bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the potential of Product Service Systems to achieve household waste prevention on new housing developments in the UK
Authors: Gottberg Annika , Longhurst Philip J. , Cook Matthew B.
Published: May 2009

Product service systems (PSS) are cleaner product concepts which have been developed to achieve improvements in resource productivity which may be realized from modern trends in service delivery. However, there is a paucity of research on the waste prevention performance of PSS in UK household markets. This paper reports the findings of exploratory research which begins to address this gap in knowledge. An exploratory waste prevention assessment was completed on four experimental PSS which were developed in conjunction with a major UK house-builder for delivery on their new housing developments. The results of the assessment show that the selected PSS concepts have potential to prevent high value and harmful Waste Electrical and Electronic Equipment (WEEE) arising in UK household waste streams. Consistent with the canon of exploratory research, the assessment also identifies a number of factors which are thought to influence PSS waste prevention performance. It is recognized that further research is needed to gain an in-depth understanding of these factors as well as to define policy measures which enable the conditions in which PSS prevent household waste on new housing developments in the UK to be created.
National solid waste management plan for Iraq
Authors: Knowles James A.
Published: May 2009

After decades of turmoil and international sanctions much of the key civil infrastructure within Iraq has fallen into disrepair, leading to a considerable decline in the provision of basic and essential municipal services. This is particularly true of waste and resource management services that have seen years of underdevelopment and deterioration. This has resulted in a lack of provision of basic public services in the waste sector which have been replaced by a burgeoning unregulated informal market in waste collection, disposal and recycling. In response, a National Solid Waste Management Plan (NSWMP) for Iraq was developed in 2007, to plan for the strategic development of all aspects of waste management in the country over the coming 20 years. In particular, the NSWMP focuses on policy development and integrated planning regarding regulatory framework, economic aspects, institutional capacity, citizen and technical education, and technical and operational development. This paper summarizes the key objectives, challenges and subsequent recommendations contained in the NSWMP for Iraq.
Wraparound Retrospective
Authors: Cox Kathy , Baker Dawniel , Wong Mary Ann
Published: May 2009

While research regarding the effectiveness of the wraparound process is steadily mounting, little is known about how this service delivery model works and for whom. Using data gathered on 176 youth who participated in the wraparound process, the authors examine client and service factors associated with outcomes. Bivariate logistic regression analyses were conducted to determine the likelihood of treatment success based on select child and service characteristics. Results reveal that youth who exhibited lower levels of impairment at service entry were most successful in transitioning to and preserving a home placement, while those who possessed higher numbers of collateral supports were more likely to attain treatment goals. Findings also underscore the value of a planning process that promotes youth and family involvement in community activities. High adherence to this element of practice was found to predict both goal attainment and youth success in transitioning to a home setting. Implications for the implementation of the wraparound process with youth who are in residential care or at risk of out-of-home placement are discussed.
On thick description and narrative inquiry in music education
Authors: Jorgensen Estelle R.
Published: May 2009

The use of `thick description' is evident in various research traditions in the social sciences. Important in American anthropology in the latter half of the 20thcentury, it has been imported somewhat uncritically into educational research. In our time, it is also seen as a means whereby scholars and scholar-practitioners can generate new descriptive knowledge and recover knowledge that has been lost or fallen into obscurity. My present task is to notice the philosophical roots of thick description in the work of Gilbert Ryle and its subsequent use by the American anthropologist, Clifford Geertz. I also note Adam Kuper's critique of Geertz's anthropological use of the term. And after `rescuing' aspects of thick description, I sketch implications for narrative inquiry in music education.
Naturalizing the Environment
Authors: Ruiz-Ballesteros Esteban , Valcuende José Maria , Quintero Victoria , Cortes José Antonio , Rubio Elena
Published: May 2009

Following the closure of the mines and the crisis in agriculture, an alternative process of cultural and natural `heritagization' has been taking place in certain areas of Andalusia with a marked tourist focus. Productive spaces have been transformed into post-mining and post-agrarian landscapes. The aim of this article is to analyse representations and perceptions of surroundings in these contexts through the discourse of those who have experienced these changes most acutely: farmers and miners. This interpretation invites reflection regarding the concept of nature in the western world. Nature is one of our most genuine cultural creations, but we cannot ignore that, in addition to its discursive dimension, it also has a perceptive component. Hence, the analysis carried out here seeks to gain a more in-depth understanding of the perceptive frames through which nature acquires meaning and significance. The dual perceptive and discursive dimension of nature yields a more comprehensive understanding of how landscapes become spaces for resistance and identity.
`At Christmas We Don't Like Pork, Just Like The MacCabees'
Authors: Avieli Nir
Published: May 2009

Every Christmas, the tiny Protestant community of Hoi An (central Vietnam) congregates and marks the day with a service, a short ceremony and a communal picnic in the church yard. In this article, based on anthropological fieldwork conducted in the town since 1998, the author explores the meanings of the culinary features of the event. By analysing the dishes and eating arrangements at the picnic, he shows how differing facets of the participants' identity — the religious, the ethnic and the regional — are exposed, defined and negotiated. He argues that, while the eating arrangements represent ethnic Vietnamese identity, the dishes themselves hint at foreignness and `double marginality': not only of a Christian minority among Buddhists but also of Protestants among Catholics. The author's findings suggest that the complicated relationship between nation-states and marginal religious groups, as well as among members of differing religious communities within the same ethnic group, are often expressed in subtle practices that are easily overlooked by outsiders but are meaningful and evocative for the participants. The discussion focuses on the meaning of the culinary arena as a sphere of socio-religious negotiation, especially within politically authoritative contexts.
From pull to push: understanding nurses' information needs
Authors: Randell Rebecca , Mitchell Natasha , Thompson Carl , McCaughan Dorothy , Dowding Dawn
Published: May 2009

Electronic access to research information for health professionals is a key component in developing evidence-based healthcare. As nurses take on extended roles and work more autonomously, it is assumed that they will take increasing advantage of these technologies. However, little is known about the decisions that nurses make and the information needs that arise within the context of those decisions. This article presents an analysis of 410 nurse—patient consultations and interviews with 76 primary care nurses, and explores nurses' information needs and their use of electronic information tools. The findings suggest that, if we wish to encourage nurses to use research information in clinical practice, we need to move from `pull' to `push' technology.
Lifetime prediction of fluorescent lamps used in photovoltaic systems
Authors: Rosillo FG , Chivelet NM
Published: May 2009

This paper approaches lifetime prediction of fluorescent lamps in photovoltaic systems by means of an analytical model. This can assist in improving ballast design and extending the lifetime of fluorescent lamps. As a result of our work, the temporal integral of the glow current to starting and the lamp voltage during normal operation normalised to nominal voltage appear to be the two independent variables that describe the influence of startup and continuous operation on lamp lifetime with an acceptable degree of accuracy. The analytical expression found explains 92.4% of the variability in lifetime. Model agreement with original data and its range of application and limitations are also analysed.
Cortical Activity in Relation to Velocity Dependent Movement Resistance in the Flexor Muscles of the Hand After Stroke
Authors: Lindberg Påvel G. , Gäverth Johan , Fagergren Anders , Fransson Peter , Forssberg Hans , Borg Jörgen
Published: May 2009

Background. The role of spinal networks in spasticity is well investigated, but little is known about possible cortical contributions to hypertonicity across a joint. Objective. The authors hypothesized that there are cortical activation correlates to spasticity in stroke patients with increased muscle tone of the wrist flexors. Methods. Stroke patients and controls were scanned using event-related functional magnetic resonance imaging (fMRI) during slow and fast passive movements of the hand with simultaneous recording of passive movement resistance (PMR). Results. Control participants had velocity-dependent activity (greater for slow than fast movements) of 2 types, in areas that were also more active in passive movement than rest (eg, relative increase in activation in contralateral S1 and M1 was greater for slow than fast) and in areas that were also more active in rest than passive movement (eg, relative decrease in activation in occipital areas and ipsilateral precentral gyrus was greater for fast than slow). In the patient group, with large interindividual variation of spasticity, we found an association between PMR and the velocity-dependent activity in ipsilateral S1 (area 3b) extending into M1 (area 4a), contralateral cingulate cortex, supplementary motor area (SMA), Brodmann Area 45 (BA 45), and cerebellum. Post hoc testing also revealed a similar correlation in S1 and M1 bilaterally in controls and showed that patients activated ipsilateral S1 and M1 more than controls in the velocity-dependent condition. Conclusions. The findings suggest the possibility of ipsilateral sensory and motor cortical involvement in spasticity after stroke, which warrant further investigation.
Self-care strategies and barriers among kidney transplant recipients: a qualitative study
Authors: Gordon Elisa J. , Prohaska Thomas R. , Gallant Mary , Siminoff Laura A.
Published: May 2009

Objectives: We investigated kidney transplant recipients' self-reported levels of exercise and fluid intake. We also examined attitudes about, barriers to undertaking, and strategies used to initiate and maintain adequate self-care for fluid intake, exercise and dietary practices.

Methods: A qualitative approach was used and supplemented by quantitative data to examine self-care among kidney transplant recipients (n = 82), including a semi-structured interview and survey of physical activity.

Results: One-third of patients (33%) reported drinking the recommended 3 L of fluid each day. However, the majority (60%) reported not receiving this or any specific fluid intake recommendation. Twenty percent reported engaging in moderate to regular physical activity while 78% were sedentary. However, many reported that clinicians did not specify the amount of exercise (39%) or did not discuss exercise (15%). Attitudes towards fluid intake, exercise and maintaining a low-salt diet were mostly positive; patients expressed relatively more negative attitudes towards maintaining a low-cholesterol diet. Major barriers to fluid intake were not feeling thirsty, difficulty breaking the habit of limiting fluid intake formed while on dialysis, feeling full and limited access to fluids. Patients devised creative strategies to initiate and maintain appropriate hydration, physical activity and dietary levels, including intentionally drinking when not thirsty, modifying the environment, tracking intake and relying on social supports.

Conclusions: Few kidney recipients practiced optimal self-care for fluid intake or physical activity. Most patients encountered barriers to self-care that should be ameliorated to assist patients with managing their transplant. Understanding barriers and strategies is essential for developing educational interventions.
Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma
Authors: Richardson Paul , Jagannath Sundar , Hussein Mohamad , Berenson James , Singhal Seema , Irwin David , Williams Stephanie F. , Bensinger William , Badros Ashraf Z. , Vescio Robert , Kenvin Laurie , Yu Zhinuan , Olesnyckyj Marta , Zeldis Jerome , Knight Robert , Anderson Kenneth C.
Published: May 2009

Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.
Type 17 CD8+ T cells display enhanced antitumor immunity
Authors: Hinrichs Christian S. , Kaiser Andrew , Paulos Chrystal M. , Cassard Lydie , Sanchez-Perez Luis , Heemskerk Bianca , Wrzesinski Claudia , Borman Zachary A. , Muranski Pawel , Restifo Nicholas P.
Published: May 2009

Interleukin-17 (IL-17)–secreting CD8+ T cells have been described, but they have not been thoroughly studied and they do not have a known role in cancer immunotherapy. We skewed CD8+ T cells to secrete IL-17 through priming in Th17-polarizing conditions. IL-17–producing CD8+ T cells demonstrated reduced expression of Eomes and diminished cytolytic differentiation in vitro. However, after adoptive transfer, these cells converted to interferon-γ–producing effector cells and mediated regression of large, established tumors. This improved antitumor immunity was associated with increased expression of IL-7R-alpha, decreased expression of killer cell lectin-like receptor G1, and enhanced persistence of the transferred cells. This report is the first description of a cancer therapy with IL-17–secreting CD8+ T cells. These findings have implications for the improvement of CD8+ T cell–based adoptive immunotherapy.
Effect of the effluent released from the canine internal mammary artery after intraluminal and extraluminal perfusion of acetylcholine and adenosine diphosphate
Authors: Matsuda Nilce Mitiko , Pearson Paul J , Schaff Hartzell V , Piccinato Carlos E , Rodrigues Alfredo J , Evora Paulo Roberto Barbosa
Published: May 2009

Segments of the canine internal mammary artery (35 mm in length) were suspended in vitro in an organ chamber containing physiological salt solution (95% O2/5% CO2, pH = 7.4, 37°C). Segments were individually cannulated and perfused at 5 ml/minute using a roller pump. Vasorelaxant activity of the effluent from the perfused internal mammary arteries was bioassayed by measuring the decrease in tension induced by the effluent of the coronary artery endothelium-free ring which had been contracted with prostaglandin F2α(2 × 10-6M). Intraluminal perfusion of adenosine diphosphate (10-5M) induced significant increase in relaxant activity in the effluent from the perfused blood vessel. However, when adenosine diphosphate (10-5M) was added extraluminally to the internal mammary artery, no change in relaxant activity in the effluent was noted. In contrast, acetylcholine produced significant increase in the relaxant activity on the effluent of the perfused internal mammary artery with both intraluminal and extraluminal perfusion. The intraluminal and extraluminal release of endothelium-derived relaxing factor (EDRF) by acetylcholine (10-5M) can be inhibited by site-specific administration of atropine (10-5M). These experiments indicate that certain agonists can induce the release of EDRF only by binding to intravascular receptors while other agonists can induce endothelium-dependent vasodilatation by acting on neural side receptors.
Mechanism of inhibitory effect of atorvastatin on resistin expression induced by tumor necrosis factor-α in macrophages
Authors: Shyu Kou-Gi , Chua Su-Kiat , Wang Bao-Wai , Kuan Peiliang
Published: May 2009

Atorvastatin has been shown to reduce resistin expression in macrophages after pro-inflammatory stimulation. However, the mechanism of reducing resistin expression by atorvastatin is not known. Therefore, we sought to investigate the molecular mechanisms of atorvastatin for reducing resistin expression after proinflammatory cytokine, tumor necrosis factor-α (TNF-α) stimulation in cultured macrophages. Cultured macrophages were obtained from human peripheral blood mononuclear cells. TNF-α stimulation increased resistin protein and mRNA expression and atorvastatin inhibited the induction of resistin by TNF-α. Addition of mevalonate induced resistin protein expression similar to TNF-α stimulation. However, atorvastatin did not have effect on resistin protein expression induced by mevalonate. SP600125 and JNK small interfering RNA (siRNA) completely attenuated the resistin protein expression induced by TNF-α and mevalonate. TNF-α induced phosphorylation of Rac, while atorvastatin and Rac-1 inhibitor inhibited the phosphorylation of Rac induced by TNF-α. The gel shift and promoter activity assay showed that TNF-α increased AP-1-binding activity and resistin promoter activity, while SP600125 and atorvastatin inhibited the AP-1-binding activity and resistin promoter activity induced by TNF-α. Recombinant resistin and TNF-α significantly reduced glucose uptake in cultured macrophages, while atorvastatin reversed the reduced glucose uptake by TNF-α. In conclusion, JNK and Rac pathway mediates the inhibitory effect of atorvastatin on resistin expression induced by TNF-α.
Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project
Authors: Grisoni Marie-Lise , Proust Carole , Alanne Mervi , DeSuremain Maylis , Salomaa Veikko , Kuulasmaa Kari , Cambien François , Nicaud Viviane , Wiklund Per-Gunnar , Virtamo Jarmo , Kee Frank , Tiret Laurence , Evans Alun , Tregouet David-Alexandre
Published: May 2009

Background

Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of theIL18gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes,IL18R1andIL18RAP, with the risk of developing CVD.

Methods

Eleven tagging SNPs, 5 inIL18R1and 6 inIL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD.

Results

We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5IL18SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful.

Conclusion

Our analysis suggests that the variability ofIL18R1andIL18RAPgenes are unlikely to contribute to modulate the risk of CVD.
Biochemical typing of pathological prion protein in aging cattle with BSE
Authors: Tester Seraina , Juillerat Valerie , Doherr Marcus G , Haase Bianca , Polak Miroslaw , Ehrensperger Felix , Leeb Tosso , Zurbriggen Andreas , Seuberlich Torsten
Published: May 2009

Background

The broad enforcement of active surveillance for bovine spongiform encephalopathy (BSE) in 2000 led to the discovery of previously unnoticed, atypical BSE phenotypes in aged cattle that differed from classical BSE (C-type) in biochemical properties of the pathological prion protein. Depending on the molecular mass and the degree of glycosylation of its proteinase K resistant core fragment (PrPres), mainly determined in samples derived from the medulla oblongata, these atypical cases are currently classified into low (L)-type or high (H)-type BSE. In the present study we address the question to what extent such atypical BSE cases are part of the BSE epidemic in Switzerland.

Results

To this end we analyzed the biochemical PrPrestype by Western blot in a total of 33 BSE cases in cattle with a minimum age of eight years, targeting up to ten different brain regions. Our work confirmed H-type BSE in a zebu but classified all other cases as C-type BSE; indicating a very low incidence of H- and L-type BSE in Switzerland. It was documented for the first time that the biochemical PrPrestype was consistent across different brain regions of aging animals with C-type and H-type BSE, i.e. independent of the neuroanatomical structure investigated.

Conclusion

Taken together this study provides further characteristics of the BSE epidemic in Switzerland and generates new baseline data for the definition of C- and H-type BSE phenotypes, thereby underpinning the notion that they indeed represent distinct prion disease entities.
Biofilm forming abilities of Salmonellaare correlated with persistence in fish meal- and feed factories
Authors: Vestby Lene K , Møretrø Trond , Langsrud Solveig , Heir Even , Nesse Live L
Published: May 2009

Background

Feed contaminated with Salmonella spp. constitutes a risk of Salmonella infections in animals, and subsequently in the consumers of animal products. Salmonella are occasionally isolated from the feed factory environment and some clones of Salmonella persist in the factory environment for several years. One hypothesis is that biofilm formation facilitates persistence by protecting bacteria against environmental stress, e.g. disinfection. The aim of this study was to investigate the biofilm forming potential of Salmonella strains from feed- and fishmeal factories. The study included 111 Salmonella strains isolated from Norwegian feed and fish meal factories in the period 1991–2006 of serovar Agona, serovar Montevideo, serovar Senftenberg and serovar Typhimurium.

Results

Significant differences were found between serovars regarding the abilities to form biofilm on polystyrene (microtiter plate assay) and in the air-liquid interface of nutrient broth (pellicle assay). Strains of serovar Agona and serovar Montevideo were good biofilm producers. In Norwegian factories, clones of these serovars have been observed to persist for several years. Most serovar Senftenberg clones appear to persist for a shorter period, and strains of this serovar were medium biofilm producers in our test systems. Strains of the serovar Typhimurium were relatively poor biofilm producers. Salmonella ser. Typhimurium clones have not been observed to persist even though this serovar is resident in Norwegian wild life. When classifying strains according to persistence or presumed non-persistence, persistent strains produced more biofilm than presumed non-persisting strains.

Conclusion

The results indicate a correlation between persistence and biofilm formation which suggests that biofilm forming ability may be an important factor for persistence of Salmonella in the factory environment.
Unraveling the disease pathogenesis behind lethal hydrolethalus syndrome revealed multiple changes in molecular and cellular level
Authors: Honkala Heli , Lahtela Jenni , Fox Heli , Gentile Massimiliano , Pakkasjärvi Niklas , Salonen Riitta , Wartiovaara Kirmo , Jauhiainen Matti , Kestilä Marjo
Published: May 2009

Background

Hydrolethalus syndrome (HLS) is a severe fetal malformation syndrome characterized by multiple developmental anomalies, including central nervous system (CNS) malformation such as hydrocephaly and absent midline structures of the brain, micrognathia, defective lobation of the lungs and polydactyly. Microscopically, immature cerebral cortex, abnormalities in radial glial cells and hypothalamic hamartoma are among key findings in the CNS of HLS fetuses. HLS is caused by a substitution of aspartic acid by glycine in the HYLS1 protein, whose function was previously unknown.

Results

To provide insight into the disease mechanism(s) of this lethal disorder we have studied different aspects of HLS and HYLS1. A genome-wide gene expression analysis indicated several upregulated genes in cell cycle regulatory cascades and in specific signal transduction pathways while many downregulated genes were associated with lipid metabolism. These changes were supported by findings in functional cell biology studies, which revealed an increased cell cycle rate and a decreased amount of apoptosis in HLS neuronal progenitor cells. Also, changes in lipid metabolism gene expression were reflected by a significant increase in the cholesterol levels of HLS liver tissues. In addition, based on our functional studies of HYLS1, we propose that HYLS1 is a transcriptional regulator that shuffles between the cytoplasm and the nucleus, and that when HYLS1 is mutated its function is significantly altered.

Conclusion

In this study, we have shown that theHYLS1mutation has significant consequences in the cellular and tissue levels in HLS fetuses. Based on these results, it can be suggested that HYLS1 is part of the cellular transcriptional regulatory machinery and that the genetic defect has a widespread effect during embryonic and fetal development. These findings add a significant amount of new information to the pathogenesis of HLS and strongly suggest an essential role for HYLS1 in normal fetal development.
Effect of methotrexate and anti-TNF on Epstein-Barr virus T-cell response and viral load in patients with rheumatoid arthritis or spondylarthropathies
Authors: Miceli-Richard Corinne , Gestermann Nicolas , Amiel Corinne , Sellam Jérémie , Ittah Marc , Pavy Stephan , Urrutia Alejandra , Girauld Isabelle , Carcelain Guislaine , Venet Alain , Mariette Xavier
Published: May 2009

Introduction

There is a suspicion of increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferations in patients with inflammatory arthritides receiving immunosuppressive drugs. We investigated the EBV load and EBV-specific T-cell response in patients treated with methotrexate (MTX) or anti-TNF therapy.

Methods

Data for patients with rheumatoid arthritis (RA) (n = 58) or spondylarthropathy (SpA) (n = 28) were analyzed at baseline in comparison with controls (n = 22) and after 3 months of MTX or anti-TNF therapy for EBV load and EBV-specific IFNγ-producing T cells in response to EBV latent-cycle and lytic-cycle peptides.

Results

The EBV load and the number of IFNγ-producing T-cells after peptide stimulation were not significantly different between groups at baseline (P = 0.61 and P = 0.89, respectively). The EBV load was not significantly modified by treatment, for RA with MTX (P = 0.74) or anti-TNF therapy (P = 0.94) or for SpA with anti-TNF therapy (P = 1.00). The number of EBV-specific T cells was not significantly modified by treatment, for RA with MTX (P = 0.58) or anti-TNF drugs (P = 0.19) or for SpA with anti-TNF therapy (P = 0.39). For all patients, the EBV load and EBV-specific T cells were significantly correlated (P = 0.017; R = 0.21). For most patients, short-term exposure (3 months) to MTX or anti-TNF did not alter the EBV load or EBV-specific T-cell response but two patients had discordant evolution.

Conclusions

These data are reassuring and suggest there is no short-term defect in EBV-immune surveillance in patients receiving MTX or anti-TNF drugs. However, in these patients, long term follow-up of EBV-specific T-cell response is necessary and the role of non-EBV-related mechanisms of lymphomagenesis is not excluded.
WNT signaling enhances breast cancer cell motility and blockade of the WNT pathway by sFRP1 suppresses MDA-MB-231 xenograft growth
Authors: Matsuda Yutaka , Schlange Thomas , Oakeley Edward J , Boulay Anne , Hynes Nancy E
Published: May 2009

Introduction

In breast cancer, deregulation of the WNT signaling pathway occurs by autocrine mechanisms. WNT ligands and Frizzled receptors are coexpressed in primary breast tumors and cancer cell lines. Moreover, many breast tumors show hypermethylation of the secreted Frizzled-related protein 1 (sFRP1) promoter region, causing low expression of this WNT antagonist. We have previously shown that the WNT pathway influences proliferation of breast cancer cell lines via activation of canonical signaling and epidermal growth factor receptor transactivation, and that interference with WNT signaling reduces proliferation. Here we examine the role of WNT signaling in breast tumor cell migration and on xenograft outgrowth.

Methods

The breast cancer cell line MDA-MB-231 was used to study WNT signaling. We examined the effects of activating or blocking the WNT pathway on cell motility by treatment with WNT ligands or by ectopic sFPR1 expression, respectively. The ability of sFRP1-expressing MDA-MB-231 cells to grow as xenografts was also tested. Microarray analyses were carried out to identify targets with roles in MDA-MB-231/sFRP1 tumor growth inhibition.

Results

We show that WNT stimulates the migratory ability of MDA-MB-231 cells. Furthermore, ectopic expression of sFRP1 in MDA-MB-231 cells blocks canonical WNT signaling and decreases their migratory potential. Moreover, the ability of MDA-MB-231/sFRP1-expressing cells to grow as xenografts in mammary glands and to form lung metastases is dramatically impaired. Microarray analyses led to the identification of two genes, CCND1 and CDKN1A, whose expression level is selectively altered in vivo in sFRP1-expressing tumors. The encoded proteins cyclin D1 and p21Cip1 were downregulated and upregulated, respectively, in sFRP1-expressing tumors, suggesting that they are downstream mediators of WNT signaling.

Conclusions

Our results show that the WNT pathway influences multiple biological properties of MDA-MB-231 breast cancer cells. WNT stimulates tumor cell motility; conversely sFRP1-mediated WNT pathway blockade reduces motility. Moreover, ectopic sFRP1 expression in MDA-MB-231 cells has a strong negative impact on tumor outgrowth and blocked lung metastases. These results suggest that interference with WNT signaling using sFRP1 to block the ligand- receptor interaction may be a valid therapeutic approach in breast cancer.
Significantly Longer Progression-Free Survival With nab-Paclitaxel Compared With Docetaxel As First-Line Therapy for Metastatic Breast Cancer
Authors: Gradishar William J. , Krasnojon Dimitry , Cheporov Sergey , Makhson Anatoly N. , Manikhas Georgiy M. , Clawson Alicia , Bhar Paul
Published: May 2009

Purpose

In patients with metastatic breast cancer (MBC), nab-paclitaxel produced significantly higher antitumor activity compared with patients who received solvent-based paclitaxel. This phase II study examined the antitumor activity and safety of weekly and every 3 week (q3w) nab-paclitaxel compared with docetaxel as first-line treatment in patients with MBC.

Patients and Methods

In this randomized, multicenter study, patients (N = 302) with previously untreated MBC received nab-paclitaxel 300 mg/m2 q3w, 100 mg/m2 weekly, or 150 mg/m2 weekly or docetaxel 100 mg/m2 q3w.

Results

nab-Paclitaxel 150 mg/m2 weekly demonstrated significantly longer progression-free survival (PFS) than docetaxel by both independent radiologist assessment (12.9 v 7.5 months, respectively; P = .0065) and investigator assessment (14.6 v 7.8 months, respectively; P = .012). On the basis of independent radiologist review, both 150 mg/m2 (49%) and 100 mg/m2 (45%) weekly of nab-paclitaxel demonstrated a higher overall response rate (ORR) than docetaxel (35%), but this did not reach statistical significance. This trend was supported by statistically significant investigator ORR for both weekly nab-paclitaxel doses versus docetaxel. nab-Paclitaxel q3w versus docetaxel was not different for PFS or ORR. On the basis of both the independent radiologist and investigator review, disease control rate was significantly higher for patients receiving either dose of weekly nab-paclitaxel compared with docetaxel. Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms. The frequency and grade of peripheral neuropathy were similar in all arms.

Conclusion

This randomized study in first-line MBC demonstrated superior efficacy and safety of weekly nab-paclitaxel compared with docetaxel, with a statistically and clinically significant prolongation of PFS (> 5 months) in patients receiving nab-paclitaxel 150 mg/m2 weekly compared with docetaxel 100 mg/m2 q3w.
Elevated Biomarkers of Inflammation Are Associated With Reduced Survival Among Breast Cancer Patients
Authors: Pierce Brandon L. , Ballard-Barbash Rachel , Bernstein Leslie , Baumgartner Richard N. , Neuhouser Marian L. , Wener Mark H. , Baumgartner Kathy B. , Gilliland Frank D. , Sorensen Bess E. , McTiernan Anne , Ulrich Cornelia M.
Published: May 2009

Purpose

Chronic inflammation is believed to contribute to the development and progression of breast cancer. Systemic C-reactive protein (CRP) and serum amyloid A (SAA) are measures of low-grade chronic inflammation and potential predictors of cancer survival.

Patients and Methods

We evaluated the relationship between circulating markers of inflammation and breast cancer survival using data from the Health, Eating, Activity, and Lifestyle (HEAL) Study (a multiethnic prospective cohort study of women diagnosed with stage 0 to IIIA breast cancer). Circulating concentrations of CRP and SAA were measured approximately 31 months after diagnosis and tested for associations with disease-free survival (approximately 4.1 years of follow-up) and overall survival (approximately 6.9 years of follow-up) in 734 disease-free breast cancer survivors. Cox proportional hazards models were used with adjustment for potential confounding factors to generate hazard ratios (HRs) and 95% CIs.

Results

Elevated SAA and CRP were associated with reduced overall survival, regardless of adjustment for age, tumor stage, race, and body mass index (SAA P trend < .0001; CRP P trend = .002). The HRs for SAA and CRP tertiles suggested a threshold effect on survival, rather than a dose-response relationship (highest v lowest tertile: SAA HR = 3.15; 95% CI, 1.73 to 5.65; CRP HR = 2.27; 95% CI, 1.27 to 4.08). Associations were similar and still significant after adjusting for self-reported history of cardiovascular events and censoring cardiovascular disease deaths. Elevated CRP and SAA were also associated with reduced disease-free survival, although these associations were of borderline significance (SAA P trend = .04; CRP P trend = .07).

Conclusion

Circulating SAA and CRP may be important prognostic markers for long-term survival in breast cancer patients, independent of race, tumor stage, and body mass index.
Duration of Chemotherapy for Advanced Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Soon Yu Yang , Stockler Martin R. , Askie Lisa M. , Boyer Michael J.
Published: May 2009

Purpose

To determine if it is preferable to extend chemotherapy beyond a standard number of cycles in patients receiving first-line chemotherapy for advanced non–small-cell lung cancer.

Methods

We searched biomedical literature databases and conference proceedings for randomized controlled trials (RCTs) comparing a defined number of cycles with continuation of the same chemotherapy until disease progression, a larger defined number of cycles of identical chemotherapy, and a defined number of cycles of identical initial chemotherapy followed by additional cycles of an alternative chemotherapy. Meta-analysis was performed using the fixed effect model. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), adverse events (AE), and health-related quality of life (HRQL).

Results

We found 13 RCTs including 3,027 patients. Extending chemotherapy improved PFS substantially (hazard ratio [HR], 0.75; 95% CI, 0.69 to 0.81; P < .00001) and OS modestly (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03). Subgroup analysis revealed that effects on PFS were greater for trials extending chemotherapy with third-generation regimens rather than older regimens (HR, 0.70 interaction v 0.92 interaction; P = .003). Extending chemotherapy was associated with more frequent AE in all trials where it was reported and impaired HRQL in two of seven trials.

Conclusion

Extending chemotherapy, particularly with a third-generation regimen, improved PFS substantially, but OS less so. Future trials should test extending treatment with more effective and/or better-tolerated agents.
Improved Survival in Metastatic Colorectal Cancer Is Associated With Adoption of Hepatic Resection and Improved Chemotherapy
Authors: Kopetz Scott , Chang George J. , Overman Michael J. , Eng Cathy , Sargent Daniel J. , Larson David W. , Grothey Axel , Vauthey Jean-Nicolas , Nagorney David M. , McWilliams Robert R.
Published: May 2009

Purpose

Fluorouracil/leucovorin as the sole therapy for metastatic colorectal cancer (CRC) provides an overall survival of 8 to 12 months. With an increase in surgical resections of metastatic disease and development of new chemotherapies, indirect evidence suggests that outcomes for patients are improving in the general population, although the incremental gain has not yet been quantified.

Methods

We performed a retrospective review of patients newly diagnosed with metastatic CRC treated at two academic centers from 1990 through 2006. Landmark analysis evaluated the association of diagnosis year and liver resection with overall survival. Additional survival analysis of the Surveillance Epidemiology and End Results (SEER) database evaluated a similar population from 1990 through 2005.

Results

Two thousand four hundred seventy patients with metastatic CRC at diagnosis received their primary treatment at the two institutions during this time period. Median overall survival for those patients diagnosed from 1990 to 1997 was 14.2 months, which increased to 18.0, 18.6, and 29.3 months for patients diagnosed in 1998 to 2000, 2001 to 2003, and 2004 to 2006, respectively. Likewise, 5-year overall survival increased from 9.1% in the earliest time period to 19.2% in 2001 to 2003. Improved outcomes from 1998 to 2004 were a result of an increase in hepatic resection, which was performed in 20% of the patients. Improvements from 2004 to 2006 were temporally associated with increased utilization of new chemotherapeutics. In the SEER registry, overall survival for the 49,459 identified patients also increased in the most recent time period.

Conclusion

Profound improvements in outcome in metastatic CRC seem to be associated with the sequential increase in the use of hepatic resection in selected patients (1998 to 2006) and advancements in medical therapy (2004 to 2006).
Insurance Status, Comorbidity Level, and Survival Among Colorectal Cancer Patients Age 18 to 64 Years in the National Cancer Data Base From 2003 to 2005
Authors: Robbins Anthony S. , Pavluck Alexandre L. , Fedewa Stacey A. , Chen Amy Y. , Ward Elizabeth M.
Published: May 2009

Purpose

Previous analyses have found that insurance status is a strong predictor of survival among patients with colorectal cancer aged 18 to 64 years. We investigated whether differences in comorbidity level may account in part for the association between insurance status and survival.

Methods

We used 2003 to 2005 data from the National Cancer Data Base, a national hospital-based cancer registry, to examine the relationship between baseline characteristics and overall survival at 1 year among 64,304 white and black patients with colorectal cancer. In race-specific analyses, we used Cox proportional hazards models to assess 1-year survival by insurance status, controlling first for age, stage, facility type, and neighborhood education level and income, and then further controlling for comorbidity level.

Results

Comorbidity level was lowest among those with private insurance, higher for those who were uninsured or insured by Medicaid, and highest for those insured by Medicare. Survival at 1 year was significantly poorer for patients without private insurance, even after adjusting for important covariates. In these multivariate models, risk of death at 1 year was approximately 50% to 90% higher for white and black patients without private insurance. Further adjustment for number of comorbidities had only a modest impact on the association between insurance status and survival. In multivariate analyses, patients with ≥ three comorbid conditions had approximately 40% to 50% higher risk of death at 1 year.

Conclusion

Among white and black patients aged 18 to 64 years, differences in comorbidity level do not account for the association between insurance status and survival in patients with colorectal cancer.
Efficacy, Safety, and Potential Biomarkers of Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study
Authors: Zhu Andrew X. , Sahani Dushyant V. , Duda Dan G. , di Tomaso Emmanuelle , Ancukiewicz Marek , Catalano Onofrio A. , Sindhwani Vivek , Blaszkowsky Lawrence S. , Yoon Sam S. , Lahdenranta Johanna , Bhargava Pankaj , Meyerhardt Jeffrey , Clark Jeffrey W. , Kwak Eunice L. , Hezel Aram F. , Miksad Rebecca , Abrams Thomas A. , Enzinger Peter C. , Fuchs Charles S. , Ryan David P. , Jain Rakesh K.
Published: May 2009

Purpose

To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.

Patients and Methods

We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment.

Results

Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1α, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome.

Conclusion

Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.
Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study
Authors: Willett Christopher G. , Duda Dan G. , di Tomaso Emmanuelle , Boucher Yves , Ancukiewicz Marek , Sahani Dushyant V. , Lahdenranta Johanna , Chung Daniel C. , Fischman Alan J. , Lauwers Gregory Y. , Shellito Paul , Czito Brian G. , Wong Terence Z. , Paulson Erik , Poleski Martin , Vujaskovic Zeljko , Bentley Rex , Chen Helen X. , Clark Jeffrey W. , Jain Rakesh K.
Published: May 2009

Purpose

To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response.

Patients and Methods

In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m2/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy.

Results

Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome.

Conclusion

Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.