bluuebunny/crossref_metadata_2025 huggingface dataset:
Accuracy and Surgical Impact of Magnetic Resonance Imaging in Breast Cancer Staging: Systematic Review and Meta-Analysis in Detection of Multifocal and Multicentric Cancer
Authors: Houssami Nehmat , Ciatto Stefano , Macaskill Petra , Lord Sarah J. , Warren Ruth M. , Dixon J. Michael , Irwig Les
Published: May 2008

Purpose

We review the evidence on magnetic resonance imaging (MRI) in staging the affected breast to determine its accuracy and impact on treatment.

Methods

Systematic review and meta-analysis of the accuracy of MRI in detection of multifocal (MF) and/or multicentric (MC) cancer not identified on conventional imaging. We estimated summary receiver operating characteristic curves, positive predictive value (PPV), true-positive (TP) to false positive (FP) ratio, and examined their variability according to quality criteria. Pooled estimates of the proportion of women whose surgery was altered were calculated.

Results

Data from 19 studies showed MRI detects additional disease in 16% of women with breast cancer (N = 2,610). MRI incremental accuracy differed according to the reference standard (RS; P = .016) decreasing from 99% to 86% as the quality of the RS increased. Summary PPV was 66% (95% CI, 52% to 77%) and TP:FP ratio was 1.91 (95% CI, 1.09 to 3.34). Conversion from wide local excision (WLE) to mastectomy was 8.1% (95% CI, 5.9 to 11.3), from WLE to more extensive surgery was 11.3% in MF/MC disease (95% CI, 6.8 to 18.3). Due to MRI-detected lesions (in women who did not have additional malignancy on histology) conversion from WLE to mastectomy was 1.1% (95% CI, 0.3 to 3.6) and from WLE to more extensive surgery was 5.5% (95% CI, 3.1 to 9.5).

Conclusion

MRI staging causes more extensive breast surgery in an important proportion of women by identifying additional cancer, however there is a need to reduce FP MRI detection. Randomized trials are needed to determine the clinical value of detecting additional disease which changes surgical treatment in women with apparently localized breast cancer.
Prospective Study to Assess Short-Term Intra-Articular and Tenosynovial Changes in the Aromatase Inhibitor–Associated Arthralgia Syndrome
Authors: Morales Leilani , Pans Steven , Verschueren Kilian , Van Calster Ben , Paridaens Robert , Westhovens Rene , Timmerman Dirk , De Smet Luc , Vergote Ignace , Christiaens Marie-Rose , Neven Patrick
Published: May 2008

Purpose

Arthralgia is an adverse class effect of aromatase inhibitors (AIs). To date, its exact mechanism remains unclear. The purpose of this study was to investigate the changes in clinical rheumatologic features and magnetic resonance imaging (MRI) of hands and wrists in AI and tamoxifen users.

Patients and Methods

This is a prospective single-center study including 17 consecutive postmenopausal patients with early breast cancer receiving either tamoxifen (n = 5) or an AI (n = 12). At baseline and after 6 months, patients filled in a rheumatologic history questionnaire and a rheumatologic examination including a grip strength test was done. At the same time points, MRI of both hands and wrists was performed. The primary end point was tenosynovial changes from baseline on MRI. Secondary end points were changes from baseline for morning stiffness, grip strength, and intra-articular fluid on MRI. Wilcoxon signed ranks was used to test changes from baseline and the Spearman correlation coefficient to assess the association between rheumatologic and MRI changes from baseline.

Results

At 6 months, patients on AI had a decrease in grip strength (P = .0049) and an increase in tenosynovial changes (P = .0010). The decrease in grip strength correlated well with the tenosynovial changes on MRI (P = .0074). Only minor changes were seen in patients on tamoxifen. AI users reported worsening of morning stiffness and showed an increase in intra-articular fluid on MRI.

Conclusion

The functional impairment of hands in the AI-associated arthralgia syndrome is characterized by tenosynovial changes on MRI correlating with a significant decrease in hand grip strength.
Phase I, Pharmacokinetic and Pharmacodynamic Study of the Anti–Insulinlike Growth Factor Type 1 Receptor Monoclonal Antibody CP-751,871 in Patients With Multiple Myeloma
Authors: Lacy Martha Q. , Alsina Melissa , Fonseca Rafael , Paccagnella M. Luisa , Melvin Carrie L. , Yin Donghua , Sharma Amarnath , Enriquez Sarano M. , Pollak Michael , Jagannath Sundar , Richardson Paul , Gualberto Antonio
Published: May 2008

Purpose

A phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti–insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.

Patients and Methods

After informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.

Results

No CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.

Conclusion

These data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.
Distribution of Obestatin and Ghrelin in Human Tissues
Authors: Grönberg Malin , Tsolakis Apostolos V. , Magnusson Linda , Janson Eva T. , Saras Jan
Published: May 2008

Obestatin and ghrelin are two peptides derived from the same prohormone. It is well established that ghrelin is produced by endocrine cells in the gastric mucosa. However, the distribution of human obestatin immunoreactive cells is not thoroughly characterized. A polyclonal antibody that specifically recognizes human obestatin was produced. Using this antibody and a commercial antibody vs ghrelin, the distribution of obestatin and ghrelin immunoreactive cells was determined in a panel of human tissues using immunohistochemistry. The two peptides were detected in the mucosa of the gastrointestinal tract, from cardia to ileum, and in the pancreatic islets. Interestingly, epithelial cells in the ducts of mammary glands showed distinct immunoreactivity for both ghrelin and obestatin. By double immunofluorescence microscopy, it was shown that all detected cells were immuno-reactive for both peptides. Furthermore, the subcellular localization of obestatin and ghrelin was essentially identical, indicating that obestatin and ghrelin are stored in the same secretory vesicles.
A Clusterwise Bilinear Multidimensional Scaling Methodology for Simultaneous Segmentation and Positioning Analyses
Authors: Desarbo Wayne S. , Grewal Rajdeep , Scott Crystal J.
Published: May 2008

The segmentation–targeting–positioning conceptual framework has been the traditional foundation and genesis of marketing strategy formulation. The authors propose a general clusterwise bilinear spatial model that simultaneously estimates market segments, their composition, a brand space, and preference/utility vectors per market segment; that is, the model performs segmentation and positioning simultaneously. After a review of related methodological research in the marketing, psychometrics, and classification literature streams, the authors present the technical details of the proposed two-way clusterwise bilinear spatial model. They develop an efficient alternating least squares procedure that estimates conditional globally optimum estimates of the model parameters within each iteration through analytic closed-form expressions. The authors present various model options. They provide a conceptual and empirical comparison with latent-class multidimensional scaling. They use an illustration of the new bilinear multidimensional scaling methodology with an actual commercial study sponsored by a large U.S. automotive manufacturer to examine buying/consideration intentions for small sport-utility vehicles. The authors conclude by summarizing the contributions of this research, discussing the marketing implications for managers, and providing several directions for further research.
The Impact of Brand Equity and Innovation on the Long-Term Effectiveness of Promotions
Authors: Slotegraaf Rebecca J. , Pauwels Koen
Published: May 2008

Although managers often hope to obtain long-term benefits with temporary marketing actions, academic studies imply that their chances are slim. Extant research has implicitly assumed that the brand itself carries no influence over whether marketing promotions have the power to lift sales permanently. Using panel data for seven years from 100 brands across seven product categories, the authors employ a two-stage approach in which long-term promotional effectiveness is first estimated with persistence modeling and then these effectiveness estimates are related to brand equity and new product introductions. By examining a broad range of brands in each category, the authors find that positive sales evolution from promotional efforts is fairly common, especially for small brands. Moreover, the authors find that both permanent and cumulative sales effects from marketing promotions are greater for brands with higher equity and more product introductions, whereas brands with low equity gain greater benefits from product introductions. These results offer new research and managerial insights into the presence and conditions for persistent benefits from marketing promotions.
How Far Can a Brand Stretch? Understanding the Role of Self-Construal
Authors: Ahluwalia Rohini
Published: May 2008

A brand's stretchability is an important avenue for growth and new product introductions. This research examines the role of an individual-difference variable (self-construal) in enhancing a brand's stretchability potential. It is postulated that an interdependent self-construal leads to a superior ability to uncover relationships among stimuli (e.g., an extension and its parent brand) and thus is likely to enhance the perceived fit of an extension and the likelihood of its acceptance. However, these beneficial effects are likely to emerge only under conditions in which the interdependent consumer is motivated to elaborate extensively on the extension information. Five experiments test the underlying mechanism, its implications for different levels of brand stretch (varying from close to far), and the marketing strategy implications of the proposed theoretical framework.
Identity Congruency Effects on Donations
Authors: Shang Jen , Reed Americus , Croson Rachel
Published: May 2008

This article describes several field and laboratory experiments that investigate an identity congruency effect on donations. Experiment 1 is a field experiment showing that consumers give more money to a public radio station if they are told that a previous donor who shares their identity also made a large contribution. This effect is more likely to occur when consumers have high collective-identity esteem (measured in Experiment 2a) and when attention is focused on others (manipulated in Experiment 2b). The authors measure these two moderators simultaneously and observe and replicate a three-way interaction. Again, the identity congruency effect is the strongest when consumers have high collective-identity esteem and when attention is focused on others (Experiment 3a and Experiment 3b). These results provide a novel understanding of the causes of the identity congruency effect on donations. The authors conclude with a discussion of the theoretical and substantive implications of these findings.
Disposition Effects and Underlying Mechanisms in E-Trading of Stocks
Authors: Lee Hyun-Jung , Park Jongwon , Lee Jin-Yong , Wyer Robert S.
Published: May 2008

People have a tendency to sell stocks more quickly if their value has increased since the time they were purchased than if their value has decreased during this period. This “disposition effect” can sometimes have negative financial consequences. Based on an analysis of transaction data in a simulated trading environment, Study 1 provides evidence of the disposition effect in a newly emerging Internet-based stock trading (“e-trading”) situation. Three laboratory studies then examine the mechanisms that underlie the effect. The magnitude of the disposition effect is unaffected by experimental manipulations of the subjective likelihood of future gains or losses. However, it is eliminated by inducing participants to define gains and losses in similar subjective units. Furthermore, the effect depends on whether participants make selling decisions on their own stocks or serve as an agent for someone else. Thus, the disposition effect is largely a result of differences in the subjective value that participants attach to possible gains and losses rather than of differences in their beliefs that these outcomes will occur. The authors discuss theoretical and managerial implications of the findings.
A New Model to Predict the Oxidation Kinetics of Zirconium Alloys in a Pressurized Water Reactor
Authors: Bouineau V. , Ambard A. , Bénier G. , Pêcheur D. , Godlewski J. , Fayette L. , Duverneix T.
Published: May 2008

The previous CEA corrosion code COCHISE provided satisfactory simulations of in-reactor corrosion of the fuel cladding when used in its validity range. In contrast, it could lead to hazardous predictions if applied out of this range due to the strongly linked parameters mainly based on the analysis of French pressurized water reactor (PWR) data. To predict the oxidation kinetics for new operating conditions or new materials, the CEA and EDF decided to develop a new model, named CORCY, which is based on a more phenomenological approach and uses separate parameters deduced from analytical experiments. The aim of this paper is to present the new model for Zircaloy-4 in PWR. The phenomenological approach is described. It is based on out- and in-pile data. Typically, since (1) the oxidation kinetics of zirconium alloys in autoclave are periodic, and (2) the oxide films formed in autoclave, in out-of-pile loop, and in-reactor all exhibit periodic lateral cracks with a period similar to the oxide thickness to transition, the oxidation kinetics in CORCY are characterized by a cyclic repetition of semi-parabolic law. Each model parameter is detailed. They are deduced separately from (a) oxidation tests performed in autoclave on fresh alloys to determine their kinetics; (b) oxidation tests performed in the out-of-pile corrosion loops Corail and Reggae to quantify the effects of thermo-hydraulic conditions; (c) data provided by Testing Material Reactors (OSIRIS and Halden reactor) during isothermal oxidation to determine the effects of irradiation; and (d) oxidation tests performed on pre-hydrided alloys to take into account the accelerated corrosion phase occurring, in reactor, for Zircaloy-4 at high burn-up. After describing both the phenomenological approach and the different model parameters, a comparison of measured and calculated corrosion data from French PWRs at a burn-up up to 65 GWd/tU is provided.
Feldeffekttransistoren für organische CMOS Technik (Field-Effect Transistors for Organic CMOS Technology)
Authors: Melzer Christian , von Seggern Heinz
Published: May 2008

Die Bereitstellung organischer CMOS Technik stellt eine Hürde für die Entwicklung organischer Logikbauelemente dar. Ausgehend von ambipolar wirkenden Feldeffekttransistoren werden in diesem Artikel Möglichkeiten zur Realisierung von organischen CMOS Bauteilen diskutiert. Konkret wird eine Methode vorgestellt, mit der n-sowie p-Typ Transistoren unter Beibehaltung des gleichen Bauteilaufbaus hergestellt werden können. Auf Basis dieser komplementär wirkenden OFETs lassen sich CMOS Inverter realisieren.
Smart Objects – Auswirkungen massengedruckter Einfachelektronik auf die IT-Infrastrukturen (Smart Objects – Effects of Mass-printed Electronics on IT Infrastructures)
Authors: Beigl Michael , Riedel Till , Decker Christian
Published: May 2008

Neue Entwicklungen in der Elektronik wie massengedruckte Einfachelektronik ermöglichen den Einsatz von Computersystemen an oder gar in Objekten, für die bisher ein solcher Einsatz nicht wirtschaftlich sinnvoll war. Dieser Beitrag untersucht die prinzipiellen Rahmenbedingungen bei der nahtlosen Integration von Smart Objects in bestehende IT-Strukturen. Probleme bei der Einbindung solcher Smart Objects in IT-Systeme — insbesondere hinsichtlich der Skalierbarkeit — werde thematisiert. Er zeigt zudem innovative Lösungsansätze wie “Active Interfaces” und Push der Geschäftslogik in Smart Objects. Der vorgestellte Systemansatz profitiert dabei von einer Vielzahl preiswerter, zusammenarbeitender Smart Objects und kann somit als Blaupause für die Informationsverarbeitung und Integration künftiger massengedruckter Elektroniksysteme in IT-Systeme gesehen werden.
Digitale Fabrik – Ein Vorgehensmodell für Virtual Reality in der Fabrik- und Anlagenplanung (Digital Factory – A Proceeding Model for Virtual Reality in Site and Plant Design)
Authors: Bracht Uwe , Eckert Clemens
Published: May 2008

Der vorliegende Artikel erläutert den Einsatz von Virtual Reality in der Fabrik- und Anlagenplanung, anhand einer am Institut für Maschinelle Anlagentechnik und Betriebsfestigkeit der TU Clausthal entwickelten Vorgehensweise. Dazu werden die bei Anwendung des beschriebenen Vorgehensmodells in Praxisprojekten feststellbaren Verlagerungen von Modellnutzungsintensität und Erstellungsaufwand beschrieben und interpretiert.
Effiziente Methoden zum Lösen von 3D-Puzzle-Problemen* (Efficient Methods for Solving 3D-Puzzle-Problems)
Authors: Winkelbach Simon
Published: May 2008

Das Zusammenfügen von 3D-Objekten aus Einzelteilen (3D-Puzzle-Problem) ist in vielen Bereichen von hoher Relevanz. Anwendungen finden sich beispielsweise in der Archäologie (Rekonstruktion von Artefakten), der Chirurgie (Richten von Knochenfrakturen), sowie der Bioinformatik (Protein-Docking) und Robotik (Fügen von Bauteilen). Dieser Artikel gibt einen Überblick über die Verfahren und erzielten Ergebnisse der Dissertation “Das 3D-Puzzle-Problem”, in der die gesamte Prozesskette von der Datenakquisition, über die allgemeine Registrierung von Oberflächen, bis hin zu speziellen Anwendungsfällen des 3D-Puzzle-Problems behandelt wird. Insbesondere werden neue Ansätze vorgestellt, mit denen Fragmente auf äußerst effiziente Weise und ohne Wissen über eine Initiallösung automatisch zusammengefügt werden können. Hierbei wird eine hohe Robustheit gegenüber Messungenauigkeiten, Fragmentschädigungen und Materialverschleiß erreicht. Darüber hinaus gelingt es, durch Ausnutzung von Symmetrieebenen und Achsen gebrochene Oberschenkel- und Beckenknochen virtuell zusammenzufügen und somit einen wichtigen Baustein für die computerassistierte Frakturbehandlung in der Chirurgie zu schaffen.
Outcome of Pregnancies at Risk for Neonatal Hemochromatosis Is Improved by Treatment With High-Dose Intravenous Immunoglobulin
Authors: Whitington Peter F. , Kelly Susan
Published: May 2008

OBJECTIVES. Neonatal hemochromatosis is the result of severe fetal liver injury that seems to result from maternal-fetal alloimmunity. Women who have had an infant affected with neonatal hemochromatosis are at high risk in subsequent pregnancies for having another affected infant. This study was designed to determine whether therapy directed at limiting the severity of gestational alloimmunity can reduce the occurrence of severe neonatal hemochromatosis in infants of women at risk. A secondary objective was to use a prospectively collected data set to examine questions of vital interest about neonatal hemochromatosis.

METHODS. Women with a history of pregnancy ending in documented neonatal hemochromatosis were treated with intravenous immunoglobulin at 1 g/kg of body weight weekly from week 18 until the end of gestation. Extensive data were prospectively collected regarding the gestational histories of the subjects. The outcomes of treated pregnancies were compared with those of previous affected pregnancies, which were used as historical controls.

RESULTS. Forty-eight women were enrolled to be treated during 53 pregnancies. The gestational histories of these women demonstrated the high risk of occurrence of neonatal hemochromatosis: 92% of pregnancies at risk resulted in intrauterine fetal demise, neonatal death, or liver failure necessitating transplant. In contrast, with gestational therapy, the 53 at-risk gestations resulted in 3 failures and 52 infants who survived intact with medical therapy alone. When compared on a per-woman or per-infant basis, the outcome of gestation at risk for neonatal hemochromatosis was improved by gestational therapy.

CONCLUSIONS. Neonatal hemochromatosis seems to be the result of a gestational alloimmune disease, and occurrence of severe neonatal hemochromatosis in at-risk pregnancies can be significantly reduced by treatment with high-dose intravenous immunoglobulin during gestation.
Occurrence and mass loadings of n-Alkanes in riverine runoff of the Pearl River Delta, South China: Global implications for levels and inputs
Authors: Wang Ji-Zhong , Ni Hong-Gang , Guan Yu-Feng , Zeng Eddy Y
Published: May 2008

Riverine runoff samples were collected monthly from March 2005 to February 2006 from the eight major outlets of the Pearl River Delta (PRD), South China, and analyzed to obtain the concentrations of n-alkanes in both the filtrate and particulate phases. The average concentrations of Σ(C15–C34) (i.e., sum of C15 to C34 normal alkanes) ranged from 0.06 to 2.97 μg/L (mean, 0.64 μg/L) in filtrate samples and from 1.00 to 98.8 μg/g (average, 19.8 μg/g dry weight) in particulate samples. Compared to results from around the world, the levels of hydrocarbon compounds in the PRD were at the high end of the global range. Evaluation of compositional indices of n-alkanes indicated that petroleum-related sources are the main contributor of n-alkanes found in the PRD, with minor contributions from high plant wax. Regression analyses appeared to suggest that n-alkanes are transported into the aquatic environment of the PRD via various pathways, and the transport mechanisms also are considerably influenced by the complex hydrologic conditions in the PRD. The annual riverine input of Σ(C15–C34) from the PRD to the coastal ocean was 360 tons/year, or the equivalent of approximately 8,800 tons/year of petroleum hydrocarbons. The emission of Σ(C15–C34) from all sources in the PRD was estimated at 39,000 tons/year, or 2.4 g/day per capita. Overall, the PRD contributes approximately 0.2% of the annual global input of n-alkanes to the coastal oceans, similar to the contributions of polycyclic aromatic hydrocarbons, further indicating that the PRD has been a significant source of hydrocarbon contamination to the global coastal marine environment.
Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac
Authors: Rattner Barnett A , Whitehead Maria A , Gasper Grace , Meteyer Carol U , Link William A , Taggart Mark A , Meharg Andrew A , Pattee Oliver H , Pain Deborah J
Published: May 2008

The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose ∼0.1–0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.
Emerging Hsp90 Inhibitors: From Discovery to Clinic
Authors: Chiosis G. , Rodina A. , Moulick K.
Published: May 2008

Hsp90 is a chaperone with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Activation of signaling pathways mediated by Hsp90 protein clients is necessary for cell proliferation, regulation of cell cycle progression and apoptosis. Additionally, gain-of-function mutations responsible for transformation often require Hsp90 for the maintenance of their folded, functionally active conformations. These characteristics promise Hsp90 as an important target in cancer therapy and prompt for the identification, development and clinical translation of small molecule inhibitors of the chaperone. This review intends to update the reader on the status of several existing and emerging classes of direct inhibitors of Hsp90 ATPase activity.
Gold Coordination Complexes as Anticancer Agents
Authors: Kostova Irena
Published: May 2008

Metal ions are known to bind with nucleic acids and thereby alter their conformation and biological function. The metal ion-base interaction depends on the nature of both metal and bases; a certain site of coordination is preferred. One of the most notable successes for inorganic drugs has been the effectiveness of platinum complexes against cancer. These advances have spurred a surge of investigations to identify new inorganic agents for use in chemotherapy with improved specificity and decreased toxic side effects. Gold(I) and gold(III) complexes, the last isostructural and isoelectronic with platinum(II) complexes, are potentially attractive as anticancer agents. The design of an effective anticancer agent is a complicated game that must encompass not only the drugs inherent inhibitory properties but also its delivery, dosage, and residence time in vivo. Gold(I) and gold(III) complexes overcome some of these challenges by forming strong covalent attachments to targets. Au(III) isoelectronic with Pt(I1)-d8 system usually forms square planar complexes in solution. Since the square planar geometry of Pt(II) is important for its action as an anticancer drug, Au(III) compounds also can be used for the same purpose with the added advantage of decreased toxicity. This, together with the recent finding that certain transitional metal complexes like Au and Pt complexes have been found to be potentially useful in cancer chemotherapy, created a renewed interest in the study of the interactions of metal ions with respect to the site of binding and the structure and stability of the complexes. This work was motivated by the thought that information on the variety of Au(III) complexes and their effects can be obtained by studying the properties of Au complexes with various ligands. Various studies in the past have shown that Au complexes are very attractive in view of their application as anticancer agents.
Understanding Apoptosis in Terms of QSAR
Authors: Verma Rajeshwar P.
Published: May 2008

Apoptosis is a cellular mechanism by which unwanted, defective, or damaged cells are rapidly and selectively eliminated to maintain healthy tissue homeostasis in multi-cellular organisms. In this review, we have developed nineteen quantitative structure-activity relationships (QSAR) for different series of compounds with respect to their apoptotic activities against five different cancer cell lines that are T47D, ZR75-1, DLD-1, H1299, and HL60 in order to understand chemical-biological interactions.
Recent Progress in the Syntheses and Biological Evaluation of Boronated Porphyrins for Boron Neutron-Capture Therapy
Authors: Renner M. W. , Miura M. , Easson M. W. , Vicente M. G.H.
Published: May 2008

Boronated porphyrins are an important class of tumor-localizing agents in two bimodal therapies for cancer currently under study experimentally and clinically; boron neutron-capture therapy (BNCT) and photodynamic therapy (PDT). The desirable properties for the boronated porphyrins are that they are easily synthesized, pure and wellcharacterized drugs, and that in vivo, they are stable, tumor-specific, with high tumor:blood and tumor:normal tissue boron concentration ratios, and cause minimal toxicity. A large number of new porphyrins and their syntheses are presented herein. The focus is primarily on porphyrins published within the past 5 years, but the implications and trends from porphyrins studied in vivo over the past 15 years are also reviewed. Many possess quite unusual, novel structures and others have appended cell-targeting moieties for greater tumor specificity. Besides the commonly used closo- and nido-ocarboranes other boron cages and modes of attachment are presented. These boron cages can selectively alter the lipophilic, hydrophilic and amphiphilic properties of the porphyrins as well as their boron content. New delivery modalities have also greatly improved the targeting potential of compounds previously deemed unsuitable for applications in BNCT.
Boron Containing Macromolecules and Nanovehicles as Delivery Agents for Neutron Capture Therapy†
Authors: Wu Gong , Barth Rolf F. , Yang Weilian , Lee Robert J. , Tjarks Werner , Backer Marina V. , Backer Joseph M.
Published: May 2008

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10 is irradiated with low energy thermal neutrons to yield high linear energy transfer (LET) alpha particles (4He) and recoiling lithium -7(7Li) nuclei. For BNCT to be successful, a sufficient number of 10B atoms (∼ 109 atoms/cell) must be selectively delivered to the tumor and enough thermal neutrons must be absorbed by them to sustain a lethal 10B(n, α) 7Li capture reaction. BNCT primarily has been used to treat patients with brain tumors, and more recently those with head and neck cancer. Two low molecular weight (LMW) boron delivery agents currently are being used clinically, sodium borocaptate and boronophenylalanine. However, a variety of high molecular weight (HMW) agents consisting of macromolecules and nanovehicles have been developed. This review will focus on the latter which include: monoclonal antibodies, dendrimers, liposomes, dextrans, polylysine, avidin, folic acid, and epidermal and vascular endothelial growth factors (EGF and VEGF). Procedures for introducing boron atoms into these HMW agents and their chemical properties will be discussed. In vivo studies on their biodistribution will be described, and the efficacy of a subset of them, which have been used for BNCT of tumors in experimental animals, will be discussed. Since brain tumors currently are the primary candidates for treatment by BNCT, delivery of these HMW agents across the blood-brain barrier presents a special challenge. Various routes of administration will be discussed including receptor-facilitated transcytosis following intravenous administration, direct intratumoral injection and convection enhanced delivery by which a pump is used to apply a pressure gradient to establish bulk flow of the HMW agent during interstitial infusion. Finally, we will conclude with a discussion relating to issues that must be addressed if these HMW agents are to be used clinically.
Polyhedral Boron Compounds as Potential Diagnostic and Therapeutic Antitumor Agents
Authors: Bregadze V. I. , Sivaev I. B. , Glazun S. A.
Published: May 2008

The use of polyhedral boron hydrides for cancer treatment is traditionally connected with boron neutron capture therapy. More recently, polyhedral borate anions were proposed as carriers of radionuclide label for targeted radionuclide therapy and diagnostics of cancer. Some metal derivatives of carboranes were found to demonstrate significant antitumor activity themselves. This review is designed to highlight the recent work concerning various fields of potential application of polyhedral boron compounds in anticancer diagnostics and therapy.
Promotion of Optimized Protein Therapy by Bioconjugation as a Polymeric DDS
Authors: Abe Yasuhiro , Shibata Hiroko , Kamada Haruhiko , Tsunoda Shin-Ichi , Tsutsumi Yasuo , Nakagawa Shinsaku
Published: May 2008

In recent years, clinical applications of recombinantly produced bioactive proteins such as cytokines have attracted attention. However, since these recombinant proteins are rather unstable in vivo, their clinical use as therapeutic agents requires frequent administration at a high dosage. This regimen disrupts homeostasis and results in severe side effects. To overcome these problems, bioactive proteins have been conjugated with water-soluble synthetic (WSS) polymeric carriers. Chemical modification of a protein with a WSS polymeric carrier (bioconjugation) regulates tissue distribution, resulting in a selective increase in its desirable therapeutic effects and a decrease in undesirable side effects. Among several drug delivery system (DDS) technologies, bioconjugation has been recognized as one of the most efficient methods for improving therapeutic potency of proteins. However, for further enhancement of the therapeutic potency and safety of conjugated bioactive proteins, more precise regulation of the in vivo behavior of each protein is necessary for selective expression of its therapeutic effect. Therefore, alternative WSS polymeric modifiers in which new functions such as targeting and controlled release of drugs can be added are required for further development of bioconjugated drugs. Recently, we have synthesized a novel polymeric drug carrier, poly(vinylpyrrolidone-co-dimethyl maleic anhydride) [PVD], which was a powerful candidate drug carrier for cancer therapy. In this review, we introduce useful information that enabled us to design polymeric drug carriers and their application for protein therapy.
Jak2 Tyrosine Kinase and Cancer: How Good Cells Get HiJAKed
Authors: Godeny Michael D. , Sayeski Peter P.
Published: May 2008

Cloned in 1992, Jak2 tyrosine kinase has emerged as a critical molecule in mammalian development, physiology, and disease. Here, we will review the early history of Jak2 as it pertains to its role in classical cellular signaling. We also review how specific structural determinants within Jak2 dictate its overall function. Finally, we will review relatively recent literature as it pertains to the role of Jak2 in neoplastic growth as well as the identification of novel Jak2 inhibitors. It is our hope that by reviewing these specific areas, we will have a better understanding of the role of Jak2 in cancer, and in turn, we may have a better idea as to how to block aberrant Jak2 function.
Src Family Nonreceptor Tyrosine Kinases as Molecular Targets for Cancer Therapy
Authors: Johnson Faye M. , Gallick Gary E.
Published: May 2008

The Src family of kinases has nine known members, all of which are nonreceptor tyrosine kinases involved in signal transduction in both normal and cancer cells. Interest in these kinases has increased recently because of the development, initial clinical success, and low toxicity of pharmacologic inhibitors. c-Src is the best-studied member of the Src family and the one most often implicated in cancer progression. c-Src has multiple substrates that lead to diverse biologic effects, including changes in proliferation, motility, invasion, survival, and angiogenesis. c-Src has been most extensively studied in colon cancer where correlative and direct experimental evidence has shown that it mediates several aspects of cancer cell progression. c-Src has a similar role in multiple tumor types, including pancreatic cancer, breast cancer, lung cancer, head and neck squamous cell carcinoma, and prostate cancer. Several inhibitors of the Src family kinases are in clinical development; three are currently being studied in clinical trials. Initial data from these trials suggest that these agents are well tolerated. Future clinical development of these inhibitors will include trials in patients with solid tumors and of combination therapy.
Synthesis and Structure-Activity Relationships of Potent Antitumor Active Quinoline and Naphthyridine Derivatives
Authors: Srivastava Sanjay K. , Jha Amrita , Agarwal Shiv K. , Mukherjee Rama , Burman Anand C.
Published: May 2008

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.
Anti-Inflammatory Drug Effects on Apoptosis of Eosinophil Granulocytes Derived from Murine Bone-Marrow: Cellular Mechanisms as Related to Lineage, Developmental Stage and Hemopoietic Environment
Authors: Elsas Maria I. C. G. , Elsas P. X.
Published: May 2008

The effects of a variety of widely used anti-inflammatory agents (dexamethasone, indomethacin, and montelukast) as well as ubiquitous mediators of inflammation (prostaglandin E2 and nitric oxide) on the development of murine eosinophils ex vivo and in vivo have been studied over the last decade. The results indicate that developing eosinophils differ markedly in their responses to these agents from the mature forms of the same lineage, studied either in allergic human subjects or experimental animal models of allergic disease. Most strikingly, glucocorticoids strongly enhance eosinophil development, both in vitro and in vivo. The enhancing effects are also observed during stress reactions and are strictly dependent on stress-induced glucocorticoid hormone production from the adrenal glands. Some, but not all, of the developmental effects of glucocorticoids on eosinophils could be accounted for their ability to prevent generation of nitric oxide through inducible NO synthase, which leads to apoptosis through the CD95-CD95L pathway. A novel mechanism for the effects of indomethacin in upregulating the development of eosinophils has also been documented. Evidence that lineage-specific as well as stage-specific cellular response programmes determine these different outcomes is discussed, along with the perspectives for future research.
Signaling Pathways Involved in Leukocyte Adhesiveness and Migration during Inflammation: Potential Targets for Therapeutic Interventions?
Authors: Barja-Fidalgo Christina , Arruda Maria A. C. , Saldanha-Gama Roberta , de Freitas Marta S.
Published: May 2008

In response to a chemotactic gradient of inflammatory mediators and chemokines, neutrophils adhere to vascular endothelium and directly migrate, leaving blood vessels, toward inflamed tissue areas, to exert their primary defense function. These events are mediated by distinct classes of cell surface receptors in human neutrophils, that not only drive cell adhesion and motility, but also interfere with the cells activation status, modulating different functions and survival. In this review we summarize the current understanding of the series of events that begins at the level of G-protein coupled receptor activation by chemoattractants, and the signaling pathways triggered by cell adhesion molecule interactions that lead to neutrophil adhesion, migration and activation during inflammation. Integrins, as adhesion receptors able to act as anchoring molecules (allowing firm cellular attachment to the ECM) and signaling receptors (transducing signals in both directions, outside-in and inside-out) are targets that potentially provide both therapeutic and diagnostic opportunities. We also present data obtained with integrin-selective ligands, the disintegrins, which could be useful tools to understand cellular processes as adhesion, migration, proliferation, activation and cell survival and may be also suggested as prototypes for designing therapeutic agents for the prevention or activation of integrin-mediated effects.
Modulation of Eosinophil Functions by Nitric Oxide: Cyclic GMPdependent and -independent Mechanisms
Authors: Ferreira Heloisa H.A. , Conran Nicola , Antunes Edson
Published: May 2008

Recruitment of eosinophils into tissues is a feature of a variety of allergic diseases, including asthma and nasal allergy. Eosinophils secrete several preformed granule proteins (eosinophil peroxidase, major basic protein, eosinophil cationic protein and eosinophil-derived neurotoxin) and newly-generated substances (oxygen-derived toxic metabolites, lipid mediators, cytokines and chemokines), which may contribute to the exacerbation of the allergic diseases. In the past decade, NO has been recognized as a major immunomodulatory mediator of inflammatory responses, particularly in the lung, where it is believed to play a pivotal role in modulating pulmonary eosinophilia and airways hyperresponsiveness in both allergic animals and humans, as evidenced by functional, biochemical and immunohistochemical studies. The NOcGMP signaling cascade was initially implicated in the modulation of eosinophil functions; however, additional studies have demonstrated that direct cGMP-independent mechanisms may also play important roles in eosinophil functions. Much progress in understanding the influence of NO on eosinophil functions has been achieved with the use of selective and non-selective NOS inhibitors, as well as NO-donor compounds, along with NOS isoform gene knock-out mice. However, these studies have resulted in numerous controversies and conflicting findings, possibly as a consequence of the diversity of experimental models used, animal species employed, methods of immunization and challenge with allergens, amongst others. The present review summarizes the role of NO in modulating, in vivo and in vitro, eosinophil adhesion, chemotaxis, airways hyperresponsiveness and apoptosis, outlining the conflicting findings in the literature, with emphasis on the allergic inflammatory responses.
Apoptosis and Atherosclerosis: The Role of Nitric Oxide
Authors: Shaw Catherine A. , Megson Ian L. , Rossi Adriano G.
Published: May 2008

Atherosclerosis, and its associated complications, are a major cause of morbidity and mortality, and it is now recognised as a chronic inflammatory disorder. Progression of inflammation depends on the balance between recruitment of inflammatory cells and their subsequent removal from a site of inflammation. Apoptosis, or programmed cell death, is a fundamental process governing cell survival and is a major determinant of the resolution of the inflammatory response. Apoptotic cells are instantly recognised for non-inflammatory clearance by phagocytes (e.g. macrophages) and removed from the vicinity of inflammation without the release of their pro-inflammatory cell contents. Nitric oxide (NO) plays an important role in many biological processes and has several anti-atherogenic properties including vasodilatation, inhibition of platelet activation and aggregation, and the regulation of apoptosis in a variety of cell types involved in atherogenesis. A critical early event during atherogenesis is injury to the endothelium. The ensuing damage results in endothelial dysfunction, including a reduction in the capacity of the endothelium to generate NO. Decreased NO bioavailability is likely to influence many cellular processes occurring within atherosclerotic lesions, including apoptosis. Modulation of apoptosis is a novel target for therapeutic intervention in the treatment of chronic inflammatory disorders, such as atherosclerosis. This modulation may help limit or resolve inflammation without the concomitant recruitment of subsequent inflammatory cells, thereby reducing the potential for further tissue damage. NO is a possible candidate for manipulation of atherosclerotic processes due to both its powerful anti-atherogenic characteristics and ability to affect apoptosis. This review highlights the role of apoptosis in atherosclerosis and discusses the therapeutic potential of NO to limit and/or resolve vascular inflammation.
Role of Apoptosis in the Pathogenesis of Contrast Media-induced Nephropathy and Hints for its Possible Prevention by Drug Treatment
Authors: Idee J.- M. , Boehm J. , Prigent P. , Ballet S. , Corot C.
Published: May 2008

Contrast-induced nephropathy (CIN) is a worrying concern in at-risk patients. Its pathophysiological mechanism remains speculative and is possibly modulated according to the risk factor(s) and clinical presentation of the patients. Overall, iodinated contrast media (CM) have been shown, in animal models, to induce medullary hypoxia. Furthermore, numerous studies have demonstrated that they have a direct cytotoxic potential on proximal (LLC-PK1) as well as distal (MDCK) tubular cell lines and mesangial cells. A pro-apoptotic potential of such molecules has been found on various cell types including renal tubular and mesangial cells, both in vitro and in vivo. This pro-apoptotic effect on tubular cells has been found to be concentration- and time-dependent. In addition to periprocedural hydration, which is the cornerstone of CIN, several drugs have been investigated for the pharmacological prophylaxis of CIN, either on pre-clinical models or in clinical studies. Some of them (theophylline, Nacetylcysteine, the prostacyclin analogue beraprost or taurine) are known to interfere with the apoptosis pathways. This article reviews and critically discusses the available data concerning the role of apoptosis in the mechanism of CIN and its pharmacological prophylaxis. It also reviews the putative interaction of gadolinium chelates, used as CM for magnetic resonance imaging, with apoptosis pathways.