bluuebunny/crossref_metadata_2025 huggingface dataset:
Acoustic emission traceable sensing
Authors: Jones B E , Yan T
Published: December 2004

To date, most acoustic emission (AE) testing has been undertaken without a proper means of calibration for AE sensors in situ. The detected AE signals are significantly affected by the positioning of the sensor on a structure, machine or process, and by the variability of the sensor-structure interface. The result is AE measurements with poor repeatability and no traceability. All that is being actually measured is the voltage (or the voltage in dB with reference to 1 μV) of the AE sensor system output, whereas what is often desired is the measurement of the actual AE source or sources; these may be some distance away from the position of the AE sensor. This paper outlines a possible hierarchy of traceability for AE energy measurements through in situ calibration of the AE sensors using artificial AE energy sources: an elastic ball impact, a thermoelastic pulsed laser irradiation, and a self-calibrating conical piezoelectric transducer.
Acoustic emission waveform simulation in multilayered composites
Authors: Banerjee S , Mal A. K
Published: December 2004

In this paper, an efficient and accurate semi-analytical method is developed to calculate the elastodynamic field produced by localized dynamic loads in a relatively thick composite plate. Two types of loads are considered: a pencil lead break source located on the surface and a localized shear delamination within the interior of the plate. In the case of the pencil lead break source, the calculated results for the surface motion are compared with those obtained in laboratory experiments on a 4.4mm thick 32 layered cross-ply graphite/epoxy using high-fidelity broadband transducers. The waveforms consist of both flexural and extensional modes; the amplitude variations of these modes are found to be strongly dependent on their propagation direction. For the delamination source, the results from the exact calculation are compared with those from an approximate laminate theory with a shear correction factor and ‘moment tensor’ representation of the source. The results obtained by the two methods are shown to have excellent agreement in the low-frequency ranges. Although the motion due to the delamination is dominated by flexural waves of lower frequency in both thin and thick plates, the presence of extensional waves are observed in thicker laminates.
A pilot study of specialized nursing care for home health patients
Authors: Baer Carol A , Williams Christy M , Vickers Leslie , Kvedar Joseph C
Published: December 2004

We conducted a pilot study to assess the feasibility of remote (Web-based) consultations for leg wounds. The wounds were photographed by a home care nurse using a digital camera and the images were transmitted to a server from the nurses' office, together with patient details. The home care nurse graded the wounds and suggested a treatment plan. Subsequently, a specialist wound-care nurse also graded them and suggested a treatment plan, using the data stored on the Web server. Thirty-four patients were studied. The Web system proved simple to use and staff responses were positive. The agreement between the home care nurses and the specialist nurse in assessing wounds was good (kappa coefficients 0.41 to 0.71). Agreement over the treatment of wounds was more variable (kappa coefficients –0.75 to 0.81). The results of the pilot study are encouraging and suggest that Web-based communication can improve the quality of care for patients with leg wounds and reduce costs.
An editor's view of telemedicine
Authors: Wootton Richard
Published: December 2004

Should an editor hold a view about telemedicine, or should an editor be entirely disinterested? The editorial role has been defined by the International Committee of Medical Journal Editors and a long list of editorial responsibilities has been set out by the World Association of Medical Editors. This represents something of a counsel of perfection, although clearly an editor should not have a personal view, in the sense of promoting telemedicine or dismissing it. Since telemedicine editors are almost bound to be active in research, they should take particular care with manuscripts involving their own work, for example standing aside from the editorial process and delegating editorial decisions to other members of the editorial staff. At the beginning of the 1990s, there were few publications about telemedicine in the peer-reviewed literature. The subsequent years have seen a rapid growth in numbers of articles and the emergence of two specialist journals. These are all healthy signs. However, there have been remarkably few studies of telemedicine's cost-effectiveness, which must represent a sign of its immaturity. On balance, the evidence seems to indicate that telemedicine research is in a healthy state.
Reconstitution in cultured cells of replicating HDV RNA from pairs of less than full-length RNAs
Authors: GUDIMA SEVERIN O. , CHANG JINHONG , TAYLOR JOHN M.
Published: December 2004

The genome of hepatitis delta virus (HDV) is a small single-stranded circular RNA that is replicated via RNA-directed RNA synthesis. This makes use of a host RNA polymerase, probably pol II, that normally transcribes DNA templates. In vivo, the host polymerase can initiate replication from transfected linear RNAs using intramolecular template-switching. The present studies report that the polymerase could also achieve intermolecular switching leading to “reconstitution” of full-length HDV RNAs following transfection with two linear RNAs that were less than full length and yet lacking different regions of the genome. These two RNAs were synthesized in vitro, gel purified, pre-annealed, and then transfected into δ293, a cell line conditionally expressing the small delta antigen that is essential for HDV replication. Northern analyses of total RNA harvested from transfected cells detected the accumulation of full-length HDV genomic and antigenomic RNAs. Such reconstitution of full-length replicating HDV RNA was also achieved using nine other pairs of antigenomic RNAs and three pairs of genomic RNAs. Annealing of the RNAs prior to transfection was required for detectable HDV reconstitution. A second cell line, Huh7, also supported reconstitution when a pair of RNAs was cotransfected together with mRNA for the small delta protein. Taken together, these results support a model that observed genome reconstitution is a special form of recombination involving intermolecular template switches and they provide insights into the mechanism of RNA-directed RNA transcription catalyzed by a host RNA polymerase.
Domain structure and three-dimensional model of a group II intron-encoded reverse transcriptase
Authors: BLOCKER FORREST J.H. , MOHR GEORG , CONLAN LORI H. , QI LI , BELFORT MARLENE , LAMBOWITZ ALAN M.
Published: December 2004

Group II intron-encoded proteins (IEPs) have both reverse transcriptase (RT) activity, which functions in intron mobility, and maturase activity, which promotes RNA splicing by stabilizing the catalytically active RNA structure. The LtrA protein encoded by the Lactococcus lactis Ll.LtrB group II intron contains an N-terminal RT domain, with conserved sequence motifs RT1 to 7 found in the fingers and palm of retroviral RTs; domain X, associated with maturase activity; and C-terminal DNA-binding and DNA endonuclease domains. Here, partial proteolysis of LtrA with trypsin and Arg-C shows major cleavage sites in RT1, and between the RT and X domains. Group II intron and related non-LTR retroelement RTs contain an N-terminal extension and several insertions relative to retroviral RTs, some with conserved features implying functional importance. Sequence alignments, secondary-structure predictions, and hydrophobicity profiles suggest that domain X is related structurally to the thumb of retroviral RTs. Three-dimensional models of LtrA constructed by “threading” the aligned sequence on X-ray crystal structures of HIV-1 RT (1) account for the proteolytic cleavage sites; (2) suggest a template–primer binding track analogous to that of HIV-1 RT; and (3) show that conserved regions in splicing-competent LtrA variants include regions of the RT and X (thumb) domains in and around the template–primer binding track, distal regions of the fingers, and patches on the protein’s back surface. These regions potentially comprise an extended RNA-binding surface that interacts with different regions of the intron for RNA splicing and reverse transcription.
Design of Zone Tariff Systems in Public Transportation
Authors: Hamacher Horst W. , Schöbel Anita
Published: December 2004

Dedicated to our doctor father and grandfather, Prof. Dr. E. Rainer Burkard, on the occasion of his 60th birthday

Given a public transportation system represented by its stops and direct connections between stops, we present OR models for two problems dealing with the prices for the customers. In the first, the fare problem, subsets of stops are already aggregated to zones and “good” tariffs have to be found in the existing zone system. Closed form solutions for the fare problem are presented for three objective functions. The second problem, the zone problem includes the design of the zones. In an exemplary way we study this problem for one of the objectives. It is NP hard and we therefore propose three heuristics which prove to be very successful in the redesign of one of Germany's transportation systems.
A Diffusion Approximation for the G/GI/n/m Queue
Authors: Whitt Ward
Published: December 2004

We develop a diffusion approximation for the queue-length stochastic process in the G/GI/n/m queueing model (having a general arrival process, independent and identically distributed service times with a general distribution, n servers, and m extra waiting spaces). We use the steady-state distribution of that diffusion process to obtain approximations for steady-state performance measures of the queueing model, focusing especially upon the steady-state delay probability. The approximations are based on heavy-traffic limits in which n tends to infinity as the traffic intensity increases. Thus, the approximations are intended for large n.

For the GI/M/n/∞ special case, Halfin and Whitt (1981) showed that scaled versions of the queue-length process converge to a diffusion process when the traffic intensity ρn approaches 1 with (1 – ρn)√n → β for 0 < β < ∞. A companion paper, Whitt (2005), extends that limit to a special class of G/GI/n/mn models in which the number of waiting places depends on n and the service-time distribution is a mixture of an exponential distribution with probability p and a unit point mass at 0 with probability 1 – p. Finite waiting rooms are treated by incorporating the additional limit mn/√n → κ for 0 < κ ≤ ∞. The approximation for the more general G/GI/n/m model developed here is consistent with those heavy-traffic limits. Heavy-traffic limits for the GI/PH/n/∞ model with phase-type service-time distributions established by Puhalskii and Reiman (2000) imply that our approximating process is not asymptotically correct for nonexponential phase-type service-time distributions, but nevertheless, the heuristic diffusion approximation developed here yields useful approximations for key performance measures such as the steady-state delay probability. The accuracy is confirmed by making comparisons with exact numerical results and simulations.
Optimal Investment Strategies for Flexible Resources, Considering Pricing and Correlated Demands
Authors: Bish Ebru K. , Wang Qiong
Published: December 2004

We study the optimal resource investment decision faced by a two-product, price-setting firm that operates in a monopolistic setting and employs a postponed pricing scheme. The firm has the option to invest in dedicated resources as well as a more expensive, flexible resource that can satisfy both products. While the resource investment decision is made under demand uncertainty, pricing and resource allocation decisions are postponed to the time when demand curves are realized. Our analysis provides the structure of the firm's optimal resource investment strategy as a function of demand parameters and investment costs, and shows that the flexible resource investment decision follows a threshold policy. We also show that it can be optimal for the firm to invest in the flexible resource even when demand patterns are perfectly positively correlated. The reason for flexible capacity investment in this case is financial rather than risk pooling. On the other hand, we show that it can be optimal for the firm not to invest in the flexible resource even when demand patterns are perfectly negatively correlated. The flexible resource investment decision in this case depends on the profitability of the two products. Based on our analysis, we provide principles on the firm's optimal resource investment decision.
On the Stability of Supply Chains
Authors: Daganzo Carlos F.
Published: December 2004

This paper examines the stability of decentralized, multistage supply chains under arbitrary demand conditions. It looks for intrinsic properties of the inventory replenishment policies that hold for all customer demand processes and for policies with desirable properties.

It is found that the overall conditions experienced by suppliers several stages removed from the final customer, e.g., the variances of the orders they receive and the inventories they keep, depend on the policy much more than on the demand process. A policy-specific but demand-independent upper bound for the order variance amplification factor of any decentralized policy is shown to exist, and its formula is presented. The bound is always tight for the suppliers at the end of a long chain so that a policy exhibits the “bullwhip effect” if and only if its bound is greater than 1.

A simple necessary condition for bullwhip avoidance is also identified in terms of a policy's “gain.” Gain is the marginal change in average inventory induced by a policy when there is a small but sustained change in the demand rate. It is shown that all policies with positive gain produce the bullwhip effect if they do not use future order commitments. Because manufacturers can reduce costs by operating with positive gain, this explains the prevalence of the bullwhip effect.

A family of commitment-based policies that can dynamically maintain any desired inventory level for any demand rate (e.g., achieve positive gain) without the bullwhip effect is also presented. The family includes just-in-time strategies as a special case. Simulation results are used as an illustration.
A General Equilibrium Model for Industries with Price and Service Competition
Authors: Bernstein Fernando , Federgruen Awi
Published: December 2004

This paper develops a stochastic general equilibrium inventory model for an oligopoly, in which all inventory constraint parameters are endogenously determined. We propose several systems of demand processes whose distributions are functions of all retailers' prices and all retailers' service levels. We proceed with the investigation of the equilibrium behavior of infinite-horizon models for industries facing this type of generalized competition, under demand uncertainty.

We systematically consider the following three competition scenarios. (1) Price competition only: Here, we assume that the firms' service levels are exogenously chosen, but characterize how the price and inventory strategy equilibrium vary with the chosen service levels. (2) Simultaneous price and service-level competition: Here, each of the firms simultaneously chooses a service level and a combined price and inventory strategy. (3) Two-stage competition: The firms make their competitive choices sequentially. In a first stage, all firms simultaneously choose a service level; in a second stage, the firms simultaneously choose a combined pricing and inventory strategy with full knowledge of the service levels selected by all competitors. We show that in all of the above settings a Nash equilibrium of infinite-horizon stationary strategies exists and that it is of a simple structure, provided a Nash equilibrium exists in a so-called reduced game.

We pay particular attention to the question of whether a firm can choose its service level on the basis of its own (input) characteristics (i.e., its cost parameters and demand function) only. We also investigate under which of the demand models a firm, under simultaneous competition, responds to a change in the exogenously specified characteristics of the various competitors by either: (i) adjusting its service level and price in the same direction, thereby compensating for price increases (decreases) by offering improved (inferior) service, or (ii) adjusting them in opposite directions, thereby simultaneously offering better or worse prices and service.
Fairness and Transaction Costs: The Contribution of Organizational Justice Theory to an Integrative Model of Economic Organization
Authors: Husted Bryan W. , Folger Robert
Published: December 2004

In this article, we begin to integrate two fields that have, until now, remained largely independent of one another: organizational justice and transaction-cost economics. Transaction costs consist of search, bargaining, monitoring, enforcement, and other costs not directly related to the production of goods or services. Usually such costs are attributed to difficulties in measurement (the metering problem) or difficulties in redeploying assets to alternative uses (asset specificity). These variables are thought to be objective features of economic transactions. Rarely are the social-psychological dimensions of these objective features taken into account. Although economic transactions are fundamentally human activities, human behavior in the economics literature is usually reduced to such simplifying assumptions as shirking and bounded rationality. In this article, we develop a model of transaction costs based on a more complete description of human psychology as it operates in exchange relationships.

We argue that transaction costs are often due to the difficulty of evaluating the fairness of a specific exchange of goods and services. Besides asset specificity and the metering problem, which are treated in the transaction-cost economics literature, the organizational justice literature is especially relevant. Beginning with the work of Ouchi (1980), the paper examines some of the ways that the organizational justice literature complements transaction-cost economics. Because mechanisms that order economic transactions are essentially conflict-resolution structures, we develop a model of economic organization in which transaction costs are related to the perception of fairness in economic exchange. In the literature, governance mechanisms are selected so as to minimize transaction costs. Based on the organizational justice framework, we suggest that the transaction-cost calculus is affected by the perception of fairness in the exchange. In addition, the relationship between the governance mechanism and the perception of fairness is moderated by the elements of interactional justice that characterize the exchange.
A Knowledge-Based Theory of the Firm—The Problem-Solving Perspective
Authors: Nickerson Jack A. , Zenger Todd R.
Published: December 2004

In this paper we develop a knowledge-based theory of the firm. While existing knowledge-based theory focuses on the efficiency of hierarchy in economizing on knowledge exchange, we develop a theory of the firm that focuses on the efficiency of alternative organizational forms in generating knowledge or capability. Our theory begins with the problem as the basic unit of analysis, arguing that a problem's complexity influences the optimal method of solution search and the optimal means of organizing that search. The distinguishing feature that differentiates among organizational alternatives is the different way each resolves conflict over the selection of solution trials, that is, the way it chooses the path of search. Our theory predicts that efficiency demands that these governance alternatives be matched in a discriminating way to problems based on their associated benefits and costs in governing solution search. Thus, our theory is among the first to simultaneously treat both the boundary choice (i.e., internal versus external) and the choice among alternative internal approaches to organizing.
The role of collective efficacy in the relations between transformational leadership and work outcomes
Authors: Walumbwa Fred O. , Wang Peng , Lawler John J. , Shi Kan
Published: December 2004

Using a sample of 402 employees from the banking and finance sectors in China and India, we found that transformational leadership is positively related to organizational commitment and job satisfaction, and negatively related to job and work withdrawal. We also found that collective efficacy mediated the contribution of transformational leadership to job and work withdrawal and partially mediated the contribution of transformational leadership to organizational commitment and job satisfaction. Implications and directions for future research are discussed.
The ‘romance of teams’: Toward an understanding of its psychological underpinnings and implications
Authors: Allen Natalie J. , Hecht Tracy D.
Published: December 2004

Although advocates of teamwork suggest that teams enhance performance, empirical evidence does not consistently, or robustly, support these claims. Still, a belief in the effectiveness of teams—among managers, employees, and the general lay population—seems very strong. What accounts for this ‘romance of teams’? In this paper, we offer a psychological answer to this question. We review evidence regarding the actual effectiveness of teams, in order to show that teams are not as effective as many believe them to be, and we argue that the romance of teams stems from the psychological benefits of group‐based activity. Specifically, we propose that team members experience both social‐emotional, and competence‐related, benefits, and we review an eclectic mix of research in support of this claim. We argue that these psychological benefits of teams lead people to assume that teams are ‘high performance’, thus, causing the romance of teams. Finally, we discuss potential implications of the romance for organizations, researchers, and employees.
Work characteristics and employee health and well‐being: Test of a model of healthy work organization
Authors: Wilson Mark G. , Dejoy David M. , Vandenberg Robert J. , Richardson Hettie A. , Mcgrath Allison L.
Published: December 2004

This paper presents an initial test and validation of a model of healthy work organization. A questionnaire based on the proposed model was completed by 1,130 employees of a national retailer. The instrument measured 29 first‐order constructs underlying the six higher‐order domains of the model. The overall model fit and relationships among the second‐order factors were examined using AMOS structural equation‐modelling procedures. The structural analyses presented here support the proposed model. An acceptable overall fit was demonstrated, and all second‐order, and second‐ to first‐order, relationships were significant. Employees' perceptions of their organization affect their perception of the climate, which impacts the way people relate to their job and see their future in the organization, ultimately impacting their work adjustment, health and well‐being. This model has implications for both research and practice.
Effect of Dietary Lipid Level on Growth Performance of Splittail at 18°C
Authors: Deng Dong-Fang , Teh Swee J , Min Tae-Sun , Hung Silas S O
Published: December 2004

A 12-week feeding trial was conducted to study the effect of dietary lipid level on growth performance of juvenile Sacramento splittail Pogonichthys macrolepidotus at 18°C. We selected this temperature to simulate their natural habitats, although an earlier study showed that their optimum temperature was 22–26°C. Six isonitrogenous and isoenergetic purified diets were formulated to contain 2–12% lipid in 2% increments, and dietary lipid was an equal mix of corn oil and cod liver oil. Fish with an average initial body weigh of 9.0 ± 0.2 g (mean ± SE, n = 24) were kept in a 24-tank, flow-through system with 15 fish per tank, and each diet was randomly assigned to four replicate tanks of fish. Fish were fed 3.0% of their body weight per day by automatic feeders, which dispensed a small amount of feed every few minutes in daylight hours. Body weight and feed efficiency increased significantly with increasing dietary lipid level up to 8%. Fish fed the diet containing 8% lipid showed significantly higher body weight increase and feed efficiency than those fed the diets containing less than 6% lipid. Dietary lipid level did not affect the hepatosomatic index, condition factor, and intraperitoneal fat ratio. Whole-body moisture was significantly lower but lipid was higher in fish fed the diet containing 8% lipid than in those fed the diets containing less than 6% lipid. Histological analysis revealed a higher prevalence of hepatocellular fatty vacuolation in fish fed the diet containing 12% lipid. Based on a broken-line analysis, a dietary lipid level of 8.4% is recommended for juvenile splittail reared at 18°C.
The role of stroma in prostatic carcinogenesis
Authors: Grossfeld G D , Hayward S W , Tlsty T D , Cunha G R
Published: December 2004

Abstract

Most human prostate tumors are adenocarcinomas which arise from the epithelial cells that line the glands and ducts of the prostate. Consequently, the malignant epithelial cell, or more specifically genetic damage suffered by that malignant epithelial cell, has been the major focus of prostate cancer research to date. There is, however, increasing evidence to suggest that alterations in the stromal microenvironment associated with a malignant epithelium may be necessary for progression of carcinogenesis.

We have recently hypothesized that interactions between the stroma and epithelium become altered as a result of genetic damage to the prostatic epithelial cell. During prostatic carcinogenesis, this abnormal signaling may lead to changes in both the prostatic epithelium and smooth muscle with concomitant loss of growth control. In this way, both a malignant epithelium and an abnormal or ‘tumor stroma’ evolve.

The purpose of this article is to describe interactions between the stroma and epithelium of the normal prostate, and then to summarize evidence suggesting that stromal cells derived from benign versus malignant sources may exert differential effects on epithelial cell growth and differentiation.

Acknowledgements

This work was supported by NIH grants DK52721, CA 59831, DK 45861, CA 64872, DK 52708 and DK 47517, and by an AFUD/Pfizer USPG Research Scholarship to GDG.
Pathological studies of apoptosis in the normal breast.
Authors: Anderson T J
Published: December 2004

Apoptosis in the normal breast has been demonstrated to be related to the menstrual cycle. The factors that influence apoptosis in the breast are reviewed, together with related variations in the degree of apoptosis to disease pathogenesis. Evidence for a relationship between mitosis and apoptosis is provided, and the implications of pregnancy and prolonged postlactational involution are discussed. Future progress will depend on active collaboration between molecular biologists and pathologists to dissect the complex signalling pathways that appear to control the apoptotic and mitotic cascades and their inter-relationships.
Clinical studies of apoptosis and proliferation in breast cancer.
Authors: Dowsett M , Archer C , Assersohn L , Gregory R K , Ellis P A , Salter J , Chang J , Mainwaring P , Boeddinghaus I , Johnston S R , Powles T J , Smith I E
Published: December 2004

The interaction between cell death and cell proliferation determines the growth dynamics of all tissues. Studies are described here which relate the changes in proliferation and apoptosis that occur in human breast cancer during medical therapeutic manoeuvres. Xenograft studies strongly support the involvement of increased apoptosis as well as decreased proliferation after oestrogen withdrawal, and limited studies in clinical samples confirm the involvement of both processes. Cytotoxic chemotherapy induces increases in apoptosis within 24 h of starting treatment. However, after 3 months therapy the residual cell population shows apoptotic and proliferation indices much below pretreatment levels. Further molecular studies of this "dormant" population are important to characterise the mechanism of their resistance to drug therapy. The early changes in proliferation and apoptosis may provide useful intermediate response indices.
Prognostic significance of apoptosis regulators in breast cancer.
Authors: Krajewski S , Krajewska M , Turner B C , Pratt C , Howard B , Zapata J M , Frenkel V , Robertson S , Ionov Y , Yamamoto H , Perucho M , Takayama S , Reed J C
Published: December 2004

Dysregulation of normal programmed cell death mechanisms plays an important role in the pathogenesis and progression of breast cancer, as well as in responses of tumors to therapeutic intervention. Overexpression of anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-X(L) has been implicated in cancer chemoresistance, whereas high levels of pro-apoptotic proteins such as Bax promote apoptosis and sensitize tumor cells to various anticancer therapies. Though the mechanisms by which Bcl-2 family proteins regulate apoptosis are diverse, ultimately they govern decision steps that determine whether certain caspase family cell death proteases remain quiescent or become active. To date, approximately 17 cellular homologs of Bcl-2 and at least 15 caspases have been identified in mammals. Other types of proteins may also modulate apoptotic responses through effects on apoptosis-regulatory proteins, such as BAG-1-a heat shock protein 70 kDa (Hsp70/Hsc70)-binding protein that can modulate stress responses and alter the functions of a variety of proteins involved in cell death and division. In this report, we summarize our attempts thus far to explore the expression of several Bcl-2 family proteins, caspase-3, and BAG-1 in primary breast cancer specimens and breast cancer cell lines. Moreover, we describe some of our preliminary observations concerning the prognostic significance of these apoptosis regulatory proteins in breast cancer patients, contrasting results derived from women with localized disease (with or without node involvement) and metastatic cancer.
Regulation of mammary epithelial cell phenotypes by the helix-loop-helix protein, Id-1.
Authors: Lin C Q , Parrinello S , Campisi J , Desprez P Y
Published: December 2004

Mammary epithelial cells undergo cycles of proliferation, invasion, differentiation and apoptotic cell-death throughout adult life. The molecular mechanisms that regulate these complex and co-ordinated developmental programs are poorly understood. We have identified Id-1 protein, a negative regulator of basic helix-loop-helix transcription factors, as a critical regulator of these normal mammary epithelial cell phenotypes. We also found that Id-1 is an important regulator of the aggressive and invasive phenotype, as well as mediator of the effects of sex steroid hormones, in human breast cancer cells.
Clinical aspects of cell death in breast cancer: the polyamine pathway as a new target for treatment.
Authors: Davidson N E , Hahm H A , McCloskey D E , Woster P M , Casero R A
Published: December 2004

Because intracellular polyamines have a critical role in cell proliferation and death pathways, the polyamine metabolic pathway represents a potential target for intervention in cancers. A number of polyamine analogues have been identified that downregulate polyamine synthesis and enhance polyamine catabolism, thereby depleting intracellular polyamines. Treatment of human breast cancer cell lines in culture with these analogues has been shown to decrease cell proliferation and induce programmed cell death. Phase I studies with one analogue are now complete, setting the stage for phase II trials to determine efficacy, in addition to preclinical studies to examine combinations of polyamine analogues and conventional cytotoxics.
Breast tumor aromatase: functional role and transcriptional regulation.
Authors: Chen S , Zhou D , Okubo T , Kao Y C , Yang C
Published: December 2004

Aromatase has been shown to be expressed at a higher level in human breast cancer tissue than in normal breast tissue, by means of enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture including MCF-7 breast cancer cells, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that estrogen production in situ plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase is believed to be able to stimulate breast cancer growth through both autocrine and paracrine pathways, as demonstrated by a three-dimensional cell culture study. RT-PCR and gene transcriptional studies have revealed that the aromatase promoter is switched from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancerous tissue. Recently, we identified and characterized a cAMP-responsive element (CREaro) upstream from promoter I.3 by DNA deletion and mutational analyses. Our results from promoter functional analysis also demonstrated an interaction between the CREaro and the silencer element (S1) that was identified previously in our laboratory. In the presence of cAMP, the positive regulatory CREaro can overcome the action of the silencer on the function of promoter I.3. On the basis of results generated from our own and other laboratories, we propose that, in normal breast adipose stromal cells and fibroblasts, aromatase expression is driven by promoter I.4 (glucocorticoid dependent), and that the action of promoters I.3 and II is suppressed by the silencer negative regulatory element. However, in cancer cells and surrounding adipose stromal cells, the cAMP level increases, and aromatase promoters are switched to cAMP-dependent promoters - I.3 and II. Furthermore, we applied the yeast one-hybrid screening method to search for proteins interacting with the silencer element, S1. The major protein identified was ERRalpha-1; however, SF-1, which is present in the ovary, is not detected in breast cancer tissue. Using a reporter plasmid with the aromatase genomic fragment containing promoter I.3 and S1, in breast cancer SK-BR-3 cells, ERRalpha-1 was found to have a positive regulatory function. It is believed that the silencer element in the human aromatase gene may function differently in different tissues, as a result of distinct expression patterns of transcription factors.
Lessons from the use of aromatase inhibitors in the neoadjuvant setting.
Authors: Dixon J M , Love C D , Renshaw L , Bellamy C , Cameron D A , Miller W R , Leonard R C
Published: December 2004

Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.
The potential of aromatase inhibitors in breast cancer prevention.
Authors: Santen R J , Yue W , Naftolin F , Mor G , Berstein L
Published: December 2004

Substantial evidence supports the concept that estrogens cause breast cancer in animals and in women but the precise mechanism is unknown. The most commonly held theory is that estrogens stimulate proliferation of breast cells and thus statistically increase the chances for genetic mutations which could result in cancer. Another theory is that estrogen metabolism generates oxygen-free radicals and quinones which produce both stable and unstable DNA adducts. Both result in genetic mutations which accumulate and could ultimately cause cancer. A major criticism of the latter hypothesis is that breast tissue contains insufficient concentrations of estrogen for accumulation of genotoxic metabolites. Our hypothesis is that breast tissue estrogen levels, as a result of in situ synthesis, are much higher than previously thought. We and others have shown that estrogen can be made in the breast itself through conversion of androgens to estrogens, a process catalyzed by the enzyme aromatase. The levels of estrogen in the breast increase when aromatase is overexpressed. With sufficient amounts of aromatase in breast tissue, enough estradiol as substrate should be available to allow formation of substantial amounts of genotoxic metabolites. We postulate that aromatase overexpression may in this way cause breast cancer. As evidence supporting this concept, four animal models of aromatase overexpression and either breast cancer or premalignant lesions have been described. We have provided evidence that normal breast tissue can make estrogen and that certain stimulatory compounds can increase aromatase activity in the breast by nearly 10,000-fold. If our concepts are correct, it might be possible to prevent breast cancer by blocking the aromatase enzyme. Drugs are currently available to inhibit aromatase nearly completely without causing significant side-effects. Aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer because of their dual role to block both initiation and promotion of breast cancer. To inhibit the initiation process, these inhibitors would reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentrations in tissue. At the same time, aromatase inhibitors would inhibit the process of tumor promotion by lowering tissue levels of estradiol and thus blocking cell proliferation. These concepts provide a strong rationale for studies of aromatase inhibitors to prevent breast cancer.
Aromatase inhibitors in relation to other forms of endocrine therapy for breast cancer.
Authors: Osborne C K
Published: December 2004

Most endocrine therapies for breast cancer inhibit tumor growth by depriving the cell of estrogen or by blocking its receptor. However, some drugs, such as tamoxifen, can bind to the estrogen receptor (ER) and have both estrogenic and antiestrogenic effects, depending on the tissue, cell, or promoter context. These mixed properties may be explained by new information on ER function at the molecular level. Whether a synthetic drug acts as an estrogen or antiestrogen on a specific gene may be dictated by the particular ensemble of ER subtype, receptor interacting proteins, other transcription factors, or specific elements within the promoter of estrogen-regulated genes. Alterations in these other factors may also play a role in resistance to hormonal therapies. Aromatase inhibitors, like ovarian ablation, inhibit growth by lowering the estrogen concentration in blood or in the tumor tissue itself. Aromatase inhibitors are effective even in postmenopausal women with low estrogen concentrations - probably because of the ability of the tumor to become hypersensitive to estrogen after prolonged estrogen deprivation. Given that the ER itself is the prime target for endocrine manipulation, the ideal endocrine therapy may be one that reduces or eliminates ER from the tumor cell. Pure steroidal antiestrogens are then of great interest because, not only do they inhibit ER-induced transactivation of estrogen regulated genes, they also induce ER degradation. Additional clinical trials are necessary to identify the optimal endocrine therapy and optimal sequence of available therapies.
Status of aromatase inhibitors in relation to other breast cancer treatment modalities.
Authors: Ragaz J
Published: December 2004

Aromatase is one of the key enzymes possibly linked with the perpetuation or even initiation of breast cancer. Modulation of its activity by the new generation inhibitors has resulted in increased responses and improved therapeutic ratio compared with those of parent aromatase inhibitors. More recent trials have shown promising results with regard to improved therapeutic ratio compared with what is seen with presently accepted second-line hormonal approaches. Present data and laboratory research indicate that new aromatase inhibitors have the potential to play an important role as adjuvants, and possibly in the prevention of human breast cancer. It is probable that it may be as adjuvants that their real therapeutic strength in terms of a beneficial impact on survival may be realized. The absence of estrogen agonist activity of new aromatase inhibitors on lipid and bone metabolism calls for more clinical studies having late mortality in breast cancer survivors as the ultimate outcome objective; in this regard, interaction of new aromatase inhibitors with new selective estrogen receptor modulators looks promising. Achievement of these outcomes, and understanding of interactions with other therapies, await the termination of present trials and the start of new initiatives.
Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands.
Authors: Tekmal R R , Kirma N , Gill K , Fowler K
Published: December 2004

To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.
Hormonal approaches to the chemoprevention of endocrine-dependent tumors.
Authors: Manni A
Published: December 2004

The estrogen dependency of human breast cancer has been successfully exploited in the treatment of early and advanced diseases and provides a unique opportunity for chemoprevention of this common malignancy. Preliminary results with the antiestrogens Tamoxifen and Raloxifene show an encouraging reduction in the incidence of breast cancer. Alternative approaches include the use of highly selective and non-toxic aromatase inhibitors and, in premenopausal women, the use of LHRH agonists in conjunction with the administration of small doses of estrogen and progesterone. The rationale for these chemopreventive strategies and their possible limitations are briefly discussed.
New pituitary oncogenes.
Authors: Heaney A P , Melmed S
Published: December 2004

Pituitary tumors are common monoclonal neoplasms which cause considerable morbidity and mortality. Several molecular events underlying pituitary tumorigenesis have been elucidated in recent years, but no tumor marker has clearly emerged which assists clinical and therapeutic decisions. Activating mutations and loss of inactivating mutations, together with hypothalamic hormones, circulating hormones, growth factors and cytokines cooperatively ensure the inexorable expansion of the initial mutated pituitary cell clone. This review describes new developments in our understanding of the molecular mechanisms involved in the pathogenesis of pituitary tumors. The availability of molecular probes will allow the early prediction of tumor behavior, identify targets for designing subcellular pituitary tumor therapy and provide novel approaches to pituitary tumor management.
The role of prostate specific antigen measurement in the detection and management of prostate cancer.
Authors: Nash A F , Melezinek I
Published: December 2004

The introduction of prostate specific antigen (PSA) testing has revolutionised the early detection, management and follow-up of patients with prostate cancer and it is considered to be one of the best biomedical markers currently available in the field of oncology. Its use with annual digital rectal examination in prostate cancer screening programmes has led to a marked change in the distribution of stage at presentation towards earlier disease and led to a significant increase in the detection of potentially curable disease. In order to improve the specificity of PSA testing and thereby reduce the number of unnecessary prostatic biopsies, a number of refinements of PSA evaluation have been proposed. These include free to total PSA ratio, PSA density, PSA density, PSA density of the transition zone, PSA velocity and age-specific PSA reference ranges. The utility of these approaches is considered in this review. The role of PSA monitoring in the detection of recurrence following radical prostatectomy and radiotherapy is discussed, as well as its role in monitoring patients treated with endocrine therapy is discussed, as well as its role in monitoring patients treated with endocrine therapy in terms of correlating PSA response with outcome, in detecting disease progression and in guiding the use of subsequent therapies. Large continuing multicentre screening and outcome studies will provide important information enabling greater refinement of the use of this important diagnostic and monitoring tool in the future detection and management of prostate cancer.