bluuebunny/crossref_metadata_2025 huggingface dataset:
Healing at fluoride‐modified implants placed in wide marginal defects: an experimental study in dogs
Authors: Abrahamsson Ingemar , Albouy Jean‐Pierre , Berglundh Tord
Published: December 2007

Objective: To study the healing at fluoride‐modified implants placed in wide circumferential defects.

Material and methods: Six mongrel dogs were used. The mandibular premolars and first molars were extracted. Three months later four implants were placed in one side of the mandible of each dog. The control implants (MicroThread™) had a TiOblast surface, while the test implants (OsseoSpeed™) had a fluoride‐modified surface. Two implants of each type were placed. The marginal 50% of the prepared canal was widened using step drills. Following installation a 1 mm wide gap occurred between the implant surface and the bone wall in the defect. All implants were submerged. The installation procedure was repeated in the opposite side of the mandible 4 weeks after the first implant surgery. Two weeks later the animals were euthanized and block biopsies containing the implant and surrounding tissues were prepared for histological analysis.

Results: The histological analysis revealed that a significantly larger area of osseointegration was established within the defect at fluoride‐modified implants than at implants with a TiOblast surface after 6 weeks of healing. Further, the degree of bone‐to‐implant contact within the defect area was larger at fluoride‐modified implants than at the TiOblast implants.

Conclusion: It is suggested that the fluoride‐modified implant surface promotes bone formation and osseointegration.
Ann Yearsley: A Literary Career Reconsidered
Authors: Andrews Kerri
Published: December 2007

In her lifetime, Ann Yearsley was viewed with a mixture of admiration and distaste; an accomplished writer of many literary styles, Yearsley's spectacular break from her first patron and discoverer would, for many, cast a shadow over her subsequent successes. More recently, critics have often divided into those who admire Yearsley as a poet of immense talent, and those who see her as an ambitious and ungrateful woman, resentful of all that her first patron, Hannah More, had done on her behalf. This article will reconsider these attitudes towards Yearsley and her eventful literary career and suggest that the more nuanced approach to her work taken by a new generation of Yearsley scholars must be developed if her writing is to receive the recognition it has long deserved. I will argue that the relationship between More and Yearsley needs to be considered within the context and long‐standing tradition of patronage and the increasing professionalism of writing. I will also consider Yearsley's later works, and argue that their neglect is a direct consequence of some critics’ refusal to look beyond the first eighteen months of a literary career that would endure for more than a decade, and which would survive one of the most turbulent periods of European history.
The effect of heme on the conformational stability of micro‐myoglobin
Authors: Ji Hong‐Fang , Shen Liang , Grandori Rita , Müller Norbert
Published: December 2007

Micro‐myoglobin, the isolated heme‐binding subdomain of myoglobin, is a valuable model system for the investigation of heme recognition and binding by proteins, and provides an example of protein folding induced by cofactor binding. Theoretical studies by molecular dynamics simulations on apo‐ and holo‐micro‐myoglobin show that, by contrast with the case of the full‐length wild‐type protein and in agreement with earlier experimental evidence, the apo‐protein is not stably folded in a native‐like conformation. With the cofactor bound, however, the protein fragment maintains its folded conformation over 1.5 ns in molecular dynamics simulations. Further inspection of the model structures reveals that the role of heme in stabilizing the folded state is not only a result of its direct interactions with binding residues (His93, Arg45 and Lys96), but also derives from its shielding effect on a long‐range electrostatic interaction between Arg45 and Asp60, which, in the molecular dynamics simulations, apparently triggers the unfolding process of apo‐micro‐myoglobin.
A qualitative analysis of how advanced practice nurses use clinical decision support systems
Authors: Weber Scott
Published: December 2007

Purpose: The purpose of this study was to generate a grounded theory that will reflect the experiences of advanced practice nurses (APNs) working as critical care nurse practitioners (NPs) and clinical nurse specialists (CNS) with computer‐based decision‐making systems.

Data sources: A study design using grounded theory qualitative research methods and convenience sampling was employed in this study. Twenty‐three APNs (13 CNS and 10 NPs) were recruited from 16 critical care units located in six large urban medical centers in the U.S. Midwest. Single‐structured in‐depth interviews with open‐ended audio‐taped questions were conducted with each APN. Through this process, APNs defined what they consider to be relevant themes and patterns of clinical decision system use in their critical care practices, and they identified the interrelatedness of the conceptual categories that emerged from the results. Data were analyzed using the constant comparative analysis method of qualitative research.

Conclusions: APN participants were predominantly female, white/non‐Hispanic, had a history of access to the clinical decision system used in their critical care settings for an average of 14 months, and had attended a formal training program to learn how to use clinical decision systems. “Forecasting decision outcomes,” which was defined as the voluntary process employed to forecast the outcomes of patient care decisions in critical care prior to actual decision making, was the core variable describing system use that emerged from the responses. This variable consisted of four user constructs or components: (a) users' perceptions of their initial system learning experience, (b) users' sense of how well they understand how system technology works, (c) users' understanding of how system inferences are created or derived, and (d) users' relative trust of system‐derived data. Each of these categories was further described through the grounded theory research process, and the relationships between the categories were identified.

Implications for practice: The findings of this study suggest that the main reason critical care APNs choose to integrate clinical decision systems into their practices is to provide an objective, scientifically derived, technology‐based backup for human forecasting of the outcomes of patient care decisions prior to their actual decision making. Implications for nursing, health care, and technology research are presented.
Suboptimal vitamin D status is a highly prevalent but treatable condition in both hospitalized patients and the general population
Authors: Moore Nicole L. , Kiebzak Gary M.
Published: December 2007

Purpose: To heighten awareness of the problems related to the high prevalence of suboptimal vitamin D status in hospitalized patients and the general population, including an overview of vitamin D biology, how vitamin D status is defined, the negative health issues associated with suboptimal vitamin D status, indications for treatment, treatment strategies, and controversies in the field.

Data sources: (a) Literature review was performed using PubMed and CINAHL databases to locate and review medical, nursing, and nutritional journals. (b) Authors’ recent prospective studies of 100 patients in a general tertiary hospital rehabilitation unit and 51 nonhospitalized volunteers.

Conclusion: Poor vitamin D status (ranging from suboptimal to overt deficiency) is common in both hospitalized patients and ostensibly healthy individuals of all ages and geographic latitude. Suboptimal vitamin D status is associated with muscle weakness, functional deficits, and perhaps longer length of stay of hospitalized patients. Predictors of vitamin D status include race, poor nutrition, advanced age, use of multivitamins, ultraviolet light exposure, and grip strength. Fortunately, treatment with 50,000 IU of vitamin D2 for several weeks is a very inexpensive and safe yet effective treatment to replete vitamin D status.

Implications for practice: NPs should be aware of the indications for monitoring vitamin D status and the appropriate treatment for suboptimal vitamin D status. Improving vitamin D status may improve a patient‘s functional ability, therefore decreasing falls and preventing fractures, decreasing length of stay in the hospital, and decreasing the cost of health care. Providers can potentially improve the life of older adults by educating patients on the importance of vitamin D supplementation.
Secrecy and New Religious Movements: Concealment, Surveillance, and Privacy in a New Age of Information
Authors: Urban Hugh B.
Published: December 2007

New religious movements offer important insights into many larger issues in contemporary culture, not least of which are the issues of religious secrecy and privacy in a new age of information. However, the role of secrecy in new religious movements is neither simple nor homogeneous, but rather extremely diverse and often changing in different social, political, and historical contexts. This article outlines five major forms of religious secrecy and examines one key example of each. To conclude, it suggests that the role of secrecy in these new religions raises profound questions about the delicate balance between religious freedom and national security in a new era of government surveillance and religious violence.
Hidden Innovation: A Reconsideration of ‘Old Economy’ Industries within ‘New Economy’ Regions
Authors: Chiang Lifang
Published: December 2007

This article will explore the role of ‘old economy’ manufacturing sectors in ‘new economy’ technology regions of advanced industrial economies. In the early 21st century, attention has increasingly shifted away from protectionist concerns about loss of manufacturing industries in regional and national economies. Attention has instead focused on globalization and the offshoring of a wide array of service and technology‐oriented industries and jobs. Yet, what is missing in this paradigm shift is an examination of the critical role that manufacturing sectors play in these ‘new economy’ regions, by spurring innovation spillover and generating economic and employment multiplier effects. This article will review the literature pertaining to linkages between advanced technology regions and more traditional, blue‐collar industrial production industries. In conclusion, the article calls for broadening the current focus on job loss in the highly skilled service and technology sectors to an integrated vision of production, knowledge and service sector activity.
Globalisation, Inequality and Climate Change: What Difference Does China Make?
Authors: Kaplinsky Raphael
Published: December 2007

The deepening of globalisation in the late 20th century saw accelerating climate change, growing inequality and obstinate levels of poverty, not just in low‐income economies, but also in the European Union and the rest of the high‐income world. These outcomes can be traced directly to the workings of the global economy. Three developments suggest a limit to deepening globalisation. Global production systems are environmentally unsustainable; global excess production capacity is leading to a race to the bottom in wages for many, not just in the developing world. China's access to the global economy, with its overwhelming resource hunger and large and educated labour force, exacerbates these developments. Indian development is around the corner. What can be done? Global production systems need to be truncated and growth needs to become more local. China, India and other newly emergent Asian economies need to be drawn into the discussions and institutions of global governance.
Deferred Legacy! The Continued Marginalization of the Atlanta Sociological Laboratory
Authors: Wright Earl
Published: December 2007

Between 1895 and 1917 the Atlanta Sociological Laboratory made substantial contributions to the discipline of sociology, including the establishment of the first American school of sociology, institutionalization of method triangulation, institutionalization of the insider researcher, and institutionalization of the public acknowledgment of one's research. Despite these contributions that predate the Chicago School, the W. E. B. Du Bois led laboratory remains in the margins of American sociological discourse. This paper examines the contributions of the Atlanta Sociological Laboratory, offers explanations for the school's more than 100‐year marginalization and examines its legacy in the discipline.
Hydroxyethyl starch and renal dysfunction
Authors: JACOB LAURENT , HEMING NICHOLAS , GUIDET BERTRAND
Published: December 2007

Large volumes of intravenous fluids may be required to stabilize and maintain hemodynamic stability in several circumstances (kidney transplantation, perioperative period, intensive care). The rationale to use hydroxyethyl starch (HES) 130/0.4 in these patients is to reduce the amounts of fluids infused compared with a pure crystalloid fluid regime. Advantages are a quicker hemodynamic stabilization at comparable volumes and infusion rates, a better practicability, and – theoretically – the avoidance of edema as crystalloids are quickly distributed into the tissue. Clinical experience with HES 130/0.4 in surgical patients, with no difference on renal function compared with patients receiving crystalloids, suggests that HES 130/0.4 is safe for the kidneys. However, in particular in septic patients, the avoidance of a further deterioration of preexisting renal dysfunction is very sensitive. Therefore, patients receiving large amount of HES 130/0.4 should be tightly studied with (i) monitoring of renal function; (ii) ensuring sufficient basic and additional rehydration; and (iii) stopping further administration of HES 130/0.4 once renal dysfunction exceeds a predefined threshold.
Hydroxyethyl starch solutions and their effect on the microcirculation and tissue oxygenation*
Authors: YURUK KORAY , ALMAC EMRE , INCE CAN
Published: December 2007

The main goal of ideal fluid therapy is not only to maintain systemic circulation, but also to restore tissue perfusion and oxygen delivery to the tissues and specifically to the microcirculation where oxygen delivery takes place. For this purpose, various kinds of crystalloid and colloid solutions are being used. The ongoing debate about the use of crystalloid versus colloid solutions has now shifted to a debate on the ideal type of colloid solution. Hydroxyethyl starch (HES) is one of the most studied plasma substitutes. Different kinds of HES solutions exist worldwide, which differ greatly in their pharmacological properties. Low‐molecular‐weight HES solutions have been successfully and safely used for intravascular volume therapy, and also to restore hemodynamic, microcirculatory and cardiorespiratory function. This article reviews their effect on the microcirculation and tissue oxygenation.
Cost of injuries from a prospective cohort study of North Carolina high school athletes
Authors: Knowles S B , Marshall S W , Miller T , Spicer R , Bowling J M , Loomis D , Millikan R W , Yang J , Mueller F O
Published: December 2007

Objective:

To estimate the economic cost of injuries in a population of US high school varsity athletes.

Design and Setting:

The North Carolina High School Athletic Injury Study, conducted from 1996 to 1999, was a prospective cohort study of injury incidence and severity. A two-stage cluster sampling technique was used to select athletic teams from 100 high schools in North Carolina. An injury cost model was used to estimate the economic cost of injury.

Participants:

Varsity athletes from 12 sports: football, girls’ and boy’s soccer, girls’ and boys’ track, girls’ and boy’s basketball, baseball, softball, wrestling, volleyball, and cheerleading.

Main outcome measures:

Descriptive data were collected at the time of injury. Three types of costs were estimated: medical, human capital (medical costs plus loss of future earnings), and comprehensive (human capital costs plus lost quality of life).

Results:

The annual statewide estimates were $9.9 million in medical costs, $44.7 million in human capital costs, and $144.6 million in comprehensive costs. The mean medical cost was $709 per injury (95% CI $542 to $927), $2223 per injury (95% CI $1709 to $2893) in human capital costs, and $10 432 per injury (95% CI $8062 to $13 449) in comprehensive costs. Sport and competition division were significant predictors of injury costs.

Conclusions:

Injuries among high school athletes represent a significant economic cost to society. Further research should estimate costs in additional populations to begin to develop cost-effective sports injury prevention programs.
Completeness and accuracy of International Classification of Disease (ICD) external cause of injury codes in emergency department electronic data
Authors: Hunt P R , Hackman H , Berenholz G , McKeown L , Davis L , Ozonoff V
Published: December 2007

The accuracy of external cause of injury codes (E codes) for work-related and non-work-related injuries in Massachusetts emergency department data were evaluated. Medical records were reviewed and coded by a nosologist with expertise in E coding for a stratified random sample of 1000 probable work-related (PWR) and 250 probable non-work-related (PNWR) cases. Cause of injury E codes were present for 98% of reviewed cases and accurate for 65% of PWR cases and 57% of PNWR cases. Place of occurrence E codes were present in less than 30% of cases. Broad cause of injury categories were accurate for about 85% of cases. Non-specific categories (not elsewhere classified, not specified) accounted for 34% of broad category misclassifications. Among specified causes, machinery injuries were misclassified most often (39/60, 65%), predominantly as cut/pierce or struck by/against. E codes reliably identify the broad mechanism of injury, but inaccuracies and incompleteness suggest areas for training of hospital admissions staff, providers, and coders.
Personality factors as predictors of persistent risky driving behavior and crash involvement among young adults
Authors: Gulliver Pauline , Begg Dorothy
Published: December 2007

Objectives:

The aim of this study was to examine the relationship between personality factors assessed during adolescence and persistent risky driving behavior and traffic crash involvement among young adults.

Design:

Data for this investigation were drawn from the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of a cohort born in Dunedin, New Zealand.

Subjects:

The study population was 1037 young people born between 1 April 1972 and 31 March 1973.

Main outcome measures:

The main outcome measures were persistent risky driving behaviors and crash involvement, collected in a face-to-face road-safety interview at ages 21 and 26.

Results:

The only outcomes for which there were sufficient numbers of females were a driver involved in any crash and a driver involved in an injury crash. Univariate logistic regression revealed that there were no significant predictors for either of these outcomes. For the males, at the univariate level, aggression, traditionalism, and alienation were the personality scales most frequently associated with risky driving behavior and crash risk. After adjusting for driving exposure, only high levels of aggression predicted being a driver involved in a crash, and alienation predicted being a driver involved in an injury crash.

Conclusion:

These results suggest that road-safety interventions seeking to deter young adult males from persistent risky driving behavior need to be directed at those who do not endorse traditional views, are aggressive, and feel alienated from the rest of society.
Understanding high traffic injury risks for children in low socioeconomic areas: a qualitative study of parents’ views
Authors: Christie N , Ward H , Kimberlee R , Towner E , Sleney J
Published: December 2007

Objective:

To gain an in-depth qualitative understanding of parents’ views about their children’s exposure to road traffic injury risk in low socioeconomic areas.

Design:

Focus groups facilitated by a moderator with content analysis of data.

Setting:

Focus groups were conducted in 10 low socioeconomic English districts that also have high rates of child pedestrian injury. Research was conducted in community venues within each area.

Subjects:

Parents of children aged 9–14 years living in low socioeconomic areas.

Results:

Parents believe that children play in their local streets for the following reasons: they like playing out with friends near home; there are few safe, secure, and well-maintained public spaces for children; children are excluded from affordable leisure venues because of their costs; insufficient parental responsibility. For children that play in the street, the key sources of risk identified by parents were: illegal riding and driving around estates and on the pavements; the speed and volume of traffic; illegal parking; drivers being poorly informed about where children play; children’s risk-taking behavior.

Conclusions:

Intervention programs need to take into account multiple reasons why children in low socioeconomic areas become exposed to hazardous environments thereby increasing their risk of injury. Multi-agency partnerships involving the community are increasingly needed to implement traditional road safety approaches, such as education, engineering, and enforcement, and provide safe and accessible public space, affordable activities for children, and greater support for parents.
An international review of head and spinal cord injuries in alpine skiing and snowboarding
Authors: Ackery A , Hagel B E , Provvidenza C , Tator C H
Published: December 2007

Background:

Alpine skiing and snowboarding are popular winter activities worldwide, enjoyed by participants of all ages and skill levels. There is some evidence that the incidence of traumatic brain injury (TBI) and spinal cord injury (SCI) in these activities may be increasing. These injuries can cause death or severe debilitation, both physically and emotionally, and also result in enormous financial burden to society. Indeed, TBI is the leading cause of death and catastrophic injury in the skiing and snowboarding population. Furthermore, there are severe limitations to therapeutic interventions to restore neurological function after TBI and SCI, and thus the emphasis must be on prevention.

Objectives:

(1) To examine the worldwide epidemiology of TBI and SCI in skiing and snowboarding; (2) to describe and examine the effectiveness of prevention strategies to reduce the incidence of TBI and SCI in skiing and snowboarding.

Search strategy:

Searches were performed on a variety of databases to identify articles relevant to catastrophic central nervous system injury in skiing and snowboarding. The databases included PubMed, Medline, EMBASE, CDSR, ACP Journal Club, DARE, CCTR, SportDiscus, CINAHL, and Advanced Google searches.

Selection criteria and data collection:

After initial prescreening, articles included in the review required epidemiological data on SCI, TBI, or both. Articles had to be directly associated with the topic of skiing and/or snowboarding and published between January 1990 and December 2004.

Results:

24 relevant articles, from 10 different countries, were identified. They indicate that the incidence of TBI and SCI in skiing and snowboarding is increasing. The increases coincide with the development and acceptance of acrobatic and high-speed activities on the mountains. There is evidence that helmets reduce the risk of head injury by 22–60%. Head injuries are the most common cause of death among skiers and snowboarders, and young male snowboarders are especially at risk of death from head injury.

Conclusions:

There should be enhanced promotion of injury prevention that includes the use of helmets and emphasizes the skier’s and snowboarder’s responsibility code.
NEW METHOD OF EVALUATING RELATIVE THERMAL STABILITIES OF PROTEINS BASED ON THEIR AMINO ACID SEQUENCES: TARGETSTAR
Authors: KIM HAEJIN , MOON EUN-JOUNG , MOON SUNGCHUL , JUNG HO-JIN , YANG YOUNG-LYEOL , PARK YOUNG-HOON , HEO MUYOUNG , CHEON MOOKYUNG , CHANG IKSOO , HAN DONG-SOO
Published: December 2007

Several computational methods have been developed to solve the problem of protein thermostabilization. One common drawback of them is that they must have the information of a backbone structure of a protein for the generation of a proper amino acid sequence. In this paper, we propose a new method called TargetStar by incorporating computational biology and statistical physics, in which an approximate partition function and a specific heat are used to calculate the folding transition temperature of a protein and then to predict the relative thermal stabilities for given proteins based only on their amino acid sequences. To evaluate the prediction accuracy of TargetStar, we calculated folding transition temperatures of 289 orthologous protein pairs using the proposed method, where each protein pair contains one hyperthermophilic protein and one mesophilic protein. According to our evaluation, hyperthermophilic and mesophilic proteins are distinguished from each other in terms of relative thermal stabilities with 77% prediction accuracy. Thus, TargetStar may serve as an efficient method to design an amino acid sequence of a target protein with the desired thermal stability prior to the expensive and time-consuming mutagenesis experiment.
SIMPLE MODEL OF MATING PREFERENCE AND EXTINCTION RISK
Authors: PȨKALSKI ANDRZEJ
Published: December 2007

We present a simple model of a population of individuals characterized by their genetic structure in the form of a double string of bits and the phenotype following from it. The population is living in an unchanging habitat preferring a certain type of phenotype (optimum). Individuals are unisex, however a pair is necessary for breeding. An individual rejects a mate if the latter's phenotype contains too many bad, i.e. different from the optimum, genes in the same places as the individual's. We show that such strategy, analogous to disassortative mating based on the major histocompatibility complex, avoiding inbreeding and incest, could be beneficial for the population and could reduce considerably the extinction risk, especially in small populations.
QUANTUM WAVE-PACKETS IN FUZZY AUTOMATA AND NEURAL ASSOCIATIVE MEMORIES
Authors: RIGATOS GERASIMOS G.
Published: December 2007

In this paper the existence of quantum wave-packets in neural structures, such as automata and associative memories, is studied. The synaptic weights are considered to be stochastic variables, with probability density functions given by the solution of Schrödinger's equation. It is shown that the weights' update can be performed with the use of unitary operators, as indicated by the postulates of quantum mechanics. Moreover, it is proved that the number of attractors of quantum associative memories increases exponentially with respect to conventional associative memories. Finally, simulation tests are used to demonstrate the improved pattern storage capabilities of quantum associative memories.
AN ALTERNATIVE SIMPLE SOLUTION OF THE SEXTIC ANHARMONIC OSCILLATOR AND PERTURBED COULOMB PROBLEMS
Authors: IKHDAIR SAMEER M. , SEVER RAMAZAN
Published: December 2007

Utilizing an appropriate ansatz to the wave function, we reproduce the exact bound-state solutions of the radial Schrödinger equation to various exactly solvable sextic anharmonic oscillator and confining perturbed Coulomb models in D-dimensions. We show that the perturbed Coulomb problem with eigenvalue E can be transformed to a sextic anharmonic oscillator problem with eigenvalue [Formula: see text]. We also check the explicit relevance of these two related problems in higher-space dimensions. It is shown that exact solutions of these potentials exist when their coupling parameters with k = D +2ℓ appearing in the wave equation satisfy certain constraints.
A SIMPLE CA MODEL FOR SIGNAL TRANSDUCTION IN PLANTS
Authors: MUKHERJEE SANGHAMITRA
Published: December 2007

The classical cellular automata model has been modified by introducing "shadow" states or perturbations to represent the application of external signals to a configuration of discrete individual units. Simple update rules are studied to determine which of them are best suited to produce the emergent computation which can simulate signal transmission within a system. The study is made with a view to understanding electrical signalling in plant cells which are known to determine plant responses to the environment.
DISCOVERING PATTERNS FOR INTER-ORGANIZATIONAL BUSINESS PROCESS COLLABORATION
Authors: NORTA ALEX , GREFEN PAUL
Published: December 2007

In the area of business-to-business (B2B) collaboration for manufacturing, original equipment manufacturers (OEMs) are confronted with the problem of spending considerable time and effort on coordinating suppliers across multiple tiers of their supply chain. In tightly integrated supply chains, the failure of providing services and goods on time leads to interruptions of the overall production and subsequently results in customer dissatisfaction. This paper proposes the concept of electronic Sourcing eSourcing as a consolidating approach for improving the coordination of service provision across several tiers of a supply chain. eSourcing allows for the harmonization of heterogenous system environments of collaborating parties without requiring a total disclosure of internal business details to the counterpart. Furthermore, with tool support in eSourcing, it is possible to verify the correct termination of processes and the contractual adherence of service provision without imposing fixed standardized routing. In this paper features of the eSourcing concept are analyzed in a pattern-based way. This paper pursues an analysis of eSourcing patterns in a top-down way for constructing collaboration configurations. The discovered and specified eSourcing construction patterns of this paper are instrumental in the EU-FP6 project CrossWork for conducting case studies with industry partners from the automobile industry.
FIESTA: A GENERIC FRAMEWORK FOR INTEGRATING NEW FUNCTIONALITIES INTO SOFTWARE ARCHITECTURES
Authors: WAIGNIER GUILLAUME , LE MEUR ANNE-FRANÇOISE , DUCHIEN LAURENCE
Published: December 2007

When an application must evolve to cope with new context and user requirements, integrating new functionalities into its software architecture is necessary. The architect has thus to manually modify the architecture description, which is often tedious and error prone.

In this paper, we propose FIESTA, a generic framework for automatically integrating new functionalities into an architecture description. Our approach is inspired by TranSAT, an integration framework. However, TranSAT is dedicated to a specific architecture description language (ADL) while our approach is ADL-independent. We have performed a domain analysis, studying for many ADLs how to integrate new functionalities. Based on this analysis, we have defined a generic ADL model to manipulate and reason about architectural elements that are involved in integration. Furthermore, we have developed a generic integration engine.
THE ART AND SCIENCE OF SOFTWARE ARCHITECTURE
Authors: BROWN ALAN W. , McDERMID JOHN A.
Published: December 2007

Experience in all aspects of software engineering has confirmed the pivotal role of focusing on architectural concerns in the development of complex software-intensive systems. Consequently, the past 20 years has seen significant investments in the theory and practice of software architecture. However, architectural deficiencies are frequently cited as a key factor in the shortcomings and failures that lead to unpredictable delivery of complex operational systems. Here, we consider the art and science of software architecture: we explore the current state of software architecture, identify key architectural trends, and directions in academia and industry, and highlight some of the architectural research challenges which need to be addressed. The paper proposes a detailed agenda of research activities to be carried out by a partnership between academia and industry. While challenges exist in many domains, for this paper we draw examples from one area of particular concern: safety-critical systems.
Targeting Protein Translation in Human Non–Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression
Authors: Legrier Marie-Emmanuelle , Yang Chia-Ping Huang , Yan Han-Guang , Lopez-Barcons Lluis , Keller Steven M. , Pérez-Soler Roman , Horwitz Susan Band , McDaid Hayley M.
Published: December 2007

Lung cancer is a genetically heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling cascades. These pathways intersect at various points, rendering this network highly redundant and suggesting that combined mitogen-activated protein/extracellular signal-regulated kinase (MEK) and mammalian target of rapamycin (mTOR) inhibition may be a promising drug combination that can overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, exhibited dose-dependent synergism in human lung cancer cell lines that was associated with suppression of proliferation rather than enhancement of cell death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis by 40% within 24 h and was associated with a decreased polysome/monosome ratio that is indicative of reduced protein translation efficiency. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone or PD0325901 at the maximum tolerated dose in nude mice bearing human lung tumor xenografts or heterotransplants. Except for a PTEN mutant, all tumor models had sustained tumor regressions and minimal toxicity. These data (a) provide evidence that both pathways converge on factors that regulate translation initiation and (b) support therapeutic strategies in lung cancer that simultaneously suppress the RAS and AKT signaling network. [Cancer Res 2007;67(23):11300–8]
An Oncolytic Adenovirus Redirected with a Tumor-Specific T-Cell Receptor
Authors: Sebestyen Zsolt , de Vrij Jeroen , Magnusson Maria , Debets Reno , Willemsen Ralph
Published: December 2007

To improve safety and specificity of oncolytic adenoviruses, we introduced T-cell receptors (TCR) specific for a unique class of truly tumor-specific antigens into the adenoviral fiber protein. The adenoviral fiber knob responsible for attachment to the coxsackie-adenoviral receptor (CAR) on target cells was replaced by a single-chain TCR (scTCR) molecule with specificity for the melanoma-associated cancer-testis antigen MAGE-A1, presented by HLA-A1, and an extrinsic trimerization motif in a replicating Ad5 vector (Ad5.R1-scTCR). The production of the recombinant virus was initiated in a novel producer cell line that expressed an antibody-based hexon-specific receptor (293T-AdR) in the cell membrane. This new production system allowed CAR-independent and target antigen–independent propagation of Ad5.R1-scTCR. Infection with adenovirus bearing the scTCR-based fiber resulted in an efficient killing of target tumor cells. The infection was cell type specific because only HLA-A1+/MAGE-A1+ melanoma cells were killed, and thus, this retargeting strategy provides a versatile tool for future clinical application. [Cancer Res 2007;67(23):11309–16]
Sustained Antigen-Specific Antitumor Recall Response Mediated by Gene-Modified CD4+ T Helper-1 and CD8+ T Cells
Authors: Moeller Maria , Kershaw Michael H. , Cameron Rachel , Westwood Jennifer A. , Trapani Joseph A. , Smyth Mark J. , Darcy Phillip K.
Published: December 2007

Given that specific subsets of T helper 1 (Th1) and T helper 2 (Th2) CD4+ T cells have been shown to play key roles in tumor rejection models, we wanted to assess the contribution of either Th1 or Th2 CD4+ cell subtypes for redirected T-cell immunotherapy. In this study, we have developed a novel method involving retroviral transduction and in vitro T-cell polarization to generate gene-engineered mouse CD4+ Th1 and Th2 cells or T helper intermediate (Thi) cells expressing an anti–erbB2-CD28-ζ chimeric receptor. Gene-modified Th1 and Th2 polarized CD4+ cells were characterized by the preferential secretion of IFN-γ and interleukin-4, respectively, whereas Thi cells secreted both cytokines following receptor ligation. In adoptive transfer studies using an erbB2+ lung metastasis model, complete survival of mice was observed when transduced Th1, Th2, or Thi CD4+ cells were transferred in combination with an equivalent number of transduced CD8+ T cells. Tumor rejection was consistently associated with transduced T cells at the tumor site and interleukin-2 secretion. However, the surviving mice treated with gene-modified Th1 CD4+ cells were significantly more resistant to a subsequent challenge with a different erbB2+ tumor (4T1.2) implanted s.c. This result correlated with both increased expansion of Th1 CD4+ and CD8+ T cells in the blood and a greater number of these cells localizing to the tumor site following rechallenge. These data support the use of gene-modified CD4+ Th1 and CD8+ T cells for mediating a sustained antitumor response. [Cancer Res 2007;67(23):11428–37]
Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells
Authors: Kim Tae-Kyung , Lee Joong-Seob , Oh Se-Yeong , Jin Xun , Choi Yun-Jaie , Lee Tae-Hoon , Lee Eun ho , Choi Young-Ki , You Seungkwon , Chung Yong Gu , Lee Jang-Bo , DePinho Ronald A. , Chin Lynda , Kim Hyunggee
Published: December 2007

IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference–mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression. [Cancer Res 2007;67(23):11133–40]
Epithelial to Mesenchymal Transition in Human Breast Epithelial Cells Transformed by 17β-Estradiol
Authors: Huang Yong , Fernandez Sandra V. , Goodwin Shirlean , Russo Patricia A. , Russo Irma H. , Sutter Thomas R. , Russo Jose
Published: December 2007

The estrogen dependence of breast cancer has long been recognized; however, the role of 17β-estradiol (E2) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E2 treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF > bcMCF >>> trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor β1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation. [Cancer Res 2007;67(23):11147–57]
Nuclear Factor-κB, an Unappreciated Tumor Suppressor
Authors: Chen Fei , Castranova Vince
Published: December 2007

The notion that nuclear factor-κB (NF-κB) is a tumor-promoting transcription factor has become a widely accepted dogma in biology. However, recent findings suggest an inhibitory role for NF-κB in carcinogenesis and tumorigenesis. Although the tumor suppressor–like effect of NF-κB remains to be rigorously established by further studies using cellular and animal models, these latest findings warrant caution with respect to blockage of NF-κB activation as a broad strategy in treating cancers. [Cancer Res 2007;67(23):11093–8]
The p38 MAPK Pathway Mediates Aryl Propionic Acid–Induced Messenger RNA Stability of p75NTR in Prostate Cancer Cells
Authors: Quann Emily J. , Khwaja Fatima , Djakiew Daniel
Published: December 2007

The p75NTR acts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75NTR expression in PC-3 and DU-145 cells leading to p75NTR-mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75NTR expression. We show that the observed increase in p75NTR protein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75NTR mRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK–specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75NTR by R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75NTR by R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75NTR expression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75NTR expression by increased mRNA stability that is mediated through the p38 MAPK pathway. [Cancer Res 2007;67(23):11402–10]
Amino-Biphosphonate–Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma
Authors: Melani Cecilia , Sangaletti Sabina , Barazzetta Francesca M. , Werb Zena , Colombo Mario P.
Published: December 2007

BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro–MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro–MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor–derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage. [Cancer Res 2007;67(23):11438–46]
Gpx2 Is an Overexpressed Gene in Rat Breast Cancers Induced by Three Different Chemical Carcinogens
Authors: Naiki-Ito Aya , Asamoto Makoto , Hokaiwado Naomi , Takahashi Satoru , Yamashita Hiroko , Tsuda Hiroyuki , Ogawa Kumiko , Shirai Tomoyuki
Published: December 2007

Gene expression alterations are essential for the process of carcinogenesis. A carcinogen may have specific mechanisms for inducing tumors, which may involve inducing characteristic gene expression alterations. In this study, we attempted to identify genes crucial for mammary carcinogenesis. For this purpose, we used human c-Ha-ras proto-oncogene transgenic rats (Hras128), which are highly sensitive to mammary carcinogens including N-methyl-N-nitrosourea, 7,12-dimethyl benz[a]anthracene, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. DNA microarray analysis revealed that glutathione peroxidase 2 (Gpx2) was commonly up-regulated in the mammary carcinomas induced by the three different carcinogens, and its up-regulation was confirmed by quantitative reverse transcriptase-PCR and Western blotting analysis. In addition, expression of GPX2 was recognized in all 41 immunohistochemically examined cases of human breast cancer. Forced suppression of GPX2 expression by siRNA resulted in significant growth inhibition in both rat and human mammary carcinoma cell lines with wild-type p53 cells. Thus, these data suggested that GPX2 may be involved in mammary carcinogenesis and cell proliferation in both rats and humans, indicating that GPX2 may be a novel target for the prevention and therapy of breast cancer. [Cancer Res 2007;67(23):11353–8]