bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpreting Gandhi Differently
Authors: Poonacha Veena
Published: March 2008

The current agrarian crisis in India makes it necessary to question the prevailing development model and search for alternatives. One such alternative paradigm that has influenced various people's struggles for sustainable development is the Gandhian model. Encoded in it is the idea of village self-sufficiency through economic decentralisation and cooperation in the socio-political life of the community. This paper does not discuss the ideological complexity or strategies adopted by institutions/movements influenced by Gandhian thought in their rural development work. It seeks to delineate the different directions in which Gandhian experiments have evolved in post-colonial India through the lives and works of two Gandhian women. Although born in different generations, both these women lay claim to the Gandhian legacy. The first is Purnima Pakvasa, a freedom fighter who works for the education of tribal women in Dang district of Gujarat; and the second is Vibha Gupta, who, having inherited the Gandhian legacy from her parents, struggles to take science to the village in Wardha, Maharashtra.
Repositioning Women in Housing Development in Nigeria
Authors: Olotuah Abiodun Olukayode , Ajayi Mary Adebola
Published: March 2008

Gender-induced discriminatory practices against women are very common in Nigeria, as in most African countries. Gendered practices are socially and culturally constructed, and are as such informed by the values and norms of societies. These practices have hampered the development of women's capabilities, and have precluded equal economic and social participation in the development of the nation leading to low levels of education and high incidence of poverty among women. This article discusses the role of women in housing development, linking this to a statistical model developed from research conducted by the authors.
On Managerial Knowledge
Authors: Chia Robert , Holt Robin
Published: March 2008

This article investigates what it means for a manager to be knowledgeable. It identifies, on the one hand, a rational tendency to sublimate knowledge as something more exact, definitive and logical than mere learning, and, on the other hand, a practical tendency to subjugate knowledge to social conventions. Articulating a third way between these views, the article critically develops the work of those management scholars for whom the objectivity of knowledge claims is perpetually upset by the recurring influence of environmental context, novel use and localized, community agreement. The influence of what Wittgenstein refers to as background conditions is identified and this background is woven into personal, empirical experiences of events as the bedrock upon which knowledgeable conditions rest. It is not profound, or inaccessibly `deep', but right there before us; it is ordinary belief. It is argued that very often it is these everyday settings that are most revealing when it comes to investigating and understanding what goes by the name managerial knowledge.
Object-mediated Learning and Strategic Renewal in a Mature Organization
Authors: Macpherson Allan , Jones Oswald
Published: March 2008

Knowledge transformation between practice-based communities is reported through a 2-year longitudinal case study. The company, PresMed, was transformed from a moribund and divided organization to one where different practice-based communities engaged in collective learning. However, the transformation involved conflict, politics and power to overcome the influence of localized and embedded knowledge. The nature of practice-based learning means investment in past activities and different organizational communities create tensions. It is suggested that mediating artefacts, or boundary objects, provide an opportunity to develop new shared conceptions of activity and new modes of action. However, at the heart of this transformation, communication, politics and power are central to pragmatic engagement in new practices. Thus, it is the social activities and the political will and skill to influence, cajole and institutionalize systemic changes and not the artefacts or objects per se that are at the heart of knowledge transformation.
Learning and Network Collaboration in Product Development: How Things Work for Human Use
Authors: Miettinen Reijo , Lehenkari Janne , Tuunainen Juha
Published: March 2008

This article studies the learning and capability formation of a biotechnology firm by analysing its development path, which is composed of successive product development and innovation processes. In collaborative product development work, network collaboration, as well as the acquisition of new competences and learning, evolves simultaneously and interactively. Searching for and encountering partners with complementary knowledge and resources is important in the emergence of new product-development processes. To improve understanding of this path formation, the article draws on cultural—historical activity theory, science and technology studies and the epistemology of things and effects. These all underline the significance of material artefacts for learning and activity. The epistemology of things and effects addresses the knowledge of how things work in experimental systems and products. Enzymes, proteins and instruments are put to work in a stabilized way as parts of new products. The effects so mastered entail the functional qualities that make products competitive in the marketplace.
Organizational Learning and Knowledge Management: Whence and Whither?
Authors: Spender J.-C.
Published: March 2008

Draws together theorizing in learning, organization and management studies in order to consider the nature of the problems by which the practice of knowledge management is animated. Though in places propositional, the points being made remain deliberately suggestive insofar as they invoke a wide-ranging past to consider what might be probable futures. The conclusion invokes a return to the past, in suggesting that the potential for knowledge management lies with its returning to a time when theorizing was grounded in what we now choose to ignore, namely managers' experiences and practices as they use their imagination in wealth-creating activity.
Race-conscious transnational activists with cameras
Authors: Mahrouse Gada
Published: March 2008

This article examines a Canadian transnational solidarity activist's efforts to publicize human suffering through visual documentation. The objectives are to examine some of the ways activists negotiate ethical dilemmas about spectatorship and a white/Western gaze, and to consider the potential of the uses of visual documentation as a tool/tactic for subverting global white hegemony. The analysis focuses an one activists' attempts to capture and narrate experiences of suffering in the light of racialized relations of domination and subordination. The article argues that the strategies used to document and display photographs constituted the photographer and the viewers' understandings of themselves in ways that reinforce rather than subvert power. The article concludes by considering the implications of white/Westerners as mediators of the Other's suffering.
Mapping the vast suburban tundra: Australian comedy from Dame Edna to Kath and Kim
Authors: Turnbull Sue
Published: March 2008

By the time of Australian Federation in 1901, almost 70 per cent of Sydney's population were living in the suburbs: a statistic that suggests that despite prevalent and enduring images of the bushman and the ocker, the 'real' Australia was, and still is, more likely to be located in what Barry Humphries has described as Australia's 'vast and unexplored suburban tundra'.1 As a satirist, Humphries has been in the forefront of an expedition to map the tragi-comic dimensions of this territory with characters such as Dame Edna Everage, who first appeared on Australian television in 1956, offering the box room of `her lovely home' as a potential billet for an athlete during the Melbourne Olympic Games.2 Some 50 years later, Dame Edna not only presided over the closing ceremony of the 2006 Commonwealth Games, but was joined on the steps of the Melbourne Town Hall, during a ceremony to award her the key to the city, by two more recent suburban icons, Kath and Kim. With the international success of Dame Edna and Kath and Kim, it seems that the Antipodean suburb is still being mapped and mined for comic effect on television both at home and abroad. This article will explore the conditions of such success within a long tradition of anti-suburbanism dating back to the nineteenth century while exploring the role of comedy in constructing a national imaginary which is now widely circulated via increasingly transnational flows in television.
Television pre-views and the meaning of hype
Authors: Gray Jonathan
Published: March 2008

Although commonsense notions of interpretation and the meaning-making process dictate that such practices begin following consumption of the text, this article argues that, through hype and previews, texts are pre-decoded before a text even exists. By focusing on marketing and previews surrounding two television programs, prior to release, the article examines how such paratexts create meaning, genre, style, tone and audience, and hence it argues for the significant primary power that these supposedly secondary intertexts hold over consumption. Not 'judging a book by its cover' and not `believing the hype' are clichéd virtues, but this article argues that covers and hype are not so easily ignored, nor, given their considerable powers to conjure the text, should they be so easily ignored by media and cultural studies analysts.
Making it after all: a reparative reading of The Mary Tyler Moore Show
Authors: Crozier Susan
Published: March 2008

This article develops a reparative reading of The Mary Tyler Moore Show (CBS, 1970—77) in order to demonstrate the ways in which Mary's emotional and imaginary significance is broader than her original context of second wave feminism in the US. The notion of reparative criticism as an alternative or supplementary approach to conventional cultural studies analyses is explained. The article develops this approach through a number of readings of Mary Richards as she appears and is invoked both within and beyond the sitcom narrative. It is argued that the ambivalence associated with Mary allows viewers to negotiate social and psychic conflicts in a process of making a possible world for themselves.
Improvement of MIG welding stability in pure Ar shielding gas using small amount of oxygen and coaxial hybrid solid wire
Authors: Nakamura T. , Hiraoka K. , Zenitani S.
Published: March 2008

Metal inert gas/metal active gas (MIG/MAG) welding is generally used in many fields because of its high efficiency. Metal inert gas welding is expected but has not been used in pure Ar shielding gas because of arc instability. Shielding gas including O2 or CO2 has been used to secure the arc stability. However, these gases cause the quality of joints to deteriorate. Therefore, the authors have investigated the case of instability using a high speed video camera system to achieve a stable MIG welding in pure Ar shielding gas. The observation showed that the unstable welding behaviour was due to the instability of a column of liquid metal generated at the wire tip. To shorten the column of liquid metal, the authors developed a welding process which uses a small amount of oxygen and a coaxial multilayer solid wire (coaxial hybrid solid wire) where the melting behaviour can be controlled. A stable welding can be achieved by employing these methods.
Effect of expulsion on peak load and energy absorption of low carbon steel resistance spot welds
Authors: Pouranvari M. , Abedi A. , Marashi P. , Goodarzi M.
Published: March 2008

The effects of weld nugget size and expulsion on the performance of low carbon steel resistance spot weld have been investigated in the present paper. Failure mode, peak load and failure energy obtained in tensile–shear test have been used to describe the performance of spot weld. The influence of voids and porosity as well as electrode indentation associated with expulsion on peak load and failure energy is discussed. The results showed that although expulsion does not reduce the load carrying capacity of spot welds, it decreases their energy absorption capability which was attributed to the change of failure location due to excessive electrode indentation associated with expulsion.
Capillary filling process during ultrasonically brazing of aluminium matrix composites
Authors: Zhao W. W. , Yan J. C. , Yang W. , Yang S. Q.
Published: March 2008

Alumina borate whisker reinforced aluminium metal matrix composites were ultrasonically brazed in air. The liquid filler metal (FM) of a Zn–Al eutectic alloy could get into the clearance between composite couples by the action of ultrasonic capillarity. The velocity of the FM getting into the clearance decreases with increasing clearance width. The time exhausted to remove completely the oxide film on the surface increases with increasing clearance width. The oxide film could be removed completely and the metallurgical bonding formed under the action of ultrasonic vibration for sufficient time. The shear strength of the bond could reach up to 145 MPa (the nominal strength of the Zn–Al filler alloy).
Relaxing welding residual stresses by diamond like carbon coating on duplex titanium alloys
Authors: Lee H.-H. , Wang S.-H. , Shih C.-Y. , Cheng C.-M. , Hsu H.-C. , Kan K. , Sung C.-M.
Published: March 2008

The distribution of welding residual stresses in titanium alloy plates composed of Ti–6Al–4V (Ti-64) and Ti–4˙5Al–3V–2Mo–2Fe (SP700) alloys was measured and calculated under the same heat input. Ti-64 alloy exhibited a higher residual tensile stress than the SP700 alloy due to the low thermal conductivity and thermal diffusivity of the former alloy, in addition to its high thermal expansion coefficient. Diamond like carbon (DLC) thin film deposited on the as welded titanium alloy plates reduced the magnitude of the welding residual stress caused by the cathodic arc physical vapour deposition (PVD) process. The distribution of the measured welding residual stresses agreed with the finite element method (FEM) simulated results very well.
Through arc sensing in gas metal arc welding with signature images
Authors: Simpson S. W.
Published: March 2008

This work presents a new method for through the arc estimation of welding parameters in gas metal arc welding based on signature images. The method is generally applicable and makes use of a novel data fitting procedure. The work covers unassisted through the arc estimation, without auxiliary techniques such as welding head oscillation. The technique is demonstrated for both pulse and short circuiting welding, with estimation of position relative to an overlap joint and a narrow gap weld, and estimation of the width of a ‘V’ groove. The accuracy of the technique is affected by how closely the welding signatures match the fitting data and the signature image quality match provides a valuable check which shows when through the arc estimates cannot be relied on. Overall, the results demonstrate that through the arc measurements can have application in specialised situations, although accuracy is ultimately limited by phenomena that affect the arc and are not correlated with the measurement.
The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph− acute lymphoblastic leukemia cells
Authors: Scuto Anna , Kirschbaum Mark , Kowolik Claudia , Kretzner Leo , Juhasz Agnes , Atadja Peter , Pullarkat Vinod , Bhatia Ravi , Forman Stephen , Yen Yun , Jove Richard
Published: March 2008

We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL). Two model human Ph− ALL cell lines (T-cell MOLT-4 and pre–B-cell Reh) were treated with LBH589 and evaluated for biologic and gene expression responses. Low nanomolar concentrations (IC50: 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph− ALL cells, including those from a relapsed patient, inducing loss of cell viability (up to 70%) and induction of GADD45G mRNA expression (up to 35-fold). Thus, LBH589 possesses potent growth inhibitory activity against including Ph− ALL cells associated with up-regulation of genes critical for DNA damage response and growth arrest. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph− ALL.
Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues
Authors: Cardona Astrid E. , Sasse Margaret E. , Liu Liping , Cardona Sandra M. , Mizutani Makiko , Savarin Carine , Hu Taofang , Ransohoff Richard M.
Published: March 2008

In vitro studies have implicated chemokine receptors in consumption and clearance of specific ligands. We studied the role that various signaling chemokine receptors play during ligand homeostasis in vivo. We examined the levels of ligands in serum and CNS tissue in mice lacking chemokine receptors. Compared with receptor-sufficient controls, Cx3cr1−/− mice exhibited augmented levels of CX3CL1 both in serum and brain, and circulating levels of CXCL1 and CXCL2 were increased in Cxcr2−/− mice. CCR2-deficient mice showed significantly increased amounts of circulating CCL2 compared with wild-type mice. Cxcr3−/− mice revealed increased levels of circulating and brain CXCL10 after experimental autoimmune encephalomyelitis (EAE) induction. CCR2-deficient peripheral blood and resident peritoneal cells exhibited reduced binding capacity and biologic responses to the CCR1 ligand CCL3, suggesting that elevated levels of CCR2 ligands had down-regulated CCR1. The results indicate that signaling chemokine receptors clear chemokines from circulation and tissues. These homeostatic functions of signaling chemokine receptors need to be integrated into safety and efficacy calculations when considering therapeutic receptor blockade.
IL-13 induces a bronchial epithelial phenotype that is profibrotic
Authors: Malavia Nikita K , Mih Justin D , Raub Christopher B , Dinh Bao T , George Steven C
Published: March 2008

Background

Inflammatory cytokines (e.g. IL-13) and mechanical perturbations (e.g. scrape injury) to the epithelium release profibrotic factors such as TGF-β2, which may, in turn, stimulate subepithelial fibrosis in asthma. We hypothesized that prolonged IL-13 exposure creates a plastic epithelial phenotype that is profibrotic through continuous secretion of soluble mediators at levels that stimulate subepithelial fibrosis.

Methods

Normal human bronchial epithelial cells (NHBE) were treated with IL-13 (0, 0.1, 1, or 10 ng/ml) for 14 days (day 7 to day 21 following seeding) at an air-liquid interface during differentiation, and then withdrawn for 1 or 7 days. Pre-treated and untreated NHBE were co-cultured for 3 days with normal human lung fibroblasts (NHLF) embedded in rat-tail collagen gels during days 22–25 or days 28–31.

Results

IL-13 induced increasing levels of MUC5AC protein, and TGF-β2, while decreasing β-Tubulin IV at day 22 and 28 in the NHBE. TGF-β2, soluble collagen in the media, salt soluble collagen in the matrix, and second harmonic generation (SHG) signal from fibrillar collagen in the matrix were elevated in the IL-13 pre-treated NHBE co-cultures at day 25, but not at day 31. A TGF-β2neutralizing antibody reversed the increase in collagen content and SHG signal.

Conclusion

Prolonged IL-13 exposure followed by withdrawal creates an epithelial phenotype, which continuously secretes TGF-β2at levels that increase collagen secretion and alters the bulk optical properties of an underlying fibroblast-embedded collagen matrix. Extended withdrawal of IL-13 from the epithelium followed by co-culture does not stimulate fibrosis, indicating plasticity of the cultured airway epithelium and an ability to return to a baseline. Hence, IL-13 may contribute to subepithelial fibrosis in asthma by stimulating biologically significant TGF-β2secretion from the airway epithelium.
Identification and characterization of a novel gene differentially expressed in zebrafish cross-subfamily cloned embryos
Authors: Pei De-Sheng , Sun Yong-Hua , Chen Chun-Hong , Chen Shang-Ping , Wang Ya-Ping , Hu Wei , Zhu Zuo-Yan
Published: March 2008

Background

Cross-species nuclear transfer has been shown to be a potent approach to retain the genetic viability of a certain species near extinction. However, most embryos produced by cross-species nuclear transfer were compromised because that they were unable to develop to later stages. Gene expression analysis of cross-species cloned embryos will yield new insights into the regulatory mechanisms involved in cross-species nuclear transfer and embryonic development.

Results

A novel gene, K31, was identified as an up-regulated gene in fish cross-subfamily cloned embryos using SSH approach and RACE method. K31 complete cDNA sequence is 1106 base pairs (bp) in length, with a 342 bp open reading frame (ORF) encoding a putative protein of 113 amino acids (aa). Comparative analysis revealed no homologous known gene in zebrafish and other species database. K31 protein contains a putative transmembrane helix and five putative phosphorylation sites but without a signal peptide. Expression pattern analysis by real time RT-PCR and whole-mount in situ hybridization (WISH) shows that it has the characteristics of constitutively expressed gene. Sub-cellular localization assay shows that K31 protein can not penetrate the nuclei. Interestingly, over-expression of K31 gene can cause lethality in the epithelioma papulosum cyprinid (EPC) cells in cell culture, which gave hint to the inefficient reprogramming events occurred in cloned embryos.

Conclusion

Taken together, our findings indicated that K31 gene is a novel gene differentially expressed in fish cross-subfamily cloned embryos and over-expression of K31 gene can cause lethality of cultured fish cells. To our knowledge, this is the first report on the determination of novel genes involved in nucleo-cytoplasmic interaction of fish cross-subfamily cloned embryos.
Rotational knee laxity: Reliability of a simple measurement device in vivo
Authors: Tsai Andrew G , Musahl Volker , Steckel Hanno , Bell Kevin M , Zantop Thore , Irrgang James J , Fu Freddie H
Published: March 2008

Background

Double bundle ACL reconstruction has been demonstrated to decrease rotational knee laxity. However, there is no simple, commercially-available device to measure knee rotation. The investigators developed a simple, non-invasive device to measure knee rotation. In conjunction with a rigid boot to rotate the tibia and a force/moment sensor to allow precise determination of torque about the knee, a magnetic tracking system measures the axial rotation of the tibia with respect to the femur. This device has been shown to have acceptable levels of test re-test reliability to measure knee rotation in cadaveric knees.

Methods

The objective of this study was to determine reliability of the device in measuring knee rotation of human subjects. Specifically, the intra-tester reliability within a single testing session, test-retest reliability between two testing sessions, and inter-tester reliability were assessed for 11 male subjects with normal knees.

Results

The 95% confidence interval for rotation was less than 5° for intra-tester, test-retest, and inter-tester reliability, and the standard error of measurement for the differences between left and right knees was found to be less than 3°.

Conclusion

It was found that the knee rotation measurements obtained with this device have acceptable limits of reliability for clinical use and interpretation.
Solution structure of the Legionella pneumophila Mip-rapamycin complex
Authors: Ceymann Andreas , Horstmann Martin , Ehses Philipp , Schweimer Kristian , Paschke Anne-Katrin , Steinert Michael , Faber Cornelius
Published: March 2008

Background

Legionella pneumphila is the causative agent of Legionnaires' disease. A major virulence factor of the pathogen is the homodimeric surface protein Mip. It shows peptidyl-prolyl cis/trans isomerase activty and is a receptor of FK506 and rapamycin, which both inhibit its enzymatic function. Insight into the binding process may be used for the design of novel Mip inhibitors as potential drugs against Legionnaires' disease.

Results

We have solved the solution structure of free Mip77–213 and the Mip77–213-rapamycin complex by NMR spectroscopy. Mip77–213 showed the typical FKBP-fold and only minor rearrangements upon binding of rapamycin. Apart from the configuration of a flexible hairpin loop, which is partly stabilized upon binding, the solution structure confirms the crystal structure. Comparisons to the structures of free FKBP12 and the FKBP12-rapamycin complex suggested an identical binding mode for both proteins.

Conclusion

The structural similarity of the Mip-rapamycin and FKBP12-rapamycin complexes suggests that FKBP12 ligands may be promising starting points for the design of novel Mip inhibitors. The search for a novel drug against Legionnaires' disease may therefore benefit from the large variety of known FKBP12 inhibitors.
MutL homologs in restriction-modification systems and the origin of eukaryotic MORC ATPases
Authors: Iyer Lakshminarayan M , Abhiman Saraswathi , Aravind L
Published: March 2008

The provenance and biochemical roles of eukaryotic MORC proteins have remained poorly understood since the discovery of their prototype MORC1, which is required for meiotic nuclear division in animals. The MORC family contains a combination of a gyrase, histidine kinase, and MutL (GHKL) and S5 domains that together constitute a catalytically active ATPase module. We identify the prokaryotic MORCs and establish that the MORC family belongs to a larger radiation of several families of GHKL proteins (paraMORCs) in prokaryotes. Using contextual information from conserved gene neighborhoods we show that these proteins primarily function in restriction-modification systems, in conjunction with diverse superfamily II DNA helicases and endonucleases. The common ancestor of these GHKL proteins, MutL and topoisomerase ATPase modules appears to have catalyzed structural reorganization of protein complexes and concomitant DNA-superstructure manipulations along with fused or standalone nuclease domains. Furthermore, contextual associations of the prokaryotic MORCs and their relatives suggest that their eukaryotic counterparts are likely to carry out chromatin remodeling by DNA superstructure manipulation in response to epigenetic signals such as histone and DNA methylation.

Reviewers

This article was reviewed by Arcady Mushegian and Gaspar Jekely.
Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein
Authors: Zerbinatti Celina V , Cordy Joanna M , Chen Ci-Di , Guillily Maria , Suon Sokreine , Ray William J , Seabrook Guy R , Abraham Carmela R , Wolozin Benjamin
Published: March 2008

Background

Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes.

Results

We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol.

Conclusion

These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.
Dynamic compression counteracts IL-1β induced inducible nitric oxide synthase and cyclo-oxygenase-2 expression in chondrocyte/agarose constructs
Authors: Chowdhury TT , Arghandawi S , Brand J , Akanji OO , Bader DL , Salter DM , Lee DA
Published: March 2008

Background

Nitric oxide and prostaglandin E2 (PGE2play pivotal roles in both the pathogenesis of osteoarthritis and catabolic processes in articular cartilage. These mediators are influenced by both IL-1β and mechanical loading, and involve alterations in the inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 enzymes. To identify the specific interactions that are activated by both types of stimuli, we examined the effects of dynamic compression on levels of expression of iNOS and COX-2 and involvement of the p38 mitogen-activated protein kinase (MAPK) pathway.

Methods

Chondrocyte/agarose constructs were cultured under free-swelling conditions with or without IL-1β and/or SB203580 (inhibitor of p38 MAPK) for up to 48 hours. Using a fully characterized bioreactor system, constructs were subjected to dynamic compression for 6, 12 and 48 hours under similar treatments. The activation or inhibition of p38 MAPK by IL-1β and/or SB203580 was analyzed by western blotting. iNOS, COX-2, aggrecan and collagen type II signals were assessed utilizing real-time quantitative PCR coupled with molecular beacons. Release of nitrite and PGE2 was quantified using biochemical assays. Two-way analysis of variance and the post hoc Bonferroni-corrected t-test were used to examine data.

Results

IL-1β activated the phosphorylation of p38 MAPK and this effect was abolished by SB203580. IL-1β induced a transient increase in iNOS expression and stimulated the production of nitrite release. Stimulation by either dynamic compression or SB203580 in isolation reduced the IL-1β induced iNOS expression and nitrite production. However, co-stimulation with both dynamic compression and SB203580 inhibited the expression levels of iNOS and production of nitrite induced by the cytokine. IL-1β induced a transient increase in COX-2 expression and stimulated the cumulative production of PGE2 release. These effects were inhibited by dynamic compression or SB203580. Co-stimulation with both dynamic compression and SB203580 restored cytokine-induced inhibition of aggrecan expression. This is in contrast to collagen type II, in which we observed no response with the cytokine and/or SB203580.

Conclusion

These data suggest that dynamic compression directly influences the expression levels of iNOS and COX-2. These molecules are current targets for pharmacological intervention, raising the possibility for integrated pharmacological and biophysical therapies for the treatment of cartilage joint disorders.
Chemoendocrine Compared With Endocrine Adjuvant Therapies for Node-Negative Breast Cancer: Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors—International Breast Cancer Study Group
Authors: Viale Giuseppe , Regan Meredith M. , Maiorano Eugenio , Mastropasqua Mauro G. , Golouh Rastko , Perin Tiziana , Brown Robert W. , Kovács Anikó , Pillay Komala , Öhlschlegel Christian , Braye Stephen , Grigolato Piergiovanni , Rusca Tiziana , Gelber Richard D. , Castiglione-Gertsch Monica , Price Karen N. , Goldhirsch Aron , Gusterson Barry A. , Coates Alan S.
Published: March 2008

Purpose

To centrally assess estrogen receptor (ER) and progesterone receptor (PgR) levels by immunohistochemistry and investigate their predictive value for benefit of chemo-endocrine compared with endocrine adjuvant therapy alone in two randomized clinical trials for node-negative breast cancer.

Patients and Methods

International Breast Cancer Study Group Trial VIII compared cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for 6 cycles followed by endocrine therapy with goserelin with either modality alone in pre- and perimenopausal patients. Trial IX compared three cycles of CMF followed by tamoxifen for 5 years versus tamoxifen alone in postmenopausal patients. Central Pathology Office reviewed 883 (83%) of 1,063 patients on Trial VIII and 1,365 (82%) of 1,669 on Trial IX and determined ER and PgR by immunohistochemistry. Disease-free survival (DFS) was compared across the spectrum of expression of each receptor using the Subpopulation Treatment Effect Pattern Plot methodology.

Results

Both receptors displayed a bimodal distribution, with substantial proportions showing no staining (receptor absent) and most of the remainder showing a high percentage of stained cells. Chemo-endocrine therapy yielded DFS superior to endocrine therapy alone for patients with receptor-absent tumors, and in some cases also for those with low levels of receptor expression. Among patients with ER-expressing tumors, additional prediction of benefit was suggested in absent or low PgR in Trial VIII but not in Trial IX.

Conclusion

Low levels of ER and PgR are predictive of the benefit of adding chemotherapy to endocrine therapy. Low PgR may add further prediction among pre- and perimenopausal but not postmenopausal patients whose tumors express ER.
Phase II Randomized Controlled Trial of an Epidermal Growth Factor Vaccine in Advanced Non–Small-Cell Lung Cancer
Authors: Vinageras Elia Neninger , de la Torre Ana , Rodríguez Marta Osorio , Ferrer Mauricio Catalá , Bravo Idania , del Pino Mario Mendoza , Abreu Daniel Abreu , Brooks Soraida Acosta , Rives Rolando , del Castillo Carrillo Concepción , Dueñas Marta González , Viada Carmen , Verdecia Beatriz García , Ramos Tania Crombet , Marinello Gisela González , Dávila Agustín Lage
Published: March 2008

Purpose

We show the result of a randomized phase II clinical trial with an epidermal growth factor (EGF)-based cancer vaccine in advanced non–small-cell lung cancer (NSCLC) patients, evaluating immunogenicity, safety, and effect on survival.

Patients and Methods

Eighty patients with stage IIIB/IV NSCLC after finishing first-line chemotherapy were randomly assigned to receive best supportive care or EGF vaccinations.

Results

Vaccination was safe. Adverse events were observed in less than 25% of cases and were grade 1 or 2 according to National Cancer Institute Common Toxicity Criteria. Good anti-EGF antibody response (GAR) was obtained in 51.3% of vaccinated patients and in none of the control group. Serum EGF concentration showed a major decrease in 64.3% of vaccinated patients. GAR patients survived significantly more than those with poor antibody response (PAR). Also, patients whose serum EGF dropped below 168 pg/mL survived significantly more than the rest. There was a trend to an increased survival for vaccinated patients compared with controls. The survival advantage for vaccinated patients compared with controls was statistically significant in the subgroup of patients with age younger than 60 years.

Conclusion

Vaccination with EGF was safe and provoked an increase in anti-EGF antibody titers and a decrease in serum EGF. There was a direct correlation between antibody response and survival. There was a direct correlation between decrease in serum EGF and survival. In patients younger than 60 years, vaccination was associated with increased survival.
Prognostic Factors for Leukemic Induction Failure in Children With Acute Lymphoblastic Leukemia and Outcome After Salvage Therapy: The FRALLE 93 Study
Authors: Oudot Caroline , Auclerc Marie-Françoise , Levy Vincent , Porcher Raphaël , Piguet Christophe , Perel Yves , Gandemer Virginie , Debre Marianne , Vermylen Christiane , Pautard Brigitte , Berger Claire , Schmitt Claudine , Leblanc Thierry , Cayuela Jean-Michel , Socie Gérard , Michel Gérard , Leverger Guy , Baruchel André
Published: March 2008

Purpose

To identify prognostic factors and to evaluate the outcome of children with acute lymphoblastic leukemia (ALL) failure after induction therapy.

Patients and Methods

Between June 1993 and December 1999, 1,395 leukemic children were included in the French Acute Lymphoblastic Leukemia 93 study.

Results

Fifty-three patients (3.8%) had a leukemic induction failure (LIF) after three- or four-drug induction therapy. In univariate analysis, high WBC count (P = .001), mediastinal mass (P = .017), T-cell phenotype (T-ALL; P = .001), t(9;22) translocation (P = .001), and a slow early response (at day 8 and/or on day 21, P = .001) were predictive of LIF. The following three prognostic groups for LIF were identified by multivariate analysis: a low-risk group with B-cell progenitor (BCP) ALL without t(9;22) (odds ratio [OR] = 1), an intermediate-risk group with T-ALL and a mediastinal mass (OR = 7.4, P < .0001), and a high-risk group with BCP-ALL and t(9;22) or T-ALL without a mediastinal mass (OR = 28.4, P < .0001). Complete remission (CR) was subsequently obtained in 43 patients (81%). The 5-year overall survival (OS) rate of the 53 patients was 30% ± 6%. The 5-year OS rate among allogeneic graft recipients, autologous graft recipients, and after chemotherapy were 30.4% ± 9.6% (50% ± 26% after genoidentical transplantation), 50% ± 17.7%, and 41.7% ± 14.2%, respectively (P = .18). Fourteen patients (26%) were still in first CR after a median of 83 months (range, 53 to 117 months).

Conclusion

Three risk categories for LIF in children with ALL were identified. Approximately one third of patients with LIF can be successfully treated with salvage therapy overall. Subsequent CR after LIF is mandatory for cure.
Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer
Authors: Graziano Francesco , Ruzzo Annamaria , Loupakis Fotios , Canestrari Emanuele , Santini Daniele , Catalano Vincenzo , Bisonni Renato , Torresi Umberto , Floriani Irene , Schiavon Gaia , Andreoni Francesca , Maltese Paolo , Rulli Eliana , Humar Bostjan , Falcone Alfredo , Giustini Lucio , Tonini Giuseppe , Fontana Andrea , Masi Gianluca , Magnani Mauro
Published: March 2008

Purpose

Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.

Patients and Methods

Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)ndinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.

Results

In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (χ2test = 12.7; P = .001) and treatment response (χ2test = 9.45; P = .008) than EGFR intron-1 L/L carriers.

Conclusion

Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.
External Validation of a Biomarker-Based Preoperative Nomogram Predicts Biochemical Recurrence After Radical Prostatectomy
Authors: Shariat Shahrokh F. , Walz Jochen , Roehrborn Claus G. , Zlotta Alexandre R. , Perrotte Paul , Suardi Nazareno , Saad Fred , Karakiewicz Pierre I.
Published: March 2008

Purpose

Biomarker signatures currently are used in several malignancies to guide clinical decision making. Recently, preoperative plasma levels of transforming growth factor-β1 (TGF-β1) and interleukin-6 soluble receptor (IL6-SR) have improved the accuracy of a clinical nomogram that predicted biochemical recurrence after radical prostatectomy. However, this model was never externally validated. We tested the accuracy of this nomogram in an independent, external cohort.

Patients and Methods

Preoperative plasma levels of TGF-β1 and IL6-SR were measured in 423 consecutive men who underwent radical prostatectomy and bilateral lymphadenectomy and were used, along with preoperative prostate-specific antigen levels, biopsy Gleason sum, and clinical stage to determine nomogram-derived probabilities of biochemical recurrence–free survival at 5 years after radical prostatectomy. The accuracy of predictions was quantified with the area under the curve (AUC) and calibration plots that graphically displayed the nomogram's performance characteristics. The statistical significance of the difference between the biomarker nomogram and a model designed on the basis of clinical variables alone was tested by using the Mantel-Haenszel statistic.

Results

Biochemical recurrence–free survival at 5 years was 77.0% (95% CI, 72.0% to 82.0%). The biomarker-based nomogram was 87.9% accurate versus 71.1% for the nomogram designed on the basis of clinical variables alone (16.8% difference; P < .001). The performance characteristics of the biomarker-based nomogram were superior to those of the clinical nomogram.

Conclusion

We confirm that plasma levels of TGF-β1 and IL6-SR considerably enhance the accuracy of the standard preoperative nomogram for the prediction of biochemical recurrence after radical prostatectomy. This model further refines our ability to identify patients at a high risk of biochemical recurrence after radical prostatectomy.
Ontario Cancer Research Ethics Board: Lessons Learned From Developing a Multicenter Regional Institutional Review Board
Authors: Saginur Raphael , Dent Susan F. , Schwartz Lisa , Heslegrave Ronald , Stacey Sid , Manzo Janet
Published: March 2008

Purpose

We describe issues and outcomes in the development of a specialized, central institutional review board (IRB) for multicenter oncology protocols. Numerous authoritative bodies have called for a change to the ethics review system to better manage multicenter trials in terms of quality, timeliness, and efficiency. In 2003, the American Society of Clinical Oncology proposed a network of regional IRBs for cancer. Previous experience with central IRBs has been met with mixed success.

Methods

We took a bottom-up approach to organizing a province-wide IRB, which was led by an IRB chair and a clinical investigator at one cancer center. Participation on the part of institutions was voluntary.

Results

Uptake in the first 2 years was modest and increased from 11 clinical trials in year 1 to 21 in year 2. In the third year, there was an apparent upsurge in the number of involved centers (14) and in the number of submitted clinical protocols (54).

Conclusion

Sponsors and investigators are loath to risk development of a novel IRB until there is a clear demonstration of quality, efficiency, and timeliness of decision. Development of a regional, specialized IRB requires considerable efforts to develop and maintain the trust of sponsors, investigators, and institutions despite prior demands for more efficient and timely ethics review. Voluntary institutional participation, clear delineation of roles and responsibilities, and effective execution promote development of this trust.
Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma with Fluorouracil, Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie
Authors: Al-Batran Salah-Eddin , Hartmann Joerg Thomas , Probst Stephan , Schmalenberg Harald , Hollerbach Stephan , Hofheinz Ralf , Rethwisch Volker , Seipelt Gernot , Homann Nils , Wilhelm Gerhard , Schuch Gunter , Stoehlmacher Jan , Derigs Hans Günter , Hegewisch-Becker Susanna , Grossmann Johannes , Pauligk Claudia , Atmaca Akin , Bokemeyer Carsten , Knuth Alexander , Jäger Elke
Published: March 2008

Purpose

This study was designed to compare fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin in patients with advanced gastric cancer.

Patients and Methods

Patients with previously untreated advanced adenocarcinoma of the stomach or esophagogastric junction were randomly assigned to receive either fluorouracil 2,600 mg/m2 via 24-hour infusion, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2 (FLO) every 2 weeks or fluorouracil 2,000 mg/m2 via 24-hour infusion, leucovorin 200 mg/m2 weekly, and cisplatin 50 mg/m2 every 2 weeks (FLP). The primary end point was progression-free survival (PFS).

Results

Two hundred twenty patients (median age, 64 years; metastatic, 94%) were randomly assigned. FLO was associated with significantly less (any grade) anemia (54% v 72%), nausea (53% v 70%), vomiting (31% v 52%), alopecia (22% v 39%), fatigue (19% v 34%), renal toxicity (11% v 34%), thromboembolic events (0.9% v 7.8%), and serious adverse events related to the treatment (9% v 19%). FLP was associated with significantly less peripheral neuropathy (22% v 63%). There was a trend toward improved median PFS with FLO versus FLP (5.8 v 3.9 months, respectively; P = .077) and no significant difference in median overall survival (10.7 v 8.8 months, respectively). However, in patients older than 65 years (n = 94), treatment with FLO resulted in significantly superior response rates (41.3% v 16.7%; P = .012), time to treatment failure (5.4 v 2.3 months; P < .001), and PFS (6.0 v 3.1 month; P = .029) and an improved OS (13.9 v 7.2 months) as compared with FLP, respectively.

Conclusion

FLO reduced toxicity as compared with FLP. In older adult patients, FLO also seemed to be associated with improved efficacy.