized conditions employed the ligand DPPF (1,1′‐bis(diphenylphosphino)ferrocene) or the diisopropyl analog DiPrPF (1,1′‐bis(diisopropylphosphino)ferrocene) in dioxane. As with the Mizoroki–Heck couplings, the existence of the cationic tricoordinated complex in dioxane was speculated to play an important role, facilitating steps such as transmetallation and CO incorporation. The mild conditions developed in all of the catalytic reactions described in this overview can be applied to the pyridine/pyrimidine core, providing highly functionalized heteroaromatic compounds in a few steps.
Cell culture plastics with immobilized interleukin‐4 for monocyte differentiation
Authors: Hansen Morten , Hjortø Gertrud M. , Met Özcan , Jakobsen Mogens H. , Svane Inge M. , Larsen Niels B.
Published: December 2010

Standard cell culture plastic was surface modified by passive adsorption or covalent attachment of interleukin (IL)‐4 and investigated for its ability to induce differentiation of human monocytes into mature dendritic cells, a process dose‐dependently regulated by IL‐4. Covalent attachment of IL‐4 proceeded via anthraquinone photochemistry to introduce amine functionalities at the surface followed by coupling of IL‐4 through a bifunctional amine‐reactive linker. X‐ray photoelectron spectroscopy showed that undesirable multilayer formation of the photoactive compound could be avoided by reaction in water instead of phosphate‐buffered saline. Passively adsorbed IL‐4 was observed to induce differentiation to dendritic cells, but analysis of cell culture supernatants revealed that leakage of IL‐4 into solution could account for the differentiation observed. Covalent attachment resulted in bound IL‐4 at similar concentrations to the passive adsorption process, as measured by enzyme‐linked immunosorbent assays, and the bound IL‐4 did not leak into solution to any measurable extent during cell culture. However, covalently bound IL‐4 was incapable of inducing monocyte differentiation. This may be caused by IL‐4 denaturation or improper epitope presentation induced by the immobilization process, or by biological irresponsiveness of monocytes to IL‐4 in immobilized formats. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2011.
Role of thiol‐complex formation in 2‐hydroxyethyl‐ methacrylate‐induced toxicity in vitro
Authors: Samuelsen J. T. , Kopperud H. M. , Holme J. A. , Dragland I. S. , Christensen T. , Dahl J. E.
Published: December 2010

Methacrylate monomers that are found to leach from cured resin‐based dental materials induce biological effects in vitro. The underlying mechanisms have not been fully elucidated although involvement of increased cellular reactive oxygen species (ROS) and DNA‐damage has been suggested. In this in vitro study we have elucidated the impact of a commonly used methacrylate monomer, HEMA, on the level and oxidation state of cellular glutathione, intracellular ROS level, as well as the formation of complex between HEMA and glutathione. HEMA exposure rapidly led to increased level of ROS and reduced level of GSH (reduced form of glutathione). Antioxidants effectively counteracted the ROS increase, but had no effect on the GSH depletion. No change in glutathione‐disulphide (GSSG; oxidized form of glutathione) concentration was detected in the HEMA treated cells, showing that oxidation of glutathione was not responsible for the reduced GSH concentration. Further we demonstrated spontaneous formation of a complex between HEMA and GSH. In conclusion, we showed that exposure to HEMA led to drop in cellular glutathione level probably caused by complex formation with HEMA. A similar covalent binding of HEMA to macromolecules combined with increased level of cellular ROS due to lower levels of GSH is suggested to be important factors triggering the toxic response. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2011.
Novel tissue‐derived biomimetic scaffold for regenerating the human nucleus pulposus
Authors: Mercuri Jeremy J. , Gill Sanjitpal S. , Simionescu Dan T.
Published: December 2010

Numerous scaffold formulations have been investigated to support the regeneration of nucleus pulposus (NP) tissue for use as an early‐stage therapy for intervertebral disc degeneration. Particular attention has focused on recreating the biochemical and mechanical properties of the native NP via the incorporation of exogenous extracellular matrix (ECM) components or synthetic surrogates. In the present study, we describe a novel approach to develop a tissue engineering (TE) scaffold comprised acellular porcine NP ECM. Complete decellularization of porcine NP was successfully achieved using a combination of chemical detergents, ultrasonication, and treatment with nucleases. Resulting NP scaffolds were devoid of host‐cell remnants and the porcine antigen alpha‐Gal. Native NP ECM components including aggrecan/chondroitin‐6‐sulfate and collagens types II, IX, and XI were found in physiologically relevant ratios within the NP scaffold. NP scaffold swelling capacity and unconfined mechanical properties were not significantly different from porcine NP tissue. Furthermore, NP scaffolds were conducive to repopulation with human adipose‐derived stem cells as cell viability and proliferative capacity were maintained. These results demonstrate the successful decellularization of porcine NP and the resultant formation of a biomimetic scaffold exhibiting potential utility for TE the human NP. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2011.
Digestive flexibility in females of the subterranean rodent ctenomys talarum in their natural habitat
Authors: del Valle Juana C. , López Mañanes Alejandra A.
Published: December 2010

We studied the occurrence of digestive strategies at different levels in females of the subterranean herbivorous rodent Ctenomys talarum living in their natural habitat. We determined the dimensions of different parts of the gastrointestinal tract and organs along as the activity of key digestive enzymes(sucrase, maltase and N‐aminopeptidase) in small intestine in females seasonally caught. Females of C. talarum did not show seasonal variations in the mass of the different parts of the gastrointestinal tract. In nonreproductive females large intestine was longer in autumn, whereas reproductive females did not show seasonal variations in the length of the different parts of the gut. Females of C. talarum exhibited a high sucrose, maltase and N‐aminopeptidase activity in small intestine, although these activities were higher in small intestine of females caught in autumn (nonreproductive) than in females caught in winter (reproductive). The results show that C. talarum females exhibit characteristics in the gut at the morphological and biochemical level, which could represent digestive strategies to face the constraints imposed by their costly particular way of life. J. Exp. Zool. 315:141–148, 2011. © 2010 Wiley‐Liss, Inc.
Antiglioma effects of combined use of a baculovirual vector expressing wild‐type p53 and sodium butyrate
Authors: Guo Haiyan , Choudhury Yukti , Yang Jing , Chen Can , Tay Felix Chang , Lim Tit Meng , Wang Shu
Published: December 2010

Background

Combination therapy is usually desirable for successful cancer treatment, especially in cancers that are resistant to single forms of therapy.

Methods

To achieve an optimal therapeutic effect against glioblastoma, we tested a strategy that combines baculovirus‐mediated transfer of the p53 tumor suppressor gene with the use of sodium butyrate, a histone deacetylase inhibitor. This strategy was designed based on the findings that the transduction efficiency of baculovirus in mammalian cells can be markedly enhanced by the addition of histone deacetylase inhibitors and that these inhibitors are effective in inducing cell cycle arrest, differentiation, or apoptosis in tumor cells.

Results

We observed a synergistic effect of the combination of the two treatments in provoking apoptosis in glioblastoma cells with mutant p53. In a mouse glioma xenograft model, the tumor inhibitory effect of baculovirus‐expressed p53 was significantly enhanced by co‐administration of sodium butyrate.

Conclusions

These findings suggest a new approach to treat glioblastoma using baculovirus‐mediated gene transfer in combination with administration of histone deacetylase inhibitor. Copyright © 2010 John Wiley & Sons, Ltd.
Morphological and behavioral changes induced by transgenic overexpression of interleukin‐1ra in the brain
Authors: Spulber Stefan , Bartfai Tamas , Winblad Bengt , Schultzberg Marianne
Published: December 2010

Interleukin‐1 (IL‐1) has a peak of expression in the brain in a period of maximal network reorganization and then virtually disappears from the normal adult brain. The aim of our study was to identify phenotypical alterations induced by chronically blocking IL‐1 signalling. We used homozygous transgenic mice overexpressing human soluble IL‐1ra and age‐matched wild‐type mice. We used littermates from litters obtained by mating heterozygous transgenic progenitors, and animals with predetermined genotype (nonlittermates). In littermates, the genotype was identified after the experiments had been completed. The mice were tested at the ages of 6 and 12 months with a battery of tests, including dark‐light preference, footprint/gait analysis, and analysis of motor performance during swimming. MR imaging was performed on formalin‐fixed brains; total and relative volumes of cortical and subcortical structures were estimated stereologically on the acquired images. Multivariate data analysis (PLS‐DA) of the behavioral data showed separation between nonlittermate wild‐type and transgenic mice at both 6 and 12 months, whereas the littermates displayed a more homogenous behavioral profile. The PLS‐DA model for brain morphology showed a clear separation between wild‐type and transgenic mice as well as between transgenic littermates and nonlittermates. Regression analysis by means of partial least squares (PLS) showed that the brain morphology accounts for the behavioral profile in a significant proportion (16.9%). In conclusion, we show that IL‐1 signalling is important for normal development of the brain, and the initial alteration resulting from prenatal exposure to IL‐1ra can be recovered provided that the IL‐1 signalling pathway is intact. © 2010 Wiley‐Liss, Inc.
Effects of nerve growth factor and Noggin‐modified bone marrow stromal cells on stroke in rats
Authors: Ding Jie , Cheng Yan , Gao Shan , Chen Jieli
Published: December 2010

Treatment with bone marrow stromal cells (BMSCs) ameliorates neurological functional deficits after stroke. Nerve growth factor (NGF) is a neurotrophic factor that supports the survival and growth of neural cells. Noggin, an antagonist of bone morphogenetic protein (BMP), promotes the differentiation of stem cells into neurons. In this study, we hypothesize that transfection of NGF and Noggin in BMSC treatment of stroke promotes BMSC neuronal differentiation and improves functional outcome after stroke. Adenovirus was used to trasfect NGF and Noggin and the transfection efficiency was measured by Western blot and immunostaining in vitro. The transfected BMSCs with NGF and/or Noggin were administered intravenously at 5 days after middle cerebral artery occlusion (MCAo) in rats. The neurological functional outcome and BMSC migration and differentiation in the ischemic brain were measured. The transplantation of BMSCs with NGF or Noggin elicited neurological functional improvement, promoted BMSCs present in the ischemic brain, and also up‐regulated neuro‐like cell differentiation as well as increased synaptophysin expression in the ischemic brain compared with nontreatment control animals (P< 0.05). Treatment of stroke with a combination of transfection of NGF and Noggin in BMSCs induced a synergistic effect on improved neurological functional outcome, BMSCs present in the ischemic brain, and synaptophysin expression in the ischemic brain compared with BMSCs transfected with an NGF‐ or Noggin‐alone group (P < 0.05). These data demonstrate that increasing NGF or Noggin expression in BMSCs contributes to brain plasticity after stroke and that a synergistic effect is induced on the coexistence of NGF and Noggin in BMSCs treatment of stroke. © 2010 Wiley‐Liss, Inc.
Insulin‐like growth factor‐I–forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor‐α‐mediated neuronal damage: Implications for human immunodeficiency virus encephalitis
Authors: Wilk Anna , Urbanska Katarzyna , Yang Shuo , Ying Wang Jin , Amini Shohreh , Del Valle Luis , Peruzzi Francesca , Meggs Leonard , Reiss Krzysztof
Published: December 2010

In HIV patients, antiretroviral medications trigger metabolic abnormalities, including insulin resistance. In addition, the inflammatory cytokine tumor necrosis factor‐α (TNFα), which is elevated in human immunodeficiency virus encephalitis (HIVE), also induces insulin resistance and inflicts neuronal damage in vitro. In differentiated PC12 cells and rat cortical neurons, high glucose (HG; 25 mM) triggers reactive oxygen species (ROS) accumulation, contributing to the retraction of neuronal processes, with only a minimal involvement of neuronal apoptosis. In the presence of TNFα, HG‐treated neurons undergo massive apoptosis. Because mammalian homolog of the Forkhead family of transcription factors, Forkhead box O transcription factor 3a (FOXO3a), controls ROS metabolism, we asked whether FOXO3a could affect the fate of differentiated neurons in the paradigm of HIVE. We observed FOXO3a nuclear translocation in HG‐treated neuronal cultures, accompanied by partial loss of mitochondrial potential and gradual retraction of neuronal processes. Addition of TNFα to HG‐treated neurons increased expression of the FOXO‐dependent proapoptotic gene Bim, which resulted in extensive apoptotic death. Insulin‐like growth factor‐I (IGF‐I) significantly lowered intracellular ROS, which was accompanied by IGF‐I‐mediated FOXO3a nuclear export and decrease in its transcriptional activity. The clinical relevance of these findings is supported by detection of nuclear FOXO3a in TUNEL‐positive cortical neurons from HIVE, especially in brain areas characterized by elevated TNFα. © 2010 Wiley‐Liss, Inc.
Map3k1, Il6st, Gzmk, and Hspb3 gene coexpression network in the mechanism of freezing reaction in mice
Authors: Kondaurova Elena M. , Naumenko Vladimir S. , Sinyakova Nadezda A. , Kulikov Alexander V.
Published: December 2010

Freezing reaction (catalepsy) is a natural passive defensive strategy in animals. An exaggerated form of catalepsy is a symptom of grave brain dysfunction. Catalepsy in mice was shown to be linked to the Map3k1, Il6st, Gzmk, and Hspb3 genes as potential candidates for a high predisposition to catalepsy. The study sought to test the hypothesis of an association between catalepsy and expression of these genes in the brain. Thegenes' mRNA levels were measured in the hypothalamus, hippocampus, frontal cortex, striatum, and midbrain of catalepsy‐resistant AKR/J strain and catalepsy‐prone strains CBA/Lac, ASC (antidepressant‐sensitive cataleptic) and the congenic line AKR.CBA‐D13M76C. No association between expression of any investigated genes and predisposition to catalepsy was found. At the same time, multivariate analysis revealed interactions among the expressions of Map3k1, Il6st, Gzmk, and Hspb3 genes in the brain structures. A factor analysis of all variables produced two independent factors explaining 76.2% of the total variance. The catalepsy‐resistant AKR strain was distinguished from the catalepsy‐prone strains CBA, ASC, and AKR.CBA‐D13M76C by factor 1. It was suggested that a high predisposition to catalepsy in mice can be defined by the Map3k1, Il6st, Gzmk, and Hspb3 genes' coexpression network. © 2010 Wiley‐Liss, Inc.
Aberrant expression of USP22 is associated with liver metastasis and poor prognosis of colorectal cancer
Authors: Liu Yan‐Long , Yang Yan‐Mei , Xu Hui , Dong Xin‐Shu
Published: December 2010

Background

The present study was aimed at clarifying the expression of ubiquitin carboxyl‐terminal hydrolase 22 (USP22), a novel deubiquitinating enzyme gene, in colorectal cancer (CRC) and its clinical significance.

Methods

USP22 expression was detected with quantitative RT‐PCR, Western blot, and immunohistochemistry (IHC) in 43 CRCs and non‐cancerous matched tissues. Furthermore, USP22 protein expression was analyzed in 192 CRC tumors by IHC to evaluate the association with survival.

Results

In 43 paired fresh tissues, the expression level of USP22 was significantly higher in primary CRCs than that in the paired non‐cancerous tissues at both mRNA and protein levels (P < 0.0001). Nuclear USP22 expression significantly increased from normal mucosa through adenoma to primary carcinoma (P < 0.0001) and from primary carcinoma to liver metastasis (P = 0.021). The incidence of positive USP22 expression was 54.16% in 192 conventional CRC tissues. Notably, high USP22 expression was significantly associated with shorter disease‐specific survival (P < 0.0001) and shorter disease‐free survival (P < 0.0001). Cox regression analysis showed USP22 was an independent prognostic parameter for CRC patients.

Conclusion

USP22 might be an independent predictive factor for CRC prognosis and aberrant expression of USP22 may play an essential role in colorectal carcinogenesis and liver metastasis. J. Surg. Oncol. 2011; 103:283–289. © 2010 Wiley‐Liss, Inc.
Seedling recruitment and survival of two desert grasses in the monte of Argentina
Authors: Busso C. A. , Bonvissuto G. L. , Torres Y. A.
Published: December 2010

In the Monte Austral Neuquino, Argentina, vegetation is arranged in patches. Understanding the mechanisms involved in their distribution is critical for preventing desertification. The working hypothesis was that vegetation patches reduce environmental stress on the plants. Plant patches were classified into four microenvironments: windward; below the dominant shrubs (subcanopy); vegetation at the patch periphery (canopy edge) and bare patch interspaces (open). We determined seedling survival of the dominant species in each microenvironment, using a marking method of seedlings established from sown seeds. In addition, we measured the environmental characteristics in the four microenvironments, and associated them with seedling survival. Study species were the perennial grassesLeymus erianthus(Phil.) Dubcovsky,Stipa neaeiNees ex Steudel andPoa ligularisNees ex Steudel, and the shrubsLarrea divaricataCav. andAtriplex lampaGill ex Moquin. Results supported the hyphothesis only forL. erianthusandS. neaei(but not for the other three species that showed higher seedling survival in the subcanopy than in the patch interspaces after 1 year from sowing). This study determined that (1) reduced environmental stress does not guarantee seed germination and seedling survival of a given species in the plant community and (2) seedling establishment will not be possible for any species of the plant community in the patch interspaces under the study conditions in the region. This is mostly because soil temperatures can reach up to 50°C in the patch interspaces in years of scanty precipitation during late spring and summer. Copyright © 2010 John Wiley & Sons, Ltd.
Land degradation: socioeconomic and environmental causes and consequences in the eastern Mediterranean
Authors: Abu Hammad A. , Tumeizi A.
Published: December 2010

Land degradation is a natural and socioeconomic cause–effect phenomenon that is widespread all over the world. This study investigated the socioeconomic factors and causes of land degradation (e.g. population growth and urbanization, poverty, overgrazing, pollution, biodiversity, erosion) in the eastern part of the Mediterranean region. The study revealed a significant land use change from agricultural and natural vegetation to urbanized areas due to the high population increase during the last ca. 80 years (51‐times the magnitude of the total built‐up area). The high poverty rate that exists in the area (57 per cent of the population can be classed as ‘poor’) has resulted in damaging environmental practices (overgrazing and intensive usage of natural plants); we found 83 per cent of the farmers admitted to the adoption of these practices. Poverty has also resulted in an inverse and significant correlation (at the 95 per cent confidence level) between holding size and the sale of land for urban uses. We also noted that 75 per cent of the smallholder farmers surveyed had sold their lands for immediate benefits to cope with poverty. This relation was affected by the education level of the farmers; we found a direct and significant (95 per cent confidence level) correlation existed between these factors. Overgrazing was practised by 70 per cent of the farmers and was found to be one of the most important environmental consequences of land use change (1600 ha have been transformed from natural grazing to built‐up (urban) in the study area).

Socio‐economic induced land degradation demands efforts to improve farmer environmental awareness as well as environmental standards, laws and bylaws and the reduction of mismanagement of land. Copyright © 2010 John Wiley & Sons, Ltd.